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: Neurologic Complications of Cancer and Its Treatment Subscribe to Continuum®: shop.lww.com/Continuum Earn CME (available only to AAN members): continpub.com/AudioCME Continuum® Aloud (verbatim audio-book style recordings of articles available only to Continuum® subscribers): continpub.com/Aloud More about the American Academy of Neurology: aan.com Social Media facebook.com/continuumcme @ContinuumAAN Host: @headacheMD Full episode transcript available here 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 fourth generations of the tyrosine kinase inhibitors too. When you look at even the year of 2020, neurologic drugs were second only to oncologic drugs and FDA approval even at the height of COVID. So, don't feel badly if you don't remember any of the drugs really changing so rapidly. And they're better ideas, they're going to be fancier Car-T cells that attempt to get around some of the adverse effects of these and neurologists will retain really important role in following some of these patients, to be sure that these improvements are actually real and durable. Dr Monteith: Excellent. Thank you so much for this wonderful conversation. Dr Pruitt: Well, thank you so much for having me. And I hope people do get information from the article. Thanks. Dr Monteith: Again, today I've been interviewing Dr Amy Pruitt about her article on neurologic complications of cancer and its treatment, 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, 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.

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: Neurologic Complications of Critical Illness Subscribe to Continuum®: shop.lww.com/Continuum Earn CME (available only to AAN members): continpub.com/AudioCME Continuum® Aloud (verbatim audio-book style recordings of articles available only to Continuum® subscribers): continpub.com/Aloud More about the American Academy of Neurology: aan.com Social Media facebook.com/continuumcme @ContinuumAAN Host: @caseyalbin Guest: @ghoshal_shivani Full episode transcript available here 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 edema and potential, even herniation. But these low-level ammonias, just like you said, like we really need to understand the baseline, how much they've changed, the context of, you know, what the ammonia sent on ice? Was it laying out in the room for hours on end? That really contextualizes this lab that we otherwise have a very hard time interpreting. Dr Ghoshal: You're absolutely right that an ammonia greater than 120, you know, from our guidelines, both in lymphatic disease along with kidney disease. So, let's say above 120, your patient may be more at risk for cerebral edema. I could also play the devil's advocate and just remind, you know, that because ammonia isn't converted into ammonium in the brain, a peripheral ammonia level really may not reflect central nervous system levels. Right? So, let's say your ammonia is a bit lower also. But let's say there's been a significant change in ammonia for the patient. That may cause some cerebral disturbance that, you know, let's say this ammonia is still below 120. I may still be worried about it just because of the trend. Right? And knowing that my serum level may not really reflect what's going on above. Dr Albin: That's such a great point. So, lots of pearls around this lab, comes back abnormal all the time. In fact, I feel like it's more frequently abnormal than it is normal in our ICU patients. And so, I really wanted to give residents and listeners a way that we who work in the ICU contextualize that. So, in this case, you've been musing, hmm, this is probably not what's really going on here. He is still having these movements at the bedside. Let me ask you, when you hear shaking in the ICU, what's your big differential there? Dr Ghoshal: I always want to know, is it something like a myoclonus? Right? Is it something like an actual coordinated movement? Is this also something like a chorea, right? There are so many movements. So, like, I think that Continuum actually in the past put out a great issue about, like, movement disorders in critical illness. But really what I want to know is, like, first of all, like, is this neurologic or not neurologic? Right? Is this a, you know, let's say a seizure? Is this something suppressible, nonsuppressible? I really want to know more about what that movement is before I could even create a differential. Dr Albin: Totally. And so, when you're in the bedside, he's doing exactly that sort of classic myoclonus. He is having these short, jerky movements. They are not rhythmic. He is intermittently following some commands through this, but inattentive would be the best neurologic term for his mental status state. But then while you're there, he actually does have a GTC and you're in the room. It's generalized, it's convulsive, no longer responsive. His eyes are rolling up and you are well-convinced this truly is a seizure. As you start to approach, now, a seizure in the ICU, walk us through kind of some of the things that you think about in terms of labs you might want, what imaging you might want, what risk factors you're most concerned about. Dr Ghoshal: It sounds like he's having two distinct types of movement, right? He's having some