Dr. Mark Burish, an expert in cluster headache, SUNCT, and SUNA, discusses the importance of accurate diagnosis and effective treatment options within the trigeminal autonomic cephalalgias family. Topics include distinguishing between headache types, first-line treatments, challenges in diagnosis, severity of pain, use of oxygen and CGRP agents. The podcast also covers circadian patterns of cluster headaches, advancements in treatment options like Galcanase Anad and occipital nerve stimulators, and Dr. Burish's article on cluster headaches in Continuum.

Most patients with migraine require acute treatment for at least some attacks. There is no one-size-fits-all acute treatment and multiple treatment trials are sometimes necessary to determine the optimal regimen for patients. In this episode, Teshamae Monteith, MD, FAAN, speaks with Rebecca Burch, MD, FAHS author of the article “Acute Treatment of Migraine,” in the Continuum April 2024 Headache 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. Burch is an assistant professor in the Department of Neurological Sciences at Larner College of Medicine, University of Vermont, Burlington, Vermont.  Additional Resources Read the article: Acute Treatment of Migraine Subscribe to Continuum: continpub.com/Spring2024 Earn CME (available only to AAN members): continpub.com/AudioCME Continuum® Aloud (verbatim audio-book style recordings of articles available only to Continuum® subscribers): continpub.com/Aloud More about the American Academy of Neurology: aan.com Social Media facebook.com/continuumcme @ContinuumAAN Host: @headacheMD Guest: @RebeccaCBurch Full Transcript Available Dr Jones: This is Dr Lyell Jones, Editor-in-Chief of Continuum, the premier topic-based neurology clinical review and CME journal from the American Academy of Neurology. Thank you for joining us on Continuum Audio, a companion podcast to the journal. Continuum Audio features conversations with the guest editors and authors of Continuum, who are the leading experts in their fields. Subscribers to the Continuum journal can read the full article or listen to verbatim recordings of the article by visiting the link in the Show Notes. Subscribers also have access to exclusive audio content not featured on the podcast. As an ad-free journal entirely supported by subscriptions, if you're not already a subscriber, we encourage you to become one. For more information on subscribing, please visit the link in the Show Notes. AAN members, stay turned after the episode to get CME for listening. Dr Monteith: This is Dr Teshamae Monteith, Associate Editor of Continuum Audio. Today I'm interviewing Dr Rebecca Burch on acute treatment of migraine, which is part of the April 2024 Continuum issue on headache. Dr Burch is an Assistant Professor at Larner College of Medicine at the University of Vermont in Burlington, Vermont. Well, hi, Rebecca - thank you so much for being on our podcast. Dr Burch: Thank you so much for having me. It's always such a pleasure to talk with you. Dr Monteith: You wrote a really excellent article on acute management of migraine - really detailed. Dr Burch: Thanks so much. I'm glad you enjoyed it. I had a lot of fun writing it. Dr Monteith: Why don't you tell our listeners, what did you set out to do in writing this article? Dr Burch: Whenever I write a review article on a topic, I aim for two things, and these were the same things that I was aiming for here with this one. One is practicality and just for it to be really applicable to clinical practice and every day what we do - the ins and outs - and that was the case here as well. I really love a good table in a paper like this. I spend a lot of time on tables. I want people to be able to print them out, use them as reference, bookmark them. So, that was one thing that I aimed for - was just for this to be really useful. The other thing is, I really wanted to instill a sense of confidence in people after reading this article. I think the management of migraine can be very overwhelming for people taking care of people with migraine. And there are so many acute treatment options, so I wanted to give a framework for how to think about acute treatment (how to approach it), and then within that framework, to really go into the nuances of all the various options, and how to choose between them, and what to do in specific circumstances. And I also really wanted to cover what to do when the first couple of options don't work. Because I think most neurologists, PCPs, are comfortable prescribing sumatriptan, and then the question is, what happens when that doesn't work or the patient doesn't tolerate it? What do you do for rescue therapy? What do you do for your fifth-line treatment? And I think that was an area that I really wanted to cover as well. Dr Monteith: Yeah, you got a lot done, for sure. So, I agree - there's been so many options, new options, even over the past five or definitely ten years. One of the things that excited me about going into headache medicine were all the options, thinking of migraine and other headache disorders as a treatable disorder. What made you interested in headache medicine? Dr Burch: Like so many other people who ended up going into headache medicine, I had a fantastic mentor in residency who was really great at treating headache patients - as Brian McGeeney at Boston Medical Center (he's now at Brigham and Women's). He was really passionate about headache medicine, and seeing patients with him was always such a delight because he always had something to try. And many other situations, it would be, like, “Well, this person, we've tried something; we don't know what else to do.” But when you work with a headache specialist as a mentor or as a preceptor, they have so many things they can do, and people largely get better. And they're so grateful - it changes people's lives to be able to treat their migraine, their other headaches effectively. So that was really inspiring. And then when I started doing headache rotations and sort of thinking about whether this was the right subspecialty for me, I quickly realized two things about headache medicine that ended up being what I really love about it to this day. One is the longitudinal relationships that we have with patients - we take care of people for a long time. And it doesn't always have to be that we're seeing people every three months and making tweaks - sometimes it's once a year. But we do get to know people. You know, I have two children. Many of my patients saw me through both of those pregnancies and ask about my kids, and it's just lovely to have that sort of personal relationship over time. And then the other aspect that I really love is that we can't see patients in isolation just as their migraine disorder or headache disorder; we really have to think about who they are as a whole person. What's going on in your life? What are your stressors? How's your job, how's your family? How are you sleeping? How's your mood? Are you exercising? What's your diet like? All of these things impact how someone's migraine disorder is going. And I like to joke, “I'm half life coach, you know, and half pharmacologist,” and I love that. I love that I bring my whole self every time I see a patient and see their whole self, too. Dr Monteith: I can just imagine how well you do that. You mentioned the power of mentorship, and that seems to be a theme when interviewing authors (that mentors are super important). And I know you've been an incredible mentor. Why don't you tell us a little bit about your academic journey? I mean, I see you in the halls at these major conferences, but I've never pulled you aside and said, “Hey, what's your journey - your academic journey – like, other than your great editorial work for neurology, of course?” Dr Burch: I did my fellowship at Brigham and Women's and then stayed on there as an attending, and ultimately took over as fellowship director before I took a break, which I'll talk about in a minute. In that time, I was doing clinical care and I had a research program and I was doing education - doing a lot of teaching for CME work, and teaching primary care and subspecialists about migraine - and I really love that piece of things - and precepting fellows. And then, I also had my editorial work on top of that. I have been a medical journal editor as long as I have been a headache specialist. We were talking about mentors, and I want to talk, at some point, about my fantastic mentor, Elizabeth Loder, who is also a research editor, in addition to being an outstanding headache medicine clinician and researcher and educator. But she got me started as an Assistant Editor for Headache in my fellowship year - the journal Headache - and I continued as an Associate Editor there. I worked as a Research Editor for the British Medical Journal for a while and then joined the journal Neurology, where I am one of the eight Associate Editors. I cover the general neurology portfolio, which includes a lot of things - includes headache medicine, includes traumatic brain injury, pain, spine, neuro-oncology, neuro-otology - there's a whole bunch of different things that I have learned a lot about since starting as an editor. So, I have always had a lot of different parts to my job, which keeps me interested. It's also a lot, and I do always talk about the fact that I ended up taking a year off because I think it's important to be real about the lives that we lead and our jobs as academic neurologist. So I ended up having a bunch of family health issues that came up in 2021, and combined with all of the other things that we're doing, I just couldn't keep it all going. And I ended up getting sort of burned out a little bit and was having trouble balancing all of that and the family health issues that were going on. And I ended up taking about a year off from clinical work. I continued with my editorial work and kind of got everything sorted out with my family, and then just started my current position in January. I'd just like to bring that up to show that – you know, not everyone's going to be able to take a year off - I recognize that. But I think it's important to normalize that just being “pedal to the metal” all the time is not feasible for anyone. And we need to recognize that it's okay to take breaks periodically. So, I'm kind of an evangelist for the “taking-a-break model.” Dr Monteith: Yeah, you took a break but you kind of didn't, because you've been doing a lot for us in neurology, and I certainly appreciate that. Speaking about all of that and feeling burnt out - what inspires you; what does keep you going? Because I know you keep going. Dr Burch: I do. Well, it's really funny - when I took my time off, I used that as an opportunity to really think about, “Okay, is this really what I want to be doing? Is this the right path for me? Do I want to rethink things?” And I ended up in the same job that I left, just in a different place. I'm still doing clinical care, and I'm the fellowship director of my current institution, and I still do all this education, and I'm getting my research program going, and I'm still an editor. So, I think the bottom line is, I have always loved what I do; it's just a question of making it all fit. So, you know, when I get up in the morning, when it's a clinic day, I am so excited to just go and talk to my patients and see how they're doing and see if there's something I can do to make them feel better. And it's just delightful to be able to play that role in people's lives, even if they're not getting better. You know, I think sometimes just being there with them is of service and is worth doing, and that feels very meaningful to me. And I have a fellow now. I love working with my fellow and teaching, and I love just talking about headache medicine and, you know, “What can we do to help people?” So, that really inspires me. On an editorial day, I'm interested in what research people are doing and seeing how neurology can publish the best research