This bonus episode of Continuum Audio features Continuum Aloud, a program of verbatim audiobook-style recordings of Continuum articles. In this episode, Dr. Michael Grasso reads the NMOSD and MOGAD article from the August 2024 issue on Autoimmune Neurology. 

This article is open access until December 2, 2024. Read it here.

Continuum Aloud is available to Continuum subscribers at the article level on ContinuumJournal.com or on the AAN's Online Learning Center at continpub.com/Aloud.

For more information on subscribing to the journal visit shop.lww.com/continuum.

Autoimmune cerebellar ataxia and other autoimmune movement disorders encompass a broad spectrum of different clinical syndromes, antibodies, and immunopathophysiologic mechanisms. Given the overlap between phenotypes and antibodies, panel testing in serum and CSF is recommended.

In this episode, Gordon Smith, MD, FAAN, speaks with Bettina Balint, MD, author of the article "Autoimmune Movement Disorders," in the Continuum August 2024 Autoimmune Neurology issue.

Dr. Smith is a Continuum® Audio interviewer and professor and chair of neurology at Kenneth and Dianne Wright Distinguished Chair in Clinical and Translational Research at Virginia Commonwealth University in Richmond, Virginia.

Dr. Balint is an assistant professor for clinical research on complex movement disorders and Parkinson's diseases, a consultant neurologist, the head of the Department of Movement Disorders, and co-lead for the Centre for Movement Disorders and Functional Neurosurgery in the Department of Neurology at the University Hospital Zurich in Zurich, Switzerland.

Additional Resources

Read the article: Autoimmune Movement Disorders

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Full episode transcript available here

Dr Jones: This is Dr Lyell Jones, Editor-in-Chief of Continuum, the premier topic-based neurology clinical review and CME journal from the American Academy of Neurology. Thank you for joining us on Continuum Audio, which features conversations with Continuum's guest editors and authors who are the leading experts in their fields. Subscribers to the Continuum journal can read the full article or listen to verbatim recordings of the article and have access to exclusive interviews not featured on the podcast. Please visit the link in the episode notes for more information on the article, subscribing to the journal, and how to get CME.

Dr Smith: This is Dr Gordon Smith. Today, I'm interviewing Dr Bettina Balint about her article on ataxia and other autoimmune movement disorders, which appears in the August 2024 Continuum issue on autoimmune neurology, which is a highly anticipated and exciting issue. Dr Balint, welcome to the podcast, and, perhaps, you can just introduce yourself to our audience and tell us a little bit about your practice and how you became interested in this topic.

Dr Balint: Thank you, Gordon, for having me. I am an assistant professor for clinical research in complex movement disorders and Parkinson's disease at the University of Zurich and the Head of the Movement Disorders Department at the University Hospital in Zurich. So while I'm originally German (from Heidelberg), I have now been to Switzerland since end of 2021.

Dr Smith: So, you know, how many movement disorder chiefs have a focus on autoimmune movement disorders? I found that really interesting. Most of the movement disorder folks I interact with, their primary interest is in neurodegeneration.

Dr Balint: Very good question. Even so, I never asked myself that question, really, but I think I'm the only one with this designated focus as such. Many people come from the neurology angle - most of them. Even so, movement-disorder people really welcome this field and are interested, but I think somebody who has dedicated their interest and time to it? I think I can't actually think of many other people.

Dr Smith: Yeah, I think it's really cool, and, of course, autoimmune neurology is the flavor of the day these days, right? I mean, I remember when I was at the University of Utah, we were recruiting Stacy Clardy (who I think many of our listeners will know). I remember thinking, you know, she's never going to be busy. How many of these autoimmune problems are there, really? And she was, like, deluged when she came. These are really common problems. I guess that was one question I had for you. You know, we think of these as rare disorders, and when we look at the article, you have these tables of these antibodies, and a lot of them are pretty uncommon – but, cumulatively, how common are autoimmune movement disorders?

Dr Balint: It's a very difficult question, because we don't have good epidemiological data. And if you look at series, I mean, most papers addressing this issue come actually from the ataxia field. And then, depending on where you look at, you might find varying numbers, and they might be also influenced by the fact that they come from ataxia centers with own certain biases. Even so, it's very close to my heart, but, I also still think it's overall very rare. So, in my practice, I see all sorts of movement disorders, and overall, they're still quite rare, but the point is that they are treatable and have important management implications, so you want to be sure not to miss any of them.

Dr Smith: Well, maybe we can go to that next. Part of the challenge here, of course, is there's just so many of these different syndromes and antibodies. Are there pearls that you can provide our listeners that would help them guide when they should be thinking about these disorders when they confront a patient with a particular phenotype? Like ataxia, for instance - you know, there are certain aspects of the clinical scenario that should trigger, "Wow, this might be an autoimmune problem".

Dr Balint: So, in general, I would say there are certain scenarios where you would want to think of an autoimmune etiology in your differential. One is a very characteristic phenotype. So, speaking broadly in terms of movement disorders, stiff-person spectrum disorders have a very characteristic phenotype which you need to recognize, and then you will be able to see it when a patient enters. Important phenotypes to know which are very characteristic are faciobrachial dystonic seizures, for example, with anti-GA1 antibodies, or pseudofinalistic movements in non-REM sleep is IgLON5 antibodies, leg myoclonus is CASPR2 antibodies. I don't want to necessarily enumerate all the scenarios. The point here is there are some characteristic phenotypes where you would think of autoimmune neurology. Another scenario where you would think of autoimmune, for example, the context of late-onset paroxysmal movement disorders. So, classically, when we think of paroxysmal dyskinesia, we think of a group of genetic disorders, but if somebody develops a paroxysmal movement disorder later in life in adulthood, then you would think of autoimmune neurology, and this applies also in the context of episodic ataxias. Another red flag might be a propensity to autoimmunity. For example, somebody with type one diabetes and vitiligo coming in for cerebellar ataxia, of course, you would think of anti-GAD ataxia. And, similarly, if somebody has recently been diagnosed with a cancer and develops a rapidly disabling syndrome, of course, then you would think of a paraneoplastic autoimmune disorder. And with autoimmune syndrome, there are some symptoms which are also like tell-tale signs. So, for example, somebody with a stiff-person spectrum disorder, an ataxia with long-lasting diarrhea over months, losing weight - investigations haven't found anything, then you would think of DPPX antibodies or celiac disease. Or, if you have, like, a neuropathic pain which is otherwise not explained, then you might think of CASPR2 antibodies in somebody with a cerebellar ataxia. So, there are some features of some antibodies. (Again, I will not now list all of them which might point you to a diagnosis.) Then, of course, another scenario which is important, I think, is if you have a hemisyndrome without a structural lesion on imaging. Classically, neurologists are trained to think of a hemisyndrome - we look for a lesion on the contralateral side. But if you have, like, for example, a hemichorea without a lesion or a hemiataxia without a lesion, one should also think of an autoimmune disorder with antibodies. And then, more generally, of course, if you have changes on brain MRI or information on CSF, of course, if the clinical cause is more rapidly progressive - and last, but not least, if somebody does not really fit into our categories of the degenerative symptoms or metabolic syndromes or functionality disorders, then, of course, one should just take a step back and think, could it be something autoimmune? Having said that, if I may, I just want to say that, I mentioned that rapid disease course, and on the other hand, it's important to stress that a slowly progressive disease cause does not exclude an autoimmune etiology.

Dr Smith: So, that was a great summary. Thank you. I don't know if you're familiar with the term "Aunt Minnie" (something I learned in medical school and radiology). There are certain findings that are "Aunt Minnie", you know what "Aunt Minnie" looks like, and if you see these particular findings, you should really think about a specific disease - and I think you gave a lot of pearls in that answer, so I appreciate that. This may seem like a bit of a random question, but it's interesting that there are some of these phenotypes that do replicate genetic phenotypes, and you used episodic ataxia, which, in a younger individual, we think of a spectrum of various genetic disorders. Is that random, or are there instances where the underlying mutation in a genetic disorder actually serves as a target for autoimmunity in a later-onset autoimmune problem? Not that the mutation causes autoimmunity, but are there shared targets - in one disease it's the mutation, and another, there's an antibody that binds to the protein, for instance?

Dr Balint: That's an excellent topic, and even though it's not addressed in the Continuum article, I actually covered this in an article in Brain from 2018, where we also discuss parallels (immunogenetic parallels) with targets seen in genetic disease or in autoimmune disease, and there are actually some examples for cerebellar ataxia, and some of the targets are, indeed, the same for the antibodies and mutation. And some targets are a little bit more difficult, because for those, the antibodies would probably not be pathogenic, but it's more like an autoimmune overall target but it's T-cell mediated. But, for example, water-gated, um, calcium channels - we have antibodies and we have mutations. Or, another example would be glycine receptor antibodies give you acquired hyperekplexia, whereas the mutations give you hereditary hyperekplexia. So, there is, indeed, a bit of an overlap between autoimmune and genetic disorders, but often, also, like, the age at onset (because that might be the next question, the age at onset), and maybe family history and associated features, should help to distinguish the two. I think more from the pathophysiological point interesting, rather than clinically too confusing.

Dr Smith: Wow, that's really cool. So, another question I have is regarding antibody panels, right? And so, I think, oftentimes (at least around here), folks confronting an unusual phenotype will send the Mayo panel - they'll send autoimmune encephalitis or a paraneoplastic panel – and, you know, I think one of the challenges I have thinking about the spectrum of phenotypes that you described, I mean, if you recognize "Aunt Minnie", then you know where to go, but it seems to me that there's a lot of these that maybe folks don't recognize "Aunt Minnie". What is the diagnostic utility and pearls and pitfalls of ordering these panels when you're not really certain? In other words, is there a risk of a false positive if the pretest probability is low? So, I guess that's a long question, but do you have guidance about when we should and maybe when we should not be ordering these panels? So, you know, undifferentiated ataxia that's chronically progressive - should we be sending a panel or not? Patients who are later-onset acute, maybe so. So, what's the guidance on when to order the panel?

Dr Balint: It's a tricky topic also for many people in our practice, because, of course, as you said, we don't want to miss something, but, indeed, with any test which you order with a low pretest probability and which is not quite appropriate, you might have false positives, and that might cause much additional trouble in security, or maybe unnecessary and invasive immunotherapy with adverse effects – so, it's really important to think well about antibody testing. And, generally speaking, like always in medicine, we shouldn't order random tests, and antibody panels and neuronal antibodies are not designed as a screening test, so you need to have a phenotype and a reasonable suspicion - and clinical acumen is really key, and that's why also the article is so much focused on the phenotype. It's clearly not that any movement disorder patient who enters the outpatient clinic should get a blood test for antibodies that will likely cause harm, and it has been shown that these antibodies can be falsely positive, both in other diseases but also in healthy controls, and much depends also on which tests you use (but, let's not go into too much detail over here) - so, generally speaking, I would say if you have a suspicion of an autoimmune disease clinically (I mentioned some scenarios where you would think of an autoimmune disorder). And then, ataxias are, of course, a bit tricky, because often, we don't have too many other handles there, and there's still also a significant number of acquired late-onset ataxia where we don't know what the cause is. I think in the ataxia scenario, if I don't have a good answer or explanation, I would order antibody tests a bit more freely - I mean, if you do it properly, you do the serum and the CSF, and that also increases your sensitivity but also the specificities, so I wouldn't then just do the serum, but then go for serum and CSF. In other movement disorders, it depends also a little bit on the phenotype. So, somebody with a phenotype fitting well with Parkinson's disease, I wouldn't do any testing. Somebody with clear PSP phenotype without any red flags or not-fitting features, it is very unlikely to have an antibody finding, and this has been shown also in cohorts. But, if you have something which is not fitting in the phenotypes - for example, you have somebody where you think it might be a PSP phenotype with predominantly axial Parkinsonism falls, but you notice that the oculomotor disturbance is not a vertical gaze palsy, but a horizontal gaze palsy – so, it's not really fitting phenotype as you know it. That's a scenario where would probably think of antibody testing. Then, if you do the testing theorem - and CSF, in general, is gold standard - there are some antibodies where theorem is good enough (like, for example, with aquaporin-4 antibodies), but the reason why we do serum and CSF, as I mentioned, is the increased sensitivity and specificity. And nowadays, in the antibody world, we have something similar to the genetics - we have the variant of unknown significance and in the neurology world, we coin the term "antibody of unknown significance" to also give a name to the problem that, sometimes, we get a test result and it is difficult to interpret. Another handle over there would be to try to confirm the test result in another test method. So for example, if you have a cell-based assay with an antibody finding, you would like to confirm that on immunohistochemistry - the staining pattern is in keeping with that.

Dr Smith: So, Bettina, that was a really great and comprehensive answer to the question with a lot of pearls packed into it, and I think the idea that, you know, oftentimes, it's helpful to do both serum and CSF testing is important - also looking for staining to further confirm the diagnosis. And, I think one of the things that I was struck by in your response was the example of a PSP patient who instead of vertical gaze palsy had horizontal gaze palsy as a red flag, and I think a lot of our listeners are probably familiar with the idea that maybe hyperkinetic movement disorders might be autoimmune, or certainly rapidly progressive ataxia, but at least I don't think of Parkinsonian syndromes as often. I know there are some that we need to consider. Maybe you can give us some pearls about when we should consider antibody testing in a patient who has a Parkinson syndrome?

Dr Balint: So, I will not cover now the paraneoplastic Parkinsonian syndromes (because they typically develop as rapidly that you would anyway think about it, hopefully), but go more into those conditions which might mimic degenerative disease - and one of the most interesting antibodies in this regard is IgLON5, and you will be aware that it has been discovered in 2014 in patients who shared a characteristic sleep movement disorder (non-REM parasomnia). The spectrum has broadened a lot, and one possible manifestation is that it could come into the differential of Parkinsonian syndromes - so, for example, if you have axial Parkinsonism and a gaze palsy, you are in a PSP phenotype, but the red flag would be maybe if the eye movement disorders are not really fitting with the PSP phenotype. Also, in PSP patients, we don't expect parasomnias at night. If the bed partner is, for example, complaining that the patient is moving in his sleep and doing movements, then this would be a red flag, and in this context, you would think of IgLON5. IgLON5 could also give you Parkinsonism and cerebellar ataxia, and they might have dysautonomia, and, of course, with a sleep movement disorder, you are now in the ballpark of MSA phenotypes; however, if there are additional features (like, for example, fasciculations) which you don't expect in MSA, that would be, again, the red flag. So, typically, even in those differentials, there are some red flags on handles which would point you to the diagnosis - it is not that it completely mimics the phenotype of our default degenerative disease, but, sometimes, you need to hunt a little bit for those handles.

Dr Smith: So, Bettina, that's really interesting. I wanted to ask you about IgLON5, and in particular, the sleep phenotype, but, you know, I wonder whether there's a risk of just confusing this with REM sleep behavior disorder and a chronic Parkinsonian syndrome - what's the time course of this, and any other wisdom in terms of how to differentiate it from, you know, a more common neurodegenerative problem?

Dr Balint: So, the spectrum of sleep disorders in IgLON5 is actually a bit broad. The characteristic thing is the non-REM sleep parasomnia with the finalistic fine movements, but classic REM sleep behavior disorder has also been reported in these patients. And one of the tricky things is IgLON5 is a slowly progressive disease (some patients had symptoms for a decade prior to diagnosis), so it's really an important differential of autoimmune disease - but as mentioned, the features not fitting in, and they are typically also the cardinal features. So, gaze palsies are very frequent, ptosis, bulbar symptoms, vocal cord palsy, sleep movement disorders which might not fit to the original phenotype, and breathing problems (for example) so severe that they require a tracheostoma – so, these are some red flags which would alert you to this diagnosis of anti-IgLON5 disease.

Dr Smith: I'm curious, Bettina, how do you keep up on all of this and keep it all straight? Right, there's a lot of information, and as I was reading your article, you've got these wonderful tables - and in fact, this whole issue for our listeners feels that way. I've read several of these articles now, and I'm just curious what your strategy is to stay up to date and stay organized. You have to be very organized to be an autoimmune neurologist, it seems to me.

Dr Balint: And having a little bit of OCD helps clearly, as always, in neurology. I think it is just that I started to be interested in this area for a while and I have in my head the clinical phenotype to most important associated antibodies, and as the field continues, I just add up on that panel. But, I don't want people to be discouraged - you're right, many antibodies, but I think the point is not to know each and every antibody but to know in which scenario to think of an autoimmune syndrome and then to know where to look it up.

Dr Smith: Well, I think that's a great way of ending our conversation, Bettina. I think your article does a great job of that, and one of the things I love about Continuum is these articles serve as point-of-care tools. I think our conversation will also serve as a useful framework, because I think you've talked a lot about how to organize your thinking, and, you know, pearls for when we should be thinking about these disorders which are uncommon, but you certainly don't want to miss one because the therapy can be very effective. So, Bettina, thank you so much for joining me. This has been a really great conversation.

Dr Balint: Thank you so much, Gordon. Thank you very much for your good questions.

Dr Smith: So, again, today, I've had the great pleasure of interviewing Dr Bettina Balint, whose article on ataxia and other autoimmune movement disorders appears in the most recent issue of Continuum, which is on autoimmune neurology. Be sure to check out Continuum Audio episodes from this and other issues. And thanks to our listeners for joining us today.

Dr Monteith: This is Dr Teshamae Monteith, Associate Editor of Continuum Audio. If you've enjoyed this episode, you'll love the journal, which is full of in-depth and clinically relevant information important for neurology practitioners. Use this link in the episode notes to learn more and subscribe. AAN members, you can get CME for listening to this interview by completing the evaluation at Continpub.com/AudioCME. Thank you for listening to Continuum Audio.

The critical care management of spontaneous subarachnoid hemorrhage (SAH) is similar to that of other acute brain injuries, with the addition of detecting and treating delayed cerebral ischemia. Recent trials are influencing practice and providing guidance for standardizing management.

In this episode, Kait Nevel, MD speaks with Soojin Park, MD, FAHA, FNCS, author of the article "Emergent Management of Spontaneous Subarachnoid Hemorrhage," in the Continuum June 2024 Neurocritical Care issue.

Dr. Nevel is a Continuum® Audio interviewer and a neurologist and neuro-oncologist at Indiana University School of Medicine in Indianapolis, Indiana.

Dr. Park is an associate professor of neurology (in biomedical informatics) at Vagelos College of Physicians and Surgeons, Columbia University in New York, New York and medical director of critical care data science and artificial intelligence at NewYork-Presbyterian Hospital in New York, New York.

Additional Resources

Read the article: Emergent Management of Spontaneous Subarachnoid Hemorrhage

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Guest: @soojin_soojin

Full episode transcript  

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 Nevel: This is Dr Kait Nevel. Today, I'm interviewing Dr Soojin Park about her article on emergent management of spontaneous subarachnoid hemorrhage, which is part of the June 2024 Continuum issue on neurocritical care. Welcome to the podcast. It's so great to be talking to you today.

Dr Park: Thank you so much, Kait. Nice to be here.

Dr Nevel: Before we get started, could you introduce yourself for the audience?

Dr Park: Sure. So, I am an Associate Professor of Neurology - also in Biomedical Informatics - at Columbia University here in New York City. I trained in vascular neurology and neurocritical care.

Dr Nevel: Great. And so, I always like to ask at the beginning of these interviews, you know, if we could take away one thing from your article — and this is specifically (I'll direct this) towards the neurologists out there that are covering inpatient consults and ER consults — and so, for our clinical neurologists listening out there, what is the most important thing that you think that they should take away from your article?

Dr Park: So, I guess the most important thing for the general neurologists out there is that it may have been a while since they were aware of some updates that have occurred. There are some recent trials that are influencing practice and will potentially influence practice in the next few years that readers should really know about, and it provides a little bit stronger guidance to drive more standardized management. There have been two recent guidelines published this year. But there remain several gray areas for management where you need to be a bit more nuanced, and so I'm hoping the article gives the readers a framework to deliver more expert care.

Dr Nevel: Yeah, and I really, of course, always urge the listeners to go back and read the article and reference the article, because I do think that you do that really nicely and are clear when there are things where there's more higher-level, evidence-based reasons for things and where there's, kind of, just more expertise and guidelines on certain things. So, could you tell the listeners a little bit more about yourself, what interests you about subarachnoid hemorrhage specifically, and how you approach that interest and clinical background in writing this article?

Dr Park: So, I mentioned that I trained in both vascular neurology and neurocritical care back when many people used to do that. As a result, I've trained or practiced in four different academic medical centers who have specialized neurointensive care units. And the patients with subarachnoid hemorrhage tend to have a substantial ICU length of stay, and the neurointensive care that we provide can have a very large impact on patient outcome. And what I saw, though (practicing across four different centers), was that the management of patients with subarach can be quite variable across institutions and across patients within institutions, and it's reflective of a couple of things. One, there's, like, complexity in detecting ischemia, even when your patient is a captive audience in their ICU room. Second, there's many clinical mimics that occur (the patients with subarachnoid hemorrhage, they have a risk for), such as hydrocephalus, seizure, and things like delirium. And then, finally, there's limitations in the technology that we even have available in terms of monitoring these patients. But, for me, it was this complexity and the variability of management that kind of posed an opportunity, and it really sparked my curiosity early on and has sustained me. So, I'm particularly interested in the role that, kind of, the complex analysis of existing monitoring technologies can play to improve outcome for patients with subarachnoid hemorrhage, and that's where the marriage of both being a neurointensive care physician and a biomedical informatics person comes in.

Dr Nevel: Yeah. That's really interesting, and I could see that, because I always felt, even during my training, that some of the management and, you know, what diagnostics were even ordered to follow patients throughout the ICU was expertise based and seemed to vary without a lot of really solid, again, high-level studies, guiding what was done. So how do you marry the bioinformatics with your interest in SAH?

Dr Park: Right. So, I have two grants on - basically, I guess you would say AI, but really data science - on how we can manage patients with bleeds, specifically ICH and subarachnoid hemorrhage and hydrocephalus. So, we use data that comes from the monitors and we process that in a multimodal fashion and apply signal processing and machine learning and we build predictive analytic tools. So, I'm very interested in this pipeline of developing clinical decision support (information that we don't really have), and we're trying to glean from all the data and turn it into information that clinicians might use. The problem in subarachnoid hemorrhage patients is that a lot of what we're looking for is subclinical - so, it's not quite obvious, either because you can't possibly be in the room to be constantly monitoring for it (and, currently, the best monitor is the human, is examination), but, specifically in patients who have disordered consciousness, even the examination can be somewhat limited, and that's where we rely upon some of our neuromonitors. So, my interest has come in taking those multimodal monitors - but even nonneurologic monitors (stuff about your physiology, like your heart rate and blood pressure, et cetera) - and able to find signals that might tell us that a patient is getting into a dangerous zone. So, that's what my research portfolio has been 100% about - it's about subarachnoid hemorrhage patients and trying to optimize management, both for prevention and intervening in a timely fashion.

Dr Nevel: Wow. That's really interesting and would be so wonderful, it sounds like, for this patient population, if, you know, something was able to be identified that you could easily monitor to kind of predict or catch things early. So, kind of segueing from that, what do you think are the most — and you outline these nicely in your article, and I'm going to reference the listeners to, I believe it's the first table (table 5-1) - but what are, just like in general, the most important initial steps a clinician should take when managing somebody with an aneurysmal subarachnoid hemorrhage?

Dr Park: So, I think it's sort of along the timeline. So, at the time of presentation of a patient with subarachnoid hemorrhage, the focus you should have should be really on differentiating the etiology of the subarachnoid hemorrhage. At the same time, if the patient has any coagulopathies, you should manage that coagulopathy reversal, blood pressure management, and then detection and management and treatment of hydrocephalus. That's first and foremost. But then there is a longer timeline of neurocritical care management, and that's really centered on prevention, detection, and treatment of delayed cerebral ischemia, and that can occur anytime from onset of subarachnoid hemorrhage to two to three weeks out. And then that period of neurocritical care is made challenging because you have early brain injury (which is the period of seventy-two hours after onset), cerebral edema, and then, like we talked about, disordered consciousness. This kind of knowing how to augment your management strategies with monitoring or imaging is really key.

Dr Nevel: Yeah. And you, you know, spend some time in your article really going through delayed cerebral ischemia really nicely. And I would love to hear your take on what is the most challenging aspects of delayed cerebral ischemia in both, you know, diagnosis and management - and you alluded to it a little bit earlier, I think, with some of your research, but I would love to hear you talk about that.