myoclonus, right, or multifocal myoclonus where he has an intact mental status, for better or worse, through it. On that sort of bucket, I'm thinking more of metabolic disturbances. So, I went through this whole thing about the ammonia. But I think what I'd really want to know is, like, what is happening with his uremia, right? What is happening to his kidney function? I think you mentioned you had nephrolithiasis on top of being, I think, critically ill. I think that's some of the things I'd be looking at. I also would like to know about his antibiotics, any medications he's taking. And then for the seizure, I may want to know some of the similar labs. Right? Even just whatever, like, what is his magnesium? What is his calcium? Like, simple things being simple. And then I can go down a little bit more of a list on what I would do for the actual seizure. Just knowing that sepsis, hepatic disease, renal disease, antibiotics themselves may all increase your risk of having a seizure. Dr Albin: Yeah, absolutely. And I think what you said about sort of knowing the labs and knowing the medications plays such a crucial role in our workup for ICU changes in neurostatus. And so, in this case, because of that nephrolithiasis, you go scroll through his labs. And it looks like his creatinine has risen to 4 quite abruptly. So, he's got a pretty severe acute kidney injury. And his BUN has risen all the way to 80 over the course of three days. And then you're looking at the med list, and he is on a bunch of antibiotics, but one of them is cefepime. And so, walk us through, with just those couple of key words, what are some of the things that you are thinking about from the neurologic perspective? Dr Ghoshal: I am, like, salivating. I love these cases. No, I'm serious, right? So, like, I'll take a few minutes at the beginning to talk about, like, uremia and uremic encephalopathy. You know, we see uremia often, and uremic encephalopathy, we think, maybe there's some part of cytotoxic edema, right? Because that urea accumulates in the brain; it accumulates similar to, like, almost ammonia, creates these toxic wanding compounds in the thalamus, like, in the cortex, wherever it may be. And that itself will cause, like, a, let's say, impaired cytokine clearance from the brain, neuronal apoptosis, also affects the blood brain barrier. So, all of these things itself, like, from urea, all right, like a worsening uremia, can cause a different sort of CNS changes that could affect both the seizure side along with the multifocal myoclonus. Dr Albin: Yeah. Just putting him at risk of two very different types of neuropathology, right in the same case. Dr Ghoshal: Totally. And you know what I'll say about like, uremia? I could talk about this for a very long time, but like, really what I want people to remember is that uremia really increases your risk of seizure. I talked a little bit about this accumulation of uremia, like a uremic exquisitely in the brain, but you have this metabolic acidosis that develops from urea and you increase the activation of your acid-sensing ion channels. Right? And these retaining creatine metabolite actually cause more inhibition of your GABA receptors and stimulation of your NMDA. Right? So, all of these things together, like I think uremia is so common that we don't really take the time to think about, like, all of these things that could be happening. Dr Albin: Yeah. And then because of the poor kidney function, there's also accumulation of drugs. And there's this risk for toxic accumulation of some of the things that are sort of more renally metabolized. Dr Ghoshal: Absolutely. And on top of that, if you include, you know, what we talked about before, let's say you have cortical edema or hypoperfusion or a disordered cerebral autoregulation just from sepsis itself. You know, all of these things do fit together, right? It's not just a one thing for every. I know that you mentioned also there, antibiotic. I loved writing the section on antibiotic-associated encephalopathy, in part because it's something we don't spend as much time thinking about. I will say just broadly, there are three subtypes of antibiotic-associated encephalopathy. The first one, I think, is the most common. That, like, I associate it with beta-lactam, cephalosporins, or penicillin. Right? And that is where we can often see, like, seizure and myoclonus, right? You're really between, like, in days from antibiotic use. We think some of that is just from competitive antagonism of GABA receptors. To quickly talk about, you know, we also have types that are associated with quinolones and macrolides. More of, like, an acute psychosis. And then absolutely metronidazole, which causes a subacute encephalopathy---takes a little bit longer, you know, and more associated with cerebellar dysfunction. But I think every time that I am looking at a patient like this, I am absolutely going through and looking at the antibiotics. Dr Albin: I love that. And because it's not- cefepime is really the classic, and it's been the poster child for that type-one complication where you get mild blueness and seizure, usually within a day or two of starting the antibiotics---but it's all cephalosporins. It can be any beta-lactam. And so, cefepime is sort of our, like, poster child, but is not the only one. And so, with