Continuum Audio

Continuum Audio features conversations with the guest editors and authors of Continuum: Lifelong Learning in Neurology, the premier topic-based neurology clinical review and CME journal from the American Academy of Neurology. AAN members can earn CME for listening to interviews for review articles and completing the evaluation on the AAN’s Online Learning Center.

Infection Risk and Vaccine Considerations in Multiple Sclerosis and Related Disorders With Dr. Avindra Nath 05/13/2026

Infection Risk and Vaccine Considerations in Multiple Sclerosis and Related Disorders With Dr. Avindra Nath Advances in immunotherapies for multiple sclerosis and related disorders have increased the risk of infections and raised important questions about vaccination efficacy. This episode reviews infection risks across treatment classes, emphasizes the importance of monitoring and patient education, and discusses optimal vaccine timing to preserve protective immune responses. In this episode, Aaron L. Berkowitz, MD, PhD, FAAN, speaks with Avindra Nath, MBBS, FAAN, coauthor of the article “Infection Risk and Vaccine Considerations in Multiple Sclerosis and Related Disorders” in the Continuum® April 2026 Multiple Sclerosis and Related Disorders issue. Dr. Berkowitz is a Continuum® Audio interviewer and a professor of neurology in the Department of Neurology at the University of California, San Francisco, in San Francisco, California. Dr. Nath is the chief of the Section of Infections of the Nervous System at the National Institute of Neurological Disorders and Stroke, National Institutes of Health, in Bethesda, Maryland Additional Resources Read the article: Infection Risk and Vaccine Considerations in Multiple Sclerosis and Related Disorders Subscribe to Continuum®: Earn CME (available only to AAN members): Continuum® Aloud (verbatim audio-book style recordings of articles available only to Continuum® subscribers): More about the American Academy of Neurology: Social Media Host: Dr Berkowitz: Over the last decades, there has been a revolution in the treatment of multiple sclerosis, neuromyelitis optica spectrum disorder, and other immune-mediated neurologic conditions with countless new, highly effective medications. However, with every new treatment comes new risks; and in the case of immunomodulatory therapy, many of those risks relate to infection. Today, I have the privilege of talking with an expert on this topic, Dr Avindra Nath, about the infectious risks of treatments for multiple sclerosis and other immune-mediated neurologic disorders. 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 Avi Nath about his article on vaccine considerations and infection risk in multiple sclerosis and related disorders, which he coauthored with Dr Amit Bar-Or. This article appears in the April 2026 Continuum issue on multiple sclerosis. Welcome to the podcast, Dr Nath, and could you please introduce yourself to our audience? Dr Nath: Thanks very much for inviting me to this podcast. I'm absolutely delighted to have the opportunity to discuss our areas of interest and expertise related to infections and vaccinations for MS patients. My area has been studying the infections of the nervous system since the beginning of the AIDS pandemic, and over the years and decades, we've developed expertise related to various types of CNS infections. That includes ones that are developing in individuals who have immune compromise due to a variety of different reasons. Dr Berkowitz: Fantastic. Well, glad to have the opportunity to speak with you today. When I was in medical school---and you were my attending, actually, we were just reminiscing, which we probably think was not that long ago, but is now over twenty years ago---there were just two medications for MS, right? Beta interferon and glatiramer acetate. And now we have over a dozen, and it's amazing to think of all the progress in these last two decades, as well as for related diseases like NMO. I don't think we even had the aquaporin-four biomarker, right, when I was working with you as a med student in the early 2000s. Dr Nath: And that certainly dates me a lot. Dr Berkowitz: Both of us. Dr Nath: Yeah. Dr Berkowitz: Of course, with all these new treatments, these have been amazing advances for our patients, right? But these come with new treatment-related risks to monitor for with the immunomodulatory medications for MS and related disorders. And one of those most important risks is that of infection. So, your article reviews the potential infectious complications of medications used to treat MS, NMO, etc, and also covers considerations related to thinking about vaccines in this patient population. So, as the MS treatment landscape grows, I can say as a general neurologist, keeping up with all these medications and what to screen for and what to worry about and when to vaccinate just becomes more challenging every year. And your article has so many helpful tables, some organized by medicine, some organized by- sorry, medication, some organized by infection, some by vaccines. So, this is gonna be a great resource for our providers to print out and tape up in their clinic rooms. We won't be able to get into all the depth and detail that you have in this article today, but I do want to focus on some of the key points here related to the common medications we use for MS and which infections to think about and which vaccine considerations we might need to keep in mind for these medications. But before we delve into the drugs, I just wanna ask you more broadly, you talk in the article about the challenge of patients with immune-mediated diseases who are on immunomodulatory therapy being at risk for both flares of their disease and for infections; and these infections can present somewhat atypically, right, in immunomodulated hosts, to maybe coin a term you can correct me on, because they can't mount the full inflammatory response. So how do you approach new symptoms in patients on these immunomodulatory medicines as far as distinguishing disease flare from a treatment-related infection? Dr Nath: So, I have to say that although a lot of new treatments have come along for MS, and they've really, you know, improved the outcome tremendously and there are so many different options, it has also kept people like me relevant because they cause a lot of various types of infections, and so keeps me in business all the same. But just as you mentioned, there's so many of them, even I have difficulty keeping track of what does what. So, you do need to be able to refer back to published literature, and the tables, I hope, will be quite useful in that regard. You're absolutely right, and you can get new infections, you can get reactivation of existing infections, and you can get atypical presentations of various types of infections that you may not normally think of. So that presents multiple challenges to the treating physician. The other interesting thing about MS is, just as you mentioned, that you already have CNS lesions to begin with. Now, on top of it, you have an infection, so now how to sort out what is the existing disease and what is the infection, it can again become challenging. But one thing is for sure: all these infections are caused by an organism. So, what you really need to do is, the underlying diagnostic is to demonstrate the presence of the organism. Whether you demonstrate it depending on the infection in the spinal fluid or in the brain or, you know, some peripheral organ system, that is going to be key to making the diagnosis. So, all your clinical acumen is good, but that alone may not be sufficient. Dr Berkowitz: Very good. So, when you see a, a patient now who has a new neurologic symptom in the context of an immune-mediated disease who's on immunomodulatory therapy, what goes through your mind? Are you thinking this disease and this drug, and sort of what are the infections, and does the syndrome match? Or are you thinking, you know, you can't always rely on the imaging to distinguish between, say, a flare of an MS and PML because white matter lesions could look similar? How do you sort of approach this scenario when it comes up? Dr Nath: So, you're right. You have to keep an open mind so that even though you know some infections are more likely to occur with certain types of medications, that doesn't mean that others cannot occur. So, I think when you first see the patient, you should not jump to conclusions, but rather have an open mind. But yes, for example, your patient is on natalizumab, the chances of PML are going to be high. It's a very interesting drug. It does not cause immune compromise in the periphery, but what it's doing is preventing these cells from getting into the brain. So, because then it's acting at the blood-brain barrier. So that means that organisms that are already present in the brain have an opportunity to get reactivated. Turns out you don't have a lot of organisms in the brain, except JC virus seems to be one of them that does somehow, in some individuals, manage to reside out there. And so that can get reactivated. It can get reactivated in the periphery and then enter the brain, too. So, where the very specific mutations have to occur in that virus in order to take residence in the brain. That would be a suspicion that you might have, and MRI can be useful in, again, helping you think about that possibility. If you have typical lesions involving the U fibers, they're demyelinating, usually you do not have much edema around them because patient is immune compromised, but certainly within the brain in these individuals. And so, then you need to demonstrate the organism. The demonstration of the organism should be in the spinal fluid and not in the blood because in the virus, it can-- is reservoir in the kidneys and in the lymph nodes, and periodically it'll shed into the blood. Detection of the organism in the blood can be a false positive, but in the spinal fluid, it shouldn't be there unless you have an infection. Or if you cause a traumatic tap, I guess, if a patient is viremic, that's a possibility, but those are extremely rare. So at least for PML, that's the way that you would diagnose it. Now, you can develop, for example, if an individual is on fingolimod, you can get a wide variety of infections. Here it's a totally different type of mechanism of action. Here the cells are trapped within the lymph nodes, so that means now your entire periphery is immune compromised, right? So here you can get viral infections, bacterial infections, fungal infections. So here, if a patient presents with new neurological symptoms, you have to have a really open mind for all these possibilities. Now, let's say a patient was on dimethyl fumarate, and dimethyl fumarate causes neutropenia early on. So here you have to worry about an individual developing bacterial infections, so latent tuberculosis or bacterial meningitis can occur in these individuals. That's something to keep in mind. It's not that other infections cannot occur with dimethyl fumarate, you can see PML and other things too, but the chances of bacterial infections are greater. So, you got to make sure that you draw all the cultures for that purpose. Similarly, if you're on a complement inhibitor, like a C5 inhibitor or the thing that I could use in NMO, there are the chances of meningococcal meningitis. So, these patients, you need to prevaccinate them before you start these kinds of treatments and look for that possibility. When you suspect bacterial infections, particularly acute bacterial meningitis, there time is of essence. Also, in some of the acute viral infections, for example---herpes encephalitis is another one---you have to be so careful, and if you suspect any of them, even if they're with possibly atypical manifestations, you treat first and then diagnose later, and draw all your cultures, whatever you need to, and just treat them. And these infections can also cause cerebral edema, so one has to be careful about doing spinal taps in these individuals. You want some kind of neuroimaging before you do them. In the days when we didn't have neuroimaging, we used to say, "Okay, if your patient has focal neurological signs or is comatose, you don't do it." But these days, you can get imaging very quickly and very easily. All the-- Because of our stroke management, we've learned how to do them so quickly. So, I think there's little excuse not to do imaging and prevent herniation from occurring. Dr Berkowitz: That's very helpful. So, using the information we know about the drug, and we're going to rapid-fire review some of that in a bit to know what infections the patient is susceptible to, but acknowledging that any patient can get any infection, right? Whether they're on particular medications or not. And then if you're not sure, based on the neuroimaging, which as you said, is helpful, but not always helpful in distinguishing between infections and flares or, as you said, in the case of meningitis, encephalitis, early on at least, especially in immunocompromised or immunomodulated, quote unquote, patient might not see the typical imaging. So really, when safe, getting CSF or cultures, PCRs, and other infectious studies too is really gonna be the definitive diagnostic maneuver here. Is that fair summary across the board? Dr Nath: I think you said that absolutely right. And you summarized that correctly. And, you know, thing about infection, a lot of neurological diseases are, you know, diagnosed by clinical acumen, like your Parkinson's and Alzheimer's and others. Think about infections is caused by an organism, demonstrate the organism, right? That should be your goal. It doesn't mean that clinical acumen is not important, but here you have an opportunity to demonstrate the organism, so you should depend upon that. Dr Berkowitz: Okay. Well, you gave us a nice segue by talking about some of the infections to worry about with some of the medications. So what I'd like to do now for the sort of second half of our interview here is to go through some of the more common medications used for MS, and if we have time, for NMO, and just sort of go kind of rapid fire here, and for each medication, if you can tell us the kind of top infectious concerns and whether when to consider them or what screening needs to take place before or during administration of the medication, and then any vaccine considerations we should be aware of. Some of these will obviously be quite short depending on the medicine. So, going back to the two medications I alluded to earlier that were the only ones in play when you and I last saw each other on the wards when I was a medical student, beta interferon, glatiramer acetate, any infections or vaccine considerations with these medications? Dr Nath: No, I think they're probably your safest medications now as far as immunomodulatory therapies are concerned. These two, and IVIG, if you ever use them, are probably the safest, do not require any vaccine considerations, per se. Dr Berkowitz: Perfect. Okay. So, moving on to fingolimod and others in the sphingosine-one phosphate receptor modulator family, what are the infectious considerations? Any prescreening or vaccination considerations? Dr Nath: I think all your patients should be prescreened for antibodies to JC virus, because there is a risk for PML, and those who are positive should be closely monitored. So, it's not an absolute contraindication for using these medications, but they just require closer monitoring. With this class of drugs, PML is of consideration. Also, these varicella-zoster virus infection, yeah, with that you can develop zoster encephalitis or myelitis. It can present with motor symptoms as well, which can be atypical. You don't usually see them otherwise in immune-competent individuals. So, varicella-zoster, sometimes you can develop encephalitis, also vasculitis with varicella-zoster, so one has to be careful. So, getting the shingles vaccine can be actually very helpful to prevent these things. And then some patients can even develop herpes simplex encephalitis also, and that can be extremely atypical. So, they don't- they can involve the basal ganglia, can involve the brain stem and cerebellum. So again, your index of suspicion should be very high. Interestingly, although HSV encephalitis has been associated with NMDA receptor encephalitis, those reports of NMDA receptor encephalitis have not been published yet with NMS patients. Not sure why, maybe they just have been missed. But that doesn't seem to be a major concern. And then there are a whole host of other infections that can occur with this class of drugs, and that can include toxo; fungal infections, particularly crypto. There's a case report of histoplasmosis; hepatitis virus, particularly hepatitis C; and then the poxvirus is a good example. You can get molluscum contagiosum; warts with papillomavirus; you can get atypical mycobacteria; and even Kaposi sarcoma, which is HHV8. So, there's a huge variety of infections with the sphingosine one phosphate receptor modulators. Dr Berkowitz: And any- aside from screening for JC virus before initiating these, any- and then continuing to monitor for JC antibody index, any other considerations as far as labs to send, monitoring before or on the drug or vaccine considerations for patients on fingolimod and the others in this category, siponimod, etcetera? Dr Nath: Yeah, there are a lot of things to consider. All the details are really available in the chapter if you look at them. But briefly, all the things that one could potentially vaccinate patients for, all these infections I mentioned, one should do so. The timing is critical so that if you can do it before treatment, I think, before starting treatment, that is absolutely important. And you got to give them at least, you know, two to three weeks for these vaccines to take effect before starting your medication. If your patient already arrives on a medication, then you got to play this game of you know, before the next dose, give them again two to three weeks before the next dose and start vaccinating them and get all the vaccines in. Broadly, about the things to worry about the vaccines are you have live vaccines, and you've got the inactivated vaccines or the subunit vaccines. You have to be careful with live vaccines, because if your patient is immunocompromised, that virus can sometimes itself cause harm. For example, you know, yellow fever is one, and there you can develop encephalitis from it. Measles, mumps, rubella, these are all live vaccines. Now, the good thing is that a lot of us have been immunized very early in childhood, but that may not be the case any longer. And so, these things, one has to be very careful with when you're giving live vaccines, that we want to avoid them as much as possible, and individuals are gonna be immune-compromised. But all the others, meningococcus, for example, you should- the HPV vaccines, the varicella zoster vaccines, all these things, you've got to pre-vaccinate and make sure that they have an antibody response to them before starting immunocompromising therapy. Dr Berkowitz: Perfect. Okay, moving on to some of the other orals. What infectious and/or vaccine considerations do we have with teriflunomide? Dr Nath: Okay, yeah. Teriflunomide is a very interesting drug. It's relatively safe. There is concern about the possibility of varicella zoster infection, people have reported that, and also tuberculosis. But PML is extremely rare, if not at all, and we haven't seen herpes encephalitis quite yet. Dr Berkowitz: Got it. How about dimethyl fumarate? Dr Nath: Yeah. So dimethyl fumarate is... as I mentioned earlier, it's interesting because it causes this neutropenia. It's transient, but it occurs early on, and these patients can be at risk of PML, although small. They can develop varicella zoster virus infection, herpes encephalitis, and also fungal infections. For example, cryptococcal infection has been... /episode/index/show/continuumjournal/id/40685260

Treatment of Multiple Sclerosis With Drs. Ellen M. Mowry and Daniel Ontaneda 05/06/2026

Treatment of Multiple Sclerosis With Drs. Ellen M. Mowry and Daniel Ontaneda There are many treatment options for people with relapsing MS. Patients should be carefully monitored to assess treatment response, and a change in treatment approach should be considered if safety concerns emerge. In this episode, Teshamae Monteith, MD, FAAN, speaks with Ellen M. Mowry, MD, MCR, and Daniel Ontaneda, MD, PhD, coauthors of the article “Treatment of Multiple Sclerosis” in the Continuum® April 2026 Multiple Sclerosis and Related 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. Mowry is the director of the Multiple Sclerosis Experimental Therapeutics Program and a professor of neurology at The Johns Hopkins University School of Medicine in Baltimore, Maryland. Dr. Ontaneda is the director of research at the Mellen Center for Multiple Sclerosis and a professor of neurology at the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University in Cleveland, Ohio. Additional Resources Read the article: Treatment of Multiple Sclerosis Subscribe to Continuum®: Earn CME (available only to AAN members): Continuum® Aloud (verbatim audio-book style recordings of articles available only to Continuum® subscribers): More about the American Academy of Neurology: Social Media Host: Guest: Dr. Monteith: There are so many new treatment strategies for multiple sclerosis, which is a blessing, but it does come with the complexity of really just trying to nail down the approach. I just got finished talking to Drs Ellen Mowry and Daniel Ontaneda about their article on treatment of multiple sclerosis. We discussed relapses, weighing escalation versus early high-effective treatment and progressive disease. This is a must-listen-to podcast. I hope you enjoy it as much as I enjoyed talking to them. 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 Ds Ellen Mowry and Daniel Ontaneda about their article on treatment of multiple sclerosis, which they wrote with Dr. Darin Okuda. This article appears in the April 2026 Continuum issue on multiple sclerosis. Welcome, both of you. How are you? Dr. Mowry: Great. And thank you so much for having us. Dr. Monteith: Absolutely. So, why don't you both introduce yourself? Dr. Ontaneda: All right. My name is Daniel Ontaneda. I'm a neurologist at the Cleveland Clinic. I spend the majority of my time doing research, but I still dedicate about a day a week to seeing people with MS in clinic. Dr. Mowry: I'm Ellen Mowry. I'm also a neurologist, but practice at the Johns Hopkins University. And similar to Dan, I mostly work on research, but also have an active clinical care component, taking care of people with MS. Dr. Monteith: Well, thank both of you for writing this article and being on our podcast. I assume you guys have probably known each other for quite a while now. Dr. Mowry: Yes. Dr. Ontaneda: Yes. Dr. Monteith: What inspired you to get into multiple sclerosis research and then clinical care? Dr. Ontaneda: I always loved neurology, and I think a lot of us who go into neurology are attracted to the complexity of the human brain and how the nervous system works. But what really hit home to me was a family member of mine who had multiple sclerosis, and he was being treated in a time where we really didn't have super effective disease-modifying medications. And so, as I went through my medical career, I always kind of kept an eye on what was happening with multiple sclerosis, and I started my training at a time where it was really flourishing in terms of the medications available, so that's what inspired me to go into MS. It's a disease that we can definitely treat, and you can change outcomes for people. So, that was it. Dr. Monteith: Yeah, that personal experience can be very impactful. Dr. Mowry: My journey started, actually, because I was thinking about whether I wanted to be a physician at all, and I happened to land, just after high school, a position with a neurologist who happened to mostly focus on multiple sclerosis and taking care of folks with multiple sclerosis. And by the end of the summer, I knew I wanted to go to med school and I wanted to be a neurologist and I wanted to work with people with MS. I thought I would be a clinician exclusively, but I think as time went on and I started to hear the consistent questions that people I served were asking in the clinic and realizing that those questions could be turned into research projects that could address their concerns, I moved more and more towards research. Dr. Monteith: Great. There are a lot of really detailed information in the article, so I think that research mind is very useful, and I see that in the writing. Why don't we talk about the goal of the article? Dr. Ontaneda: So, I think the goal of the article was to set out kind of what the large view of what treatment for multiple sclerosis looks like. And, you know, many times we divide the treatment of multiple sclerosis into these large pillars, and I think that's what we did in the article. The first was, you know, what do you do with a person who has an MS attack or relapse? The second is, what medications do we use to treat the relapsing forms of multiple sclerosis where there is a lot of acute inflammation, focal inflammatory lesions that are occurring? And then the final one is, what do you do with individuals who have a more progressive form of the disease where they're accruing disability slowly and gradually? Dr. Monteith: And what were some of the main points? Dr. Mowry: Dr. Okuda provided a really nice section on the treatment of acute relapses in multiple sclerosis, and it's important to understand what we talk about when we are saying “relapse”. For people with MS, many symptoms can fluctuate and occur and then get better over time, and sometimes people with MS use the same term of “relapse” to describe those symptom fluctuations. As neurologists, when we're thinking about relapse, we're really trying to think about symptoms that can be attributed to new focal inflammatory events somewhere in the central nervous system. Typically, these are accompanied---if you were to get an MRI at the same time---by a new lesion or MS spot, as I like to call them, on MRI scan. And so, it's important to distinguish when somebody is talking about symptoms, whether they are true new symptoms that could be mapped to a place in the central nervous system. Because alternatively, a lot of people who've had attacks or relapses in the past can have what we call pseudo-relapses, and these are essentially recrudescence of old symptoms, typically in a similar pattern as what had occurred in the past. And these can be brought out by things like fever or infection, sometimes stress. And pseudo-relapses are not thought to be due to new development of immune system-induced injury and therefore would be less likely to respond to treatment; and in fact, treatment may be contraindicated for those events. We also talked a little bit in that article about how relapses are treated, talking about the use of high-dose steroids for true new relapses, but also kind of cautioning that those are not necessarily free of concerns, especially if you have a pseudo-relapse or there could be an infection going on. And that ultimately, the decision as to whether to treat a relapse really is a shared decision-making because it's thought that although the steroids can speed up recovery from a relapse, they may not have a major impact on ultimate recovery. And so, a lot of the shared decision-making comes in here because for a mild relapse, you might choose to forego a course of high-dose steroids. Dr. Monteith: Daniel, any other main points? Dr. Ontaneda: Yeah. On the side of treating relapses, I think one of the other things that probably has changed a lot, at least during the course of my training, is that in the past, whenever we had identified a relapse, as Dr. Mowry has clearly defined, we would typically treat with intravenous high-dose corticosteroids, typically with methylprednisolone. And that was kind of our go-to. We would either do it in an infusion center or we would set it up with home care. And I think one of the things that our field learned over, I would say, the last five or ten years is there's an abundance of studies that show that you can give that same dose of methylprednisolone. Rather than giving it IV, you can give it orally. No pun intended, as I tell my patients, a lot of pills to swallow because we use fifty-milligram prednisone pills, and they have to take 1,250 a day. The pharmacy always pushes back on that many pills, but really the advantage of being able to take steroids orally that way for three to five days is really, I think, one, better for people with MS because they can do it in the comfort of their own home, and two, I think also when you look at the costs associated with that treatment, it is the most cost-effective option. Dr. Monteith: And what are some of the latest developments that you're really excited about that weren't in the article? Dr. Mowry: A lot of the article focused on the approach to treatment of people with what we've traditionally called relapsing/remitting multiple sclerosis. So, this is the kind of MS that traditionally presents with a relapse or an attack initially, although some of that nomenclature is changing, actually. And the article focused a lot on the strategies surrounding treatment of somebody with newly diagnosed relapsing MS, and thinking about this vast number of disease-modifying therapies that are available to people with MS and their clinicians, and how to think about the strategy with respect to largely centered around the efficacy class of the medication, whether people should take an approach of using a higher-efficacy therapy---meaning a medicine that in clinical trials was more likely on average to suppress relapses as well as new lesions---or whether there's still a good argument for the case of using an escalation approach, using some of the more modest efficacy medications that also probably in general have lower risks, monitoring for response to treatment and changing if the medication isn't working. And so, there's still a lot of debate in the field, I would say, even though many people have moved towards a one-size-fits-all kind of approach. I think there's still a lot of debate in the field about the evidence underlying that. And, you know, full disclosure, Dr. Ontaneda and I are each running parallel and very complementary clinical trial programs to address this very question, the results of which should be available within the next year, year and a half. Dr. Monteith: Well, we can't wait that long. Give me some clinical pearls to how we initiate these modifying therapies. Like, what are the pearls that we need to have in our mind? Dr. Ontaneda: Yeah. I think when we think about starting the disease-modifying therapy in an individual who has an active form of multiple sclerosis, I think, you know, one of the cornerstones I would say of making that decision is shared decision-making. I think we tend to sit down with the patient and analyze the data that we have at hand, what we know about their multiple sclerosis, and we use several factors to inform how likely we think their disease is gonna be active or potentially might not respond to the initial treatment you give. And we look heavily at the MRI. The MRI is really a useful marker because it shows us, one, how many lesions a person might have---both, you know, where those lesions are and also kind of the amount of lesions. Lesions, certainly, that are in the spinal cord, a very large burden of diseases. A lot of active lesions, which we determine by the presence of contrast-enhancing lesions, really helps us inform on disease severity. I would say that was our number one tool that we use to decide and help us decide how we think that person's MS is gonna do over time. And then the second thing that we put into the equation also is, you know, how well do we think this person is going to tolerate our medications? All our disease-modifying medications act through suppression of the immune system, and we know that that carries some risks associated with it. Some of those risks are stuff like infections. Some of those can be simple infections that really don't have major consequences, but some of them can be quite serious, including the need for hospitalizations or prolonged antibiotic treatment courses. And so, we also look at what, you know, the underlying risk of a person has for infection. This kind of is determined by, one, A, how many infections they've had up to date, and also how much disability they had. I would say in our average patient who when we see them, they're probably typically pretty young, in their twenties, thirties, forties, they typically don't have a lot of infectious risks. And therefore, I think there's kind of a move to saying, "Well, actually their risk of infections is quite low." And we put that together with, you know, also what the preference of the patient might want. So, do they prefer to take a pill, for example? Do they prefer a medication where they receive that via infusion every six months and they don't really have to think about it? There are some people that don't like going into a hospital, and they might prefer an injection type of those medications. And so, after a complex discussion of all those factors, we take into consideration how much risk the patient wants to take as well, and we come up with a rational choice of a couple of medication options. So, I think it's challenging sometimes because we have over two dozen medications. There's the risk of you saying, "There are these twenty-four medications, you can pick one." And I think our job as neurologists is to kind of pare those down, talk about, in a person like yourself, these are the two or three medications that I would recommend using. Why don't you review them? And then we bring them back, and we kind of make a final decision with, one of the key factors that I think is important to remind people is that you're gonna start this medication, and we are gonna monitor to make sure it's working. We're gonna monitor to make sure you're tolerating it well. And although it's an important, the first decision you make, I think one key theme that we tell people is, we can revise our strategy whenever we like. We just have to think about it and do it in a way that we think is gonna make sure that their MS is under the best control. And then we think about the ultimate goal of treatment, which, in multiple sclerosis, is the absence of any attacks and also the absence of any new lesions on MRI. And that's where whether you are offering more of the high-effective medications or more moderate- or low-efficacy medications, that's where there's a little bit of controversy still in our field, and that's what our trials are trying to answer. Dr. Monteith: Excellent. So now we've selected a particular option- and I love those points with shared decision-making, using the MRI to guide and then kind of risk tolerance related to infection. But now a patient's still having relapses, and I know the goal is zero, but, you know, there's some margin. What are the pearls to advance to more high-efficacy therapies? Dr. Mowry: Yeah, that's a great question. Dr. Ontaneda in the article actually talked about the literature surrounding monitoring for breakthrough disease and when to say this much is too much, and there's actually not a definite right answer. It's clear that more active disease early in the course is probably more of concern than, say, developing, you know, a new spot in your fifties or something to that effect. So, different people have different thresholds. I know at our center, we tend to be pretty on top of making changes for breakthrough disease. So, what we typically do is reimage people about six months after they start a medication to establish a new baseline. And sometimes, because of delays in starting or because the medications take a while to kick in, there might be a new spot or two. So, if that's the case, I really only get concerned if the spots are also taking up the dye or enhancing to indicate they're really quite recent, and I think, "Ugh, that's not something I'd like to see six months after starting a medication." And so that otherwise is sort of the reference scan, moving forward, to evaluate the medication, and I have a very low threshold for changing, particularly if somebody is on a moderate-efficacy therapy. To me, I think, well, our goal of trying the moderate efficacy therapy is essentially to see if we could get away with a medicine that is probably, on average, safer and that will still work for your MS. But if the answer is no, I personally don't like to stick around too much on them. One caveat I would say is that if somebody develops what appears to be a new lesion or spot on higher-efficacy therapy, before presuming that that new area of activity is a definite new MS event, I always like to rethink carefully, did I get the diagnosis correct? Or could this be an early infection such as, you know, progressive multifocal leukoencephalopathy in people on natalizumab in particular? Because I see breakthrough activity so rarely in people on higher-efficacy therapies that I just like to rethink my diagnosis and the differential prior to making switches to, typically, another higher-efficacy therapy in that case. But that, again, is a little bit of shared decision-making. It's sometimes contextual. If a person is using a self-administered medication and they have a little breakthrough, sometimes you can solicit some history, saying, "Oh, I actually kind of stopped taking it for a few weeks because something was going on, and I really want to retry." And that's very reasonable as well. Dan, do you have any other thoughts? Dr. Ontaneda: No, I think I agree. That's really close to how I practice myself as well, and the majority of people at my center. I think that we are learning that when you start a treatment, many times---depending on how deeply you look---you can find evidence of ongoing disease, and that's something that we struggle with. It's almost like we have tools to treat inflammation in terms of new MS lesions and new relapses. And so, when those are present, it's pretty clear that you probably have to switch medication. I think a slightly trickier issue is when, for example, you have a person who might be stable. They don't have an attack. But you notice that they're worsening, and they tell you they're worsening. I think our ability and tools for that is a little bit harder, and we recognize that that can actually happen fairly early in the disease. And that's why we're trying to rethink this mantra that we've had for many years, where we kind of divide MS up into relapsing and progressive, and we see people develop progressive MS 10 to 15 years after they've had a relapsing form of the disease. So, I think that's just a reality of clinical practice. And we don't have as many tools to treat that gradual worsening, which is kind of what the rest of our article spent some time talking about. Dr. Monteith: You've also written about the clinical trial long-term extension studies. And what are the few points that you take away from the emergence of these types of... /episode/index/show/continuumjournal/id/40685055

Neuromyelitis Optica Spectrum Disorder With Dr. Sara Mariotto 04/29/2026

Neuromyelitis Optica Spectrum Disorder With Dr. Sara Mariotto Although rare, recognizing NMOSD is crucial for improving patient outcomes through correct diagnostic and treatment approaches. Reports of atypical forms and increasing knowledge of clinical, imaging, and laboratory-specific features are fundamental for the accurate recognition of this condition. Research on targeted therapies and biomarkers measuring and predicting disease activity will improve NMOSD management. In this episode, Gordon Smith, MD, FAAN, speaks with Sara Mariotto, MD, PhD, coauthor of the article “Neuromyelitis Optica Spectrum Disorder” in the Continuum® April 2026 Multiple Sclerosis and Related 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. Mariotto is a neurologist in the Neurology Unit in the Department of Neurosciences, Biomedicine, and Movement Sciences at the University of Verona in Verona, Italy. Additional Resources Read the article: Neuromyelitis Optica Spectrum Disorder Subscribe to Continuum®: Earn CME (available only to AAN members): Continuum® Aloud (verbatim audio-book style recordings of articles available only to Continuum® subscribers): More about the American Academy of Neurology: Social Media Host: Dr Smith: Neurology is an increasingly therapeutic specialty, and across many of our subspecialty areas, lots of new drugs are being approved. Are you interested in learning more about a historically disabling disorder for which we now have a spectrum of new therapies that, if used appropriately and promptly in the right clinical situation, promise to dramatically improve patient outcomes? If so, keep listening. My name's Dr Gordon Smith. Today I'll be talking with Dr Sara Mariotto about her article on neuromyelitis optica spectrum disorder or NMOSD, which she wrote with Dr Romain Marignier. This article appears in the April 2026 Continuum issue on multiple sclerosis. Dr Jones: This is Dr Lyell Jones, Editor-in-Chief of Continuum. Thank you for listening to Continuum Audio. Be sure to visit the links in the episode notes for information about earning CME, subscribing to the journal, and exclusive access to interviews not featured on the podcast. Dr Smith: This is Dr Gordon Smith. Today, I'm interviewing Dr Sara Mariotto about her article on neuromyelitis optica spectrum disorder or NMOSD, which she wrote with Dr Romain Marignier. This article appears in the April 2026 Continuum issue on multiple sclerosis. Sara, welcome to the podcast, and maybe you can start by introducing yourself to our audience. Dr Mariotto: Yes. Thanks, Gordon. I'm Sara Mariotto. I'm a neurologist, and I work at the Neurology Unit, University of Verona, where I do both clinical diagnosis and research into neuroimmunology---so, in particular, autoimmune encephalitis, NMOSD, and MOGAD. Dr Smith: Well, this is a super exciting area. Whenever I hear about NMOSD, I think of one specific patient I had, and I always think of her when I come across something like your article, which is really fantastic. So, before we dive into the details, I wonder if maybe you can just explain to our listeners who aren't up to speed on what NMOSD is, what the disorder is, and maybe why it's so important that all of our listeners learn how to recognize it quickly and get people started on therapy. Dr Mariotto: Yes, sure. So, neuromyelitis optica is an inflammatory autoimmune CNS disorder usually associated with aquaporin-4 antibodies, although there are a few cases, around 10%, who can be antibody-negative. And I think it's very much important to have in mind this disease and recognize it because it can be severe, as you pointed out; can present with very severe optic neuritis, myelitis, the brain stem, or area postrema syndrome. So, it can be really severe, affect quite young people around 40 years of age---although it can affect also the pediatric population and elderly people---and, importantly, it can be treated. It's very much important to treat this patient in the acute stage very quickly with steroids or plasma exchange in addition, and then to start a chronic treatment. So, we have treatment for this condition. So, it's very much important to, to recognize it quickly and treat the patient properly. Dr Smith: So, I wonder if we can talk a little bit about the diagnostic criteria and boundaries of NMOSD, right? So, someone who comes in with bilateral op- severe long segment optic neuritis or long segment myelitis, we think about it. But what are the boundaries? Should we be looking for this, for instance, in someone who comes in with a unilateral optic neuritis or looks like typical multiple sclerosis? Is it important to get aquaporin-4 antibodies in those patients? What do the diagnostic criteria say about this? Dr Mariotto: So, I wouldn't test aquaporin-4 antibodies in all patients with demyelinating conditions because although aquaporin-4 antibody assay is very specific, as for all assay and all antibody testing---also for MOG antibodies, for example---some false positive results can come out. So, I would suggest to test aquaporin-4 antibodies not in typical MS cases but in those who could be suggestive for not being MS, so in all those cases with atypical optic neuritis and myelitis or other syndromes. For those cases, it's important to test aquaporin-4 antibodies, but I wouldn't test them in all typical, classical MS cases. As I said, it's quite specific, the assay, so it's uncommon to have false positive results, but it can be. Dr Smith: Serum, CSF, both? Dr Mariotto: So, for aquaporin-4 antibodies, they're usually present in serum. They can be positive also in the CSF. And there are a few reports of isolated CSF positivity. But if we analyze larger samples volume, then it becomes clear that isolated CSF positivity is so, so rare that it's not recommended to test them in the CSF when serum is negative. So, for aquaporin-4 antibodies, the recommended matrix of testing is serum, which is different for MOG, which is not the topic of our article but is important to mention because MOG antibodies should be tested in serum and CSF. But aquaporin-4, I would recommend to test serum. Dr Smith: What are the boundaries between MOGAD and NMOSD? And you talked about the differential testing of antibodies, which I was going to ask about. But when should we think of NMOSD relative to MOG? Dr Mariotto: Yeah. There are aspects which are the one mentioned in the criteria, highly suggestive for NMOSD. But the clinical spectrum can be similar to that of MOGAD. Usually, although there are some clinical aspect---like, for example cortical encephalitis or ADEM, which is more typical for MOGAD, or others like area postrema syndrome, which are more typical of NMOSD. The spectrum can be similar among the two conditions, so that's why in our clinical experience, usually they ask both aquaporin-4 and MOG antibodies in patients. It's- for experts, it can be easy to differentiate the two conditions, but for nonexperts can not be so easy. Dr Smith: Can you define area postrema syndrome? I think not all of our listeners see that every day. Dr Mariotto: Yeah, sure. This is a syndrome which is highly suggestive of NMOSD. That's why I mention it. And it's characterized by nausea, vomiting, hiccups are known as the syndrome. And it is very, very suggestive because of the expression of aquaporin-4 in that area of NMOSD. That's why I strongly recommend for all patients who comes out to have this syndrome to test for aquaporin-4 antibodies. MOGAD is hardly ever positive for that, so I think that whenever you see a patient with that syndrome, you should think about NMOSD. Dr Smith: I'm just curious, aquaporin-4 is a water channel, which is kind of an interesting concept. Our conversation, I really want to make sure we give clinically important information to folks, but it's so curious to me at least, how does this actually result in a inflammatory demyelinating syndrome? For a simple neuromuscular guy, what's the immunopathogenesis of this? Dr Mariotto: Yeah, the immunopathogenesis is quite complicated, as in all CNS disorders. And of course, aquaporin-4 antibodies are the main focus, but they are not the only one. As you said, aquaporin-4 antibodies have a target, this water channel, which is at the basis of the disease, and they are produced by the interplay between T cells, B cells, and plasma cells. But then also eosinophils, macrophages, cytokines, and chemokines are involved, enter the CNS, and then another important component is complement, which is highly activated in this disease. At the end, we have astrocyte damage because astrocytes are the main target of the disease, but also axon and myelin are involved. So, it's a quite complex pathogenesis based on the antibodies, but not only on that. Dr Smith: And this will become important when we start talking about treatment. There seems to be a recurring theme of long segment demyelination, right? Optic neuritis is typically a large percentage of the length of the optic nerve, and obviously the myelitis se- more than three segments. Do you see other long segment areas of CNS demyelination, corpus callosum or things like that? Any ideas why that is, if that's true? Dr Mariotto: Of note, this is quite interesting because usually when we have NMOSD, we have a longitudinal involvement, especially of the optic nerve and spinal cord, while brain lesions are quite different. Like, we usually do not have the typical Dawsen fingers-like lesions that we have in MS, for example, or the classical periventricular or subcortical extensive lesions that we can see and we have in mind when we think about MS. In some cases with NMOSD, the brain is completely negative, so we do not see anything. And Dawsen lesion’s quite suggestive of NMOSD. So, you're right. I mean, this is related partially to the expression of aquaporin-4, and that's why we have this typical involvement also for area postrema, for example, and maybe also our other examples of clinical aspect that we can see in these conditions. But it's basically linked with the expression of aquaporin-4, which is the main target of the disease. And that's why usually the brain doesn't show so much involvement as we can see in MS, for example. Dr Smith: I was actually really interested in some of the unusual manifestations or phenotypes, and I don't want to get into arcadia, really, but which of these should our listeners be familiar with that would really suggest that they should be thinking about NMOSD beyond the area postrema and other features that we've already talked about that are part of the core criteria? Dr Mariotto: Yeah. I mean, I think that the encephalic syndromes or also ADEM, which is most typical of MOGAD but can be observed also in NMOSD or PRES, for example, are syndromes that can be considered in patients with NMOSD. There are the typical ones, which are the ones showed in the criteria, but whenever we have a brainstem involvement or, like, these encephalic syndromes or also PRES, we should think about NMOSD also. Dr Smith: Another area I was interested in are red flags. In your article, you talk about red flags that might suggest an alternative diagnosis, right? And then this presumably is particularly important in seronegative patients, which 10% is not a reasonably high number, I suppose. What are red flags we should be thinking about for some other diagnosis? Dr Mariotto: Yeah. I would here mention two very important red flags. The first one is a very hyperacute onset. Usually these conditions, these inflammatory conditions have a subacute onset, so whenever you have a very, very acute onset, you should think about something else. This can occur sometimes also in NMOSD, but hardly ever occur. Like, a very acute myelitis, the first thing we should think about is a vascular origin, for example, with a lot of pain and not about NMOSD, although sometimes the differential diagnosis is not so easy. The second thing is a progression independently of relapses, which hardly ever occur in NMOSD. Usually in NMOSD, we have the onset, and then we have a relapsing disease course. That's why we have to treat patients always and not to stop treatment. But we do not have progression in the meanwhile, while we can have, for example, this in MS. Same thing is for MOGAD. So, these are two things that I think is very much important to keep in mind. Dr Smith: I want to pivot to talk about treatment because that's been super exciting. But rumor has it there are new diagnostic criteria coming for NMOSD in the next year. I bet you know a bit about those. Can you give our listeners any indication about kind of where the puck is going on this? Not so much what the criteria are specifically, but what sort of diagnostic challenges are the new criteria going to help us with once they come out? Dr Mariotto: Yeah. So basically, we are working on that, so you will read them in the next future. This is the good point of the conversation on the new criteria. And we work a lot on the definition, on the new definition and nomenclature of NMOSD; on the definition of seronegative NMOSD, which is also quite tricky; and then on the assay we should use to test aquaporin-4 antibodies, and also on potentially new syndromes which should be included into the main feature of the disease. But hopefully you will read about this very soon. Dr Smith: Looking forward to it. And Continuum Audio listeners, you heard it here first, so thank you. Let's pivot to treatment. This has been super exciting, and I wonder if the way to approach this is to start with acute management and then sort of chronic management. Would that make sense? Dr Mariotto: Sure. Dr Smith: Let's say I go on service on Friday, and I have a patient who comes in with positive aquaporin-4 and bilateral optic neuritis. What's the acute approach to managing that patient? Dr Mariotto: So, the first approach is to administer intravenous steroids, but I would not wait to escalate to plasma exchange. There is quite good evidence that we should treat the patient with additional plasma exchange very quickly, and every day of delay of plasma exchange can cause increased disability. So, we should treat patients with steroids first, and then if we are not satisfied by the recovery, soon start with a plasma exchange. There is also some evidence, although less, for IVIG, but it's important to try to treat them very quickly, even if it's Friday, you know, there is the weekend and so on. But I think it's very much important to start with steroids after excluding other infectious causes or so on, and then to start quickly with plasma exchange. The main problem could be that we do not have the results of the antibody yet. Dr Smith: Right. So, let me ask that question. You know, let's say my patient comes in on Friday, and clinical syndrome that really looks like NMOSD, and we're waiting for the aquaporin-4. There are many places where it's hard to get plasma exchange over weekends. And so, in that setting, are you better off doing the steroids over the weekend then PLEX on Monday, or should we just give IVIG because maybe it's as good as PLEX? What's your advice there? I'm trying to get ready for Friday because I know one's coming in. Dr Mariotto: That's true, that's true. Usually they come on Friday or Saturday. I think it's acceptable to have three days of steroids and see how the patient improves, and then after three days to start with plasma exchange. Actually, we have a very good improvement if we start between three and five days after onset. So, I think waiting for three days is acceptable just because we can see if the steroids work properly or not, and then we can quickly start to plasma exchange. But I would not wait, like, 10 days, you know, before starting with a plasma exchange, and I would not wait for antibody results. Dr Smith: Got it. Super helpful. And I'm actually not joking around, I learned recently that I have a reputation among our residents for having lots of optic neuritis when I'm on service, which I think is sort of karmic justice for being a peripheral nerve expert. But let me ask another question. So, let's say we do that, and the patient gets three or five days of pulse methylprednisolone and five courses of PLEX, and they're not doing well. Do you then just move right along into another agent B cell depletion therapy? I mean, what's your next step in escalation in the acute setting? Dr Mariotto: I would for sure start to, as you said, with steroids, plasma exchange, and in case IVIG, and then quickly move to chronic treatment. And for patients who are not recovering well, I would think of something which has a quick effect so we can really start treating patients very quickly. There are different options. And all over the world, there are different rules for using immunosuppression in NMOSD. Like in Italy, for example, it's different from US or other countries, Germany, for example. There are different approved treatments and different rules of using them before or after rituximab, for example. We all know that there are treatments approved for NMOSD all over the world. But in some countries, like for example in Italy, we should use rituximab first, and then if it doesn't work, escalate to the approved treatment. I know in the US it's different. But anyway, for a patient who does not improve quickly, I would start with something which has a quick effect on the disease. Dr Smith: And then rituximab versus inebilizumab, you know, CD20, CD19, what's your advice there? Is one preferable to the other, you know, if we have options to do either? Dr Mariotto: Yeah. So, between rituximab and inebilizumab, we know that the target, well, is different, but is anyway B cells, so CD19 and CD20. With CD19, we can affect both plasma blast, plasma cells, and B cells. That's why the target is broader. And of note, this is an approved drug, while rituximab is, in most countries, used as off-label treatment. Dr Smith: So inebilizumab would probably be preferable if we're able to do that. Dr Mariotto: Unfortunately, there are not so many studies comparing rituximab with the approved drug, which is, of course, a pity, but that's the case. While we have clinical trials for all the approved drugs, and although the trials were designed differently, as we mentioned in the Continuum paper, we can argue something of the comparison between the approved drugs. But it is not so clear the comparison between rituximab and the new drugs, which is also something that we should work on. Dr Smith: And then for chronic suppressive management, what other options are there? Dr Mariotto: So, in addition to B cells, target can be interleukin-6, as we know with tocilizumab or satralizumab, and then complement with eculizumab. These drugs are both based on the pathogenesis of the disease. That's why we also discuss it in the paper, which shows a clear involvement of complement, and among cytokines of interleukin-6. So, targeting these made clear that could improve the disease quite well, and that's why they designed some clinical trials on these drugs, which are now approved, as we said, for NMOSD. Dr Smith: Wow, so many options, and a lot of questions, but limited time. Let me just ask a couple of more. I see a lot of myasthenia patients, and there's a lot of variability, as you know, in patients with myasthenia, the extent to which complement is an important mechanism versus other, you know, important mechanisms. To what extent is response to a complement... /episode/index/show/continuumjournal/id/40684785