Dr Park: Yeah. And actually, this is probably one of - if there was a controversial area in this topic, it would be about this - because there does not seem to be one best way to operationalize how you either survey for, or monitor for, delayed cerebral ischemia. There has been, historically, a merging of these definitions of vasospasm and delayed cerebral ischemia, which are not the same thing.  And so, if you were to draw a Venn diagram, not all patients who have cerebral vasospasm end up having symptomatic or delayed cerebral ischemia, and not all patients who have delayed cerebral ischemia have any discernable vasospasm - and, so, to use the terms interchangeably leads to a little bit of confusion. I mentioned the clinical mimics - you know, the causes of which are myriad (could be delirium, or hydrocephalus, or early brain injury) - and so that also poses another challenge. And, so, what I always say is that delayed cerebral ischemia, sometimes - when you're thinking about it in the context of subarachnoid hemorrhage - is sometimes a retrospective diagnosis. And it really kind of came from a really earnest attempt to standardize what the community is talking about, so that we can better understand how to define (if you understand how to define it better, then you can tailor treatments, study treatments, you're talking about the same disease) - but we're still not there, and I think that's where a lot of the controversy or confusion comes from. My personal approach is really to focus on the symptomatology, so, if a patient has vasospasm - whether that is, you know, screened for with a transcranial Doppler (if your institution does use transcranial Dopplers, it might be a nice screening tool) - but the fact of the matter is that not all patients can get a transcranial Doppler every single day. You know, most of the institutions that I have worked in offer that technology Monday through Friday and not on holidays, not on weekends, and so you can't fully rely upon something like that. The advantage of it is that it has pretty high sensitivity but it does have a lower specificity (so it overcalls vasospasms), so to treat just based on a TCD would probably be erroneous. Not all people agree, but I think that's the majority of the sentiment - is that you should then be triggered to go look for confirmation with some neuroimaging and really potentially wait for symptoms so that it might be a trigger to optimize the patient in terms of volume and blood pressure, but not necessarily to treat. So, yeah, operationalizing that workflow of how do you trigger, you know, confirmatory neuroimaging, what type of neuroimaging you should then choose? This is where the variability exists. But, in general, I focus on symptomatology. The extra challenge comes in the patients who have disordered consciousness. And so, at an institution like mine, we do rely upon invasive neuromonitoring, and that's now called for in the guidelines as well.

Dr Nevel: And I imagine these are high-intensity situations where also I would suspect decisions, you know, need to be made quickly on some of these things that you're talking about, too.

Dr Park: That's right.

Dr Nevel: What do you think is a misconception - or maybe (I hate to call it a mistake, but for lack of a better term) like an easy mistake that one can make - when treating patients with aneurysmal subarachnoid hemorrhage?

Dr Park: Hmm, an easy mistake. I guess, you know, time is brain, so it's an opportunity to miss ischemia - or actually attribute everything to ischemia and ignore the possibility for things like seizure (so nonconvulsive seizures), a resurgence of more of a delayed hydrocephalus - and so, I think it's important as you're managing a patient not to get kind of pigeonholed into looking for one particular thing (only looking for delayed cerebral ischemia), but being really vigilant that there could be lots of different reasons for a neurological change of a patient. And so, timely monitoring - kind of figuring out the etiology of a change in neurological status - is really important. And then, also, on the flip side of that, is we're really good at being aggressive in both inducing hypertension or managing a patient (trying to prevent ischemia), we're not that great about starting to pull back - and so I think being vigilant about opportunities to reassess your patient's risk for ongoing ischemia and deciding when that period of risk is over and starting to peel back on therapies, because these patients are also at risk for the down sides of inducing hypertension, which is PRES - and we have seen that in patients, and, you know, the phenotype of that will look very much like ischemia.

Dr Nevel: Yeah, it's complicated because you're taking care of patients with often impaired consciousness who have a lot of symptoms that could represent many different diagnoses that you would treat very differently, so I could see that that might be easy to do to kind of fall into the mindset of thinking that it's definitely one thing without fully evaluating for everything. So, caring for patients with aneurysmal subarachnoid hemorrhage obviously can be really, you know, challenging from the medical perspective, but also from the perspective of, you know, communication with families, and families asking questions about prognosis and things like that (and you mentioned this in your article about prognostication a little bit) - and can you talk a little bit about our ability to prognosticate long-term outcomes for patients who are in that acute phase (maybe even early first, you know, couple of days or a week) with a subarachnoid hemorrhage?

Dr Park: I think one of the most rewarding aspects of caring for patients with subarachnoid hemorrhage is that these patients can look, really, very sick in the beginning, and they're quite complex to manage, but you can see some very impressive recovery. And from a neurointensivist perspective, seeing that recovery in kind of a rapid timeline is rare - and we get to see that in subarach patients. We see patients who just have refractory recurrent vasospasm and delayed cerebral ischemia getting all of the tools thrown at them and you're really kind of, you know, concerned that there seems to be no end - but there is this peak of that injury, and then after that window of secondary brain injury risk kind of resolves, the patient can very much recover (so seeing patients who look the sickest be able to leave and go home). I think there is a hidden cost to subarachnoid hemorrhage where, maybe on our gross measures of outcome, patients look great, but there are this hidden cost of social psychological outcome that is unmeasured the way that we are currently measuring it. And I think our field is getting better at adopting some of the ability to measure those kind of hidden costs, and we're able to see that, even a year out, patients are really not back to where they were before (even though on the scales we currently have, they do look great, right, in terms of motor function, and things like that) - so, I think as clinicians, we have to be sensitive to that. So, when we talk to families, we have to remain hopeful that they are going to have a remarkable potential recovery but prepare families that they really should be on the lookout for any opportunity to rehabilitate in all aspects of function.

Dr Nevel: Yeah. And you mentioned in your article that as we're moving into the future  - and even currently - that there is some focus on gathering more patient-reported outcomes for people who are, you know, out of the ICU back in their normal lives after subarachnoid hemorrhage (which speaks to this that you're talking about, that even if their motor function is normal, they may not be back to their normal lives). So, what is something you think that's really important that we've learned in the past ten years - I'll give it ten years, you can go back further, make that time frame shorter if you want, but about the past ten years - about subarachnoid hemorrhage's impact on patient care, and then what do you think we're going to learn in the next ten years that will impact the way we care for these patients?

Dr Park: So, you know, subarach - in terms of the literature that is forming, that has formed - like I said, the guidelines had not been updated for over a decade, and we're fortunate to have not just one, but two sets of guidelines from two professional societies that were published right next to each other this past year in 2023 - but the field is fast moving, so even after the publication of those guidelines, there was one of the first randomized controlled trials in the field to be published maybe a month or two after that (that was the early lumbar drain trial). So, the key areas that I think where the literature has really helped strengthen our practice in terms of bringing standardization is in the antifibrinolytics. And so, in that space, recently, there was a very nicely performed randomized controlled trial for early administration of antifibrinolytics. It's a practice that, even when I was training, was sort of based on old literature back when we used to treat subarachnoid patients very differently - so we were really kind of extrapolating from that literature into our practice, and we were all sort of just giving it uniformly to patients early on with the good intention to try to prevent rebleeding, (which we understood, prior to aneurysm securement, was a high source of morbidity/mortality). So, in trying to reduce that risk of rebleeding (which happens very early) as much as we could, we were giving it. But the length of treatment (you know, who should we give that medication to) was really kind of uncertain - and this recent randomized controlled trial really gave a definitive answer to this, which is that it probably makes no difference. It should be seen with a caveat, though, that the trial (like any trial) was a very specific population. So, it could probably be said that for patients who are secured very early, there's no role for antifibrinolytic therapy, but, potentially, for patients who may be in a lower-middle-income environment or lower-income environment or for whatever reason can't reach aneurysm securement within that seventy two-hour period - you could consider, you know, greater than twenty-four hours you should consider the use of antifibrinolytics - but largely has brought an end to uniform administration of antifibrinolytics. This is where that expert nuanced care comes to, right?

Dr Nevel: Mm-hmm.

Dr Park: Another area is, really, kind of something as basic as blood pressure management. I think we were taught very early on that we should be very rigorous, bring that blood pressure down - and so, I think, across all types of stroke now, we're realizing there is a little bit of nuance, right? You have to think about your patient, about prior existing renal failure, about prior existing chronic hypertension that's poorly controlled - and in subarachnoid hemorrhage, the additional impact of that early brain injury. If you have cerebral edema, you should be considering, do we really want to control our blood pressure that low? Because we might be inducing secondary brain injury from our presumed protective intervention. So, these types of things are being revisited - so, the language around that in the new guidelines is a little bit softer, and it does sort of refer more to, "let's consider the whole patient".

Dr Nevel: Yeah, rather than making a blanket statement that doesn't apply to maybe everybody.

Dr Park: Yeah. And you also asked about future.

Dr Nevel: Yeah. Where do you think things are heading in the future? What's exciting in research, and if you had a crystal ball, what do you think we're going to figure out in the next ten years that's going to impact care?

Dr Park: Well, fortunately, for patients with subarachnoid hemorrhage and for people like me who are treating patients with subarachnoid hemorrhage, there's a lot going on. So, I mentioned lumbar drainage because there was a very nice trial that was published - I think we'll see in the next few years how much of that diffusion of innovation travels across the country in the world about the usage of this. There are some who point to prior studies that may have conflicting results and so want to wait and see it be validated. Others are pretty convinced, you know, by the quality of the study that was done and are trying to incorporate it into their protocols now. I think we're going to see more usage and more study of things like intravenous milrinone, early stellate ganglion blockade, intraventricular nicardipine, and even maybe optimized goals for cerebral perfusion or blood pressure - and this is for looking at a myriad of outcomes, including the prevention and treatment of vasospasm and ischemia, improving outcomes, and preventing infarction. There's also a lot to come about early brain injury (and I kind of talked about that). It's like a seventy-two-hour period window after subarachnoid hemorrhage, and it comprises processes like microcirculatory dysfunction, blood-brain barrier breakdown, and things like oxidative cascades, et cetera. While currently, there doesn't exist any practice besides, like, the nuance and expert determination of blood pressure goals prior to aneurysm securement, I think this will be an area that hopefully will become a target for intervention, because it has an independent and influential impact on poor outcomes for subarachnoid hemorrhage patients. So, watch the space.

Dr Nevel: Yes, absolutely. Looking forward to seeing what comes. Well, thank you so much for talking to me, Dr Park, and joining me on Continuum Audio.

Dr Park: It was my pleasure.

Dr Nevel: Again, today, I've been interviewing Dr Soojin Park, whose article on emergent management of spontaneous subarachnoid hemorrhage appears in the most recent issue of Continuum in neurocritical care. Be sure to check out Continuum Audio episodes from this and other issues. And thank you to our listeners for joining today.

Dr Monteith: This is Dr Teshamae Monteith, Associate Editor of Continuum Audio. If you've enjoyed this episode, you'll love the journal, which is full of in-depth and clinically relevant information important for neurology practice - and 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.

Management of stroke due to large vessel occlusion (LVO) has undergone unprecedented change in the past decade. Early identification and aggressive treatment are important in mitigating negative effects on patients' prognoses.

In this episode, Allison Weathers, MD, FAAN, speaks with T. M. Leslie-Mazwi, MD, author of the article "Neurocritical Care for Patients With Ischemic Stroke," in the Continuum June 2024 Neurocritical Care issue.

Dr. Weathers is a Continuum® Audio interviewer and an associate chief medical information officer at Cleveland Clinic in Cleveland, Ohio.

Dr. Leslie-Mazwi is a professor and chair in the department of neurology at the University of Washington in Seattle, Washington.

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Read the article: Neurocritical Care for Patients With Ischemic Stroke

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Transcript

Full transcript available

In neurocritical care, the initial evaluation is often fast paced, and assessment and management go hand in hand. History, clinical examination, and workup should be obtained while considering therapeutic implications and the need for lifesaving interventions.

In this episode, Aaron Berkowitz, MD, PhD FAAN, speaks with Sarah Wahlster, MD, an author of the article "The Neurocritical Care Examination and Workup," in the Continuum June 2024 Neurocritical Care issue.

Dr. Berkowitz is a Continuum® Audio interviewer and a professor of clinical neurology at the University of California, San Francisco

Dr. Wahlster is an associate professor of neurology in the departments of neurology, neurological surgery, and anesthesiology and pain medicine at Harborview Medical Center, University of Washington in Seattle, Washington.

Additional Resources

Read the article: The Neurocritical Care Examination and Workup

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Earn CME (available only to AAN members): continpub.com/AudioCME

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Host: @AaronLBerkowitz

Guest: @SWahlster

Full Episode Transcript

Sarah Wahlster, MD

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 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 Show Notes. AAN members: stay tuned after the episode to hear how you can get CME for listening. 

Dr Berkowitz: This is Dr Aaron Berkowitz, and today I'm interviewing Dr Sarah Wahlster about her article on examination and workup of the neurocritical care patient, which is part of the June 2024 Continuum issue on neurocritical care. Welcome to the podcast, Dr Wahlster. Can you please introduce yourself to the audience?

Dr Wahlster: Thank you very much, Aaron. I'm Sarah Wahlster. I'm a neurologist and neurontensivist at Harborview Medical Center at the University of Washington.

Dr Berkowitz: Well, Sarah and I know each other for many, many years. Sarah was my senior resident at Mass General and Brigham and Women's Hospital. Actually, Sarah was at my interview dinner for that program, and I remember meeting her and thinking, "If such brilliant, kind, talented people are in this program, I should try to see if I can find my way here so I can learn from them." So, I learned a lot from Sarah as a resident, I learned a lot from this article, and excited for all of us to learn from Sarah, today, talking about this important topic. So, to start off, let's take a common scenario that we see often. We're called to the emergency room because a patient is found down, unresponsive, and neurology is called to see the patient. So, what's running through your mind? And then, walk us through your approach as you're getting to the bedside and as you're at the bedside.

Dr Wahlster: Yeah, absolutely. This was a fun topic to write about because I think this initial kind of mystery of a patient and the initial approach is something that is one of the puzzles in neurology. And I think, especially if you're thinking about an emergency, the tricky part is that the evaluation and management go hand in hand. The thinking I've adapted as a neurointensivist is really thinking about "column A" (what is likely?) and "column B" (what are must-not-miss things?). It's actually something I learned from Steve Greenberg, who was a mutual mentor of us - but he always talked me through that. There's always things at the back of your head that you just want to rule out. I do think you evaluate the patient having in mind, "What are time-sensitive, critical interventions that this patient might need?" And so, I think that is usually my approach. Those things are usually anything with elevated intracranial pressure: Is the patient at risk of herniating imminently and would need a neurosurgical intervention, such as an EVD or decompression? Is there a neurovascular emergency, such as an acute ischemic stroke, a large-vessel occlusion, a subarachnoid hemorrhage that needs emergent intervention? And then other things you think about are seizures, convulsive/nonconvulsive status, CNS infection, spinal cord compression. But I think, just thinking about these pathologies somewhere and then really approaching the patient by just, very quickly, trying to gather as much possible information through a combination of exam and history.

Dr Berkowitz: Great. So, you're thinking about all these not-to-miss diagnoses that would be life-threatening for the patient and you're getting to the bedside. So, how do you approach the exam? Often, this is a different scenario than usual, where the patient's not going to be able to give us a history or maybe necessarily even participate in the exam, and yet, as you said, the stakes are high to determine if there are neurologic conditions playing into this patient's status. So, how do you approach a patient at the bedside?

Dr Wahlster: So, I think first step in an ICU setting (especially if the patient has a breathing tube) is you think about any confounders (especially sedation or metabolic confounders) - you want to remove as soon as possible, if able. I think as you do the exam, you try to kind of incorporate snippets of the history and really try to see - you know, localize the problem. And also kind of see, you know, what is the time course of the deterioration, what is the time course of the presentation. And that is something I actually learned from you. I know you've always had this framework of "what is it, where is it?" But I think in terms of just a clinical exam, I would look at localizing signs. I think, in the absence of being able to do the full head-to-toe neuro exam and interact with the patient, you really try to look at the brainstem findings. I always look at the eyes right away and look at, I think, just things like, you know, the gaze (how is it aligned? is there deviation? is there a skew? what do the pupils look like? [pupillary reactivity]). I think that's usually often a first step - that I just look at the patient's eyes. I think other objective findings, such as brainstem reflexes and motor responses, are also helpful. And then you just look whether there's any kind of focality in terms of - you know, is there any difference in size? But I think those are kind of the imminent things I look at quickly.

Dr Berkowitz: Fantastic. Most of the time, this evaluation is happening kind of en route to the CT scanner or maybe a CT has already happened. So, let's say you're seeing a patient who's found down, the CT has either happened or you asked for it to happen somewhat quickly after you've done your exam, and let's say it's not particularly revealing early on. What are the sort things on your exam that would then push you to think about an MRI, a lumbar puncture, an EEG? You and I both spend time in large community hospitals, right, where "found down" is one of the most common chief concerns. In many cases, there isn't something to see on the CT or something obvious in the initial labs, and the question always comes up, "Who gets an MRI? Who gets an LP? Who gets an EEG?" - and I'm not sure I have a great framework for this. Obviously, you see focality on your exam, you know you need to look further. But, any factors in the history or exam that, even with a normal CT, raise your suspicion that you need to go further?

Dr Wahlster: It's always a challenge, especially at a community hospital, because some of these patients come in at 1 AM where the EEG is not imminently available. But I think - let's say the CT scan is absolutely normal and doesn't give me a cause, but as an acute concerning deterioration, I think both EEG and LP would cross my mind. MRI I kind of see a little bit as a second-day test. I think there's very rare situation where an acute MRI would inform my imminent management. It's very informative, right, because you can see very small-vessel strokes. We had this patient that actually had this really bad vasculitis and we were able to see the small strokes everywhere on the MRI the day later, or sometimes helps you visualize acute brainstem pathology. But I think, even that - if you rule out a large-vessel occlusion on your CTA, there's brainstem pathology that is not imminently visible on the CT - it's nothing you need to go after. So, I do think the CT is a critical part of that initial eval, and whereas I always admire the neurological subspecialties, such as movements, where you just – like, your exam is everything. I think, to determine these acute time-sensitive interventions, the CT is key. And also, seeing a normal CT makes me a little less worried. You always look at these "four H" (they're big hypodensity, hyperdensity, any shift; is there hydrocephalus or herniation). I think if I don't have an explanation, my mind would imminently jump to seizure or CNS infection, or sometimes both. And I think then I would really kind of - to guide those decisions and whether I want to call in the EEG tech at 2 AM - I would, you know, again, look at the history and exam, see if there's any gaze deviation, tongue biting, incontinence - anything leading up towards seizure. I think, though, even if I didn't have any of those, those would strengthen my suspicion. If I really, absolutely don't have an explanation and the patient off sedation is just absolutely altered, I would still advocate for an EEG and maybe, in the meantime, do a small treatment trial. And I think with CNS infection - obviously, there are patients that are high risk for it - I would try to go back and get history about prodromes and, you know, look at things like the white count, fevers, and all of that. But again, I think if there's such a profound alteration in neurologic exam, there's nothing in the CT, and there's no other explanation, I would tend to do these things up front because, again, you don't want to miss them.

Dr Berkowitz: Yeah, perfect. So many pearls in there, but one I just want to highlight because I'm not sure I've heard the mnemonic - can you tell us the four Hs again of sort of neurologic emergencies on CT?

Dr Wahlster: Yeah. So, it's funny; for ages - I'm actually not sure where that's coming from, and I learned it from one of my fellows, one of our neurocritical care fellows - he's a fantastic teacher and he would teach our EM and anesthesia residents about it and his approach to CT. But yeah, the four H - he was always kind of like, "Look at the CT. Do you see any acute hypodensities, any hyperdensities?" And hypodensities would be involving infarct or edema; hyperdensities would be, most likely, hemorrhage (sometimes calcification or other things). Then, "Do you see hydrocephalus?" (because that needs an intervention). And, "Look at the midline structures and the ventricles." And then, "Do you see any signs of herniation?" And he would go through the different types of herniation. But I thought that's a very good framework for looking at the "noncon" and just identifying critical pathology that needs some intervention.

Dr Berkowitz: Yeah – so, hypodensity, hyperdensity, herniation, hydrocephalus. That's a good one – the four Hs; fantastic. Okay. So, a point that comes up a few times in your article - which I thought was very helpful to walk through and I'd love to pick your brain about a little bit – is, which patients need to be intubated for a neurologic indication? So, often we do consultations in medical, surgical ICUs; patients are intubated for medical respiratory reasons, but sometimes patients are intubated for neurologic reasons. So, can you walk us through your thinking on how to decide who needs to be intubated for the concern of depressed level of consciousness?

Dr. Wahlster: It's an excellent question, and I think I would bet there's a lot of variation in practice and difference in opinion. There was actually the 2020 ESICM guidelines kind of commented on it, and those are great guidelines in terms of just intubation, mechanical ventilation of patients, and just acknowledging how there is a lack of really strong evidence. I would say the typical mantra ("GCS 8, intubate") has been proposed in the trauma literature. And at some point, I actually dug into this to look behind the evidence, and there's actually not as much evidence as it's been put forth in guidelines and that kind of surprised me - that was just recently. I was like, "Actually, let me look this up." I would say I didn't find a ton of strong evidence for it. I would say, as neurologist – you know, I'm amazed because GCS, I think is a - in some ways, a good tool to track things because it's so widely used across the board. But I would say, as neurologists, we all know that it sometimes doesn't account for some sort of nuances; you know, if a patient is aphasic, if a patient has an eyelid-opening apraxia - it can always be a little confounded. I'm amazed that GCS is still so widely used, to be frank. But I would say there is some literature - some school of thought - that maybe just blindly going by that mantra could be harmful or could not be ideal. I would say – I mean, I look at the two kind of functional things: oxygenation and ventilation. I think, in a neuro patient, you always think about airway protection or the decreased level of consciousness being a major issue (What is truly airway protection? Probably a mix of things). Then there's the issue of respiratory centers and respiratory drive - I think those are two issues you think about. But ultimately, if it leads to insufficient oxygenation - hypoxia early on is bad and that's been shown in several neurologic acute brain injuries. I think you also want to think about ventilation, especially if the mental status is poor to the point that the PCO2 elevates, that could also augment an ICP or exacerbate an ICP crisis. Or sometimes, I think there's just dysregulation of ventilation and there's hyperventilation to the point that the PCO2 is so low that I worry about cerebral vasoconstriction. So, I worry about these markers. I think, the oxygenation, I usually just kind of initially track on the sats. Sometimes, if the patient is profoundly altered, I do look at an arterial blood gas. And then there are things like breathing sounds (stridor, stertor [the work of breathing]). And I think something that also makes me have a lower threshold to intubate is if I'm worried and I want to scan, and I'm worried that the patient can't tolerate it - I want an imminent scan to just see why the patient is altered, or seizing, or presenting a certain way.

Dr Berkowitz: All great pearls for how to think through this. Yeah - it's hard to think of hard and fast rules, and you can get to eight on the GCS in many different ways, as you said, some of which may not involve the respiratory mechanics at all. So, that's a helpful way of thinking about it that involves both the mental state, kind of the tracheal apparatus and how it's being managed by the neurologic system, and also the oxygen and carbon dioxide (sort of, respiratory parameters) – so, linking all those together; that's very helpful. And, related question – so, that's sort of for that patient with central nervous system pathology, who we're thinking about whether they need to be intubated for a primary neurologic indication. What about from the acute neuromuscular perspective (so, patients with Guillain-Barré syndrome or myasthenic crisis); how do you think about when to intubate those patients?

Dr Wahlster: Yeah, absolutely - I think that's a really important one. And I think especially in a patient that is rapidly progressing, you always kind of think about that, and you want them in a supervised setting, either the ER or the ICU. I mean, there's some scores - I think there's the EGRIS score; there's some kind of models that predict it. I would say, the factors within that model, and based on my experience, often the pace of progression of reflex motor syndrome. I often see things like, kind of, changes in voice. You know, myasthenia, you look at things like head extension, flexion - those are the kind of factors. I would say there's this "20/30/40 rule" about various measures of, like, NIF and vital capacities, which is great. I would say in practice, I sometimes see that sometimes the participation in how the NIF is obtained is a little bit funky, so I wouldn't always blindly go by these numbers but sometimes it's helpful to track them. If you get a reliable kind of sixty and suddenly it drops to twenty, that makes me very concerned. But I would say, in general, it's really a little bit the work of breathing - looking at how the patient looks like. There's also (at some point) ABG abnormalities, but we always say, once those happen, you're kind of later in the game, so you should really - I think anyone that is in respiratory distress, you should think about it and have a low threshold to do it, and, at a minimum, monitor very closely.