removing that antibiotic by getting him on a continual renal replacement therapy, this patient actually does quite well. And I think this is a take-home message for all of us, that helping the critical care team limit the risk to the patient from a medication perspective, us helping them say, you know, can we pull this off? Can we switch this to something that's going to be more neuro-friendly from their antibiotic perspective? really can make a huge amount of difference to that patient's long-term outcomes. Dr Ghoshal: Totally. Dr Albin: I think that you and I could talk about this all day long. I mean, this is just the, like, bread and butter of these complex patients that we see. But I think I'll summarize it for our listeners that really have to think about what procedures did the patient get, opening some of those notes to figure out where are their complications, and then taking a very holistic approach to the ICU patient and making sure that you're characterizing what kind of abnormal movements are they having? What are their labs? Being mindful about the context the lab was sent in and the patient's baseline, like we talked about with that hyperammonemia, really matters where the patient's been. And then that medication list is- can be culprit number one, two, and three for bad things that are happening to the patient. Again today. I've been interviewing Dr Shivani Ghoshal on her article on neurologic complications of critical illness, which appears in the February 2026 Continuum issue on neurology of systemic disease. Be sure to check out Continuum Audio episodes from this and all other issues. And thank you so much to our listeners and to Dr Ghoshal for joining today. It was a pleasure. Dr Ghoshal: Thank you 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.

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: Neurologic Complications of Hematologic Disorders Subscribe to Continuum®: shop.lww.com/Continuum Earn CME (available only to AAN members): continpub.com/AudioCME Continuum® Aloud (verbatim audio-book style recordings of articles available only to Continuum® subscribers): continpub.com/Aloud More about the American Academy of Neurology: aan.com Social Media facebook.com/continuumcme @ContinuumAAN Host: @IUneurodocmom Full episode transcript available here 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.

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: Neurologic Complications of Endocrine Disorders Subscribe to Continuum®: shop.lww.com/Continuum Earn CME (available only to AAN members): continpub.com/AudioCME Continuum® Aloud (verbatim audio-book style recordings of articles available only to Continuum® subscribers): continpub.com/Aloud More about the American Academy of Neurology: aan.com Social Media facebook.com/continuumcme @ContinuumAAN Host: @gordonsmithMD Guest: @RafidMustafa Full episode transcript available here 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 appropriately when they encounter patients with these debilitating diseases that can improve significantly. Dr Smith: So, I have one other diabetes question. That's a central nervous system complication that I wasn't particularly familiar with, and I'd love to hear you talk about a little more. And that is the diabetic striatopathy. Am I saying that right? Dr Mustafa: Absolutely. Yeah, yeah. Dr Smith: Yeah. Talk to us about that. That's pretty cool. Dr Mustafa: Yeah. You know, I think many of us that practice in the hospital setting will encounter patients with severe hyperglycemia. We're trained to recognize it as a stroke mimic. So many times these patients will come in, you know, glucose is in the six hundreds, thousands. And they might be just comatose, they might have focal neurologic signs that can mimic stroke. But one unique feature to be on the lookout for is diabetic striatopathy. And it's really thought to be an influence of out-of-range glycemic control on the basal ganglia itself. And so, these patients can present with unilateral hemibilismus, hemichorrhea, essentially a basal ganglia disorder. If you image them, you'll often see T1 hyperintensity in the striatum on MRI. And as you control the glycemic status, these patients improve. And it's just a unique phenomenon, but it's not- you know, many neurologists will see one of these probably in their careers. So, it's not something that's super rare that you'll never see it. Dr Smith: I think we're probably about out of time, Rafid. I wonder if there's anything that I didn't ask you about that you really think our listeners would like to hear. What nugget did I miss? And there are a great many from which you have to pick, I'm sure. Dr Mustafa: I think you've done such a great job. It's been a pleasure to chat with you. For me, the biggest takeaway for everyone to be aware of is oftentimes the first manifestation of something being off with the endocrine system will be something neurologic. And so, these patients may present to the neurologist first, or the neurologist will be consulted first, for something that seems purely neurologic. But it's important for us to have a high index of suspicion that the root cause could be something outside of the nervous system to help guide management down the line. When you're facing a patient with coma or peripheral neuropathy or myopathy or unique syndromes like the LRPN, remember to look beyond the nervous system, as this could be a very big clue to helping patients recover from disorders that are very, very treatable. Dr Smith: Rafid, thank you so much. It's been a great conversation. Your article is truly outstanding. Topic is kind of complicated, but it's not as complicated as I thought it was going into it. And I certainly learned a lot and enjoyed it a great deal. So, thank you for spending time with me today.  