Myelin Oligodendrocyte Glycoprotein Antibody–Associated Disease With Dr. Eoin P. Flanagan 04/22/2026

Myelin Oligodendrocyte Glycoprotein Antibody–Associated Disease With Dr. Eoin P. Flanagan Familiarity with the clinical, MRI, CSF, and serologic features of MOGAD can help neurologists recognize this condition in clinical practice. Awareness of the utility and pitfalls of the MOG antibody test is critical. The current therapeutic approach is guided by retrospective studies and the application of immunotherapies used in other autoimmune neurologic disorders. In this episode, Gordon Smith, MD, FAAN, speaks with Eoin P. Flanagan, MBBCh, coauthor of the article “Myelin Oligodendrocyte Glycoprotein Antibody–Associated Disease” in the Continuum® April 2026 Multiple Sclerosis and Related 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. Flanagan is a professor of neurology and the division chair of the Division of Multiple Sclerosis and Autoimmune Neurology in the Department of Neurology at Mayo Clinic in Rochester, Minnesota. Additional Resources Read the article: Myelin Oligodendrocyte Glycoprotein Antibody–Associated Disease Subscribe to Continuum®: Earn CME (available only to AAN members): Continuum® Aloud (verbatim audio-book style recordings of articles available only to Continuum® subscribers): More about the American Academy of Neurology: Social Media Host: Dr Smith: So, what neurological disorder can cause bilateral optic neuritis, transverse myelitis, ADEM, or can mimic acute flaccid myelitis, intracranial hypertension, viral encephalitis, or cause seizures? Sounds like the great imitator, perhaps. If you want to know and learn more about this syndrome and how you can treat it---and it is very treatable---keep listening. My name is Gordon Smith, and today I have the great opportunity to talk with Dr Eoin Flanagan from the Mayo Clinic on his article on myelin oligodendrocyte glycoprotein antibody associated disease, or MOGAD, which is in the April 2026 issue of Continuum on Multiple Sclerosis and Related Disorders. Dr Jones: This is Dr Lyell Jones, Editor-in-Chief of Continuum. Thank you for listening to Continuum Audio. Be sure to visit the links in the episode notes for information about earning CME, subscribing to the journal, and exclusive access to interviews not featured on the podcast. Dr Smith: This is Dr Gordon Smith. Today I'm interviewing Dr Eoin Flanagan about his article on myelin oligodendrocyte glycoprotein associated disease, or MOGAD, which appears in the April 2026 Continuum issue on multiple sclerosis and related disorders. Eoin, welcome to the podcast, and please introduce yourself to our audience. Dr Flanagan: Yeah, thanks so much. I'm Eoin Flanagan. I'm a neurologist at the Mayo Clinic. I'm originally from Ireland. I work in the neuroimmunology lab at the Mayo Clinic, and work and see patients with MS, MOG, and autoimmune disorders here in Rochester, Minnesota. Dr Smith: Your article is super interesting, I think, and this has been a really rapidly evolving area over the last, you know, many years. We have many more antibodies, and MOG is something that's been around for a while, but we've certainly learned a lot more about it. This is a topic that I think will be familiar to most of our listeners, but I wonder if maybe you can just begin by laying the foundation. Like, what is MOG? What's its typical presentation? Dr Flanagan: So, MOG is a protein on the surface of the oligodendrocyte or its CNS myelin, and it was always of interest as a potential antibody target, and initially it was investigated in multiple sclerosis. But subsequently, we recognized that the antibodies to MOG have a specific syndrome, of which about a quarter of patients are pediatric and then the remainder are adults. And they can present with a variety of syndromes, probably most commonly optic neuritis, but also acute disseminated encephalomyelitis, or ADEM. Transverse myelitis can also occur, and then some other unusual brain and brainstem cerebellar syndromes can also occur. Dr Smith: I was really impressed in the very broad phenotypic spectrum of MOG. We'll talk more about that, of course. But I wonder if maybe you can tell us when we should be ordering MOG antibody? Given this broad variability, does anyone who has a CNS demyelinating disease need a MOG assay, only specific phenotypes? What guidance do you have for our listeners? Dr Flanagan: Yeah. It's a great question. So, I think you have to be a little bit careful because the MOG antibody test is a little bit sticky. So sometimes we can see some low-positive false positives. So, we don't wanna order it in every single patient with classical MS. So, I suppose we'll start with who not to order it in. I think it's also a very optic nerve- and optic neuritis-central disease, so I think you really need to be considering this in a patient with optic neuritis who does not have lesions in the brain suggestive of multiple sclerosis. And then we think about some of the features: if the lesion, the enhancement along the optic nerve is long, if it's bilateral, if there's a lot of optic disc edema accompanying that, we tend to think about MOG antibodies. And then children with demyelinating disease, MOG is over-represented in that cohort, so it accounts for about a third of those. So, if you have a child with CNS demyelinating disease, particularly if they're under twelve, with ADEM presentations or other presentations, you probably want to be ordering the MOG antibody test. And then a longitudinally extensive transverse myelitis in adults, certain types of cerebral phenotypes that we can get into, you would want to consider ordering MOG antibodies too. Dr Smith: Now, you point out in the article that it's really important that laboratories use the cell-based assay for MOG as opposed to an ELISA, for instance. Is this something folks need to be very attentive to, or are all of the commercial laboratories now using a cell-based assay? Dr Flanagan: Yeah. I think all of the commercial labs are using cell-based assays, so we don't really get into much of an issue. There are some differences between serum and CSF, so really, serum is the optimal sample to order. There is also some differences between the live cell-based assay and the fixed cell-based assay, where the live cell-based assay may have some advantages in terms of sensitivity. And then CSF is kind of still under evaluation about its role in the condition. So in general, it's a serum test. And then we have to remember that the antibody tends to be highest at the onset, and then it goes down over time. So, if you delay your testing or you're testing a patient long after the condition, it can go negative, for example. So it tends to be highest both around the relapses and particularly at the onset of the condition. Dr Smith: You mentioned earlier that the test is sticky, which I take to mean that there is some risk for low-titer false positives. How do you navigate that situation? When should we be suspicious about a false positive? Dr Flanagan: Yeah. I think there's some very useful features that can help you. You know, the main differential diagnosis is going to be multiple sclerosis, particularly in the US, in regions of the northern US where MS is particularly common. So, you really wanna be making sure that if you get a positive result, low positive, that it's not multiple sclerosis. And some of the best discriminating features are CSF oligoclonal bands. They're about 85% in MS and about 15% in MOG, so an easy number to remember, 85 and 15. And then the lesions in MOG, the brain lesions, tend to disappear over time. So, if you have the advantage of that follow-up MRI a year down the line, about 70% of lesions in MOGAD will resolve, while in MS, as we know, the term means multiple scars, so the MS lesions tend to persist over time. So, they are two quite useful features that can help discriminate. Dr Smith: And how about specific phenotypes or areas of involvement or imaging abnormalities that suggest MOG? One of the things I found really interesting in your article is there are a host of different syndromes that I think had largely been previously described, many of them, that became clear later that these were really tied to MOG antibodies. Presumably, that's helpful in interpreting the antibody assay in that patients who have, perhaps, a borderline low titer, for instance, but have a very typical phenotype are more likely to have MOG than those who have a more clearly MS-type phenotype. Dr Flanagan: Yeah, absolutely right. Yes. So, there's certain phenotypes that we don't tend to see with MS. The acute disseminated encephalomyelitis, or ADEM, is one that's particularly common in children. And about half of people that have ADEM will be positive for the MOG antibody. So that's a syndrome you need to look out for, which would be often in children, encephalopathy, and they would have multifocal white matter lesions, sometimes involving the gray matter. A second syndrome that was an interesting discovery from a Japanese group was this unilateral cerebral cortical encephalitis, where patients can have this swelling and T2 hyperintensity, often just on one side of the brain. And it's in the cortex, and some of those patients won't have any white matter lesions. And in that situation, it's important to order the MOG antibody, and that seems to be a specific phenotype of MOGAD. But sometimes people don't think about it because the white matter is not involved. So, if you see these patients, they often present with seizures, sometimes they even have fever accompanied by it. And if you see those patients and see this radiological feature, then you really want to consider ordering the MOG antibody too. Dr Smith: Yeah, I found that really interesting. And I- actually, my next question is perhaps a good follow-up on that, is, what are the diagnostic pitfalls? You give a lot of examples of situations and I think some cases where it's easy to get tripped up and misdiagnose someone who has MOG with another fairly common neurological problem. Dr Flanagan: Yeah, I think some of the things that can help you when you're determining if the MOG is a true positive or false positive is the level of the antibodies. The super high titers, if it's a clear positive or very strong positive, the likelihood is that that is much more likely to be MOGAD than those low positives just above the cutoff. So that can be useful to help you discriminate from false positives. Those lesions, again, if all the lesions persist over time, that's going to be more suggestive of multiple sclerosis. Other diagnostic pitfalls, I suppose, if it's a syndrome that's not really associated with MOG, like peripheral neuropathy or other syndromes where we'll see some case reports, but usually I would be very cautious about those kind of presentations. So usually, having the antibody at a high level, and then also if they've had other symptoms suggestive of MOGAD, like if a patient has had recurrent optic neuritis and then they have an unusual brain syndrome, or they start out with an unusual brain syndrome and then have recurrent optic neuritis. You know, there are situations that make it more likely if they're having other typical phenotypes of the MOGAD where we can kind of expand the spectrum, but we have to be careful. Dr Smith: I was really curious about the dynamic imaging findings. And you point this out both in terms of the resolution of imaging findings, but also in that patients who have an acute MOG syndrome often have very rapid evolution of the imaging abnormalities. I'm just curious, you know, why is that, and what do you make of it? Does it have a mechanistic implication, do you think? Dr Flanagan: I don't think we know for sure. I think there's probably a lot more happening than we see on MRIs sometimes. What sometimes can happen in about 10% of patients is the initial MRI can be normal. We don't tend to see that with multiple sclerosis or NMOSD. Then what we see is it evolving over time. So, at that time, if you do a CSF, you'll often see inflammation, but we don't see the lesions. Now, that might be because the MRI is not very good at picking up cortical involvement. That can be difficult to see in MRI. Or there could be other factors. It could be a functional effect on the MOG but without frank demyelination yet, for example. Or there could be edema that you- myelin edema that you can't see as a lesion yet on MRI. But we do see that if you repeat the MRI, sometimes it'll change a lot. So, you may go from one or two lesions on the first MRI to twenty lesions on the second MRI a week later. So, it does tend to change a lot. And then over time, those lesions also resolve. So, what I say is if it's a very suspicious situation---like a child comes in with new-onset encephalitis, has inflammatory CSF---you might wanna consider repeating that MRI down the line and seeing if it's changing. And then over time, you know, a repeat MRI a year after the onset when there's brain or spinal cord lesions can be very helpful just to make sure you're on the right track, because lots of those lesions will then disappear, and that's a very clear discriminator from multiple sclerosis. Dr Smith: Yeah, thanks. I mean, I was wondering the same thing about whether that particular feature might imply, you know, a functional abnormality as opposed to more of a structural abnormality. So probably a lot more to learn as we move forward. There are now consensus diagnostic criteria that were published a couple of years ago. I think you've already touched on kind of the general approach, but do you want to speak to those? I found your summary pretty helpful. Dr Flanagan: Yeah, I think that those criteria are quite useful. They have three main parts to them. The first part is having a characteristic clinical syndrome. So, we talked about ADEM, we talked about cerebral cortical encephalitis, transverse myelitis that's often longitudinally extensive, and optic neuritis being the main syndromes, but sometimes other brainstem or cerebellar involvement can be seen. And then the second part is having a positive MOG antibody. And then there's some caveats there. So, if you have a high positive, then you don't really need any additional supportive criteria. On the other hand, if you're low positive, to get at those sticky antibodies that make sure it's not a false positive, you need some additional supportive clinical or MRI criteria. Or if you're only positive in CSF, you need that additional criteria. You also need to be negative for the aquaporin-4 antibody, because they can overlap clinically. And some of those supportive criteria are things that we talked about a little bit earlier, longer lesions within the optic nerve, bilateral involvement, involvement of the nerve sheath or optic disc edema. This is a situation, MOG antibody disease, where your fundoscope is useful and looking in the back of the eye and seeing swelling, because we don't tend to see that quite as often. It's less common in multiple sclerosis, but we often see prominent edema in MOGAD. And then in the spinal cord, the lesions tend to be central in the cord. Sometimes they form this H sign where it's restricted to the gray matter, and they tend to be longer, sometimes involving the conus. Patients will often have neurogenic bowel or bladder. And then in the brain, deep gray involvement, those large lesions along the cortex with swelling are some of the typical features. And then the final step is exclusion of another diagnosis. Just like with any test that we do in neurology, our final step is going to be to put that into context. So that's just a normal thing that we will always do when we get a group of test results back that we don't know what it means. We have to put it into context. So, make sure it's not multiple sclerosis, everything else does not look like multiple sclerosis, and then you can be on your way to make a diagnosis. Dr Smith: Definitely encourage listeners to read your article. I guess I say that with every time I- or with everyone I talk to for Continuum Audio, but the images are really fantastic and the cases are fantastic. So, everything you've described is well-illustrated, including really nice schematic sort of diagrams that help differentiate NMO from MOG and MS. So, if you like MRI scans and good imaging frameworks, then this is the article for you. Dr Flanagan: I think that's true, and the other thing is that the imaging is quite helpful because it takes a while for that antibody to come back. We're lucky at Mayo Clinic, if you work here, it, it comes back faster for you. But for many places, that time of sending it in, so a lot of times you don't know right away. So, looking at scrutinizing that MRI can be very helpful to guide you on your way and to know what you're dealing with and how to approach both the acute treatment and plans to have potentially a steroid taper after the acute treatment and those kind of things that can help guide you in that regard. Dr Smith: Yeah. So, let's talk about treatment. You know, what's your approach to treating a patient who has an acute demyelinating syndrome related to MOG? Dr Flanagan: So similar to other things, MOG is very steroid responsive. So, we use high-dose IV methylprednisolone in adults. That would be one gram IV for five days. And then we also will sometimes use oral steroids, twelve hundred and fifty milligrams. That's a bit of a hassle because it's twenty-five fifty-milligram tablets, it doesn't come in a larger tablet version. But it's very helpful to patients because they can get started on it right away. You don't have to set up an infusion center. So, we have used those oral steroids often in people who don't have access to an infusion center, are not in the hospital. And particularly as it's often optic neuritis, some of those patients are seen in the outpatient setting, so we can get in with treatment quickly. In patients where it's more severe, it doesn't recover quickly with steroids, then we would consider escalating to plasma exchange as our second-line treatment, and there's some retrospective data that suggests that plasma exchange can be useful. That's gonna be particularly for those people who don't have that quick response to steroids, or maybe more severe phenotypes like that brain involvement with ADEM or cerebral cortical encephalitis, where those patients might be in the hospital and quite unwell. I will say, we might get on to this, that sometimes MOG can be very, very severe and even fulminant, where there can be increased intracranial pressure, and these patients can be in the ICU, and it can be life-threatening. And so, it's really important to treat those patients aggressively, and some patients have even required hemicraniectomy or additional treatment. Sometimes IL-6 blocking medications have been used in that situation. So, monitoring and treating increased intracranial pressure in those rare patients, probably 2 or 3% that have the very severe attack, is important. Dr Smith: I think one of the things I found interesting, and then I'd love to get your feedback on this, is that most patients with MOG seem to have a very readily treatable disorder that's monophasic, right? You treat them with steroids, and they do well. On the other extreme, there are these patients that have a much more malignant presentation, and there are some that sound like they benefit from prophylactic or some chronic therapy. What's your approach, right? In MS, we do serial scans to monitor, and obviously, our patients are on, you know, chronic disease-modifying therapy. How do... /episode/index/show/continuumjournal/id/40684590

Adult-Onset Leukodystrophies Mimicking Multiple Sclerosis With Dr. Roberta La Piana 04/15/2026

Adult-Onset Leukodystrophies Mimicking Multiple Sclerosis With Dr. Roberta La Piana Adult‑onset leukodystrophies, though rare, can closely mimic MS on both clinical presentation and neuroimaging, posing a significant diagnostic challenge. This episode highlights key clinical and radiologic red flags that can help distinguish these disorders from MS, preventing misdiagnosis and avoiding inappropriate treatment while enabling timely genetic counseling and targeted therapies. In this episode, Teshamae Monteith, MD, FAAN, speaks with Roberta La Piana, MD, PhD, coauthor of the article “Adult-Onset Leukodystrophies Mimicking Multiple Sclerosis” in the Continuum® April 2026 Multiple Sclerosis and Related 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. La Piana is an associate professor in the Department of Neurology and Neurosurgery at the Montreal Neurological Institute, McGill University, and an associate member of the Department of Diagnostic Radiology at McGill University in Montreal, Quebec, Canada. Additional Resources Read the article: Adult-Onset Leukodystrophies Mimicking Multiple Sclerosis Subscribe to Continuum®: Earn CME (available only to AAN members): Continuum® Aloud (verbatim audio-book style recordings of articles available only to Continuum® subscribers): More about the American Academy of Neurology: Social Media Host: Dr Monteith: You just saw a patient in clinic. And you're clear, the diagnosis is multiple sclerosis. Not everything fits, but it kind of looks like multiple sclerosis. You see the patient back years later. There’re some treatment issues, the patient’s not responding to treatment, and things look different. Have you thought about a genetic inherited problem like leukodystrophy or a genetic white matter disorder? Listen to this podcast. We're going to help you figure it out. 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 Roberta La Piana about her article on adult-onset leukodystrophies mimicking multiple sclerosis, which she wrote with Dr Gabrielle Macaron. This article appears in the April 2026 Continuum issue on multiple sclerosis. Welcome to our podcast. Dr La Piana: Thank you. Thank you for having me. Dr Monteith: Absolutely. Why don't we start off with you introducing yourself? Dr La Piana: So, my name is Roberta La Piana. I'm a pediatric neurologist. I trained in Italy, I did my medical school, I did my residency in pediatric neurology there. And then I moved here to Montreal, to the Montreal Neurological Institute, to do a PhD in neuroscience. And that's where I specialized in adult-onset genetic white matter diseases. And after my PhD, I was recruited as an assistant professor here. So, that's where I got into this field. Dr Monteith: This big field, highly specialized; lots of disorders, but highly specialized. And what got you into this? Neuroscience is huge. So, was it a mentor, or…? Dr La Piana: No, actually, it was because of my background, because I trained as a pediatric neurologist and I loved the genetic white matter disorders in the pediatric population. So, when I came to the Montreal Neurological Institute, initially it was mainly to have a better expertise in imaging. And being at an adult neurology institute, I started seeing patients with adult genetic white matter diseases, and I was immediately fascinated by how different they were from their pediatric counterparts. Because in pediatric genetic white matter diseases, pediatric leukodystrophies look very diffuse, look very confluentous, so it's difficult to mistake them. But in adults, in the adult forms, I was initially driven by how often they can be misdiagnosed as multiple sclerosis or as other acquired white matter disorders. So that's why I got really interested in in this field. Dr Monteith: You're, like, literally the perfect person for this discussion. Dr La Piana: I'm not sure- *laughs* Dr Monteith: Why don't we start off with what your objectives were when writing this article? Dr La Piana: With writing this article, the goal is what I have been, actually, doing for the past ten years or so. So, really try to get more attention into the field because of the high rate of potential misdiagnosis of patients. So, that's exactly the reason why I really would like to raise the interest of neurologists for these disorders, because they are not considered enough in the differential diagnosis of patients, of adult patients presenting with white matter disorders. They are considered rare---which are, they are rare, definitely. But collectively, while each single form is rare, collectively they are not as rare. So- and thus, the risk of misdiagnosis and the potential impact of misdiagnosis on them with, you know, you can imagine giving patients inappropriate treatment or missing the possibility of a prenatal genetic diagnosis is so high that I really would like people to keep these disorders in the differential. Dr Monteith: And it sounds like more than ever, this is really important because some of the newer developments in the field. Dr La Piana: Yes. Specifically, we have now tools that will allow to diagnose these patients quite quickly. All the genetic techniques that are available nowadays can really, with one single shot, we can now sequence hundreds of genes so we can have a quicker diagnosis. And this thing was impossible up until ten years ago. So that's definitely the first huge improvement that makes these disorders now easily diagnosed. Dr Monteith: Yeah. So why don't we talk a little bit about how common is this misdiagnosis for these rare subtypes? Dr La Piana: Yeah, the misdiagnosis, it depends on the cohorts. Generally speaking, I would say that the rate of that misdiagnosis for these forms is up to 25% or even more in some other cohorts. And it really depends on the forms. Like, there are clearly some forms, especially those that present with multifocal white matter diseases, that present with nonspecific clinical presentations like migraines, image---and especially for female patients, and for which migraine is so common, having multifocal with other abnormalities is so common, the rate of diagnosis increases even further. So, these are all things that we need to keep in mind. I know these are rare, but still, we need to always have them on the back of our minds. Dr Monteith: Are there any particular disorders that are more often misdiagnosed? And you spoke about progressive forms of multiple sclerosis being a common kind of misdiagnosis. Dr La Piana: Yeah. So, there are definitely forms that are more commonly misdiagnosed. And these are those that, as I probably repeated already too many times, is the word multifocal, which is key. So, all those genetic white matter disorders that present with multifocal white matter abnormalities are not initially considered as genetic. So, I'm thinking about all of the leukovasculopathies, so, the small vessel diseases which are genetic in origin. For example, CADASIL; for example, the disorders related to collagen-4; so, the COL4 A1 or A2-related disorders. Those are clearly more commonly misdiagnosed initially. Another big group, unfortunately, is the CSF1R-related disorders. I know I'm saying a lot of gene names, but due to the fact that they start with multifocal abnormalities and they start with quite nonspecific, slowly progressive symptoms, the rate of misdiagnosis is definitely higher. Dr Monteith: And can you discuss some of the clinical challenges when seeing patients that might lead to this misdiagnosis? Dr La Piana: There are multiple clinical challenges. One is definitely the presence of nonspecific or initially mild clinical symptoms that sometimes don't raise initially the red flag of something, degenerative or progressive or genetic. One category that I would mention are psychiatric disturbances, especially in the form of depression, anxiety, or apathy. This is quite common in patients with some forms of genetic white matter disorders, and they are initially misdirected to psychiatrists and taken care in that domain. But it's only when some even mild neurological symptoms like a gait disturbance or hyperreflexia, or we had patients with, like, a urinary incontinence. It's only at that time, but maybe years have passed meanwhile, that these patients are finally referred to the neurologist Dr Monteith: You spoke about some of these clinical symptoms. Can you give us some other clinical red flags? Dr La Piana: Well, some other clinical red flags can be, for example, the extraneurological involvement. So, we have patients where- and there's a reason immediately to some specific disorders. For example, infertility. The presence of infertility in a female patient with white matter disorders should immediately form the consideration of the specific genetic white matter diseases that are associated with these forms. And this is not something that neurologists tend to ask about in the collection of the clinical history. And this is something that can make the difference and can accelerate the diagnosis. Dr Monteith: What are some other things? I mean, I know we can think about treatment, lack of a common treatment response, maybe, to steroids. You gave a great example of optic neuritis, for example. Give us some other things that we should say, hey, this doesn't fit the picture. Red flag. Dr La Piana: In this case, I think we want to talk more about the specific misdiagnosis of MS. Because these patients are often misdiagnosed with MS, but they might sometimes be misdiagnosed with other forms of acquired white matter diseases. When we consider MS, definitely the presence of being treatment resistant: so, patients that are not responsive to the common MS-targeting treatment should be always a red flag. The evolution as well. So, for example, the presence of a more slowly progressive course is another red flag. The presence of optic neuritis. Sometimes it's tricky because it's not common in the genetic white matter disorders, it's used as a criterion to orient correctly towards a multiple sclerosis. But we need to keep in mind that there are forms, genetic forms, especially the mitochondrial forms, that can present with optic neuritis and are really at the overlap with the multiple sclerosis spectrum. Then, if we want to move forward beyond the clinical side and go into the laboratory, of course a negative lumbar puncture with no oligoclonal bands should be a major red flag. Dr Monteith: What about some of the radiographic features? Dr La Piana: So, the radiographic features is something we are really working on in the field, especially with the new criteria used in MS. So, for example the paramagnetic rim lesions or the central vein sign, they are considered the specific forms. But it's true- and don't have an answer for that. I want to be clear, but it's true that they haven't been assessed yet extensively in patients with genetic white matter disorders. Anecdotally, I can say, because I have already reported this at conferences, that we have seen patients with genetic white matter conditions reaching a threshold for a central vein sign that can be considered diagnostic for MS. And we have seen that in some patients. Again, no study has been carried out extensively to date, but I think we should consider that with a grain of salt. But yeah, the paramagnetic rim in lesions is probably more accurate to distinguish between genetic and acquired white matter disorders. Dr Monteith: And what about some of the genetic white matter disorders that mimic MS? You spoke about things like CADASIL; what are other things that we should keep in the back of our mind? And you have great charts, to our listeners, and they're going to have to review those charts, because they're excellent. I think maybe they need to find a way to make that a little bookmark you walk around with on the ward. But what are some other conditions that kind of commonly mischaracterized? Dr La Piana: Two of the main groups are the one that you mentioned. So, leukovasculopathy is- so, CADASIL, is definitely one of the most common misdiagnoses of MS. And the presence, as we said, of some clinical features like migraine, especially when it's complicated migraine with visual aura, we all know that. But especially in the context of a positive family history for either a psychiatry condition or migraine as well, or strokes, these are all factors that should prompt the consideration of these disorders in the differential of a patient with white matter disorders. Another category are definitely mitochondrial disorders, which I think are more neglected than others because we don't think about mitochondrial disorders when we see white matter disease; we tend to consider that mitochondrial disorders are a problem of the gray matter, but they are not. There are white matter diseases that have definitely mitochondrial. And the third category are probably microgliocytes, which are represented by the CSF1R-related disorder. And this is also something that is clearly quite prevalent, relatively prevalent, in the field of genetic white matter disorders misdiagnosed as MS. Dr Monteith: Yeah. Why don't we go through some of the, kind of, key history, you know, some of the key questions you would ask in the history to try and differentiate? You mentioned kind of subtle symptoms, longstanding progressive symptoms. I know things that we look at like relapsing/remitting and some trigger factors can actually be associated with some of these genetic disorders. So how do you approach a patient? What are some of the key questions? You talked about family history and you talked about medical history, but why don't you kind of give us a nice way to kind of hone in on to the patient? Dr La Piana: There are a couple of questions that we usually ask. I should make a disclaimer, though, that I work very closely with the MS clinics, so we are ready to receive patients that are prescreened. So, these are already patients that people working on acquired white matter disorders feel like they are atypical, so they want our opinion. But usually, there are two groups of questions that we always ask. One is about the family history. And by saying family history, I really dig into the family history. I don't just want to know whether there are family members with neurological disorders. I ask specifically about migraine. I ask specifically about infertility issues. I ask specifically about psychiatric issues. These three things are always on the top of my mind when asking about family history. The other thing is a family history for neurodevelopmental disorder, because you know that some people might not remember that some genetic white matter diseases can present at different ages. So, in the same family, there might be cases with a pediatric-onset leukodystrophy, and that can manifest at a later age in other family members. So, this is something that we always explore. In terms of the clinical history, one question that I recommend always to ask is really about more subtle symptoms. So, for example, many of our patients present with progressive balance problems or progressive mobility issues that have been going on for a while. So, we always ask how they were when they were in their teenage years, for instance. And it's frequent that they say, actually, I was a bit clumsy. Actually, I was not the first being picked in school at phys-ed sports. And these are all interesting aspects. Maybe they are totally incidental, and sometimes they suggest that there was probably something going on for a long time. The other thing is the presence, for example, of learning difficulties. Again, these are things that are subtle but testify that there was probably a process that was more longstanding. Dr Monteith: You talked about things like rim lesions. Are there other types of sequences that might be useful to better characterize demyelinating diseases that are genetic in origin? I assume higher levels of MRI might be better at differentiating. Dr La Piana: Yeah. So, in the clinical setting, there are a couple of sequences that are very useful. One is the diffusion, because as opposed to multiple sclerosis, the presence of persistently restricted areas of diffusion can point immediately towards some genetic white matter diseases. One is CSF1R-related disorders. But there are also some other, more rare tremor and ataxia syndrome that present with persistent areas of restricted diffusion as well as others. The presence of calcification. So, adding an SWI, susceptibility weighted imaging, to check not just for calcifications that can immediately orient towards some disorders, but can also identify areas of microhemorrhages that, if we are going back to the leukovasculopathies, to the genetic leukovasculopathies, can tell us that we are on the right track for excluding those type of diseases. Basically, these are the two that are available in every scanner without even going into fancy, more advanced techniques. Dr Monteith: I was going to ask you that question, how often should we think about this next-generation sequencing when you're kind of on the fence, allowing for some negative results to come back in the abundance of caution? Dr La Piana: The problem with the panel, of course, is that you run a panel and you don't know what's coming back. So, then having to deal with variants of unknown significance in genes, then you have to deal with them, and then you have to deal with results that maybe are not as black or white as you would expect initially. So, I'll answer to your question when to do that, our recommendation would be to do that every time you are presented with a patient that presents those atypical features that we summarized in the paper, and that basically raise multiple red flags for an atypical white matter disease that is not multiple sclerosis. And then what to do when you have results? I still believe that having access, of course, to genetic counselors, to neurogeneticists, is critical, but also having access and being in contact with the network of people working on this. Because we are a network; we put the website address on the paper of the white matter rounds because this is an international network that we built over the years, and we connect monthly, on a monthly basis, with meetings to discuss exactly this type of patient. So, we are all learning together, and it's very frequent that people ask us to present cases at the white matter rounds because they have a presented with unusual or atypical genetic findings and they want the opinion of experts. Dr Monteith: Great. Well, I'm really glad that resource is available. And I'm also really glad that you wrote that article with your colleague. Thank you so much. Dr La Piana: Thank you so much, Tesha. Dr Monteith: Today I have been interviewing Dr Roberta La Piana about her article on adult-onset leukodystrophies mimicking multiple sclerosis, which she wrote with Dr Gabrielle Macaron. This article appears in the April 2026 Continuum issue on multiple sclerosis. 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/index/show/continuumjournal/id/40684390

Diagnostic Neuroimaging Biomarkers for Multiple Sclerosis With Dr. Jiwon Oh 04/08/2026