Dr Berkowitz: Yeah, we have those numbers, but so often, our patients who are weak, from a neuromuscular perspective, often have facial and other bulbar weakness and can't make a seal on the device that is used to check these numbers, and it can look very concerning when the patient may not, or can be a little bit difficult to interpret. So, I appreciate you giving us sort of the protocol and then the pearls of the caveats of how to interpret them and going sort of back to basics. So, just looking at the patient at the bedside and how hard they are working to breathe, or how difficult it is for them to clear their secretions from bulbar weakness. Moving on to another topic, you have a really wonderful section in your article on detecting clinical deterioration in patients in the neuro ICU. Many patients in the neuro ICU - for example, due to head trauma or large ischemic stroke or intracerebral hemorrhage, subarachnoid hemorrhage, or status epilepticus - they can't communicate with us to tell us something is getting worse, and they can't (in many cases) participate in the examination. They may be intubated, as you said, sedated or maybe even not sedated, and there's not necessarily much to follow on the exam to begin with if the GCS is very low. So, I'd love to hear your thoughts and your pearls, as someone who rounds in the neuro-ICU almost every day. What are you looking for at the bedside to try to detect sort of covert deterioration, if you will, in patients who already have major neurologic deficits, major neurologic injury or disease that we're aware of? I'm trying to see if there is some type of difference at the bedside that would lead you to be concerned for some underlying change and go back to the scanner or repeat EEG, LP, et cetera.

Dr Wahlster: Yeah. I think that's an excellent question because that's a lot of what we do in the neuro ICU, right? And when you read your Clans, your residency, like, "Ah, QNR neuro checks, [IG1]  " right? We often do that in many patients. But I think in the right patient, it can really be life or death a matter, and it is the exam that really then drives a whole cascade of changes in management and detects the need for lifesaving procedure. I would say it depends very much on the process and what you anticipate, right? If you have, for example, someone with a large ischemic stroke, large MCA stroke, especially, right, then there's sometimes conversations about doing a surgical procedure before they herniate. But let's say, kind of watch them and are worried that they will, you do worry about uncal herniation, and you pay attention to the pupil, because often, if the inferior division is infarcted, you know, you can see that kind of temporal tickling the uncus already. And so, I think those are patients that I torture with those NPi checks and checking the pupil very vigilantly. I would say, if it's a cerebellar stroke, for example, right, then you think about, you know, hydrocephalus. And often patients with cerebellar stroke - you know, the beauty of it is that if you detect it early, those patients can do so well, but they can die, and will die if they develop hydrocephalus start swelling. But I think, often something I always like to teach trainees is looking at the eye movements in upgaze and downgaze because, often, as the aqueduct, the third ventricle gets compressed and there's pressure on the colliculi – you kind of see vertical gaze get worse. But I would say I think it's always good to know what the process is and then what deterioration would look like. For example, in subarachnoid hemorrhage, where you talk about vasospasm - it's funny - I think a really good, experienced nurse is actually the best tool in this, but they will sometimes come to you and say, "I see this flavor," and it's actually a constellation of symptoms, especially in the anterior ACA (ACom) aneurysms. You sometimes see patients suddenly, like, making funky jokes or saying really weird things. And then you see that in combination with, sometimes, a sodium drop, a little bit of subfebrile temperature; blood pressure shoot up sometimes, and that is a way the brain is sometimes regulating. But it's often a constellation of things, and I think it depends a little on the process that you're worried about.

Dr Berkowitz: Yeah, that's very helpful. You just gave us some pearls for detecting deterioration related to vasospasm and subarachnoid hemorrhage; some pearls for detecting malignant edema in an MCA stroke or fourth ventricular compression in a large cerebellar stroke. Patients I find often very challenging to get a sense of what's going on and often get scanned over and over and back on EEG, not necessarily find something: patients with large intracerebral hemorrhage (particularly, in my experience, if the thalamus is involved) just can fluctuate a lot, and it's not clear to me actually what the fluctuation is. But you're looking for whether they're developing hydrocephalus from third ventricular compression with a thalamic hemorrhage (probably shouldn't be seizing from the thalamus, but if it's a large hemorrhage and cortical networks are disrupted and it's beyond sort of the subcortical gray matter, or has the hemorrhage expanded or ruptured it into the ventricular system?) And yet, you scan these patients over and over, sometimes, and just see it's the same thalamic hemorrhage and there's some, probably, just fluctuation level of arousal from the thalamic lesion. How do you, as someone who sees a lot of these patients, decide which patients with intracerebral hemorrhage - what are you looking for as far as deterioration? How do you decide who to keep scanning when you're seeing the same fluctuations? I find it so challenging - I'm curious to hear your perspective.

Dr Wahlster: Yeah, no - that is a very tricky one. I mean, unfortunately, in patients with deeper hemorrhages or deeper lesions - you know, thalamic or then affecting brainstem - I think those are the ones that ultimately don't have good, consistent airway protection and do end up needing a trach, just because there's so much fluctuation. But I agree - it's so tricky, and I don't think I can give a perfect answer. I would say, a little bit I lean on the imaging. And for example - let's say there's a thalamic hemorrhage. We recently actually had a patient - I was on service last week - we had a thalamic hemorrhage with a fair amount of edema on it that was also kind of pressing on the aqueduct and didn't have a lot of IVH, right? But it was, like, from the outside pushing on it and where we ended up getting more scans. And I have to say, that patient actually just did fine and actually got the drain out and didn't need a shunt or anything, and actually never drained. We put an EVD and actually drained very little. So, I think we're still bad at gauging those. But I think, in general, my index of suspicion or threshold to scan would be lower if there was something, like, you know, a lot of IVH associated, if, you know, just kind of push on the aqueduct. It's very hard to say, I think. Sometimes, as you get to know your patients, you can get a little bit of a flavor of what is within normal fluctuation. I think it's probably true for every patient, right? - that there's always some fluctuation within the realm of like, "that's what he does," and then there's something more profound. Yeah, sorry - I wish I could give a better answer, but I would say it's very tricky and requires experience and, ideally, you really taking the time to examine the patient yourself (ideally, several times). Sometimes, we see the patient - we get really worried. Or the typical thing we see the ICU is that the neurosurgeons walk around at 5 AM and say, like, "She's altered, she's different, she's changed." And then the nurse will tell you at 8 AM, like, "No, they woke up and they ate their breakfast." So, I think really working with your nurse and examining the patient yourself and just getting a flavor for what the realm of fluctuation is.

Dr Berkowitz: Yeah - that's helpful to hear how challenging it is, even for a neurocritical care expert. I'm often taking care of these patients when they come out of the ICU and I'm thinking, "Am I scanning these patients too much?" Because I just don't sort of see the initial stage, and then, you know, you realize, "If I'm concerned and this is not fitting, then I should get a CT scan," and sometimes you can't sort it out of the bedside. So, far from apologizing for your answer, it's reassuring, right, that sometimes you really can't tell at the bedside, as much as we value our exam. And the stakes are quite high if this patient's developed intraventricular hemorrhage or hydrocephalus, and these would change the management. Sometimes you have these patients the first few days in the ICU (for us, when they come out of the ICU) are getting scanned more often than you would like to. But then you get a sense of, "Oh, yeah - these times of day, they're hard to arouse," or, "They're hard to arouse, but they are arousable this way," and then, "When they are aroused, this is what they can do, and that's kind of what we saw yesterday." And yet, as you said, if anyone on the team (the resident, the nurse, the student, our neurosurgery colleague) says, "I don't think this is how they were yesterday," then, very low threshold to just go back and get a CT and make sure we're not missing something.

Dr. Wahlster: Exactly. Yeah. I would say the other thing is also certain time intervals, right? If I'm seeing a patient that may be in vasospasm kind of around the days seven to ten, for the first fourteen day, I would be a little bit more nervous. Or with swelling - acute ischemic stroke says that could peak swelling, when knowing which [IG2]  , I would just be more anxious or have a lower threshold to scan. Yeah.

Dr Berkowitz: Yeah - very helpful. Well, thank you so much for joining me today on Continuum Audio.

Dr Wahlster: Thank you very much, Aaron.

Dr Berkowitz: Again, today we've been interviewing Dr Sarah Wahlster, whose article, "Examination and Workup of the Neurocritical Care Patient" appears in the most recent issue of Continuum, on neurocritical care. Be sure to check out Continuum Audio episodes from this and other issues. And thank you so much to our listeners for joining us today.

Dr Monteith: This is Dr Teshamae Monteith, Associate Editor of Continuum Audio. If you've enjoyed this episode, you'll love the journal, which is full of in-depth and clinically relevant information important for neurology practice. And 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.

In this episode, Lyell K. Jones Jr, MD, FAAN, speaks with Ariane Lewis, MD, who served as the guest editor of the Continuum® June 2024 Neurocritical Care issue. They provide a preview of the issue, which published on June 3, 2024.

Dr. Jones is the editor-in-chief of Continuum: Lifelong Learning in Neurology® and is a professor of neurology at Mayo Clinic in Rochester, Minnesota.

Dr. Lewis is a professor of neurology and neurosurgery and director of the Division of Neurocritical Care at NYU Langone Medical Center in New York, New York.

Additional Resources

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facebook.com/continuumcme

@ContinuumAAN

Host: @LyellJ

Full episode transcript 

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.

Dr Jones: This is Dr Lyell Jones, Editor-in-Chief of Continuum: Lifelong Learning in Neurology. Today, I'm interviewing Dr Ariane Lewis, who recently served as Continuum's guest editor for our latest issue on neurocritical care. Dr Lewis is a Professor of Neurology and Neurosurgery at NYU, where she serves as the Director of the Division of Neurocritical Care. Dr Lewis, welcome. Thank you for joining us today. Why don't you introduce yourself to our listeners? Tell us a little bit about yourself.

Dr Lewis: Thank you so much for having me, Dr Jones. It was a pleasure to be an editor of this issue, and I'm really excited for it to come out. As you mentioned, I'm a Professor of Neurology and Neurosurgery at NYU. I'm also a fellow of the American Academy of Neurology and a fellow of the Neurocritical Care Society. I serve on the Ethics Law and Humanities Committee for the AAN. I was a past chair of the Ethics Committee for the Neurocritical Care Society and also the past chair of the Ethics Committee at NYU.

Dr Jones: So, pretty diverse professional interests. And I was going to ask you about the ethics - that feels like something that ties in pretty well to neurocritical care. I imagine that expertise comes in handy, right?

Dr Lewis: Yes, absolutely. My area of expertise is related to brain death and ethical, social, and legal complications related to brain death determination.

Dr Jones: Got it. And when we were talking before we started recording here, you're from the New York area and a lifelong Yankees fan, is that right?

Dr Lewis: Yes, that's correct.

Dr Jones: How are they going to do this year?

Dr Lewis: We're hoping we're going all the way.

Dr Jones: Okay.

Dr Lewis: In a while.

Dr Jones: Our listeners heard it here first. So, the issue – let's get into the neurocritical care topics – phenomenal issue, full of detailed diagnosis and management strategies for patients with, you know, all manners of severe neurologic disorders requiring critical level of care. With your perspective (which is a unique perspective) - you've just edited a full issue on neurocritical care, you got to delve into all the topics - what were you most surprised to learn, Dr Lewis?

Dr Lewis: Well, you know, I think that one of the most exciting things about this issue is the fact that, in addition to dealing with the typical topics related to neurocritical care - like hypoxic ischemic brain injury and stroke and intracerebral hemorrhage and subarachnoid hemorrhage, of course - the issue delves into some very unique topics related to neurocritical care. There's an article written by Dr Barry Czeisler that focuses on emergent management of tumefactive and aggressive demyelinating disorders, Dr Casey Albin wrote about neuromuscular emergencies, and doctors Maciel and Busl wrote about neuroonc emergencies – and I think that these areas are really important areas for neurologists and trainees to know about, and they're not talked about all that often. And these topics are often focused on, of course, by other subspecialties, but the perspective of a neurointensivist related to these topics is infrequently addressed. So I think that these are really the most exciting aspects of this issue, because it's something so unique in terms of the spin on these topics.

Dr Jones: Fantastic. And what else can we look for in this issue? What other topics can our listeners and readers expect to find there? 

Dr Lewis: So, the issue starts off with the examination and workup of the neurocritical care patient. Dr Sarah Wahlster and Nick Johnson from the University of Washington did an awesome job really bringing the reader into the topic of neurocritical care as they address an overview of neuroemergencies, red flags related to life-threatening conditions, herniation syndromes, vascular territories, and mechanisms and management of acute neurodeterioration, and they summarize monitoring modalities in neurocritical care and clinical and radiographic scales and scores that are commonly used in neurocritical care – and that's a really nice overview to introduce the reader to this issue. The rest of the issue focuses on a wide range of topics pertaining to the emergent management of neurocritical care issues, including hypoxic ischemic brain injury (which was addressed by Dr Steinberg from the University of Pittsburgh),  management of stroke due to large vessel occlusion (which was addressed by Dr Leslie-Mazwi from the University of Washington), management of ICH (addressed by Dr Murthy from Weill Cornell), and then also management of spontaneous subarachnoid hemorrhage (addressed by Dr Soojin Park). Dr Clio Rubinos addressed emergent management of status epilepticus. Emergent management of TBI and spinal cord injury was addressed by Dr Podell and Dr Morris from the University of Maryland. And then neuroinfectious emergencies – which, again, is another unique topic in this issue – was  addressed by Dr Reynolds from Mount Sinai. And then the issue concludes with a paper that focuses on prognostication and neurocritical care by Dr Susanne Muehlschlegel from Johns Hopkins University. 

Dr Jones: Yeah. And what a great list of authors and expertise. And really, you know,  having seen these articles, really just phenomenal guidance on a lot of different subtopics. And I imagine – you know, this is a dynamic area, there's a lot of evidence – but, you know, sometimes, there are controversies or debates or unresolved questions in the field. Having just reviewed and edited the issue, what do you think the biggest debate or controversy is in neurocritical care right now? 

Dr Lewis: So there's definitely a lot of controversies that are addressed in each of these individual articles. For example, in the paper on subarachnoid hemorrhage, Dr Soojin Park provides a summary that compares the guidelines on management of subarachnoid hemorrhage that were written by the Neurocritical Care Society and the American Health Association / American Stroke Association in 2023 and really walks through what's similar and what's different between these guidelines. For the most part, they are very similar, but there are areas of differences. Additionally, in terms of management of acute neuroemergencies related to neuromuscular issues (in some cases, it's not clear whether to treat patients with IVIG or with plasmapheresis), Dr Casey Albin creates a nice summary addressing these issues in terms of what are the pluses and minuses associated with each of these medications. Additionally, there are a number of novel therapies that are not traditionally considered for various neuroemergencies that are walked through in each of the individual articles. For example, in the paper that focuses on management of status epilepticus, Dr Rubinos addresses alternative therapies, like immunomodulatory agents or neuromodulation, for management of super-refractory status epilepticus. So, I think, in addition to addressing the more traditional therapies for various neuroemergencies, the issue really goes above and beyond to address novel interventions. 

Dr Jones: That's fantastic. And obviously, it continues to be a rapidly evolving area.  When you look out to the horizon – and the next generation of care for patients with critical neurologic illness – what do you see on the horizon? What should our listeners and readers be aware of to watch out for? 

Dr Lewis: I think one thing that is really important to be aware of related to patients with neuroemergencies is the Curing Coma Campaign (which is organized by the Neurocritical Care Society), which focuses on research in terms of improving the clinical management, the prognostication, and the care of patients and addresses the goals for  improving recovery for patients who are comatose. And obviously, coma can be due to a wide range of different etiologies (many of which are described in this issue), and so I think that their work as we move ahead will be incredibly important and interesting to see how things evolve in that domain.

Dr Jones: We will be on the lookout for the Curing Coma Campaign – sounds like a great initiative. And, I think, medicine is a team endeavor, right? We were talking about the Yankees earlier (baseball) as a team sport – so is medicine. When you think about the importance of teams, it's hard to imagine a setting where it's more critical to have, you know, well-functioning teams than in the neuro ICU. But there's also parts of the team (people on the team) who are outside the neuro ICU – and I'm thinking of other neurologists, our listeners and readers who might work in the inpatient setting, but not in this really specialized environment. When you think about those neurologists, is there a key message for those hospitalist neurologists or inpatient neurologists that you would want to share from your perspective as a neurocritical care specialist? 

Dr Lewis: So, I think it's imperative for all neurologists to have an understanding of the existence of various neuroemergencies and the identification of when a patient is  having a neuroemergency so that they can escalate the management if it's something beyond their skills or expertise to somebody who is capable of appropriately managing the patient. Each of these articles walks through the differential diagnosis, the identification of the neuroemergency, the first steps in terms of management, the laboratory workup, and then the subsequent steps as well. And I think that, you know, for all neurologists, really, the key things to know about (even if you're not specializing in  neurocritical care) is how to identify a neuroemergency and what needs to be done as the first steps in terms of intervening and diagnosing these emergencies.

Dr Jones: Great message, and that's one of the key things we learn in training, right,  is when to recognize that someone's sick and you need to escalate their level of care. What about – you know, I imagine the neurocritical care field is a relatively small community, and you know a lot of these folks – any key message that you would want to share with that audience?

Dr Lewis: So, I think that this issue is still really important for all neurointensivists (in addition to for general neurologists and trainees), because of the fact that every article  really addresses in depth each of these aspects of neurocritical care and provides tidbits of information that not every neurointensivist would know. So, I think that the issue is beneficial both for trainees, general neurologists, and people who have expertise in the field of neurocritical care.

Dr Jones: That's a great point. I think the fact that it is such a rapidly changing and broad field (you mentioned all the different article topics that are in the issue), it's a challenge to stay up to date on everything. And I think that's what this issue really brings  to the neurointensivist – is, you know, this is all (as of what's the latest in 2024) for the care of patients with critical illness. It's all there, right? 

Dr Lewis: Absolutely. I think, you know, the issue is unique because neurocritical care is unique in that our role involves taking care of patients with a wide range of different neurologic disorders. So, the issue touches upon stroke (both ischemic and hemorrhagic). It touches upon seizure management. It touches upon management of traumatic brain injury. It addresses demyelination (so types of aggressive MS and other demyelinating disorders), neuromuscular issues, neuroonc issues – so I think that, really, there are so many subspecialties within neurology that it's important for them to have awareness of the emergencies that can emerge within their individual field.

Dr Jones: So, we know that neurocritical care is pretty specialized work, and I imagine the expertise and the resources are not necessarily going to be available in every community. Are you aware, Dr Lewis, of any disparities in access or outcomes to neurointensivist expertise? 

Dr Lewis: Yeah, absolutely. Unfortunately, as you look internationally, first, there are many places that don't have neurointensivists, so patients with neuroemergencies are being taken care of, in some cases, not even by general neurologists, but by specialists just in medicine. Additionally, the resources are often not available in terms of having an intensive care unit, having nurses with a good ratio to care for neurocritical care patients, having access to therapists who can participate in rehab and promote rehab, for patients having access to medications that are necessary, having access to various interventions (such as access to neurosurgeons who can do neurosurgical procedures or placement of an external ventricular drain), or other monitoring modalities are not available and accessible. So, all of these issues – in terms of resources, in terms of funding, in terms of other issues related to the existence of protocols as to how to  manage patients in the neuro ICU – all impact the outcome for patients in neurocritical care. Additionally, social issues and cultural issues can impact the outcome for patients in the neuro ICU. So, there's a lot of issues pertaining to equity in terms of the management of neurocritical care patients around the world. 

Dr Jones: Those are great points. I know you and I both work with trainees in our field,  and when I talk to residents who are interested in neurocritical care, I think part of what draws them in is when they are exposed to it and they see how much, you know, the value of what their expertise brings to the outcome for that patient. I mean, it really does make a difference to understand the brain when you're caring for people with these critical neurologic disorders – and I think that's part of the appeal, right? 

Dr Lewis: Yeah, absolutely. I think that people who are interested in going into the field of neurocritical care are interested in the more fast-paced aspect of neurology, rapid decision making, dealing with emergencies, also dealing with prognostication,  discussions (unfortunately, at end of life) – so that's really the kind of individual who turns to the field to specialize in.

Dr Jones: And what about you, Dr Lewis? What drew you to this, you know, pretty high-pressure, intense, dynamic environment? 

Dr Lewis: So I think, actually, you know, all the buzzwords you just used are really the things that made me want to go into neurocritical care. I am interested in much more  fast-paced management of patients, and, you know, unfortunately, obviously emergencies happen, and I find them to be exciting to be able to manage patients in that setting. And, you know, as you mentioned earlier, in the neuro ICU, it's a very multidisciplinary team, and I really enjoy being able to work with nursing, social work, care management, therapists, a variety of consultants – and addressing very acute issues with these individuals as a team in the ICU setting is really very rewarding. 

Dr Jones: Yeah, and I hear that from others who are drawn to the field, and I think you really have to have kind of a broad skill set to manage actively, you know, critically ill patients, but also do the communication competencies and other things that are necessary. So, anecdotally, I would say I see more interest among trainees in this field. I don't know if you've seen the same thing in your world.

Dr Lewis: Yeah. I think that, you know, as you mentioned, it's really important to emphasize that being a neurointensivist does not  just require expertise in the medical aspects of care for these patients, but really, also it's very important to ensure that we  promote education related to communication and neuroprognostication. So, our last article on this issue (by Dr Susanne Muehlschlegel) addresses prognostication and includes a variety of different details about how to address uncertainty, how to implement family and patient-centered prognostication and promote shared decision-making – and these topics are so important for everyone to know about when they're communicating with patients and families to address goals of care and to prognosticate.

Dr Jones: Yeah. Thank you. And before we wrap up our discussion here, Dr Lewis, in addition to being a neurointensivist and being an expert on ethics and all of your clinical and research work, you do editorial work. You have editorial responsibilities not only for this issue of Continuum, but also at Seminars in Neurology and at "The Green Journal".  For our listeners who might be interested in that career pathway, how did you get into that? 

Dr Lewis: I very much enjoyed writing, and so I published a lot. And then I think that, you know, making connections is incredibly important and really looking out for those types of opportunities. Once you build a semblance of expertise in an area, then that often tends to lead to opportunities. So, I'm a Deputy Editor for the Disputes and Debate section of the Neurology journal. I'm also a Deputy Editor of Seminars in Neurology. I edited a book with Dr Jim Burnett on advances in neuroethics related to death determination by neurologic criteria, areas of controversy and consensus. And then I've also been a Guest Editor for a number of other journals, like the AMA Journal of Ethics that focused on socially situated brain death, a neurosurgical focus issue on primary and secondary infections of the brain, and a issue of Seminars in Neurology focused on ethics in neurology.

Dr Jones: You must have like a twenty-eight or twenty-nine-hour day, Dr Lewis. I don't know how you do all that. I wasn't even aware of all those things that you do, but I can tell you, having looked at this issue, your editorial skills are off the charts. I really want to thank you not just for a wonderful issue, but for joining us today and for such a thoughtful, fascinating, and thorough discussion on the field of neurocritical care.

Dr Lewis: Thank you so much. I'm so excited for all the readers to look at our issue and learn about all of these different topics. 

Dr Jones: Again, we've been speaking with Dr Ariane Lewis, Guest Editor for Continuum's most recent issue on neurocritical care. Please check it out. And thank you to our listeners for joining today. 

Dr Monteith: This is Dr. Teshamae Monteith, Associate Editor of Continuum Audio. If you've enjoyed this episode, you'll love the journal, which is full of in-depth and clinically relevant information important for neurology practice - and 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. Thank you for listening to Continuum Audio.

Indomethacin-responsive headache disorders are rare conditions whose hallmark is an absolute response to the medicine and include paroxysmal hemicrania and hemicrania continua.

In this episode, Gordon Smith, MD, FAAN, speaks with Peter Goadsby, MD, PhD, FRS, author of the article "Indomethacin-Responsive Headache Disorders," in the Continuum® April 2024 Headache issue.

Dr. Smith is a Continuum® Audio interviewer and professor and chair of neurology at Kenneth and Dianne Wright Distinguished Chair in Clinical and Translational Research at Virginia Commonwealth University in Richmond, Virginia.

Dr. Goadsby is a professor of neurology at King's College London in London, United Kingdom and professor emeritus of neurology at the University of California, Los Angeles in Los Angeles, California.

Additional Resources

Read the article: Indomethacin-Responsive Headache Disorders

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: @gordonsmithMD

Transcript

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 Smith: This is Dr Gordon Smith. Today, I've got the great pleasure of interviewing Dr Peter Goadsby on indomethacin-responsive headache disorders, which is part of the April 2024 Continuum issue on headache. Dr. Goadsby is a Professor of Neurology at King's College London, in London, United Kingdom and a Professor Emeritus of Neurology at the University of California, Los Angeles, which is located in Los Angeles, California. Dr Goadsby, welcome to the podcast. Well Peter, I'm super excited to have the opportunity to talk to you. And I think, before we begin, we probably ought to expand on your introduction. I think there may be three or four neurologists who don't know who you are, and I think they should know who you are because you've got a really amazing story. These are exciting times in headache, right? And a lot of that's because of your work and you've been widely acknowledged for that; you received the appropriately named "Brain Prize," which (if I'm correct) is the largest neuroscience award in the world; got to meet Danish royalty; you're - more recently, the ABF Scientific Breakthrough Award, which is super excited. So, particularly interested in hearing about your Continuum article. But before we get there, I think it would be really great to hear your story. How did you get into this in the beginning, and what's inspired you along the way to the many achievements you've had?