Dr Mustafa: Thank you so much for having me. I appreciate it. Dr Smith: Again, today I've been interviewing Dr Rafid Mustafa from the Mayo Clinic about his article on neurologic complications of endocrine disorders, 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 of Continuum, and thanks for joining us today. Dr Monteith: This is Dr Teshamae Monteith, Associate Editor of Continuum Audio. If you've enjoyed this episode, you'll love the journal, which is full of in-depth and clinically relevant information important for neurology practitioners. Use the link in the episode notes to learn more and subscribe. AAN members, you can get CME for listening to this interview by completing the evaluation at continpub.com/audioCME. Thank you for listening to Continuum Audio.

Many serious medical illnesses are associated with some degree of serum electrolyte abnormality, renal impairment, or both. The neurologist must determine if the patient's neurologic symptoms are related to the renal and electrolyte disturbances or whether a concurrent primary neurologic process is at play. In this episode, Casey Albin, MD, speaks with Eelco F. M. Wijdicks, MD, PhD, FAAN, FACP, FNCS, author of the article "Neurologic Manifestations of Renal and Electrolyte Disorders" 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. Wijdicks is a professor of neurology and attending neurointensivist for the Neurosciences Intensive Care Unit at Mayo Clinic in Rochester, Minnesota. Additional Resources Read the article: Neurologic Manifestations of Renal and Electrolyte Disorders Subscribe to Continuum®: shop.lww.com/Continuum Earn CME (available only to AAN members): continpub.com/AudioCME Continuum® Aloud (verbatim audio-book style recordings of articles available only to Continuum® subscribers): continpub.com/Aloud More about the American Academy of Neurology: aan.com Social Media facebook.com/continuumcme @ContinuumAAN Host: @caseyalbin Guest: @EWijdicks Full episode transcript available here

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: continuum.aan.com Subscribe to Continuum®: shop.lww.com/Continuum Continuum® Aloud (verbatim audio-book style recordings of articles available only to Continuum® subscribers): continpub.com/Aloud More about the American Academy of Neurology: aan.com Social Media facebook.com/continuumcme @ContinuumAAN Host: @LyellJ Guest: @AaronLBerkowitz Full episode transcript available here 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 answers to how often can this neurology be the primary feature of this rheumatologic disease with no systemic manifestations and when should we look or as we mentioned, the complicated endocarditis consult. I won't say we covered everything. This could be, and is, textbook-sized, and there are textbooks on this topic. But I think on the contrary, authors came back and had sections on things that I might not have thought to ask- to cover. Dr Sarah LaHue, my colleague here at UCSF, I asked for an article, as traditionally in this issue, on the neurology of pregnancy in the postpartum state and included, I think probably for the first time in Continuum, a fantastic review of neurologic considerations in patients in menopause, which I'm not sure has been covered before. So, things that I wouldn't have even thought to ask for. Our authors came back with some fantastic stuff. And the ICU article by Dr Shivani Ghoshal, instead of focusing just on altered mental status in the ICU, weakness in the ICU---those are all in there---I also asked her to discuss complications of procedures in the ICU. How often do procedures in the ICU cause local neuropathies or vascular injury, these types of things. Dr Jones: Yeah, me too. And I guess that's a great advertisement, that there probably are things that we didn't cover, but if there are, we can't think of them. We've done as best as we can. So now let's come back to our Continuum Audio trivia question for our listeners. And I'll repeat the question: what neurologic complication can occur from correcting hyperglycemia too quickly? And I actually think there might be two correct answers to this one. Dr Berkowitz, what do you think? Dr Berkowitz: Yeah, I was thinking of two things. I hope these are the things you're thinking of as well. One is what I think used to be referred to as insulin neuritis, sort of an acute painful small fiber neuropathy from after the initiation of insulin, I think also called treatment-induced diabetic neuropathy or something of that nature. And then the other one described, defined and classified by your colleagues there in Rochester, the diabetic lumbosacral radiculoplexis neuropathy or Bruns-Garland syndrome or a diabetic amyotropy, I think, can also---if I'm not mistaken---also occur in this context; you should have weight loss in association with diet treatment of diabetes. But how