Diagnostic Neuroimaging Biomarkers for Multiple Sclerosis With Dr. Jiwon Oh Novel MRI biomarkers, including cortical lesions, the central vein sign, and paramagnetic rim lesions, are highly specific for MS and can aid diagnosis in select clinical scenarios, particularly early in the disease course or in atypical presentations. When used with appropriate MRI sequences, these markers can improve diagnostic sensitivity while helping prevent misdiagnosis. In this episode, Casey Albin, MD, speaks with Jiwon Oh, MD, PhD, FRCPC, FAAN, author of the article “Diagnostic Neuroimaging Biomarkers for Multiple Sclerosis” in the Continuum® April 2026 Multiple Sclerosis and Related 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. Oh is the medical director of the Barlo Multiple Sclerosis Program at St. Michael’s Hospital and an associate professor at the University of Toronto in Toronto, Ontario, Canada. Additional Resources Read the article: Diagnostic Neuroimaging Biomarkers for Multiple Sclerosis Subscribe to Continuum®: Earn CME (available only to AAN members): Continuum® Aloud (verbatim audio-book style recordings of articles available only to Continuum® subscribers): More about the American Academy of Neurology: Social Media Host: Dr Albin: Spend any time in a neurology conference, and you are certain to hear about the new central vein sign, which, as I learn, is not actually all that new. But have you heard about cortical lesions or these paramagnetic rim lesions? Because today I have the privilege of talking to Dr Jiwon Oh about her article, and we're going to unpack all these new biomarkers in MS. 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 Jiwon Oh about her article on diagnostic neuroimaging biomarkers for Multiple Sclerosis, which appears in the April 2026 Continuum issue on multiple sclerosis. Welcome to the podcast. Thank you so much for being here. I'd love to start by having you introduce yourself to our listeners. Dr Oh: Thanks, Casey. Hi, everybody. My name is Jiwon Oh and I'm a neurologist, mainly an MS specialist at Saint Michael's Hospital at the University of Toronto, and I'm the medical director of our MS program. Dr Albin: And you have written a really fantastic article that dives deep into some of the nitty gritty about these new diagnostic biomarkers that we find on the MRI that we're getting for our patients with multiple sclerosis. And I think we are going to get into a lot of that nitty gritty. How do we look for them? How do they improve our diagnostic specificity? This is really come a long way in shaping the advances for multiple sclerosis. And I'd kind of like to just start with the big picture. Like why do we need these more specific biomarkers? Dr Oh: This set of diagnostic criteria in MS, it's actually a huge change in the field, and particularly for people like me who are really interested in developing new MRI measures, we're really, really excited because it's actually the first time since MRI was officially incorporated into the MS Diagnostic criteria, which was way back in 2001. It's the first time that we've actually been able to get newer, more advanced imaging measures beyond just simply detecting, new T2 lesions in the MS diagnostic criteria. So, it's a big moment in the field, and many of us are really excited about it in terms of why we need some of these newer, more specific imaging measures. Well, you know, diagnostic criteria always evolve over time for any disease state, and MS is one that we've recognized over the years. By the time someone actually presents with typical clinical symptoms and has diagnosed, whatever has been happening from a patho-biological standpoint has been happening probably for almost 5 to 10 years before that individual actually presents. And so, because of this recognition in the field and the fact that we're recognizing how important it is to first diagnose MS and then treat MS earlier and earlier, because we know that early treatment helps prevent more clinical outcomes. Diagnostic criteria over time have become much more permissive, meaning that we're doing everything that we can to try to facilitate a diagnosis of MS when we know that someone biologically has MS. But the problem with making diagnostic criteria more permissive, and it's obviously a good thing because you want to capture as many people with MS as early on as possible. The problem with making it permissive is there is this terrible risk of misdiagnosis. As clinicians, we all think we never make mistakes. But it turns out when you actually do studies, you do. And even at MS specialty centers, when studies have been done, 10% to 20% of people with MS are misdiagnosed. So, this is exactly why we need in diagnostic criteria that really help to facilitate a diagnosis. We need things that help us prevent misdiagnosis as well. And these are these specific imaging measures that have now been incorporated into the diagnostic criteria in many settings that will help to facilitate a diagnosis. But the really big perk is if you use them, you can help to prevent misdiagnosis as well. Dr Albin: Yeah, that really shone through in your article that this was such a big step in towards being more specific about who were diagnosing. Also capturing more people, right? Trying to get those people that we, we don't want to miss because of all the things you say, you know, that allows them to accumulate more disability, have worse outcomes. Early diagnosis is so important. But I really did take away from your article just how critical these are and sharping our diagnostic acumen. And so just to jump right in, and you describe these three new biomarkers, these cortical lesions the central vein sign and paramagnetic rim lesions. And so just to kick things off let's start with cortical lesions I sort of conceptualize multiple sclerosis a disease of white matter. So, what's going on here? Dr Oh: Yes. MS classically has always been described as a white matter disease. But it turns out when you look at brain and spinal cord tissue, as well as when you use kind of better sequences to actually look for lesions in the gray matter, it actually turns out there's a ton of lesions in the gray matter as well. And in fact, what's interesting is that regardless of whether it's the cortex or the deep gray matter, it's lesions within these areas that seem to have the highest relevance for clinical disability in MS. So, all this to say, of course, MS is a lesion that does affect white matter, but it also affects gray matter a lot. And maybe pathology within the gray matter is even more relevant to clinical disability. So, this is why we're really interested in being able to develop methods using MRI to more accurately visualize the gray matter, particularly the cortex, as well as deep gray matter structures like the thalamus. I should add the caveat that cortical lesions were actually included in the 2017 diagnostic criteria revisions, but they were included together with juxtacortical lesions, which are a typical area that MS lesions form. And so, this imaging measure, despite the fact that it is relatively novel and we consider it advanced, it hasn't been used that much only because it's not that easy to detect lesions within the cortex. And reasons for this include that you usually need higher field magnet platforms. And so, the typical clinical MRI scanners that are available kind of widely, regardless of whether you're at an academic center or a community center, are 1.5 Tesla magnets. And cortical lesions are actually really difficult to detect on those typical scanners. But when you get to like, say, three Tesla or seven Tesla, they're a lot easier to detect. But obviously that's a big hindrance to widespread use. And then you actually need very specialized sequences to adequately visualize cortical lesions. And these are not sequences that are usually collected for clinical purposes. So, it kind of requires convincing your radiologists that you need this additional sequence. And then it actually takes a lot of time and training to be able to adequately, accurately detect cortical lesions. So, despite the fact that it's actually very useful when you do have the appropriate MRI sequences and scanners to detect cortical lesions, even though they were incorporated into the 2017 criteria outside of specialty centers, they're not actually widely used. But when you do have the appropriate sequences, cortical lesions are actually pretty specific for MS. So, very helpful for a diagnosis in certain settings. But there's all these practical limitations that have really limited its widespread use. Dr Albin: That is a beautiful summary. So, it sounds like once we kind of get up to speed in terms of like the protocols for this, having the magnet strength for this, this will be really a game changer in terms of increasing the specificity and also maybe finding things that impact patient's clinical presentation and therefore quite meaningful. But it sounds like for most of us, this is probably not something that they're going to be adopting right away. Is that a fair assessment? Dr Oh: Yes. And you know, they were included in the last diagnostic criteria revisions. And it really hasn't changed things very much, only because of these difficulties with, you know, requiring higher field magnet strengths and these specialized sequences and then needing training to kind of figure out how you can adequately detect cortical lesions. Dr Albin: Totally. So, the other thing we've heard a lot about, and I have to say, I was in the AAN fall conference not too long ago, and this came up quite a bit, was the central vein sign and the fascination with that, because it tells us a lot about the MS pathophysiology and again, increasing that specificity. And it seems like maybe this is one that we can more easily adopt in clinical practice. So, tell our listeners about what that is, how they detect it. How many do you need to find? Dr Oh: Sure. And so, this is one of the imaging measures I'm really excited about. So, the central vein sign heard about it recently. And probably in the last ten years particularly in the MS field we're talking about it all the time. But just wanted to emphasize that the central vein sign is not something that is new. Even back in the 1800s, when Charcot described MS lesions in these ancient textbooks, he actually very clearly described that MS lesions form around the central vein. And that makes sense, because we know that these waves of peripherally mediated inflammation somehow get through the blood-brain barrier and cause this cascade of events leading to inflammation in the brain and spinal cord, which is what MS is. But we know that B cells in T cells require veins to get into the central nervous system. And so, it's no surprise, really, that MS lesions form around veins. And so, this is something that's been known pathologically. But the reason we're so excited about it now is because we actually have good enough iron-sensitive MRI sequences that allow us to see a central vein when it is present within a white matter lesion. As a neurologist, we know that there's probably hundreds and hundreds of different things that can cause white matter lesions in the brain. But when you use an appropriate iron-sensitive sequence and you see that many of them, if not most of them, actually have visible central veins, that tells you that this person very likely has MS. And so that's why we're so excited about it, because there have been many studies done in the last ten years. In fact, so much evidence generated in the last ten years that there have been I think it's now four systematic reviews and meta analyzes. Looking at the diagnostic properties of the central vein sign. And, you know, it turns out that when you look at people with MS, most of them have a pretty high proportion of white matter lesions that have visible central veins. And there's a lot of questions about, you know, how to best use the central vein sign. But when 40% or more of the white matter lesions that you see have visible central veins, then the likelihood of a diagnosis of MS is very high. So, this is why we're so excited about it in the MS field because it's a really useful diagnostic tool. You know, again when you have appropriate ion sensitive sequences, if you see someone with white matter lesions and you see that 40% or more of them have visible central veins, this tells you that this person very likely has MS. Dr Albin: So, Dr Oh, I hear you say, you know, 40% of the lesions. Does that mean the neuro radiologist needs to look at every single lesion and then count how many have the central veins, or is there an easier way to do this? Dr Oh: Great question. Casey, there is definitely an easier way because our neuro radiologists would not be our friends anymore if we made them look at every white matter lesion and make sure that 40% of them had the central vein sign. So, because it's so time-consuming to use that 40% threshold, there's an easier criterion that has actually made it into the diagnostic criteria. And it's called Select Six. And what this means is when you have more than ten lesions, as long as you show that six of them have a visible central vein, you just have to count six with the central vein. Then you're done. So that means you're Select Six positive or central veins nine positive. However, if you have ten or fewer lesions, as long as you show that more than 50% of them show a visible central vein, then you are select six positive, and then you're done. So, as you can see, it's a much simpler criterion to apply, and it seems to perform almost as well as that 40% threshold, which is why that is the criterion that's made it into the new diagnostic criteria. Dr Albin: Perfect. I love that we definitely do not want to make enemies with our neuro radiology colleagues, but yet they do so much for us. So perfect. I'm glad that we can, make their jobs a little easier without losing any specificity there, or just losing a touch of specificity there. All right. If I am working with a, you know, in a center that maybe doesn't do this all the time, am I just getting a run of the mill SWI sequence? Do I need to ask my radiologist for a special sequence? Or is this just, you know, you can get it from the typical array of what our patients are getting. Dr Oh: You know, SWI is a widely available commercial sequence that's iron-sensitive, the ones that are typically commercially available, they can detect central veins, but there actually are little tweaks that you can do to make it a little more optimal. With the recent diagnostic criteria publication, which was, led by Xavier Montalban and recently published in Lancet Neurology. There's actually a companion MRI paper that was led by Frederick Barkov and Danny Wright. And the reason I'm specifically citing those papers is in that companion MRI paper, there's a table that has kind of optimal sequence parameters that you can use even with a conventional SWI sequence, to try to best detect the central vein sign. And then there's a wide range of different iron-sensitive sequences, and SWI is one of them, but the one that seems to have emerged as most sensitive to detect the central vein sign is something called the 3D T2*-EPI sequence. But the bottom line is there's a whole bunch of different iron-sensitive sequences that you can use, little tweaks that you can do to make them optimal, to be able to visualize central veins when they're present within white matter lesions. Dr Albin: Incredible. So like partner with your neuro radiologist, there is a great sounds like a field guide almost to this. So, it makes it easy to pick up in your standard of care so that you can make sure that you are detecting them at the optimal level to see that more specific diagnostic biomarker. Dr Oh: Yes. And you know, in contrast to what we were talking about with cortical lesions, you can actually detect central veins when you use these iron-sensitive sequences at any field magnet. So even at 1.5 Tesla, particularly when you use contrast, which is often given with the diagnostic scan anyway, you can very easily detect a central vein. So that's a huge benefit because it allows for widespread use. As long as you work with your radiologist to get the right iron-sensitive sequences in. Dr Albin: Yeah, that's incredible. I mean, I think that it really will be practice-changing. And then the last one that I think was honestly new to me, I feel like I had heard a lot about the central vein sign, but the whole new to me term was this paramagnetic rim lesion. So, what does that tell us about the underlying biology of MS? And are there any other things that might also have this finding that we should sort of be aware of? And how specific is it? Dr Oh: You know, the central vein sign is kind of the main, really new imaging measure that's made it into every part of the MS diagnostic criteria. And then together with that paramagnetic rim lesions or we call them PRL or pearls for short, they've made it as well, but in a much more limited way only because there's not as much evidence that has accumulated over time to support the diagnostic utility of pearls. But first of all, what are pearls? So, people in the MS field are really excited about pearls, because we know that they capture a subset of what we call chronic active lesions. So, MS lesions will form acutely and over time, some of them will become inactive. And then some of them are chronic active lesions, meaning that they have this rim of activated microglia around them. Over time, they continue to slowly expand. And it's almost like this slow burn. And the reason why we focus a lot on chronic active lesions is because we know that they're a driver of progressive disease biology and MS, meaning that in people who have progressive MS or who have pretty severe disability, global disability or cognitive disability, we know that they have a high burden of pearls. And so that's why there's so much excitement in MS about being able to image chronic active lesions. It's because we're always looking for an imaging measure that allows us to accurately predict progression or to, measure progression over time. So that's why there's so much excitement in MS about pearls. But as kind of an added bonus, it turns out pearls are also really specific for MS. And so, when you use the same iron-sensitive sequences, by the way, that's used to detect the central vein sign when you use appropriate iron‑sensitive sequence. And if you see that someone has a pearl, the likelihood of a diagnosis of MS is very high. The one exception to that is Susac syndrome, where pearls have been observed. But other than that, with many other white matter diseases like neuro rheumatology disease, NMOSD, MOGAD, you really don't see pearls. And so, this is why it's made it into the new diagnostic criteria. In contrast to the central vein sign, though, not everybody with MS has a pearl, so the sensitivity isn't as high. However, it's really, really specific in the range of, you know, 90 to 95%. So, this is why it's been added as, an imaging measure in certain settings. It can help facilitate a diagnosis. But the real utility, again, is when you use it, it helps you to prevent misdiagnosis. Dr Albin: It's fantastic. And hearing you talk about that, this one stands out to me as a biomarker that not only helps... /episode/index/show/continuumjournal/id/40684210

April 2026 Multiple Sclerosis and Related Disorders Issue With Dr. Andrew J. Solomon 04/01/2026

April 2026 Multiple Sclerosis and Related Disorders Issue With Dr. Andrew J. Solomon In this episode, Lyell K. Jones Jr, MD, FAAN, speaks with Andrew J. Solomon, MD, FAAN, who served as the guest editor of the April 2026 Multiple Sclerosis and Related Disorders issue. They provide a preview of the issue, which publishes on April 2, 2026. 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. Solomon is the Division Chief of Multiple Sclerosis and a Professor in the Larner College of Medicine at the University of Vermont in Burlington, Vermont. Additional Resources Read the issue: Subscribe to Continuum®: Continuum® Aloud (verbatim audio-book style recordings of articles available only to Continuum® subscribers): More about the American Academy of Neurology: Social Media Host: Dr Jones: It's been more than 150 years since Jean-Martin Charcot first described the disease that we now know as multiple sclerosis. Since then, the tools we have to diagnose and treat this disorder have expanded enormously. So why are the diagnostic criteria for MS. still evolving? Today we're speaking with Dr Andrew Solomon, guest editor of our latest issue of Continuum on MS and related disorders. To learn more about this question and much more. 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 Andrew Solomon, who is Continuums guest editor for our latest issue of Continuum on multiple sclerosis and related disorders. Dr Solomon is a professor of neurological sciences at the University of Vermont, where he also serves as the division chief of multiple sclerosis. Dr Solomon is an internationally recognized authority on MS, particularly on the diagnostic approach to this complex disorder. Dr Solomon, welcome. Thank you for joining us today. Why don't you introduce yourself to our listeners? Dr Solomon: Hi, everyone. This is Andy Solomon. It's a pleasure to be here with you. And I feel honored to have helped this collaborative effort that created this important tool for trainees and clinicians in practice, the Continuum issue on multiple sclerosis and related disorders. Dr Jones: Obviously, we're grateful that you've taken us on. A lot has happened in the world of MS and other neuroinflammatory disorders in the last few years, so lots to update. But as we've done over the last few podcasts, I'm going to start off the interview today, Dr Solomon, with a trivia question. And then we'll come back at the end of the podcast and give the answer. So, the trivia question is this. There are now more than 20 drugs approved by the FDA for the treatment of MS. What was the first disease-modifying therapy approved for MS? And when was it approved? So, don't answer because I know you know the answer. But we'll come back to it at the end of the interview. And our listeners can think about that question. So, let's get right to it. As many of our listeners know, the diagnostic criteria for MS. were recently revised. And you were involved with that revision. So, you're the perfect person to ask what were the major changes in the 2024 McDonald criteria, and why did we need to update them in the first place? Dr Solomon: I'm very excited about the 2024 McDonald criteria, and it was an honor to be part of that process that resulted in that manuscript. When we revise the diagnostic criteria for MS usually it's driven by accumulating data that suggests some changes or revisions might help us diagnose patients either earlier or with more accuracy. And that's certainly the case with this criteria. There was accumulating data that suggested some particular changes were important. You know, there's a lot of expert opinion involved as well. You know, there's many experts who are involved in the collaborative decisions that go into these revisions. And some of the changes in our field also pushed some of the revisions to where maybe there's not as much evidence, but where we felt it would improve care for patients with MS. This criteria, I would argue, is probably one of the most substantial revisions in over 20 years. There's multiple changes that are potentially impactful for the diagnosis of MS. Some very important changes involve the incorporation of new paraclinical tools that we can use to assess the visual pathway, as well as, imaging tools that provide high specificity for MS that we can use to substitute or dissemination in time, for instance, as well as other tools that may allow us to diagnose patients earlier than we would have in prior criteria. There's also some opportunities with the new criteria to potentially provide access in regions where some tools are more available than others. For instance, the incorporation of Kappa Free Light Chains as a substitute for oligoclonal bands may open up opportunities in regions where expertise for oligoclonal band testing are not available. That's a very qualitative test, whereas Kappa Free Light Chain index is more quantitative, less expensive and may allow CSF testing to be performed to aid the diagnosis of MS in some regions where it wasn't available previously. This criteria provides multiple pathways to the diagnosis of MS, many more than we've had in prior criteria. So, it's important to emphasize that while there's all these new tools and changes that have been incorporated, not every pathway needs to be available where you practice. What it incorporates as flexibility. It is a bit more complex looking at all of these different possibilities, but the point is this flexibility allows clinicians or providers to diagnose MS early with high accuracy based on the tools they have available. Dr Jones: I think it will be a learning curve, right? I think any time we make a change in how clinicians get accustomed to approaching a diagnosis of a disorder, it will take some time for folks to incorporate it. And I see what you mean about the complexity, but I think that's a really great point, that emphasizing the different pathways to the diagnosis is really a strength of the revision, right? Dr Solomon: I agree, I think, you know, in other disorders, particularly if you think about rheumatologic disorders, systemic rheumatologic disorders or inflammatory disorders, where over time we've not had very highly specific and sensitive biomarkers. And we've incorporated a variety of clinical and prior clinical findings, testing, laboratory testing and biopsy and other things to confirm a diagnosis. These approaches to these disorders are sort of a checklist. And I think that clinicians became familiar with that approach and were able to make diagnoses accurately this way. And I think of the new criteria in a similar way. It's not quite amenable to a checklist, but the pathways are sort of simplified with multiple options. Hopefully, using the figures, clinicians can look at the paper and see what tools they have available to help them confirm a diagnosis of MS. I think it's really important to emphasize that the diagnostic criteria for MS still does not discriminate MS from other disorders. Everyone who's listening here, you do, the clinicians do. So, to enter the diagnostic criteria and these pathways, we first have to feel confident that the patient has a clinical presentation and an MRI presentation or MRI findings that are highly suggestive of MS. That aspect of the criteria hasn't changed since, the Schumacher criteria in the 1960s. This concept of no better explanation. So, we still need to know what's typical for MS. And we need to know what signs or symptoms or findings are that might suggest another disorder, because the criteria are really only validated and tested in patients who have these presentations to start with that are typical for MS. A major change in this particular criteria is that we can now diagnose patients who are asymptomatic. Previously just called radiological isolated syndrome. Not every patient with an MRI finding concerning for MS and now being diagnosed with MS. There's other features that, must be present, but even more than before, knowing what the typical appearance of MRI lesions suggestive of MS, it is even more critical now than it was before, because in those patients who have either no symptoms or a nonspecific presentation, if we have an MRI that's highly convincing for MS and some other prior clinical findings, we can make the diagnosis. But we first need to know with some confidence what that MRI should look like. Dr Jones: So, there is a little circularity when we do these diagnostic criteria. I think our listeners who see patients will be reassured that the clinician is still in the loop. We haven't been automated out of the process yet. Dr Solomon: We need a highly sensitive and specific biomarker or a set of biomarkers for MS. We're getting closer with some of these advanced imaging findings like central vein sign and paramagnetic rim lesions. But not every patient can be diagnosed with those. And they're not required for the diagnostic criteria. In lieu of a highly sensitive and specific test. Our clinical acumen, for what we find a neurologic exam. And what we see on imaging in particular, is quite critical for ensuring that the criteria perform as well as we hope they will. Dr Jones: So, you've had the opportunity, the vantage point, to review all of these articles covering a wide variety of topics, MS, other neuroinflammatory disorders like aquaporin‑4–positive neuromyelitis optica spectrum disorder (NMOSD), myelin oligodendrocyte glycoprotein antibody-associated disease, MOGAD. Anything that surprised you in these articles as you were reading through them? Dr Solomon: I think maybe for listeners, what may be surprising to some of them is that despite guidelines surrounding the use of some of our disease modifying therapies in pregnancy and breastfeeding that are published by regulatory authorities in the United States or Europe or other places, we are making other decisions for patients based on the data we have, the best data we have. Thinking about family planning is really important for us with patients who are newly diagnosed with MS, as well as through the course of their disease. This is a conversation we should be having shortly after diagnosis, because there are strategies we can take to minimize the risk of exposure of DMT around conception and to make plans for how we're going to think about DMT surrounding breastfeeding, to ensure the health of mom and the baby, and reduce risks as much as we can with the knowledge we have. I think in medicine it's quite common for us to use medications off label, right? I mean, so medications are often FDA approved for one indication. And in neurology, for instance, we find a lot of medications after their approval were quite effective for migraine prophylaxis for instance. Right? And so, it's not unusual for us to prescribe medications beyond the label. And I'm not suggesting that we necessarily ignore the advice of our regulatory authorities. But sometimes the data is accumulating really fast around some of these therapies after they’re approved. Sometimes we can look towards experts and how we can navigate pregnancy and breastfeeding in MS. Dr Jones: I think that's a great point about the importance of family planning and having to use judgment. I do want to highlight to our listeners and our subscribers a fantastic article in the issue on family planning and MS and other neuroinflammatory disorders. This was written by Dr Ruth Dobson and Dr Kersten Hellwig, and I think it covers a lot of that gray area where we have to use our clinical judgment to manage these diseases in the absence of a regulatory approval. And I think, again, that's an important gap that the issue fills. And really, that's just a wonderfully written article that I think is a must-read. So, we cover lots of topics in this issue. And one of them is again a relatively newly characterized disorder, MOGAD. What's the latest in the world of MOGAD, what should our listeners be aware of? Dr Solomon: I agree, I think we're in an exciting time in CNS inflammatory disease. And this is a recently described disorder. You know, and the diagnostic criteria now is only a few years old. So, I think importantly, readers should be aware of the diagnostic criteria. This is something that, really will help us distinguish this disorder from NO spectrum disorder and MS. There's a key overlap between the MS diagnostic criteria and MOGAD. Two decades ago we saw a pediatric MS included somewhat atypical presentations like bilateral optic neuritis or acute disseminated encephalomyelitis. And we had caveats in our approaches to pediatric presentations of presumed MS, suggesting that there could be something very different than adult MS. Subsequently, we've realized that pediatric MS presents quite similarly to adult MS in terms of its clinical syndromes and MRI appearance, and many of those pediatric patients who had initially been diagnosed with MS and MOGAD. MOGAD is actually probably more common demyelinating syndrome in patients who are under 12 years old. So, the MS diagnostic criteria requires testing for MOG-IgG with a good assay, a cell-based assay, any patient being evaluated under the age of 12 or with a demyelinating syndrome to avoid misdiagnosis. Dr Jones: Thanks for that. Obviously, MOGAD is one of several disorders that have been more recently characterized and, something that our readers need to be familiar with, and there's plenty of updates within the issue on that and other topics. Okay. So now back to our Continuum audio trivia question. And just to remind our listeners, there are now more than 20 drugs approved by the FDA for the treatment of MS. What was the first disease-modifying therapy approved for MS? And when was it approved? Dr Solomon, do you want to take the honors and answer the question? Dr Solomon: Sure. It was way back in 1993. You had to get on a wait list, I believe, initially to get on it. There was some sort of lottery, and it was Betaseron. Dr Jones: Betaseron in 1993, was the first disease-modifying therapy approved by the FDA for the treatment of MS. It just shows how much water under the bridge we've had since then. 1993 was also the first year of the Jurassic Park series of movies. It was the biggest movie of the year, the song of the year in 1993 was “I Will Always Love You” by Whitney Houston. It was also the year you can tell that I look back into 1993 to see what else happened. It was also the first year the World Wide Web became publicly available, which is it kind of puts brackets on the era or the epoch of MS disease modifying therapy. And finally, the Super Bowl champs that year were the Dallas Cowboys, who unfortunately, have not had much luck in Super Bowls since the 1990s. Maybe they will have more opportunities like we've seen with MS therapeutics. So, Dr Solomon, I want to thank you for joining us today. I want to thank you for such a wonderful discussion of the latest in MS. I think the updated diagnostic criteria are really going to be critical for our listeners to understand and incorporate into their practice. Really grateful for your leadership of the issue, putting together a really stellar group of experts for all of our articles and grateful for your time today. Thank you for joining us. Dr Solomon: Thanks so much for having me. Thank all the other listeners out there for joining us as well. I'm really excited about this issue of Continuum. Dr Jones: Again, we've been speaking with Dr Andrew Solomon, guest editor of Continuums most recent issue on multiple sclerosis and related disorders. 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. /episode/index/show/continuumjournal/id/40683385

Neurologic Complications of Drug and Alcohol Use With Dr. Adeline L. Goss 03/25/2026

Neurologic Complications of Drug and Alcohol Use With Dr. Adeline L. Goss Neurologic complications of substance use may be the first symptoms that lead patients with substance use disorders to seek care. Neurologists have a key role in identifying patients with substance use disorders and connecting them to treatment. In this episode, Lyell K. Jones Jr, MD, FAAN, speaks with Adeline L. Goss, MD, author of the article “Neurologic Complications of Drug and Alcohol Use” in the Continuum® February 2026 Neurology of Systemic Disease issue. Dr. Jones is the editor-in-chief of Continuum: Lifelong Learning in Neurology® and is a professor of neurology at Mayo Clinic in Rochester, Minnesota. Dr. Goss is a neurohospitalist and associate chief of neurology for Highland Hospital in Oakland, California. Additional Resources Read the article: Subscribe to Continuum®: Earn CME (available only to AAN members): Continuum® Aloud (verbatim audio-book style recordings of articles available only to Continuum® subscribers): More about the American Academy of Neurology: Social Media Host: Dr Jones: A big part of neurology is solving mysteries. Patients can show up with all kinds of mysterious symptoms. Sometimes the diagnosis comes from within, some internal disruption of neurophysiology. But sometimes the problem is a complication of drug or alcohol use. Today we have the pleasure of speaking with Dr Adeline Goss, who recently authored an article for Continuum on this exact problem, a topic all neurologists need to be familiar with. 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 Jones: This is Dr Lyell Jones, Editor-in-Chief of Continuum: Lifelong Learning in Neurology. Today I'm interviewing Dr Adeline Goss, who recently authored an article on the neurologic complications of drug and alcohol use for our latest issue of Continuum on the neurology of systemic disease. Dr Goss is a neurohospitalist and the associate chief of neurology at Highland Hospital in Oakland, California. She's also an accomplished writer, broadcaster and podcaster. Dr Goss, welcome, and thank you for joining us today. Why don't you introduce yourself to our listeners? Dr Goss: Great to speak with you, Dr Jones. Yes, I'm Adeline. I also go by Addie Goss. Dr Jones: So, before we get into the discussion, we're going to start off today with something fairly new to the podcast, the Continuum Audio trivia question. So, we all know that alcohol and other substances have many potential complications in that use of these substances fluctuates over time. But this one stood out to me from your article, Dr Goss, just for the sheer size of the change. So, for our listeners, here's the question. Accidental exposures to what substance increased a whopping 1,375% between 2017 and 2021? I'll read that again. Accidental exposures to what substance increased 1,375% between 2017 and 2021? So, stick around to the end of our interview for the answer. And let's get right to it, Dr Goss. If you had a single most important message to our listeners from your article, what would it be? Dr Goss: Well, I mean, many of us went into neurology because of the way that neurologic illnesses can be life-changing for patients. And I work as a neurohospitalist at a public hospital in Oakland, California. Many of my patients are admitted for neurologic conditions related to substance use. And when I see my patients later in the discharge clinic, many tell me that the last day that they used meth or the last day they used cocaine, the last day they smoked, was the day they had their stroke or whatever they came into the hospital for. I think the most important message is that hospitalization for a neurologic condition related to substance use can interrupt use patterns, can motivate change. And therefore, as neurologists, we really have an opportunity to connect to our patients and connect our patients to substance use treatment and make a dramatic difference in people's lives in this regard. Dr Jones: I think that's a fantastic point. I enjoyed a point you made in your article---and I can't remember exactly how you phrased it, I won't say it as well---that you think of the syndromes through which alcohol and drug exposures can present. Those syndromes almost always could end up of other primary neurologic disorders. So, put a different way, when a patient presents with a neurologic problem, most of the time an exposure could be on the differential. And so, we really do have a responsibility as neurologists to be familiar with these. Dr Goss: To be familiar with these and to know how to connect patients to resources to try to get treatment. Dr Jones: Totally agree. And you touched on the public health aspect of this. It's really hard to talk about drug or alcohol use without acknowledging the public health impact particularly of opioids, which has been a crisis for most of this century. Right? And I think most of our listeners will be familiar with the rapid rise in opioid-related deaths. But there might be a glimmer of optimism there. Is what I've seen true, that opioid-related deaths may have plateaued? Dr Goss: So, yes, it's true that opioid-related deaths, overdose deaths in general, have begun to decline, actually, since 2023. And that's in part because overdose deaths really surged early on in the Covid-19 pandemic, in the setting of all of the social disruption, reduced access to services, and social isolation that occurred with the pandemic. But there were really multiple factors there. So, as you mentioned, there was this really rapid rise in illicitly manufactured fentanyl. Fentanyl became a major driver in overdose deaths starting in the mid-2010s. And by the late 2010s, it overtook heroin and prescription opioids as drivers of overdose deaths. And then this just collided with the pandemic in 2020, causing skyrocketing deaths. So, as we know as neurologists, fentanyl is more potent, it's shorter-acting, and it's also cheaper than heroin. It can cost as little as 50 cents or a dollar a pill. Thankfully, as services have rebooted and also as naloxone has become more widely distributed, there has begun to be a decline in opioid overdose-related deaths. So, we're relying on provisional data from the CDC for the most recent years, but that shows about a 24% decline in annual overdose deaths, comparing late 2023 to late 2024. And that's real. That comes out to 70 lives saved per day. Unfortunately, deaths still remain above prepandemic levels, and we're still talking about 87,000 drug overdoses per year. So, I would agree, a glimmer of hope. But we're still seeing overdose as the leading cause of death among young Americans aged 18 to 44. And there's a very long way to go. Dr Jones: 23% is a big number, and that is certainly exciting to think about, but we're still above that long-term secular trend. So, hopefully whatever is happening to bring that down, hopefully it continues. And we talk a lot about- appropriately, we talk a lot about opioid exposures and some of the neurologic presentations of opioid use and toxicity, but alcohol use disorder is the most common substance use disorder, correct? I learned that from your article. And it has been for some time, and it has well-known acute and chronic toxicities. But I think many of us have been taught something of a myth in the acute treatment of patients who may have thiamin deficiency or Wernicke's encephalopathy. Can you tell us a little more about that? Dr Goss: Yeah, sure. So, boy, what is my favorite vitamin? As a neurologist, I think thiamin is my favorite vitamin. Thiamin is a cofactor in- for several enzymes that are involved in glucose catabolism. And it's necessary to synthesize myelin and several neurotransmitters. And as we know, alcohol use disorder leads to reduced nutritional intake and impaired digestion and absorption of nutrients. And this can lead to deficiencies in water-soluble B vitamins, including thiamin, as well as trace elements. The thing about thiamin is that thiamin deficiency often appears first, because the body's stores of thiamin deplete in about 4 to 6 weeks. You know, we're traditionally taught if a patient presents with symptoms concerning for Wernicke's encephalopathy, that if they're also hypoglycemic or just in general, we have to get glucose into them first, because we don't want to tax these thiamin-dependent glucose catabolism pathways. But really, there's no reported case of a single glucose bolus precipitating some dramatic symptomatic thiamin deficiency. It's thought that harm would come potentially from prolonged carbohydrate administration without thiamin. And so, if a patient in front of you is both thiamin deficient and hypoglycemic, you just treat both. You treat both emergently. But it doesn't really matter in what order you do so. Dr Jones: That's good to know that doing the right thing for the patient can involve using either of those in whatever order. And I agree with you, I don't think I've ever hurt anybody by giving them thiamin. It's an easy one to miss and an important one to remember in the right context. And speaking of, and I think a lot about in your article, Dr Goss, I can see a neurologist seeing a patient in the emergency department or in the hospital or even in the clinic thinking about the wonderful points in your article. But we know that when alcohol or substance use enters our mind on the differential, the next impulse is to test for it. And we also know there are pitfalls of drug screening, doing urine drug screens, etc. How do you approach testing when you think about a potential drug-related complication in their differential? Dr Goss: So, like most people, I would start with a urine drug screen for any patient who's presenting with a possible toxidrome or some substance-related neurological presentation. These urine drug screens, they're rapid, they're inexpensive, they're immunoassays for traditional drugs and their metabolites. So, usually amphetamines, cocaine, opiates, plus/minus cannabis. But I think the first thing to note is that they miss entire categories of drugs, and not just drugs that are not in that list. They miss synthetic opioids, including fentanyl. One group is keeping track of this number. So, I have an update for mid-2025. And that's that 30% of U.S. ED overdose encounters as of mid-2025 included fentanyl testing. Only 30% for patients who are presenting with an overdose syndrome. Dr Jones: And that's for one of the most widely used synthetic opioids. So that's really a striking number. Dr Goss: Yeah, one of the most widely used and one with the greatest rate of complications. So, states can make a difference here. In 2022, California passed a law requiring fentanyl testing on hospital urine drug screens and several states have followed. And so that number is rising, the rate of testing for fentanyl. But that's just a really key thing to know, that that one is often missed. Other just important pitfalls, the timing of the urine drug screen matters because for most substances, it only picks up the drug within 24 to 72 hours after the last use. With amphetamines and cocaine going out a couple more days after that, especially in patients who use repeatedly. And then also, notably, there's a risk of false positives. This is especially true with amphetamine use, and beta blockers are one of the drugs that can lead to false positives on an amphetamine test, on a urine drug screen. So, I'll share that I've had several patients who have presented with intracerebral hemorrhage and who tested positive on the emergency department’s urine drug screen and who adamantly stated that they do not use amphetamines, they've never used amphetamines, and they didn't ingest anything that could have contained amphetamines. And when we did serum confirmatory testing, in fact, their amphetamine testing was negative, and all those patients had received esmelol or the labetalol in the ED to treat their blood pressure related to their ICH. So false positives can occur with, you know, other medications like decongestants and certain antidepressants. But beta blockers are a key one to know. And then finally, there are just a number of things outside of that short list of substances that I mentioned, including a huge range of novel psychoactive substances that would not be tested for on a standard urine drug screen. And for those, you'd require serum testing, or at some large academic centers or specialty toxicology labs, you can actually do liquid chromatography high-resolution mass spectrometry, with- which is basically unbiased testing for any substance that's present in the patient sample. So, I guess, you know, you asked about my approach. Start with the urine drug screen, but there's no substitute for good history-taking and close examination of your patient's general examination, not just their neurologic presentation. And if patients are presenting with a toxidrome that I would expect would show up on a urine drug screen but it's negative, there are other confirmatory tests that can be sent, although they're often send-out labs and come back in a very delayed fashion. Dr Jones: So, in other words, it's complicated, which usually means it's humbling. And if I'm understanding it correctly, there's the risk of the false positive on the urine drug screen. And then there's the risk of the false negative if we think we're screening for something that might not even be on that initial screen. So, that's a wonderful reminder that these are clinical diagnoses and we have to keep our clinician hats on while we're thinking about how to establish these diagnoses or exclude them. So, back to opioids, Dr Gross. There are some really peculiar neurologic syndromes associated with opioid overdose. Tell us a little about those. Dr Goss: Well, I mean, some of these were described first with heroin. So, we can start with the one that almost anybody has heard of, heroin-associated spongiform leukoencephalopathy, which we know is associated with a practice known as “chasing the dragon,” which is inhaling vapors of heroin heated on foil. But we know now that this syndrome can occur with other opioids, including fentanyl. The clinical features are, you know, apathy, cerebellar signs, quadriparesis, parkinsonism, myoclonus, and some patients progress to coma or even death. But on MRI you're seeing, you know, these confluence symmetric white matter diffusion restriction and T2 hyperintensities in the cerebellar white matter and the posterior limb of the internal capsule that spare the subcortical U-fibers. So, you know, I think this is kind of the classic example of something that's symmetric, that has a very obvious and interesting MRI pattern. But as time is passing, we're seeing more and more similar types of syndromes of leukoencephalopathies, but with different clinical presentations and MRI characteristics. So, another of these is CHANTER syndrome. This is an opioid overdose-related presentation where people have stupor and coma. And on the MRI there, you see bilateral symmetric diffusion restriction in the cerebellar cortex, in the hippocampi, in the basal ganglia. And it spares the cerebral cortex. And notably in these cases, patients can progress to cerebellar edema, to obstructive hydrocephalus. And some require suboccipital craniotomy. I had a week recently at Highland Hospital, where I work, where we had two of these cases in the same week, in just a community hospital. And there's a similar syndrome in children known as POUNCE syndrome with profound cerebellar edema, and many patients require posterior decompression. So that's another different distribution of findings with a different outcome. Fortunately, there's a milder sort of phenotype of opioid-associated amnestic syndrome, is what it's been described, where there's primarily DWI changes in the hippocampi and the globus pallidus. So, patients primarily present with an amnestic syndrome, mostly anterograde amnesia. Seeing these in practice, I'm not sure that patients always fall into one bucket or another. But in general, you'll see some degree of symmetric diffusion restriction or symmetric white matter changes that clearly point to a toxic presentation, a toxic syndrome, as opposed to pure anoxia, for example. And it's important to know that because from a prognostic standpoint, anoxic brain injury, which can occur after cardiac arrest and after opioid overdose, can look different than some of these syndromes. Finally, heroin has been associated with myelopathy, but also that's been reported on with fentanyl. So, I think some of these conditions got their reputation from heroin. But as fentanyl has proliferated---and prior to that as prescription opioid, you know, misuse had proliferated---we're seeing similar syndromes with all of the opiates. Dr Jones: And I think it's a good case in point that you can have multifocal disease and it be a manifestation of an intoxication, and I think that's a really good reminder that we have to have many of these syndromes in our differential, we have to be aware of them, otherwise we might miss them or attribute them to another mechanism. Dr Goss, our last issue of Continuum that was dedicated to the neurology of systemic disease came out in 2023, and here we are in 2026 publishing our latest issue, including your article and this podcast. Since 2023, have there been any emerging patterns or novel agents of abuse or misuse out there? Dr Goss: The short answer is yes, and I would say the reason is just the supply is moving at more and more rapid speed. The relationship between the internet and drug supply has really informed what's out there at any given moment. So, the turnover in the market can change in weeks, not in years. And there's all of this distribution through social media and encrypted apps. And then manufacturers are kind of continuously tweaking chemical structures to evade law enforcement. In the process of researching this article, I came across some, I mean, really wild examples. To be clear, these are not- not all these are common substances, but I think the general phenomenon should be known that people can walk into a vape shop or walk into a gas station or meander around online and buy some really weird stuff. So, in 2024, there was this nationwide recall of a product called Diamond Shrooms that was sold online and in smoke and vape shops, and this was billed as, like, a hemp and mushroom mixture. But it led to multiple- I mean, over 100 cases of seizures and agitation and depressed consciousness and a few possible deaths. And when the contents were analyzed, they included psilocybin analogs and pregabalin. I mean, some weird stuff. And so, those have been pulled. But people are constantly inventing and marketing these different substances. I think another example… we all know about nitrous oxide and its association with B12 myopathy. But the use of nitrous oxide has really changed. Companies are selling large canisters online and in vape shops, and they're flavored, like, in blue raspberry flavor. And unfortunately, there's been a rise of nitrous among youth. So, we're seeing not just increased cases of myelopathy, but also a 2025 study in JAMA found a spike in deaths attributed to actual nitrous oxide overdose. And so nitrous, I think, had not been that commonly used a few years ago, but has become more common in the last couple of years. A final one I'll just mention is ketamine. So, ketamine has certainly appeared in reviews of neurological syndromes related to substance use for a long time, and it's also been studied and used off-label for mood disorders in outpatient infusion clinics... /episode/index/show/continuumjournal/id/39968225

Neurologic Complications of Pregnancy and Menopause With Dr. Sara C. LaHue 03/18/2026