Dr Goadsby: Why, it's a very kind introduction. People have been nice to me. It has to be said, Danish royalty were very nice, I have to say, and the very jolly chap, the Prince of Denmark. I got into neurology - I guess it's all about mentoring for me. I got into neurology because I got into medical school pretty much by accident. I really wasn't that interested and heard a lecture by James Lance, who was Professor of Neurology, University of New South Wales, at the time. He was talking about a nondominant parietal lobe. I'd seen the case as a medical student; it sort of just seemed weird to me and I wasn't that interested. But he set out this way of thinking about things to try and understand why a clinical presentation is what it is - what he described as a physiological approach to clinical neurology. He described a number of things, but he described that in this lecture and then gave a reference to some work that Mountcastle did on nondominant parietal recordings from awake behaving monkeys in the Journal of Neurophysiology. And I thought to myself, "Wow, this is really interesting - you could really get to the bottom of something," and had that sort of "puzzle-y" thing going on. And I thought Lance was just wonderful, so I became interested in that. And then eventually I asked him about research - actually, I asked him about research after a lecture he gave on migraine, and the explanation of the time was some circulating substance - probably just as silly now. I went up to him afterwards and said to him, I thought the explanation he was giving was wrong. Like, here was a global person - he described Lance-Adams syndrome; this was someone who trained at Mass General, trained at Queen Square; was the first professor of neurology in Australia. I was just – like, it was a stupid thing to do. But I couldn't resist myself - I told him I thought it was wrong. And he's very polite, and he said, "Well, perhaps you could come and help us by doing some research." And I thought, "Okay, that's a very nice response." Interestingly, his daughter described him as unfailingly polite at his funeral. Of the many things you'd say about him, he was a kind person. Whether it's science or just the way you practice - that word (kind) - you can know as much about a subject as you like, but if you're not kind to patients, you're probably in the wrong game. He taught me to be curious about a problem and got me interested in headache, and to be kind in clinical practice - just kind – and I think they were very important lessons. So, I got into it because of excellent mentoring, and I'd like to think I've helped some others along the way.

Dr Smith: Well, you certainly have helped a lot of people, Peter, and what a great story. I'm reflecting - I think the first vignette in The Man Who Mistook His Wife for a Hat was a right parietal syndrome - wasn't it? You've read that book?

Dr Goadsby: Yes, I have. And I've met Sacks. When Sacks came to Australia, he wanted to see Lance, and Lance said, "Fine, but you have to meet me between the morning round and the afternoon clinical meeting." And he got him to come and have lunch with him in the hospital cafeteria at the Prince Henry Hospital and invited me to this lunch. And I sat there and watched them chat. But it was a measure of Lance and how people were interested in him that Oliver Sacks had to get in a taxi and come out to a hospital cafeteria to have lunch if you wanted to have a chat. Because it was - it was a privilege to train with the person. You know, I've done okay, but I only do okay if you've got – you know, you can work with patients, you've got great collaborators, and you've got someone you can get advice from (a great mentor).

Dr Smith: Yeah, that's actually really great words of wisdom for the residents and fellows and junior faculty listening to this. Maybe we should actually talk about your article, which was really great. Your article was on indomethacin-responsive headaches - and we can maybe talk about some specific questions - but what's the main take-home point? If our listeners needed to take or were to take home one point from your article, what would it be, other than it's indomethacin-responsive (that's in the title)?

Dr Goadsby: Yeah, it's what it says on the jar. Well, I think the one thing to take home is that there are forms of headache that seem relatively pedestrian, like one-sided headache that feels like it ought to be migraine that's strictly one-sided, and a small percentage of them respond almost like switching a light off to indomethacin. So, I think you have to have a high index of suspicion. And I'm sure I give indomethacin to ten, twenty times as many people - or thirty - who end up (or even more, probably) who end up having a response. But we do it for a short period of time. For those who get the response - I can tell you, when they come back, they're crying, their partners crying, or the other day I saw one, their child's crying, because all of a sudden, you've basically fixed the problem up. So, the message would be, if you've heard about something and it feels a bit "maybe, could be" - you've heard this indomethacin thing - just do it for a couple of weeks. The worst thing that can happen is nothing (nothing happens). For a couple of weeks, they're not going to have a problem with the tummy (and I'm not advocating taking people with a active gastric ulcer, trying to bump them off). But you cover them properly, you give them a short trial, and occasionally in your practice, you will be so rewarded by that - you will dance home.

Dr Smith: Well, this is going to be my next question. There are very specific criteria, right, for defining cluster, SUNCT, SUNA (and there was a really great Continuum Audio conversation I had with Mark Burish I'll refer our listeners to about cluster, SUNCT, and SUNA), but the indomethacin-responsive headaches - and even migraine - that sounds to me, as someone who's not a headache person, like, that could be challenging to sort out. If you see someone who has consistent, unilateral headache, do you just do an indomethacin trial, or do you select based on other criteria from the classification system?

Dr Goadsby: I'd like to think I was aware of the criteria, and I am. But the longer I practice, the more I'm inclined simply to give the indomethacin and get the question off the table because I don't think there's a sine qua non; there's nothing that will - apart from the indomethacin effect - there's nothing that will convince me 100% to be able to not do it. I've seen enough people who haven't clearly read the classification in detail (patients, I mean) and took indomethacin, and got a response where you wouldn't have predicted it, and they're very happy and the story ends well. So, I would advise people not to worry too much about whether it ought to or not respond, but find out if it does.

Dr Smith: So, the obvious next question is, how does this work? It's pretty unusual in medicine, certainly in neurology, to have something that's so dramatically effective. What's the mechanism?

Dr Goadsby: Well, that's the easiest question - we don't understand it. It is particular to indomethacin - it's weird. Some patients will say, "We'll give you a little bit of a hint by telling you (maybe) that ibuprofen was useful," but most don't give you that much of a hint (some will even say aspirin is useful). But we haven't really gotten to the bottom of it. What are the current thoughts? It must be something that's not simply cyclo-oxygenase because other cyclo-oxygenase inhibitors don't do that – so, that's helpful. The other broad things people think about are whether there's a nitrergic aspect to it. We've got some basic science work that can show that nitrergically induced changes in experimental animal model of these trigeminal autonomic cephalalgias can be modified by indomethacin in one part of the model, where naproxen (for example) can't. So, we think there may be a nitrergic component to it. The other thing is the structure of the molecule makes you think about melatonin, if you put the two up – it's a work in progress. Of the things I would like to do in my life, I'd really like to get to the bottom of it, I have to tell you, because if we could work out what it is that's great about indomethacin and then get rid of the GI thing . . . Then, if you talk about cure - because when people get a response to this (you know, the oldest reported case with a response took it for thirty-seven years; they died of something else) - and continue to respond. It's one of the sort of upsides and downsides when you diagnose it - you can tell a person that they're going to continue to respond (take a breath) until they die basically, because unfortunately, the problem doesn't tend to settle down - at least the treatment stays consistent. If we could get rid of the tummy problem, that would be real progress.

Dr Smith: So, what do you do with the patient who has the tummy problem? Is there another approach?

Dr Goadsby: Well, there's a range of things you try and do; you use PPIs (proton pump inhibitors) and H2 blockers pretty liberally; you try to get the lowest dose, and that's usually best done by the patient. I give them the ordinary-release indomethacin; it's an impression that I have, over the years, that the slow-release indomethacin is not as efficient (just as a recommendation). I let patients - they take it three times a day, or twice - I let them work out what the littlest amount is that they need, having given them a regime to iron it out, because they can work it out for themselves. It's a partnership. It'll be very individual. If someone wants to take two in the morning and one at night and feels happy, have at it. If they want to take one three times a day, if they want to take one at lunchtime - whatever they - let them work out the minimal amount. And the other thing that we found useful - small percentage (maybe one in five) will find the coxibs useful (like celecoxib), but that's not universal at all; it generally takes the edge off. A palpable percentage will find adding melatonin in can be indomethacin sparing. Then the other (probably most important) thing is that the noninvasive vagal nerve stimulator can be very useful in reducing indomethacin dosing or even getting patients entirely off indomethacin dosing. How that works, of course, is as mysterious in the sense of these problems as is indomethacin. But that's something really worth thinking about - can be very, very useful in getting the doses down.

Dr Smith: You've been doing this for a while, right? And you've seen a lot of –

Dr Goadsby: Let's not emphasize that "for a while" side, right, okay?

Dr Smith: For a while – just a little while, Peter.

Dr Goadsby: A little while.

Dr Smith: I'm just thinking - and I'm a neuromuscular guy, so give me a little latitude - but when I was a resident, our concept of headache was pretty simple; it was migraine, classic or common, and we knew a little bit about cluster. And no one talked about SUNCT or SUNA or all these other things, and wow, what an amazing several decades it's been. What's the future look like? And - maybe think big – so, is a cure for migraine in the foreseeable future? What's coming next?

Dr Goadsby: If you think really big (and I'll think really big), if "cure" means that we could control it sufficiently that you wouldn't notice it, I think that's very much - it's almost here, for some. Now, I think of it like cholesterol - someone's got high cholesterol; they take a statin, and if they don't get any problems, the cholesterol normalizes. I'm simplifying things (I'm not a cardiologist), but you take your cholesterol tablet - you take it once a day; everything's fine and dandy. You never get "cured," as such, but the effect is an effective cure from manifestations of the problem - and I am simplifying things a little bit. If I look at it like that, then I think we're getting to a place where some patients, we can treat them so well, and the problem is so suppressed, and they have so few problems with side effects (and some have none), that we're really getting there. We saw a study of the promontory phase of migraine using a gepant (ubrogepant), and we saw the ability (if you recognize the attack early enough) to treat and never have pain. Never have pain. Well, that's pretty close. It might sound crazy to think about it as a cure because someone will say, "Well, they've still got their genes," and so on. Fine. But migraine is about disability, and if you can stop the disability and give a person full function in their life, well, you're pretty much there. And we're getting there, as we understand the disease.

Dr Smith: Really amazing. I have another question that I've actually been really dying to ask you. I'm a peripheral nerve guy, and you may not be aware of this, but those of us who are interested in therapeutic development in peripheral neuropathy, or advocacy, or recognition of neuropathy as a substantive, meaningful entity, are inspired by the work of you and your colleagues in headache. Examples might be advocacy for federal funding or having CDMRP funding - things like this. But an area where - I'm just curious - we spent a lot of effort (and it seems like it's been really transformational for you guys) is having taxonomy, which isn't a particularly sexy topic. But maybe you can talk about the power of having a taxonomic classification and getting towards a cure. Because looking through this Continuum issue - it's really remarkable – it's just all sorts of things that I never would have thought of twenty years ago, and each of them is treated a bit differently.

Dr Goadsby: Yes. As with all things in medicine, if you don't get the diagnosis, you can't get to the base - you've got to be able to get a diagnosis. And our taxonomy, the International Classification of Headache Disorders, has gone through three editions. We're working on the fourth. I have the privilege of being the chairman for the fourth edition (the first three were chaired by Jes Olesen). I do think it's one of the absolute achievements of our field (and Olesen needs to be really feted for doing this) that we have a definition system - it's operational; it's reasonably straightforward; it's been translated into, like, forty languages; that every government on the planet that I know of - and I'm talking about (I think I'd better mention no governments) but every big government you can think of, without exception, has adopted ('cause I'll just get in trouble with the ones I've mentioned) have all adopted this classification; all the health technology assessments (the FDA, for example; the European Medicine, for another example), the Chinese government (People's Republic), Taiwan. Just, all over the world, people use one thing. So, if we do a randomized control trial - there's one recently came out; it doesn't really matter which gepant it is - but you look at the results in North America, and then you look at the results that were done by the Chinese and the South Koreans in a study, and the placebo rates and the active rates are more or less identical. Because what we've been able to do is homogenize who gets into clinical trials and understand what's happening. So, if I get up and talk about whatever we're going to talk about now, like, in rural India, people will know what we're talking about; all the neurologists will be on the same page and so we can make progress. And when we make progress, it's global progress because we sing from the same hymn sheets. I think the taxonomy has been really important for this. And, of course, if you get the diagnosis right, then you can start to begin to get the treatments right and you can bring all the knowledge from randomized controlled trials. There's no point having a whole lot of data if you can't apply it, and what's great about our taxonomy is we can apply it everywhere in the world.

Dr Smith: Wow, what a cool answer. So, I have a follow up question for you, Peter, which has to do with reproducibility. This is a huge issue, right? In reproducibility and clinical trial evidence and in many fields, this has been a big issue - in psychiatry and other areas of neurology, where trials are nonreproducible. To what extent do you think this problem in other fields is a taxonomic problem, or a internal validity problem, in terms of the populations being recruited? I'm really impressed to hear that you don't have that problem in headache.

Dr Goadsby: I do think one of the advantages that the International Classification of Headache Disorders has given us (International Headache Society being the proponent of that) is that there's clinical homogeneity, relatively speaking, in our clinical trial populations. This comes back to the clinic; good clinical trials are as much about the clinicians who are involved and the care they take in recruiting patients, and so on. Which is not to say that psychiatrists are not careful - not at all. But I do think that if you want to just test a question, everyone in the laboratory will tell you that you need to have - say you're doing work with rodents, for example; you want about the same weight, you want the same strain, they're eating about the same, they're up and down at night - everything is about the same. If you want to do good clinical trial work, you have to tidy up as much as you can so the only thing that's really impacting upon the question is the medicine, or the placebo, or whatever that you're testing. So, I think you're right. I think sometimes the pain people struggle with this because, as you say, a painful neuropathy can come from a lot of places. Well, if you just take all of those etiologies, you throw them into one study, and you test it against something, it doesn't surprise me that that's not so useful, compared to taking an individual thing that's really well defined - where you've understood the clinical side, you've understood the pathophysiology as much as you could - and just test that, one at a time. I think that's been a good lesson for us. And that's why there's nothing that's ever failed in a migraine clinical trial (a properly designed one) that ever was useful, and nothing that was ever successful that didn't continue to be successful. Now, some things were successful, and they produced, like, liver enzyme problems - so, that's "no win-no foul" situation. But the homogeneity's been quite important, I think. And it comes back to good clinical practice.

Dr Smith: Well, thank you for the roadmap - that's really, really interesting. I'd like to finish up with another shift in gears, and to talk about workforce. Obviously, we have a national shortage of neurologists in the United States. We're never going to be able to train enough headache neurologists to take care of all headache patients, and we need to think about systems of care, which I guess we could talk about. But my question for you is, what would you say - a lot of residents listen to Continuum Audio, and hopefully, more medical students in the future and now - what do you say to them about a career in headache? Listening to this, I kind of feel like I want to go do a headache fellowship - it's pretty exciting. What's your pitch to them?

Dr Goadsby: I'll tell you one small thing first before I say that; I did do twelve months in clinical neurophysiology, doing nerve conduction, muscle biopsies, evoked potentials. I actually did over ninety muscle biopsies (needle muscle biopsies) when I was training, so I understand your feeling. But I just got the feeling many years earlier than you've had it. What do I say to residents? Well, headache is an area where you can make a diagnosis, you can manage the patient, and you can make them better. I'd say to the resident, "Ask - just look in the mirror and ask yourself, why did you get into medicine?" You got into medicine to help people, and headache is an area where you can really help them. Plus, there's tens of millions of people with the problem, so you will always be in demand. And one of the great things about headache (I think it's probably true of neuromuscular) is it's also a very good lifestyle choice because our problems are generally with primary headache disorders - are not emergent (people don't tend to ring you up at night), and it's not really an on-call issue. You can have a proper balanced existence (work-life balance), and you can do it in a way that's really enjoyable. And then there's an extra bonus: there's all the wonderful neuroscience and neuropharmacology that's going on in headache. I just think if a resident looks in the mirror and says, "Why am I doing this?" most of them are going to look back at themselves and say, "Because I want to do good." And they also want to do good in a way that they can have a proper life themselves. And if they're the two answers you got back when you look in the mirror ("I want to do good" and "I want to have some life myself") - headache - that's the place to go, because there's plenty of room and you can do both.

Dr Smith: Well Peter, that's great - sign me up. And I think people know where to find you to call for a recommendation. What a great conversation and a really great article. And again, I'll refer our listeners to Mark Burish's article on cluster, which is a really great companion to your article 'cause it gives you the full spectrum of trigeminal autonomic cephalgias (which is pretty cool), and the rest of the issue is equally amazing. Peter, you don't disappoint. The next time you see the Danish Crown Prince, say "Hi" from me (I love Denmark - it's a lovely place to be). And thanks again for doing this.

Dr Goadsby: Well, thank you, and thanks for the Academy for organizing. And the other thing about residents - if you want to stay in touch with neurology, stay in touch with the Academy; they're a pretty good bunch.

Dr Smith: Couldn't agree more, couldn't agree more. Again, today we've been interviewing Dr. Peter Goadsby. His article on indomethacin-responsive headache disorders appears in the most recent issue of Continuum, on headache. Be sure to check out our Continuum Audio podcasts from this and other issues. And listeners, thank you very much for joining us today.

Dr. Monteith: This is Dr Teshamae Monteith, Associate Editor of Continuum Audio. If you've enjoyed this episode, you'll love the journal, which is full of in-depth and clinically relevant information important for neurology 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.

Cranial neuralgias comprise a distinct set of disorders typified by short-lasting attacks of intense pain in the distribution of a particular nerve in the cranium. Cranial neuralgia syndromes are rare but can be debilitating and go undiagnosed or misdiagnosed for years.

In this episode, Lyell Jones, MD, FAAN, speaks with Stephanie J. Nahas, MD, MSEd, FAAN, MD, an author of the article "Cranial Neuralgias," in the Continuum® April 2024 Headache issue.

Dr. Jones is the editor-in-chief of Continuum: Lifelong Learning in Neurology® and is a professor of neurology at Mayo Clinic in Rochester, Minnesota.

Dr. Nahas is an associate professor of neurology at Thomas Jefferson University and assistant director of the Headache Medicine Fellowship Program at Jefferson Headache Center in Philadelphia, Pennsylvania.

Additional Resources

Read the article: Cranial Neuralgias

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

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@ContinuumAAN

Host: @ LyellJ

Guest: @stephanieJnahas

Full transcript available here 

Dr Jones: This is Dr. Lyell Jones, Editor-in-Chief of Continuum, the premier topic-based neurology clinical review and CME journal from the American Academy of Neurology. Thank you for joining us on Continuum Audio, a companion podcast to the journal. Continuum Audio features conversations with the guest editors and authors of Continuum, who are the leading experts in their fields. Subscribers to the Continuum journal 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 Jones: This is Dr. Lyell Jones, Editor-in-Chief of Continuum: Lifelong Learning in Neurology. Today, I'm interviewing Dr. Stephanie Nahas, who has recently authored an article on cranial neuralgias in the latest issue of Continuum on headache. Dr. Nahas is a neurologist at Thomas Jefferson University where she is an Associate Professor of Neurology and serves as Assistant Program Director of the Headache Fellowship program there. Dr. Nahas, welcome, and thank you for joining us today.

Dr Nahas: Thanks for having me. Glad to be here.

Dr Jones: So, for our listeners who are new to Continuum, Continuum is a journal dedicated to helping clinicians deliver the highest possible quality neurologic care to their patients, and we do so with high quality and current clinical reviews. Dr. Nahas, your article is a perfect example of that - it's full of really helpful (and I think clinically relevant) recommendations for neurologists who take care of patients with cranial neuralgias. And now that at this moment (during this podcast interview), you have the attention of a huge audience of neurologists - what's the one most important practice change that you would like to see in the care of these patients? 

Dr Nahas: I would like to see the recognition of these cranial neuralgias and related syndromes as distinct and overlapping with other primary headaches much more often. I think far too often, clinicians will try to pigeonhole these headache and facial pain diagnoses and try to make just one diagnosis the main one, and any other symptomatology that comes along with it – "Oh, that's just a weird part of your primary syndrome, right?" I know I've fallen into this trap a number of times, because mostly what we see in a headache clinic is going to be migraine, so we kind of have a laser focus towards migraine-type symptoms (and we know migraine can do just about anything). So then when we hear a little bit about a facial pain, a little bit about some sort of neuralgia, we just try to wrap it up into migraine - but that's not always necessarily the case. You know, we know that any person on the planet can have as many diseases as they darn well please, so why not ascribe two diagnoses when it's appropriate? That can lead to better treatment outcomes, in fact. If you are focusing your treatment on two distinct, but overlapping, entities, you tend to get better results, because the treatments may not be identical (and they rarely are).

Dr Jones: And that's a great example of it's Occam's razor on one side (there's one problem) versus - what is it, Hickam's Dictum?

Dr Nahas: Something like that.

Dr Jones:  - where you can have as many problems as the patient wants to have, so I think that's a great example of that. And, earlier, in the same issue on headache, we do have a wonderful article by Dr. Deb Friedman, who walks through that really important history component of trying to, you know, determine which headache syndrome the patient is dealing with (which is obviously a prerequisite for the diagnosis and management) - so that's a great point. So that's the one takeaway - recognition of cranial neuralgias as a distinct entity. Keep it in mind – otherwise, we'll miss it. Is that right?

Dr Nahas: You got it.

Dr Jones: Okay, good. If we learn nothing else, we'll take that away. So, speaking of the history, Dr. Nahas, for many pain syndromes (including these), the history is really paramount in establishing the diagnosis for patients, specifically with trigeminal neuralgia. How do they usually describe that pain to you? 

Dr Nahas: The whole spectrum of descriptors for trigeminal neuralgia-form pain is, actually, maybe broader than you would think, and I actually find that, sometimes, patients have a real hard time verbalizing and describing the way it feels, because it's so unusual - it doesn't remind them of anything they've necessarily felt before.  Sometimes, it can. For example, a patient who's no stranger to having lots of dental work - that pain that when they drill in or if they hit an irritated part of the tooth or the gums, that's usually kind of neuralgia form-like. But at the same time, patients will say, "It's still not quite like that. You know, it's really hard for me to explain. It's sharp and it's terrible like that, but it has a different quality." And I think they just don't necessarily have the terminology, but I encourage them to try to be creative. You know, some of my patients will personify the pain - they'll describe as if there's some little creature in there that's clawing, or scraping, or pulling, or stabbing. Or they might use other descriptors, such as burning like a fire (like a blow torch is there). Or they may even use colors. You know, some of my patients are really creative, and I don't know if they actually have synesthesia or they're just bordering on that, but they'll describe different colors for the qualities of pain. ("Is it more red? Is it more like icy blue? Is it black or white?") I don't hear that too often, but I do like to just open the door and let my patients describe for themselves in their own words - and if they can't have any words, I give them some examples and that usually gets the ball rolling.

Dr Jones: So, a combination (like we usually do) with some open-ended questions, and then some directed ones to kind of clarify. That's really interesting, and it gives you some immediate empathy and sympathy for the discomfort these patients have to deal with, right (as when they describe it in those burning, clawing kind of terms)?

Dr Nahas: Exactly, and they'll also put it into context for you - so not just describing what the quality of the pain is like, but they'll give you good examples of when they feel these symptoms, what brings them on, what alleviates them, how the symptoms may change from day to day depending on the situation or circumstance. And again, it just gives them an open door to express themselves, and it really does help to strengthen that alliance you're trying to create and maintain with your patient. You do get useful and valuable information when you just let them go on and describe things.

Dr Jones: So, there are, I think, misconceptions in the popular world and also in the clinical side of care that, you know, folks will have a perception of a disorder that maybe doesn't really match reality. What do you think is a common misconception you've encountered in taking care of patients with cranial neuralgias? 

Dr Nahas: The patients that I see tend not to have the clear-cut textbook descriptions  (like it's almost as if they're reading the criteria when they tell you your symptomatology) - because those cases are a little bit easier, they get identified more readily, they get appropriate treatment sooner, their disease doesn't necessarily progress and become complicated by, you know, any number of things that can happen with unmanaged neuralgia-form craniofacial pain. The ones that I see - they've been around the block several times, because maybe their syndrome isn't quite so typical. Maybe they didn't really have the terminology to be able to describe their symptoms. Maybe nobody really opened that door for them and invited them to just talk about what it is. Perhaps they, or whoever they were seeing, were more focused on diagnostic testing, and so their focus is more on, "Why is my MRI not showing anything? Why is my x-ray completely normal? You know, I have these symptoms. There must be an explanation." Because that's what patients want - they want solutions. They have a problem, they want to know why they have it, and they want a solution to it. And they can get too focused on the hard data and ignore that it's a subjective experience that really guides us to help treat their symptoms, especially when we don't have necessarily an anatomic target to go after. (When we do, that's great.) But again, these straightforward cases tend not to come to me, because they're easier to take care of.