did I do? Dr Jones: Yeah, you win the prize, the first-ever prize. There's no monetary value to the prize, but pride, I think, is a good one. Yeah, those were the two I was thinking of. The treatment-induced neuropathy of diabetes is really nicely covered in Dr Rafid Mustafa's article on the neurologic complications of endocrine disorders. It's a rare condition characterized by the acute/subacute onset of diffuse neuropathic pain and some usually some autonomic dysfunction. And it occurs when you have rapid and substantial reductions in blood glucose levels. And you can almost map it out. There was a study from 2015 which is referenced in the article, which found that a drop in hemoglobin A1c of 2 to 3% over three months confers about a 20% absolute risk of developing this treatment-induced neuropathy of diabetes, and a drop of more than 4%, more than 80% risk. So, very substantial. And then in the other---we see this commonly in patients with diabetic lumbosacral radiculoplexis neuropathy---they have the subacute onset of usually asymmetric pain and weakness in the lower limbs that tends to occur more frequently in patients who have had recent better control of their sugar. We can also see it in the upper limbs too. So, you get a perfect score. Dr Berkowitz, well done. Again, I want to thank you. I want to thank you for such a great issue, a great article to kick off the issue, and a great discussion of the neurology of systemic disease. Today I learned a lot talking today, I learned a lot reading the issue. Really grateful for your leadership of putting it together, pulling together a really great author panel, and I think it will come in handy not just for our junior readers and listeners, but also our more experienced subscribers as well. Dr Berkowitz: Thank you so much. Like I said, it was a big honor to be invited to guest edit this issue. I've read it every three years since I started residency. It's always one of my favorite issues. As you said, a manual for consultative neurology, and I learned a ton from our authors and really appreciate the opportunity to work with you and the amazing Continuum team to bring this from an idea, as you said, probably over a year ago to a printed issue. So, thanks again, Lyell. Dr Jones: Thank you. And again, we've been speaking with Dr Aaron Berkowitz, guest editor of Continuum's most recent issue on the neurology of systemic disease. 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.

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: Managing Prognostic Uncertainty in Neurologic Disease Subscribe to Continuum®: shop.lww.com/Continuum Earn CME (available only to AAN members): continpub.com/AudioCME Continuum® Aloud (verbatim audio-book style recordings of articles available only to Continuum® subscribers): continpub.com/Aloud More about the American Academy of Neurology: aan.com Social Media facebook.com/continuumcme @ContinuumAAN Host: @caseyalbin Full episode transcript available here Dr Jones: This is Dr Lyell Jones, Editor-in-Chief of Continuum. Thank you for listening to Continuum Audio. Be sure to visit the links in the episode notes for information about earning CME, subscribing to the journal, and exclusive access to interviews not featured on the podcast. Dr Albin: Hello, this is Dr Casey Albin. Today I'm interviewing Dr 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 reasons. One is that, just, the illness uncertainty of all of our great therapies are just going to be creating more uncertainty for the future. And precision medicine is paradoxical, and that actually it creates more uncertainty. So, I think we need to be prepared that we have to manage prognostic uncertainty better, because it's definitely going to increase. And two, it's what I said earlier, is that actually managing prognostic uncertainty is not an end to itself. It's actually helping patients and families adapt to their new and sometimes harsh new reality and actually help them to ultimately get to a place where maybe either their condition is neither dreaded, but actually they can accept it as their new reality and actually achieve some sort of existential well-being and existential health. I think that we have a lot more to emphasize in this area. And for far too long, we've focused on the certainty aspect of our field and not enough on the uncertainty in the world of medicine to help our patients and families. Dr Albin: And gosh, isn't there just so much uncertainty? And I think this has been beautiful. So, thank you again for coming and sharing your expertise. Dr Holloway: Thank you very much. It's been a pleasure. Dr Albin: For all of our listeners out there, this is a truly fantastic article, and I would just like to direct you to going to read the cases because not only do the cases offer a little bit of practical advice, but there's one that's actually sort of a philosophical discussion about, what does it mean to be alive and confront death? There's some beautiful artwork that's featured as well. So this is just a really unique article, and I'm excited for our listeners to have a chance to check it out. So again, today I've been 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. Be sure to check out Continuum Audio episodes from this and other issues. 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.