possible. We're all moving the field forward and it's just delightful to see what people are doing. I don't know - I like all of it. Dr Monteith: Yeah - you spoke about talking to patients and having that interaction. I'm thinking about migraine and patients going into status, having severe attacks. Is there any case that really moved you, made you think differently? Dr Burch: What really sticks out in my mind when I think about acute treatment, in particular, is what doesn't necessarily fit neatly into the algorithms that we develop. The situations where creativity and persistence and working together really make a big difference for a patient. I am the first person to tell you we do not know everything yet, and maybe we will never know everything. And I think sometimes we need to think outside the box. We need to “listen between the lines” to what people are telling us, and really work together to figure out a very individualized, well-crafted plan. I'm thinking about times that - for example, someone came to me and said, “I'm having these intermittent episodes where I get all of the symptoms of migraine but I don't get headache pain. You know, I get the nausea and I get the photophobia and I'm irritable and, you know, what do I do about this?” And we ended up saying, “Okay, well, take your triptan and let's see what happens,” after trying some other things. And it worked, and it turned out to be the only thing that worked. And that's maybe something we wouldn't think about because we talk about pain all the time and that was really key to improving that person's quality of life. Or, you know, trying to figure out - if there's a situation that provokes an attack pretty reliably, how do we decide when this person is going to take their acute medication ahead of time to try and prevent that from happening? So, for example, somebody who always gets a migraine when they get on the airplane - can we maybe think about doing that? Is it part of the algorithm that we all think of? No, but it's what's right for that person. I feel like I am doing my best work when I really sit with the person and their individual story and listen to how they describe their experience, and then partner with them to come up with something that really works for their specific situation. Dr. Monteith: Give us a few tips. You mentioned the use of triptans, even thinking about most bothersome symptoms, associated symptoms. Let's say they tried the triptan, they have a severe migraine, and still with pain two hours later - what do we say? Dr Burch: Yeah, and I think this is - like I said at the beginning, this is where people often start to feel a little anxious sometimes; you've tried the triptan, it's not necessarily working - what do you do? I think there's a couple of things. First of all, triptans are still first line for migraine - in the absence of vascular risk factors, that's still what we start with. The guidelines ask us to try two different triptans before we try switching to a different class. So, the first thing - most people start with sumatriptan (it’s the oldest one; it's usually covered well by insurance). So, first thing to ask is, what was the patient's experience with it? Was it not strong enough? Did it not work fast enough? Was it too strong? And then you think about - based on that response, are we going to go to eletriptan, which is kind of considered to be the strongest or most effective of the triptans? Are we going to go to rizatriptan, which is faster onset? Are we going to go to naratriptan or frovatriptan, which lasts longer? Then, if the second triptan doesn't work, we think about moving to a gepant - that's what the guidelines are currently recommending. The other thing to consider is whether someone needs an antinausea medication or an antiemetic, because if people are feeling queasy, they're worried about vomiting, then they may be reluctant to take medication. Or it could be that their GI system just isn't working as well, so we need to think about better absorption of the oral medications as well. There are lots of other tips and tricks also. I don't want to go through the whole list, but one of the things that I put in the article is a whole set of things to do if triptans are not effective or if your acute treatment is not effective. It's also things like making sure they're treating early, using combinations of medications - there's a whole list. Then that brings us to rescue therapy. And I think that's also essential; we don't talk enough about rescue therapy. We do think about it, but we think about it when we get the phone call to our clinic, where we get the message that says, “I took my treatment didn't work. And this is the second time this has happened. And I'm desperate, and what do I do?” That's not when you want to be managing this. You want to be managing this at the visit, before it happens. So, I think anybody who has an attack occasionally that doesn't respond to treatment needs a rescue plan. There's a bunch of different things you can do - I talk about this in the article as well - but some backup, like an injectable sumatriptan, might be helpful. Sometimes we use sedating medications to just try and help people go to sleep. I personally really like to give phenothiazine antiemetics because they have intrinsic antimigraine properties as well as being sedating and helping with nausea, so I sometimes use those. But there are a lot of different strategies and it's just worthwhile looking through them and getting comfortable with a few of them to give patients as a backup plan. Dr Monteith: I loved – I did love your tables. I love that you put the devices in the tables because usually when we think about neuromodulation, that's almost like usually a separate article. But you went ahead and combined it because all of the devices may have some acute benefits for patients. So, how do you think about devices? How do you talk to patients about devices? Dr Burch: Yeah, well, all of them were originally tested for acute treatment before their preventive indications. So, I think it's appropriate; if we're thinking about a plan, we want to have everything in one place, which is why I always include neuromodulation. The neuromodulation device that has the strongest evidence is remote electrical neuromodulation, which is the band that patient wears on their arm and uses as an acute strategy. The others may be helpful for individual patients, but I tend to lean towards the remote electrical neuromodulation as my acute treatment of choice just because of the strength of the evidence. I also haven't had as much trouble getting it for patients. The big barrier for all of these neuromodulation devices is cost because, relatively - I mean, they're not cheap and they're almost never covered by insurance (sometimes they are, but not always), and many of our patients are going to be able to access them and many of our patients are not. So, I'm always judicious in the way that I talk about them because I don't really want to put people in the situation of having to say, “I can't afford this thing that you think would be great for me.” Which, of course, comes up - not just with neuromodulation but with medication as well. But, you know, I think they're good for people who don't want to take medication or who are taking medications too often, and we need something to throw in there that is not a medication to prevent the development of medication overuse headache. Some people just prefer them. The evidence is not as strong for neuromodulation as it is for acute medications - and some of that just has to do with the challenges in blinding people to treatment arm in a clinical trial - but I think they have their place. Dr Monteith: When I'm just looking at the data, and then, as you mentioned, there are multiple options in terms of the latest developments. What are the things that you're most excited about in terms of either nonpharmacological, pharmacological interventions, or even patient populations like pregnant patients or patients with cardiovascular disease. Dr Burch: It is such an exciting time to be a headache specialist. I feel like things are coming out all the time, even in between writing this article and sending the final draft in, and now new things have come out. The zavegepant nasal spray is now FDA approved for acute treatment of migraine, and that was not the case when I wrote the final draft of this article. So, new formulations of medications are coming out and that's just really exciting. I think different patients prefer different things, and so I kind of like having different options to give them. I'm really interested in a couple of different things. There's been a lot of research coming out recently about the migraine prodrome - this sensation or symptom constellation that some patients get before what we think of as the more typical migraine – so, before the pain, maybe even before the more typical sensory hypersensitivity. Some patients know that an attack is coming, and there has been some research very recently coming out showing that, with gepants, taking the gepant before the attack actually happens in the prodromal phase can stave off an attack. I think that's cutting edge. I haven't really started talking to patients about it, but I'm interested to see what happens when that research is fully published and we kind of start test driving it. I'm also interested in the way that gepants don't seem to cause medication overuse headache in the same way that triptans or frequent use of NSAIDs do. I'm kind of thinking that the line between acute treatment and preventive treatment may start to get blurred a little bit with gepants. Dr Monteith: It's already blurred. Dr Burch: It's already blurred! It’s pretty blurred, right? Dr Monteith: I agree. And it'd be cool to see an update on this article. It might need to be just a whole - imagine a whole kind of issue on its own, on just acute treatments. Dr Burch: Yes, for sure. Dr Monteith: Great. Thank you so much for being here. Dr Burch: Thanks. It's always a pleasure to talk to you, and I'm really excited for this article to make it out into the wild in the real world and for people to get a chance to take a look at it. Dr Monteith: Yeah, I know our listeners are going to love this article - they're going to get a lot out of it. And most importantly, their patients are going to get a lot out of it. Dr Burch: That's my goal. Dr Monteith: Again, today we've been interviewing Dr Rebecca Burch, whose article on acute treatment of migraine appears in the most recent issue of Continuum, on headache. Be sure to check out Continuum audio podcasts from this and other issues. And thank you to our listeners for joining me 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 practice. Right now, during our Spring Special, all subscriptions are 15% off. Go to Continpub.com/Spring2024, or use the link in the episode notes to learn more and take advantage of this great discount. This offer ends June 30, 2024. AAN members: go to the link in the episode notes and complete the evaluation to get CME. Thank you for listening to Continuum Audio.

Headache specialist Dr. Deborah Friedman discusses the importance of patient history in headache medicine. Topics include optimizing headache interviews, efficient information gathering, uncommon causes of secondary headaches, and the importance of headache history in patient evaluation.

Neurologist Dr. Amy Gelfand discusses the April 2024 Headache issue with Dr. Lyell Jones. They explore migraine treatment evolution, editor-in-chief responsibilities, and reading preferences. Gelfand shares practice-changing tips for headache disorders and even ties in a humorous reference to chicken farming.

Dr. Kathy Chuang discusses symptomatic treatment of myelopathy with Dr. Lyell Jones. They cover multidisciplinary care, innovative treatments like nerve transfers and stem cell trials, and the importance of merging medical residencies for better patient care.