Dr Jones: Still, just as legitimate a diagnosis, even with a normal MRI, right? I do find it's sometimes hard to kind of get around that with a patient, isn't it?

Dr Nahas: Absolutely, it is. You know, they're both relieved and disappointed. I often find if we order imaging for an unusual syndrome (or even a typical syndrome) and they see that, "Well, there's nothing on this report to go for. What does that mean? Does that mean that I'm crazy? Does it mean that this is all in my head, that I'm imagining it, that I'm amplifying my symptoms somehow? Is this my fault?" You know, all this self-doubt comes in, and you have to reassure these patients that, "Yes, your symptoms are real. They are in your head, because your brain is in your head, and your brain is the source of your perception and your experience. So, let's take your symptoms at face value and let's give you treatments that are directed at those symptoms."

Dr Jones: Well said, and that's where we like to keep it, the brain inside the head. I think that was day one of neuroanatomy. I know that the treatment for many of these cranial neuralgias overlaps, right? There's some common approaches to several of these. There are some things that we put in our academic writing, but there are some things that we just kind of learn from experience. Do you have any tips or tricks that you would like to share with our listeners about the management of the cranial neuralgias? 

Dr Nahas: First and foremost (and I think this kind of goes for any of the disorders in the spectrum of headache and facial pain) is you need to be patient, and you need to set up appropriate expectations that, by and large, this is a trial-and-error process where we need to introduce a therapeutic intervention gradually and titrate the dose gently to effect while following for clinical response, but also keeping an eye on what our guardrails are. What do I mean by that? Let's say, for example, we're using oxcarbazepine for some sort of neuralgia-form disorder (I mean, take your pick for any of them – it's fair game for most of these as a good initial trial).

Dr Jones: Sure. Yeah.

Dr Nahas: So, you want to start it at a low dose, start building it up slowly, and in addition to following for their clinical response - which I counsel them it may take a while  (even once we hit a target dose, it may take several more weeks, we've got to give it time) - you can monitor a serum level of oxcarbazepine and certain other antiseizure medicines for that matter. So, that can help guide you to know how high you can go. This is a little bit different from the situation with epilepsy, where you're checking levels to ensure that it's in a therapeutic range to make sure that it's not toxic - maybe to assess for adherence - but here, we're using it as a guide to know how much farther can we push the dose on this drug. And, of course, also, you want to be monitoring for any adverse events that can occur with that drug (such as hyponatremia, or changes in the CBC, et cetera) - so I do monitor these folks a little bit more closely than I otherwise ordinarily would, especially when I have a therapeutic intervention where I can actually monitor the drug level of it and be very, very precise in trying to maximize and optimize their treatment.

Dr Jones: Got it. So, patience with each trial, and then patience that there might be (and I mean patience with a 'c' that there might be) multiple trials – I think that's a good takeaway for all of these cranial neuralgias with pretty much all of the medication treatments, right?

Dr Nahas: Yes, and I do find that in some cases, one treatment is not quite enough. Because most of the treatments we draw from our antiseizure medication category, it can get complex trying to balance two, or even three, antiseizure medicines and finding the optimal dose for each. Do we push all of them to the max? Do we say this one is the undercurrent (we just want to keep it at a low level) and these other two are going to be doing the lion's share of the work? It becomes kind of fun if you like uncertainty and if you like to be creative. If you're the type of person who likes checkboxes and checklists and cut and dried results, you know this is not the game that you want to play - but that's one of the reasons that I enjoy doing this, because I have so much freedom to be creative and really finely tailor and tune the treatment specifically to the individual patient's needs.

Dr Jones: That's fantastic, and in a minute, I think we can come back to maybe what drew you to this - I'm curious to hear that. But before we get to that, you know, when we think about the medications that are available (and again, your article does a phenomenal job summarizing the therapeutic approaches to the cranial neuralgias) - what do you see on the horizon, Dr. Nahas, for the care of these patients? 

Dr Nahas: I want to see a lot more research being done in this population of patients and across this spectrum of disorders. What makes it so hard is because they are somewhat rare, and because they very often co-occur with another primary headache disorder - so that makes it extraordinarily difficult to create a research study on a population that's so heterogeneous, right? That's, I think, the biggest challenge - is that we have so little to guide us other than our own clinical experience. There are not a ton of clinical trials for any of these disorders. I think one in particular that can be both underdiagnosed and overdiagnosed is occipital neuralgia - and I mentioned before that I, myself, have found myself falling into this trap of once I see a signal for migraine, I just call everything migraine, right? And, sure, with migraine, there can be allodynia in the scalp, and oh, sure, we all hear that if you push on something sore, you can have some lancinating pain. Oh, that occipital neuralgia that somebody told you about? No, no, that's just part of your migraine. You don't actually have occipital neuralgia. Well, you know, if you look at clinic-based studies (there's one in particular that I cited), most of the presentations of occipital neuralgia actually co-occurred with another headache diagnosis (either primary or secondary), and very commonly, it was migraine or probable migraine or chronic migraine. And why this is important is because you need to validate for these patients that they do have more than just migraine. They have a separate problem that, yes, it's interrelated, it's interconnected, they can influence each other - but we might have to treat them both differently. So, you have your suite of migraine treatments which might not include an antiseizure medication. Then, for the occipital neuralgia, maybe you are pulling in an antiseizure medication, or maybe you're focusing more on peripheral nerve blockade or physical therapy - or even considering a surgical referral, because as surgical treatments for nerve decompression or ablation or other interventional procedures also continue to evolve, that helps to give us some more hope in giving  these patients more relief with fewer complications. I'd also like to see some more creative solutions, not just more antiseizure medicines, not just more targeted anatomic interventions. But, hey, is there a role for some other peptides or neurotransmitters that we just haven't identified yet? Might some novel treatment approaches actually be useful for some of these patients? And, you know, again, how do we get at those answers? It's going to be challenging, because the patients - while they're out there, they're not really a homogeneous group, and the results from a particular study might not be so generalizable.

Dr Jones: And we've seen such great success in the world of migraine, right (looking for novel targets) And so it would be nice to transport that over to the cranial neuralgias, right?

Dr Nahas: Yes, absolutely.

Dr Jones: Yeah. We should always be mindful of disparities in care of patients who have neurological problems. Are you aware of any literature around the care of these patients related to health care disparities that our listeners should be aware of?

Dr Nahas: Nothing focused specifically on disparities in this population or subpopulations within this population (based, for example, on ethnicity, or race, or socioeconomic status). You're looking for subpopulations within a huge population, almost like a needle in a haystack - not quite that difficult, but again, it takes a lot of effort and diligence to try to find these individuals and then to get them to agree to enroll in some sort of research study, even if it's just a survey study or doing interviews with them trying to understand their symptomatology better. It can be quite challenging. And then again, let alone designing a rigorous clinical trial for these folks - who, again, such a heterogeneous presentation - and the willingness to participate in a placebo-controlled trial for pain that can be so heinous can be very, very challenging. You know, we've seen this as a challenge with cluster headache, too - not just because of the nature of the disease (when the cycles come and go somewhat unpredictably). But these folks aren't necessarily willing to forgo treatment for the purposes of a clinical trial - I mean, many are, and I thank them - this is another one of the reasons that research is really lacking in some of these rarer syndromes.

Dr Jones: So, another part of the rationale for more investigation for these uncommon and probably underserved disorders. So, Dr Nahas, I know caring  for patients with craniofacial pain, I imagine it can be challenging. I can imagine it's also pretty rewarding as well. What drew you to this work, and what do you find most exciting about it? 

Dr Nahas: Well, what brought me to headache to begin with was kind of random chance, and really, it revolves around mentorship. When I very first started as a neurology resident, Dr. Silberstein took me under his wing and wanted to turn me into a headache specialist (that was one of his goals). And, thankfully, he was successful, although he didn't really have an easy job of it, because back then, I didn't really see or understand how studying headache and facial pain could really satisfy that hunger that I have to understand the brain and the nervous system. I mean, that's why I became a neurologist in the first place, right? (I think that's why most of us did.) You know, not only are we drawn to medicine to help people and be altruistic and to study a fascinating topic, but particularly with the brain and the nervous system - I mean, this is what makes us human. This is what's so fascinating to me. And until I started to learn more about headache, I thought the best way to really learn about brain function is through disease (such as stroke or epilepsy, or movement disorders, cognitive disorders, degenerative disorders). This is how we learn, right? This is what I was taught, at least in college and med school. And then you get to the real world of actually practicing medicine or being in training. You start talking with these folks, and you hear their stories and how distinct they are from the textbooks. And again, when you invite them to really describe their experience, you see the human side of it, and you listen to them describe their symptoms - and you start to imagine yourself, what's really going on in their brain and their nervous system for them to experience that? So you start reading a lot of the literature about cortical spreading depolarization and how that can activate the trigeminal system and sensitize it - how that might be linked to the expression of aura (for example) - then, you can actually really parse out the anatomy and understand why somebody experiences those symptoms when you understand the anatomy. And there are just countless examples of this - about how studying the symptoms and what brings them about, what the pathophysiology is, and then what the treatment is, how that really informs our understanding of how the brain functions - that's really what's kept me excited about this. That, and again, forming relationships with patients and sometimes being the first person who ever just sat down and listened to them and let them talk, and they really feel like they're cared about and like they're important - because they are. I think far too often, patients with headache and facial pain disorders are stigmatized, and they're left feeling like it's not worth it trying to get better, that there is no solution. Society has beat them down, the medical system has let them down, and they just want to give up. Then, when we can finally sit and listen and give them some hope, and they see some improvement - the transformation that occurs right before your eyes is extraordinarily gratifying.

Dr Jones: So, it's fascinating, and you can help people - and I can't think of a better advertisement for headache fellowship for all those neurology trainees out there.  Well said, Dr Nahas. So I've got one more question for you before we close. And I know that the headache community, including yourself, are very strong advocates for your patients and for more research (as we've talked about today) into headache disorders, understanding the pathophysiology, developing better treatments. What is it about purple hair? I've seen several headache specialists (and maybe someone on this call) post online some purple hair. What's the story behind that?

Dr Nahas: A number of years ago, as part of advocacy efforts, we recognized there's got to be a way to really improve the awareness of such a common condition, of headache in general. It affects so many people, it almost becomes, again, brushed off. We say headache, it's just a nuisance. Well, no it's not. It's actually fascinating as part of the human condition. One of the things we needed was a color - our signature color - and we chose purple. We know that we share this color with other advocacy groups, but it's a great color, it's eye-catching, and you can utilize it in a number of different ways. One of the early ways was people dressing up in all kinds of purple garb - putting purple makeup on, purple sunglasses, purple tutus, purple T-shirts, and even purple wigs. A lot of us have been donning purple wigs for advocacy and for awareness efforts, particularly for events (such as Miles for Migraine, for example) - but some of us have been so bold as to not just put on a purple wig, but to actually go to a salon, bleach the hair, and dye it bright purple. I have at least one male colleague who also did this to his beard. Last year, we did it together at the same salon, took a bunch of pictures to post about. It really created a big splash online and for our social media efforts and outreach, and it caught on. Lots more people now are thinking about dying their hair purple. One of our current fellows actually did it this year. At our center, we have about 30 different purple wigs that we bought with some funds that we procured, and on the Shades for Migraine Day (June 21), we all went out parading around Center City, Philadelphia wearing our purple T-shirts and our purple wigs, and handing out flyers trying to raise awareness. We got a lot of strange looks, but we also got a lot of good feedback. And I think we actually reached some people who didn't realize that there's such a thing as a headache center that they could actually come and see us and get relief for this problem they thought was just a part of everyday life. That was kind of a long-winded answer, but -

Dr Jones: No, that's great, and it worked. It got me to ask you about it, right? And I will say I admire your commitment and dedication. The best I could do today, Dr Nahas, was wear a purple tie, but I'm sure your patients appreciate that level of investment, too. It's really, really cool. Really impressive.

Dr Nahas: Yeah. A lot of them this past year have asked me, "Where's the purple hair? I thought you were going to do it every year around this time." And, you know, it is a bit of a commitment.

Dr Jones: It's a commitment, yeah.

Dr Nahas: And there's some upkeep that is required and you're kind of stuck with it for a while (unless you want to go to the trouble of reversing the process, but that's really just covering it up). I said, "We've moved beyond dying the hair. We're doing wigs, and we're thinking of the next thing." 

Dr Jones: Good for you. Dr Nahas, thank you so much for joining us, and thank you for such a thorough and fascinating discussion on symptomatic management of cranial neuralgias and such a wonderful article in the latest issue of Continuum.  Really appreciate you being here today.

Dr Nahas: I can't thank you enough. It's been my pleasure.

Dr Jones: Again, we've been speaking with Dr Stephanie Nahas, author of an article on cranial neuralgias in Continuum's most recent issue on headache. Please check it out, and thank you to our listeners for joining today. 

Dr Monteith: This is Dr. Teshamae Monteith, Associate Editor of Continuum Audio. If you've enjoyed this episode, you'll love the journal which is full of in-depth and clinically relevant information important for neurology practice - and 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.

The majority of children and adolescents experience headache, with pooled estimates suggesting that approximately 60% of youth are affected. Migraine and tension-type headache are the leading cause of neurologic disability among children and adolescents 10 years and older.

In this episode, Allison Weathers, MD, FAAN speaks with Serena Orr, MD, MSc, FRCPC, author of the article "Headache in Children and Adolescents," in the Continuum® April 2024 Headache issue.

Dr. Weathers is a Continuum® Audio interviewer and an associate chief medical information officer at Cleveland Clinic in Cleveland, Ohio.

Dr. Orr is an assistant professor in the departments of Pediatrics, Community Health Sciences, and Clinical Neurosciences at Cumming School of Medicine, University of Calgary and a pediatric neurologist at Alberta Children's Hospital in Calgary, Alberta, Canada.

Additional Resources

Read the article: Headache in Children and Adolescents

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

Guest: @SerenaLOrr

Transcript 

 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. Serena Orr on pediatric headache, which is part of the April 2024 Continuum issue on headache. Dr. Orr is an Assistant Professor at the University of Calgary, and a Pediatric Neurologist at Alberta Children's Hospital in Calgary, Alberta, Canada. Welcome to the podcast. So, thank you, Dr. Orr, for taking the time to speak with me about this fantastic article that covers such an important topic – headache in the pediatric population, in children and adolescents. First, I'd love to start by learning a little bit about you. Where do you practice, and how did you get interested in this topic? I love learning more about the authors of these incredible articles and how they became interested in their fields. So, you know, pediatric neurology is already a pretty subspecialized area of medicine – how did you become interested even further subspecializing in headache?

Dr Orr: Well, thank you for the invitation. Nice to meet you, Dr. Weathers. I'm Serena Orr. I'm a clinician-scientist, pediatric neurologist, and headache specialist based in Canada at the Alberta Children's Hospital in Calgary, Alberta, just outside of the Rockies. I'm really passionate about headache medicine. I think I came to it because it allowed me to marry my interests in neurology and psychology together. I did my undergraduate studies at McGill in psychology and really wanted to take a biopsychosocial approach to my practice. The first child neurology patient I ever saw was a child who was experiencing migraine and having a lot of disability from it, with lots of impacts on her life - and I really saw an opportunity to take a holistic approach to the patient and marry my interests in neuroscience, neurology, and psychology together. So, I'm very excited to talk to you today about this topic that I'm really passionate about and that I think is underserved – um, hopefully get more people excited about it.

Dr Weathers: But so great, and I'm sure we will do that just based on how excited I was just reading your article. So, I always like to start, actually, with what you feel is the most important clinical message of your article. What is your biggest takeaway you want to leave our listeners with?

Dr Orr: Yeah, well I think this is a really big topic in neurology. So, if you look at the reasons for consulting a child neurologist, headache falls into the top three. 60% of youth experience headache in youth. If we look at what presents to neurology in terms of headache, the majority is migraine – and so that's a big focus of this article, because anywhere between a half to 88% of headache consultations in neurology are for migraine. And as I kind of alluded to in discussing my interests in this area, you know, it's really important to take a biopsychosocial approach to managing any chronic pain disorder, including migraine and headache disorders. Another big takeaway point from the article is that - specific to pediatric headache - there's really high placebo response rates that we're still trying to understand and grapple with in the field, and I think this underscores the importance in really doing patient-centered care and ensuring that you're educating patients and families about the level of evidence that we have about the placebo response rates and engaging in shared decision-making when you're choosing treatments together. So, I think those would be the main take-home points.

Dr Weathers: I think both really critical. And I think even without – I'll put my plug in – even without the placebo effect, I think that shared decision-making is such an important concept for all of us in neurology to think about - but I think you make such the important point that with it, it becomes absolutely critical. I want to expand on a concept that you were just talking about. Pediatric headaches are so incredibly common, and you make the point in the article so well that they're one of the leading causes of neurological disability in pediatric patients. They have such a significant impact that really touches all aspects of these children's lives - both at school, how they impact their hobbies - pretty much everything that they do, and these long-reaching impacts. But then you go on to say that pediatric headache remains the most underfunded pediatric disease category when you take into account allocated public research dollars, which was just staggering to me. Why do you think this is?

Dr Orr: I think there's a few reasons. So, one of the main reasons, I think, is that headache medicine has been underserved - there haven't been enough people who have gravitated to this field. I think this is rapidly changing as we train more people and show the world how important this topic is and how much exciting translational research is going on. But, historically, this has been a very small subspecialty that's been underserved relative to disease burden (so not enough scientists equals less research funding) - but there's another aspect to this as well. There was a paper published in 2020 by Mirin – who actually looked at research dollars in NIH based on disease burden and whether the diseases were male or female dominant - and found that there's a significant gender bias in research funding. Male-dominant diseases tend to be significantly overfunded relative to female-dominant diseases when you look at disease burden - and if you look at the female-dominant disease table, headache disorders and migraine are in the top three most underfunded disease categories amongst the underfunded female-dominant diseases. That data has been replicated looking at NIH dollars on the pediatric side as well. They didn't look at gender breakdown in the pediatric paper that was published a couple of years ago, but found, actually, that pediatric headache disorders are the most underfunded in terms of NIH research dollars to pediatric diseases – so, top underfunded relative to disease burden. So, yeah, being underserved as a field - and then, I think, gender bias has also played a significant role in what gets funded over time.

Dr Weathers: Wow, that is hard to think about. And I think those are really insightful points and ones we really need to think about as we think about the bias in our research and our funding. Why is access to care and treatment for these children and adolescents so important? I know this seems like a super obvious one, but it feels like the answer is actually really much more complex.

Dr Orr: Well, there's data to show that earlier diagnosis can lead to better long-term outcomes for youth with migraine - and this is really important, because if you look at the incidence curves for migraine, you see that at least a third, if not more, of incident cases occur before adulthood. We also know there's some GWAS data to show that youth-onset migraine has a higher genetic loading when looking at polygenic risk scores than adult-onset migraine, so people who have migraine onset in youth may be more genetically loaded (that may be important). And we also know that early access to diagnosis and treatment gives them a better long-term prognosis. We know that headache disorders and migraine are associated not only with long-term potential for disability on the physical side, but also increase the risk of psychiatric comorbidities developing over time, so there's really a huge opportunity in accessing a diagnosis and treatment early to improve long-term function - both on the medical side, but also potentially avert poor mental health outcomes - and also diagnose and treat a subset of people with the disease that may be more genetically loaded. We don't know if that impacts outcomes, but potentially, it does. So there's lots of reasons, I think, that we can get in there early and make a big impact – and even for those who it takes a while to find effective treatment for, really having access to education early so that they understand their disease and also ways that they can engage in self-management strategies, I think, is really empowering to the patient and really important (even if we're struggling to find the best medical therapy).

Dr Weathers: You laid out a lot of really important reasons, and again, it goes back to the arguments made at the beginning about why it's so important to increase the funding so that this is no longer an area that's underserved, so that we are able to increase the access, and that everybody who needs this kind of care is able to get it. I want to shift a little bit and think about how we diagnose and work up patients who present with a headache. So as a neurologist - and also as a parent - one of the scariest considerations for me is figuring out if a headache is just a headache or if it's a sign of something else (you know, what we think of as a secondary headache disorder). What is your approach to distinguishing between the two?

Dr Orr: We take a very clinical approach to diagnosis. We don't have specific biomarkers for different headache disorders, so we're still, you know, relying on a really detailed history and physical exam in order to sort out the diagnosis. As I discussed in the article, really the key first branch point (like you say) is, is this a primary headache disorder or a secondary headache disorder? There's some tools that we can use in practice to try to get at that, I think the most useful of which is the SNOOP tool - it's an acronym that goes over headache, red and orange flags. Every time I write an article where I discuss this, it's expanded to include more red or orange flags (it's in its probably third or fourth iteration now), but there's a nice table in the article that goes over some of these red and orange flags. It includes things like systemic feature (like headache, nuchal rigidity), if there's a history of cancer, if there's associated, you know, headache waking child up in the morning with vomiting - and a variety of features. I have to say the level of evidence for some of the features is relatively low, and our understanding of some of the red flags has changed over time. As one example, we used to think occipital headaches in youth were almost always associated with a secondary headache disorder, but now there's more emerging data to show that it's actually relatively common for youth with migraine to have an occipital location. So, really, using the tool is about kind of putting the whole picture together to try to risk stratify. In the majority of youth who present with recurrent headaches, who don't have any red or orange flags, and who have an unremarkable neurological examination without focal deficits, it typically is such that we don't have to do further investigation - but any red or orange flags (or a combination of them), any focal deficits on exam, would typically be where we would be considering neuroimaging. It's very unusual that we have an indication to do an EEG or large amounts of blood work in youth with headache, but it is context specific - for example, a case presenting with recurrent hemiplegia (you may have Todd's paralysis on the differential and you may want to do an EEG), or in a youth who also has GI symptoms (I picked up some youth with celiac disorder who have chronic headaches as well). So there are specific circumstances where blood work, EEG may be indicated (or obviously lumbar puncture in the case of suspected infection, et cetera), but for the most part, we're really relying on a very thorough history and physical exam to sort out our pretest probability of a secondary headache disorder and whether we need to do neuroimaging and further investigations.

Dr Weathers: I think keeping in mind that systematic approach and really working through the algorithm is really reassuring and makes sense that, one, you won't miss something kind of worrisome, but on the other hand, that you're also not doing unnecessary testing, either. Along those lines, what do you think is the easiest mistake to make when treating children and adolescents with headache, and how do you avoid it?

Dr Orr: I think the easiest mistake to make is undertreatment. Both for acute and preventive therapies, I often see undertreatment. I think families are often hesitant to give medication to their children, and so I have a lot of families say, "Oh, well, you know we typically wait the attacks out until they get more severe, we try to avoid medication, we use cold compresses, et cetera." So, explaining to families that acute treatment (of course, we don't want to overuse it) and overusing simple analgesics (NSAIDS) more than three days a week can increase the risk of higher frequency of attacks and medication overuse headache - but undertreatment is a risk, too. And the way I like to explain it to families is in the scientific basis of pain chronification - so I'll say to families, "You know, we have these pain pathways in our brain. If we let them go off for long periods of time, they get stronger (and so that's where we want to get medication in quickly to try to shorten the exposure of the attacks). When you don't do that, those pain pathways may start out like a dirt road - and maybe then you have lots of long attacks, and then it gets paved, and then it becomes a highway." I find it's a useful way to help families understand the concept of pain chronification and why we want them to treat attacks. The same thing goes for undertreatment on the preventive side. If you know a youth is having frequent attacks that are impacting their life and their ability to function, we really should be thinking about a daily preventive treatment, because we know that pill-based interventions will result in a significant reduction in headache frequency in at least two-thirds of youth - and again, allowing the youth to have frequent attacks contributes to that pain chronification (and explain it to families in a similar way to what I just explained for acute treatment) - but there can be a lot of hesitancy to engage with pill-based treatments, even though we know that they can be helpful.