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: Neuropalliative Medicine in Pediatric Neurology Subscribe to Continuum®: shop.lww.com/Continuum Earn CME (available only to AAN members): continpub.com/AudioCME Continuum® Aloud (verbatim audio-book style recordings of articles available only to Continuum® subscribers): continpub.com/Aloud More about the American Academy of Neurology: aan.com Social Media facebook.com/continuumcme @ContinuumAAN Host: @gordonsmithMD Full episode transcript available here Dr Jones: This is Dr Lyell Jones, Editor-in-Chief of Continuum. Thank you for listening to Continuum Audio. Be sure to visit the links in the episode notes for information about earning CME, subscribing to the journal, and exclusive access to interviews not featured on the podcast. Dr Smith: This is 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, and maybe what's your pitch? Dr Treat: I'm just going to give a little bit of a snippet from a poem by Andrea Gibson, who's a poet, that I think speaks really clearly to this. They say a difficult life is not less worth living than a gentle one. Joy is simply easier to carry than sorrow. I think that sums these things up really well, that we find a lot of meaning in the work that we do. And it's not that it's easier or harder, it's just that these things all matter. I'm going to speak now, Gordon, to your question about how I got to my journey. When I went into pediatrics and then neuro in my training, I have always loved the brain. It's always been so crucial to what I wanted to do and how I wanted to be in the world. And when I was in my training, I saw that a lot of the really impactful conversations that we were having felt like we left something out. It felt like we couldn't talk about some of the anticipated struggles that we would anticipate on a human level. We could talk about the rate and the volume of the G tube, but we couldn't talk about how this was going to impact a mother's sense of being able to nourish and bond and care for their child because we didn't have answers for those things. And as I went on in my journey, I realized that even if we don't have answers, it's still important for us to acknowledge those things and talk about them and be there for our patients in those conversations. Dr Smith: Well, Lauren, what a great way to end, and what a wonderful conversation, and what a great article. Congratulations and thank you. Dr Treat: Thank you, Gordon. It was a pleasure to be here. Dr Smith: Again today, I've been interviewing Dr Lauren Treat about her really great article on neuropalliative medicine in pediatric neurology practice. This article appears in the December 2025 Continuum issue on neuropalliative care. Be sure to check out Continuum Audio episodes from this issue and other issues. And thanks again to you, our listeners, for joining us today. Dr Monteith: This is Dr Teshamae Monteith, associate editor of Continuum Audio. If you've enjoyed this episode, you'll love the journal, which is full of in-depth and clinically relevant information important for neurology practitioners. Use the link in the episode notes to learn more and subscribe. AAN members, you can get CME for listening to this interview by completing the evaluation at continpub.com/audioCME. Thank you for listening to Continuum Audio.