This bonus episode of Continuum Audio features Continuum Aloud with Dr. Michael Kentris narrating the Selected Topics in Neurology Practice article from the February 2024 issue on Spinal Cord Disorders. Dr. Michael Kentris is a Neurologist at Bon Secours Mercy Health in Youngstown, Ohio and Continuum Aloud program lead. Continuum Aloud is verbatim, audiobook-style recordings of each Continuum article. It is a Continuum subscriber-only benefit, and audio files are available at ContinuumJournal.com at the article level or on the AAN’s Online Learning Center at continpub.com/Aloud. Additional Resources Read the article for free: Continuum 2024 and Beyond Listen to all of the Continuum Aloud articles: continpub.com/Aloud Subscribe to Continuum: shop.lww.com/continuum Social Media: @ContinuumAAN @DrKentris @LyellJ

Too much, or not enough? A wide range of nutritional deficiencies and toxic exposures may cause spinal cord dysfunction. To make matters even more confusing, the clinical presentations for these disorders may overlap. In this episode, Teshamae Monteith, MD, FAAN, speaks with Kathryn Holroyd, MD, an author of the article “Metabolic and Toxic Myelopathies,” in the Continuum February 2024 Spinal Cord Disorders issue. Dr. Monteith is the associate editor of Continuum® Audio and an associate professor of clinical neurology at the University of Miami Miller School of Medicine in Miami, Florida. Dr. Holroyd is an instructor in the Department of Neurology at Yale School of Medicine in New Haven, Connecticut. Additional Resources Read the article: Metabolic and Toxic Myelopathies 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 Transcript  Full transcript available on Libsyn Dr Jones: This is Dr Lyell Jones, Editor-in-Chief of Continuum, the premier topic-based neurology clinical review and CME journal from the American Academy of Neurology. Thank you for joining us on Continuum Audio, a companion podcast to the journal. Continuum Audio features conversations with the guest editors and authors of Continuum, who are the leading experts in their fields. Subscribers to the Continuum journal can read the full article or listen to verbatim recordings of the article by visiting the link in the show notes. Subscribers also have access to exclusive audio content not featured on the podcast. As an ad-free journal entirely supported by subscriptions, if you’re not already a subscriber, we encourage you to become one. For more information on subscribing, please visit the link in the show notes. AAN members, stay tuned after the episode to hear how you can get CME for listening. Dr Monteith: This is Dr Teshamae Monteith, Associate Editor of Continuum Audio. Today, I'm interviewing Dr Kathryn Holroyd on toxic metabolic myelopathies, which is part of the February Continuum issue on spinal cord disorders. Dr. Holroyd is an instructor in the Department of Neurology at Yale School of Medicine in New Haven, Connecticut. Katie, thank you so much for being with us on the podcast, and thank you so much for your excellent article. It was filled with a lot of really great tips. Dr Holroyd: Thank you - happy to be here. Dr. Monteith: I want to start off with knowing, how did you gain expertise in spinal cord diseases? Dr Holroyd: Yeah, I have a fairly diverse clinical background. My primary work now is as a neurohospitalist. But after residency training, I did two one-year fellowships: one in neuroimmunology and one in neuroinfectious diseases. I think, with those things together – you know, a lot of these, especially acute-onset myelopathies, tend to present inpatient for diagnosis – so, we see a lot of those in my hospital practice. Then, I think, specifically for toxic metabolic myelopathies - to identify these, you often have to know what it's not. So, my experience with some of the other autoimmune and infectious disorders really comes into play. Then finally, I kind of focused on global health work, which is why I primarily do neurohospitalist work - to allow for travel. I spent the past year working at a neuro HIV research site in Thailand, and I've done some work (mainly with education) in Zambia. But I've seen that, kind of, all how people's environments and local areas can really affect what disorders are more common, and I think it's really important to take that into account with especially this topic, as well. Dr Monteith: Well, your work in global health could be a whole other area, a whole other podcast that I would really want to record with you. But let's start with, what did you seek to accomplish when writing your article? Dr Holroyd: I think, when I was writing the article along with Dr. Berkowitz, the co-author, we really wanted to focus on things that would be clinically relevant, not just for neurologists, but for clinicians all over who may not have access to a subspecialist neurologist. We tried to focus less on metabolic pathways or disturbances and focus more on clinical pearls. I tried to think, “When I see these patients, what are the questions that I have that are not easily answerable from Google or UpToDate or a textbook? And how can we really use primary evidence to answer some of those questions? For example, what percent of patients with B12 deficiency actually have an abnormal MRI? Those are the things we were asking ourselves and, hopefully, that we were able to answer through the article. We focused on three main categories of toxic metabolic myelopathies, as you can see from the work. Dr Monteith: So, specifically, you've been writing about nutritional deficiencies, environmental and dietary toxins, drug abuse, medical illnesses, and oncological treatments. When you wrote your article and, comparing it to even, like, five or ten years ago, what has changed? Dr Holroyd: It's a great question because, I think, even when I started writing the article, it's easy to feel like not much has changed in these particular disorders. But if you go deeper, I think that's not the case. The main ways in which things have changed, I think, on the nutritional front, is there’s been an increase in weight loss and weight-loss surgery, which is one of the main contributors to all nutritional deficiencies. The second main category is - in some of these toxic myelopathies - is the increasing rates of drug use, particularly heroin, which we talk about in detail in the article. Additionally, along those lines, with climate change - we often don't think about the way that climate change can really affect disorders that are related to nutrition or the way that certain foods are prepared, especially with increasing rates of drought, and that really relates to konzo. Finally, there's been great advances in the treatment of all sorts of cancers, particularly with immunologic therapy. The one immunologic complication we talk about is with immune checkpoint inhibitors, and I think there's been a huge increase in clinicians seeing these as complications of checkpoint inhibition. So, those are the three main ways that I think these have evolved in the past decade. Dr Monteith: Great. You spoke about your interest in clinical pearls - can you describe some essential points that you wanted readers to take away with when diagnosing and managing patients that are presenting with myelopathies thought to be due to toxic or metabolic etiologies? Dr Holroyd: Yeah, and a lot of these are so different it's hard to find overarching themes, but I think there are a few that come through in the article. The first is that a lot - not all, but a lot - of these are reversible. Diagnosing them early is important and can really make a difference in patient outcomes. The second is a real clinical principle of all neurology that I learned from Dr Berkowitz, my co-author - is that neurology really is time course and localization. Amongst these, I think it's important to look at the time course, whether it's acute or subacute, and the location in the cord, whether it's a subacute combined degeneration or a more dorsal-column-only-predominant myelopathy - that can help you narrow the differential. A couple other small things is that, overall, these toxic myelopathies tend to be more thoracic cord-predominant and affect the legs more than the arms. In the majority of cases, the MRI will actually be normal, which is a big difference from a lot of the other autoimmune or infectious myelopathies. I think those are some main takeaways. And finally, you really have to be careful when you're interpreting the lab tests and make sure that the clinical picture fits with the lab tests that you're measuring - for example, the vitamin or other cause - and make sure that you really are correlating the diagnosis with that test. Then, I think the cause of the deficiency will affect your treatment choice; whether you're dosing supplements orally or IV, and what dose you choose - those are the major things to take into account. Dr Monteith: I really like what you say because, I think, as neurologists, we are always thinking about localization, localization, localization, but that time course also matters for a number of diseases. Dr Holroyd: And to that point, I think the clinical diagnosis is particularly important in resource-limited settings, where advanced diagnostics, such as MRI or lumbar puncture, may not be available. For example, konzo - the WHO has very clear clinical criteria of how to define this disorder, given that in most of the regions where cassava root is primarily eaten, there are not these diagnostics. I think we can apply that globally or even in our own practice in areas of the US or other places - to really rely on your clinical judgment and the time course and the localization of the biolopathy[IG1] . Dr Monteith: Yeah. What was that like when you were practicing in Zambia? Dr Holroyd: I worked primarily with Dr Deanna Saylor, who is there funding and working with neurology residents, and we would see a wide variety of clinical cases but have very little real-time information. So, I really admire the residents who train and work in Zambia and have to make clinical decisions with very little information. In those settings, the history – so, asking people about recent ingestions, any drugs, diet at home, any exposures that might cause increased risk of these conditions - is very important. And sometimes you have to rely on empiric treatments, such as vitamin B12, in cases where you may not be able to send for those tests - especially more specific tests, such as methylmalonic acid or homocysteine. Dr Monteith: With your hospitalist experience, can you think of some cases, or like, one case that stands out that made you lose sleep at night, that you cracked the puzzle? Just so that we have this on our radar. Dr Holroyd: Yeah, I think that there's some more unusual causes of toxic myelopathies. We saw a young woman who came in with a very acute, very severe myelopathy after studying for a test. She had a dorsal column-predominant hyperintensity, but all of her other diagnostics - lumbar puncture, everything else - was completely normal. We weren't really thinking of nutritional deficiencies because it was such an acute onset in such a young woman; we are really thinking this must be autoimmune or something else. And it actually came out that she had been ingesting whippets – so, inhaled nitric oxide, which came out a bit later in the history. And we checked for a B12, which was very low, and it turned out to be a nitric oxide-induced vitamin B12 myelopathy, which can be seen but is relatively rare and really stuck out in my mind. Thankfully, she made a full recovery with the supplementation of vitamin B12 and cessation of drug use. Dr Monteith: Wow, that is an impressive story. I'm glad that was on your mind and you figured it out. Dr Holroyd: Thanks. Yeah - team effort. Dr Monteith: What should we take away about nutritional deficiencies? Dr Holroyd: Nutritional myelopathies – I think there are kind of the four main ones that we speak about in the article - vitamin B12, folate, vitamin E and copper - and I think these really have more similarities than differences. They all present clinically very similarly, with the subacute combined degeneration of the cord (the dorsal columns and the corticospinal tracts) - that's going to give you, basically, spasticity and upper motor neuron signs, as well as sensory symptoms (loss of vibration and proprioception). Weakness can be a part of it, but that's usually a bit later in the course. Secondly, they all have similar diagnostics. As I mentioned, the MRI is going to be normal in over 50% of cases of all of these, but when it's abnormal, generally they'll be a T2/FLAIR hyperintensity in the dorsal column, and that will be the most common finding. Often, we don't have a lot of lumbar puncture data from these conditions, but generally, when lumbar puncture is performed, it will be relatively normal or noninflammatory. So, those are some of the similarities. Some of the differences are the risk factors. Vitamin B12 - the risks are going to be mainly bariatric surgery, a vegan diet, or autoimmune pernicious anemia. Folate deficiency from nutritional causes is very rare, so that's usually going to come from someone with an increased folate requirement (sickle cell anemia or certain hematologic malignancies). Vitamin E often comes from malabsorption, as seen in cystic fibrosis, or abetalipoproteinemia, or hepatobiliary disorders. And then finally, copper generally comes from gastric surgeries or from excessive zinc intake, the classic example of being denture cream. I think one way to differentiate these is by looking at the person's risk factors. Finally, I think I tried to categorize them in my head in a few different ways with clues that might give you a specific clue. So, if someone comes in