Neurologic Complications of Pregnancy and Menopause With Dr. Sara C. LaHue Neurologic care during pregnancy and menopause requires careful attention to the dynamic interplay between hormonal transitions, evolving evidence on diagnostic and treatment safety, and the lifelong risks associated with neurologic complications of pregnancy. In this episode, Katie Grouse, MD, FAAN, speaks with Sara C. LaHue, MD, author of the article “Neurologic Complications of Pregnancy and Menopause” in the Continuum® February 2026 Neurology of Systemic Disease 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. LaHue is an assistant professor of neurology for the Weill Institute for Neurosciences in the Department of Neurology at the University of California, San Francisco School of Medicine in San Francisco, California Additional Resources Read the article: Subscribe to Continuum®: Earn CME (available only to AAN members): Continuum® Aloud (verbatim audio-book style recordings of articles available only to Continuum® subscribers): More about the American Academy of Neurology: Social Media Dr Grouse: Despite the high prevalence of neurologic conditions in women, critical gaps remain in training, research, and clinical guidelines on sex and gender specific considerations across the lifespan. Today, I have the opportunity to speak with an expert on neurologic complications of pregnancy and menopause and coauthor of the and women's neurology curriculum core competencies, Dr Sara LaHue about the latest issue of Continuum on neurology of systemic disease. Dr Jones: This is Dr 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 Sara LaHue about her article, Neurologic Complications of Pregnancy and Menopause, which appears in the February 2026 Continuum issue on Neurology of Systemic Disease. Welcome to the podcast and please tell us more about yourself. Dr LaHue: Well, thanks so much for having me. I'm really excited to talk about this topic. So, I'm Sara LaHue. I'm a neurologist at UCSF, assistant professor of neurology, and a neurohospitalist. So much of my role is taking care of people who are coming into the hospital with urgent and emergent neurologic conditions. And so that's very much a framing that I come to this chapter with. Dr Grouse: I just want to start by congratulating you on your article, which is such a phenomenal compendium of important neurologic issues related to pregnancy and menopause, which I think I really needed and a lot of us really need and was missing, I think, in all of the literature out there. This article will be such an important clinical resource. I know for me, and I'm sure for many of our listeners, this may be a difficult question to answer because of how comprehensive the article is. But what do you hope will be the main takeaway for those who read your article? Dr LaHue: So, I really hope that listeners walk away with understanding that pregnancy and menopause are not contraindications to providing excellent neurologic care. I think too often we default to withholding treatment, pseudo-assumed risk, rather than actual evidence of harm. And so, I think that the key message here is that protecting maternal health is protecting fetal health, and that under-treating neurologic conditions during pregnancy can harm both mother and baby. Dr Grouse: You did say specifically in your article that I thought it was so important that presumption of harm from medications during pregnancy, due to lack of evidence rather than evidence of harm, was something that we really had to be aware of, of that bias. And how do you recommend neurologists listening to this podcast approach situations where diagnostic or management strategies become less certain due to safety considerations in pregnancy? Dr LaHue: Yeah, that's such an important question. I really frame it as a risk-benefit calculation with a patient, and I'm very transparent about what we know and what we don't know. And I emphasize that untreated disease may also impact fetal health. I use resources like LactMed and pregnancy registries that can help provide some of the more latest data. And then when evidence is limited, I document our discussion thoroughly, and I'll often involve maternal-fetal medicine colleagues for their multidisciplinary input. So, the goal is really to have an informed, shared decision-making process rather than a reflexive avoidance of all treatments. Dr Grouse: I think that's really important to reiterate, and I think something that we're all I think working on as we try to manage these difficult situations and conditions. Now, I want to switch gears a little bit and ask. Your article was so comprehensive and so helpful, but what isn't in the article that you wanted to put in? Dr LaHue: There was a fair amount that I ended up having to take out. So, this is a question that's near and dear to my heart. So, I would have liked to include more on the neurodevelopmental outcomes for children who are exposed to various neurologic medications in utero. And I also wanted to discuss more about transgender and non-binary individuals who are experiencing pregnancy and menopause, as they're often underrepresented in research. They've faced unique challenges accessing care. Dr Grouse: Now, I was really struck by one statistic in your article, specifically that intimate partner violence is a leading cause of head injury during pregnancy, and that actually homicide is a leading cause of death during pregnancy in the postpartum period in the US, which was absolutely a surprising statistic to me. What does this mean for our listeners caring for pregnant patients with concussions and head injuries? What should we be doing differently? Dr LaHue: This is also something that really struck me when I first encountered it. I think that the statistics should really fundamentally change how we approach head injuries in pregnant patients. I think we need to screen everyone routinely and privately for violence in the home and in the relationships, and to document injuries very carefully. But we also need to be prepared if someone does screen positive. And so, it's important to be familiar with what's available in terms of resources within your community, where you work, and also to remember that that strangulation in particular is something that can cause dissection and stroke. And so, to maintain a high index of suspicion for any kind of vascular injury in these cases. So not just thinking about head injury itself, but also thinking about complications of strangulation as well. Dr Grouse: Really a great reminder of the role that we can play in our own careers and our own clinical settings when we see cases like this. So, I really appreciate that this point was made, and I hope this will change people's practice. Now switching gears to stroke in pregnancy. Could you walk us through your evaluation and management of a patient who comes in with acute stroke in the peripartum period? Dr LaHue: This is such an important topic, and I think the first thing I'd like to emphasize is that time is brain. Whether or not you're pregnant. It's important to get whatever imaging modality is going to be fastest. Get the CT or get the MRI as soon as you can. Don't delay for fetal concerns. The radiation risk is minimal compared to missing a treatable, disabling stroke. In terms of treatment, thrombolysis and mechanical thrombectomy should be considered just as in a non-pregnant person, when the benefits outweigh the risks. And so, I think the key is involving obstetrics early for shared decision making, and being very transparent with what treatment options are available for the individual, and to not let pregnancy alone stop you from offering standard stroke therapies. Dr Grouse: Definitely a helpful resource, and I think the resources that you put in specifically around the considerations and differentials in these various populations. Postpartum, while still pregnant during the period of period, I think is all just so helpful and a great review. So, I encourage our listeners to check that out. Now switching over to the topic of menopause. I have to say, I really appreciated your coverage of neurologic issues related to the perimenopause period. What do you think is the biggest debate or controversy in this area? Dr LaHue: I think this has to be our understanding of the use of menopausal hormone therapy. The pendulum, when using menopausal hormone therapy, has really swung dramatically. So, we went from routine use to predominantly avoidance. After the Women's Health Initiative was published in 2002, and now we're finding that we're starting to come more to a middle ground. I think there's still great debate when it comes around timing of initiation, formulation of the different therapies, a route of administration and also the dosing, as well as just including how to individualize therapy for individuals with neurologic conditions. Dr Grouse: Well, going into that a little further, I know I get a lot of questions about the use of hormone therapy as it relates to stroke risk and particularly in higher risk patients such as patients who've had prior strokes, dissections, a history of migraine with aura. And I find it hard to get the answers in the literature that's out there. How are you counseling these patients? Dr LaHue: So, I think this is where discussions around the route of administration and dosing become especially important. And this is where there's emerging literature that I think is helping to guide some of these discussions. So, for higher risk patients, I discuss how low dose transdermal formulations which can bypass hepatic metabolism and reduce clotting risk. These are medications that can appear safer in those higher risk individuals. I think the key is really individualizing the risk-benefit discussion with the patient. For a woman with severe vasomotor symptoms that are affecting sleep and cognition, who had a remote stroke. I think this is a person for whom low dose transdermal patch might be a reasonable option. All of these factors end up being considerations for that shared decision-making. Dr Grouse: Now your article covers another topic that I often get questions about, and that's specifically regarding safety of vaginal delivery for patients with neurologic conditions that are sensitive to increased intracranial pressure. Could you summarize your advice for these types of questions when they come up? Dr LaHue: So broadly speaking, most neurologic conditions don't require C-section delivery. And this is a procedure that, just globally speaking, as has been increasing dramatically. And so, I think that's the key message that really, most neurologic conditions don't require a C-section as a main indication. And really, the indication should be based on obstetric considerations. For most conditions, like controlled idiopathic intracranial hypertension, a vaginal delivery is fine. But for patients with mass effect or obstruction at the foramen magnum, a C-section with general anesthesia, it's probably going to be safer. The transient increase in intracerebral pressure that can come with pushing. It hasn't really been shown to harm patients who have stable, treated neurologic conditions. Dr Grouse: I really appreciated the advice that you given in the article, which was that if generally you feel like this would be a patient who would be safe to get a lumbar puncture, you have a little less concern about vaginal delivery versus those that you feel would not be safe to get a lumbar puncture, that you'd be more leaning towards a C-section. Dr LaHue: Yeah, that's exactly right. Dr Grouse: Now, why do you think we have so many gaps in our understanding of how pregnancy and menopause affect neurologic conditions? Dr LaHue: So, I think it really comes down to a perfect storm of factors. So, in 1977, the USFDA came down with the recommendation, stating that it was best to exclude all women of reproductive potential from both phase one and phase two studies. And this recommendation wasn't reversed until 1993. And there are also concerns around liability and also the fact that pregnancy is a temporary state is something that may falsely minimize the potential for delays. The potential for harms that come with delays in treatment. And I think that the fact of menopause is also historically been dismissed, despite this is something that is affecting half of the population. I think we need systemic change. We need to mandate inclusion in research. We need funding for dedicated studies. We also need to recognize women's health as a core competency and not just a special interest. Dr Grouse: That all sounds like a great roadmap for improving our knowledge. And I really hope we get there. But hearing you talk about it really does give me hope that we can improve how we are understanding and treating these conditions. Now, your article included a really helpful overview of headaches in pregnancy, and that's certainly something I think many of our listeners are very familiar with. We do have a lot of questions around that, and I think there's a lot of areas where we don't really always know what the best thing to do is. I think that your article really gave a lot of great information and a really great framework to think about. It would be wonderful to hear you walk through your approach to evaluation of a patient who was pregnant with a new onset headache. Dr LaHue: You'll see in this chapter that I introduce a mnemonic that's spelled out pericardium as a framework for thinking about headache and pregnancy. And here are the you specifically points to an unusual headache, referring to a new or atypical presentation of headache for the patient. I think this is an important place to start, because one of the initial considerations should be this is a new headache, or is this an old headache? If this is a patient who already has a preexisting diagnosis of migraine or some other primary headache disorder, then it's certainly possible that the headache that they're experiencing during pregnancy is also a continuation of their primary headache disorder. But certainly, our role is to make sure that we're not missing a scary complication, a secondary headache that could be dangerous to the patient. And so, then this is where I also think about, well, where are they in the course of their pregnancy. Is this person currently pregnant or are we in the postpartum period? When someone is after 20 weeks gestation, one of the first things to consider is going to be preeclampsia. And so, it's important in those individuals to check blood pressure, check urine to rule out preeclampsia, as this is always going to be top of mind after 20 weeks. I think it's also important to emphasize that preeclampsia is not just a condition that can occur when someone is pregnant. This is also something that can occur postpartum. One needs to be vigilant for looking out for this complication during both time periods. And then I think for new headaches, I really want to focus on what the timing is and any other red flags. For example, if it's a thunderclap headache and onset, then I might be worried about something like RCBS or cerebral venous sinus thrombosis. If the headache itself is orthostatic and patient may have had an epidural, then I might think about a post-dural puncture headache, which is a, unfortunately very common complication and reason for headache in the postpartum period. I think the key is that most dangerous headaches often will occur late in the third trimester or early postpartum. And I think it's also important to remember that if you need imaging to make the diagnosis, and you should get it. The risks of missing something serious far outweigh concerns that one might have around imaging. And when possible, it's certainly preferred to get an MRI if that's available. Dr Grouse: I really did appreciate articles, overview of the various imaging modalities out there and the overview of risk versus benefits and times where they may or may not be needed. So, yet another very useful piece of information that I think that our listeners will appreciate in your article. Now, I'm curious how did you get interested in this area of neurology? Dr LaHue: So, it really was my interest in both reproductive health and neurology that led me to go to medical school in the first place. I knew early on at the beginning of medical school that I was interested in neurology, but I also was very drawn to obstetrics, and I recognized in medical school and then further on as, as a resident, just how vast the knowledge gaps were. When I was counseling my own patients and I found this to be just a very frequent source of frustration as both a clinician and a researcher, I very much feel an obligation to try to help fill these gaps. And I've also just been very encouraged by an outstanding community of other neurologists that I've been able to meet in this space. It's been a just a wonderful collaborative network that we've been able to grow, both within United States and even more globally, when it comes to other neurologists who are interested in this topic. And I'm just very excited to see the direction that this field is going in. Dr Grouse: Well, we can't wait to learn more as this field develops and more is understood about the right way to approach these types of diagnostics and treatments. So, thank you for all your work in this space. And it's been absolutely fascinating reading your article and talking with you today. Dr LaHue: Well, thank you so much for having me, and I'm just so thrilled that these important topics are going to be part of this issue of Continuum. Dr Grouse: Again, today, I've been interviewing Dr Sara LaHue about her article and Neurologic Complications of Pregnancy and Menopause, which appears in the February 2026 Continuum issue on Neurology of systemic 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 AA and members. You can get to me for listening to this interview by completing the evaluation at continpub.com/audioCME. Thank you for listening to Continuum Audio. /episode/index/show/continuumjournal/id/39968180

Neurologic Complications of Cancer and Its Treatment With Dr. Amy A. Pruitt 03/11/2026

Neurologic Complications of Cancer and Its Treatment With Dr. Amy A. Pruitt Prompt recognition of direct and indirect neurologic complications of systemic cancers and their evolving treatments is essential. Neurologists should be familiar with common and rare neurologic toxicities of conventional chemotherapy, immune checkpoint inhibitors, and CAR T-cell therapy. In this episode, Teshamae Monteith, MD, FAAN, speaks with Amy A. Pruitt, MD, FAAN, author of the article “Neurologic Complications of Cancer and Its Treatment” in the Continuum® February 2026 Neurology of Systemic Disease 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. Pruitt is the William N. Kelley Professor of Neurology, Vice Chair for Education, and Division Chief in the Department of General Neurology for the Perelman School of Medicine at the University of Pennsylvania in Philadelphia, Pennsylvania. Additional Resources Read the article: Subscribe to Continuum®: Earn CME (available only to AAN members): Continuum® Aloud (verbatim audio-book style recordings of articles available only to Continuum® subscribers): More about the American Academy of Neurology: Social Media Host: Dr Monteith: As neurologists, we have a critical role in diagnosing neurologic complications of cancer from metastatic disease, seizures to neuropathies. Increasingly, the rapid development of novel treatments themselves, like immunotherapies, Car-T cells, and targeted drugs are causing new neurologic side effects, which we need to recognize, manage and anticipate as therapeutic developments evolve. Dr Jones: This is Dr 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: Hi, this is Dr Teshamae Monteith. Today I'm interviewing Dr Amy Pruitt about her article on neurologic complications of cancer and its treatment, which appears in the February 2026 issue on neurology of systemic disease. Welcome to our podcast. How are you? Dr Pruitt: Thanks for having me. Dr Monteith: Absolutely. Why don't you introduce yourself? Dr Pruitt: As you said, my name is Dr Amy Pruitt. I'm a professor of neurology at the University of Pennsylvania, where I am also the clerkship director and have been for a long time. I'm the division chief of general neurology and the vice chair for education in my department. Dr Monteith: You have a lot of hats. Dr Pruitt: I do. Dr Monteith: Okay. So, before we dive into all this great work that you did in the article, why don't you just let us know just a little bit about what led you to this career path? Dr Pruitt: Sure. So, I've always been interested in the intersection between internal medicine and neurology; in fact had I've not been a neurologist. I probably would have been either an oncologist or infectious disease specialist. And that leads to doing neuro oncology and seeing a fair amount of CNS infections. I see both inpatients and outpatients and really enjoy my neuro hospitalist time because, honestly, as all of you who do consults on inpatient services know, there is an incredibly changing landscape of consequences of cancer therapies. And if you haven't been on service for a while, you probably don't even know the name, is much less the adverse effects of these medicines. Dr Monteith: Okay, so you were just like me to write this article. Dr Pruitt: Well, I think where it is directed, I think, as I said, that people who are seeing a lot of inpatients and who may not know it's a new consequences of cytotoxic or immunotherapies or T cell therapies and the different appearances and really prognoses, which have changed dramatically in the last few years in the field of systemic cancer. Dr Monteith: Any other essential points of your article? Dr Pruitt: So, I think there are certain areas where neurologists are going to intersect with oncologic patients even before oncologists do so, what tumors might present synchronously in the brain and the rest of the body. And those would include things like small cell and non-small cell lung cancer and melanoma, to a lesser extent, women who are surviving much longer now with good therapies for various versions of breast cancers, have one of the solid tumors most likely to present at first relapse in the brain, either in the brain metastases category or in the leptomeninges. So, these are the areas where I think it most likely that our neurologists are going to intersect with oncology. And then there is the burgeoning, thankfully, realm of long-term survivors who have had cancer therapies in young adult lives, sometimes in childhood. And we need to be abreast of the ever-changing spectrum of complications that will plague these people all their lives. And we can do a great deal to improve the quality of survival in these patients. Dr Monteith: And of course, there has been a lot of great development in cancer research, which has led to novel therapeutics. So, can you tell us about a few of these therapeutics and their complications that neurologists need to know about? Dr Pruitt: Sure. Well, as I said, some of the cancers you're most likely to encounter are lung cancer and melanoma. And here the prognosis has changed dramatically. A few years ago, someone with metastatic melanoma might have had a couple months prognosis. And now we're talking honestly about long term survivors, complete responses in lung cancer and melanoma, and really good responses in the breast cancer realm as well. So, these are dramatic changes. And these are ways neurologists need to know what the actual nuanced and much more variable prognosis is among patients with brain metastases. In order to give the patients good advice and also to give the radiation oncologist and the oncologist, the medical oncologist, good advice. So, for example, just in the realm of brain metastases, a stage change has been that people with asymptomatic metastases for, let's say, non-small cell lung cancer or melanoma might have systemic therapy rather than local therapy, local therapy being gamma knife radiation or less likely, whole brain radiation therapy, but really systemic therapy with responses and the brands that are nearly as good as those in the rest of the body. And sustained, durable responses. The article goes into great detail about what's available in the way of therapies for these cancers, like breast, HER2-positive breast cancer, like EGFR‑positive lung cancer and melanoma of various types. It's really quite amazing actually, to have anybody quote a seven-year survival of little over 40% in people who presented with non-symptomatic melanoma metastases. Unheard of, really. So, I think if you're still practicing, quote unquote old school neuro-oncology, you need to get up to date because you're giving patients and their caregivers good advice that will lead them to the very important therapies. You mentioned some of the immunotherapies. If we have time, I'm happy to go into those because those are really important for neurologic consultants in the hospital. Dr Monteith: Yeah. Let's talk about immune checkpoint inhibitors. What do we need to know about them and their complications? Dr Pruitt: So, they have a novel set of central nervous system and peripheral nervous system complications. These include both acute and subacute presentations. They can arise after the very first dose and usually do so within the first several doses. Importantly, even though the patient may be quite sick, about three quarters will recover entirely. However, the most common ones are actually the peripheral nervous system, and they have the highest morbidity and mortality rate. So, a very unfortunate combination of myasthenia, myocarditis and skeletal myositis has a high mortality rate and is very hard to treat in a group of people who have received these immune checkpoint inhibitors in the central nervous system, there can be cerebellitis, encephalitis. These again can be acute or subacute presentations. And the big discussion with the attending oncologist is, can we continue these therapies after we've withdrawn them, and for instance, treated them with steroids? Because you can imagine that if you knock down the immune system with steroids, you might make the patient temporarily better. But in so doing, you're negating the important consequences of the mechanisms of immune checkpoint inhibitors. So, I would say probably in a given week on the inpatient service, I'll see five or so. So nearly a daily event when I see some major complication of immune checkpoint inhibitors. And again, I've already mentioned the histology in which those have been useful, but they're not indicated for a variety of other malignancies as well. And the Car-T cell therapies are a whole different set of side effects. And some of your listeners may know about cytokine release syndrome, which is nearly universal right after the infusion of the car T cells. But a few days later is where we come into action with the immune effector cell-associated neurotoxicity syndrome. Or ICANS can say that I'll refer to it as ICANS since then. These include focal neurologic symptoms and the form of what's often a conduction sort of aphasia, a predictable deterioration, and handwriting along with confusion. As far as the radiology of that syndrome, that's really pretty odd. It can range from a dramatic cerebellitis, just a dramatic basal ganglia syndrome, a dramatic and enhancing leptomeningeal syndrome to an absolutely normal MRI scan. And the important thing for our consultant consultants to remember is that the patient can look really, really ill, and you can turn to the team and say, you know what, there's a very good chance that it's going to get all better. So, supporting people through what are very good diagnostic and therapeutic algorithms that exist in the literature and are quoted in the Continuum chapter to help know when you should be giving steroids, when you should be giving tocilizumab, etc. these are tried and true therapies now, and the Car-T world has improved not only the prognosis of patients. And I remember seeing some of the very first Car-T patients, and we really didn't know what to do to help them, how to turn off the cascade of this immunologic reaction. Now we know how to do that. And it's important to stay up to date on those algorithms because you can make a big difference for these patients. Dr Monteith: Yeah. So, this is great. We're going to dive back into the diagnostics, which is really related to my follow up question. I think you gave a really great pearl. And it's always can we keep going? Do we stop? So, I want to like dive into that question. And I assume that there are categories. Yes. You can, somewhere in between, and absolutely not. And so, tell me a little bit more about that thinking. Dr Pruitt: Well that's a very nuanced question. And so, the answer that some oncologists will give you as well, they've had such a dramatic response. So maybe we don't need it anymore. It's never the neurologist’s decision. It's always the joint decision with the oncologist. So, for instance, with a Merkel cell cancer patient develops a severe anti‑AChR syndrome on an immune checkpoint inhibitor. And we tell the oncologist maybe you shouldn't go back and do that again. And the person says, never mind, he'll be fine. He's already had the response that we want, but that's a difficult question to answer because, for instance, in a slightly different subset, let's look at multiple myeloma patients. And I spent a fair amount of time on multiple myeloma in the article because it affects the nervous system in so many ways. And we have so many different therapies for these patients, one of which is a Car T-cell. And this is a B-cell maturation antigen, Car-T. It's different from the ones that we know for lymphoma and leukemia. And it has a different set of neurologic problems, which unfortunately do preclude going back to taking a Car-T cell therapy again. And just to make a long story short, this particular complication makes the patient look Parkinsonian. The consult you're probably going to get from the medical services is patients weak. Well, the patient is not exactly weak. He is Parkinsonian. He has a extrapyramidal rigidity, sometimes a tremor a negative cat scan and a B-cell maturation antigen syndrome occurs not at the sort of 5 to 7 day mark about ICANS that we just discussed, but rather a month or so out and a month or so out. It's not when you're expecting to see Car-T cell therapies. So, patients end up getting worked up extensively for, let's say, some sort of infection, when in fact, what we should be looking at is a newly described complication of Car-T cell therapy. So, the part of my article on multiple myeloma is one that's really important because as you know, it's such a common hematologic problem among older people. And many of these people may have direct complications of multiple myeloma, such as direct tumor infiltration of nerves. POEMS syndrome. So, it's really a wealth of neurological issues for us to contend with for these people. Dr Monteith: Yeah. And I know you've really done a great job of adding lots of wonderful charts, including understanding the time course of some of these complications, when to anticipate, because I think some of it is about when to anticipate some of these complications. Dr Pruitt: Well, exactly. Yes. Given the time constraints, I've made a lot of tables because there was a lot of information. And those, I think, are the kinds of things that a consultant should know: what should I be thinking about at this point in time? And that sort of leads us to what are the later complications of these things. And those include many medical things, from failure due to neoplasia, morbidity, radiation, chemotherapy agents, the long-term and medium-term consequences of these things for people. Are going to come back to our office as well. Immunocompromised patients, such as the ones and heavily treated patients that I just mentioned, may lack a robust inflammatory response. And they can have infections really at any time out. Some are predictable, as in our leukemia patients who have had hematopoietic cell transplant. So, we kind of know when to expect viral infections, nosocomial infections, progressive multifocal leukoencephalopathy, many other things down the road. But in this era of COVID, we know that these patients are more susceptible to the dire effects of COVID, and they may not mount a good vaccination response. We have seen types of neurologic complications of all sorts of infections, including babesiosis this year, and persistent enteric viral meningitis. So, the patient can present a very atypical fashion. And the neurologic consultant has to keep a really open mind about the broad differential of what might be happening. Dr Monteith: And you do have a section under imaging and metastatic disease. Are there any like new sequences or a way to kind of tease out complexities? Dr Pruitt: So, there is marked variability in the radiographic appearance of brain metastases. And I must confess that I made a very large collage of all the different representative types of things. And I think that's important for neurologic consultants to recognize that some metastases don't enhance. They don't all look like ring-enhancing lesions. Some can be much more diffuse, particularly if the patient has received something like a VEGF inhibitor like bevacizumab therapy can look exceedingly different. They can involve the dura, which should be treated differently. There can be simultaneous leptomeningeal and disease. So as far as I know, sequences perhaps not so much. Although if one is thinking about the differential between radiation-related injury and someone who's already been treated versus tumor recurrence, then we have some pretty good microscopic data, some susceptibility weighted images, other ways of getting whether this is really radiation related change or tumor recurrence, a major problem obviously. What we also know about radiation is kind of a theme of the article is use it as infrequently as possible, because we just talked about some of the other therapies that we have. We may need to give local therapy for symptomatic patients, but we give as little as possible, and we try never to give whole brain radiation therapy. I'll go on record as saying that it's certainly necessary. Sometimes people have diffuse lymphoma, this disease that's recurred, they have multiple metastases in a sort of miliary fashion may be necessary, but if you can use gamma knife radiation, if you cause any use form of focal radiation, new in the leptomeningeal world is proton therapy for spinal metastases. So quick sparing techniques. And this is something that should always be considered when you're consulting on someone in a place in which you have the option of proton therapy. So, I would say that distinguishing between radiation necrosis and recurrent tumor and the use of protons are the big news in the radiation therapy world. And don't give whole brain radiation therapy if you can avoid it. Dr Monteith: Yeah. I'm getting a flashback from residency because, you know, that always happens. And the radiologist saying, you know, we need more information when you put in those orders. And so, I think with this whole era of new chemotherapeutic agents and how they could present on imaging and give the radiologists as much information, including the type of chemotherapeutic agent used. Dr Pruitt: Yeah, I think particularly in the transplant world. So, the leukemia lymphoma patients who have received one of the calcineurin inhibitors, like tacrolimus or cyclosporine, that induces a whole set of complications, some of which are visible radiographically. There's a delayed leukoencephalopathy. There can be stroke. There can be SMART syndrome, stroke like migraine after radiation therapy. And perhaps many of our listeners have been confronted with someone who has a prolonged focal deficit, say, a hemianopia and maybe a hemisensory deficit with or without a subsequent headache. It goes on for days to hours. It looks peculiar on the MRI scan because it's not then a vascular distribution. There's sort of diffuse gyral swelling, flattening of the EEG on that side, the patients getting steroids and valproate and anticoagulation and angiography and all. It doesn't need any of that. The syndrome of stroke, like migraine after radiation therapy, needs to be recognized. And best thing to do is don't just do something. Stand there. You should wait until it goes away. And so, I think that's we are seeing this increasingly, that we first reported this in young adults who had been treated years ago for medulloblastoma. So, it was posterior fossa tumors primarily. But this has now been broadened, as you know, to include supratentorial tumors of many types and adults at various times out from their radiation therapy from a few months to many years. Dr Monteith: I should ask you in writing this article, clearly you have a wealth of knowledge, but in kind of just putting this together, what surprised you? Dr Pruitt: I think what surprised me is the increasing range of complications and that virtually anything needs to be thought of central nervous system or peripheral nervous system. With some of these newer therapies. There is a chart in there about the conventional cytotoxic therapies, and we're all familiar with things like methotrexate and that sort of thing. But what surprised me really is the increasing diversity of complications of these newer drugs, and also the fact that I didn't know some of the third and... /episode/index/show/continuumjournal/id/39968120

Neurologic Complications of Critical Illness With Dr. Shivani Ghoshal 03/04/2026

Neurologic Complications of Critical Illness With Dr. Shivani Ghoshal Nearly one in five patients in intensive care units (ICUs) requires neurologic consultation. The neurologic complications of critical illness can be unique to its underlying processes and can persist as independent disease states even after resolution of the inciting critical illness. In this episode, Casey Albin, MD, speaks with Shivani Ghoshal, MD, author of the article “Neurologic Complications of Critical Illness” in the Continuum® February 2026 Neurology of Systemic Disease 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. Ghoshal is an assistant professor of neurology for the Columbia University Vagelos College of Physicians and Surgeons in New York, New York. Additional Resources Read the article: Subscribe to Continuum®: Earn CME (available only to AAN members): Continuum® Aloud (verbatim audio-book style recordings of articles available only to Continuum® subscribers): More about the American Academy of Neurology: Social Media Host: Guest: Dr Albin: The ICU can be such an intimidating place. There's unresponsive patients, there's beeping equipment and a seemingly endless way in which the nervous system can be compromised. But fortunately, today I have the opportunity to speak with Dr Shivani Ghoshal about her paper, Neurologic Complications of Critical Illness, which is going to help us demystify the approach to these patients and provide some clinical pearls that you can take to your next consult in the ICU. 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 Kasey Albin. Today I'm interviewing Dr Shivani Ghoshal about her article on neurologic complications of critical illness, which appears in the February 2026 Continuum issue on neurology of systemic disease. Welcome to the podcast, Dr Ghoshal. It's really such a treat for me to get to interview you, someone who I know and have worked with in the past. But for those who do not know you, please give us a little background about what brought you to this topic and what you do in your clinical life. Dr Ghoshal: Thank you so much. It's a thrill to be interviewed by someone that I know well and get to work with. Outside of writing this article for Continuum, I am a neurointensivist. I'm an assistant professor of neurology at Columbia University and the program director for the Neurocritical Care Fellowship between Columbia Cornell and New York Presbyterian. So, a lot of what I do in my day-to-day is thinking about acute brain injury along with the neurology of systemic disease and how, really, the two interplay with each other, of how neurologic complications can arise from systemic illness and the other way around. Dr Albin: Yeah, you are the absolute perfect person to kind of walk us through the complexity of the brain and body connection. Dr Ghoshal: I don't know if I can deal with that kind of praise, but thank you. Dr Albin: And you’ve really written a powerhouse article on just the myriad of complications that really arise in the ICU, and you've broken it down into what I think is a very thoughtful way of sort of bucketing these complications. So, tell us a little bit about the approach you took here. Dr Ghoshal: I love this article because neurologic complications are just so common in so many types of acute critical illness. And I think we have to think for each organ system, how does this affect the brain, and then how does the brain then interplay, let's say, in kidney failure, in hepatic failure, in sepsis, right? Which is so common that I think we don't even think a lot about, like, what are types of septic encephalopathy for all the antibiotics we give; like, what are the implications of this? I really enjoy taking each system and thinking about, how does it specifically affect neurologic complications? Dr Albin: Yeah. And then there was a really nice breakdown in terms of some of the procedures that will happen within the ICU in general. You know, the things that are happening to the patients at the bedside also put them at risk for neurologic complications. Then there are those neurologic changes that are happening because of some of the underlying problem that brought those patients to the ICU. And then the unfortunate number of problems that arise because the patient has been in the ICU for such a long period of time. Dr Ghoshal: You know- and I think that that first part you mentioned, just about procedures in the neuro-ICU, right? Or in the ICU in general. I think that we don't think about that on a day-to-day level, right? Just like arterial lines are one of the most associated with any kind of peripheral nerve injury, especially axillary arterial lines. I learned quite a bit, even going through this article and then looking at other sources. So, thank you also for pointing that part out. Dr Albin: Yeah. When I was thinking about how do we distill all of what was covered through this article, I actually really thought it would be sort of most interesting to have you model sort of your approach to these patient complications and how you approach the complexity of an ICU patient. And so, if it's okay with you, we'll just walk through a couple cases. Dr Ghoshal: Oh my gosh, let's do it. Dr Albin: All right. So, these are all, of course, composite cases. You know, there is no patient violation here. Let's say that this is a 64-year-old patient and they're admitted with influenza, and they develop ARDS. And they're in the MICU. And this patient, they were pretty sick on arrival and they were intubated for three days. But now the patient's been extubated, and the MICU team calls you because today she's having trouble swallowing and her voice, you know, the family says that this is not what she normally sounds like. And the team is really quite worried that she's had a stroke. And so they are calling for a neurology consult because they want to know what they should do. So, walk us through your approach to that patient. Dr Ghoshal: Well, I think the primary team being concerned for a stroke is definitely reasonable, but I think, taking a bigger step back, what I would first want to think about, is this neurologic or non-neurologic? Neurology, you know, there's a parcel of things we can go through, but even just a non-neurologic, like, is this just primary injury to the vocal cords, right? I think about the cough were there, the ET tube, it wasn’t overinflated which caused direct damage, right? And then after that, then I would think a little bit more about my approach for what is going on neurologically. Thinking about either, is this a brain process or is this a- more of like a spinal cord cervical cord injury process or more cranial nerve issue? Dr Albin: Yeah. How would you approach the exam in that patient? Dr Ghoshal: Yeah. You know, I- and just to, again, take a step back, right? To remember that when we do intubate someone, the physical maneuvers that we have are a chin lift and regular endoscopy, right? They have, like, significant movement for the cervical spine. So, I might want to know even before I examine the patient, right, or their history, right, do they have anything like, do they have known cervical stenosis? Do they have any, like, cervical spine pathology? Was it a difficult intubation? Right? So, these are the kind of the things I'd want to know even from the history, along with whatever vascular risk factors they may have. And then, to your question about the actual exam. Yes, you know, I may look for, like, crossed findings, right? If we're thinking about, let's say, a medullary lesion, etc. I think all listening to this podcast know about MRI testing there. But beyond what I would be looking for, let's say, in a medullary stroke, I'd also want to be looking at just, like, water paresis, right? I might want to be interested in, let's say, signs of neurogenic shock. You know, you mentioned they're in septic shock, ARDS. I might want to actually take a look to see, like, was this all septic, right? Or what are their other shock types present. Dr Albin: So, what I hear you're saying is you're evaluating A, first of all, answering the consulting question, you know, is there a real risk for some sort of cerebrovascular phenomenon, but then actually going to the bedside to examine the patient, to say, does that make sense? Do we see hemibody involvement here? And it's a good thing that you're approaching it that way. Because actually, when you go to the bedside, she does have some difficulty speaking. And reading the notes, this was actually quite a difficult intubation. From just the cranial nerve, you know, where she has maybe some dysphonia and dysphagia. But you also, on exam, then find that she's got some pretty symmetric distal weakness in her arms bilaterally. And so, when you find that, what are some of the imaging that you're going to think through to try to pin down exactly what's going on here? Dr Ghoshal: I love these cases because it's not so straightforward. Now, let's say if she has, like, an upper extremity weakness and lower cranial nerve deficits, you know, things I'd be looking for, like any injury to, like, hypoglossal nerve, vagus nerve. The vagus nerve is going to be hard to tell, right? Recurrent laryngeal nerve, you know, the lingual nerve. I might be thinking more about stretch injury, which we think of as tapia syndrome, right? So, just a textbook answer. The hypoglossal recurrent laryngeal nerve injury. And what we're going to be looking for is dysphonia, dysphagia, and unilateral tongue paralysis. Could be a bilateral as well. But I guess, then, the next question after I'm going through my physical exam findings is thinking about my imaging choice. Dr Albin: So, for this patient, given that she's got this bilateral upper extremity, maybe some tepia syndrome where there may have been some stretch injury to some of those hypoglossal nerves. She may have also just had some trauma to the vocal cords. Like, as you said, these procedures can really put patients at risk for just mechanical injury to some of those structures. But knowing that upper extremity weakness, what kind of imaging, then, do you look at for the court? Dr Ghoshal: I think it's not unreasonable to do an MRI brain, right; with that, it then cuts through the brain stem. And then doing an MRI of the cervical spine. I guess the point that you mentioned at the very beginning, that this is three days after she was intubated… you do run the risk beyond 72 hours of, let's say, a primary injury. Let's say if she had, you know, God forbid, an injury to the cervical spine, those hyperintensities, especially when associated with ligamentous injury, they can pseudonormalize beyond that time. I would say yes, absolutely. MRI of the brain, cervical spine, then cuts through the brain stem. But I would worry that if too much time elapses, you may miss some of those injuries that you would otherwise find. Dr Albin: Yeah. I think those are some really important take-home pearls, and when we're thinking about the cord injury that could occur through the intubation process, that we really do need to be aware of student normalization of the T2 hyperintensities after that 72 hours. And so, I think that's a really important pearl for us to take home. So, kind of summarizing this case here, there was probably a multitude of things going on, which highlights to me the complexity of ICU patients. Less likely in this case, and they did not find a stroke. But that is, of course, something that we must keep on the differential for any critical care, critically injured, critically ill patient. But tapia syndrome where you have some stretch injury to the hypoglossal nerve and the recurrent laryngeal nerve, which can put people at risk for dysphasia or dystonia after intubation. And then that hyperextension injury that can happen for patients who are intubated, because people, especially for difficult intubations, are really having to manipulate the neck. And for an elderly patient who may have some cervical stenosis, that hyperextension can actually result in a central cord syndrome, which is what they discovered with the C-spine MRI in this case. So, cognizant of all of the cervical injuries that might accompany the procedure of intubation. Dr Ghoshal: And you know what I would say, right. Because I think that our population is overall aging. I think with that, we're going to end up with, like, more cervical spine pathology for these patients that are ongoing intubation, just as you, you know, very astutely pointed out. Right? Trying to have at least, like, manual inline stabilization, right, or even like, considering fiber optic intubation in some of these patients is probably going to be a safer way to go to avoid these kind of injuries. Dr Albin: Yeah, I think that that's so true and really emphasizes the importance of communication between the neurology team and the critical care team. Dr Ghoshal: Totally. Dr Albin: Neurology is probably not the person intubating the patient. Right? But it's really important for any of these consults to have a good appreciation and that robust communication with the critical care team about what has been going on systemically for this patient, even opening that intubation note and saying, was this an easy intubation? Was it a difficult intubation? I think sometimes we forget that key skill of just communicating across the teams to have a holistic picture of what's been happening in MICU. Dr Ghoshal: Yeah, I totally agree. It's kind of why my first part of this case you mentioned is just like asking the team, like, what happened during the intubation, right? Dr Albin: It's a really important takeaway. All right. We're going to shift gears from procedural complications, reminding our listeners there is a fantastic summary of all of the things that can happen to ICU patients, just because we're doing things to them, putting needles in places where needles aren't usually, such as for arterial lines, for central lines, intubating patients; all of these have complications that can affect neurologic function downstream. But let's shift gears and let's talk now about a 72-year-old man. And he's admitted to the ICU with pyelonephritis and bacteremia. He's got nephrolithiasis. And the team calls you because he, like many patients in the ICU, has some, quote, “shaking events.” And he's altered, and they want to know what to do. Dr Ghoshal: So, there's a lot to unpack there. Sepsis is so common, right? When you're saying this patient is altered, sepsis-associated encephalopathy occurs in 70% of patients. So, like, in sepsis or septic shock. And we know that, you know, they say it affects mortality, long-term cognitive outcomes. But because, I think, it's so common, we don't really take the time to think about what is going on in sepsis in the brain. Dr Albin: The brain is an end organ perfusion. And the end organs are what we're sort of monitoring in sepsis, and the brain is such a key marker of that. Dr Ghoshal: Absolutely. I think there are a lot of things that happen with sepsis in the brain. But if I were going to pick like 1 or 2 points that I really wanted to hone in on, it’s thinking about that blood brain barrier disruption that happens in sepsis. And so, what that does when you disrupt the blood brain barrier is that you end up with this inflammatory milieu, for lack of a better term, that, like, comes into the brain. You have, like, a disordered sort of microglial activation, cytokine release. You know, all of these things are creating more oxidative stress, neuronal damage. And the other hand of this, right, along with that blood brain barrier disruption, is disordered cerebral auto regulation. Dr Albin: And I think that those two things are probably underappreciated. The complications and why, maybe, they lead to this downstream difficulty in recovering and then probably are also setting the patient up to be at risk of downstream delirium that is so frequent in the ICU. Dr Ghoshal: I couldn't agree more. And, you know, for this patient's case, right, where you're saying, like, they're altered, they're shaking, I bring up this idea of cerebral autoregulation. Right? Just because for normal patients---or normal people, rather, right?---normal cerebral autoregulation allows us to have, like, stable brain perfusion through whatever range of pressures we have. A lot of these patients are septic; whether they are hypertensive or not, they have significant changes in cerebral vasoconstriction, vasodilation, right? And this can create anything from, let's say, like, neuronal excitotoxicity, metabolic alterations. Right? Just in that setting of cerebral inflammation. So, these patients, yes, are at a very high risk of encephalopathy. And then from these changes, right, from blood brain barrier disruption, whether that's from a cerebral autoregulation or just from that inflammatory milieu, they're at a super high risk of stroke and seizure. Dr Albin: Yeah. So, they… in calling you to the bedside, someone comes to meet you and they say, we sent a bunch of labs off and we just got one back, and it's his ammonia, and his ammonia is 92. So, do you think that's what's going on here? This is so common. Right? Hyperammonemia. Give us sort of your approach to kind of triaging, is the hyperammonemia really a problem or is it just some sort of bystander? Dr Ghoshal: Oh, you know, ammonia is such a slippery lab, right? That… well, it's very hard not to have a strong opinion on it one way or the other. And so, I think what I would say is that ammonia can be elevated for, like, a parcel of reasons. Right? Like if someone has tonic colonic movements, you can have ammonia. That's just, like, part of like enteral metabolism, muscle breakdown, whatever it may be. And ammonia can go up for a lot of reasons. And it's true also that ammonia can contribute encephalopathy. And there are a few mechanisms that can go through in a little bit. I would first want to know… a part of understanding, I guess, any lab is understanding in this context of, like, what was the ammonia before? Right? What is their baseline ammonia? Is this a significant rise? Like, how much of a rise should you care about? Dr Albin: Yeah, absolutely. So, you look back and they live sort of at the upper range of normal with 60 being their sort of baseline. Dr Ghoshal: Yeah. You know, I don't know that I would be so concerned about this particular ammonia level. I may trend it. But, you know, just to talk a little bit about ammonia and why we care about encephalopathy, right? So, the reason why it's so concerning, I guess I should say, in any kind of acute illness is that ammonia will cross the blood brain barrier. And then it's converted into ammonium ions, and it will go into astrocytes and, like, they can increase interstellar osmolarity. Right? So, these cells swell. Right? And because water is drawn into the astrocytes, they cannot interfere with actual functioning of the astrocytes. Also worsen cerebral auto regulation and cause, I guess, sort of an excitotoxic environment. Right? So, ammonia can be concerning, I think when you send in a lab, right? I think it's important to remember that there's no direct relationship between ammonia level and encephalopathy severity. Dr Albin: Right. I think that's a really key point to drive home that it's usually not until we're in the hyperammonemic ranges above the 120s-150s up into the high two, three, four hundreds that we really need to be concerned about that cerebral... /episode/index/show/continuumjournal/id/39968055