Dr Weathers: I think that's a really powerful point - and I think something we also, frankly, probably tend to do on the adult side as well – but, especially, I could see where there's even probably more hesitancy in children and adolescents (this concern that we're going to overtreat them and then end up inadequately treating, which leads to increased problems). And also goes back to the concept you were talking about earlier about the importance of shared decision-making and really engaging with the patient and their families in the discussion early on to help avoid that, as well to have everybody aware of the benefits and the side effects of all of the different options, I think is so critical. I was also really excited to see you (in the article) write about the importance of a trauma-informed care approach. This is an area I'm really passionate about in my work as a clinical informaticist and how we can leverage the electronic health record to support trauma-informed care and raising awareness of what a patient's triggers may be. Can you explain to our listeners who may not be knowledgeable about this approach what it means, and why you think that this might be applicable to children adolescents with headache?

Dr Orr: Thanks for bringing that up. I think it's really important as well. We've done some work in my lab (and many others have as well) to show that there's a relationship between adverse childhood experiences and the development of headache disorders in youth and adults. By adverse childhood experiences, I mean exposure to highly stressful (like toxic stress) environments in early childhood, such as experiencing death of a parent, divorce, abuse, neglect. So, we know that adverse childhood experiences are associated with higher risk of developing migraine and headache disorders, and knowing that and how common these are amongst our patients - really think it's important to advocate for screening all children, adolescents coming in with recurrent headaches for adverse childhood experiences and exposure to trauma, because it really will impact not only how you interact with the patient, but also potentially what you will screen them for on the mental health side. And so providing trauma-informed care, I think - of course we want it to be targeted - but really taking this approach with all patients is actually a good way to think about it, because trauma is very common in our society, and some of the ways that we've measured trauma in the past (like some of the examples that I gave, divorce, death of a parent) are really narrow and don't encompass broader aspects of trauma (like systemic racism and other things that people are experiencing that haven't been adequately measured). So what trauma-informed care is - you know, there's a few core aspects, and one is screening all patients for trauma. The way I do that in clinic is just asking them if they've had any major stressful life events (and then I give a few examples), but there are standardized questionnaires that can be used for this as well. And then really trying to develop a nurturing rapport with the patient - an open listening strategy, asking open-ended questions, being empathic with patients and families - I know we all try to do this, anyway, but really focusing on that, especially in the context of trauma. And then thinking carefully about not only how you're talking to the patient, but how you're approaching them during the physical exam (so, for example, asking permission before touching the patient rather than just diving into the exam to be sensitive to that). And then also recognizing, like I said, that some of the ways that we've conceptualized trauma have been a little bit narrow, and that trauma may occur in context outside of what we traditionally think of.

Dr Weathers: Again, I think that's so important and could be certainly much more broadly applied than even just to this one field, but thrilled to see that you're incorporating it into your work and your research (and again, it was discussed in the article) - and, absolutely, I think that the more that we incorporate it as well here, I think, that the better off for all of our patients and the improved care we provide. Moving on from that, I always like to end my interviews on a positive and hopeful note, and so I'd love to hear from you what you're most excited about in the field of pediatric headache. What breakthroughs do you think are coming, or what's giving you the most hope?

Dr Orr: There's so much, there's so much exciting stuff going on in our field (and so, you know, I'll have to rein in myself in here), but one thing is there's been an explosion of novel treatment options on the adult migraine side in the last five to ten years, including agents targeted at the CGRP pathway, calcitonin gene-related peptide, some monoclonal antibodies, and receptor antagonists. There's been an explosion of neuromodulation options with now five devices that have various levels of FDA clearance for use in adults and/or youth with migraine. And there are, for most of these devices and novel drugs, either published studies or ongoing research into how they may be used in youth, so I'm hopeful that we will have more treatment options that are evidence based for youth going forward. This is in part due to the Pediatric Research Equity Act that came out a couple of decades ago now that has put requirements for pediatric studies when new drugs are approved by the FDA for adults - so I think that has had an impact, and I'm hopeful that we'll have an expanded treatment landscape in the years to come. There's also a lot of really exciting, more kind of fundamental research going on that I think will help us move the pediatric field forward more rapidly. In the past, we have really often borrowed from what the adult neurologists are doing for adults with headache disorders without really understanding some of the fundamental biological and psychosocial differences between headache disorders onset in youth versus adulthood, and so there is more and more research going on to understand the biology of migraine in youth and some of the risk factors at this age and some of the features that may make youth a little bit different, because it's very rare that youth are just little versions of adults for any disease or problem. And then, you know, I've seen a really large expansion in the number of trainees who are interested in headache medicine since I've entered this field (I've even got one of our residents who's going to do a headache fellowship, which is exciting), and seeing the growth and interest in headache medicine and the number of people being trained really gives me a lot of hope for the future, because there's so much work to be done in this area, and, really, that's where we're going to have the largest impact - is in mentoring and fostering the next generation of headache neurologists. So, there's lots of reasons to be excited, and I would say to the trainees listening that if you want an exciting career where there's lots of opportunity to make impact both clinically on your patients and in terms of educating the next generation and spearheading research initiatives, headache medicine is for you.

Dr Weathers: I think that is incredibly inspiring and will hopefully get a lot of our listeners excited about joining this incredible field. Well, thank you for, again, this great article and for all of your time this evening, I've learned so much and really enjoyed speaking with you.

Dr Orr: Thank you. Likewise, it was great to have this opportunity. I really enjoyed it.

Dr Weathers: Again, today, we've been interviewing Dr. Serena Orr whose article on pediatric headache 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 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. And 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.

New daily persistent headache is a syndrome characterized by the acute onset of a continuous headache in the absence of any alternative cause. Triggers are commonly reported by patients at headache onset and include an infection or stressful life event.

In this episode, Aaron Berkowitz, MD, PhD, FAAN, speaks with Matthew Robbins, MD, FAAN, FAHS, author of the article "New Daily Persistent Headache," in the Continuum® April 2024 Headache issue.

Dr. Berkowitz is a Continuum® Audio interviewer and a professor of clinical neurology at the University of California, San Francisco

Dr. Robbins is an associate professor of neurology and director of the Neurology Residency Program at New York-Presbyterian/Weill Cornell Medical Center in New York, New York.

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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 Berkowitz: This is Dr Aaron Berkowitz, and today I'm interviewing Dr Matthew Robbins about his article on new daily persistent headache, from the April 2024 Continuum issue on headache. Dr Robbins is an Associate Professor of Neurology and Director of the Neurology Residency Program at New York-Presbyterian/Weill Cornell Medical Center, in New York. Welcome to the podcast.

Dr Robbins: It's great to be with you, Dr Berkowitz.

Dr Berkowitz: Well, thanks so much for joining us this morning. To start, what is new daily persistent headache? I think it's an entity maybe that might be new to some of our listeners.

Dr Robbins: Yeah - it's an entity that also struck me when I was in training. I didn't hear much of it as a neurology trainee until I did a fellowship in headache, where, all of a sudden, we were seeing patients with this syndrome (and labeled as such) all the time. And that actually inspired me to begin a research project to better characterize it - a clinical project that ended up helping to broaden the diagnostic criteria. New daily persistent headache really is just defined by what it says - it's new; it's every day; it persists; it's a headache. It can't be from some other identifiable cause, which includes both secondary disorders (you know, something that, where headache is a symptom of) or a primary headache disorder; distinguishes itself from, say, migraine or tension-type headache because there's no real headache history and there's an abrupt onset of a daily and continuous headache that has to last for at least three months since onset. And the onset is typically remembered - it's usually acute or abrupt; there may or may not be some circumstances that surrounded the onset that might have some diagnostic or causal or associated implications that we can explore.

Dr Berkowitz: Okay. So, I always find it challenging in headache medicine and some other areas where we don't have a biomarker, per se - an imaging finding, a lab finding; we have an eloquent and detailed clinical description - to know how comfortable to be making a diagnosis like this. In this case, particularly, right - you said it has to be going on for three months. What if I see a patient one month into something I think could be this, but I can't technically say, per the criteria, right (it's three months)? When do you start thinking about this diagnosis in patients, and what are some of the main considerations in confirming the diagnosis, and what needs to be ruled out or excluded for making the diagnosis?

Dr Robbins: I think traditionally, in headache, the term "chronic" has that three-month time period. The reasons are twofold: one is that, typically, if there's some secondary disorder that might have some distinguishing feature (something that really evokes the headache or some other neurological accompaniment that develops in addition to headache), it would pretty much be likely to declare itself by the three-month mark. Or if it was something that was very self-limited, it would probably go away before three months have elapsed. Or if it resolved after some days or weeks but then declared itself as a more episodic disorder, then we might say someone who begins with continuous headache that might, for example, resemble migraine (maybe it presented a status migrainosis but then it devolved into a more episodic disorder that might just be migraine overall). So, I think that's pretty much why the three-month mark has been so prevalent in the International Classification of Headache Disorders, including how new daily persistent headache is diagnosed. But at the same time, there's lots of disorders that might mimic (or might be misdiagnosed as) new daily persistent headache, and they really are a secondary disorder. Probably the most common one that we think about is a disorder of intracranial pressure or volume, mainly because routine MRI features could be normal or could be easily missed if they had subtle abnormalities. The defining symptom of those disorders are also continuous headache, often from onset, with an abrupt and remembered nature. So, that's often the main category of secondary headache that might be misdiagnosed as primary headache. I think, probably, idiopathic intracranial hypertension as the prototypical disorder of high pressure often declares itself with visual symptoms, pulsatile tinnitus, and other abnormalities. And nowadays, there's much more increasing recognition for MRI abnormalities or even MRV abnormalities with such patients. But spontaneous intracranial hypotension (despite increasing recognition of CSF leaks in the spine that lead to intracranial hypotension or hypovolemia) really remains an underdiagnosed entity. I think that's one disorder where - for example, if I'm seeing a patient with new daily persistent headache and there's no orthostatic or positional nature to their headache - I will still do an MRI, with and without contrast, to be sure. But that the chances of them having a spontaneous CSF leak are low if that scan is unremarkable.

Dr Berkowitz: That's very helpful. Yeah. It's interesting; when you talked about the criteria for this condition - that it has an acute onset, which is a red flag, right, and it is persistent for months, which for a new headache would also be a red flag. So, this is a condition - correct me if I'm wrong – that, if you're considering it, there's no way that you're going to make this diagnosis without neuroimaging because there are two red flags, in a way, embedded in the criteria before we get to the other diagnoses being excluded. Is that right? So, this would only be a diagnosis made clinically but after neuroimaging is obtained, given that two red flags are part of the criteria – isn't that right?

Dr Robbins That's absolutely right. So, I can't imagine there's anyone who has new daily persistent headache who hasn't had appropriate neuroimaging, and that typically should include an MRI, with and without contrast, unless there's some compelling reason to avoid that. There's some other workup that could be done that's not universal but - for example, in clinic-based studies of patients who have new daily persistent headache versus those who may have, say, chronic migraine or chronic tension-type headache, you may find more abnormalities. The biggest and more compelling example of that is hypothyroidism, which presumably would be somewhat subclinical if it hadn't been brought to someone's medical attention earlier. It doesn't mean that hypothyroidism is the cause of new daily persistent headache, but it could be some type of triggering or priming factor that leads to headache perpetuation in some patients. Sometimes, if that hasn't been done already, that would be a blood test I might think about sending. And, of course, the context of onset; if someone lived in a place where tick-borne illnesses are endemic, if there are other neurological symptoms, that might prompt looking for serological evidence of Lyme disease, as one example.

Dr Berkowitz: We see a lot of headache. I'm a general neurologist; I know you're a headache specialist; we all see a lot of patients with headache. You and I both work closely with residents. Often, residents will come to present a headache patient to me and they'll say, "The patient seems to have a new daily persistent headache. They haven't been imaged yet. They have a completely normal exam. The history fits." And I always ask them, "Okay, we have to get neuroimaging, right? There's at least one red flag of the chronicity, maybe the red flag of something beginning relatively abruptly. Even though you're looking at the patients - I'm pretty sure that imaging is going to be normal, but we've got to do it." But I always encourage residents, "Try to predict - do you think the imaging is going to be normal (this is a rule out) or do you think you're going to see something (this is a rule in)? - just to sort of work on calibrating your clinical judgment." I'd love to ask you - as a headache specialist, when you're looking at the patient and say, "I know I need to get neuroimaging here to fully make this diagnosis of exclusion," or you've heard something that sounds like a red flag; you know you're obligated to image, but your clinical suspicion of finding anything more than something incidental is pretty low. How often are you surprised in practice in a sort of enriched tertiary headache population?

Dr Robbins: That's a great way to frame such a presentation on how a resident would present to you the case and whether it's a rule in or rule out. I totally agree with your approach. I think much of it depends on the clinical story. I think if it was just a spontaneous onset of headache that kind of resembles migraine that just continued, then likely the MRI is being done to just be sure we're not missing anything else. However, if the headache started – really, say someone coughed vigorously or bent over and the headache started, and there was some clear change that you could perceive in - that was, say, the Valsalva or a transiently raised intracranial pressure, or some other maneuver; then you might really say, "Well, this really could be a spontaneous CSF leak," for example. Even if the MRI of the brain, with and without contrast, is totally normal, I'm not really sure I'm convinced - that you might even take it further. For example, you might do an MRI of the total spine, with a CSF-leak-type protocol, to see if there's some sign of a spontaneous CSF leak or an extradural collection. So, I think in the cases where the preclinical suspicion is higher for a secondary headache, it might not stop at an MRI of the brain (with and without contrast) that's normal. Patients with spontaneous CSF leaks - about eighty percent of them have abnormal brain MRIs, but twenty percent don't. We found, from some observational studies, that a newer cause of intracranial hypotension, such as a CSF venous fistula in the spine, is more likely to present than other causes of CSF leak - with say, Valsalva-associated headache or cough-associated headache. That might prompt us to really take a workup more deeply into that territory, rather than someone where it really just sounds like chronic migraine that switched on. And maybe in those patients, when you dig around, they were carsick as a kid, or they were colicky babies, or they used to get stomachaches and missed school as a teenager here and there, and you think migraine biology is at play.

Dr Berkowitz: So, if you're thinking of this diagnosis before you can make it, these patients are going to get an MRI, with and without contrast. And it sounds like the main things you're looking to make sure you're not missing are idiopathic intracranial hypertension or intracranial hypotension from some type of leak. Any other secondary headaches you worry about potentially missing in these patients or want to rule out with any particular testing?

Dr Robbins: Yeah - I think sometimes we think of other vascular disorders, especially - when these patients come to medical attention, it's often a total change from what they're used to experiencing. They may present to the emergency room. So, it depends on the circumstance. You might need to rule out cerebral venous thrombosis. Or if there was a very abrupt onset or a relapsing nature of abrupt-onset headaches with sort of interictal persistent headache, we might think of other arteriopathies, such as reversible cerebral vasoconstriction syndrome. There's the more common things to rule out - or commonly identified conditions to rule out - like neoplasm and maybe a Chiari malformation in certain circumstances; those usually would declare themselves pretty easily and obviously on scan or even on clinical exam.

Dr Berkowitz: Another question I'd love to ask you as a headache specialist, in your population - sometimes we see this type of new daily persistent headache presentation in older patients, and the teaching is always to rule out giant cell arteritis with an ESR and CRP, in the sense that older patients can present with just headache. Again, my clinical experience as a general neurologist - I wanted to ask you as a headache specialist – is, for the countless times I've done this (older patient has gotten their neuroimaging; we've gotten ESR and CRP), I've never made a diagnosis of giant cell arteritis based on a headache alone, without jaw claudication, scalp tenderness, visual symptoms or signs. Have you picked this up just based on a new headache, older person, ESR, CRP? I'm going to keep doing it either way, but just curious - your experience.

Dr. Robbins: Yeah. We're taught in the textbooks (I'm sure we're taught by past Continuum issues and maybe even in this very issue) about that dictum that's classically in neurology teaching. But I agree - I've never really seen pure daily headache from onset, without any other accompaniments, to end up being giant cell arteritis. Then again, someone like that might walk in tomorrow, and the epidemiology of giant cell arteritis supports doing that in people over the age of fifty. But almost always, it's not the answer; I totally agree with you.

Dr Berkowitz: Good to compare notes on that one. Okay - so let's say you're considering this diagnosis. You've gotten your neuroimaging, you've gotten (if the patient is over fifty) your ESR and CRP, and you ruled out any dangerous secondary causes here. You have a nice discussion in your article about the primary headache differential diagnosis here. So, now we're sort of really getting into pure clinical reasoning, right, where we're looking at descriptions (colleagues like yourself and your colleagues have come up with these descriptions in the International Classification of Headache Disorders). Here again, we're in a "biomarker-free zone," right? We're really going on the history alone. What are some of the other primary headache disorders that would be management changing here, were you to make a diagnosis of a separate primary headache disorder, as compared to new daily persistent headache?

Dr Robbins: I think the two main disorders really are chronic migraine and chronic tension-type headache. Now, what we're taught about chronic migraine and chronic tension-type headache is that they are disorders that begin in their episodic counterparts (episodic migraine, episodic tension-type headache) and then they evolve, over time, to reach or culminate in this daily and continuous headache pattern, typically in the presence of risk factors for that epidemiologic shift we know to exist but that may happen on the individual level, which does include things that we can't modify, like increasing age, women more than men, some social determinants of health (like low socioeconomic status), a head injury (even if it didn't cause a concussion or clear TBI), a stressful life event, medication overuse, having comorbid psychiatric or pain disorders in addition to the headache problem, having sleep apnea that's untreated, and so on. New daily persistent headache - by definition, it should really be kind of "switched on." Many years ago, Dr Bill Young and Dr. Jerry Swanson wrote an editorial where they labeled new daily persistent headache as the "switched-on headache." Then, we're taught in headache pathophysiology that this chronification process happens over time because of, perhaps, markers of central sensitization that might clinically express itself as allodynia in trigeminal or extratrigeminal distributions. So, we're not comfortable with this new daily persistent headache, where we think the biology is like chronic migraine that gets switched on abruptly, but in so many patients, it seems to be so - it behaves like chronic migraine otherwise; the comorbidities might be the same; the treatments might still work similarly for both disorders in parallel. So, I think those are the two that we think about. Obviously, if there's unilateral headache, we might think of a trigeminal autonomic cephalalgia that's continuous, even if it doesn't have associated autonomic signs like ptosis or rhinorrhea (which is hemicrania continua) - and in those patients, we would think about a trial of indomethacin. But otherwise, I think chronic migraine and chronic tension-type headache are the two that phenotypically can look like new daily persistent headache. In patients with new daily persistent headache, about half have migraine-type features and about half have tension-type features. When I was a fellow, the International Headache Society and the classification only allowed for those who have more tension-type features to be diagnosed as new daily persistent headache. But we (and many other groups) have found that migraine-type features are very common in people who fulfill rigorously the criteria for new daily persistent headache otherwise. And then the latest iteration of the classification has allowed for us to apply that diagnosis to those with migraine features.

Dr Berkowitz: That's very helpful. So, we've ruled out secondary causes and now you're really trying to get into the nuances of the history to determine, did this truly have its abrupt onset or did it evolve from an episodic migraine or tension-type headache? But it could be described by the patient as migrainous, be described by the patient as having tension features The key characteristics (as you mentioned a few times) should be abrupt onset and a continuous nature. Let's say, now you (by history) zeroed in on this diagnosis of new daily persistent headache. You've ruled out potential secondary causes. You're pretty convinced, based on the history, that this is the appropriate primary headache designation. How do you treat these patients?

Dr Robbins: Well, that's a great question, Dr Berkowitz, because there's this notoriety to the syndrome that suggests that patients just don't respond to treatments at all. In clinical practice, I can't dispute that to a degree. I think, in general, people who have this syndrome seem to not respond as well, to those who have clear established primary headache disorders. Part of that might be the biology of the disorder; maybe the disorder is turned on by mechanisms that are different to migraine (even though it resembles chronic migraine) and therefore, the medications we know to work for migraine may not be as effective. In some, it could be other factors. There's just a resistance to appreciating that you have this headache disorder that - one day you were normal, the next day you're afflicted by headache that's continuous. And there's almost this nihilism that, "Nothing will work for me, because it's not fair - there's this injustice that I have this continuous headache problem." And often people with new daily persistent headache may be resistant to, say, behavioral therapies that often are really helpful for migraine or tension-type headache because of this sort of difficult with adjustment to it. But at least there's observational studies that suggest that most of the treatments that work for migraine work for new daily persistent headache. There's been studies that show that people can respond to triptans. In my clinical experience, CGRP antagonists that work for the acute treatment of migraine may work. There is evidence that many of the traditional, older medicines (like tricyclic antidepressants, topiramate, valproate, beta-blockers, probably candesartan) and others that we use for migraine may work. There's observational studies specifically for new daily persistent headache that show that anti-CGRP therapies in the form of monoclonal antibodies and botulinum toxin can work for the disorder. Are there anything specific for some of the new daily persistent headache that might work? Not that we really know. There's been some attempts to say, "Well, if you get these people in the hospital early and try to reduce the risk of headache persistence by giving them DHE, or dexamethasone, or lidocaine, or ketamine, will you reduce the chances of headache persistence at that three-month mark or longer?" We don't really know (there's some people who believe that, though). Maybe there's good reason to do some type of elective hospitalization for aggressive treatment because we know that, notoriously, the treatment response is very mixed. There's been specific treatments that people have looked at. There's been some anecdotes about doxycycline as a broad anti-inflammatory type of treatment that might be used in a variety of neurological disorders, but there's really nothing in the peer-reviewed literature that suggests that is effective or safe, necessarily. And I think a lot of people in new daily persistent headache do develop a profile that resembles chronic migraine (they can develop medication overuse very easily). Often, goal setting is really important in the counseling of such patients. You really have to suggest that the goal for them might be difficult to have them pain-free at zero and cured, but we want this to be treated so the peaks of severity flatten out a bit, and then the baseline level of pain diminishes so that it devolves into a much more episodic disorder over time that looks like regular migraine or regular tension-type headache.

Dr Berkowitz: I see. So, in addition to starting a migraine-type prophylactic agent based on the patient's comorbidities and potential benefits of the medication (the same way we would choose a migraine prophylactic), do you do anything, typically, to try to, quote, "break the cycle" - a quick pulse of steroids as an outpatient or a triptan in the office - and see how they do, or do you typically start a prophylactic agent and go from there?

Dr Robbins: I think, like all things, it kind of depends on the distress of the patient and how they are functioning. If it's someone who's just out of work, cannot function - and someone like that might be very amenable to an elective hospitalization or some parenteral therapy, or maybe an earlier threshold to use a preventative treatment than we would be doing otherwise in someone with migraine overall - I think that it really depends on that type of a disability that's apparent early. I think it's compelling that, with new daily persistent headache, about a third of people report some antecedent infection that was around at the time. When new daily persistent headache was first described by this Canadian neurologist, Dr Vanast, in the 1980s, it was described in the context of Epstein-Barr virus infection, or at least a higher rate of serologies that are positive for, perhaps, recent Epstein-Barr exposure. And we know that Epstein-Barr is obviously implicated in lots of neurological diseases, like multiple sclerosis. And I mean, I think about these things all the time, and especially with COVID now. So, it's compelling - as a postinfectious disorder, do we, as neurologists (who are so comfortable with using pulse-dose steroids, IVIG) - do we use these things for a new daily persistent headache? But there's no great evidence that enduring inflammation in the dura that would spill into CSF analyses is really present in such patients. There was one study that looked at markers, such as TNF-alpha, in the CSF, but the rates of seeing that were the same in new daily persistent headache and chronic migraine, so there isn't really a specificity to that. Many people we see with new persistent headaches since 2020 may have it as part of a long COVID syndrome (or postacute COVID syndrome), and in those cases, often it's more like "new daily persistent headache-plus." They might have something that resembles POTS (postural orthostatic tachycardia syndrome); they might have something that resembles fibromyalgia, chronic fatigue. Often in those patients, it takes management of the whole collection of neurological syndromes to get them better, not just the headache alone.

Dr Berkowitz: Well, this sounds like such a challenging condition to treat. How do you counsel patients when you've made this diagnosis - what to expect, what the goals are, what this condition is, and how you developed your certainty? It's often challenging (isn't it?) sometimes with patients with headache disorders, when we're not relying on an MRI or lab test to say, "This is the diagnosis"; telling them, it's just our opinion, based on their collection of symptoms and signs. So, how do you give the diagnosis and how do you counsel patients on what it means to them?

Dr Robbins: Yeah, it's a great question because it's high stakes, because people will read online, or on social media, or on support groups that this is a dreadful condition - that no one gets better, that they're going to be afflicted with this forever, and the doctors don't know what they're doing, and, "Just don't bother seeing them." And the truth is not that; there's so many people who can get substantially better. I tell people that it's common; in some epidemiologic studies, one in one thousand people in any given year develop new daily persistent headache, and most of those people get better (they don't seek medical care eventually, or they do, just in the beginning, and then they don't have follow-up because they got all better) - and I think that really happens. I think the people who we see in, say, a headache clinic (or even in general neurology practice) are typically the ones who are the worst of the worst. But even amongst those, we see so many stories of people who get better. So, I really try to reset expectations - like we mentioned before about assessing for treatment response and understanding that improvement will not just mean one day it switches off like it switched on (which seems unfair), but that the spikes will flatten out of pain (first), that the baseline level of intensity will then improve (second); that we turn it into a more manageable day-to-day disorder that really will have less of an impact on someone's quality of life. Sometimes people embrace that and sometimes people have a hard time. But it does require, like many conditions in neurology, incremental care to get people better.