with a subacute myelopathy and they also have a macrocytic anemia, that would push you more towards vitamin B12 or folate. However, if they're presenting with a myeloneuropathy (so, that's upper motor neuron signs) but also a peripheral neuropathy on exam, you might think more vitamin B12 or copper. Then finally, if someone comes in with a myelopathy as well as ataxia, you might think more likely vitamin E deficiency. Those are some ways to categorize these that may otherwise appear very similar. But I think, at the end of the day, and someone with a subacute myelopathy and a nutritional risk factor, you'll end up sending all four of these blood tests to evaluate for appropriate treatment. Dr Monteith: Well, let's move on to climate change. It's not often that we see climate change in a neurology article, but yet it's a thing that affects patients. Can you talk about konzo? I wasn't familiar with the term before reading your article, so thank you. Dr Holroyd: Yeah, it's one of these that we debated - should we include this in the article (because it is relatively rare). But I think it is important to keep a global perspective. Konzo and lathyrism are the two nutritional toxic myelopathies that we talk about, but I'll just focus on konzo for brevity. This occurs in populations that rely on the cassava root for nutrition and generally occurs in times of drought, and that's because drought increases the cyanide content in the cassava root. After higher rates of ingestion, especially in people with protein malnutrition (so, a lot of children and young women), you can actually get a toxic myelopathy from cyanide. And the mechanism is not totally understood, but it tends to be quite acute onset, primarily with spasticity, impaired gait, and weakness. It will self-stabilize, but there really is no way to improve symptoms after it's occurred. It is relatively permanent. There really isn't a lot of data on MRI findings or CSF findings, but the few case reports that have been published, they tend to be normal. I think what's important is that there are very easy public health interventions to prevent these toxicities – so, by simply increasing the wetting time of the cassava root (so, soaking it for longer), you can reduce the cyanide content and really effectively prevent this condition. So, I think the big picture takeaway that can be connected to a lot of other neurologic disorders globally is that we need to be aware of how climate change will affect our environment - and dietary changes, environmental exposures - and focus on early public health interventions to prevent these. So, how can we help prevent these rather than treat them once they happen. Dr Monteith: Are we seeing more of it, or is it just better diagnosed? Dr Holroyd: There's not great public health data on the rates throughout areas. It (so far) has only been reported in the African continent. There have been increases and decreases in numbers based on, I think, both the climate (so, times of drought or worse, malnutrition), but also, I think the reporting - I think it fluctuates not only with the weather but also with the amount of ability to publish on cases. So, I don't think we have a good grasp on whether, globally, their rates of konzo or lathyrism are increasing or not. Dr Monteith: Then, heroin - we have to talk about heroin, right? It's just simply remarkable that close to a million individuals in the US over the age of twelve use heroin in 2020. So, now you just have to talk to us about heroin myelopathy because it's something that we could see. Dr Holroyd: Absolutely. It's not something that I think most clinicians are familiar with as the complication of heroin use. But I'm sure that heroin touches all of our lives as clinicians in any field. There are two types of myelopathy related to heroin. There can be a slower, subacute myelopathy with chronic use. But what's more common, actually, is in people who have a long history of heroin use and then abstain for days to weeks and then use heroin again. This causes a very acute-onset longitudinal myelopathy that often has MRI abnormalities as well and can affect both the cervical and the thoracic cord and be quite severe, affecting all modalities (sensation as well as weakness). The mechanism really is not well understood for this and, therefore, the treatments really aren't well understood, either. Some case reports have trialed IV corticosteroids, but really, there's an unclear benefit for this. Most people will regain some recovery of function, but often it's not full recovery, and some may have no recovery. I think the follow-up question to this is, as we see the composition of drugs change – so, now there's a predominance of fentanyl, actually, whereas most of these case reports were from more traditional heroin. I was actually looking into it - this isn't covered in the article - but there has been one case report in 2019 about fentanyl use in someone who primarily used heroin, was abstinent for eight days but continued to use fentanyl patch, and developed an acute-onset, severe cervical myelopathy quite similar to this traditional heroin myelopathy. So, it seems like fentanyl will probably still have the same risks, but it's slightly less well understood at this point. Dr Monteith: And important also for chronic pain – just, like, poorly managed chronic pain that we might see, as you do during a hospital consultation. Dr Holroyd: Absolutely, yes - especially because this was from a fentanyl patch itself. Dr Monteith: Great. So, why don't you wrap up the most important clinical takeaways from your article? Dr Holroyd: I think one takeaway that we haven't really focused on is that, actually, most of the primary literature on a lot of these topics, especially the nutritional topics, are twenty to thirty years old, and I think updated case series would really inform clinical practice. When it came down to it, actually - folate deficiency - we really only found four to five case reports in all the literature, which I really think is disproportionate to how much we learned about it in medical school and residency. I think, really, a better understanding of (in this era) what the prevalence of these disorders are, how they're presenting, and effective treatments, is really needed. I think that a lot of the exciting work will also occur in the field of oncology, with new treatments, with immune checkpoint inhibitors, and better understanding of how we can mitigate the risks of neurologic complications while still allowing patients the benefit of their cancer treatment. So, I think diagnosing toxic metabolic myelopathies early is very important. And in someone with a subacute, or even acute myelopathy without a clear cause, you should really delve into nutritional, drug use, demographics (kind of, where they're from) - all of these things that we often don't take time to do on history but might be more important in these cases because a lot of them are treatable - it's really important to get to those risk factors early on. I think that's what I would like clinicians to take away from our article. Dr Monteith: Well, I think the article is fully packed with a lot of clinical tips - important tips - but a lot of public health relevance in a really special way that it was written. Any exciting breakthroughs that you're excited about or use of technologies to advance this area? Dr Holroyd: Right now, there really aren't a lot of novel technologies in these areas, or diagnostics. I think, in the future, with some of the more cancer-related radiotherapies or intrathecal chemotherapies, the neuro-oncologists and oncologists will really be at the forefront of minimizing these toxicities. Again, I really think that's where a lot of the more advanced diagnostics will come into play. For the others, I think it's really about early diagnosis and public health awareness, especially as it relates to heroin myelopathy in the US. Dr Monteith: Well, excellent, and thank you for being a part of that public health awareness. Thank you for being on the podcast. Dr Holroyd: Thank you. Thank you so much for having me. Dr Monteith: Thank you, Dr Holroyd for joining me on Continuum Audio. Again, today we've been interviewing Dr Kathryn Holroyd, whose article on toxic metabolic myelopathies appears in the most recent issue of Continuum, on spinal cord disorders. Be sure to check out Continuum Audio podcasts 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, please consider subscribing to the journal. There's a link in the episode notes. We'd also appreciate you following the podcast and rating or reviewing it. AAN members: go to the link in the episode notes and complete the evaluation to get CME for this episode. Thank you for listening to Continuum Audio.

The explosion in diagnostic tools to identify immune-mediated myelopathies has led to much more precise diagnosis and treatment of these patients, but also created gaps in knowledge. In this episode, Kait Nevel, MD speaks with Michael Levy, MD, PhD, FAAN author of the article “Immune-Mediated Myelopathies,” in the Continuum February 2024 Spinal Cord Disorders issue. Dr. Nevel is a Continuum® Audio interviewer and a neurologist and neuro-oncologist at Indiana University School of Medicine in Indianapolis, Indiana. Dr. Levy is an associate professor at Massachusetts General Hospital and Harvard Medical School in Boston, Massachusetts.  Additional Resources Read the article: Immune-Mediated Myelopathies Subscribe to Continuum: shop.lww.com/Continuum Earn CME (available only to AAN members): continpub.com/AudioCME Continuum® Aloud (verbatim audio-book style recordings of articles available only to Continuum® subscribers): continpub.com/Aloud More about the American Academy of Neurology: aan.com Social Media facebook.com/continuumcme @ContinuumAAN Host: @IUneurodocmom Guest: @mlevy18 Transcript  Full transcript available on Libsyn Dr Jones: This is Dr Lyell Jones, Editor-in-Chief of Continuum, the premier topic-based neurology clinical review and CME journal from the American Academy of Neurology. Thank you for joining us on Continuum Audio, a companion podcast to the journal. Continuum Audio features conversations with the guest editors and authors of Continuum, who are the leading experts in their fields. Subscribers to the Continuum journal can read the full article or listen to verbatim recordings of the article by visiting the link in the show notes. Subscribers also have access to exclusive audio content not featured on the podcast. As an ad-free journal entirely supported by subscriptions, if you're not already a subscriber, we encourage you to become one. For more information on subscribing, please visit the link in the episode notes. AAN members, stay tuned after the episode to hear how you can get CME for listening. Dr Nevel: This is Dr Kait Nevel. Today, I'm interviewing Dr Michael Levy on immune-mediated myelopathies, which is part of the February 2024 Continuum issue on spinal cord disorders. Dr Levy is an Associate Professor at Massachusetts General Hospital in Harvard Medical School in Boston, Massachusetts. Welcome to the podcast. Thank you so much for being here today and chatting with me about your article. I really enjoyed reading your article. I read through it, and it felt like, you know, just really enjoyable. I had no concept of time when I was reading it. I encourage all of the listeners to read the article, too. I'll start with just a really broad question, with - what is the most important, clinically relevant thing from your article that you'd like the neurologist listening today to know? Dr Levy: I would say that the group of conditions in which the immune system can attack the spinal cord are growing. We're getting better at identifying the specific antigens, like in the case of NMO neuromyelitis optica and in MOG antibody disease. We're getting better at identifying targets for treatment, like with neurosarcoidosis - identifying those biologics that seem to help. And then, we're even beginning to characterize some of the idiopathic forms, some of which follow covid, or vaccines, or other conditions. I think the message is that we're getting a lot better out there, and if you have a case of inflammation in the spinal cord, then this is something that has a good workup now (and people should be paying attention to articles like this that give them an idea for how to work this up), and then the most appropriate treatment. Dr Nevel: Right. And not to get too much “in the weeds,” but in your article, you really outlined very nicely an algorithm or stepwise approach in evaluating patients with suspected immune-mediated myelopathies. Could you just briefly go through the general principles of that evaluation and stepwise approach, and what you would consider really necessary tests to order for these patients? Dr Levy: Sure. I would say that the first thing that you want to do is to make sure that it's inflammatory. And to do that, we have – the blood tests are few and far in between. If you're dealing with inflammation in the spinal cord, the few ways that we have to convince ourselves that there's truly inflammation - there are MRI and spinal fluid - and those objective tests need to be considered in the appropriate clinical context. The order of events is: patient comes in, reports certain neurological functions that localize to the spinal cord - that's step one, Step two, neurological exam that confirms that there's a neurological problem that localizes to the spinal cord. And then, numbers three, four, five are objective workups, including MRI of the spinal cord and other parts of the neuraxis, CSF testing, and blood testing, all of which then support your differential diagnosis. For each diagnosis, that order is the same, and