Neurologic Complications of Hematologic Disorders With Drs. Lauren Patrick and Mark Terrelonge 02/25/2026

Neurologic Complications of Hematologic Disorders With Drs. Lauren Patrick and Mark Terrelonge Neurologic complications of hematologic disorders are frequently encountered in clinical practice and can involve both the central and peripheral nervous systems. Early recognition and appropriate management in collaboration with a hematologist are essential to reduce morbidity and mortality. In this episode, Kait Nevel, MD, speaks with Lauren Patrick, MD, and Mark Terrelonge, MD, MPH, authors of the article “Neurologic Complications of Hematologic Disorders” in the Continuum® February 2026 Neurology of Systemic Disease issue. Dr. Nevel is a Continuum® Audio interviewer and a neurologist and neuro-oncologist at Indiana University School of Medicine in Indianapolis, Indiana. Dr. Patrick is an assistant professor of neurology at the University of California, San Francisco, in San Francisco, California. Dr. Terrelonge is an associate professor of neurology at the University of California, San Francisco, in San Francisco, California. Additional Resources Read the article: Subscribe to Continuum®: Earn CME (available only to AAN members): Continuum® Aloud (verbatim audio-book style recordings of articles available only to Continuum® subscribers): More about the American Academy of Neurology: Social Media Host: Dr Nevel: Thick blood, thin blood. These are terms often used by patients and caregivers to describe some of the hematologic disorders that can lead to neurological diseases such as stroke. So, when should we consider a hematologic disorder as a potential cause for neurological conditions, such as stroke or neuropathy. Today I have the opportunity to interview Drs Lauren Patrick and Mark Terrelonge to learn more about neurologic complications of hematologic disorders in their recent article in Continuum. 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 Drs Lauren Patrick and Mark Terrelonge about their article on neurologic complications of hematologic disorders. This article appears in the February 2026 Continuum issue on neurology of systemic disease. Welcome to the podcast, and please introduce yourself to the audience. Dr Patrick: Thank you for having us. We're both thrilled to be here. I'm Lauren Patrick, a vascular neurologist and assistant professor at the University of California, San Francisco, and program director for the Vascular Neurology Fellowship here. Dr Terrelonge: And I'm Mark Terrelonge, I'm an associate professor of neurology and neuromuscular medicine here at UCSF and one of the associate program directors for the adult neurology residency. Nice to meet you. Dr Nevel: Nice to meet you both. Really looking forward to getting into your article and learning more. So, to kind of kick us off, I always like to ask what do you think is the most important takeaway from your article for the practicing neurologist? And maybe since there are two of you and I suspect you covered slightly different aspects of this article, maybe you could give us two most important takeaways. Dr Patrick: Sure. I think the biggest takeaway is to keep hematologic disorders on the differential when evaluating patients with neurologic symptoms. Conditions like sickle cell disease, myeloproliferative neoplasms, or plasma cell dyscrasias and paraproteinemia can cause strokes or peripheral neuropathies, and many have specific and targetable treatments. The early recognition and collaboration with our hematology colleagues can truly change patient outcomes, whether that's by initiating cytoreductive therapy, managing thrombocytopenia, or optimizing antithrombotic therapy. Dr Nevel: Great. So, this is a really big and diverse topic. As always, I'm going to urge our listeners to read the article because there is a lot of really good stuff in your article that we just don't have time to get into during this interview today. But you cover a lot of different hematological disorders and how they can cause neurological complications. One of the major neurological complications of hematological disorders is cerebral vascular events. So, I'm hoping, Warren, that you can walk us through a little bit. When should we consider workup of potential hematologic disorder as a cause when we see a patient with ischemic stroke, because certainly not all patients with ischemic stroke should be getting a broad hematological disorder work up. So how can we kind of identify early on that there might be something else at play? Dr Patrick: Absolutely, great question. So, in many cases, the underlying hematologic disorder is already known, such as sickle cell disease or polycythemia vera. But sometimes stroke is the initial presentation or manifestation of the disease. So red flags can include young age, recurrent cryptogenic strokes or thrombosis, and unusual locations like the cerebral venous system. Laboratory clues such as unexplained erythrocytosis, thrombocytosis, thrombocytopenia, or hemolytic anemia should raise suspicion for an occult hematologic disorder. In the setting of acute illness, immune-mediated or heparin-induced thrombocytopenia or thrombotic microangiopathies should be suspected in patients that have hemorrhagic and or thrombotic complications, particularly when relevant lab disturbances are present. Acquired thrombophilia such as anti-phospholipid antibody syndrome should be considered in young patients with autoimmune disease, prior venous or arterial thrombotic complications, or pregnancy morbidity. Now, these are rare causes overall, but they're important to catch because the management can differ dramatically from our typical stroke care. Dr Nevel: Great. And what are some of the most common inherited or acquired thrombophilias and when should we be sending these labs? Dr Patrick: The hematologic causes really account for small minority of arterial strokes approximately one to two percent, but among those, sickle cell disease, anti-phospholipid antibody syndrome and the myeloproliferative neoplasms are the most common. Timing of testing is key. So, the genetic thrombophilia panels can be drawn at presentation, but lab values such as protein C, protein S, and antithrombin levels may be falsely low during acute thrombosis, so they're often repeated weeks later. Similarly, for anti-phospholipid antibody testing that should be done at presentation and when positive, confirmed at twelve weeks, since transient positivity can occur with affections or acute events. So, in patients that are already anticoagulated for anti-phospholipid antibody syndrome, testing becomes particularly tricky, especially with lupus anticoagulant assays. Some results need to be interpreted carefully or repeated when feasible. The main message is to collaborate early with our hematology colleagues to guide the timing and interpretation of these studies. Dr Nevel: Yeah, wonderful. Thank you. I'll ask some similar questions about neuropathy. So when should we consider an underlying hematologic disorder as being the cause for someone's neuropathy? Dr Terrelonge: So, luckily for a neurologist, then serum protein electrophoresis or an SPEP is already a part of the first pass evaluation for even the most common neuropathies we see, technically already considered every time we do an evaluation. However, we do know that most neuropathies progress very slowly and don't really lead to significant limitations in patient activities of daily living. And for those, the initial workup step, you may not need to do any additional search for any hematologic diseases after that first step. Within patients who start to have more unusual features with their neuropathy, including a rapid progression, early proximal weakness, significant and extremely painful neuropathies, significant ataxia, or new tremor or anything that's kind of outside of the garden variety neuropathy, then you should start to think about a hematologic cause. Additionally, if a patient already has a known hematologic malignancy or process before their neuropathy, there should be some form of assessment to see through exam or electrodiagnostically if the two are correlated. I do have to add one caveat, though, and that's just because someone has a hematologic malignancy or a paraprotein seen in their blood, their neuropathy and the neurologic syndrome don't necessarily have to be causally related. So, we have to do some additional testing to determine if the patient's presentation of the paraprotein are actually linked. Dr Nevel: Can you walk us through a little bit how we determine if they're associated or just coincidental? Dr Terrelonge: Yeah. So, for some of the proteins, there's a specific phenotype that will come with the specific protein. For example, an anti MAG proteinopathies or MAG standing for a myelin associated glycoprotein, it usually leads to a distal sensor and motor polyneuropathy where the most distal portions of nerves are affected. So, in that case, people might notice that they have numbness and weakness in their toes and their fingers, and it doesn't follow that typical length dependent pattern. So, in that case, if you have the anti mag neuropathy and the electrodiagnostic signature of an anti mag neuropathy along with the symptoms, you're more likely to think that the two are related then if not. Dr Nevel: Great. Thank you. And I was hoping you could speak a little bit more about amyloidosis just because I think that that's one that can be really tricky to diagnose. And I see patients, you know, have sometimes more drawn out evaluations or see multiple providers before a diagnosis is reached. So, can you speak a little bit more to how we diagnose amyloidosis in relationship to neuropathy or other neurological conditions and when we should push for more invasive testing like a nerve biopsy? Dr Terrelonge: So, amyloidosis certainly is a tricky diagnosis. I've been tricked by it and I think most of my neuromuscular colleagues have probably been tricked by it at least once. It's a hard diagnosis to make is it usually requires a pretty high index of suspicion, and also requires a tissue diagnosis to cinch. There're some patients who will come in with a prior history of amyloidosis and they're a little bit easier to figure out if the neuropathy is related. Maybe it's started in their heart or their kidney first and then you can just see if the type of amyloid they have usually deposits in nerve, and that may be enough. But if there's any diagnostic uncertainty, you could go forward with tissue biopsy. But it's patients in which the neuropathy is the first symptom that amyloidosis can be especially tricky to diagnose. It's a primarily light chain disease. So, if you do only an SPEP as a part of your initial neuropathy evaluation, you could miss it. But usually, the patients will have either a severely painful neuropathy, early autonomic dysfunction, or really prominent bilateral carpal tunnel syndrome. So, if they have any of those, usually we'll add in an amyloid workup as a part of that of the rest of the workup, which would include both light chain evaluations to see if there's any increase in Lambda or Kappa light chains and then also biopsy. Biopsy can be of the skin or fat pad first, which have reasonable sensitivity for picking up disease, but they're not necessarily a hundred percent. So if the suspicion remains high in those cases, a nerve biopsy should be considered. And the reason why this is important is that the chemotherapeutic agents that we have now can actually help arrest a lot of these diseases and stop further organ involvement. So, if you think about it, it is important to keep pushing and looking until you find it. Dr Nevel: Thank you so much for that. And a follow up question to that, once patients are started on appropriate therapy, the diagnosis is made, chemotherapy is started, what's the typical clinical course that you see in terms of their neuropathy? Do you ever see improvement or is it arrest of worsening? Dr Terrelonge: Usually for amyloid, there is an arrest of disease, but in some patients, they could have some improvement, not necessarily a dramatic improvement, but some patients could see some reversal of symptoms. That may not necessarily be because nerves injured nerves are regrowing, but because of reorganization of nerves to muscle, they could have some strength increases or at least less pain. Dr Nevel: Yeah, thank you. So, when should we involve a hematologist in aiding in the evaluation of patients we suspect may have an underlying hematological disorder? You guys really outlined very nicely in your article some of the laboratory workup or other workup like you just talked about with amyloidosis. But at what point in that workup should we reach out to our hematology colleagues? Dr Patrick: I would say almost always. So, these disorders are inherently multi-system and benefit from early co-management. In acute sickle cell stroke, for example, hematology helps direct emergent exchange transfusion. For myeloproliferative disorders they guide cyto reduction and long term antithrombotic strategy. And for antibody mediated or plasma cell disorders, hematology determines disease specific therapies. So, neurology may help with identifying the presentation, but the definitive management is almost always shared with our hematology colleagues. Dr Nevel: And as you both have mentioned that a lot of times in these cases, their hematologic disorder may be already known before they present with their neurological symptoms. So, I imagine obviously in those cases that a hematologist hopefully is already heavily involved in their care. What do you think is the most difficult aspect of identifying and diagnosing patients with neurologic illness as having an underlying hematological disorder? Dr Patrick: The hardest part is maintaining a high index of suspicion, especially since hematologic causes account for a very small minority of arterial strokes. Most strokes are from traditional vascular risk factors like you mentioned, or cardio embolism, so it's easy to stop diagnostic evaluation after standard studies have been performed. An example of a challenging case is a patient that's young, they've had recurrent cryptogenic stroke, and they could have antiphospholipid antibody syndrome, but it can be easy to miss if their antibody titers are borderline or if they're already anticoagulated, which would complicate retesting. So, it's about balancing the urge to over-test with recognizing the few cases where identifying A hematologic cause truly changes that management. Dr Terrelonge: And then on the neuropathy side, probably the hardest part is deciding what's causal and what's coincidence. Monoclonal gammopathy of unknown significance, or MGUS, is really common in older adults, so not every M-spike on an SPEP explains a neuropathy. And even sometimes there's times when the neurologic picture will develop a little bit faster than the hematologic one. So, it's hard to put the two together. Dr Nevel: Yeah. What's the most rewarding aspect of taking care of patients with complications from their hematologic disorders? Dr Patrick: It's deeply rewarding when a targeted diagnosis leads to a tangible improvement in that patient's care. For example, identifying A cryptogenic stroke is being due to myeloproliferative neoplasm or an inherited thrombophilia allows us to move from empiric treatment to possible disease specific strategy. It’s really gratifying to give patients that clarity, to give them a diagnosis and in some cases prevent future events. Dr Terrelonge: Agreed. And even on the neuropathy side, almost all of the neuropathies that are hematologically related are treatable. So, it's so satisfying whenever you have a patient with say an anti-MAG neuropathy or Waldenström can start the patient on therapy, and you can see someone who's been having a progressive decline to stability and in those cases sometimes even significant recovery. Dr Nevel: Yeah, absolutely. Very rewarding when you can identify the problem and make it better. That's what it's all about. So, what are the future areas of research in this area? What do we still need to learn? Dr Patrick: There's still a lot to learn. I think we need better data on the safety of acute reperfusion therapy and antithrombotic agents, particularly in patients that are at dual risk for bleeding and thrombosis. Other examples, secondary prevention strategies and anti-phospholipid antibody syndrome. What's the best target INR? Do you add aspirin to warfarin or not? All of that is often left up to expert opinion. What's the best management for adults with sickle cell stroke? There are many open questions there. A lot of the protocols that we have in place for sickle cell patients that are adults as derived from pediatric literature and there's vast potential in terms of disease modifying therapies, especially in the fields of sickle cell disease and amyloidosis. And we'll need to reassess how those treatments may change neurologic outcomes. Dr Terrelonge: I think on the neuropathy side that having some form of new biomarkers to help us clearly know of the neuropathy and that hematologic illness are associated would be very helpful. On the treatment side, a lot of this is really being driven by the hematology space, but new therapies that treat hematologic plasma cell disorders, including some of the new BTK inhibitor, may be incorporated relatively soon into the algorithm for how we treat many of our patients. I'm excited to see what's to come from this. Dr Nevel: Wonderful. Thank you so much for sharing your knowledge with us today. I know I've certainly learned a lot by reading your article and through our discussion today. Highly encourage our listeners to read your wonderful article, which is a very thorough review of hematologic disorders and neurological complications. Again, today I've been interviewing Dr Lauren Patrick and Dr Mark Terrelonge on their article Neurologic Complications of Hematologic Disorders, which appears in the February 2026 Continuum issue on Neurology of Systemic Disease. Please be sure to check out Continuum Audio episodes from this and other issues. And as always, thank you so much to our listeners for joining today, and thank you so much to Lauren and Mark. Dr Terrelonge: Yeah, thank you so much for having us. Dr Patrick: Thank you so much for having us and for highlighting this topic. We hope the issue encourages clinicians to think broadly about hematologic causes of neurologic disease and to continue collaborating closely with our hematology colleagues. It's a complex but very fascinating intersection for both of our fields. Dr Monteith: This is Dr Teshamae Monteith, associate editor of Continuum Audio. If you've enjoyed this episode, you'll love the journal, which is full of in depth and clinically relevant information important for neurology practitioners. Use this link in the episode notes to learn more and subscribe. AAN members, you can get CME for listening to this interview by completing the evaluation at continpub.com/AudioCME. Thank you for listening to Continuum Audio. /episode/index/show/continuumjournal/id/39967950

Neurologic Complications of Endocrine Disorders With Dr. Rafid Mustafa 02/18/2026

Neurologic Complications of Endocrine Disorders With Dr. Rafid Mustafa Neurologic complications of endocrine disorders are diverse and may arise before systemic manifestations. Early recognition is essential because neurologic symptoms may represent the presentation of an undiagnosed underlying endocrine disorder, and because many neurologic complications of endocrine disorders are reversible with timely treatment. In this episode, Gordon Smith, MD, FAAN, speaks with Rafid Mustafa, MD, author of the article “Neurologic Complications of Endocrine Disorders” in the Continuum® February 2026 Neurology of Systemic Disease 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. Mustafa is an assistant professor of neurology for the Department of Neurology at Mayo Clinic in Rochester, Minnesota. Additional Resources Read the article: Subscribe to Continuum®: Earn CME (available only to AAN members): Continuum® Aloud (verbatim audio-book style recordings of articles available only to Continuum® subscribers): More about the American Academy of Neurology: Social Media Host: Guest: Dr Smith: So what group of disorders causes cognitive changes, weakness, fatigue, neuropathy, and seizures? Kind of sounds like all of neurology in one, doesn't it? It turns out that disorders of the endocrine system can cause all of these neurological problems and others. And kind of reminds me of William Osler, who famously said at the end of the 19th century that “he or she who knows syphilis knows medicine.” Syphilis was the great imitator of his time. I wonder if in our time, the great imitator is actually endocrine disorders because it can cause all of these different problems. Today I have the great opportunity to talk with Dr Rafid Mustafa from Mayo Clinic about the neurological complications of endocrine disorders, which is a really terrific article in the February 2026 issue of Continuum. Dr Jones: This is Dr Lyell Jones, Editor-in-Chief of Continuum. Thank you for listening to Continuum Audio. Be sure to visit the links in the episode notes for information about earning CME, subscribing to the journal, and exclusive access to interviews not featured on the podcast. Dr Smith: This is Dr Gordon Smith. Today I'm interviewing Dr Rafid Mustafa about his article on neurological complications of endocrine disorders, which appears in the February 2026 Continuum issue on neurology of systemic disease. Rafid, welcome to the podcast, and please introduce yourself to our listeners. Dr Mustafa: Well, thank you for having me, Dr Smith. Like you had mentioned, I'm Dr Rafid Mustafa. I'm a neurohospitalist at the Mayo Clinic and I had the pleasure of writing this issue with Dr Aaron Berkowitz, and it's been such a fun ride to be a part of Continuum for this issue. Dr Smith: Yeah, it's a really exciting issue. And I have to say, I was really excited to have the opportunity to talk to you. Even though my research is in diabetes and I'm looking forward to talking about that---not my research, but about diabetes---I think the area of endocrine and neurological complications of endocrine disorders is confusing to us. And I guess maybe you could begin by just this concept that most of us check a few endocrine labs on just about everything. But how do you bring order to this when there's a group of disorders that all cause just about every domain of neurological problem, be it weakness, neuropathy, cognitive changes, and so forth? Dr Mustafa: Yeah, I think it's super interesting. I think that's why, you know, this issue on systemic diseases is fun. I had a mentor one time telling me that your interim year in residency is important so you can learn about all these organ systems that are there to keep the brain alive. And so, I think neurologic complications of systemic disease are fun. You know, like you said, the endocrine system, whenever it goes awry, you can get all sorts of neurologic complications. Putting order to it can be challenging. I think it's important to know what the different parts of the endocrine system do, the different glands and how they're connected, and what to look out for when you encounter neurologic problems, because sometimes those neurologic manifestations can be the very earliest sign of something wrong with different parts of the endocrine system. Dr Smith: You knew exactly where I was heading without having to tip my cards. I mean, that's exactly where I wanted to begin, because I think of this as an intimidating topic, but in reading your article, you outlined kind of the glandular structure or anatomy of the endocrine system and sort of the logic of its function. And actually, it's not as complicated as I was thinking going in. You did a good job of framing. And I wonder if maybe you can begin by just reminding our listeners the basic anatomy and functional logic that they'll need to keep in mind. Dr Mustafa: Yeah, absolutely. The system itself is this network of different glands and hormones that work to influence each other, just like our, you know, our nervous system is all interconnected as well, too. But this is more ensuring homeostasis in various ways. So, you have the hypothalamus all the way at top that secretes things, usually just to stimulate the pituitary, which often ends up being the controller of the endocrine system. And then there are these various other organs that have different jobs or things to do. So, there's, you know, the thyroid, parathyroid, adrenal glands; you have your pancreas, there's gonads. And all of these different things have different roles to keep us healthy and regulated. to function appropriately, you know, whether that's just generalized metabolic things from the thyroid gland or more flight or fight responses from the adrenal gland, even, you know, renin, aldosterone, etc, etc, from the adrenal. And then you know, the pancreas, diabetes, all sorts of things there. Gonads are important for sexual health. It's kind of cool how it's all regulated together and there's these feedback loops and- ah, we'll have fun talking about it. Dr Smith: Just listening to you, it kind of feels almost like the endocrine system is part of the nervous system, isn't it? I mean- and there are these sort of relationships between the two that I know we'll get into. We think of insulin sensitivity, for instance, and, you know, patients with diabetes. I mean, there's neuronal insulin resistance as well. So, they're very, very interconnected systems. Dr Mustafa: Absolutely. You're absolutely right. Dr Smith: I wonder if you can talk about this idea of feedback loops. This is something that we all learned in medical school, but probably worth reminding ourselves of as we begin the conversation. Dr Mustafa: Yeah, one part of the endocrine system is important for secreting a hormone that will influence another part of the endocrine system. And that new end target will have some kind of function, and then it all loops together. So, for example, the hypothalamus, it secrets out thyrotropin-releasing hormone and that stimulates the anterior pituitary gland to secrete thyroid-stimulating hormone, and then that hormone acts on the thyroid gland itself to produce the final-acting thyroid hormones themselves, like T3 and T4. Now, if any of these are thrown off, then it throws off other parts of the system. So, for example, maybe you’re hyperthyroid and you have too much T3 and T4 coming from the thyroid gland. That may signal the hypothalamus and pituitary to reduce levels of thyrotropin-releasing hormone and thyroid-stimulating hormone to in turn affect the thyroid gland and help reduce production of those end-target thyroid hormone. Or vice versa, it just depends on the condition. You can see this at all aspects of the system at various accesses. So, it's kind of this complicated neural network in a way, but just from endocrine purposes, glands and hormones. Dr Smith: I wonder if we can start talking about the pituitary gland. Your article has all kinds of really cool information. One pearl that I wasn't really aware of is that 10% of adults have a pituitary microadenoma. It's pretty amazing. You point out that most of these aren't clinically significant, but they clearly come up on, kind of, an evaluation now and again. I mean, how should our listeners sort through how to approach these situations, right? Most of them aren't clinically significant, but some of them are. What does a neurologist need to know about this? Dr Mustafa: Yeah, To me, it's like anything else in our field. You scan enough people, you're going to find incidental things. You scan a spine, you're probably going to find a disc herniation. The question is, how clinically relevant is that and how is that affecting your patient? What are the things you need to be worried about and how do you work through it? As you mentioned, yeah, 10% of the population has a pituitary microadenoma. Those are the small ones. Most of them are clinically insignificant. So, if you find it, you know, usually it's not something to worry about too much. You might repeat serial imaging just to make sure it's not growing. But if they're not having neurologic symptoms because of mass effect or physiologic symptoms because of hormonal effect, then most of the time it's just an incidental finding and you just have to work really hard to reassure your patient. Now sometimes, there can be mass effect as the tumor itself grows, as benign tumor, or there can be hormonal effects. And then you might start thinking about how you're going to intervene. Dr Smith: Let's talk about macroadenomas and mass effect. You spend some time, and I actually have a really good example of pituitary apoplexy as well as the relationship between macroadenomas and other headache syndromes. So maybe you can talk about the relationship between macroadenomas and headache? Dr Mustafa: Yeah. So, you know, when pituitary adenomas become large, usually over 10 millimeters or so, we call it a macroadenoma. And the neurologic symptoms that come to play are usually because of mass effect. I think many of us are trained to recognize visual defects like a, you know, bitemporal hemianopia from compression of the optic chiasm. That's one of the classic things. But even just the mass effect alone in that area can cause symptoms like headache. Many of this will be, you know, migrainous in nature. Sometimes you can get a typical trigeminal-type phenomenon, just given everything that's in the region. And with something like pituitary apoplexy that you alluded to, I mean, that usually comes on very quickly. It can be a thunderclap headache. So, not all thunderclap headaches are subarachnoid hemorrhage from aneurysms. You have to think about other things on the differential, and that includes pituitary apoplexy. Dr Smith: Yeah, I mean, I think one of the things I found interesting was the fact that headaches can be associated with pituitary macronoma that are migranous or even look like a trigeminal autonomic cephalgia. I mean, is that something that commonly influences your management of either the headache or the macroadenoma? I mean, if you have a patient with a macroadenoma, do you treat the headache syndrome any differently, or are you particularly attentive for pituitary findings in someone that you're scanning because of headache? Dr Mustafa: Yeah. From my perspective, if I know there's a pituitary macroadenoma and they have these associated headaches, my practice is in general to treat the headache symptomatically, focusing on the phenotype, whether it's migrainous or more, you know, like an attack, a trigeminal autonomic cephalalgia. Now if it starts with they had an atypical headache like a trigeminal autonomic cephalgia, maybe I'm doing the imaging as a result of that to explore why they may be having this from a structural perspective. And if indeed it is because of a pituitary macroadenoma, we'll probably be monitoring the characteristics of the adenoma on a serial basis to see how it transforms over time. And if it's enlarging, you know, those symptoms might be a reason to consider intervention from a surgical resection standpoint. Dr Smith: So, I wonder if we should pivot and talk a little bit about how neurologists encounter patients who have symptoms related to endocrine disorders. And presumably the clues come with the impact of the distal endocrine gland, for instance, either over- or underproduction of the thyroid hormone. Is that the right way of thinking of it? And then, you know, having identified that, you'll start to look whether it's a primary glandular problem or upstream in the pituitary. Dr Mustafa: Absolutely. That's in general my approach. You know, often these patients are coming to the neurologist with specific symptomatology, and being familiar with how that's related to the endocrine system is what's important. So, I try to organize this article kind of by parts of the endocrine system and how that's related to neurologic manifestations. But really, it's about being familiar. So, if the patient presents in a comatose status and it's not a clear-cut structural reason, neurologically, as to why they're comatose, you might be exploring metabolic reasons for their coma. You may find disturbances in thyroid hormone levels, and that can influence you to work your way back up the axis---just like you mentioned, Gordon---to see where the problem is coming from that influences the thyroid problem. Dr Smith: So, you know, maybe we can use that as a good hook to hang our coat on, right? So we have a patient in the unit, comatose, not clear why. Are there specific pearls or indicators that would trigger you to really think about, is this a thyroid problem? Is it adrenal or whatnot? I mean, you give some great examples of, like, myxedema coma, which is very interesting. But what's the clue that we should be going down this pathway? Or, you know, on the other extreme, do you just look for thyroid abnormalities in everyone with a coma that you're having a hard time figuring out? Dr Mustafa: Great question. I am slightly more of a traditionalist in my approach to neurologic disease that, instead of shotgunning every single possible test, I try to localize in any way I can. And what's cool about these disorders of the endocrine system is that there's so much on your examination that can help clue you in. And it's not just the neurologic exam, it's the systemic exam as well, too. So, important to keep an eye out for those things. Since we're on the topic of thyroid, patients with mixed edema coma, you know, they may have neurologic signs like myoedema, etc, but they may also have systemic signs like hair loss, changes in weight, changes in temperature regulation, that you can pick up on history as well, too. And it's putting all that together to localize to not just part of the nervous system now, but part of the body that helps you with your testing. And that's how I tend to approach things. Dr Smith: So, so many questions I have for you. I wonder, can we talk a little bit about Hashimoto's encephalopathy? Dr Mustafa: Oh, yes, absolutely. Dr Smith: What's the deal there? That's something I've always found a little bit challenging. So, when should we think about it? There are lots of people out there with elevated thyroperoxase antibodies. How do you make the connection between serology and clinical phenotype and management? Dr Mustafa: Yeah, it's a great point of contention among groups, this diagnosis of Hashimoto encephalopathy. There are those that believe in this is a distinct autoimmune, essentially encephalitis entity associated with abnormal thyroid antibodies. And then there are those that believe that patients have this encephalopathy, but it's just incidental that we find these abnormalities in thyroid testing. What I'll tell you is there's been some really nice studies looking at Hashimoto's or what's to be Hashimoto's encephalopathy, and most patients that present with what is thought to be that actually have normal thyroid function studies. The other thing is finding abnormal antithyroid antibodies is also pretty prevalent in the general population. So, I think in my approach to thinking about Hashimoto's encephalopathy, you’ve just got to take everything with a grain of salt. You got to recognize that some things are just very prevalent, and you have to keep your clinical suspicion high for what you normally would see and consider other things on the differential. My personal thought is that there probably is some unique antibody-driven disease process that represents what we think of as Hashimoto's encephalopathy, but we just haven't fully classified what that antibody may be quite yet. And then there's probably some overlap, because in general a lot of these thyroid diseases themselves are reflective of underlying autoimmunity. So, there's probably something going on, but I don't think it's a direct effect of something like, you know, thyroid peroxidase antibodies. Dr Smith: Maybe we should pivot and spend a little time talking about the most common endocrine disorder that we encounter in neurologic practice, which is diabetes. And as I mentioned earlier, it's a topic near and dear to my heart. What's the latest that our listeners should know about regarding peripheral nervous system complications of diabetes? We're all familiar with distal symmetric polyneuropathy. Or are there other new updates or pearls that we should be thinking about? Dr Mustafa: Absolutely. So, the complications on the nervous system extend far beyond just your distal symmetric polyneuropathy is probably the most common thing we see, but you can get all sorts of unique manifestations. In fact, I recently just took care of a patient that had many of these. You can get a single thoracic radiculopathy. You can have what we see often at Mayo Clinic here, a diabetic lamosacral radicule plexus neuropathy where patients have profound, initially, usually pain in their lower limbs, and then this spreading of profound weakness in their lower limbs. That can be a huge complication of association with rapid control of glycemic status. And especially this day and age where we have newer medications that are very effective at controlling diabetes, we're seeing this more and more. I wrote this article before some recent publications that come out highlighting the association with GLP-1 agonists. But with these types of medication, rapid glycemic control can result in, you know, associated DLRPN quite frequently. Dr Smith: Yeah, it's interesting. I think we think of the, kind of the neuro-ophthalmological manifestations or risks of GLP-1 agonists, but the relationship too, of treatment-induced neuropathy and diabetes. And I'm curious of your experience. My sense is that if you aren't attuned to these sort of problems, you often miss them. And you certainly see people that come close to having surgical interventions or, you know, end up going off in the wrong direction with these acute neuropathies that I think are probably a little more common than we often give them credit for. Dr Mustafa: Absolutely. Yeah. I think, you know, learning about these things and being familiar is very important. It's important to keep a good broad differential because there can be mimickers, whether it's infectious things or malignant things like lymphoma, but I wanted to highlight in this article how common something like diabetic radiculoplexus, Lumbosacral radiculoplexus neuropathy can be. I mean, in fact, we see this more than things like Guillain-Barré syndrome, CIDP, etc. And so, I think practicing neurologists everywhere should at least be familiar and know what to look for so that they can make the diagnosis... /episode/index/show/continuumjournal/id/39967895

Neurologic Manifestations of Renal and Electrolyte Disorders With Dr. Eelco Wijdicks 02/11/2026

February 2026 Neurology of Systemic Disease Issue With Dr. Aaron Berkowitz 02/04/2026

February 2026 Neurology of Systemic Disease Issue With Dr. Aaron Berkowitz In this episode, Lyell K. Jones Jr, MD, FAAN, speaks with Aaron L. Berkowitz, MD, PhD, FAAN, who served as the guest editor of the February 2026 Neurology of Systemic Disease issue. They provide a preview of the issue, which publishes on February 2, 2026. 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. Berkowitz is a Continuum® Audio interviewer and a professor of neurology in the Department of Neurology at the University of California, San Francisco, in San Francisco, California. Additional Resources Read the issue: Subscribe to Continuum®: Continuum® Aloud (verbatim audio-book style recordings of articles available only to Continuum® subscribers): More about the American Academy of Neurology: Social Media Host: Guest: Dr Jones: The human nervous system is so complex. You can spend your whole career studying it and still have plenty to learn. But the human brain does not exist in isolation. It's intricately connected with and reliant on other bodily systems. When those systems go awry, sometimes the first sign is in the nervous system. Today we will speak with Dr Aaron Berkowitz, an expert on the neurology of systemic disease, and learn a little about how these disorders can present and what we can do about it. 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 Aaron Berkowitz, who is Continuum's guest editor for our latest issue of Continuum on the neurology of systemic disease. Dr Berkowitz is a professor of clinical neurology at the University of California, San Francisco, and he has an active practice as a neurohospitalist and in outpatient general neurology---and, importantly, as a clinician educator. In addition to numerous teaching awards, Dr Berkowitz has published several books and also serves on our editorial board for Continuum. Dr Berkowitz, welcome. Thank you for joining us. Why don't you introduce yourself to our listeners? Dr Berkowitz: Thanks, Lyell. As you mentioned, I'm a general neurologist and neurohospitalist here in San Francisco, California at UCSF and very involved in resident education as well. And I was honored, flattered and a little bit frightened when I received the invitation to guest edit this massive issue on the neurology of systemic disease. But I've learned a ton, and it's been great to work with you and the incredible authors we recruited to write for us. And I'm excited to have the issue out in the world. Dr Jones: Yeah, me too. And you and I have talked about it before: you're one of a very small group of people who have guest edited multiple issues on different topics, right? Dr Berkowitz: That's right. I did the neuroinfectious disease issue in… was it 2020? 2021? Something like that. Dr Jones: Yeah. So, congratulations, more people have walked on the moon than done what you've done. And I'm looking forward to chatting, Aaron, and really grateful for your work putting together a fantastic issue. I think our listeners will appreciate that the nervous system does not function in isolation. It's important to understand the neurologic manifestations of diseases that originate within the brain, spinal cord, nerves, muscles, etc., but also the manifestations of diseases that begin in other systems and, you know, may masquerade as a primary neurologic disorder. So, it's obviously an important topic for neurologists, since many of these patients are receiving care in another setting, perhaps from another specialist. I almost think of this issue of Continuum as a handbook for the consultant neurologist, inpatient or outpatient. I don't know. Do you think that's a fair characterization of the topic? Dr Berkowitz: Absolutely. I completely agree with you. I think, yeah, many of us go into neurology interested in our primary diseases, whether it's stroke or Parkinson's or neuropathy or particular interest in neurologic symptoms, whether they're cognitive, motor, sensory, visual. And we quickly learn in residency, right? As you said, a lot of what we see is neurologic manifestations of primary diseases. So, I don't know how similar this is to other training programs. But it seemed like, if I'm remembering correctly, my first year of residency was mostly on primary neurology services, general stroke, ICU. And we moved into the consultant role more in the PGY-3 year the next year. And I remember explaining to students rotating with us on the consult services, this is actually much more complex in a way, because the patient has some type of symptom in a much broader and much more complicated context of multiple things going on. And I call it “neurology in the wild.” There's, like, neurology of, this patient’s had a stroke and we know they have a stroke and we're trying to figure out why and treat it. That's all interesting. But our question here, is there a stroke needle buried in this haystack of all of these medical or surgical complications? And learning what I call neurology of X, which is really what this issue is; as you said, that there's a neurology of everything. There's a neurology of cardiac disease. There's a neurology of the peripartum. There's a neurology of rheumatologic disease. There's every new treatment that comes out in oncology has a neurology we learn, right? There's a neurology of everything. Dr Jones: There's a lot of axes, right? There's the heart-brain axis and the kidney-brain axis. And… I think we cover everything except the spleen-brain axis, which maybe that's a thing, maybe not. I'll probably hear from all the spleen fans out there. So, I want to do a little bit of an experiment. We're going to do something new today on the podcast. Before we get into the questions, we're going to start with a Continuum Audio trivia question. So, this will be a first time ever. Dr Berkowitz, we all know that chronic hyperglycemia, or diabetes, can lead to many neurologic and systemic complications and that optimal glucose control is our goal. For our listeners, here's the question: what neurologic complication can occur from correcting hyperglycemia too quickly? What neurologic complication can occur from correcting hyperglycemia too quickly? Stick around to the end of our interview for the answer. So, Aaron, let's get right to it. You had a chance to review all the articles in this issue on the neurology of systemic disease. What do you think in all of those is the most exciting recent development for patients who fit into this category? Dr Berkowitz: Yeah, that's a great question. I think we talked about when we were putting this issue together, right, a lot of the Continuum subspecialty topics; there should have been updates on particular disease diagnostics, treatments, new phenotypes. Whereas here probably a lot less has changed in primary heart disease, primary cancer. As I'd like to say to our students trying to excite them about neurology, most specialties have new treatments, but I can name a large number of new diseases, right, that have been discovered since we've been out of training. So, a lot of the primary medicine stays the same, and the neurologic complications stay the same. But probably the thing that many readers will want to keep handy and will probably be much in need of update again in three years are the neurologic complications of all the new cancer treatments. So, if we think back to I finished training just over ten years ago when a lot of the fill-in-the-blank-umabs were coming out, CAR T therapy, and we were starting to see a lot of neurology, I remember, related to these and telling the oncologists and they said, oh, you just wait. We are seeing at the conferences that there's a lot of neurology to these. And I feel like that is always a moving target. And I think we are seeing a lot of those and it's hard to keep up with which treatments can cause which complications, which syndromes and which severities require holding the treatment when you can rechallenge longer-term complications of CAR T cell therapies now that we've learned more about the acute complications. So, Amy Pruitt from Penn has written us a fantastic article for this issue that covers a lot of the updates there. And I learned a lot from that. I feel like that's the one that just like every time the carnioplastic diseases are reviewed in Continuum, it seems like the table is another page longer from your colleagues there in Rochester teaching us about new antibodies. And I feel like, for this issue, that's one of the areas that felt like there was a lot of very new content to keep up with since last time. Dr Jones: That's good news, right? It's good that we have new immunotherapies for cancer, but it does lead to neurologic catastrophes sometimes, and it is a moving target, really rapid. So, you mentioned that just over ten years ago you finished your training and now we see a lot more of these complex immunotherapy-related neurologic complications. What about in the other direction? Are there any things that you see less commonly now in your practice than you might have seen ten years ago right when you were finishing training? Dr Berkowitz: I would say no, I think. I think we're seeing a lot of new stuff, and we're still seeing a high volume of the classic consults we tend to get, whether that's altered mental status in a patient who's systemically ill; weakness or difficulty reading from the ventilator in a patient who's critically ill; patient has endocarditis and has a stroke hemorrhage or mycotic aneurysm, what do we do? Yeah, one of the parts that was really fun and educational editing this issue is, I really wanted to ask the experts the questions I find that are really troubling and challenging and make sure we could understand their perspective on things like the endocarditis consult, which I always feel like each time there's some twist that even though the question is what do we do about this stroke and/or hemorrhage and/or aneurysm and is surgery safe? It seems like each time I always feel like I'm reinventing the wheel, trying to really sort out how to think about this. And we have a great article from Alvin Doss at Beth Israel and Steve Feskey from Boston Medical Center. It covers a lot of cardiology, as you know, in that article about a great section on endocarditis where every time it came back for review, I would say, but what about this? This comes up. What about this? Can you explain how you think about this for our readers? I don't know. I'd be curious to hear your perspective. It sounds like we agree on what has become more common. I don't think anything in neurology seems to become less… Dr Jones: Well, no, I guess we haven't really solved anything, I guess we haven't cured any problem. But that's okay, right? I mean, it's building on an established foundation of experience and history in our field. And you know, we mentioned earlier that in many ways this issue is kind of like a neurology consultant's handbook. We did something a little different with it in that sense. In addition to you serving as the guest editor, you have authored an article in the issue. It touches on something that we've talked about a couple of times, and I'd be interested to hear you talk through it with our listeners a little bit on how to approach the neurologic consultation. Tell us a little more about that and your article and how you approached it. Dr Berkowitz: Oh, yeah, thanks. Well, thanks first of all for inviting me to think about a sort of introductory article to this issue. And I was trying to think about what to write about because, as you've said and we've been talking about, no one could know every neurologic complication of every medical disease, treatment, surgery, hospital context. Probably many of us don't even know all the muscle diseases, right, within neurology. So how could we know all this stuff? And we need some type of manual from our colleagues that can explain, okay, I know this patient has inflammatory bowel disease and they've had a stroke. Is that- are these related? Are these unrelated? And I thought the articles kind of answer all of these questions. What would I say beyond this patient has disease X and is on drug Y? Well, look up in this issue disease X and see what the neurology can be, common and rare and how often it's associated, how often it's the presenting feature, how often it means the treatment is failing, etc. I thought, I'm not sure there's much to say there. That's about a paragraph. And I thought, well, let's think even more broadly about neurologic consultation. And as you know, I like to think about diagnostic reasoning and clinical reasoning. And we talk a lot about framing bias right? And I think that is very common in consultative neurology because we'll be told in the consult or in the page or E-consult or whatever it is, this is a blank-year-old blank with a history of blank on treatment blank. And right away your mind is starting to say, oh, well, the patient just had heart disease, or, the patient is nine months pregnant, or, the patient is on an immune checkpoint inhibitor. And whether you want to do it or not, your mind is associating the patient's neurology with that. And it's- even if we know we're framing or anchoring, it's hard to kind of pull away from that. And most of the time, common things being common, a patient with cancer develops new neurology, It's probably the cancer, the treatment, or sometimes a paraneoplastic syndrome. But I've definitely found if you do a lot of inpatient neurology and a lot of consults that you're seeing so much and you have no choice but to apply these heuristics, because you're seeing a lot of volume quickly and the patients are in the hospital or they're being closely followed and outpatient setting by another specialist. You presume if you didn't get it quite right the first time, it's going to come back to you. And there's a little bit of difficulty figuring out, this is a case, actually, of all the altered mental status in acutely ill patients I got today, this is the one I should dig deeper in that I think this could turn out to be a stroke or encephalitis as opposed to delirium. I felt like that I really haven't approached that except knowing that it's easy to fall into traps. And so, I started to think about framing bias. You know, we talked about if we become aware of our biases, right, we're better at not falling prey to them. But it's subconscious. So, we might be applying it without even realizing, or even saying, I might be framing this case the wrong way, you can go right on framing it the wrong way. So, I want to kind of get a little more granular on what types of framing biases actually are relevant, specifically, to the console setting. And so, I tried to come up with a few more specific examples and try to think about ways that we could at least have a quick, if our knee-jerk is to associate primary disease X that the patient has or primary treatment X with neurologic symptom Y, what's at least a quick counter-knee jerk to say, what if it could be something else? So, for example, one of them I call “low signal-to-noise ratio bias.” Altered mental status in the acutely ill hospitalized patient. What would you say, Lyell? 99 out of 100- 99.9 out of 100, it's not a primary neurologic disease. Is that fair to say? Dr Jones: Very high, yep. I agree. Dr Berkowitz: Yeah. But could it be a stroke? Could it be non-convulsive status epilepticus, meningitis encephalitis? So, how do we sort of counteract low signal-to-noise ratio bias, acknowledging it exists, acknowledging most of the time there is a low signal-to-noise, that it's not going to be neurology---to just for example, use the time course. This is pretty acute. Have I convinced myself this is not a stroke or a seizure or an acute neurologic infection? And if I'm not sure at the bedside, should I err on the side of more testing? Or the “curbside bias,” as I call when your colleague just sends you a text message on your phone, No need to even open the chart, Dr Jones. Patient had a cerebellar stroke. Incidental. They're here for something else. Aspirin, right? Just like a super tentorial stroke. And you might reply thumbs up. And then imagine you open the CT scan and it's a huge cerebellar stroke with fourth ventricular compression- and patient can hide a lot of stroke back there, might just have a little ataxia. You were curbsided and that framed you to think, oh, they asked me, is aspirin okay for a cerebellar stroke and I said yes, without realizing actually the question should have been posed is, how do you manage a huge stroke with mass effect in the posterior fossa? So, these types of biases, I come up with five of them, I won't go through all of them. I'm in the article to sort of acknowledge for the reader, most of the time it's going to be what you look up in this issue, but how to think about the times where it might not be and how to be more precise about what framing is and different types of framing that occur specifically in the consultant arena. Dr Jones: And I think the longer we practice, the more of those low-frequency exceptions that you see. And, you know, and then it sticks in our mind and sometimes the bias swings the other way; people, you know, think primarily about the low frequency. And so, it's tricky. And what I really enjoyed about that article, we started talking about this probably more than a year ago, and more than a year ago, I would say relatively few clinicians were using a now widely popular large language model for clinical decision-making; we won't name the model. And now I think most clinicians are using it almost every day, right? And I think it puts a premium on how to think and how to engage with the patient, and less about the facts and the lists that a lot of conventional medical education really is derived from. So, I really appreciate that article. We can pat ourselves in the back. We had some foresight to put it in the issue, and I think it's a great addition to it. Dr Berkowitz: Thank you. Dr Jones: So, the list of potential topics when we think about the neurologic manifestations of systemic disease, we tend to break it down by organ systems, right? But the amount of things that could end up in the issue is almost infinite. Is there anything that, when you were putting this issue together---either in terms of the topics or editing the articles---is there anything that you wanted to include, but we just didn't have room? Dr Berkowitz: I certainly won't say we covered everything, but I will say we were able to recruit a fantastic team of authors. And as you and I also talked about at the beginning, although you could say, we're doing the movement disorders issue, let's find all the top movement disorders folks who are expert specialists in this field, there's not really a neurohematologist or a neurogastroenterologist out here. So, you and I put our heads together to think of phenomenal general neurologists in most cases, some subspecialists who know a lot about this but were also excited to read a lot more about it and assemble the existing knowledge by the practicing neurologist for the practicing neurologist. And I think with that approach and letting folks have kind of, you know, I asked some specific questions. These are topics I hope you'll cover. These are vexing questions in this area. I hope you'll find some... /episode/index/show/continuumjournal/id/39850600