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: Neuropalliative Care in Movement Disorders Subscribe to Continuum®: shop.lww.com/Continuum Earn CME (available only to AAN members): continpub.com/AudioCME Continuum® Aloud (verbatim audio-book style recordings of articles available only to Continuum® subscribers): continpub.com/Aloud More about the American Academy of Neurology: aan.com Social Media facebook.com/continuumcme @ContinuumAAN Host: @AaronLBerkowitz Guest: @BenziKluger Full episode transcript available here Dr Jones: This is Dr Lyell Jones, Editor-in-Chief of Continuum. Thank you for listening to Continuum Audio. Be sure to visit the links in the episode notes for information about earning CME, subscribing to the journal, and exclusive access to interviews not featured on the podcast. Dr Berkowitz: This is Dr Aaron Berkowitz, and today I'm interviewing Dr 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 grief and loss and changes in independence. And then I would say, you know, I want to make sure that we have time to talk about this, and we'll connect you to our chaplain or counselors so that you can talk about and process your grief. And at the same time, I want to make sure that we don't lose sight that there are still opportunities for joy and love and meaning in your life. And I want to make sure that we make space and time to talk about those things too. So, it's creating that balance. That's a transition that, even when you're on a very heavy subject---in fact, I would say maybe even particularly when you're getting into a heavy subject---that you can talk about joy and love and meaning. I gave a talk at the American Academy of Neurology a few years ago where I referred to them as weapons that you can use against some curable illnesses. One example is, my approach to chronic pain often centers around joy. So, I'll have somebody who comes in with back pain. My goal with that person is not for them to take Percocet four times a day to eliminate their back pain. When I talk to that person, I may find out that their grandson's soccer games and boxing class are the two most important things in their life. So maybe we take Percocet three or four times a week a half-hour before those activities so that you can get that joy back in your life. And so, we kind of use joy as a way and as a goal to reclaim those parts of your life that are most important to you. So, that's a pretty concrete example. Even for people nearing end of life, it could be giving people permission to eat more of their favorite food, often times ice creams, milkshakes---which is great, because we want people to gain weight at that point. Getting out into nature, even if they can't hike or do things the way they used to, that they might be able to go out with their family. Having simple touch, spending time together, really trying to prioritize what's most important. In the article, we talk about the total joy of life or the total enjoyment of living. But I like to be systematic about thinking about opportunities for living and make sure that we're just as systematic about thinking about what are the opportunities for joy as we are about thinking about the sources of suffering. Dr Berkowitz: I'm sure I only sort of scratched the surface of palliative care in general, let alone specifically related to Parkinson's disease and other related disorders. For our listeners who may be interested in learning more about neuropalliative care specifically or getting a little more training in this, any recommendations? Dr Kluger: Yeah, absolutely. Thanks for asking me that. There is a growing community of people interested in neuropalliative care, and so I would really encourage people who are passionate about this and want to get connected to this community to consider joining the International Neuropalliative Care Society. We're a young and growing community. I think you'll find a lot of like-minded individuals. And whether you're thinking about going into neuropalliative care as a specialty or doing a fellowship or just making it more a part of your practice, you'll find a lot of like-minded individuals. And then at the end of the article, there are some websites, but there are opportunities: for example, Vital Talk, the education palliative and end-of-life care neurology curriculum out of Northwestern, where people can dig deeper and kind of do their own mini-fellowship to try to bolster these skills. Dr Berkowitz: Gives, certainly, me a lot to think about. I'm sure it gives our listeners a lot to think about as well in implementing some of the palliative care concepts you tell us about today and discuss in much more detail in your article as we see these patients and, hopefully, can refer them to talented expert colleagues like yourself in palliative care, but don't always have that opportunity. And as you said, there's always opportunities to be practicing palliative care, even though we're not palliative care specialists. So, I encourage all the listeners to read your article, which goes through these concepts and many more as well some sort of key points and strategies for implementing them as you gave us many examples today. So again, today I've been 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. Be sure to check out Continuum Audio episodes from this and other issues, and thank you again to our listeners for joining us today. Dr Monteith: This is Dr Teshamae Monteith, Associate Editor of Continuum Audio. If you've enjoyed this episode, you'll love the journal, which is full of in-depth and clinically relevant information important for neurology practitioners. Use the link in the episode notes to learn more and subscribe. AAN members, you can get CME for listening to this interview by completing the evaluation at continpub.com/audioCME. Thank you for listening to Continuum Audio.