it should always result in an answer for you, which ultimately may all be negative (and then we have a plan for that, too). If all your workup is negative, you don't know what caused it - at least a plan to deal with that as well. Dr Nevel: Building off of that - in your article, you mentioned that there are shared features between the different immune-mediated myelopathies. We have some tests that can help us differentiate, but what are some of the limitations or strengths of our currently available diagnostic evaluations - our clinical clues to help us differentiate between the different types? Dr Levy: The biggest limitation, of course, is that it's hard to access the spinal cord. We're not going to biopsy almost any patient unless we really have to rule out cancer. Otherwise, we don't want to take a punch out of a very small spinal cord that's carrying a bunch of fibers going in and out of the brain. So, that is our biggest limitation. We can't physically see it under the microscope, so we have to infer what's going on with MRIs and spinal fluid. And of course, spinal fluid isn't necessarily directly in touch with the inflammation - it could just be around it and bathing it. But we're hoping that there are clues from the spinal cord that shed into the spinal fluid that we can detect by lumbar puncture. I do think that we're getting better and also we're identifying things in the bloodstream that could also impact the spinal cord. And of course, blood tests are much easier to do, and some of these blood tests look for antibodies, which we know last for months and months. So, even if a person is having trouble getting their workup done on time, these antibody tests are still useful, even months after onset. Dr Nevel: Yeah. In your opinion, what have been some of the bigger breakthroughs? And I know there's been a lot in immune-mediated myelopathies over, let's say, the past five to ten years. That's a long timeframe, and I know a lot of things have happened during that timeframe – but what do you think has made the biggest impact in either evaluation and/or treatment for these patients? Dr Levy: When I was training, everything in the spinal cord was always MS. It was just - everything was multiple sclerosis in this big bucket of MS that we thought was heterogeneous. Now we're identifying the biomarkers that actually are distinguishing these patients from MS. We know what the immune system is targeting now in many of these conditions. Then, based on that immunological pathway, there are drug targets that have been developed. So, for even a very small disease, with 20,000 people in the US (one in 100,000) who have neuromyelitis optica, we now have three FDA-approved drugs because the science is so well worked out. And now there are two trials in MOG antibody disease, for example. As we identify new biomarkers based on the antigen specificity of the disease, I think we're going to have more and more specific therapies for each of these conditions, even if they're rare diseases. Dr Nevel: Yeah, that's great. Thanks for mentioning those, and I urge the listeners to check out the article to read a little bit more about some of those treatments for NMO spectrum disorder and MOG antibody disease that are in trials. What's the most common mistake that clinicians can make when evaluating or treating patients with immune-mediated myelopathies. What should we watch out for or to try to avoid doing? Dr Levy: I would say, at the beginning, there might be an urge to overtreat because we know that “time is spinal cord” - we don't want to waste time; we don't want to lose time. Some clinicians might just be inclined to give high doses of steroids, even in cases that they're not sure are inflammatory. The big overlap here is especially in older people who might have vascular myelopathy, where steroids might make things worse and it might delay their care. So that's the first problem – is, when physicians rush to judgment. Then the other big problem is when they take their time, and they say, “Well, this is just multiple sclerosis, probably. And we know that, in the end, MS patients do the same whether they're treated or not treated, and so we can take our time with this.” Whereas if we know that this is actually NMOSD, time is spinal cord and destruction is ongoing and potentially irreversible. I would say that there's problems on both sides of the time window. My approach is to be aggressive very early on and try to identify whether or not it's inflammatory. And then if it's not, then you can take a step back and go to the other chapters in this continuum - try to figure out what this is – and if it is inflammatory, then you definitely want to get on top of the treatment. Dr Nevel: Yeah, finding that sweet spot; making sure that you're not waiting too long but that you're not treating inappropriately or the wrong thing. So, what do you think - let's say you have a patient with an immune-mediated myelopathy; you've diagnosed them, they're undergoing treatment. What's the most challenging part of ongoing management of a person who has an immune-mediated myelopathy? Dr Levy: I would say that one of the most satisfying parts of my career lately has been that we're good at preventing the next attack once we know what the disease is. So, for NMO and for MOG and MS, we're good at that. We can suppress the immune system or modulate it in a way that we're preventing the next attack from occurring, and patients are excited about that. But when they come into clinic and I say, “Great job, no new attacks,” then they look at me and they go, “But how do I get out of my wheelchair now?” Because the damage done from prior attacks is not touched by any of these meds. So, there's a huge unmet need in that area of regeneration and recovery of function because, while it's all great that we can prevent the next attack and with all these great drugs that are approved, patients are still suffering. They have mobility problems, bowel/bladder problems, and pain, especially neuropathic pain, that really causes a lot of disability, and that's from damage that's already done. It's the same as spinal cord injury from trauma or from tumors or whatever - the spinal cord injury is the same and there's still a huge unmet need in that area. Dr Nevel: On that note, who else do you usually consider part of the team, if you will - who else should be involved in the management of these patients? Dr Levy: A lot of people. We have urologists involved for bladder, we have physical therapists involved for mobility, and occupational therapy for things related to hand and hand function. We have psychiatrists related to mental illness and also just dealing with these issues, because even if you don't have clinical depression, you still have an adjustment from the disease process and from all the treatments. Social workers, because this is a huge financial burden for a lot of people. An often rheumatologists, because NMO, for example, has about 25 percent overlap with other diseases. We don't want to double treat - we’ll often choose a treatment that's applicable to both the rheumatologic disease and the neurological disease. So, I'd say that we don't work alone in almost any case; it’s usually quite a big team involved. Dr Nevel: One of the questions that I always like to ask is, what do you think the next big breakthrough is going to be in immune-mediated myelopathies? What's most exciting to you - what do you think is on the horizon here? Dr Levy: I think probably the most exciting area is in multiple sclerosis, where we're starting to understand the role of the Epstein-Barr virus in triggering the disease, and potentially, even in driving the disease. Up to now, we've been suppressing immune systems in people with MS. But maybe we should be looking more at how can we prevent MS from occurring in the first place. And in cases where MS has already started, how does the virus play a role, and can we potentially modulate the outcome of disease with something like antivirals against EBV? So, I think that's the huge, exciting area. It's dominating a lot of the conversations at neuroimmunology conferences. But I think it's well worth the investigation because if MS turns out to be just an Epstein-Barr virus infection, I think a lot of what we've been doing up to now might not be as relevant. So, this is something that's very important. Dr Nevel: Yeah - to have a way to prevent disease rather than treating it after, too, would be a super powerful thing. Dr. Levy: And there are lots of Epstein-Barr virus vaccines that are being developed. But then the question comes up, “Well, are we going to prevent one in a thousand people from getting MS by vaccinating all thousand kids?” Is that really worth it? Can we pick out the ones who are more high risk for developing MS and just vaccinate those kids? A lot of ethical questions involved in that, too. Then what happens if we don't let our population get infected with EBV? We've evolved with that virus for hundreds of thousands of years. What if we abolish it all of a sudden - what does that do? Does it have any implications? I don't know. Dr Nevel: Yeah, lots of really complicated things to think through, with exciting potential but a lot of unknowns. Dr Levy: A lot of unknowns. Dr. Nevel: Talking about patients with seronegative relapsing transverse myelitis - what's your general approach to those patients? When you feel like you've exhausted the extent of your workup but they have a relapsing transverse myelitis, how do we approach those patients and take care of them? Dr Levy: “Seronegative” refers to patients who test negative for aquaporin-4, which is NMO, and test negative for MOG antibody disease (so they are double seronegative), but they have a recurring disease that looks an awful lot like one of the two. We generally stratify these patients into the “aquaporin-4-like,” “MOG-like” or “MS- like.” So, we try to put them into a category even if they're seronegative because we think that the treatments would be the same. So, for the MOG-like, for example: these are patients who have recurring attacks; they're not necessarily all long, but they do tend to remyelinate, and they can be severe at first but then they do get better over time. That's “MOG-ish,” so we treat those people with MOG treatments. Whereas people who have this sort of aquaporin-4 type, they have severe attacks and they really don't get better, and they have a lot of necrosis if you look at it under the microscope. And those people we tend to treat with aquaporin-4 NMO drugs. And then we have the MS type that kind of lingers or is more focal white matter lesions. Even if they don't have a lot of brain lesions, they might be oligoclonal band-positive; we put them in the category of MS. But we have a very active research effort to identify new antibodies in case any of these diseases that are seronegative and don't fit into any category - it's certainly possible that there's an antigen of their own that they're attacking, so we'd like to try to identify that in these novel assays that we’re doing in the lab. Dr Nevel: How do you counsel patients on what to expect in the future, who you're seeing in the hospital with their first episode of transverse myelitis, for whatever the cause? Because one of the biggest questions I suspect most patients ask is, “Am I going to get better? Is this going to happen to me again?” How do you navigate those tough discussions, and what do you tell patients? Dr Levy: In the hospital, it's tough, because a lot of our testing takes time - it takes ten, fourteen days. So, in the hospital, I say, “Look, we're going to focus on here and now - we're going to suppress the inflation; we're going to try to get you better from this event.” It could have been a severe optic neuritis or transverse myelitis, or brain stem injury, or whatever - we're going to try to focus on that. And then I say, “When you come back to my clinic, we'll have the results from all of your testing and we’re able to talk about the future and how to prevent the next one, if we have to.” It does take time, unfortunately, to get all that data back, and it is a little bit suspenseful for patients, but that's what we have at the moment. Dr Nevel: Yeah, the most honest answer that you can give them is always the best one. And that's the scenario when you're in the hospital - that there just isn't full answers. Dr Levy: Yeah. One of the reassuring things I can say is, “We have a lot of medications that target different parts of the immune system, so no matter what you have, we can probably treat it.” Dr Nevel: Right. Obviously, really important to give people a sense of hope and reassurance that you're there and you're going to help find a treatment that's going to help them in the future. Well, thank you so much for chatting with me today. I really enjoyed our conversation and reading your article and learning more about immune-mediated myelopathies. Dr Levy: It's been a pleasure. Thank you. Dr Nevel: Thank you, Dr Levy, for joining me on Continuum Audio. Again, today we've been interviewing Dr Michael Levy, whose article on immune-mediated myelopathies appears in the most recent issue of Continuum, on spinal cord disorders. Be sure to check out Continuum Audio podcasts from this and other issues, and thank you to our listeners for joining us today. Dr. Monteith: This is Dr Teshamae Monteith, Associate Editor of Continuum Audio. If you've enjoyed this episode, please consider subscribing to the journal. There's a link in the episode notes. We'd also appreciate you following the podcast and rating or reviewing it. AAN members: go to the link in the episode notes and complete the evaluation to get CME for this episode. Thank you for listening to Continuum Audio.