Managing Prognostic Uncertainty in Neurologic Disease With Dr. Robert G. Holloway 01/28/2026

Managing Prognostic Uncertainty in Neurologic Disease With Dr. Robert G. Holloway Clinicians and patients are in a state of prognostic uncertainty when they are unsure about the future course of an illness. By embracing uncertainty while cultivating prognostic awareness, neurologists can serve the critical role of supporting patients and families through the living and dying process. In this episode, Casey Albin, MD, speaks with Robert G. Holloway, MD, MPH, FAAN, author of the article “Managing Prognostic Uncertainty in Neurologic Disease” in the Continuum® December 2025 Neuropalliative Care 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. Holloway is the Edward and Alma Vollertsen Rykenboer Chair and a professor of neurology in the department of neurology at the University of Rochester School of Medicine and Dentistry in Rochester, New York. Additional Resources Read the article: Subscribe to Continuum®: Earn CME (available only to AAN members): Continuum® Aloud (verbatim audio-book style recordings of articles available only to Continuum® subscribers): More about the American Academy of Neurology: Social Media Host: 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 Bob Holloway about his article on managing prognostic uncertainty in neurologic disease, which appears in the December 2025 Continuum issue on neuropalliative care. Welcome to the podcast, and please introduce yourself to our audience. Dr Holloway: Hi, Casey, and thank you. Again, my name is Bob Holloway. I'm a clinician and neurologist up in Rochester, New York, and I've been doing both neurology and palliative care for many years. Dr Albin: Well, that's fantastic. And I really wanted to emphasize how much I really enjoyed reading this article. I know that we're going to get into some of the pearls that you offer, but I really want to tell the listeners, like, this is a great one to read because not only does it have sort of a philosophical take, but you also really provide some pragmatic tips of how we can help our patients manage this prognostic uncertainty. But maybe just tell us a little bit, what is prognostic uncertainty? Dr Holloway: Yes, thank you. Well, I think everyone has a sense of what prognostic uncertainty is. And it's just the uncertain futures that we as clinicians and our patients face. And I would just say that a way to summarize it is just, how do we manage the “not yet” of neurologic illness? Dr Albin: I love that. In neurologic illness, there is so much “not yet” and there are so many unknowns. And what I thought was really helpful about your article is you kind of give us three buckets in which we can think about the different types of uncertainty our patients are facing. What are those? Dr Holloway: This is, I think, an area that really is of interest to me, thinking about how to organize the prognostic “not yet” or that landscape. And one way I've tried to simplify it is to think about it as data-centered. And that's the world that we mostly live in as neurologists. That's the probability distributions. We also have kind of system-level uncertainties, and that's the uncertainties that our health system affords for our patients. And then we have, also, the patient-centered uncertainties and the uncertainties that those two prior categories cause for our patients. And that's a big uncertainty that we often don't address. Dr Albin: In reading the article, I was really struck by, we spend a lot of time thinking about data uncertainty. Can we get population-based research? Can we sort of look at prognostication scoring? I live in the ICU, and so we think a lot about these, like, scoring metrics and putting patients into buckets and helping us derive their care based on where their severity index is. And I'm sure that is true in many of the divisions of neurology. But what I did not really appreciate---and I thought you did a really fantastic job of kind of drawing our attention to---is there's a lot of system-centered uncertainty. Can you give us a little bit of examples, like, what is system-based uncertainty? Dr Holloway: I think system-level uncertainties just encompass the practical information gaps that may arise during our healthcare encounter. And a lot of, I think, the uncertainty that our patients face and families, they actually describe it as they feel captive by the uncertainty. And it's just the unknowns, not just what affords from the actual information about the disease and its prognosis in the future, but actually the level of the system, like, who's going to take care of them? How do you manage arranging for nurses to come into the home or all those practical-level uncertainties that the system provides that sometimes we don't do a good job of road-mapping for patients. Dr Albin: Absolutely. Because I feel like we have a little bit of a gap in that often as physicians. Like, the family asks, what will hospice at home look like? Well, you know, that's a question for case management. I think they'll come in and they'll tell you. But it strikes me that that's a real gap of my being able to walk patients through. Will they get home health care? Will they have transportation set up? Will there be a nurse who comes in to check? How often are they available? What's the cost going to be? All of these practical aspects of dealing with an illness that are beyond sort of our scope of knowledge, but probably have a huge practical impact to the patient. Dr Holloway: Without question, every encounter patients wonder about, that kind of future wish landscape that we- all our future-oriented desires and hopes. And so much of that is the practical aspects of our health system, which is often fragmented, kind of unknown, uncertain. And that's a huge source of uncertainty for our patients and families. And then that leads to many other uncertainties that we need to address. Dr Albin: Absolutely. I think another one that we, again, maybe don't spend quite as much time thinking about is this patient-level uncertainty. What's going on there? Dr Holloway: Yeah. So, I think patient-level uncertainty is that uncertainty that they experience when confronted with the two other types of uncertainty: the actual data-centered uncertainty and the system-level uncertainty. And that's that, kind of, very huge kind of uncertainty about what it means for them and their family and their future futures. And that's a source of huge stress and anxiety, and often frankly bordering on dread and fear for our patients and families. That actually gets into very levels of uncertainty that I would call maybe over even in the existential realm. Patient-level uncertainty in the actual existential questions or the fear and the dread or the kind of just unnerving aspect of it is actually even more important to patients than the scientific or data-centered uncertainty that we focus most of our attention on. Dr Albin: Yeah, I think this is, to me, was getting towards that, like, what does the patient care about and how are they coping with what is in many times a really dramatic shift in their life expectancy or morbidity expectations and this sort of radical renegotiation about what it means to have a neurologic illness? And how does that shift their thinking about who they are and their priorities in the world? Is that right? Dr Holloway: One thousand percent, and in fact, I will say---and I think is one of the main take home messages is that, you know, managing prognostic certainty is not an end in itself. It really is to help patients and families adaptively cope to their new and often harsh new reality, that we could help them adapt to their new normal. I think that is one of our main tasks as neurologists in our care teams is to help patients find and ultimately maybe achieve existential or spiritual or well-being even in their new health states. You know, that you certainly often see in the intensive care unit, but we often always see in the outpatient realm as well, and all our other diseases. Dr Albin: I think that's really hard to do. I think those conversations are incredibly difficult and trying to navigate where patients want to be, what would bring meaning, what would bring value. I think many of us struggle to have these pretty real and intense conversations with families about what really is important. And one of the things I really liked about this article is you kind of walk us through some steps that we as clinicians can take to get a little bit more comfortable. Maybe just walk us through, what are some of the things that you have found most helpful in trying to get families and patients to open up about what brings them meaning? How are they navigating this new, really uncertain time in their life? Dr Holloway: Yeah, so I do kind of have a ten-point recommendations of how to help cultivate a more integrated awareness of an uncertain future. I mean, I think the most important thing is actually just recognizing that embracing uncertainty as an amazingly remarkable cognitive tool. I mean, let's face it, uncertainty, when it happens with neurologic illness and disease, is often fearful. It's scary. It kind of changes our world. But on the flip side of it, it's a remarkable cognitive tool that actually can help us find new ways and new paths and new creativity. And I think we can use that kind of opposites to help our patients find new meaning in very difficult situations. So, thinking about uncertainty, kind of being courageous, leaning into it and recognizing that it does create anxieties and fear, but it also can kind of help create new solutions and new ideas to help people navigate. Dr Albin: I was hoping that maybe you could give us an example of, like, how would you do that? If a patient comes in and they're dealing with, you know, a new diagnosis and they're navigating this new uncertainty, what are some of the things that you ask to help them reframe that, to kind of take some of the good about that uncertainty? How do you navigate that? Dr Holloway: One of the other recommendations is actually just resetting the timeline and expectations for these conversations. That it shouldn't be expected that patients should accept their harsh new reality immediately, that it takes time in a trusted environment. And that there's this, like, oscillating nature of hopes and fears and dread, and you’ve just got to work with them over time. And with time, and once you understand who the patient and family are and understand where they find meaning and where they find, actually, joy in their life, or what actually brings them meaning, you can start recasting their futures into credible narratives in their kind of future landscape in ways that I think can help them enter into their new realities within the, you know, framework of disease management that you can offer them within your healthcare team or your healthcare system or wherever you are in the world and the available resources that you have to offer patients and families. Dr Albin: So, this sounds like a lot to me like active listening and really trying to get to know what is important to the family, what is important to the patient. And I guess probably just creating that space even in that busy clinical environment. Do I have that right? Dr Holloway: You can absolutely do that, right. You know, and honestly, active listening, we are challenged in our busy healthcare system to do this, but I think with the right listening skills and the appropriate ways of paying attention, you can definitely illuminate these possible, kind of future-oriented worlds for patients and help them navigate those new terrains with them. Frankly, I think that's a real new space for us in neurology. We don't think about and train how to create credible narratives for patients and families. We do it on the fly, but I think there's so much more work to do. How do you actually keep, you know, that best-case, worst-case, most likely credible narratives for patients that can help them adapt to their new realities and support them on their new journeys? Dr Albin: I love that best-case, worst-case, most likely case. I find that framework really helpful. But you talk in your article, it's not just about using that best case or worst case or most likely, but it's actually building some forecasting into that and having some real data to kind of support what you're saying. And there's a lot of growth towards actually becoming good as a medical forecaster. Can you describe a little bit, what did you mean by that? Dr Holloway: You're absolutely right. I think, actually, one of the skillsets of becoming and managing prognostic uncertainty is actually becoming a skilled medical forecaster. And it's a really tall order. So, we’ve got to be both good medical forecasters as well as helping patients adaptively cope to their new reality. But the good medical forecasting is actually now going more quantitative in thinking about the data that's available to help think about the important outcomes for patients and families and then predicting what their probabilities are so you can shape those futures around. So, yes, we do have to have an open mindset. We do have to actually look at the data that's available and actually think about, what are those long-term probabilities and outcomes? And we can be honest about those and even communicate them with families. But it's a really good skill set to have. Dr Albin: Yeah. This to me was a little bit about, how do you bring in the data knowledge that we try to get over time as we develop our expertise? You're developing not just a reliance on population-based data, but in my experience, I have seen this. And that sort of ability to kind of look at the patient in front of you, think about the big picture, but also a little bit about their unique medical comorbidities or prior life experiences. So, some of that database knowledge, and then bringing in and getting to know what is important to the patient. And so, sort of marrying that data-centric/patient-centric mindset. Dr Holloway: I love it. I guess the other way of saying that, too, is we need to think with precision, but communicate in narratives. And it's okay to gently put more precise estimates on our probability predictions with patients and families, what we think is the most likely case, best and worst case. Because patients and families want us to be more precise. We often shy away from it, but- so, it's okay to think in precisions, but we’ve got to put those in narratives in the most likely, best-, and worst-case scenarios. And don't be afraid if you think in terms of ninety percents, ten percents, fifty percents; most patients and families don't mind that. And what they're telling us is they actually want to hear that, if you are comfortable talking in those terms. Dr Albin: Yeah, absolutely. And giving a sense of the humility to say, like, this is my best guess based on medical data and my experience, I would say, but again, none of us have a crystal ball. And I do think families, as long as you're sort of couching your expectations into the sort of imperfect, but I'm doing my best, really appreciate that. Dr Holloway: They totally do all the time. Just say, I simply don't know for certain, but these are my best estimates. That's a good way of just phrasing that. Dr Albin: Yeah. So powerful. I don't know for certain. And then I wanted to just kind of close out, because there's this one term that you use that I thought was so interesting. And I wanted you to kind of tell our listeners a little bit about what you mean here, which is that, when you're actively open-minded, you're using this, quote, “dragonfly eyes.” What do you mean by that? Dr Holloway: So, the dragonfly eyes, as you know, they can look at three sixty around them and they just, they move in all directions. Being actively open minded, I guess the biggest example I would say is, I don't like the term prognostic discordance, which means that there's a difference of subjective estimates of prognosis between patients and families. Being openly minded is actually embracing the potential information that the family has about prognosis and incorporating that into your estimates. So, I wouldn't say it’s discordances, per se; I think being really actively open-minded is taking that all in and utilizing that as, you know what, they know more than you do about the patient and their loved ones, and they may have insights that can inform your best estimates of prognosis. So, the true dragonfly prognosticator actually is one who embraces and doesn't consider it discord, but considers it kind of new, useful information that I just need to weigh in so I can help the family in my best professional way in terms of developing a prognosis, whatever the condition may be. Dr Albin: I can imagine this is just so challenging and something that takes a long time to sort of perfect all of this. I think you say right below that, you need a growth mindset to do this because it is hard, and it's going to take an active participation and an active desire to get better at these conversations with our families. Dr Holloway: One thousand percent. You are so right that it takes time, effort, and not feeling like you're being challenged, but that actually you are including them in your entire body of knowledge, that you're just- it's part of all you're collecting. And even, I was on service last week, and I talked to residents and students about that very issue. It’s like take their prognosis. And someone who came in, we thought CJB, very sad, tragic case, but we were thinking about what the future may look like and how do we actually work with the family who had very what we thought was unrealistic expectations. I said, well, no, this is not discordance. This is just useful information that we can take understand where they're coming from and incorporate that into the ways we want to build relationships, build trust, and over time we'll get to a point where we hopefully can work with them and have them have that fully integrated awareness of their future. Dr Albin: Yeah, that's beautiful. It really is this ongoing negotiation that really requires so much listening, understanding, and then obviously information and expertise about the data that we're presenting and the likelihood outcome, recognizing that there's a lot of uncertainty in all of this. Which, you know, again, this is kind of a 360 talk. At every level there is uncertainty, and that's what makes it so hard. Dr Holloway: Yeah, you're absolutely right. And actually, even in the article I kind of used the term radical uncertainty as that, no matter how resolvable all this uncertainty is, there will always still remain that radical element of our existence which we have to actually incorporate and be prepared for. And actually, not only of ourselves, but actually for patients and families and helping manage that. Using narratives and credible narratives and kind of ranges of possibilities is the best way to do that in a personalized way. Dr Albin: Well, this has been a fantastic conversation, and I know that we are running a bit short on time. So, as we wrap up and you think about this topic, are there any key take-home messages that you hope our listeners will walk away with? Dr Holloway: I think one main emphasis is that despite all the successes we feel we have in neurology, is that we all have to recognize that prognostic uncertainty is just going to increase in the future. But this is going to be for several... /episode/index/show/continuumjournal/id/39184770

Neuropalliative Medicine in Pediatric Neurology With Dr. Lauren Treat 01/21/2026

Neuropalliative Medicine in Pediatric Neurology With Dr. Lauren Treat Pediatric neuropalliative medicine is an emerging area of subspecialty practice that emphasizes the human experience elements of serious neurologic illness. Child neurologists care daily for patients who can benefit from the communication strategies and management practices central to pediatric neuropalliative medicine, whether at the primary or subspecialty level. In this episode, Gordon Smith, MD, FAAN, speaks with Lauren Treat, MD, author of the article “Neuropalliative Medicine in Pediatric Neurology” in the Continuum® December 2025 Neuropalliative Care 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. Treat is an associate professor in the divisions of child neurology and palliative medicine at the University of Colorado School of Medicine in Aurora, Colorado. Additional Resources Read the article: Subscribe to Continuum®: Earn CME (available only to AAN members): Continuum® Aloud (verbatim audio-book style recordings of articles available only to Continuum® subscribers): More about the American Academy of Neurology: Social Media Host: 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 Gordon Smith. Today I've got the great pleasure of interviewing my good friend Dr Lauren Treat about her article on neuropalliative medicine in pediatric neurology practice. This article appears in the December 2025 Continuum issue on neuropalliative care. Lauren, welcome to the Continuum podcast, and maybe you can introduce yourself to our listeners. Dr Treat: Such a delight to be here, Gordon. Thank you. I am a pediatric neurologist and palliative medicine doctor at the University of Colorado, Children's Hospital Colorado, and I am practicing in both areas. I do general child neurology, and I also run a pediatric neuropalliative medicine clinic. So, I'm happy to be here to talk about it. Dr Smith: And, truth in advertising, I tried very hard to get Dr Treat to move to VC to work with me. And I haven't given up yet. I'm looking forward to the conversation. And Lauren, I wonder- one, I'm really excited about this issue, by the way. This is the second podcast I've done. And I'd like to ask the same question I asked of David Oliver, who's amazing. What a great article and conversation we had. And that question is, can you define palliative care? I think a lot of people think of it as, like, end-of-life care or things like that. And is the definition a little different in the pediatric space than it is in the adult space? Dr Treat: Such a great place to start, Gordon. I absolutely think that there are nuances that are very important in pediatrics. And we especially acknowledge in pediatrics that there is a very longitudinal component of this. And even moreso, I think, then in adult neuropalliative medicine, in pediatrics, we are seeing people=even prenatally or early in their first hours and days of life, and walking with them on a journey that might last days or weeks, but might last years or decades. And so, there is this sense that we are going to come alongside them and be part of the ups and the downs. So yes, neuropalliative medicine is a kind of medicine that is a very natural partner to where neurology is in its current field. We're doing a lot of exciting things with modifying diseases, diagnosing things early, and we have a very high reliance on the things that we can measure in medicine. And not all things can be measured that are worthwhile about one's quality of life. A family very poignantly told me very recently, making sure someone stays alive is different from making sure they have a life. And that's what neuropalliative medicine is about. Dr Smith: Well, great summary, and I definitely want to follow up on several aspects of that, but there's one point I was really curious about as I've been thinking about this, you know, these are really exciting times and neurology in general and in child neurology in particular. And we've got all of these exciting new therapies. And as you know, I'm a neuromuscular person, so it's hard not to think back on SMA and not be super excited. And so, I wonder about the impact of these positive developments on the practice of neuropalliative care in kids. You know, I'm just thinking, you know, you mentioned it's a journey with ups and downs. And I wonder, the complexity of that must be really interesting. And I bet your job looks different now than it did seven or eight years ago. Dr Treat: That's absolutely true. I will self-reference here one of the figures in the paper. Figure 2 in my section is about those trajectories, about how these journeys can have lots of ups and downs and whether this person had a normal health status to begin with or whether they started out life with a lot of challenges. Those ups and downs inherently involve a lot of uncertainty. And that's where palliative medicine shines. Not because we have the answer---everyone would love for us to have the answer---but because we consider ourselves uncertainty specialists in the way that we have to figure out what do we know, what can we ground ourselves in, and how can we continue to move forward even if we don't have all the answers? That is a particular aspect of neurology that is incredibly challenging for families and clinicians, and it can't stand as a barrier to moving forward and trying to figure out what's best for this child, what's best for this family. What do we know to be true about them as people, and how can we integrate that with all of the quantitative measures that we know and love in neurology? Dr Smith: So, I love the comment about prognostication, and this really ties into positive uncertainty or negative undercertainty in terms of therapeutic development. I wonder if you can talk a little bit about your approach to prognostication, particularly in a highly fluid situation. And are there pearls and pitfalls that our listeners should consider when they're discussing prognosis for children, particularly maybe young children who have severe neurological problems? Dr Treat: It's such a pivotal issue, a central issue, to child neurology practice. Again, because we are often meeting people very, very early on in their journey---earlier than we ever have before, sometimes, because of this opportunity to have a diagnosis, you know, prenatally or genetically or whatever else it is---sometimes we are seeing the very early signs of something as compared to previously where we wouldn't have a diagnosis until something was in its more kind of full-blown state. This idea of having a spectrum and giving people the range of possible outcomes is absolutely still what we need to do. However, we need to add on another skill on top of that in helping people anchor into what feels like the most likely situation and what the milestones are going to be in the near future, about how we're going to walk this journey and what we'll be on the lookout for that will help us branch into those different areas of the map down the road. Dr Smith: So, I wonder if we can go back to the framework you mentioned, two answers ago, I think? You and the article, you know, provide four different types of situations kind of based on temporal progression. I wonder if maybe the best way of approaching is to give an example and how that impacts your thoughts of how you manage a particular situation. Dr Treat: Absolutely. So, this figure in particular is helpful in multiple ways. One is to just give a visual of what these disease trajectories are doing, because we're doing that when and we take a history from a patient. But actually, to put it into an external visual for yourself, for your team, but also perhaps for the family can be really powerful. It helps you contextualize the episode of care in which you're meeting the family right now. And it also helps, sometimes, provide some sense of alignment or point out some discrepancies about how you're viewing that child's health and quality of life as compared to how the family might be viewing it. And so, if you say, you know, it sounds like during those five years before we met, you were up here, and now we find ourselves down here, and we're kind of in the middle of the range of where I've seen this person's health status be. Do I have that right? Families feel really seen when you do that and when you can get it accurately. And it also invites a dialogue between the two parties to be able to say, well, maybe I would adjust this. I think we had good health or good quality of life in this season. But you're right, it's getting harder. It's kind of that “show, don't tell” approach of bringing together all the facts to put together the relative position of where we are now in the context of everything they've been through. Dr Smith: You know, I wonder if you could talk a little bit more about the differences between palliative care and adult patients and in children? Dr Treat: Absolutely. One of the key features in pediatrics is this kind of overriding sense of an out-of-order event in the family's life. Children are not supposed to have illness. Children are not supposed to have disability. Children are not supposed to die before their parents. And that layer of tragedy is incredibly heavy and pervasive. It's not every encounter that you have in child neurology, but it does kind of permeate some of the conversations that neurologists have with their patients, especially patients who have serious neurological disease. So that could be things like epileptic encephalopathies, birth injuries, other traumatic brain injuries down the line. In the paper, I'd go through many different categories of the types of conditions that are eligible for pediatric neuropalliative medicine, that kind of support. When we think about that layer of tragedy in the relation to where we're meeting these families, they deserve extra support, not just to think about the medicines and the treatments, but also, what can we hope for? How can we give this child the best possible life in whatever circumstance that they're in? How can we show up in whatever medical decision-making circumstances present themselves to us and feel like we've done right by this child? It's a complex task, and pediatric neural palliative medicine is evolving to be able to be in those spaces with families in a very meaningful way. Dr Smith: So, of course, one of the differences is the, you know, very important role of parents in the situation, right? Obviously, parents are involved in adult palliative care issues and family is very important. But I wonder if you can talk about specific considerations given the parent-child relationship? Dr Treat: So, pediatric neuropalliative medicine really helps facilitate discussions not just about, again, those things that we have data on, but also about what is meaningful and foundational for those families. What's possible at home, what's possible in the community. In pediatrics, parents are making decisions on behalf of their child, often as a dyad, and I don't think this gets enough attention. We know from adult literature that making decisions on behalf of someone else is different from making decisions on behalf of oneself. We call this proxy decision-making. And proxies are more likely to be conservative on behalf of someone else than they are on behalf of themselves, and they're also more likely to overestimate the tolerability of a medical intervention. So, they might say, I wouldn't want this, or, I wouldn't accept this risk on behalf of myself, or, I don't think I'd want to have to persevere through something, but on behalf of this other person, I think they can do it or I will help them through it or something else like this, or, I can't accept the risk on behalf of them. So that's not good or bad. That's just different about making a decision on behalf of oneself as compared to making a decision on behalf of someone else. When there's two people trying to be proxies on behalf of a third person, on behalf of a child, that's a really, really complex task, and it deserves support. And so, pediatric neural palliative medicine can function, then, as this neutral space, as this kind of almost coaching opportunity alongside the other medical doctors to give parents an opportunity when their minds are calm---not in the heat of the moment---to talk about how they see their child, how they've shown up themselves, what they've seen go well, what they've struggled with. And how,, then we can feel prepared for future decision making times, future high-stress encounters, about what will be important to ground them in those moments, even though we can't predict fully what those circumstances might be. Dr Smith: It sounds, you know, from talking to you and having read the article, that these sorts of issues evolve over time, right? And you have commented on this already from your very first answer. And you do describe a framework for how parents think---their mental model, I guess---of, you know, a child with a serious illness. And this sounds like appreciation of that's really important in providing care. Maybe you can talk us through that topic? Dr Treat: I refer to this concept of prognostic awareness in all of the conversations that we have with families. So, what I mean by prognostic awareness is the degree of insight that an individual has about what's currently happening with their child and what may happen in the future regarding the disease and/or the complications. And when we meet people early on in their journey, often their prognostic awareness, that sense of insight about what's going on, can be limited because it requires lived experience to build. Oftentimes time is a factor in that, we gain more lived experience over time, but it's not just time that goes into building that. It's often having a child who has a complication. Sometimes it's experiencing a hospitalization. That transfer from a cognitive understanding of what's going on, from a lived experience about what's going on, really amplifies that prognostic awareness, and it changes season by season in terms of what that family is going through and what they're willing to tolerate. Dr Smith: You introduced a new term for me, which is hyper-capableism. Can you talk about that? I found that really interesting and, you know, it reminds me a lot of the epiphanies that we've had about coma and coma prognosis. So, what's hyper-capableism? Dr Treat: Yes. In neurology, we have to be very aware of our views on ableism, on understanding how we prognosticate in relation to what we value about our abilities. And hyper-capableism refers to someone who feels very competent both cognitively and from a motor standpoint and fosters that sense of value around those two aspects to a high degree. I'm referencing that in the article with regard to medicine, because medicine, the rigors of training, the rigors of practice, require that someone has mental and motor fortitude. That neurology practice and medical practice in general can breed this attitude around the value of skills in both of those areas. And we have to be careful in order to give our patients and families the best care, to not overly project our values and our sense of what's good and bad in the world regarding ableism. Impairments can look different in different social contexts. And when the social context doesn't support an impairment, that's where people struggle. That's where people have stigma. And I think there's a lot of work that we can do in society at large to help improve accommodations for impairment so that we have less ableism in society. Dr Smith: Another term that I found really interesting kind of going back to parents is the “good parent identity.” Maybe you can talk about that? Dr Treat: Good parent identity, good parent narrative, is something that is inherent to the journey when you're trying to take care of and make decisions on behalf of a child. And whether you're in a medical context or outside of a medical context, all parents have this either explicit or implicit sense of themselves about what it means to do right by their child. This comes up very poignantly in complex medical conditions because there are so many narratives about what parents ought to do on behalf of their child, and some of those roles can be in tension with one another. It's a whole lot of verbs that often fall under that identity. It's about being able to love and support and take good care of and make good decisions on behalf of someone. But it's also about protecting them from harm and treating their pain and being able to respond to them and know their cues and know these details about them. And you can't, sometimes, do multiple of those things at once. You can't give them as much safety and health as possible and also protect them from pain and suffering when they have a serious illness, when they need care in the hospital that might require a treatment that might be invasive or burdensome to them. And so, trying to be a good parent in the face of not being able to fulfill all those different verbs or ideas about what a good parent might do is a big task. And it can help to make it an explicit part of the conversation about what that family feels like their good parent roles might be in a particular situation. Dr Smith: I want to shift a little bit, Lauren, that's a really great answer. And just, you know, listening to you, your language and your tongue is incredibly positive, which is exciting. But, you know, you have talked about up and downs, and I wanted you to comment on a quote. I actually wrote it down, I'm going to read it to you, because you mentioned this early on in your article: “the heavy emotional and psychological impacts of bearing witness to suffering as a child neurologist.” I think all of us, no matter how excited we are about all the therapeutic development, see patients who are suffering. And it's hard when it's a child and you're seeing a family. I wonder if you could talk a little bit about that comment and how you balance that. You're clearly- you're energized in your career, but you do have to bear witness to suffering. Dr Treat: You're right. Child neurologists do incredible work, it's an incredible, exciting field, and there are a lot of challenges that we see people face. And we see it impacts their lives in really intense ways over the course of time. We bear witness to marriages that fall apart. We bear witness to families that lose jobs or have to transition big pieces of their identity in order to care for their children. And that impacts us. And we hold the collective weight of the things that we are trying to improve but sometimes feel less efficacious than we hoped that we could around some of these aspects of people's lives. And so, pediatric neuropalliative medicine is also about supporting colleagues and being able to talk to colleagues about how the care of the patients and the really real effort that we exert on their behalf and the caring that we have in our hearts for them, how that matters. Even if the outcome doesn't change, it's something that matters for our work and for our connections with these families. It's really important. Dr Smith: I wonder, maybe we can end by learning a little bit about your journey? And maybe this is your opportunity to- I know we have students and residents who listen to us, and junior faculty. I think neuropalliative care is obviously an important issue. There's a whole Continuum issue on it---no pun intended---but what was your journey,... /episode/index/show/continuumjournal/id/39184695