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: Neuropalliative Care in Dementia Subscribe to Continuum®: shop.lww.com/Continuum Earn CME (available only to AAN members): continpub.com/AudioCME Continuum® Aloud (verbatim audio-book style recordings of articles available only to Continuum® subscribers): continpub.com/Aloud More about the American Academy of Neurology: aan.com Social Media facebook.com/continuumcme @ContinuumAAN Full episode transcript available here Dr Jones: This is Dr Lyell Jones, Editor-in-Chief of Continuum. Thank you for listening to Continuum Audio. Be sure to visit the links in the episode notes for information about earning CME, subscribing to the journal, and exclusive access to interviews not featured on the podcast. Dr Grouse: This is Dr Katie Grouse. Today I'm interviewing Dr 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 care of patients who have dementia. And there's so much emotion in the families when they're having this discussion. And I think really acknowledging there's a huge emotional piece of the conversation is one key piece. For families and caregivers, they're thinking, I don't want my loved one to starve to death. That's usually the most important thing in their mind. We have to address that concern in the conversation, or they're never going to get to a point of satisfaction with the decision that's being made. So, I think while there is still some controversy in the literature about artificial nutrition for patients who have dementia, the bulk of data indicates that it is not helpful for patients. It may exacerbate dementia, it leads to more restraint. And so, I think unless there's some reversible medical condition that we're just trying to do artificial nutrition to get them through, like, they have a stroke and we're expecting that their dysphasia is going to improve because of the stroke is going to heal. Those situations might be a good reason, but if we really think that the driving factor behind their dysphasia is their dementia, I think we should be guiding the families away from that. And I think that explaining that as dementia gets really advanced, the body is slowly shutting down. The body is not needing as much nutrition, and forcing more nutrition in has not been shown to help people who have dementia. Really putting it in that sort of language is going to help the families understand and be comfortable with that decision. I also think that it's really helpful to consider talking to families about what they can do and not have the entire conversation be about what we're not doing or not putting in a feeding tube for artificial nutrition. So, I think really good counseling about, we can do comfort feeding, we can expand what food we're giving the person who has dementia and really focus on foods that they really enjoy and not worry so much about the health and nutrition anymore. I think that focus on what they can take control of can also help make the decision easier for families.  Dr Grouse: I really like that approach. And I agree, it does seem that it being such an emotional decision with just so much a concern about this underlying feeling of not caring for their family member. I think that is a really great way to look at it  and to kind of start off that conversation. Now, I'd love to hear more about what drew you to this field when you first got into your career as a neurologist. Dr Weisbrod: I had an interesting journey to doing neuropalliative care. Definitely didn't know that's what I was going to do when I started neurology residency. At University of Rochester, we had amazing palliative care physicians that were involved in medical school, and so I got a little bit of exposure to it early on. Then when I was in neurology residency, I first of all realized that I really enjoyed making sure that what we were doing respected a patient's wishes. And so, as other people seemed to run away from those conversations, I was really drawn to them. And so that definitely made me realize that that might be more of the right field for me. But also, as I went through neurology residency, I really discovered that I love so many different things in neurology, and that made me not want to subspecialize and focus on a narrower set of conditions in neurology. So, doing palliative care fellowship was a really good way of getting a specialist tool set and expanding my knowledge in one area, but staying a neurologist, generalist. And I think it also really enhances a lot of the other things I do in neurology. It gives me a lot of additional skills on how to counsel patients and how to prepare for the future in general. I think there's a lot about just good bedside manner in palliative care education. I feel like it helped me become a better neurologist, and I decided that I really loved the palliative care piece as well.  Dr Grouse: Well, we're certainly all grateful that you found this aspect of your career and have been able to share the skills you've honed with us as well. And we really appreciate you taking the time to talk with us about your excellent article today, which I encourage everybody to read.  Dr Weisbrod: Yeah, thank you. It's been wonderful to be on, and I hope that people can take away a few small points from the article. Dr Grouse: Again, today I've been interviewing Dr Neal Weisbrod about his article on neuropalliative care in dementia, 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 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.