While collectively uncommon, the clinical presentation of genetically-mediated spinal cord disorders frequently overlaps with other neurologic conditions. Our understanding of these disorders has grown considerably. In this episode, Kait Nevel, MD, speaks with Kara Stavros, MD, FAAN, author of the article “Genetic Myelopathies,” in the Continuum February 2024 Spinal Cord Disorders issue. Dr. Nevel is a Continuum® Audio interviewer and a neurologist and neuro-oncologist at Indiana University School of Medicine in Indianapolis, Indiana. Dr. Stavros is an associate professor of neurology and clinician educator at Warren Alpert Medical School of Brown University in Providence, Rhode Island. Additional Resources Read the article: Genetic Myelopathies Subscribe to Continuum: shop.lww.com/Continuum Earn CME (available only to AAN members): continpub.com/AudioCME Continuum® Aloud (verbatim audio-book style recordings of articles available only to Continuum® subscribers): continpub.com/Aloud More about the American Academy of Neurology: aan.com Social Media facebook.com/continuumcme @ContinuumAAN Host: @IUneurodocmom Guest: @StavrosKara Transcript  Full transcript available on Libsyn Dr Jones: This is Dr. Lyell Jones, Editor-in-Chief of Continuum, the premier topic-based neurology clinical review and CME journal, from the American Academy of Neurology. Thank you for joining us on Continuum Audio, a companion podcast of the journal. Continuum Audio features conversations with the guest editors and authors of Continuum, who are the leading experts in their fields. Subscribers to the Continuum journal can read the full article or listen to verbatim recordings of the article by clicking on the link in the show notes. Subscribers also have access to exclusive audio content not featured on the podcast. As an ad-free journal entirely supported by subscriptions, if you’re not already a subscriber, we encourage you to become one. For more information on subscribing, please visit the link in the episode notes. AAN members, stay tuned after the episode to hear how you can get CME for listening. Dr Nevel: This is Dr Kait Nevel. Today, I'm interviewing Dr Kara Stavros on genetic myelopathies, which is part of the February 2024 Continuum issue on spinal cord disorders. Dr Stavros is an Associate Professor of Neurology and Clinician Educator at Warren Alpert Medical School at Brown University in Providence, Rhode Island. Welcome to the podcast. What is the biggest takeaway from your article that you'd like the neurologists listening to this to know? Dr Stavros: I would have to say that there's maybe two big takeaways that I would want to highlight. One would be that, generally speaking, in a nutshell, the genetic myelopathies can present with chronic and progressive symptoms, oftentimes (but not always) a family history of similar symptoms, and involvement of other structures outside of the spinal cord. Exclusion of the more treatable causes of myelopathy is a really key and important step in the diagnostic process. And because there are many different causes of genetic myelopathies, in some cases, the symptoms can overlap. I think this really underscores the utility of doing genetic testing to really confirm the precise underlying neurologic condition. The second takeaway that I would want to highlight is that, while treatment for most of these conditions is typically supportive, there have been a number of recent therapeutic breakthroughs for treatments in ALS, spinal muscular atrophy, adrenal myeloneuropathy, and Friedreich ataxia. While these aren't cures, it's really exciting and gratifying to see new therapeutics emerge via different mechanisms for patients with conditions that we've had very little treatment options for in the past. Dr Nevel: Yeah, I really enjoyed reading that in your article - about these treatments that have been coming out over the past several years. The one with Friedreich’s ataxia, too - that looked like it was really just recently approved this year. Dr Stavros: Yes. Dr Nevel: And so, kind of jumping off of that topic - there have been these exciting treatments that have been coming through. What do you think is going to be the next big thing? Or what do you think is the next thing that might come through? Or what's going on in research in genetic myelopathies that might help our patients? Dr Stavros: That's a really great question. I think that, as far as the future in this area, genetic testing has definitely grown in terms of being able to identify more genes now that are implicated in these disorders than ever before. But this is still an area where our knowledge is continuing to evolve. So, I think the future holds further advancements in our ability to successfully diagnose patients who have these conditions and provide them with the sense of closure that having a definitive diagnosis brings, as well as opening the door to potentially targeted treatment options once a specific diagnosis is made. Another thing I think the future holds is continued development of expanded treatment options for patients with these conditions, both in terms of advancing our supportive care capabilities and then also providing more disease-modifying therapies. Again, as I mentioned, in recent years, new disease-modifying treatments have actually become available for several of these conditions. And I think that's just the beginning. There's going to be more to come, for sure. Dr. Nevel: Yeah, that would be great. Going back to the genetic testing and how things are - we're finding more and more and more genes. When you decide that genetic testing is indicated, how do you counsel your patients about genetic testing and walk them through that process? Dr Stavros: Okay - I would say that it usually starts with having a conversation with the patient about whether they want to pursue genetic testing or not for the particular condition or conditions that are suspected. Genetic testing is really helpful to, again, confirm the diagnosis once the initial diagnostic workup perhaps has given you some clues as to what the underlying condition might be. Again, because sometimes the clinical symptoms can overlap in different genetic myelopathies in particular, the genetic diagnosis can be really important as far as getting a definitive, final diagnosis. Usually testing is pretty carefully considered and the risks versus the benefits are explored with the patient. Oftentimes, this is done in conjunction with a genetic counselor or with genetics clinic. So, there's a lot of teamwork there in working with the genetics department, at least in my experience. There's a lot of options that might include testing a panel of genes for the suspected condition, to up to whole-exome sequencing. Again, this is really like an evolving landscape. So, we have a current understanding of the genes that are implicated in some of the genetic myelopathies, but there's still so much that we don't know. So, a lot of times, testing can result inconclusive or may be falsely negative, and it can be tough because a negative test doesn't necessarily exclude a potential genetic etiology. It becomes a very nuanced, I think, conversation and journey with the patient. Dr Nevel: Yeah, and in your article you mentioned some of the health care disparities that exist around genetic testing and access to genetic testing, specifically. How do we, as clinicians, try to mitigate inequities in regard to access, or in regards to being able to offer our patients genetic testing - is there anything that we can do? Dr Stavros: I do think there are some resources available, where free or sponsored testing can be utilized from nonprofit organizations or pharmaceutical companies. But you're right that this is a real area for potential health care disparities. And making sure that we have equitable access to genetic testing is really important. Some of the issues that come up are: limited access due to location; due to socioeconomic factors; a lack of awareness on the part of the patient or sometimes the provider about testing that's available; cost, of course, being a big issue, oftentimes; and sometimes, distrust of how the medical information, the genetic information, might be used or protected. Dr Nevel: What do you think is one of the most challenging things about managing patients with genetic myelopathies? Dr Stavros: I think one of the more challenging aspects of the care is the diagnostic journey. I think that some of these conditions - most of them are not terribly common – and they may not always be at the top of our differential diagnosis in the course of a workup for myelopathy. The first step, I think, is really continuing to be aware of these conditions and not letting them become a “blind spot” when we're formulating a differential diagnosis for a patient with myelopathic symptoms. I think it can really take some time to reach the ultimate diagnosis for most of these conditions. Another challenging aspect, which I alluded to earlier, is sometimes when genetic testing might come back inconclusive or nonrevealing, and there remains some diagnostic uncertainty despite best efforts and a thorough workup -that can be frustrating as well, sometimes. Again, our knowledge of these genetics and the genetic mutations underlying these disorders is still really evolving. But on the flip side, there's a lot of rewarding aspects as well. I think one of the most rewarding aspects is trying to help patients identify interventions that improve their quality of life, and working with the patients and their families (who oftentimes become very expert in their own rare conditions in their own right), and working amongst the interdisciplinary teams. So many of these conditions are associated with extraneurologic manifestations, and so patients need coordination of care with other specialists. Hereditary spastic paraplegia is a great example, as well as Friedreich ataxia, where you often work closely with the cardiologist and of course, ALS, where there are a lot of multidisciplinary needs. Dr Nevel: Yeah, I'm so glad that you mentioned that because, in neurology in general (and specifically in this area), I can imagine the benefit to patients when there are multiple specialists involved in their care who are experts in the various aspects that are impacted from their underlying condition. Shifting gears a little bit - but going back to something that you've mentioned a few times, about making sure that we don't have a blind spot to genetic myelopathies, and that we consider this in part of our differential diagnosis when we're evaluating patients - in the patient who doesn't have an extensive family history of the exact same neurological symptoms, when should we consider genetic testing for patients that we're seeing in clinic? Like, at what point should we say, “Okay, we've done the other tests and now is the time to consider genetic testing.” Because I think, unless somebody has that really strong family history, it's probably not on the top of your list to do it right away, for a variety of reasons. Dr Stavros: I think you make a great point. Family history is tricky because, typically, we use that as a really strong clue of an inherited disorder of any type. But it can be tricky because, for a variety of reasons, it might be negative. Sometimes there is a de novo mutation, or there's variable phenotypes within the family, variable penetrance within the same family. Autosomal recessive inheritance can actually be, sometimes, hard to pick out. Or sometimes, patients don't have knowledge of their family members’ medical histories. For all of these reasons, there may be information lacking in the family history. But I would say one of the most important things to exclude when you're working up patients initially is, of course, acquired causes of myelopathy, because you wouldn't want to miss a more treatable cause. And so, things like structural causes, nutritional, vascular or demyelinating causes (things that are explored more deeply in some of the other articles in this issue) are important. But if you've excluded acquired causes despite lacking a strong family history, I think, at that point, it's worth broadening your differential diagnosis to consider whether you might have reason to suspect a genetic myelopathy, particularly if you have some extraneurologic manifestations, some systemic symptoms that might be a clue towards a more systemic process. In genetic myelopathy, sometimes imaging can actually be quite helpful. It helps you exclude - MRI of the spine can help you exclude acquired causes, but it also helps you sometimes get clues toward a genetic cause. Typically, the finding might be either normal or show some spinal cord atrophy (but typically without signal change, so that can sometimes be a clue). Dr Nevel: What's one mistake that is made in managing patients with genetic myelopathies? Maybe “mistake” is too strong a word; maybe “misconception” about treating patients with genetic myelopathies. Dr Stavros: That’s a great question. I think that one of the, maybe, misconceptions might be that these are homogeneous entities, these different diseases. But one of the things that surprised me anew in going back to research this topic and prepare this article was a reminder of just how variable both the genotypes and the phenotypes are within what we consider sometimes just one diagnosis, like hereditary spastic paraplegia, for example, spinocerebellar ataxia. There's so many different presentations and genotypes associated with these. It's really a family of different conditions. You could say the same thing about ALS as well. So, the spectrum of disease, I think, is important to recognize. Dr Nevel: Yeah, and I can imagine because of that spectrum of disease, just having an open mind in considering genetic testing and not excluding a potential genetic cause because it doesn't fit into what we think is the most typical presentation of that genetic condition. Dr Stavros: Yes - I'm in total agreement. Dr Nevel: I've asked you about what some of the misconceptions are and what some of the challenges are, but what's the most rewarding part about taking care of patients with genetic myelopathies for you? Dr Stavros: I think one of the most rewarding parts has to be working with the patients and the families. Like I mentioned earlier, sometimes they become so expert in their own conditions - it's amazing. And, working with them, working with the interdisciplinary teams, is a really rewarding process. I think that the more I've encountered patients with some of these rare conditions, the more I've learned from their stories and experiences, and so, that's, I think, been the most rewarding aspect to me. Dr Nevel: You've mentioned the multidisciplinary team a couple of times that we've talked about this, but who specifically do you usually include or contributes to the care of these patients? Dr Stavros: It may depend on the condition in question. So, for example, for Friedreich ataxia, there's always going to be a cardiologist involved in the patient's care. For ALS, there's going to be a larger team. For those who are familiar with ALS multidisciplinary clinics, this often includes physical therapy, speech therapy, nursing, pulmonary, and many others. And so, it really depends. I think in most cases though, genetics evaluation and genetic counseling is a really important piece. Dr Nevel: How do you work with the genetic counselors in counseling families about testing other family members? Because that's something that's really challenging in genetic conditions, especially for people with children that may be underage, and this is a really complicated topic. But how do you approach that? Dr Stavros: I think that it may depend on your particular institution. Where I'm at, typically, that's something that our genetics department will take the lead on and they will meet with the patient first and then also meet with and bring in any interested family members who are hoping to pursue the possibility of testing themselves. There's a bit of controversy or differing opinions around genetic testing, specifically for presymptomatic individuals for inherited ALS, because - certainly, there's pros and cons for being tested for any condition, but some special considerations come into play when someone is presymptomatic. There's actually been studies done, in particular, on patients who have a family history of ALS who are presymptomatic, and generally, the studies have shown that those patients are usually - the majority - in favor of being tested. But it does certainly bring up some ethical implications. Of course, any discussion is going to be undertaken with the goal of informing the patient and discussing the risks versus the benefits in detail. There's actually recommendations on the principles and the practice of presymptomatic testing for ALS, which is available and referenced in the article. Dr Nevel: Do you think as - hopefully, in the future, as more treatments become available - that presymptomatic genetic testing could play a role in how we manage patients? Dr Stavros: I think that's a great thought. I think it may, especially as more treatments become available, I think there may be a greater interest in demand for finding out early whether you might have a likelihood of developing a certain condition so that you can plan accordingly and perhaps even pursue treatments early on. Dr Nevel: You know, you mentioned this (and this isn't maybe quite exactly the same thing), but in SMA - you mentioned newborn screening for SMA and new treatment for SMA, and that newborn screening is not always a standard, and that there's controversy around that, now that we have treatment for it. Dr Stavros: Yes. That's another area where some controversy comes up as well, as far as cost and treatment, for sure. Dr Nevel: Thank you, Dr Stavros, for joining me on Continuum Audio. Again, today we've been interviewing Dr Kara Stavros, whose article on genetic myelopathies appears in the most recent issue of Continuum on spinal cord disorders. Be sure to check out Continuum Audio podcasts 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, please consider subscribing to the journal. There's a link in the episode notes. We'd also appreciate you following the podcast and rating or reviewing it. AAN members, go to the link in the episode notes and complete the evaluation to get CME for this episode. Thank you for listening to Continuum Audio.

Tumors affecting the spine are fortunately uncommon, and may arise within the spine or metastasize from malignancies elsewhere. Effective treatment is determined by tumor type, location, and urgency. In this episode, Allison Weathers, MD, FAAN, speaks with J. Ricardo McFaline-Figueroa, MD, PhD, author of the article “Spinal Cord Neoplasms,” in the Continuum February 2024 Spinal Cord Disorders issue. Dr. Weathers is a Continuum® Audio interviewer and the associate chief medical information officer at Cleveland Clinic in Cleveland, Ohio. Dr. McFaline-Figueroa is a physician at Dana-Farber Cancer Institute and instructor in neurology at Brigham and Women’s Hospital and Harvard Medical School in Boston, Massachusetts. Additional Resources Read the article: Spinal Cord Neoplasms Subscribe to Continuum: shop.lww.com/Continuum Earn CME (available only to AAN members): continpub.com/AudioCME Continuum® Aloud (verbatim audio-book style recordings of articles available only to Continuum® subscribers): continpub.com/Aloud More about the American Academy of Neurology: aan.com Social Media facebook.com/continuumcme @ContinuumAAN Transcript  Full transcript available on Libsyn Dr Jones: This is Dr Lyell Jones, Editor-in-Chief of Continuum, the premier topic-based neurology clinical review and CME journal from the American Academy of Neurology. Thank you for joining us on Continuum Audio, a companion podcast to the journal. Continuum Audio features conversations with the guest editors and authors of Continuum, who are the leading experts in their fields. Subscribers to the Continuum journal can read the full article or listen to verbatim recordings of the article by visiting the link in the show notes. Subscribers also have access to exclusive audio content not featured on the podcast. As an ad-free journal entirely supported by subscriptions, if you’re not already a subscriber, we encourage you to become one. For more information on subscribing, please visit the link in the show notes. AAN members, stay tuned after the episode to hear how you can get CME for listening. Dr Weathers: This is Dr Allison Weathers. Today I'm interviewing Dr Riccardo McFaline-Figueroa on spinal cord neoplasms, which is part of the February Continuum issue on spinal cord disorders. Dr McFaline-Figueroa is a physician at Dana Farber Cancer Institute in Boston, Massachusetts, an instructor in neurology at Brigham and Women's Hospital and Harvard Medical School in Boston, Massachusetts. Welcome to the podcast. You do a really fantastic job in the article providing a comprehensive overview. But if you had to come up with the most important clinical takeaway from the article that you want our listeners to walk away with, what would that be? Dr McFaline-Figueroa: I think the most important thing to remember about tumors of the spinal cord is, one, that there is no specific diagnostic feature on imaging that can be used to determine what a neoplasm of the spinal cord is or even if it is a neoplasm - I think, going in broadly, when you're looking at a mass lesion of the spinal cord, is very important. Then the second is just to know that there's just such a wide range of cancer possibilities that can do this, that getting an appropriate diagnosis becomes very important. Dr Weathers: I think two really salient points right there. I want to explore something that you said a little bit more. You talk about the concept that there's no one diagnostic feature of the MRI, and actually, I was thinking about this as I was reading your article. What struck me, too, is that that holds true, actually, for the patient’s presenting signs and symptoms, right? As a neurohospitalist, I'm constantly struggling with always how to balance not missing a diagnosis such as this (a diagnosis of spinal cord tumor), versus putting a patient through what can be an often unnecessary and very costly workup, right? So, this is such a rare diagnosis, but the presenting symptoms and signs, just back radicular pain and weakness, are shared by so many common conditions. What's your approach to distinguishing between them, and what are some of the red flags you look for to know when further workup really is indicated? Dr McFaline-Figueroa: Certainly. I think there's not one way to decide whether you need to go down the route of exploring a neoplasm of the spinal cord, but there are certainly things that would clue someone into this needing to be the case. I think, one, as opposed to a lot of the monophasic illnesses that we see in neurology, certainly it's something that is progressive; is certainly something that increases the certainty, and it's different from ischemia of the spinal cord or an acute demyelinating event. I think another important feature is also just the context. I think, even though these are rare, when you're dealing with a patient with a known history of cancer, that's when “the rare” becomes common, and that's when you have to really start thinking about it being a neoplasm of the spinal cord. It's still not perfect; it covers some of the side effects of treatment that can look a little bit like a spinal cord neoplasm. But certainly, that should increase the level of suspicion for something going on in that compartment that's neoplastic. Dr Weathers: I think that's such a great take-home quote for our listeners to think about - when the rare becomes common. You actually hit on the point that I wanted to ask you about next. In neurology, we always talk about how important the history and the exam are - it's kind of our core of what we do. But it feels especially true when talking about neoplasms of the spinal cord. You mentioned, obviously - the big one is that if they have a history of cancer, especially in active history, that's a pretty big clue that something more serious could be going on. But what else is key in the history? Why are the history and the exam so especially important when you're concerned about or dealing with neoplasms of the spinal cord? Dr McFaline-Figueroa: When we're dealing with the spinal cord, we're dealing with a lot of different compartments. I think, to your question, the one where thinking about history and physical becomes the most important is when you're thinking about the possibility of leptomeningeal involvement, right? The leptomeningeal space is not easily imaged, right? We can't really see much what's going on in the CSF. And so, we rely on - imaging-wise - on there being deposition of cancer cells along the dura or along the direct surface of the cord. But oftentimes, that's not the case. That's when knowing exactly what someone's cancer history is, what their stage in the natural history is, whether they're progressing or not progressing, have some knowledge of what the oncologic medications that they're on are (because brain penetration is different for several of them), and then really hearing for those signs and symptoms that are connected to that compartment - signs of increased intracranial pressure, signs of