Neuropalliative Care in Movement Disorders With Dr. Benzi M. Kluger 01/14/2026

Neuropalliative Care in Movement Disorders With Dr. Benzi M. Kluger Patients with Parkinson disease and other movement disorders have significant palliative care needs that are poorly met under traditional models of care. Clinical trials demonstrate that specialist palliative care can improve many patient and family outcomes. In this episode, Aaron Berkowitz, MD, PhD, FAAN, speaks with Benzi M. Kluger, MD, MS, FAAN, author of the article “Neuropalliative Care in Movement Disorders” in the Continuum® December 2025 Neuropalliative Care 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. Kluger is the Julius, Helen, and Robert Fine Distinguished Professor of Neurology in the Departments of Neurology and Medicine (Palliative Care) at the University of Rochester in Rochester, New York. Additional Resources Read the article: Subscribe to Continuum®: Earn CME (available only to AAN members): Continuum® Aloud (verbatim audio-book style recordings of articles available only to Continuum® subscribers): More about the American Academy of Neurology: Social Media Host: Guest: 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 Benzi Kluger about his article on neuropalliative care in Parkinson disease and related movement disorders, which is found in the December 2025 Continuum issue on neuropalliative care. Welcome to the podcast, Dr Kluger, and could you please introduce yourself to our audience? Dr Kluger: I'm Benzi Kluger. I'm a professor of neurology and palliative medicine at the University of Rochester. I'm the chief of our neuropalliative care service, I'm the director of our Palliative Care Research Center, and I'm also the founding president of the International Neuropalliative Care Society. Dr Berkowitz: Wow, that is a large number of hats that you wear in a very important area of palliative care. So, your article is a fantastic article that covers a lot of concepts in palliative care that I myself was not familiar with and really applies them in a very nuanced way to patients with Parkinson's disease and related disorders. So, I'm looking forward to learning from you today to discuss some of the concepts you talk about in the article and how you apply them in your daily practice of palliative care in this particular patient population. So, one of the key points in your article is that we're often so focused on treating the motor symptoms of Parkinson's disease and other degenerative movement disorders that we are often at risk of underdiagnosing and undertreating the nonmotor symptoms, which in some cases, as you mentioned in the article, are more disabling to the patient than the motor symptoms that we tend to focus on. So, from a palliative care perspective, what are some of the nonmotor symptoms that you find tend to be underdiagnosed and undertreated in this patient population? Dr Kluger: The literature suggests---and we've replicated it, actually, Lisa Schulman published a paper twenty-five years ago and the data is almost exactly the same when it comes to things like depression, pain, fatigue, constipation, sleep---that you miss it about 50% of the time. And there's a number of reasons for that. One is that these are subjects that people don't always like to talk about. People don't like talking about depression. People don't like talking about poop and constipation. And I think there are things that neither the patient or the caregiver nor the physician are necessarily comfortable with. And they're also sometimes confusing of, which doctor should I talk to this about? Should I talk to my primary care doctor, should I talk to my neurologist? And so I think the key here is really having a checklist and being proactive about it. In the article, I suggest a template or previsit questionnaire that you can use, but I think it's just about being automatic about it. And it just takes the burden off of the patient and the family to bring them up and letting them know that this is a safe space and this is the right space to talk about these symptoms. Dr Berkowitz: That's very helpful to know. So, having some type of checklist or template just so we go all through them and, as you said, it sort of destigmatizes, just, this is the list of things, and I'm going to just ask about all of them. So we check in on those particular symptoms, whether they're present or not. Are there any particular symptoms that jump out to you as ones that tend to be missed---either because we don't ask about them or patients are less comfortable mentioning them---that in your practice, when you've elicited them, have allowed for particular intervention that's really improved the quality of life for patients in this group? Dr Kluger: Yeah, I'll mention a few that I think come up and are very pertinent. One is mood. And, to use depression---but we could also use anxiety as an example---again, these are topics that people don't always want to talk about. And I think it's important---we may get to this a little bit more later---is being careful to distinguish between depression and grief, sadness, normal worry, frustration. A lot of times the way I'll ask that when I'm talking to a patient is, you know, I hear you're using the word depressed. I want to make sure. does this feel to you like normal sadness given that you have an illness that sucks, or does this really feel like it's above and beyond that and you feel like you'd need a little extra help to get your emotions under control? The second one, which is kind of related, is other behavioral symptoms, including PD psychosis and hallucinations. And there, I think, the thing is that people are quite frankly afraid that they're losing their mind or going insane. So, I think that's another critical one. And then one that, you know, it's kind of a low-hanging fruit but people don't want to talk about, is constipation. And when we did our large randomized control trial of palliative care, our single biggest effect size was actually that we did a better job of treating constipation than usual care. And I think the only trick there is that we asked about it. Dr Berkowitz: I see. So, do you then as part of your routine practice and seeing these patients with Parkinson's disease in particular, you have a particular checklist you go through during the appointment or, as you mentioned, you- one could do it before the appointment. But you tend to go through this in the visit, and is there any palliative care wisdom you have for us, those who are not trained in palliative care, to making sure we really elicit these symptoms in an effective way and how much they're bothering the patient? Dr Kluger: Two things that I've seen work---and we've done a lot of implementation studies. One is that, if it works for your practice, having patients fill out a questionnaire or survey in advance. And I think one of the highest-yield things there too is for blank lines to allow patients to write in what their top three problems are. And I've found when we've used it, and I think other people have found, that it's a huge time saver. People hand them the form, they look to see what's at checked a yes or what's checked as high, and then that becomes the agenda for the visit. The other thing that I think works equally well is just having a template, and at this point its just kind of, like, hard-wired into my neurons that, you know, no matter what we talked about in the HPI, I'll always ask about sleep and mood and bowel and bladder and pain to make sure that I don't miss those things. Dr Berkowitz: You mentioned in your article that palliative care needs in patients with Parkinson's disease really differ over the course of the illness and may be different at the time the initial diagnosis is given versus as the disease progresses versus the latest, most advanced stages of the disease. Can you talk a little bit more about how your approach to these patients changes over time from a palliative care perspective? Dr Kluger: Yes. And I'll also add, I think some of this is going to be more relevant to our listeners than to me. I'm now almost entirely in a neuropalliative care clinic, but for early-stage illness, it's really primary palliative care. And just to reinforce, this is palliative care that's provided by neurologists and primary care doctors, not specialist palliative care. I think that mindset's particularly important around the time of diagnosis. One of the things that, for me, was most eye-opening when we were doing qualitative interviews and studies was how devastating the diagnosis of Parkinson's disease was for patients and their families. And that was not something that I really anticipated. I think, like a lot of people and a lot of movement disorder doctors, I kind of thought of Parkinson's disease as a relatively good-news diagnosis. And that was often the way I pitched it, and we talked about Sinemet and DBS and exercise and all these things, but I have a relativity bias. And that bias is, I know that Parkinson's is better than PSP or MSA or brain cancer. But for the individual getting that diagnosis, that's it's not good news because their relativity bias is, I didn't have Parkinson's before and now I do. And for the rest of my life I'm going to have Parkinson's. And for the rest of my life, there may be things that I can do today that I won't be able to do tomorrow or next week. And so that was… yeah. And I think it really changed my practice and was pretty eye-opening for me. In the article, I mentioned the SPIKES (S-P-I-K-E-S) protocol for talking about serious conversations or talking about bad news. But I think one of the keys there for the time of diagnosis is asking people about their perceptions of Parkinson's. And part of that's also asking them what they know and what they're worried about. And you may be surprised that when you ask somebody about Parkinson's, you know, sometimes they may say it was good news. It's been three years, I've been trying to find an answer, and I feel like I've been being blown off. And sometimes you might say, this is the thing I feared the most. My uncle died of Parkinson's in a nursing home. And I also find that more often than not, even in end-of-life, that a lot of times the serious illness conversations I have, the facts that I have to present people, are better than their fears. And that's true at the time of diagnosis. But I think if we don't go into it and we don't ask people what they're feeling and what their perceptions are, then we miss this opportunity to support them. So that's the early stage. And in midstage, I think the, you know, the real keys there are to catch nonmotor symptoms early, to catch things like pain and depression and constipation before they become really bad or even lead to a hospital stay. And also starting to plant the seed and maybe doing some advanced care planning so that we are- people feel more prepared for the end stages of Parkinson's. And I think there, too, people ask about the future; when we tell them everyone's different or you don't have to worry about that now, that doesn't help an individual very much. So, oftentimes in the middle stages of the illness, people do want to know, am I going to go to a nursing home? How much longer is this going to be? You don't need a crystal ball, but if you can give people the best case, the worst case, the most likely case, that can be very helpful for life planning. And then as we're getting to more advanced and endstage, the lens that I'm looking at people with really is, should we begin talking about hospice? And we know again, from data that as a system---not just neurologists, but as a system---we're missing this all the time. And that if you have Parkinson's disease, you're about 50% chance of dying in a hospital, which is not where people want to die. And so, when I see people with more advanced disease, I'm asking questions about weight loss, and are they sleeping more during the day, and is there an acceleration in their decline of function? So, not just asking about where they are, but what's the rate of decline so that I can give people months of hospice as opposed to either them dying in a hospital or just scrambling for hospice in the last few days of their life. Dr Berkowitz: Another important palliative care concept you discussed in this article that was new to me is the concept of total pain, where you talk about aspects of pain beyond the physical and emotional pain we often think of when we hear the word pain. Can you talk a little bit about this concept of total pain, and then in particular how you apply it specifically when caring for patients with Parkinson's disease and related disorders? Dr Kluger: Yeah, absolutely. In the article there's a figure, and this is a- one of the foundational concepts of palliative care is this idea of total pain. Which is that the pain of a serious illness, whether that be cancer or Parkinson's, is not simply physical. There's also emotional components. And that also goes beyond the psychiatric. So, that includes grief and worry and frustration, and it also includes loneliness. And I think with Parkinson's disease, actually, one of one of the quotes that really sticks with me from some of our qualitative interviews was a woman who talked about her Parkinson's as a “flamboyant illness” because her tremor and her dyskinesias were always coming out at inopportune times. And it wasn't something I thought about, but there's this cosmetic aspect of having a movement disorder. There's also a cosmetic aspect of drooling or of using a walker. And so, there is a social stigma associated with Parkinson's, and people also lose a lot of social capital. Part of that is that often times neighbors and friends and family don't feel comfortable being around that person anymore. They don't know what to say. And so, sometimes coaching or connecting them with a chaplain or a counselor can be helpful in maintaining those social networks. There's a social pain. There's a spiritual and existential pain. And when I ask people a question, I ask almost everybody, is, what's the toughest part of this for you? A lot of times things fall into that bucket. And it's my loss of independence. I'm no longer able to do the things that bring me joy. I feel guilty that I'm going to be a burden to my family. My relationships are changing. So those are things that are essentially spiritual and existential. And then the last bucket, there are logistical things. And this can be lost driving and how do I get around, the cost of doctor visits, spending time with doctors, co-pays for medications; in the case of Parkinson's disease, the logistics of taking medication every two to three hours. So those all contribute to the total pain or the multiple dimensions of suffering. And that is something that I think about---in fact, in our assessment and plan, one of the things I like to mark out is sources of suffering. And that could be from any of those parts of the pie chart. Dr Berkowitz: And how do you approach this at the bedside? So, there are different concepts here. Obviously, physical pain, everyone is familiar with probably the concept of emotional pain. But as you get out in these concentric circles into sort of spiritual, existential pain, how do you sort of start these discussions with patients to elicit some of these aspects of their suffering? Dr Kluger: You know, the most common question I ask is, what's the toughest part of this for you? And very often that's going to lead into these existential and spiritual issues. I'll also ask people at the start of visits is, just tell me overall, big picture, how's your quality of life? Sometimes the answer is pretty good. Sometimes it sucks. Sometimes it’s I have none. I know we're going to talk a little bit about joy later. But I'll also often times follow that up with, what do you enjoy or look forward to? And sometimes I get a response to that, and sometimes I get there's nothing in my life right now. But foundationally, I feel like those are all, you know, definitely spiritual and existential issues. And I'll ask people, too, where do you find meaning? What are your sources of support? I know for different physicians, people have different comfort with this, but I do find it helpful also to ask people, are you spiritual or religious? Because that can sometimes open up a window to other means of coping. An example of that---I mean, not everybody is going to have access to a chaplain. Some people will. But oftentimes one of the things that I do is encourage people to reconnect with their spiritual community. And so, I've had some very heartwarming winds where somebody would say, you know what, I haven't been to church for a while. And people at churches or synagogues or mosques are often looking for opportunities to help. And so that I think is another, I think, really important message. But I think one of the- my favorite parts of my job is kind of opening up these bridges and opening up these connections. And helping people to recognize, I would kind of put it under a larger practice of grace, is that asking for help can be a gift to another person. And if you're strong enough to ask for help, you're giving, you know, sometimes a really tremendous gift to another individual. If somebody has a strong community that they're connected with, doesn't have to be religious. it could be that they were a high school sports coach, it could be that they were involved in a book club, it could be that they were DJ or ran a restaurant or who knows what. Those all can provide opportunities for bringing people together and bringing together community. And again, thinking about the total pain of having a neurologic illness like Parkinson's, that loss of community, that loss of connection, is one of the things that's most painful. Dr Berkowitz: So, when people think about palliative care, they tend to think about pain and suffering and a lot of the topics we've been talking about. But you also talk about joy in your article, and you alluded to it a moment ago, working with your patients to find what brings them joy, opportunities for joy. As I was reading this, I was trying to imagine sitting across from a patient who has maybe just received the diagnosis of Parkinson's or is in a stage of the disease where, as you mentioned, they might be quite depressed, whether that's capital-D depression or sadness related to their loss of independence and other aspect. Sitting across from a patient who is suffering so much and has come maybe to a palliative care doctor such as yourself to alleviate suffering and have pain and other symptoms addressed, how do you begin a conversation about joy in that context and have the patient feel comfortable to open up? And how do you then use that conversation to help them improve their quality of life? Dr Kluger: Yeah, that's a great question. And it's one that actually comes up every time I talk about joy because it can be daunting. And there certainly are situations where I don't bring it up. You know, if we are deep into a session about grief or we're talking about kind of an unexpected bad turn of events, there's times where it would be insensitive to try to push, you know, an agenda of joy or something like that. And yet I would say that particularly residents and students who work with me, you know, may be surprised at how often I do bring it up. And I would say it's probably 95% of the time or more where I am able to talk about joy. And as an example, you know, we might be talking about... /episode/index/show/continuumjournal/id/39184660

Neuropalliative Care in Dementia With Dr. Neal Weisbrod 01/07/2026

Neuropalliative Care in Dementia With Dr. Neal Weisbrod Dementia is often a highly burdensome disease process for patients, their caregivers and families, and the community at large. Palliating symptoms and providing guidance surrounding advance care planning and prognostication are integral components of the management plan. In this episode, Katie Grouse, MD, FAAN, speaks with Neal Weisbrod, MD, an author of the article “Neuropalliative Care in Dementia” in the Continuum® December 2025 Neuropalliative Care 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. Weisbrod is a neurologist at Hartford Healthcare with the Ayer Neuroscience Institute in Mystic, Conneticut. Additional Resources Read the article: Subscribe to Continuum®: Earn CME (available only to AAN members): Continuum® Aloud (verbatim audio-book style recordings of articles available only to Continuum® subscribers): More about the American Academy of Neurology: Social Media 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 Neal Weisbrod about his article on neuropalliative care in dementia, which appears in the December 2025 Continuum issue on neuropalliative care. Welcome to the podcast, and please introduce yourself to our audience. Dr Weisbrod: Thank you. I'm really excited to be here. I'm Neal Weisbrod. I'm a neurologist and palliative care physician currently working at Hartford Healthcare in Mystic, Connecticut. Dr Grouse: To start, I'd like to ask why you think it's important that neurologists read your article? Dr Weisbrod: The primary reason I think it's really important to read the article is because these are just really common problems that neurologists run into in clinical practice. So, Alzheimer disease and many other dementias are extremely common, and managing the burdensome symptoms and the complex discussions that we have to have with the patients and their families as they go through the course of dementia is something that is very common in clinical practice. And so my hope is that by reading this article, clinicians will pick up a few tools, a few new ideas for how to make these conversations easier and for how to help these patients get through the disease with a little bit less suffering. Dr Grouse: I learned a lot from reading your article, and I really encourage our listeners to check it out. But I was curious what you feel that you discussing your article would come as the biggest surprise to our listeners? Dr Weisbrod: So, I think that the most surprising thing a lot of people will see reading this article is the section on prognosis. A lot of times it seems families are counseled, when they're talking about the prognosis of Alzheimer disease, that it could be ten years or longer. But really, the data show that for many patients, the median prognosis is closer to three to eight years. And that is a little bit longer for Alzheimer disease than many other types of dementia, but also gets significantly shorter as patients get older. So, we're looking at a closer to three-year median prognosis for patients who are over eighty-five, whereas patients in their sixties are probably closer to the eight or nine-year median prognosis. And so I think that piece will hopefully help people give a little bit more accurate counseling about prognosis. Dr Grouse: I'm glad you brought that up because I was wondering, why is it so important that we are careful to make sure that we're giving prognostic information for our patients and maybe even updating it as their clinical status changes? Dr Weisbrod: I think first of all, it's a really common thing that patients and families are thinking about and worried about. They don't necessarily always seem to ask as much as they want to know. I think there's a lot of fear around that conversation, even though it's really important. And then there's also often tension between the family and caregivers tend to want to know more than patients do. I think that it really helps people plan for the future as well as possible to know what their future might be. And we have a lot of limitations in predicting the future, but using the best information we can, laying out what we think the likely range is, allows people to make a lot more clear plans for their future. Dr Grouse: I'd imagine it's also pretty helpful for hospice referrals, too, having that data. Dr Weisbrod: Yeah, definitely. And there's a lot of angst about when to refer patients who have dementia to hospice. The most important thing I think about when I'm making a hospice referral is that I don't have to be right. And I think it takes a lot of that concern off to just say, all I'm doing is making a connection, getting someone who's potentially interested in the hospice, who has a really advanced serious illness connected to a hospice agency. And then they can go through the full evaluation with the hospice and the hospice medical director and determine whether they're eligible. So, I think there are really helpful thresholds to think about that would be a good trigger. Like a patient who we think has advanced dementia, who has a hospitalization for pneumonia or a fracture of the hip or some other really serious acute medical condition, I think is a really good trigger to start to think about hospice. But most importantly, it's just the connection, and I tell the patients that upfront. I tell them that you're going to have a conversation and we'll decide whether you're a good fit, and if not, the hospice will usually just check in with you over time and decide when is the right time in the future. Dr Grouse: That's really helpful. And I think just a really great reminder to our listeners about thinking about hospice sooner or at certain critical points in their patient care rather than waiting, maybe, before it's gone on too long and may be of less use later on. I was wondering, in your own clinical practice, what do you think is the most challenging aspect of providing care to patients with dementia? Dr Weisbrod: I think this one's easy. I would say managing the time has to be the most difficult part. I think that taking care of patients who have dementia is time-consuming. There's a lot of different priorities that we have to manage the time around. How much time are we going to spend doing cognitive testing? How much time are we going to spend doing counseling? How much time are we going to spend making up a treatment plan and discussing medications? How much time are we going to spend on advanced care planning? And the way I try to combat that is really just trying to think about what I'm going to prioritize in a certain visit and not try to accomplish everything. I'll tell patients and their families, the next time you come in, we're going to have a conversation focusing on advanced care planning. Or, the next time you come in, we're going to sit down and try to talk through all the questions you have about what the future might hold. That way I in that visit, I don't feel like, oh, I have to do updated cognitive testing and I have to review all the next steps in medication, and that allows me to take it in more bite-sized chunks. Dr Grouse: You made some of the great points, and specifically you mentioned advanced care planning. Your article makes a really strong case for the importance of advanced care planning, yet you definitely acknowledge the many barriers to initiating discussions that clinicians face. In your patients with dementia, can you walk us through how you integrate discussions about advanced care planning with your patients and their families? Dr Weisbrod: Yeah, I think this is still something that is evolving in my practice, and I don't think there's any perfect way of doing it. I think there's a lot of right ways of doing it, and as long as we're thinking about it a lot and bringing it up periodically, that's probably the best. What I try to do, though, is after I discuss what I think is the most likely diagnosis with patients and their families, I try to have a fairly close follow-up visit after that. Allow them to digest that information, to often do a little bit of their own research, to talk about it as a family. And then when they come in for that next appointment, I try to at least lay some groundwork about advanced care planning, asking them what they've completed already, and then based on what they've already done to that point, talking to them about what I think the next step would be. If they have done nothing, usually it's just, hey, I really think you should start to think about who would be making decisions for you if you lose the ability to make your own decisions and counsel them about power of attorney paperwork and establishing a healthcare surrogate. When it's patients who have already done some of that initial prep, I think that it's really important to keep in mind it's a longitudinal discussion and you can take it in small pieces over time. Often that helps because you can really establish that rapport and that trust. And then I like to just keep checking in whenever there's major changes in the patient's health or condition, like admission to the hospital or transfer to an assisted living facility or memory care clinic. Those are good times to remember, hey, I really need to revisit this conversation. Dr Grouse: It's probably good to also mention another really important point from your article, which was that impairment of decision-making in patients with dementia can actually start significantly even in the phase of mild cognitive impairment. Yet these patients will need to make many medical decisions with their neurologist as they go through this journey. How can we make sure our patients have capacity and make decisions appropriately regarding their care? Dr Weisbrod: Yeah, I think that's a definite challenge of taking care of patients with cognitive disorders of any type, including those with stroke and multiple sclerosis, that have some cognitive impairment. In my opinion, the most important way to help manage that is to make sure when we are making important decisions about the future that we're having a deep exploration of the values and the reasoning behind that. And definitely teach back is the most helpful way that I use to explore those values and the logic behind patients’ decisions. So, I think we have to have a really low threshold to move on to a formal evaluation of capacity; if there's any inconsistency between what the patient's saying now and what their families say they've said in the past, or if they're having struggled to come up with a really clear logic behind their decision, then I think we have to have a low threshold to move on to a formal evaluation of capacity. So, I think having the family involved, having other people who know the patient really well, usually helps identify some of those periods where it seems like the patient's not making the decision that really reflects their true wishes. Dr Grouse: Now I wanted to switch gears a little bit and get into the management of neuropsychiatric symptoms, which you spend a lot of time on and I think a lot of neurologists find very challenging. What are some nonpharmacologic approaches that can help patients with significant neuropsychiatric symptoms? Dr Weisbrod: I really like the DICE paradigm for coming up with nonpharmacologic approaches. The DICE paradigm is an acronym. The D is Describe, I is Investigate, C is Create, and E is Evaluate. The idea is that we're exploring what's happening behind the symptoms, we're creating a plan to intervene, and then we're evaluating the outcome of that plan and creating a sort of feedback loop there. But ultimately, I think, when we're creating a solution, thinking about how we can change the environment is the most important thing. We have very limited ability to change the way that someone who has severe cognitive dysfunction reacts to their environment, but we can often change the environment to not produce that reaction in the first place. One example is with wandering behaviors. Trying to change the environment where you put locks that don't have deadbolts that you can use on the inside of the house, you have to have a key on the inside of the house, and then the family can put that key somewhere safe where the patient is not likely to find it and be able to unlock the door and wander out unsafely. I also think it's really important to acknowledge that as doctors, we are maybe not the best people to always have the answer when it comes to changing a patient's environment. And so, I think we really need to rely on the wisdom of support groups and other people who are going through the challenge of dementia. Our interdisciplinary care teams like social workers and nurses who have experience in managing dementia, and really try to plug the caregivers into as many of these avenues as possible so that they can learn from all of that community of wealth and not always rely on the doctor to have the answer. Dr Grouse: Switching gears to pharmacologic management, which is a lot of what we do for patients as neurologists. Thinking about agitation, pharmacologic management of agitation can be very challenging. And reading your article, it reminds me how disheartening it is to reflect and how modest the effect of the available options are, along with the many potential risks of their use, When nonpharmacologic interventions fail, what should neurologists recommend for their patients with agitation? Dr Weisbrod: Yeah, I definitely agree. It's every time I go back and look at this literature and look at what's new, it is a bit disheartening. But even in the face of all that, I really feel like SSRIs are my first-line therapy for most of these patients. I always try to ask myself what might be causing the patient discomfort that they are then manifesting as agitation because they don't have a better way of expressing themselves. Often, I feel like that's anxiety or depression or some other psychological symptom that we might be able to address with an SSRI. So, I tend to use sertraline and escitalopram, start those early and as long as patients are tolerating it, give it a really good trial. Outside of that, escalating to other pharmacologic approaches, even though there's such controversy in the data about antipsychotics and even though there are very real risks, sometimes I think we essentially do need a chemical sedative. And I think that it's important to have a very frank conversation upfront with the caregivers and the medical decision maker for that patient. Make sure we are counseling them on the risk, the increased risk of mortality, and also to make it a time-limited trial. So, I think that saying we're going to try this medication (if the patient's decision maker agrees, obviously) for a month or two months or three months. But I definitely wouldn't want them to just have an open-ended plan where they're going to stay on it indefinitely. It should have some end point where we say, hey, is this working or not? And if it's working, then we'd make a decision, is the improvement in quality of life worth the risks? And if we're not seeing that improvement, then we definitely need to stop it. Dr Grouse: That seems very reasonable. And then thinking more towards some of the other types of symptoms that can be really challenging, I was really surprised to see how often uncontrolled pain is a significant contributor in patients with dementia. And certainly, both uncontrolled pain and poor sleep can worsen cognitive function and neuropsychiatric symptoms in general. But of course, there's ongoing concerns about side effects of these therapies and how they can also potentially worsen things. How should we be approaching management of pain and insomnia or poor sleep in these patients? Dr Weisbrod: I think the key is just to start with really low burden treatments and escalate carefully and start with low doses of higher risk medications. So, when I think the low burden treatments for pain, scheduling acetaminophen, 1000 milligrams every eight hours, seems like a trivial thing to do, maybe? But it's actually surprising how much scheduled acetaminophen can take the edge off of pain and might be able to avoid some of these flare-ups of neuropsychiatric symptoms, may be able to really improve that pain a little bit. I do think it really has to be scheduled, though. Trying to rely on patients who have significant cognitive dysfunction to use a PRN medication is going to lead to a lot of problems and undertreatment. And then on the sleep disorder side, I think starting with low-dose Trazodone and gradually increasing the dose of Trazodone as a really safe way of initially approaching the insomnia. And then only when it's a more refractory case do I reach for the high-risk medications. Like for pain, we're talking about opiates. I think there's a lot of very reasonable concern about using opioids in patients who have cognitive dysfunction. But if there is a really good reason to think that they have severe pain, like they have a past pain disorder, I think that just like with antipsychotics, there are definitely real risks to these medications. But at the end of the day, if we are improving someone's quality of life dramatically and the patient's medical decision maker is willing to take on those risks, then we're really doing the patients a favor. Dr Grouse: Now, another issue that you mentioned in your article, which I see a lot and often struggle with myself, is how and when to deprescribe certain types of medications such as cholinesterase inhibitors and memantine. Any tips or tricks to how to approach this? Dr Weisbrod: My approach to this has also evolved a bit over the years. The new data that cholinesterase inhibitors may have a mortality benefit in patients with Alzheimer disease has changed my thinking a little bit. But there are still lots of situations where it's just too burdensome or patients seem to be having side effects. And so, I think about deprescribing. The most important thing in my mind is really thorough counseling before deprescribing with the patient's family and medical decision maker. I think that letting them know that we might actually be holding things more stable with the medication than we realize, there could be a flare-up, that we can resume the medication if that flare-up happens but we don't always guarantee getting back to the same point. I think having that conversation ahead of time will ward off some of the worst issues that you have afterwards. And then I think doing a taper of cholinesterase inhibitors over two weeks to a month is probably the most prudent because of some of the data about withdrawal and exacerbation of neuropsychiatric symptoms or cognitive worsening. Memantine, I think the data is a lot more shaky on withdrawal. And so, I think it's less important to gradually taper memantine. But I think that once again, just having the conversation upfront and letting the family know these are the things we have to look out for and these are the risks is going to be the most important. Dr Grouse: That's really helpful and a great strategy to take advantage of. Another, I think, really difficult topic that I wanted to ask you about was the discussion around nutrition and whether or not to consider putting in some type of a permanent tube for tube feeds. How do you approach that conversation? Certainly a difficult one. Dr Weisbrod: Yeah, I think it's easily one of the most difficult conversations to have in the... /episode/index/show/continuumjournal/id/39184630

Neuropalliative Care in Neuromuscular Disorders With Dr. David J. Oliver 12/31/2025

Neuropalliative Care in Neuromuscular Disorders With Dr. David J. Oliver Careful assessment and individualized care, provided by a skilled multidisciplinary care team, are emphasized in the holistic approach to neuropalliative care, which considers physical, psychological, social, spiritual, and existential aspects for people with neuromuscular diseases. In this episode, Gordon Smith, MD, FAAN, speaks with David J. Oliver, PhD, FRCP, FRCGP, FEAN, author of the article “Neuropalliative Care in Neuromuscular Disorders” in the Continuum® December 2025 Neuropalliative Care 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. Oliver is an honorary professor of Tizard Centre at the University of Kent in Canterbury, United Kingdom. Additional Resources Read the article: Subscribe to Continuum®: Earn CME (available only to AAN members): Continuum® Aloud (verbatim audio-book style recordings of articles available only to Continuum® subscribers): More about the American Academy of Neurology: Social Media Host: 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: Hello, this is Dr Gordon Smith. Today I've got the great pleasure of interviewing Dr David Oliver about his article on neuropalliative care and neuromuscular disorders, which appears in the December 2025 Continuum issue on neuropalliative care. David, welcome to the Continuum podcast, and please introduce yourself to our audience. Dr Oliver: Thank you. It's a pleasure and a privilege to be here. I'm a retired consultant in palliative medicine in the UK. I worked at the Wisdom Hospice in Rochester for over thirty years, and I'm also an honorary professor at the University of Kent in Canterbury in the UK. I've had a long interest in palliative care in neurological diseases. Hopefully we can talk about a bit later. Dr Smith: I really look forward to learning a little bit more about your path and experiences. But I wonder if, before we get into the meat of neuropalliative care with a focus on neuromuscular, if maybe you can kind of set the stage by just defining palliative care. I mean, my experience is that people think of this in different ways, and a lot of folks think- hear palliative care, and they immediately go to end-of-life care or comfort care. So, what- how should we think about maybe the discipline of palliative care or neuropalliative care? Dr Oliver: I see palliative care as very much responding to people's needs, whether that's physical needs, psychological needs, social or spiritual or existential. So, it can be much earlier in the disease progression. And I think particularly for neurological diseases, early involvement may be very important. Dr Smith: That was actually going to be my first substantive question, really, was when to begin the conversation and what does that look like and how does it evolve over time. You have a really great figure in the article that kind of emphasizes the various stages within a patient's journey that, you know, palliative care can become involved. But I wonder if you could use ALS as a good example and describe what that looks like from when a patient is first diagnosed with ALS through their course? Dr Oliver: I think particularly in ALS at the beginning, soon after diagnosis, someone may have a lot of distress and a lot of questions that they need answering. This is a disease they've not had any contact with before. And they don't understand what's going on, they don't understand the disease. So, there may be a great need to have the opportunity to talk about the disease, what may happen, what is happening, how it's going to affect them and their family. As think time goes on, there may be later they develop swallowing problems, and that will need to be talking about a feeding tube and gastrostomy. And again, there may be a lot of issues for the person and their family. As they deteriorate, they may have respiratory problems and need to have discussion about ventilatory support, either by PAP, noninvasive ventilation, or even tracheostomy. And again, I think that's a big issue that needs wide discussion. And then it may be at the final few months of the disease, where they are deteriorating, that they may have increased needs, and their families may have those needs after the death. And I think often families bereaved from someone with a neurological disease such as ALS need a great deal of support, having many mixed emotions. There may be a feeling of relief that they're not involved in that caring, but then a feeling of guilt that they shouldn't be having those feelings. So, I think that can happen over a period of… what with ALS it may be two, three, four years, but it may be similar changes over time with any patient with a neurological disease. It may be ten or fifteen years with Parkinson's or five to ten years with a progressive supranuclear palsy, but there'll be this similar need to look at palliative care during their disease progression. Dr Smith: So, I'm curious at the time of diagnosis of ALS, how far out in the future do you provide information? So a specific question would be, do you talk about end-of-life management? In my experience, ALS patients are sometimes interested in knowing about that. Or do you really focus on what's in front of you in the next three to six months, for instance? Dr Oliver: I think it's both. Obviously, we need to talk about the next three to six months, but often giving patients the opportunity to talk about what's going to happen in the future, what may happen at the end of life, I think is important. And I think a disease like ALS, if they look it up on the Internet, they may have a lot of very distressing entries there. There's a lot about how distressing dying with ALS is. And actually confront those and discuss those issues early is really important. Dr Smith: So of course, the other thing that comes up immediately with an ALS diagnosis---or, for that matter, with any other neurodegenerative problem---is prognosis. Do you have guidance and how our listeners who are giving a diagnosis of ALS or similar disorder should approach the prognostication discussion? Dr Oliver: It's often very difficult. Certainly in the UK, people may have- be a year into their disease from their first symptoms before they're diagnosed, and I've seen figures, that’s similar across the world. So, people may be actually quite way through their disease progression, but I do think we have to remember that the figures show that at five years, 25% of people are still alive, and 5 to 10% are still alive at ten years. We mustn't say you are going to die in the next two or three years, because that may not be so. And I think to have the vagueness but also the opportunity to talk, that we are talking of a deterioration over time and we don't know how that will be for you. I always stress how individual I think ALS is for patients. Dr Smith: One of the other concepts that is familiar with anyone who does ALS and clearly comes through in your article---which is really outstanding, by the way. So, thank you and congratulations for that---is the importance of multidisciplinary teams. Can you talk a little bit about how neuropalliative care sits within a multidisciplinary care model? Dr Oliver: I think the care should be multidisciplinary. Certainly in the UK, we recommended multidisciplinary team care for ALS in particular, from the time of diagnosis. And I think palliative care should be part of that multidisciplinary team. It may be a member of the team who has that palliative care experience or someone with specialist experience. Because I think the important thing is that everyone caring for someone with ALS or other neuromuscular diseases should be providing palliative care to some extent: listening to people, discussing their goals, managing their symptoms. And a specialist may only be needed if those are more complicated or particularly difficult. So, I think it is that the team needs to work together to support people and their families. So, looking at the physical aspects where the physiotherapist or occupational therapist may be very important, the psychologicals are a counsellor or psychologist. The social aspects, most of our patients are part of wider families, and we need to be looking at supporting their carers and within their family as well as the person. And so that may involve social work and other professionals. And the spiritual, the why me, their fears about the future, may involve a spiritual counsellor or a chaplain or, if appropriate, a religious leader appropriate to that- for that person. So, I think it is that wider care provided by the team. Dr Smith: I'm just reflecting on, again, your earlier answers about the Continuum of neuropalliative care. Knowing your patient is super valuable here. So, having come to know someone through their disease course must pay dividends as you get to some of these harder questions that come up later during the disease progression. Dr Oliver: I think that's the very important use of palliative care from early on in the diagnosis. It's much easier to talk about, perhaps, the existential fears of someone while they can still talk openly. To do that through a communication aid can be very difficult. To talk about someone's fear of death through a communication aid is really very, very difficult. The multidisciplinary team, I think, works well if all the members are talking together. So that perhaps the speech therapist has been to see someone and has noticed their breathing is more difficult, comes back and talks to the doctor and the physiotherapist. The social worker notices the speech is more difficult and comes back and speaks to the speech therapist. So, I think that sort of team where people are working very closely together can really optimize the care. And as you said, knowing the person, and for them to know you and to trust you, I think that's important. Those first times that people meet is so important in establishing trust. And if you only meet people when they're very disabled and perhaps not able to communicate very easily, that's really difficult. Dr Smith: I think you're reading my mind, actually, because I was really interested in talking about communication. And you mentioned a few times in your article about voice banking, which is likely to be a new concept for many of our listeners. And I would imagine the spectrum of tools that are becoming available for augmented communication for patients who have ALS or other disorders that impair speech must be impressive. I wonder if you could give us an update on what the state of the art is in terms of approaching communication. Dr Oliver: Well, I think we all remember Stephen Hawking, the professor from Cambridge, who had a very robotic voice which wasn't his. Now people may have their own voice on a communication aid. I think the use of whether it's a mobile phone or iPad, other computer systems, can actually turn what someone types into their own voice. And voice banking is much easier than it used to be. Only a few years ago, someone would have to read for an hour or two hours so the computer could pick up all the different aspects of their voice. Now it's a few minutes. And it has been even- I've known that people have taken their answer phone off a telephone and used that to produce a voice that is very, very near to the person. So that when someone does type out, the voice that comes out will be very similar to their own. I remember one video of someone who'd done this and they called their dog, and the dog just jumped into the air when he suddenly heard his master's voice for the first time in several months. So, I think it's very dramatic and very helpful for the person, who no longer feels a robot, but also for their family that can recognize their father, their husband, their wife's speech again. Dr Smith: Very humanizing, isn't it? Dr Oliver: There is a stigma of having the robotic voice. And if we can remove that stigma and someone can feel more normal, that would be our aim. Dr Smith: As you've alluded to, and for the large majority---really all of our ALS patients, barring something unexpected---we end up in preparing for death and preparing for end of life. I wonder what advice you have in that process, managing fear of death and working with our patients as they approach the end of their journey. Dr Oliver: I think the most important thing is listening and trying to find what their particular concerns are. And as I said earlier, they may have understood from what they've read in books or the Internet that the death from ALS is very distressing. However, I think we can say there are several studies now from various countries where people have looked at what happens at the end of life for people with ALS. Choking to death, being very distressed, are very, very rare if the symptoms are managed effectively beforehand, preparations are made so that perhaps medication can be given quickly if someone does develop some distress so that it doesn't become a distressing crisis. So, I think we can say that distress at the end of life with ALS is unusual, and probably no different to any other disease group. It's important to make sure that people realize that with good symptom control, with good palliative care, there is a very small risk of choking or of great distress at the end of life. Dr Smith: Now, I would imagine many patients have multiple different types of fear of death; one, process, what's the pain and experience going to be like? But there's also being dead, you know, fear of the end of life. And then this gets into comments you made earlier about spirituality and psychology. How do you- what's your experience in handling that? Because that's a harder problem, it seems, to really provide concrete advice about. Dr Oliver: Yeah. And so, I think it's always important to know when someone says they're frightened of the future, to check whether it is the dying process or after death. I've got no answer for what's going to happen afterwards, but I can listen to what someone may have in their past, their concerns, their experience. You know, is their experience of someone dying their memories of someone screaming in pain in an upstairs bedroom while they were a child? Was their grandfather died? Trying to find out what particular things may be really a problem to them and that we can try and address. But others, we can't answer what's going to happen after death. If someone is particularly wanting to look at that, I think that may be involving a spiritual advisor or their local spiritual/religious leader. But often I think it's just listening and understanding where they are. Dr Smith: So, you brought up bereavement earlier and you discussed it in the article. In my experience is that oftentimes the families are very, very impacted by the journey of ALS. And while ALS patients are remarkably resilient, it's a huge burden on family, loved ones, and their community. Can you talk a bit about the role of palliative care in the bereavement process, maybe preparing for bereavement and then after the loss of their loved one? Dr Oliver: Throughout the disease progression, we need to be supporting the carers as much as we are the patient. They are very much involved. As you said, the burden of care may be quite profound and very difficult for them. So, it's listening, supporting them, finding out what their particular concerns are. Are they frightened about what's going to happen at the end of life as well? Are they concerned of how they're going to cope or how the person's going to cope? And then after the death, it's allowing them to talk about what's happened and how they are feeling now, cause I think having had that enormous input in care, then suddenly everything stops. And also, the support systems they've had for perhaps months of the carers coming in, the doctor, the nurse, the physiotherapist, everyone coming in, they all stop coming. So, their whole social system suddenly stops and becomes much reduced. And I'm afraid certainly in the UK if someone is bereaved, they may not have the contact with their friends and family because they're afraid to come and see them. So, they may become quite isolated and reduced in what they can do. So, I think it's allowing them to discuss what has happened. And I think that's as important sometimes for members of the multidisciplinary team, because we as doctors, nurses and the wider team will also have some aspects of bereavement as we face not seeing that person who we've looked after for many years and perhaps in quite an intensive way. So, we need to be looking at how we support ourselves. And I think that's another important role of the multidisciplinary team. I always remember in our team, sometimes I would say, I find this person really difficult to cope with. And the rest of the people around the team would go have a sigh of relief because they felt the same, but they didn't like to say. And once we could talk about it, we could support each other and work out what we could do to help us help the patient in the most effective way. Dr Smith: Well, David, I think that's a great point to end on. I think you've done a really great job of capturing why someone would want to be a palliative care specialist or be involved in palliative care, because one of the themes throughout this conversation is the very significant personal and care impact that you have on patients and families. So, I really appreciate your sharing your wisdom. I really encourage all of our listeners to check out the article, it's really outstanding. I wonder if maybe you might just briefly tell us a little bit about how you got into this space? It's obviously one for which you have a great deal of passion and wisdom. How did you end up where you are? Dr Oliver: I became interested in palliative care as a medical student, and actually I trained as a family doctor, but I went to Saint Christopher's Hospice following that. I had actually had contact with them while I was a medical student, so I worked Saint Christopher's Hospice in South London when Dame Cecily Saunders was still working there. And at that time Christopher's had sixty-two beds, and at least eight of those beds were reserved for people with ALS or other neurological diseases. And I became very involved in one or two patients and their care. And Dame Sicily Saunders asked me to write something on ALS for their bookshelf that they had on the education area. So, I wrote, I think, four drafts. I went from sort of C minus to just about passable on the fourth draft. And that became my big interest in particularly ALS, and as time went on, in other neurological diseases. When I went to the Wisdom Hospice as a consultant, I was very keen to carry on looking after people with ALS, and we involved ourselves with other neurological patients. That's how I got started. Having that interest, listening to patients, documenting what we did became important as a way of showing how palliative care could have a big role in neurological disease. And over the years, I've been pressing again and again for the early involvement of palliative care in neurological diseases. And I think that is so important so that there can be a proper holistic assessment of people, that they can build up the trust in their carers and in the multidisciplinary team so that they can live as positively as possible. And as a result of that, that their death will be without distress and with their family with them. Dr Smith: Well, David, you've convinced and... /episode/index/show/continuumjournal/id/39184605

Neuropalliative Care in Severe Acute Brain Injury and Stroke With Dr. Claire Creutzfeldt 12/24/2025