Dr Berkowitz: Fantastic. Well, Dr Robbins, thanks so much for taking the time to speak with us today. I've learned so much from your expertise in talking to you and getting to pick your brain about this and some broader concepts and challenges in headache medicine. And I encourage all our listeners to seek out your article on this condition that has even more clinical pearls on how to diagnose and treat patients with this disorder.

Dr Robbins: Thanks Dr. Berkowitz - great to be with you.

Dr Berkowitz: Again, for our listeners today, I've been interviewing Dr Matthew Robbins, whose article on new daily persistent headache appears in the most recent issue of Continuum, on headache. Be sure to check out other Continuum Audio episodes from this and other issues. And thank you to our listeners for joining today.

Dr. Monteith: This is Dr Teshamae Monteith, Associate Editor of Continuum Audio. If you've enjoyed this episode, you'll love the journal, which is full of in-depth and clinically relevant information important for neurology 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.

Posttraumatic headache is an increasingly recognized secondary headache disorder. Posttraumatic headaches begin within 7 days of the causative injury and their characteristics most commonly resemble those of migraine or tension-type headache.

In this episode, Aaron Berkowitz, MD, PhD, FAAN, speaks with Todd Schwedt, MD, FAAN, author of the article "Posttraumatic Headache," in the Continuum April 2024 Headache issue.

Dr. Berkowitz is a Continuum® Audio interviewer and a professor of clinical neurology at the University of California, San Francisco

Dr. Schwedt is a professor of neurology at Mayo Clinic in Phoenix, Arizona.

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Read the article: Posttraumatic Headache

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Guest: @schwedtt

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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 Berkowitz: This is Dr Aaron Berkowitz, and today, I'm interviewing Dr. Todd Schwedt about his article on post-traumatic headache from the April 2024 Continuum issue on headache. Dr. Schwedt is a Professor of Neurology at Mayo Clinic in Phoenix, Arizona. Welcome to the podcast today, Dr. Schwedt.   

Dr Schwedt: Well, thanks so much. It's a real pleasure to be here.   

Dr Berkowitz: Thanks. We're very happy to have you. So, head trauma is common, and headache following head trauma is also very common. Let's say you're seeing an otherwise healthy young patient in your clinic who had a minor car accident a few weeks ago with some head strike and whiplash, presenting now for evaluation of headache again a few weeks out from the accident. Walk us through your approach to the history and exam here when you're seeing one of these patients.

Dr Schwedt: Yeah, absolutely. I'd be happy to do so. I'll start by saying, as you mentioned, this is such a common problem - patients that are coming in with post-traumatic headache). Of course, like almost everything in neurology, it's super important to get a detailed history to start with (so, doing the appropriate interview), and I usually like to start by getting some information about the injury itself - the mechanism of the injury, and the severity, and, of course, the symptoms that went along with the potential traumatic brain injury – so things we all know about. Then, of course, it's very important to understand how the patient felt prior to the injury because we know that, amongst people presenting with post-traumatic headache, oftentimes they might have had headaches even prior to their injury, and that's because having preinjury headaches is a risk factor for developing post-traumatic headache, as well as the persistence of that post-traumatic headache. If someone had headaches prior to their injury, then of course we want to know if that actually changed or not - is there a difference in the severity, or the frequency, or in the characteristics of the headaches they've been experiencing since their injury? Then, of course, you're going to ask about exactly what the symptoms are they're having now and what's concerning them the most, realizing that for a diagnosis of post-traumatic headache, it's very important to understand the timing of the onset of these headaches in relation to the injury. By definition, post-traumatic headache should have onset within seven days of the inciting traumatic brain injury - so the diagnosis of PTH, I mean, really is dependent upon that timing -  so, using ICHD (which is International Classification of Headache Disorders) criteria, it's got to start (or be reported to have started) within seven days. It's important to realize there are no specific headache characteristics that help to actually rule in or rule out post-traumatic headaches; the criteria themselves just say "any headache," as long as it was within that seven-day period. Having said that, though, the vast majority of people who come into the clinic for evaluation - their post-traumatic headache is going to be very similar to migraine. So, like, in other words, if they didn't tell you and you didn't ask about when the headache started and you just asked about symptoms, it would seem a lot like migraines – so, very common for the headache to be moderate and severe in intensity, be associated with light sensitivity and sound sensitivity and nausea, be worse with physical and mental exertion (very much the migraine-type characteristics). As far as diagnosis, it's also, of course, important to think about other sequelae of traumatic brain injury that could be causing the headache. For example, if you're under the impression it's a mild traumatic brain injury, but in fact, there's an intracranial hemorrhage - it wouldn't necessarily be mild any longer, but of course, that could cause headaches. We should be thinking about whether there could have been injuries to the cervical spine or the musculature of the neck that could be causing more of a muscular, cervicogenic-type headache. Think about rare possibilities, like if there was a cervical artery dissection, or if there's actually a spinal fluid leak, or, again, other things that after an injury could be causing headache. Most of the time, that's not going to be the case and you would move forward with your diagnosis of post-traumatic headache. 

Dr Berkowitz: Fantastic. That's very helpful to hear your approach. You just mentioned, as you said, most patients who've had minor head trauma and are presenting with headache, fortunately, have not suffered a cervical artery dissection or CSF leak or have an evolving subdural. But when you're in this early stage (just a few weeks after the initial injury) and there is headache, what features of the history or exam would clue you into thinking that this patient does need neuroimaging to look for some of these less common, but obviously very serious, sequelae of head trauma? 

Dr Schwedt: So, it's things that, as neurologists, we all know about, right? But certainly, if you're concerned about a spinal fluid leak, then really someone who has a prominent orthostatic component to their headache (so, you know, much worse when they sit up or stand up, compared to lying down) could be concerning. With a cervical artery dissection, almost always you're going to have focal neurologic deficits in addition to the headaches. With intracranial hemorrhage - again, usually it's going to be fairly obvious, in that the symptoms that someone's presenting with are much more diffuse and more severe, and maybe they're actually having progression of symptoms over time rather than stability or even early improvement. Then, as we would always say, the exam is essential, right? I mean, certainly someone who's had a mild traumatic brain injury might have very subtle deficits in things like their cognition and memory of events around the injury itself - and perhaps some ocular motor deficits and some vestibular dysfunction - but they should be relatively minor compared to somebody who has one of these other etiologies for a postinjury headache. We'll point out, of course, not everyone requires imaging, again, as there's all these decision rules out there about who needs CT, for example, after an injury (and certainly not everyone does). But, you know, if people have red flags, then of course it makes sense to initially get a CT of the head, and then if symptoms persist, perhaps an MRI.

Dr Berkowitz: So, once you're confident that this is a primary headache disorder - and presuming again (as in the example I gave to start us off here) that we're just a few weeks out from the initial trauma - and the patient's presenting to you for evaluation of their headache, how do you approach treatment in these patients?

Dr Schwedt: Yeah, so the specificity of your question, I think, is actually quite important - so considering the timing of when you're seeing that patient really is essential. So, if we're a couple weeks out or a few weeks out and the person is still having symptoms, that tells us something to start. The majority of people who have postconcussion symptoms are going to have resolution within a few days, or a week or two, so if someone's still having symptoms at, let's say, two weeks, three weeks, four weeks, well, then that's an indicator that, unfortunately, they're likely to continue to have symptoms for some time - when we want to be a little more aggressive, if you will, with the diagnostics and management of that patient. So, like, very early on - let's say within the first few days, or even the first week or two - some patients won't require any treatment. So, if they're having mild headaches, and maybe they take something over the counter every once in a while as it gets a little more severe, that's oftentimes fine, actually. If someone's having much more severe problems with headache (even in that very acute setting), then maybe we would give them a prescription medicine just to take for their more severe headaches. But then as symptoms progress and persist, then we should of course be thinking about other ways to - in more of a preventive approach of how to - help the patient, because, unfortunately, we don't have high-quality evidence for how to treat both acute and persistent post-traumatic headaches. The recommendation for many years (and it continues to be) is that you determine the other headache type that the PTH most resembles and you treat it like that. For example, if someone has PTH and a lot of migraine symptoms, well, then you would treat it like migraine. That might mean actually giving people specific acute migraine medications. It might mean, perhaps, putting them on migraine-preventive medications. Certainly, using other forms of therapy besides medications - maybe physical therapy is needed if someone has a lot of muscular involvement of the neck. And if they're having vestibular dysfunction from the injury, maybe they need vestibular rehab. Cognitive behavioral therapies - there's some evidence, at least, to suggest that can be helpful after an injury - so, kind of the multimodal approach. We need to make sure that people are getting good sleep, or doing what we can for that to occur (we know that sleep problems, including insomnia, are quite common after a concussion, for example), and really making sure that we're treating the whole patient. The person who is still having headaches at multiple weeks after their injury - likely they're still having other symptoms, too (some of which I just named, but other symptoms as well), like symptoms of autonomic dysfunction are quite common (like orthostatic problems; autonomic type of orthostatic problems) after an injury, cognitive problems, emotional issues - people probably are anxious and not feeling well. A lot of these folks are quite healthy prior to their injury, and all of a sudden, they have, really, a significant problem, and maybe they're missing work and missing school, and so we really have to treat the patient as a whole, of course.

Dr Berkowitz: Along those same lines, I was wondering - at this early stage - the patient has had still relatively recent head trauma (they are a few weeks out from this initial injury) but still having symptoms which, as you importantly highlighted, can go well beyond headache and a number of other neurologic symptoms they might have. Very common for the patient to ask, "How long is this going to last? How long am I going to feel like this?" How do you counsel patients? Obviously, the outcomes are very variable. How do you counsel patients as an expert here,  based on seeing so many of these patients a few weeks out - as you said, an otherwise healthy patient, minor head trauma, having headache, and potentially even other concussion symptoms as you mentioned - how do you counsel them on what to expect? 

Dr Schwedt: I'll start by saying that this is an area of really high interest to me and my research team, as well as my clinical team - so we're not good enough yet in being able to actually predict recovery and the timing of that recovery - but this is an absolutely essential point, and for multiple reasons. The main reason is based on the question you just asked. Of course, our patients want to know, "When am I going to get better? How long is it going to take? When can I get back to my normal life (whether that be work, or playing sports, or military, or other scenarios)?" – so, that's the most important reason. And it's important as well, because from the clinician's standpoint, if you know (or if you think you know) based on prediction that someone's highly likely to continue to have symptoms – well, again, that might help you make the decision about how (you know, I'll use the word aggressive) to be with their treatment and how closely to have them follow up, and this type of thing. It's also important for research. I already mentioned that, unfortunately, there really isn't decent quality evidence (for example, for what treatments to use for post-traumatic headache), and part of that reason for that is that there have been attempts at large clinical trials, and they've failed in a sense, and I think part of the reason for that is because there is, fortunately, such a high rate of natural resolution of symptoms that if you end up enrolling those patients into these prospective clinical trials, it makes it difficult to actually study any difference you might see between a treatment and your placebo. So, if we can have and develop good, clinically useful predictive models, that would really help in each of those domains. So what do I do now? I mean, basically, it's a little bit of a cop-out answer, but what I do is, I try to look at the trajectory that the patient has had thus far (and so, you know, this is all just logical and obvious), but if a patient is already having some degree of improvement - even if they still have symptoms, but they're having some improvement over those first three weeks - well, you would more or less consider the slope of that recovery to persist more or less at the same level. On the flip side, though, if someone's there and it's been multiple weeks - and they've just had absolutely no recovery and maybe they're even feeling worse - then I'm more concerned that this might be a longer-term issue.

Dr Berkowitz: That's helpful to understand both your approach and the challenges in making a firm statement on counseling our patients and using (as has been a theme in many of your helpful responses today) just, sort of, the clinical trajectory and what information that patient's giving you to try to help with the prognosis (however ambiguous it may be) and just needing time to see how the patient does.

Dr Schwedt: I might just add as well, though, that there are studies that have suggested there are certain risk factors for prolonged recovery from post-traumatic headache (and there's some limitations to these studies, so, really, validation is needed), but for post-traumatic headaches specifically, I mean, probably the biggest risk factor for persistence of the post-traumatic headache is having headaches prior to the injury. So, for example, people who have migraine before TBI that then are having an exacerbation or a new headache after the injury - unfortunately, they're less likely to have resolution during the acute phase. Other factors include the severity of the injury itself - so there are certain features of the injury that if, you know, it is seemingly more severe, maybe their likelihood for resolution in the acute phase is lower. And then there are multiple other factors that have been suggested as well, including the patient's own expectations for recovery, which I find to be quite an interesting one. 

Dr Berkowitz: Yeah - very important points. So, let's say that, unfortunately, the patient does continue to have headache now several months out after the trauma; how do you approach these patients with respect to treatment?

Dr Schwedt: Yeah. Once someone's gotten to that point, they probably really are going to need more in the way of preventive measures (and, you know, I did mention some of these). So, if someone's having migraine-like PTH, well, then I'm probably going to end up putting them on medicines that I would use for prevention of migraine. You know, you do have to be especially careful, though, in these individuals who have had TBIs, because you want to make sure that the treatments you're starting aren't going to actually exacerbate their other symptoms, right? So, of course we know some of our migraine preventives can cause things like hypotension, or, you know, cause things like insomnia or cognitive problems, as side effects, and if people are already having those issues from their TBI, then we could actually make them overall feel worse even if we make some progress for their headaches. So, you know of course, we're always careful when thinking about side effects from these medications, but especially so, perhaps, in the patient with a concussion who's having some of these symptoms anyway. And then again - just to highlight, it's not all about medication - that's one small aspect here (one important, but perhaps small, aspect here). So, really, trying to get at lifestyle measures that can be helpful - so, again, sleep, and trying to help people to moderate their stress levels, and making sure that they have an environment that's going to facilitate the recovery (meaning, if they're having a lot of light sensitivity and sound sensitivity and these types of things, you know, doing what we can to help these individuals to be in environments that will allow them to recover).

Dr Berkowitz: Yeah, all very important points - medication being just one part of treatment for these patients, as you said. But to just ask another question about medication so our listeners can learn from your expertise - I'm a general neurologist, and my experience with patients with post-traumatic headache and migraine and otherwise is that it's hard to predict who will respond to which medication (and some patients who failed many pharmaceutical medications will have an amazing response to riboflavin and vice versa) - in your experience (acknowledging that we are very limited in terms of data here), are there any migraine prophylactic agents that you feel, anecdotally, have been particularly helpful in patients with post-traumatic headaches or similar to the general migraine/tension headache population? It's very hard to predict, and it's trial and error and picking the right medication and finding the right dose (just depends on the patient). It requires the patient's patience - and our patience as well - as we sort of go through some trial and error.

Dr Schwedt: Yeah, I guess. You can hardly even imagine how much I want to answer this question by saying, "Yes, with my experience, I've found that it's these two classes of medications that really work the best for folks with acute or persistent post-traumatic headache," - but that would be disingenuous. It's so much like it is in migraine, where there is some trial and error, and, you know, again, as you say, it's so difficult to predict exactly which one is going to be the right pharmacologic agent for which patient. If access was no issue, I would go to medications that have the least side effects (which tend to be some of the newer medicines that we have for migraine), but we all know the realities of practice, and oftentimes, that's not a possibility due to access issues. Almost all of our patients that have significant postconcussion symptoms are also being managed by our neuropsychologists - and so, again, they're getting things like cognitive behavioral therapy and getting things like cognitive rehab, and they also are very helpful when it comes to workplace or school-place recommendations and accommodations. Many of our patients are being seen by our vestibular audiologists, as well, to work on their vestibular dysfunction, and vestibular rehab with physical therapy and occupational therapy. And so, you know, as you say, once you get out to multiple months, this is really a multidisciplinary, comprehensive type of treatment approach. 

Dr Berkowitz: Let's say the patient has now gone one to two years out from their initial injury and you had started them on a prophylactic agent (or found the one that works for them maybe after a few trials), and they're doing great (no headaches for several months; otherwise young, healthy person), and they ask you, "Well, do you think I can just go ahead and try coming off these medications now? My injury is a long time ago. While those first few months were awful - thank you for helping me to get these headaches under control - do you think if I go off this medicine, that my headaches will come back, or am I sort of in the clear now?" How do you think about tapering patients off of preventive medications when they've had a good response at a year or so out?

Dr Schwedt: That's so important, right? I mean, I think we all see patients that we inherit that end up kind of being left on medications that perhaps aren't even needed anymore, and it's certainly a mistake we wouldn't want to make. Post-traumatic headache - unlike primary headaches like migraine that tend to be present for decades - they can go away; they can resolve, and they usually do. I mean, we can't lose sight of that, right? Usually, it's going to go away on its own (as I mentioned, you know, within the first few days or weeks), and even after it's become persistent, if you can get a good treatment response, then, absolutely, after several months of that good treatment response, we should be tapering people off. Just like with any headache patient who's on a preventive, I would recommend tapering off of the effective treatment slowly, so if that's a medication, I'm usually very slowly just reducing the dose over several weeks or months (depends on how long they've been on it), usually not because I'm concerned about side effects of withdrawing the medication, but you're just testing it to make sure that the headaches aren't starting to creep back as you reduce the dose of that medication. So, it's a test, and if headaches do start to come back as you're lowering the dose, well, then, presumably you can more quickly get control of it again by elevating the dose back to where it was previously effective. For medications and treatments that don't really have dosing, the other way of doing it - so, you know, some of our medicines, of course, are given at one dose but given at intervals (like, let's say, each month or every three months) where you can't really reduce the dose - you can increase the interval between treatments. So, if you're supposed to have a treatment every month, well, if someone's doing really well, then maybe you say, "You know what? Give it an extra week." Maybe do it in five weeks instead of four or six weeks. In that same way, you're kind of testing whether or not the medication is still really needed.

Dr Berkowitz: Yeah, that makes sense as an approach here. In addition to your clinical expertise, Dr Schwedt, you're also a researcher in this area. Tell us, what's on the horizon for the future of diagnosis and treatment of patients with post-traumatic headache? 

Dr Schwedt: There's a lot of exciting things on the horizon. It's really encouraging that despite, for example, the lack of evidence currently that we have for treatment, and perhaps not as much preclinical and clinical research into post-traumatic headache as we need, the exciting part is that there's a lot going on. Fortunately, the funding environment for such research has been decent over the past so many years, and so, again, there's almost certainly going to be meaningful breakthroughs here in the near future. Some of our own work - for example, we do a lot of neuroimaging research of post-traumatic headache. One of the main areas of controversy in the headache field is whether or not post-traumatic headache and migraine are really the same thing or are they truly distinct headache disorders? And so, like, a lot of our work has gone towards addressing that - both through neuroimaging, as well as just examining outcomes and symptoms and whatnot - to see where there are similarities and differences. And I'm absolutely biased when it comes to addressing this, but I feel strongly that they really are distinct headache disorders. And that's important, because that means that we need to continue to study them as distinct disorders and we can't just fall back to the idea of saying, "Well, PTH of a migraine phenotype is migraine, and we already have migraine therapy, so let's just use those," because I think all of us that see patients with PTH in clinical practice realize that our migraine treatments don't work as well for PTH as they do for migraine. So, we really need to continue down the path of understanding the mechanisms underlying PTH, the mechanisms of what makes PTH persist (you know, why it persists in some people and not others), and then what we can do to intervene. I think a major topic, I believe, in determining best treatment approaches is also kind of related to the way you were asking me these questions - it's related to the timing of the intervention. Much of what's been done in studying treatment of PTH is done after it's already persistent, and so in some of these studies, including ours (I mean, it's not a criticism; including ours) - sometimes, these people have had post-traumatic headache for five years or ten years at the time that you enroll them into a study. And, you know, at that point, that's probably a very different population as far as mechanisms and who might respond to which treatments (compared to if you were studying those folks, let's say, in the first few weeks or in the first couple months). There's preclinical evidence (from rodent models of mild traumatic brain injury and post-traumatic headache) that the earlier you intervene, the more effective that intervention is going to be in treating that headache and preventing its persistence, and I would think we could logically presume that's probably the case in people as well. But, of course, we don't want to expose everybody early on to treatments if they don't need it (I mean, if they're going to have natural resolution, then that would actually be inappropriate [to expose them to treatments]). And that's where the prediction comes in. If we had good predictive models of - oh, you know, even though they're only a week into their headache, based on their pre-TBI factors and other characteristics, that they're very likely to have persistence - well, maybe that's the patient where they should have an earlier intervention, and, you know, in another patient, maybe not. 

Dr Berkowitz: It's great to hear about your work and the work of others to help us understand this very, very common condition (and that's been a theme in many of our questions), one in which we do our best, but are often limited by, our scientific understanding and the data on how to best manage these patients' headaches. I've learned a lot from our discussion - both clinically, and I'm excited to have learned more about your work and what's on the horizon to help us take care of these patients. Thank you very much, Dr Schwedt, for joining me on Continuum Audio today. Again, for our listeners, I've been interviewing Dr Todd Schwedt, whose article on posttraumatic headache appears in the most recent issue of Continuum on headache. Be sure to check out other Continuum Audio podcasts from this and other issues. Thank you so much to our listeners for joining today. 

Dr Monteith: This is Dr. Teshamae Monteith, Associate Editor of Continuum Audio. If you've enjoyed this episode, you'll love the journal, which is full of in-depth and clinically relevant information important for neurology practice. And 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.

The trigeminal autonomic cephalalgias are a group of headache disorders that appear similar to each other and other headache disorders but have important differences. Proper diagnosis is crucial for proper treatment.

 In this episode, Gordon Smith, MD, FAAN, speaks with Mark Burish, MD, PhD author of the article "Cluster Headache, SUNCT, and SUNA," in the Continuum April 2024 Headache issue.

Dr. Smith is a Continuum Audio interviewer and professor and chair of neurology at Kenneth and Dianne Wright Distinguished Chair in Clinical and Translational Research at Virginia Commonwealth University in Richmond, Virginia.

Dr. Burish is an associate professor at UT Health Houston in Houston, Texas.

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Host: @gordonsmithMD

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 tuned after the episode to hear how you can get CME for listening.

Dr Smith: This is Dr Gordon Smith. Today, I'm interviewing Dr. Mark Burish on cluster headache, which is part of the April 2024 Continuum issue on headache. Dr Burish is an Associate Professor of Neurology at the University of Texas Health Science Center at Houston, which is located in Houston, Texas. Mark, thanks so much for joining me today on Continuum Audio. I was really excited to be asked to talk with you about this article. When I recertified from my boards the last time (and actually, it will be the last time I have to take the exam), I did the AAN course on all of neurology. And I'm a neuromuscular guy, right, and so I was actually kind of worried about the headache part because I thought, "How interesting could that be?" And I was blown away at how fascinating headache has become, and in particular, your topic (cluster, SUNCT, SUNA, the trigeminal autonomic cephalalgias) - such a great topic. But before we start talking about them, I'd love to just hear more about how you got interested in this area - both headache, this topic in particular. What's your story, Mark?

Dr Burish: Well, thank you very much for having me. I'm honored to be part of this. I got into headache probably the way many people do; is, in residency, you figure out what you like, and your residency clinic tends to start collecting patients that you like (not that you're trading them with other residents, but you see certain patients). And mine (by the end of residency) had a lot of headache and pain patients into it. Then, I was very fortunate and had the opportunity to do some research as part of my career. I'm an MD-PhD, and I spend about half my time now doing research on cluster headaches, so I'm very fascinated by these types of diseases.

Dr Smith: Can you tell us really briefly what you're working on in your research?

Dr Burish: Cluster headache is such a poorly researched area. There's not a lot of people in it, so we do a little bit of everything: we have a clinical trial going; we do some basic science on the circadian mechanisms (cluster gets this very weird timing to it, where the headaches happen same time every day); and we do a little bit of starting to wade into the genetics.

Dr Smith: Well, super exciting. I was actually blown away by the statistics on cluster (as common as multiple sclerosis), and the severity of pain I was amazed to learn is above that of childbirth (it was, like, between nine and ten out of ten, which is really crazy). And I'm worried that I missed these patients in my neuromuscular clinic. So, maybe we can begin by - just tell us what you think our listeners need to know. If they have to drop off right now, what message do they need to remember from our conversation?