cranial neuropathy that may or may not be evidence on imaging, radiculopathies. So those are the things that are very important in all investigations of spinal cord tumors. But certainly for leptomeninges, it's often the case that, really, history and physical are all you have to try to get the diagnosis right. Dr Weathers: You make, actually, a really great point in the article that I think it bears mentioning here. Because I was embarrassed when I read it, because I said, “I have been guilty of that” - that the history of, kind of, these very generic histories of cancer; you know, “Oh, they had lung cancer” - is probably not sufficient, right? That there's value in getting really specific. Why is that? Dr McFaline-Figueroa: That's certainly why we all specialize in different things, right? For a neuro-oncology standpoint, it sounds very different to me to hear the same history in a patient with melanoma versus the patient with bladder cancer. You think of melanoma from a neuro-oncologic standpoint, you're thinking of a cancer that is incredibly trophic for the brain and spinal cord, probably because it's derived also from ectoderm (so it's kind of the same origin of the cells), and it just makes your level of suspicion go so much higher when you are in that mind space. Thinking of a melanoma patient versus someone with a tumor, that very rarely (if it all) goes to the central nervous system. I think that's something that's really important. And those are two big extremes. But even - like I mentioned - even in lung cancer, certainly, small cell versus non-small cell are very different in terms of when and how they can affect the spinal cord or any part of the central nervous system. So, that one is a little bit more nuanced and, being a neuro-oncologist - but still, it’s specific as you can be when you're discussing with your neuro-oncology colleagues or medical oncology colleagues, and the better for trying to figure these things out. Dr Weathers: An excellent pro tip right there. You were very gracious about it - about that we all have different specialties. I was reflecting on that, too - this is such an important yet definitely pretty specialized topic; how did you become interested and develop your expertise in it? Dr McFaline-Figueroa: My clinical work is on all sorts of tumors of the central nervous system. Actually, in neuro-oncology, we also do a little bit of peripheral nervous system tumors, depending on how they present. And it's all a continuum. Not to use that - well, we just happen to be on Continuum. But it's all a continuum: brain, spinal cord - it's all one big compartment. And it forces you to be really familiar with all of those. And I think it's an interesting topic - we don't talk about it as much as we do for some of the other – you know, cancers of the brain, for example. In terms of becoming an expert, for me, I mean a lot of it is just, at this point, experience. And I will say, a lot of reading, because you don't see all of these. I cover some topics, like primary glioneuronal tumors of the leptomeninges, which are incredibly rare - I've never seen a patient with one. But it's one of those things where you should know the basics of these, at least for my field, and certainly beyond. Dr Weathers: What about neuro-oncology in general? How did you decide that you wanted to specialize in that? Dr McFaline-Figueroa: Well actually, me, personally - I spent a lot of my residency trying to decide between being a neurointensivist and being a neuro-oncologist. I think, for me is that I like taking care of patients who are potentially very sick. I think I just enjoyed the process of the more longitudinal relationship you have as a neuro-oncologist - seeing people in clinic, walking them through all these treatments and difficult disease courses – and that, to me, I just found really fulfilling, while still having lots of internal medicine to think about, lots of interesting neurology, just in a different context. Dr Weathers: It's such an interesting field. And I was also really thinking about this - that while neurology overall has had so many incredible advancements in terms of diagnostic and therapeutic capabilities in the last several years, neuro-oncology, in some ways, is almost like an entirely different field since I was in residency training, which wasn't all that long ago. How have these changes impacted how you diagnose and manage spinal cord tumors? Dr McFaline-Figueroa: Certainly, there's been a lot of changes in technology that I think have been helpful. And then, certainly, slowly but surely, we are coming up with better treatments for patients. When I speak of technologies, one thing that, for example, comes to mind is - historically, it's just so difficult to diagnose. I keep coming to the same anatomic compartment, but it's so difficult to diagnose leptomeningeal carcinomatosis or leptomeningeal involvement by a tumor, even more so, I think, in the spinal cord, because it's just difficult to catch on imaging. But over the last few years, so many advances in, like, molecular testing of cerebral spinal fluid to be able to look for cell-free DNA; to be able to enrich for rare cell populations and then identify them, which really, kind of, have changed that “we need to do three LPs” mentality. We have things that are sensitive enough that are rolling out. And in terms of treatment, certainly, the field is changing. There's so many now targeted therapies emerging for tumors as we understand the biology, which is probably the biggest roadblock to better care for the primary spinal cord tumors - it's also a very exciting time to be in neuro-oncology because of that. Dr Weathers: On perhaps a less positive note - the fields change so quickly; has this led to any controversies in the field? Dr McFaline-Figueroa: I think the biggest controversies are less so controversies in the traditional sense, in that I don’t think anyone's fighting with each other. But it's become really difficult to know, particularly as those therapies that I mentioned come out, what is the right first step. Is the right first step for somebody to have, for example – well, actually, this is less controversial now - but for example, someone with von Hippel-Lindau, who might have multiple hemangioblastomas. We're reaching a point that, with approvals of targeted therapies for that disease, you might not necessarily go for surgery (which could be quite morbid in some instances) or radiation for progressive disease. So, I think one of the issues there is that we're not necessarily at the point where we are sure that, you know, definitely the intervention with the longest survival is targeted therapy first, and then maybe surgery, and then maybe radiation, versus the other. I think the order at which we treat these tumors is just a little bit in flux. Dr Weathers: Hopefully, with time and more evidence, that will become more definitive and clear. You just mentioned - just in that answer alone - surgery and radiation. The other really fascinating thing about this topic (about neoplasms of the spinal cord) is how truly a multidisciplinary effort the management of patients with spinal cord tumors is. What other specialists do you work with to diagnose and manage this patient population, and what's everyone's role in these cases? Dr McFaline-Figueroa: Certainly, neurosurgery still plays a huge role, particularly because even when you are relatively sure that it's a tumor of the spine (particularly if you think it's a primary tumor of the spine), there's really no - again, just no diagnostic test; that's just imaging. The only way that we have to establish the diagnosis is through tissue examination. In neurosurgery, in a lot of diseases, still plays a huge role. For example, ependymoma is one where, really, gross total resection is one of the biggest (if not the biggest) prognostic factor in treatment. Radiation oncology - there are still histologies that we have no good systemic therapies for. For example, for diffuse midline gliomas, most of them are not very sensitive to the therapies that we have that are systemic. So, for these tumors, it becomes important to do radiation as the most significant step in management that we have - we just don't have anything efficacious for those tumors, at the moment, although we're learning a lot about the biology. A lot of these have histone mutations that people are trying to target for more effective treatments. So, radiation oncology, again, still plays a huge role in the treatment of our patients. Certainly, when you're dealing with patients with metastatic cancer to the spine, medical oncology is huge. And that's where - me, as a neuro-oncologist, I'm less of an oncologist and more as a person who the medical oncology can bounce ideas from. We talk about - sit down and talk about - their expertise in how to treat these tumor types. And then, me bringing in what might be brain-penetrant, what things may or may not be toxic to the nervous system - stuff like that. It's really a group effort, and that's not even mentioning nurses, nurse practitioners, amazing people who coordinate care, and stuff like that. And like I mentioned early on, one of the most important things is to know exactly what type of tumor or cancer these are before proceeding with any conversation about treatment. And that's where our neuropathologists really drive the direction of what we're doing. Dr Weathers: Even as I was thinking about this question, in my mind, what I thought your response point may be - that was even more of a complex team than I think I had envisioned, and it really speaks to, again, the true multidisciplinary effort, the “team of teams” that's needed to provide care for these patients. And I think I heard you say this in your - that wonderful answer, but that as things are evolving and as we are better understanding the biology, that we're getting better with our targeted treatments. But that could possibly include, at some point, even targeted therapies for midline gliomas, which would be incredible. I know that's always been one with, not only especially poor prognosis, but given the population it tends to affect (younger patients), it can be quite devastating. That definitely struck me as I heard you say it. So, I think this is a field where we're going to continue to see so many breakthroughs. And that leads me, actually, into my last question. I always like ending these on a hopeful note, and I think that certainly does it. But we've talked about so many changes already, and again, I know even more to come. What do you think the next big breakthrough will be? Did we cover it already? Is there anything else that you're excited about that's coming down the pike? Dr McFaline-Figueroa: I think we covered some of it, which is really being able to bring more systemic therapies (more oral therapies or intravenous therapies) that treat these tumors, as opposed to things like aggressive surgery or radiation, which are effective. But the hope here is that we can delay those so that we can have people living longer with these cancers, or cured of these cancers, and trying to spare them as many side effects of treatment as we can - which historically, in the spinal cord, is quite significant because it's a difficult space to do surgery on and it tolerates only a certain amount of radiation before coming into toxicity. So, I think it's a really exciting time to be on the medical side of things as a neuro-oncologist and see all these treatments coming in that really improve people's quality of life. Dr Weathers: Definitely an exciting time to do what you do. Well, again, thank you for the incredible article, for taking the time to speak with me today. Any last thoughts for our listeners? Dr McFaline-Figueroa: Just be mindful when working up those spinal cord tumors. There's a lot to think about, but there's also a lot of good can be done by doing good diagnostic workup. Dr Weathers: Thank you, Dr McFaline-Figueroa for joining me on Continuum Audio. Again, today we've been interviewing Dr. Riccardo McFaline-Figueroa, whose article on spinal cord neoplasms appears in the most recent issue of Continuum, on spinal cord disorders. Be sure to check out Continuum Audio podcasts from this and other issues. And thank you to our listeners for joining today. Dr. Monteith: This is Teshamae Monteith, Associate Editor of Continuum Audio. If you've enjoyed this episode, please consider subscribing to the journal. There's a link in the episode notes. We'd also appreciate you following the podcast and rating or reviewing it. AAN members: go to the link in the episode notes and complete the evaluation to get CME for this episode. Thank you for listening to Continuum Audio.