Neuropalliative Care in Severe Acute Brain Injury and Stroke With Dr. Claire Creutzfeldt Severe acute brain injury presents acute and longitudinal challenges. Addressing total pain involves managing physical symptoms and providing emotional, social, and spiritual support to enhance quality of life for patients and their families. In this episode, Kait Nevel, MD, speaks with Claire J. Creutzfeldt, MD, author of the article “Neuropalliative Care in Severe Acute Brain Injury and Stroke” in the Continuum® December 2025 Neuropalliative Care issue. Dr. Nevel is a Continuum® Audio interviewer and a neurologist and neuro-oncologist at Indiana University School of Medicine in Indianapolis, Indiana. Dr. Liewluck is a professor in the department of neurology at the University of Washington in Seattle, Washington. Additional Resources Read the article: Subscribe to Continuum®: Earn CME (available only to AAN members): Continuum® Aloud (verbatim audio-book style recordings of articles available only to Continuum® subscribers): More about the American Academy of Neurology: Social Media Host: Guest: 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 Kait Nevel. Today I'm interviewing Dr Claire Creutzfeldt about her article on neuropalliative care in severe acute brain injury and stroke, which appears in the December 2025 Continuum issue on neuropalliative care. Claire, welcome to the podcast, and please introduce yourself to the audience. Dr Creutzfeldt: Thanks, thanks for having me. Yeah, I'm an associate professor of neurology at the University of Washington. I'm a stroke neurologist and palliative care researcher and really have focused my career on how we can best integrate palliative care principles into the care of patients with severe stroke and other neurocritical illness. Dr Nevel: Wonderful. Well, I'm looking forward to talking to you today about your excellent article that I really enjoyed reading. To get us started, can you tell us what you feel is the most important takeaway from your article for the practicing neurologist? Dr Creutzfeldt: Yeah. You know, I think one is always a little biased by what one is working on currently. And I think what I'm most excited about or feel more strongly about is this idea that stroke and severe acute brain injury are not an event, but really a chronic illness that people are left with usually for the rest of their lives, that change their life radically. And I think that education, research funding, also the clinical setting, current healthcare models aren't set up for that. And this idea that severe acute brain injury, you know, should be viewed as a lifelong condition that requires support across all ranges of goals of care. So curative, restorative, palliative and end-of-life care. Dr Nevel: Yeah, I love that part of your article, how you really highlighted that concept. And I think obviously that's something that we see in neurology and learn, especially as we transition out of our residency stages. But I think especially for the trainees listening, can sometimes be hospital inpatient-heavy, if you will, that kind of you can lose sight of that, that these acute strokes, severe acute brain injury, it turns into a chronic illness or condition that patients are dealing with lifelong. Dr Creutzfeldt: Often what we do in a very acute setting is like, is really cool and sexy and like, we can cure people from their stroke if they come, you know, at the right time with the right kind of stroke to the right hospital. And often the symptoms that people come in with much later on are harder to treat and address, partly because the focus in education, clinical and research just hasn't been as much on that time. Dr Nevel: Yeah, absolutely. So, can you talk to us about this concept of total pain? What does it mean, and how do we incorporate this concept into the way that we view our approach, our patient care? Dr Creutzfeldt: Total pain is a very old word, but it's sort of coming back into fashion in the palliative care world because it really describes all those sources of suffering or sources of distress, like, beyond what we sort of really think of as sort of the physical symptoms in recovery of stroke. As many of you know, palliative care often thinks in this multidimensional way of the physical distress, physical pain, but also psychological, emotional, social and spiritual, existential. And both- we sort of created sort of a figure that incorporates all of them and also includes both patients and their family members. They share some of these sources of distress, but they also have distinct ones that need to be addressed. And at the core of that total pain is what we need to provide, is sort of optimal communication and goals-of-care prognosis. Dr Nevel: Yeah, I'm thinking about all of those aspects and not just focusing on one. How does the disease trajectory of severe acute brain injury and stroke play a role in the palliative care approach? And how should we kind of going back to that original point of this idea of severe acute brain injury being an acute event and then oftentimes turning into kind of a chronic condition? How does that play a role in how we address palliative care with our patients, or kind of the stages of palliative care with our patients? Dr Creutzfeldt: Yeah, I think several things, especially for neurologists, is the more traditional palliative care illnesses, like cancer or congestive heart failure, illnesses where people are diagnosed when they're still functioning at a relatively high level and tend to have time to consider their prognosis and their goals of care in the end of life wishes and to meet with palliative care and to consider their personhood. Who am I? What's most important for me? And stroke, people with stroke, they not only present at their worst, they meet us at their worst, at a time when the patient themselves usually can't speak for themselves, when their personhood has been stripped from them. And then as providers, we, you know, we often really just get that one opportunity to get the conversation right and to guide people towards, you know, what we would call optimal and goal-concordant care. So, the challenges are many. I do think that the burden of these early conversations is on neurologists and really requires the neurologists to show compassion, to learn communication skills, think really hard about how you want to communicate prognosis and goals of care early on, because it's going to color people's experiences and decisions longitudinally. You asked about, sort of, this trajectory. And I do think it's important to think about, you know, what really happens even after the thrombectomy or even after we discharge people, especially from the ICU. Because for us, often after sort of day five or six, you know, we're sort of done. We're thinking about secondary stroke prevention. And, you know, how do I get the patient to rehab or out of the hospital? For the patients and families, this is when it really all just starts. You know, this is when they- when they're first memories are usually, you know, they hardly remember that acute setting. And so, when they are medically stable, we're done with the acute blood pressure treatment where we've removed the Foley, we've made a decision about nutrition. For us that tends to be a time where we let go a little; for patients and families that tends to actually be the time when they have to think about how am I going to live with this and what are the next several months or years going to look like? And so being there for them is important. Dr Nevel: That's such a, I think, important point, that when we have our plan in place, we know medically what the plan is for that patient and we're starting to step back, think about rehab or discharge. That's when oftentimes more quote-unquote “reality” steps in for patients and families about what their future is going to look like. Dr Creutzfeldt: And medical stability is not even close to neurological stability. And so, they are still in the middle of real prognostic uncertainty, and often waxing and waning symptoms or new symptoms coming up for them. Like pain, you know, post thalamic pain syndrome, just as an example, tends to be something that doesn't develop until later. Dr Nevel: Right, right. Absolutely. And since you touched on this concept of prognostic uncertainty, and, you know, that's something that's so challenging in severe acute brain injury, especially the early days when you talk about this, you know, that things tend to become a little bit more certain as more time passes. But these are really hard conversations because a lot of times feel like big decisions that need to be made early on, you know? Dr Creutzfeldt: Huge! Dr Nevel: Sometimes things like trach and PEG and things like that. How do you approach that conversation? I know you talk about that a little bit in your article. You touch on that, some of the, kind of, strategies or concepts that we use in palliative care to approach this prognostic uncertainty with patients. Dr Creutzfeldt: Yeah, I think the challenge is to balance this acknowledging uncertainty with still being able to guide the families and allow them to trust you. So, there are a few things that I have said in the past, and I have taught in the past, and I don't use anymore. They include sentences like I don't have a crystal ball, for example. Nobody was asking you for one. The other one that I want us to avoid, I think, is the sentence we are terrible at prognosticating. Because what I have seen is that that sentence carries on for families. And families at nine months are still saying, well, you guys are terrible at prognosticating. That's what you told me. First of all, it's all relative, and relative to non-neural providers---even at this time using Google and AI, we're actually quite good at prognosticating. It's just that a wide range early on. So that's how I would change that sentence is, early on after stroke, the range of possible outcomes is still very wide. And so, you've communicated uncertainty without saying I have no idea what I'm doing, which is not true. That is in order to help families be able to trust you and also to trust the person who comes after you, because we all know that a week or two after admission, we do know a lot more. And if we told them on day one that we’re terrible at prognosticating, it's hard to sort of build that trust again later. You also asked about, you know, communication strategies. And I think it's this range of possible outcomes that I think is a good guideline for us to work on. And that range, sort of like a confidence interval, is still very wide early on. And as we collect more information over time, both about the clinical scenario that is evolving in front of us and about the patient who we are learning more about over time, this confidence interval becomes smaller. And that's where this idea of the best case/worst case scenario sort of conversation, for example, comes from: that range of possible outcomes. Dr Nevel: So, what to you is most challenging about palliative care for patients with severe acute brain injury and stroke? Dr Creutzfeldt: I think the biggest challenge in stroke care is balancing restorative and curative care with palliative and end-of-life. And that is especially early on when sort of everything is possible, when patients and families want to hear the good news and, I think, are also quite willing to hear the bad news, and probably should. So, I think that that communication is hard when, you know, really we want to provide goal-concordant care. We want to make sure that people get that care that is most important to them and can meet the outcomes that are most important to them. Dr Nevel: Yeah, agree. What is most rewarding? Dr Creutzfeldt: I think these patients and families have enormous needs and are extremely grateful if they can find someone that they can trust and who can guide them and who will stick with them. And when I say someone, I think that can be a team. That always depends on how we communicate. In the ideal world, it would be the same person following someone over time, the patient and the family over time. But in our current healthcare system, we're usually moving on from one place to another and being able to communicate with the people that come after you. Telling the family that you're a team and supporting them through that, I think, is really important. Dr Nevel: Yeah. And like you touched upon, patients and families, I think oftentimes they're looking for, you mentioned, you know, the sharing and communication and they're looking for information. Dr Creutzfeldt: You know, what's really rewarding is working with a team. And health care has really excelled at that. And I think we have a lot done from them is that it's not always the MD that family needs. And we have a lot of people at our side, and I think we need more of them. Chaplains, social workers; psychologists, actually, I think; and nurses or- in an ideal world, would really work together to support these multidisciplinary, multidimensional symptoms. Dr Nevel: Yeah. I think it benefits both the patient and the care team, too. Dr Creutzfeldt: Absolutely! Dr Nevel: It’s helpful to be part of a team. You know, there's camaraderie in that and, like, a shared goal, and I think the thought is rewarding, too. Dr Creutzfeldt: If we really try and think about severe stroke as a chronic illness or severe acute brain injury as a chronic illness not unlike cancer, then if you think about the systems that have been built for cancer where an entire team of providers follows the patient and their family member over time, I think we need that, too. Dr Nevel: Yeah, I agree. That point, every member of the team has overlapping things, but has a slightly individual role to a degree too, which is also helpful to the patient and the family. You talked about this a little bit in your article, and I want to hear more from you about what we know about healthcare disparities in this area of medicine and in providing palliative care for patients with severe acute brain injury and stroke. Dr Creutzfeldt: Yeah, I think actually a lot of the huge decisions that we make, especially early on, are highly variable. And can identify people by various things, whether it's their race or ethnicity or sex or age, or even where they live in the United States. But decisions tend to be made differently. And so, just as an example, we know that I think people who identify as black, for sure, are less likely to receive the acute, often life-saving interventions like TNK or thrombectomy and more likely to undergo longer-term, life-prolonging treatment like PEG and trach. That seems true, after adjusting for clinical severity and things like that. And so disparities like that may be based on cultural preferences or well-informed decisions, and then we can support them. But of course, unfortunately there's a clear idea when we see, often, unexplained variability that a lot is due to uninformed decisions and poor communication and possibly racism in certain parts. And that is, of course, something that has to be addressed. Dr Nevel: Yeah, absolutely. What are future areas of research in this area? I know you do a lot of research in this area and I'd love to hear about some of it and what you think is exciting or kind of new and going to change the way we think about things, perhaps. Dr Creutzfeldt: I think every aspect of stroke continues to be exciting and just, you know, our focus of today and my research is on palliative care. I mean, obviously, the things we can do in rehab these days have to be embraced, and the acute stuff. But I think this longitudinal support, an ideally longitudinal multidisciplinary support for patients and families, requires more research. I think it will help us with prognosis. It will help us with communicating things early on and learning more about sort of multidimensional symptoms of these patients over time. That requires more research. And then, how can we change the healthcare system---in a sustainable way, obviously---to maximize quality of life for the survivors and their families? Dr Nevel: Going back to that total pain again, making sure that we're incorporating that longitudinally. Dr Creutzfeldt: I think there are currently 94 million people worldwide living with the aftermath of a stroke. I joined a stroke survivor support group recently. People are supporting each other that have that had their stroke, like, 14 years ago and are still in that just to show that this is not one and done. People are still struggling with symptoms afterwards and want support. Dr Nevel: Before we close out, is there anything else that you'd like to add? Dr Creutzfeldt: Your questions have all been great, and I think one observation is that we've talked a lot about, sort of, new ideas of the need for longitudinal care for patients after severe stroke. There's still a ton for all of us to do to optimize the care we provide in the very acute setting, to optimize the way we communicate in the very acute setting. To make sure we are, for example, providing the same message as our team members and providing truly compassionate goal-concordant care from the time they hit the emergency room throughout. Including time-limited trials, for example. Dr Nevel: Well, thank you so much for chatting with me today about your article on this really important topic. Again, today I've been interviewing Dr Claire Creutzfeldt about her article on neuropalliative care in severe acute brain injury and stroke, which appears in the December 2025 Continuum issue on neuropalliative care. Be sure to check out Continuum Audio episodes from this and other issues. And as always, to our listeners, please check out the article. It's great, highly recommend. And thank you to our listeners for joining us today. And thank you so much, Claire, for sharing your expertise with us today. Dr Creutzfeldt: Thanks for having me. Dr Monteith: This is Dr Teshamae Monteith, Associate Editor of Continuum Audio. If you've enjoyed this episode, you'll love the journal, which is full of in-depth and clinically relevant information important for neurology practitioners. Use 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. /episode/index/show/continuumjournal/id/39184595

End-of-Life Care and Hospice With Dr. Claudia Chou 12/17/2025

End-of-Life Care and Hospice With Dr. Claudia Chou In the hospital setting, neurologists may be responsible for managing common end-of-life symptoms. Comprehensive end-of-life care integrates knowledge of the biomedical aspects of disease with patients’ values and preferences for care; psychosocial, cultural, and spiritual needs; and support for patients and their families. In this episode, Teshamae Monteith, MD, FAAN, speaks with Claudia Z. Chou, MD, author of the article “End-of-Life Care and Hospice” in the Continuum® December 2025 Neuropalliative Care issue. Dr. Monteith is the associate editor of Continuum® Audio and an associate professor of clinical neurology at the University of Miami Miller School of Medicine in Miami, Florida. Dr. Chou is an assistant professor of neurology and a consultant in the Division of Community Internal Medicine, Geriatrics and Palliative Care at Mayo Clinic in Rochester, Minnesota. Additional Resources Read the article: Subscribe to Continuum®: Earn CME (available only to AAN members): Continuum® Aloud (verbatim audio-book style recordings of articles available only to Continuum® subscribers): More about the American Academy of Neurology: Social Media Host: 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 Claudia Chou about her article on end-of-life care and hospice, which is found in the December 2025 Continuum issue on neuropalliative care. Welcome to our podcast. How are you? Dr Chou: I'm doing well. Thank you for having me. This is really exciting to be here. Dr Monteith: Absolutely. So, why don't you introduce yourself to our audience? Dr Chou: Sure. My name is Claudia Chou. I am a full time hospice and palliative medicine physician at Mayo Clinic in Rochester. I'm trained in neurology, movement disorders, and hospice and palliative medicine. I'm also passionate about education, and I'm the program director for the Hospice and Palliative Medicine fellowship here. Dr Monteith: Cool. So just learning about your training, I kind of have an idea of how you got into this work, but why don't you tell me what inspired you to get into this area? Dr Chou: It was chance, actually. And really just good luck, being in the right place at the right time. I was in my residency and felt like I was missing something in my training. I was seeing these patients who were suffering strokes and had acute decline in functional status. We were seeing patients with new diagnosis of glioblastoma and knowing what that future looked like for them. And while I went into neurology because of a love of neuroscience, localizing the lesion, all of those things that we all love about neurology, I still felt like I didn't have the skill set to serve patients where they perhaps needed me the most in those difficult times where they were dealing with serious illness and functional decline. And so, the serendipitous thing was that I saw a grand rounds presentation by someone who works in neurology and palliative care for people with Parkinson's disease. And truly, it's not an exaggeration to say that by the end of that lecture, I said, I need to do palliative care, I need to rotate in this, I need to learn more. I think this is what I've been missing. And I had plans to practice both movement disorders neurology and palliative care, but I finished training in 2020… and that was not a long time ago. We can think of all the things that were going on, all the different global forces that were influencing our day-to-day decisions. And the way things worked out, staying in palliative care was really what my family and I needed. Dr Monteith: Wow, so that's really interesting. Must have been a great lecturer. Dr Chou: Yes, like one of the best. Dr Monteith: So why don't you tell me about the objectives of your article? Dr Chou: The objectives may be to fill in some of the gaps in knowledge that may be present for the general neurologist. We learn so much in neurology training, so much about how to diagnose and treat diseases, and I think I would argue that this really is part and parcel of all we should be doing. We are the experts in these diseases, and just because we're shifting to end-of-life or transitioning to a different type of care doesn't mean that we back out of someone's care entirely or transition over to a hospice or palliative care expert. It is part of our job to be there and guide patients and their care partners through this next phase. You know, I'm not saying we all need to be hospice and palliative care experts, but we need to be able to take those first steps with patients and their care partners. And so, I think objectives are really to focus in on, what are those core pieces of knowledge for end-of-life care and understanding hospice so we can take those first steps with patients and their care partners? Dr Monteith: So, why don't you give us some of those essential points in your article? Dr Chou: Yeah. In one section of the article, I talk about common symptoms that someone might experience at the end of life and how we might manage those. These days, a lot of hospitals have order sets that talk us through those symptoms. We can check things off of a drop-down menu. And yet I think there's a little bit more nuance to that. There may be situations in which we would choose one medication over another. There may be medications that we've never really thought of in terms of symptom management before. Something that I learned in my hospice and palliative medicine fellowship was that haloperidol can be helpful for nausea. I know that's usually not one of our go-tos in neurology for any number of reasons. So, I think that extra knowledge can take us pretty far when we're managing end of life symptoms, particularly in the hospital setting. And then I think the other component is the hospice component. A lot of us may have not had experience talking about hospice, talking about what hospice can provide, and again, knowing how to take those first steps with patients. We may be referring to social work or palliative medicine to start those conversations. But again, I think this is something that's definitely learnable and something that should be part of our skill set in neurology. Dr Monteith: Great. And so, when you speak about symptom management and being more comfortable with the tools that we have, how can we be more efficient and more effective at that? Dr Chou: Think about what the common symptoms are at end of life. We may know this kind of intuitively, but what we commonly see are things like pain, nausea, dyspnea, anxiety, delirium or agitation. And so, I think having a little bit of a checklist in mind can be helpful. You know, how can I systematically think through a differential, almost, for why my patient might be uncomfortable? Why they might be restless? Have I thought through these different symptoms? Can I try a medication from my tool kit? See if that works, and if it does, we can continue on. If not, what's the next thing that I can pivot to? So, I think these are common skills for a little bit of a differential diagnosis, if you will, and how to work through these problems just with the end-of-life lens on it. Dr Monteith: So, are there any, like, validated tools or checklists that are freely available? Dr Chou: I don't think there's been anything particularly validated for end-of-life care in neurologic disease. And so, a lot of our treatments and our approaches are empiric, but I don't think there's been anything validated, per se. Dr Monteith: Great. So, why don't we talk a little bit about the approach to discussions on hospice? We all, as you kind of alluded to, want to be effective neurologists, care for our patients, but we sometimes deal with very debilitating diseases. And so, when we think that or suspect that our patient is kind of terminally ill, how do we approach that to our patients? Of course, our patients come from different backgrounds, different experiences. So, what is your approach? Dr Chou: So, when we talk about hospice and when a patient may be appropriate for hospice, we have to acknowledge that we think that they may be in the last six months of their disease. We as the neurologist are the experts in their disease and the best ones to weigh in on that prognosis. The patient and their care partners then have to accept that the type of care that hospice provides is what makes sense for them. Hospice focuses on comfort and treating a patient's comfort as the primary goal. Hospice is not as interested in treating cancer, say, to prolong life. Hospice is not as interested in life-prolonging measures and treatments that are not focused at comfort and quality of life. And so, when we have that alignment between our understanding of a patient's disease and their prognosis and the patient care partner’s goal is to focus on comfort and quality of life above all else, that's when we have a patient who might be appropriate for hospice and ready to hear more about what that actually entails. Dr Monteith: And what are some, maybe, myths that neurologist healthcare professionals may have about hospice that you really want us to kind of have some clarity on? Dr Chou: That's a great question. What we often tell patients is that hospice's goal is to help patients live as well as possible in the time that they have left. Again, our primary objective is not life prolongation, but quality of life. Hospice's goal is also not to speed up or slow down the natural dying process. Sometimes we do get questions about that: can't you make this go faster or we're ready for the end. But really, we are there to help patients along the natural journey that their body is taking them on. And I think hospice care can actually be complex. In the inpatient setting, in particular in neurology, we may be seeing patients who have suffered large strokes and have perhaps only days to a few weeks of life left. But in the outpatient setting and in the home hospice setting, patients can be on hospice for many months, and so they will have new care needs, new urinary tract infections, sometimes new rashes, the need to change their insulin regimens around to avoid extremes of hyperglycemia or hypoglycemia. So, there is a lot of complexity in that care and a lot that can be wrapped up under that quality-of-life and comfort umbrella. Dr Monteith: And to get someone to hospice requires a bit of prognostication, right? Six months of prediction in terms of a terminal illness. I know there's some nuances to that. So how can you make us feel more comfortable about making the recommendations for hospice? Dr Chou: I think this is a big challenge in the field. We're normally guided by Medicare guidelines that say when a patient might be hospice-appropriate. And so, for a neurologic disease, this really only encompasses four conditions: ALS, stroke, coma, and Alzheimer's dementia. And we can think of all the other diseases that are not encompassed in those four. And so, I think we say that we paint the picture of what it means to have a prognosis of six months or less. So, from the neurologic side, that can be, what do you know about this disease and what end-stage might look like? What is the pattern of the patient's functional decline? What are they needing more help with? Are there other factors at play such as heart failure or COPD that may in and of themselves not be a qualifying diagnosis for hospice, but when it's taken together in the whole clinical picture, you have a patient who's very ill and one that you're worried may die in the next six months or less? Dr Monteith: Then you also had some nice charts on kind of disease-specific guidelines. Can you take us a little bit through that? Dr Chou: The article does contain tables about specific criteria that may qualify someone for hospice with these neurologic conditions. And they are pretty dense. I know they're a checklist of a lot of different things. And so, how we practice is by trying to refer patients to hospice based on those guidelines as much as possible and then using our own clinical judgment as well, what we have seen through taking care of patients through the years. So, again, really going back to that decline. What is making you feel uncomfortable about this patient's prognosis? What is making you feel like, gosh, this patient could be well supported by hospice, and they could have six months or less? So, all of that should go into your decision as well. And all of that should go into your discussion with the patient and their care partners. Dr Monteith: Yeah. And reading your article, what stood out was all the services that patients can receive under hospice. So, I think sometimes people think, okay, this is terminal illness, let's get to hospice for whatever reasons, but not necessarily all the lists and lists and lists of benefits of hospice. So, I don't know that everyone's aware of all those benefits. So, can you talk to us a little bit about that? Dr Chou: Yeah, I like that you brought that up because that's also something that I often say to patients and their care partners when we're talking about hospice. When the time is right for a patient to enroll in hospice, they should not feel like they're giving anything up. There should be no more clinical trial that they're hoping to chase down, and so they should just feel like they're gaining all of those good supports: care that comes to their home, a team that knows them well, someone that's available twenty-four hours a day by phone and can actually even come into the home setting if needed to help with symptom management. Hospice comes as well with the psychosocial supports for just coping with what dying looks like. We know that's not easy to be thinking about dying for oneself, or for a family member or care partner to be losing their loved one. So, all of those supports are built into hospice. I did want to make a distinction, too, that hospice does not provide custodial care, which I explain to patients as care of the body, those daily needs for bathing, dressing, eating, etc. Sometimes patients are interested in hospice because they're needing more help at home, and I have to tell them that unfortunately, our healthcare system is not built for that. And if that's the sole reason that someone is interested in hospice, we have to think about a different approach, because that is not part of the hospice benefit. Dr Monteith: Thank you for that. And then I learned about concurrent care. So why don't you tell us a little bit about that? That's a little bit of a nuance, right? Dr Chou: Yeah, that is a little bit of a nuance. And so, typically when patients are enrolling in hospice, they are transitioning from care the way that it's normally conducted in our healthcare system. So, outpatient visits to all of the specialists and to their primary care providers, the chance to go to the ER or the ICU for higher levels of care. And yet there are a subset of patients who can still have all of those cares alongside hospice care. That really applies to two specific populations: veterans who are receiving care through the Veterans Administration, and then younger patients, so twenty six years old and less, can receive that care through, essentially, a pediatric carve out. Dr Monteith: Great. Well, I mean, you gave so much information in your article, so our listeners are going to have to read it. I don’t want you to spill everything, but if you can just kind of give me a sense what you want a neurologist to take away from your article, I think that would be helpful. Dr Chou: I think what I want neurologist to take away is that, again, this is something that is part of what we do as neurologists. This is part of our skill set, and this is part of what it means to take good care of patients. I think what we do in this transition period from kind of usual cares, diagnosis, full treatment to end of life, really can have impact on patients and their care partners. It's not uncommon for me to hear from family members who have had another loved one go through hospice about how that experience was positive or negative. And so, we can think about the influence for years to come, even, because of how well we can handle these transitions. That really can be more than the patient in front of us in their journey. That is really important, but it can also have wide-reaching implications beyond that. Dr Monteith: Excellent. And I know we were talking earlier a little bit about your excitement with the field and where it's going. So why don't you share some of that excitement? Dr Chou: Yeah. And so, I think there is a lot still to come in the field of neuropalliative care, particularly from an evidence base. I know we talked a lot about the soft skills, about presence and communication, but we are clinicians at heart, and we need to practice from an evidence base. I know that's been harder in palliative care, but we have some international work groups that really are trying to come together, see what our approaches look like, see where standardization may need to happen or where our differences are actually our strength. I think there can be a lot of variability in what palliative care looks like. So, my hope is that evidence base is coming through these collaborations. I know it's hard to have a conversation these days without talking about artificial intelligence, but that is certainly a hope. When you look at morbidity, when you look at patients with these complicated disease courses, what is pointing you in the direction of, again, a prognosis of six months or less or a patient who may do better with this disease versus not? And so, I think there's a lot to come from the artificial intelligence and big data realm. For the trainees listening out there, there is no better time to be excited about neuropalliative care and to be thinking about neuropalliative care. I said that I stumbled upon this field, and hopefully someone is inspired as well by listening to these podcasts and reading Continuum to know what this field is really about. And so, it's been exponential growth since I joined this field. We have medical students now who want to come into neuropalliative care as a profession. We have clinicians who are directors of neuropalliative care at their institutions. We have an international neuropalliative care society and neuropalliative care at AAN. And I think we are moving closer to that dream for all of us, which is that patients living with serious neurologic illness can be supported throughout that journey. High-quality, evidence-based palliative care. We're not there yet, but I think it is a possibility that we reach that in my lifetime. Dr Monteith: Well, excellent. I look forward to maybe another revision of this article with some of that work incorporated. And it's been wonderful to talk to you and to reflect on how better to approach patients that are towards the end of life and to help them with that decision-making process. Thank you so much. Dr Chou: Yeah, thank you for having me. And we're very excited about this issue. Dr Monteith: Today. I've been interviewing Dr Claudia Chou about her article on end-of-life care and hospice, which is found in the December 2025 Continuum issue on neuropalliative care. 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... /episode/index/show/continuumjournal/id/39184550

The Approach to Serious-Illness Conversations With Dr. Jessica Besbris 12/10/2025

The Approach to Serious-Illness Conversations With Dr. Jessica Besbris Neurologists are privileged to act as guides for patients as they navigate the complex course of serious neurologic illnesses. Because of the impact on quality of life, personhood, and prognosis, neurologists must be able to conduct serious-illness conversations to improve rapport, reduce patient anxiety and depression, and increase the likelihood that treatment choices agree with patient goals and values. In this episode, Teshamae Monteith, MD, FAAN speaks with Jessica M. Besbris, MD, author of the article “The Approach to Serious-Illness Conversations” in the Continuum® December 2025 Neuropalliative Care issue. Dr. Monteith is the associate editor of Continuum® Audio and an associate professor of clinical neurology at the University of Miami Miller School of Medicine in Miami, Florida. Dr. Besbris is an assistant professor of neurology and internal medicine and the Director of Neuropalliative Care at Cedars-Sinai Medical Center in Los Angeles, California. Additional Resources Read the article: Subscribe to Continuum®: Earn CME (available only to AAN members): Continuum® Aloud (verbatim audio-book style recordings of articles available only to Continuum® subscribers): More about the American Academy of Neurology: Social Media Host: Guest: 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: Hi, this is Dr Teshamae Monteith. Today I'm interviewing Dr Jessica Besbris about her article on the approach to serious illness conversation, which is found in the December 2025 Continuum issue on neuropalliative care. How are you? Dr Besbris: I'm doing great. Thank you so much for having me here today. Dr Monteith: Well, thank you for being on our podcast. Dr Besbris: My pleasure. Dr Monteith: Why don't we start off with you introducing yourself? Dr Besbris: Sure. So, my name is Jessica Besbris. I am a neurologist with fellowship training in palliative care, and I am currently at Cedars Sinai Medical Center in Los Angeles, where I am the director of our neuropalliative care program. Dr Monteith: Excellent. So, how did you get involved in that? Dr Besbris: Like, I think, many neurologists, I always knew I wanted to be a neurologist---or, I should say, from the moment I decided to be a doctor I knew that that was the type of doctor I wanted to be, a neurologist. So, I went into medical school with the aim of becoming a neurologist. And very quickly, when I started my clinical years, I was exposed to patients who were living with very serious illnesses. And I found myself really drawn to opportunities to help, opportunities to make people feel better, opportunities to improve quality of life in situations that on the face of it seemed really challenging, where maybe it seemed like our usual treatments were not necessarily the answer or were not the only answer. And so, I pretty quickly recognized that taking care of patients with serious illness was going to be a big part of my life as a neurologist and that palliative care was the way I wanted to help these patients and families. Dr Monteith: And you mentioned you're leading the group. So, how many colleagues do you have in the program? Dr Besbris: We have a very large palliative care group, but within neuropalliative care, it's myself and one other physician, a nurse practitioner, and a social worker. Dr Monteith: Okay, well, I know you guys are busy. Dr Besbris: Yes, we are very happy to be busy. Dr Monteith: Yes. So, let's talk about the objectives of your article. Dr Besbris: Sure. So, the goal of this article is to impress upon neurologists that it really is all of our jobs as neurologists to be having these conversations with our patients who are affected with serious illness. And then, in most areas of neurology, these conversations will come up. Whether it's giving a life changing diagnosis, or talking about treatment choices, or treatment not going the way that we had hoped, or even sometimes progression of disease or end-of-life care. These topics will come up for most of us in neurology, and really, we're hoping that this article not only makes the case that neurologists can and should be having these conversations, but that there are skills that we can teach in this article and with other resources to improve the skill level and sense of confidence that neurologists have when they enter into these conversations. Dr Monteith: Great. I read that there are some developments in the field, on organizational levels, about really making these skills part of standard of care in terms of education. So, can you speak to that? Dr Besbris: Yes. So, there have been a couple of really landmark papers and changes in the educational landscape that I think have really brought neuropalliative care in general, and serious illness conversation in particular, to the forefront. So, there were the position statements released by the American Academy of Neurology in 1996 and 2022, both of which really said, hey, all neurologists should be doing this and receive training on how to have these conversations and provide this care. And the ACGME, the Accreditation Council for Graduate Medical Education, also requires neurology residency programs to learn how to communicate with patients and families, assess goals, and talk about end-of-life care. So, there's a real structural imperative now for neurologists to learn early on how to have serious illness conversations with their patients. Dr Monteith: Great. If there's anything for our listeners to get out of this conversation, what are the essential points? Dr Besbris: If you only take away one or two things from this conversation, I hope that they're that this is an awesome responsibility to be in a moment with a patient going through something challenging, to meet them in that moment with thoughtful, honest, empathic conversations about who they are and what's important to them. And that, just like any other procedure, these are skills that can be taught so that you can feel really confident and comfortable being in these moments. Dr Monteith: Excellent. Wow. Okay, I feel your energy and your empathy already. And so, why don't we just talk about skills? What is the best way to deliver tough news? I read this wonderful chart on SPIKES protocol. Dr Besbris: Yeah, the SPIKES protocol is one really well-known way to deliver serious news. And what's nice about SPIKES is it gives a mnemonic. And as neurology learners, we all love a good mnemonic to help you really center yourself when you're entering into these conversations so that you have a structured format to follow, just like with any procedure. So, the SPIKES protocol stands for Setting: so, making sure you have the right environment; Perception, or assessing what your patient or surrogate decision maker knows already so that you know where to begin; receiving an Invitation to deliver serious news. And then K stands for Knowledge, delivering in a clear and concise way the information that you want to make sure the family or patient walk away with. E for exploring Emotion; and S for really Summarizing what's been discussed and Strategizing on next steps. I think that having these kinds of conversations, it's just like being expert in anything. When you first start learning, it's helpful to have a set of very concrete steps you can follow. And you might even think through the mnemonic as you get ready to walk into that room. And as you become more expert, the flow becomes more natural. And maybe what you do before walking in to prepare is just honing what is that headline? What is that concise statement that I'm really going to give? And the rest may start to feel more natural and less protocolized. Dr Monteith: And there are a few other mnemonics. There's the NURSE mnemonic, which I like. You know, there's a balance between saying things and sounding kind of… you know, sometimes they're like, well, how could you understand what I'm going through? Have you been through something like this? And people shy away, and they're afraid to kind of be a part of these conversations. So how do we approach that with this, a NURSE mnemonic in a way that's kind of sincere? Dr Besbris: Absolutely. So, the NURSE mnemonic, unlike SPIKES, is not a step-by-step protocol. So, NURSE is a mnemonic, but you don't go through each letter and sort of give a naming statement and then an understanding statement and then a respecting statement and so on. Nurse is really a toolkit of different types of statements that we can give in response to emotions so that when you find yourself in a situation where a patient or family member is tearful, is scared, is angry, is expressing feelings, you have some phrases ready that feel authentic to you and that you feel are going to meet the moment and allow you to empathically respond to those emotions. Because until we do that, we really can't move further in this conversation with our patients and families feeling heard and respected. So, that NURSE mnemonic, those Naming, Understanding, Respecting, Supporting and Exploring statements, are really examples of statements that we can use to meet that moment with empathy and understanding and without implying that we have walked in their shoes. We want to avoid being presumptuous and really focus on just being present and empathic. Dr Monteith: So, let's just kind of run through, I think it's really important. Let's run through some of these examples. Maybe if someone's crying hysterically, how would we respond to that? Dr Besbris: So, this is an opportunity for Naming. And I made this one, I think, in the chart, a little bit obvious, meaning that we recognize when someone is crying that they are feeling probably very sad. This is an opportunity for us to name and thus normalize that emotion. I just think something as simple as, I think anyone would be really sad hearing this. These responses are not intended to fix this emotion. I'm not trying to get someone to stop crying or to, you know, necessarily not feel sad. It's really just to say, yeah, it's normal that you're feeling sad. It's okay. I'm here with you while you're feeling sad. And I'm going to be with you no matter what you're bringing to the table. Dr Monteith: Yeah. Let's go through just a couple of others. I mean, these are really good. Dr Besbris: Sure. Maybe Respecting. Dr Monteith: Yeah. So, my Dad is a fighter. Only God, not doctors, can know the future. Dr Besbris: Yeah. So, I love giving these examples with our learners because these statements, things like my Dad is a fighter or God will bring me a miracle or you don't know the answer. Only God knows what's going to happen, I think that they give a lot of doctors a feeling of confrontation, a feeling of anxiety. And I think there are a few reasons for that. And I think one of the main ones is that they’re statements that imply that we as doctors are not all-powerful and it's our patients or families sort of looking for a different locus of control, whether it's internal fortitude or a higher power. They're looking to something other than us, and maybe that makes us feel a little bit uncomfortable. And I think that sometimes physicians think that these statements imply that someone doesn't even understand what's going on. But maybe they're coming to this from a place of denial. And I would argue that when someone comes to you with a statement like my dad is a fighter or, you know, I'm looking to God to bring me a miracle or to show me the future. I think that what they're really saying is, wow, I'm really hearing that things are serious, so much so that I'm reaching for these other resources to give me strength and hope. I don't think anyone asks for a miracle if they think that a miracle is not needed, if the problem is easy to fix. And so, rather than come to these types of statements from a confrontational place of I'm the doctor and I know best, I think this is a great opportunity to show some respect and give some respecting statements. Your dad is a fighter. I don't think he could have come this far without being a fighter. Or, you know, I am so grateful that you have your faith to lean on during times like these to give you strength. These are also nice opportunities for exploring statements. For example, I'm so grateful to learn more about your dad. Can you tell me what it is that he has been fighting for all of this time? Dr Monteith: I love that. It's like a follow-up, and also validating. Dr Besbris: Yeah, it's validating. And it allows us to learn a little bit more about this person and to learn, well, is he fighting for a life that we can still achieve with our interventions to lead into the next part of a conversation? Or, is God is going to bring me a miracle? Well, tell me what a miracle looks like for you. I can't tell you how many times I thought someone was going to tell me that a miracle would be cure. And sometimes that is what comes up. But other times I hear, a miracle would be, you know, my loved one surviving long enough for the rest of the family to gather. And, you know, that is certainly something we can work towards together. Dr Monteith: So, why don't we talk a little bit about approach to goals of care discussions? They are tough, and let's just put it into perspective to the critical care team. It's time, the person's been in the ICU, the family wants everything thrown at medically. And it's to the point that the assessment is that would be medical futility. Dr Besbris: Lots to unpack there. Dr Monteith: I wanted to make it hard for you. Dr Besbris: No, no, this is good! I mean, this is something- I work in a, you know, almost one thousand-bed hospital with a massive critical care building. And so, these are not unusual circumstances at all. First of all, I would just say that goals of care conversations are not only about end-of-life care. And I make that point a few different times in the article because I think when people imagine goals of care, and one of the reasons that I think clinicians may sometimes shy away from goals of care discussions, is that they think they have to be sad, they have to be scary, they have to be about death and dying. And I would argue that, really, goals of care discussions are about understanding who a person is, how they live their life, what's most important to them. Most of these conversations should be about living. How are we going to together achieve a quality of life that is meaningful for you and treatments that are going to fit your needs and your preferences? But there is a little slice of that pie in the pie chart of goals of care discussions that is in the arena of end-of-life care. For example, ICU care with, really, the highest levels of intensity of care, and having to talk about whether that still is meeting the moment from the perspective of goals as well as the perspective of efficacy. So, from the goals standpoint, I approach these conversations just like any other goals of care conversation. Usually at this point, we're speaking to family members and not our patients because in a neurocritical care unit, if someone is that sick, they probably are incapacitated. And so, it's a moment to really sit down with family and say, please tell me about the human being lying in that bed. They can't introduce themselves. What would they tell me about themselves if they could speak right now? What kinds of things were important to them in the course of their treatment? What kind of a life did they want to live or do they want to live? So that then we can reflect on, well, can our treatment achieve that? And this process is called shared decision making. This is really where we take in data from the family, who are experts in the patient, and then our own expertise in the illness and what our treatments can achieve, and then bring all of that information together to make a recommendation that aligns with what we believe is right for a particular patient. So, in the example that you gave, the extreme circumstance where someone is receiving maximal intensive care and we're starting to reach the point of futility, I think that we need to first really understand, well, what does futility mean for this particular patient? Is it that we as healthcare providers would not value living in the state this person is in? Or is it that the treatments truly cannot physiologically keep them alive or meet their stated goals? If it's the first one, that I wouldn't want to be on machines unconscious, you know, at the end of my life, well, I have to set that aside. It's really about what this patient wants. and if the family is telling you they valued every breath, every moment, and if we have care that can achieve that, we should continue to offer and recommend that care. And as healthcare providers, it is so important that we do explain when treatments are not going to be able to physiologically meet a patient's needs or achieve their goals. And that's where we can say, I'm going to continue to do everything I can, for example, to, you know, keep your loved one here for these meaningful moments. And we are at a point where performing CPR would no longer be able to restart his heart. And I just wanted to let you know that that's not something that we're going to do because I have an obligation not to provide painful medical treatments that will not work. So, my approach to futility is really different than my approach to shared decision-making because in the context of objective futility, it's not about necessarily- it's not about decision-making, it's not about shared decision-making as much as it is explaining why something is simply not going to work. Does that make sense? Dr Monteith: Absolutely. And what I love in your article is that, you know, you go beyond the skills, but also potential communication challenges---for example, patients’ neurologic status, their ability to understand complex communication, or even cultural differences. So, can you speak about that briefly? Dr Besbris: Absolutely. In the world of neurological serious illness, it is incredibly common for our patients to face challenges in communication. That might be because they are aphasic, because they have a motor speech deficit, it might be because they're intubated, it might be because their capacity is diminished or absent. And so, there are a lot of challenges to keeping patients in these conversations. And in the article, I summarize what those challenges can look like and some strategies that we can use to continue to engage our patients in these conversations to the greatest extent possible and also turn to their surrogate decision makers where the patients themselves are no longer able to participate or participate fully. In terms of cultural considerations, I mean, there could be an entire article or an entire Continuum just on cultural considerations in neurology and in serious illness communication. And so, the key points that I really tried to focus on were exploring from a place of cultural humility what the beliefs and practices of a particular patient and family are in their cultural context, to ask questions to help you understand how those cultural differences may impact the way you approach these conversations. And being sensitive to folks with limited English proficiency, to ensure that we are using medical interpreters whenever possible. Dr Monteith: Excellent. Well, there's so much in the article. There's already so much that we just discussed, but our listeners are going to have to go to the article to get the rest of this. I do want to ask you to just kind of reflect on, you know, all the different cases and experiences that you have, and just, if you can give us a... /episode/index/show/continuumjournal/id/39184510

December 2025 Neuropalliative Care Issue With Dr. Maisha T. Robinson 12/03/2025

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: Subscribe to Continuum®: Continuum® Aloud (verbatim audio-book style recordings of articles available only to Continuum® subscribers): More about the American Academy of Neurology: Social Media Host: Guest: 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... /episode/index/show/continuumjournal/id/39184480

Dystrophinopathies With Dr. Divya Jayaraman 11/26/2025

Dystrophinopathies With Dr. Divya Jayaraman 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: Subscribe to Continuum®: Earn CME (available only to AAN members): Continuum® Aloud (verbatim audio-book style recordings of articles available only to Continuum® subscribers): More about the American Academy of Neurology: Social Media Host: 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... /episode/index/show/continuumjournal/id/38133340

Myotonic Dystrophy With Dr. Paloma Gonzalez Perez 11/19/2025

Myotonic Dystrophy With Dr. Paloma Gonzalez Perez 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: Subscribe to Continuum®: Earn CME (available only to AAN members): Continuum® Aloud (verbatim audio-book style recordings of articles available only to Continuum® subscribers): More about the American Academy of Neurology: Social Media Host: 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... /episode/index/show/continuumjournal/id/38133305

Muscle Channelopathies and Rhabdomyolysis with Dr. Hani Kushlaf 11/12/2025

Muscle Channelopathies and Rhabdomyolysis with Dr. Hani Kushlaf 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: Subscribe to Continuum®: Earn CME (available only to AAN members): Continuum® Aloud (verbatim audio-book style recordings of articles available only to Continuum® subscribers): More about the American Academy of Neurology: Social Media Host: Guest: 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... /episode/index/show/continuumjournal/id/38133260

Idiopathic Inflammatory Myopathies With Dr. Anthony Amato 11/05/2025

Idiopathic Inflammatory Myopathies With Dr. Anthony Amato 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: Subscribe to Continuum®: Earn CME (available only to AAN members): Continuum® Aloud (verbatim audio-book style recordings of articles available only to Continuum® subscribers): More about the American Academy of Neurology: Social Media 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. /episode/index/show/continuumjournal/id/38133235

Inclusion Body Myositis With Dr. Elie Naddaf 10/29/2025

Inclusion Body Myositis With Dr. Elie Naddaf 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: Subscribe to Continuum®: Earn CME (available only to AAN members): Continuum® Aloud (verbatim audio-book style recordings of articles available only to Continuum® subscribers): More about the American Academy of Neurology: Social Media Host: Guest: 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... /episode/index/show/continuumjournal/id/38133195

Limb-Girdle Muscular Dystrophies With Dr. Teerin Liewluck 10/22/2025

Limb-Girdle Muscular Dystrophies With Dr. Teerin Liewluck 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: Subscribe to Continuum®: Earn CME (available only to AAN members): Continuum® Aloud (verbatim audio-book style recordings of articles available only to Continuum® subscribers): More about the American Academy of Neurology: Social Media Host: Guest: 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. /episode/index/show/continuumjournal/id/38133140

Continuum Audio

TOPICS