Dr Burish: I think there's two things. First of all, the first-line treatments for these headaches have not changed recently. For cluster headache, you still treat it with oxygen, the triptans (the faster triptans; not the oral ones, but the injectables and nasals), and you prevent them with verapamil. For SUNCT and SUNA, you use lamotrigine. So, those have not changed over time. There are some new treatments, which we'll talk about later. Then the second point is, there are four different types of headaches in this family and they all look very, very similar (one-sided pain, autonomic features, ipsilateral lacrimation, rhinorrhea - that type of thing). They differ in the treatments and how long they last. If you get them wrong (if you misdiagnose them), you're probably not going to give them correct treatment. Indomethacin works very well for two of them (the ones with hemicrania in the name, so not the ones we're going to discuss today). And then SUNCT, SUNA, and cluster headache - indomethacin does not work very well. So, it's important to distinguish them and get them right.

Dr Smith: Maybe we can start there, Mark. I mean, I was kind of appalled to learn that the average delay in diagnosis is four to nine years in your article, and given the severity of pain and the impact it has on these patients, that's clearly a challenge. What's so hard about this? And do you have pearls on how we can recognize these patients? And how do you sort this out practically in clinic?

Dr Burish: For cluster headache patients especially, it is a lot more common than we would think it is, but it still goes misdiagnosed, partly because most cluster headache patients are episodic. So, there's an episodic version where you get them every day for a few weeks and then they might go away for a year. So, I think what happens is that patients start to get into a cycle and they either get confused for sinusitis (because it happens in the spring), or they schedule a visit with a neurologist or somebody else, but the headaches are over by the time they see them, and they cancel the visit. So, I think they get misdiagnosed partly because it's either confused or they don't see doctors fast enough. I think a little bit more awareness of what this disease is and then, somehow, a mechanism to get these patients in a little bit more urgently is probably what's necessary.

Dr Smith: Well, Mark, access is a real issue in neurology more broadly, and I'd love to talk to you about that in a moment, but I wonder if we could go back. You talked about how similar these are to one another, yet the treatments are different. How do you sort out the diagnosis when you're seeing a patient? Let's say you have someone who comes in who has episodic, unilateral, very severe pain and some of these autonomic features. What are the pearls for differentiating cluster, SUNCT, and SUNA from each other?

Dr Burish: The big difference between all these different headaches is the timing. As a general rule, SUNCT and SUNA attacks last seconds (they're very similar to trigeminal neuralgia); paroxysmal hemicrania (that's one of the hemicrania ones, where indomethacin helps) - those attacks last minutes; cluster headache attacks last about an hour; and the hemicrania continua is constant (that's the other hemicrania one where indomethacin works). The other part is how often they happen. Again, SUNCT and SUNA - very similar to trigeminal neuralgia, may happen hundreds of times a day; paroxysmal hemicrania - dozens of times a day; cluster headache - maybe a handful of times; and then, hemicrania is constant. Based on how long the attacks are and how frequent the attacks are, you can generally separate them out. And if you're not sure, just try indomethacin. And then if it doesn't work, you're trying to distinguish between SUNCT and SUNA, which lasts seconds, and cluster headache, which lasts an hour, so fairly easy to distinguish those.

Dr Smith: How long does it take to medicine to work in a patient with hemicrania continua or paroxysmal hemicrania? I'll remind our listeners - there's a separate article in the same issue of Continuum on that topic - but for our purposes, let's say you try that; how long do you need to try it?

Dr Burish: Yeah, there's a great, another article about how much to give and how it works. It is generally pretty quick. I have noticed with most patients that the onset is twenty-four to forty-eight hours. And then, if you stop the medicine, the same thing - offset is kind of twenty-four to forty-eight hours. So, patients know pretty quick whether it's going to work.

Dr Smith: Wow - that's awesome. One of the things I was interested in was so-called "secondary cluster." So, you've seen your patient and let's say you've diagnosed them with cluster (primary cluster). Do you do additional testing? Do they need imaging or other laboratory workup?

Dr Burish: Yeah. The differential for cluster (and cluster is the one that we know the most about; it is the most common of all the trigeminal autonomic cephalalgias) - it's a fascinating differential. If you don't know much about them, migraine is probably the most common. If you do know a lot about them, hemicrania continua and paroxysmal hemicrania are very common. But there's all these secondary headaches that can look identical to cluster headache; these pituitary hormone-secreting tumors (prolactinomas) - things like that. So, because all these other secondary causes can happen, they generally recommend everybody gets an MRI of the brain, with or without contrast. If that is normal and the patients continue to not respond to the medicines like you expect them to (verapamil doesn't work, oxygen doesn't work, and so forth), then you might do some additional testing for pituitary bloodwork. So, just kind of a panel of hormones, looking at blood vessels (because there are some cases that dissections or AVMs can cause cluster headaches). And then sometimes get imaging of the apex of the lung because there's some data that - with the Horner syndrome - that that might be relevant.

Dr Smith: I'll refer our listeners to your article, just in general, because they really need to read it. It's fantastic. But your discussion about the neuroanatomy is really cool, and probably more than we want to get into right now, but the intersection of the neuroanatomy with therapeutics, and some of these other potential etiologies. So, one thing I was really amazed by (or appalled by, frankly) was the frequency with which these patients have suicidal ideation, given the severity of the pain and, I assume, the long time it often takes to get this sorted out. How do you handle that in clinic? Do you have conversations with people about this? How often do you appreciate it? And any words of wisdom for those of us who might encounter these patients?

Dr Burish: Yeah. It's not hard to imagine why patients would be suicidal with this. When you have pain that is a ten out of ten - and patients who have also had childbirth and cluster, they consider childbirth more around a seven - so you can imagine how painful this is and what thoughts might be going through people's heads. It tends to be (in my personal experience and some emerging data) that they are suicidal during a cycle. So, for these episodic patients (most patients are episodic with cluster headache for a few weeks), they are suicidal during those weeks. And when the headaches go away, much less risk of suicide. So, during the cycle, I try to get my patients in as fast as possible, get the medications in as fast as possible, but basically just be there to let them know that we have options, and so that they consider me as their first option, rather than something darker.

Dr Smith: How successful is first-line therapy in these patients and what's your success rate with your initial attempt at treatment?

Dr Burish: On the acute side, the as-needed medicines (sumatriptan, oxygen) - if you give an injection (not the oral; that takes too long) - incredibly effective; for most patients, one or both of those will work. We usually prescribe both because the injections - usually you can't get that many (they can be quite expensive, realistically speaking). But also, just practically speaking, patients can have headaches up to eight times a day and you're not really supposed to be taking sumatriptan eight times a day, so we also give oxygen (but then again, oxygen is not very portable, so that's where the sumatriptan comes in). On the preventive side - not great. There's been some studies suggest maybe fifty percent is as good as any preventive is going to work for you, and that's not considering side effects and other things that patients might stop them. So, we do need to have a few different preventive options and you may have to go through a few different things. Chronic cluster headache (which is the more rare version, where patients have them year-round) is anecdotally much more refractory to treatment.

Dr Smith: Can you talk a little bit about bridge therapy? You differentiate bridge from prophylactic therapy in your article.

Dr Burish: Yeah. When you're approaching one of these patients - let's say they're completely naive to any medications - usually we will give them a couple of as-needed, acute medications (sumatriptan injections and oxygen). We'll give them a preventive like verapamil, but the verapamil takes a few weeks to kick in. So, the obvious question is, "What am I supposed to do in the meantime, while you're ramping it up and it's kicking in?" So, we use these short-term preventives, which we call bridge therapies or transitional therapies. These are short-acting preventives; they kick in quick, but you can't take them for very long. The most common by far is prednisone. Or an occipital nerve block with some sort of steroid (so, steroids in some sort of fashion). We will usually give them right at the beginning of a cycle (right at the beginning of a flare for chronic cluster headache patients) while we are uptitrating something like verapamil.

Dr Smith: This may be a really silly question, but the next time I see one of these folks and I want to start oxygen, how do I do it? What are the logistics of giving someone oxygen for this, and how do patients navigate that, right? If you're having eight attacks a day during a cluster and you work as a nurse in the headache clinic, you probably have oxygen there. But you get where I'm going, right? - it's logistically challenging. How do you order it, and do you have words of wisdom to make it easier for patients to use?

Dr Burish: There's a whole kind of system of oxygen, durable medical equipment - stuff that I've had to learn. To boil it down, there are basically two types of oxygen. There's a concentrator - kind of just a machine that takes room air and turns it into about ten percent oxygen - that is sometimes effective for patients. But sometimes ten liters per minute (which is the highest that can give) is not enough and you need fifteen liters per minute. In that case, you need an oxygen tank (the big metal cylinders that you see with a extra device on top called a regulator, that can crank it up to fifteen liters a minute. For both of these - fifteen liters a minute - you're going to need a mask. The nasal canula is just - it doesn't get up to fifteen; it's not going to be enough, so we give you this bag mask (the non-rebreather mask, or the bag hanging out below it). You really need high dose, pure oxygen for these things to work, so you have to write orders that say, "fifteen liters a minute, with regulator and non-rebreather mask."

Dr Smith: I'll refer our listeners to your Continuum article. I know a lot of our listeners use Continuum at point of care. And, of course, you can access it electronically, so there's really great pearls there. Another question for you: CGRP agents have really transformed migraine; what role do they play, if any, in management of these headaches (cluster, SUNCT, and SUNA)?

Dr Burish: I think this is a fascinating emerging area of cluster headache research. One of the studies in the last three years came out that it was successful for episodic cluster headache, called galcanezumab, and it did not work for chronic cluster headache. Meanwhile, a couple other CGRP companies have tried them and they were unsuccessful, at least according to the data on ClinicalTrials.gov. And some other CGRP studies are still emerging. We know that both migraine and cluster headache work on the trigeminal system (I mean, this is a trigeminal autonomic cephalalgia - it's in the name) and CGRP is involved in the trigeminal system. That's probably where the commonality between migraine and cluster headache come from - they both work on the same pain system. But why all of them seem to work for migraine and only some of them – you know, some of these medicines work for cluster headache - is a fascinating thing. Does that mean that we don't have the dose right? Does that mean that we don't have the timing of these clinical trials right? Does that mean it's just not as effective? And there's other things that are involved in cluster headache - it's an interesting mechanism that we can start to explore.

Dr Smith: I wanted to learn more about the circadian aspects of this - I found that really interesting, and you commented that you're interested in that in a research perspective. Can you describe that phenomena a little bit and just tell us what your thoughts are?

Dr Burish: The interesting thing about cluster headaches, specifically, is that the headaches happen, for most patients, the exact same time every day – so, within an hour each day. So, my patient usually will say, "They're at two AM." Across different time zones, every study that's been done - well, not every study, but many studies have been done - two AM is the most common time of day. But if you ask an individual patient, patient number one will say, "They happen every day at two AM; patient number two will say, "They happen every day at three in the afternoon." I had a patient who was, I think, kind of getting fed up with all the questions I was asking about his headaches, and he said, "Dr Burish, it's three o'clock; if you want to wait until three fifteen, I'm going to get a headache - you can see what it's like." That's how sure he was about when the headaches were going to happen. And other than maybe hypnic headache, there are a few other headaches that have that level of circadian predictability. So, it's just an odd, curious, unique thing to these headaches and we don't quite understand why yet.

Dr Smith: So, I'm curious if the time of day patients get their headaches is in any way correlated with other aspects of sleep phenotype, right? There's broad variability in your sleep phase - the length of it, when it starts and ends. Is there any relationship, in your experience, between the time of day (two AM, ten PM) and other aspects of their sleep?

Dr Burish: We haven't seen that, to my knowledge. People have looked, for example, at sleep studies while patients are having attacks. These attacks occur out of REM sleep, non-REM sleep - it doesn't seem to matter. Anecdotally, patients will say, "My cycle last year - I had headaches every day at two AM. But my cycle this year - I have headaches every day at five in the afternoon." So, even a same patient who, theoretically, is not having big sleep changes over different years, has different timing of attacks.

Dr Smith: Mark, what's the latest thing? What's most exciting in the field that you can tell our listeners about?

Dr Burish: There are a lot of new treatments for cluster headache. There's the galcanezumab, which we discussed a little bit. There is a new dose for prednisone. We weren't sure how effective it was; now we're using kind of neuroimmunology-level doses of prednisone (100 milligrams daily; kind of titrating down from there). And then there's an occipital nerve stimulator for the chronic cluster headache patients. Since the last Continuum review on this topic, these three trials have been successful, and I think what gets lost is how impressive each one of these is in different ways. The prednisone study is impressive because you had to study that medicine (which we thought worked but didn't have a good clinical trial), and it's really hard to enroll patients in a placebo-controlled study where you already think it works. Another was done by a large pharmaceutical company. This is not an advertisement for or against, but these companies have rarely ventured into studying cluster headache until recently. The third study, the stimulator study, was a ten-year, multisite study involving surgeons and neurologists - just a monumental effort. It's because of these impressive studies that we now have data on how to treat the patient.

Dr Smith: Just so interesting. I tell you what - I mean, if you told me twenty years ago I would be this interested in headache, I would have said, "You're crazy." But now I see why our residents are so interested in it and why you are. This is fascinating. I could keep going for another hour or two asking you questions, Mark, but maybe we can pivot back to where we began. You told us your story about enriching your resident clinic - and for those residents listening, those are words of wisdom right there, my friend. But here's my question for you: we've already talked about access to care and how you manage access for these patients, but we have a huge access issue in neurology broadly and we desperately need more neurologists. As you're probably aware, there are some of our colleagues that don't think pain is neurology (I'm not one of them, but I know some of them and respect them otherwise). If there's an access issue for neurology, there's a access crisis for pain neurologists. And you don't just see headache, as I understand it; you see other patients with pain. So, I want to give you the last few minutes of our Continuum Audio episode to do your pitch, right? What do you have to say to the residents that are listening to us (or students) about why you find managing pain so rewarding and why they should consider this as a field?

Dr Burish: Yes - I also did a fellowship in pain medicine, in addition to my headache research, so I see a little bit of both. For me, the patients are very appreciative because you are talking with them about what they are interested in. They are not interested in the change in the MRI between last time - I mean, they are interested in it, but not as much as, "I hurt today." So, patients are more than happy - they're very grateful that you are addressing their primary concern, the thing that they're going home with that day that they're worried about. For me, seeing these patients has been very rewarding. From the research side. I think it's fascinating that there's just not enough research in this area - you can create your own niche; you can look into your own mechanisms - there's just not a lot of people in this field. And then, I think from a clinical side, other than the rewarding nature of it, there's a lot of options that we have. There's all of these neuropathic medications; there's all these different headache medications. If you want to wade into the procedural side of things (which I did with pain management), you can get into fluoro-guided procedures and spinal cord stimulators and all these different options that we have for these patients that help them, in addition to whatever they're going through. I have patients that then come back and say, "Well, by the way, I have these seizures; do you mind helping me kind of just go through my antiepileptics." And they're generally well controlled and they consider me kind of a general neurologist for them. So, I've found it extremely rewarding and I wouldn't do anything different.

Dr Smith: Well, that's really great information and I hope our resident listeners will take that to heart. Your article is truly amazing, Mark. I can't tell you how much I was impressed with it, and for our listeners - you gotta check it out. I've got a list of ten other things on my piece of paper here I could ask Mark about, but I think we're probably at time. So, Mark, thank you so much. Congratulations on an amazing article and really fascinating and exciting area of neurology.

Dr Burish: Thank you. Thank you very much for having me.

Dr Smith: Again, today we've been interviewing Dr Mark Burish whose article on cluster headache - appears in the most recent issue of Continuum, which is on headache. Be sure to check out Continuum audio podcasts from this and other issues, and thank you very much to our listeners for joining us today.

Dr. Monteith: This is Dr Teshamae Monteith, Associate Editor of Continuum Audio. If you've enjoyed this episode, you'll love the journal, which is full of in-depth and clinically relevant information important for neurology 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.

Awareness of the specific clinical and MRI features associated with AQP4-NMOSD and MOGAD and the limitations of currently available antibody testing assays is crucial for a correct diagnosis and differentiation from MS. Growing availability of effective treatment options will lead to personalized therapies and improved outcomes.

In this episode, Gordon Smith, MD, FAAN speaks with Elia Sechi, MD, author of the article "NMOSD and MOGAD," in the Continuum August 2024 Autoimmune Neurology issue.

Dr. Smith is a Continuum® Audio interviewer and professor and chair of neurology at Kenneth and Dianne Wright Distinguished Chair in Clinical and Translational Research at Virginia Commonwealth University in Richmond, Virginia.

Dr. Sechi is a neurology consultant in the neurology unit of the Department of Medical, Surgical and Experimental Sciences at the University Hospital of Sassari in Sassari, Italy.

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Host: @gordonsmithMD

Guest: @EliaSechi

Full episode transcript available here

Dr Jones: This is Dr Lyell Jones, Editor-in-Chief of Continuum, the premier topic-based neurology clinical review and CME journal from the American Academy of Neurology. Thank you for joining us on Continuum Audio, which features conversations with Continuum's guest editors and authors, who are the leading experts in their fields. Subscribers to the Continuum journal can read the full article or listen to verbatim recordings of the article and have access to exclusive interviews not featured on the podcast. Please visit the link in the episode notes for more information on the article, subscribing to the journal, and how to get CME.

Dr Smith: Hello. This is Dr Gordon Smith. Today, I've got the great pleasure of interviewing Dr Elia Sechi about his article on aquaporin-4 antibody-positive NMOSD and MOGAD, which appears in the August 2024 Continuum issue on autoimmune neurology. Dr Sechi, before we dig into this really exciting topic about NMOSD and MOGAD, perhaps you can tell our listeners a little bit about yourself, where you practice, how you got interested in this topic.

Dr Sechi: Hi, Dr Smith, and thank you for having me. So, my story begins here in Italy, actually - I did my med school and residency in neurology at the University Hospital of Sassari here in Sardinia. And after residency, I was lucky enough to be accepted at the Mayo Clinic in Rochester, Minnesota for a research fellowship - and that's where I spent the next three-and-a-half years, approximately. My fellowship was focused on autoimmune neurology, specifically demyelinating diseases of the CNS associated with antibodies – so, of course, NMOSD and MOGAD mostly, but also myelitis, MS, and autoimmune encephalitis – so, there's where I built most of my expertise in the field. And then, it was at the beginning of the pandemic (of the COVID pandemic) that I came back here to Italy to practice. And now, I work mostly as a neurohospitalist, and I also have my subspecialty outpatient service for patients with autoimmune neurological diseases.

Dr Smith: I wonder if you might just give us a minute or two about what it was like training in Mayo? I went to medical school there, and, you know, at the time, I thought that was just normal healthcare and normal training, and, you know, it was only later that I realized how amazing that was. I mean, this is where aquaporin-4 was discovered - I mean, what was that like? It must have been really cool training there with that team.

Dr Sechi: Yeah. You know, it's the temple of autoimmune neurology. It's fantastic. It's a great environment, very stimulating. You know, I think the great strength is that they see many patients with rare diseases, so, you get really confident with MRI features and clinical features with the history of the diseases, and this is important to recognize the typical features and differentiate from MS to do a good differential. And, of course, you know, the team is fantastic - superstars in the field. It's very, very stimulating. So, it's something that I definitely recommend. It was a fantastic experience.

Dr Smith: Well, you know what's great is, I don't know if you follow sports, but, you know, like, in the United States and college football, people refer to Gator Nation – right, these are all people who are fans of the Florida Gators. Or, maybe it's AC Milan nation in Italy. I don't want to get there (Roma, whatever), but there are all these people who've trained at Mayo, and, uh, what's great is it's a small world, right? So, I'm super excited to meet you and talk about this, because - I'm going to add you to my Rolodex, because when I see these patients (I'm a neuromuscular guy, but I do a fair bit of inpatient time), I'm always calling a small number of people, so I'm really pleased to meet you so I can put you on speed dial and ask you questions about these patients. I wonder if, maybe, we can begin? You know, in our preparatory discussions, I shared that I just came off our hospital service, and we had several of these patients, you know, where we were thinking about NMO or MOGAD as a cause for their problem - and I wonder if you just have any pearls or pitfalls in when we should suspect this, right? Most of us recognize bilateral optic neuritis, longitudinally extensive myelitis - we need to be thinking about these. Any pearls or pitfalls for when we should or should not be looking for these disorders?

Dr Sechi: Yeah, I think this is a great question. I think the first thing to pay attention is the phenotype. So, the clinical MRI phenotype that are typically associated with NMOSD and MOGAD, they are quite characteristic - and it's important to be aware of those phenotypes and how they differ from MS, because in my experience, one of the common misinterpretation (misconception) in clinical practice is just to test for AQP-4 and MOG antibodies in any patient with new-onset demyelinating disease of the CNS, even if it's typical MS. And, this is quite wrong, because MS is way more common in clinical practice - it's sixty, eighty times more common than NMO and MOGAD - and so, if you test all those patients without filter (indiscriminately) for antibodies, you increase the risk of false positivity exponentially, even if you have a highly specific test. So, first of all, I think it's good to select the right patients to test. As you said, patients with LTM, extensive involvement of the optic nerves on MRI, ADEM - there's also patients with cortical encephalitis phenotype (which is a rare phenotype of MOGAD), but not definitely good to test the typical MS patients. This is the first thing.

Dr Smith: Yeah, I mean, that's an issue in all of neurology, isn't it, right? I mean, it's an issue in sort of just sending, you know, the Mayo panel, the autoimmune encephalitis panels - you need to select patients carefully, but I think this attention to prior probability is something that we need to really focus on in multiple areas. So, I wonder if you might expand a little bit on assays. I do a lot of work in myasthenia and I know which labs do a really good job with, you know, acetylcholine receptor antibody testing and those that maybe do not, and there are different methodologies for testing - do you have any wisdom in terms of how to select a lab, what to look for, and how to interpret the results you see based on the particular assay that's being used?

 Dr Sechi: Yeah, that's a critical point. I agree. And especially if you work in myasthenia, you're very well aware of the differences between different assays, and nowadays, most of the high-quality assays are cell-based assays (either fixed or live) - it's the same in myasthenia, and people need to pay attention to some of the less-specific assays. Let's say ELISA, for instance - testing AQP-4 and MOG antibodies with ELISA is quite dangerous, because the risk of false positivity is quite high. So, it's good to know what assays to trust most and also good to know what's the right specimen to send for antibody test. For instance, with AQP-4, we know that serum testing is recommended only, and the CSF doesn't add much, but with MOG, we know that approximately 10% of patients have an isolated positivity in the CSF, which is interesting, because it means that when you have a patient with a strong diagnostic suspicion as a phenotype that is highly suggestive for MOGAD and the serum testing is negative, you may consider testing the CSF to increase your sensitivity. So, this is very important.

Dr Smith: So, I have a question for you that may seem a little naïve, but I bet other people are thinking it - can you tell us why it is that these disorders affect optic nerve and spinal cord preferentially? And I think, for NMO, the whole area postrema thing seems awfully specific to me. What's the deal? Why are these areas preferentially affected by these antibody-mediated disorders?

Dr Sechi: This is a tough question. For NMO, we know, probably, there is higher expression of some of the isoforms. Let's say there is a higher density of AQP-4 molecules that target the most affected regions - so, of course, AQP-4 is preferentially expressed in the subependymal regions around the ventricles and in the spinal cord and optic nerves, but you may have, also, solutions along the cortical spinal tracts in case of the brain involvement. The area postrema is kind of a different explanation, because there is a sort of permeability - increased permeability - of the blood-brain barrier there. So, there are several factors in MOGAD - this is not very clear, so, this is a great topic to study in the future, I think.

Dr Smith: This is a really interesting area, and one that's really benefited by significant therapeutic development. I wonder if you might look a little bit in the future and tell us, maybe, the agent, or perhaps the target, that you're most excited about therapeutically that's coming down the road these days?

Dr Sechi: There are trials ongoing for MOGAD, which is the real need in terms of treatment, because for NMO, we already have three, four drugs that have been approved and which efficacy have been demonstrated by randomized clinical trials, and those are B-cell depleting agents, IL-6 inhibitors, and complement inhibitors. For MOGAD, this is still a gray zone, because the optimal treatment strategies remains to be defined. There are ongoing trials that are quite promising on IL-6 inhibitors and the inhibitors of the neonatal Fc receptor (which is also used in myasthenia gravis as you know). And something that seems to be quite effective - a good option for long-term treatment in these patients and relapse prevention - is also the periodic administration of IVIG (intravenous immunoglobulin), which is a nice option, for instance, in the children where you want to avoid immunosuppressants of other types. So, I think IL-6 is going to show to be very effective in the end. We'll see. We'll see.

Dr Smith: So, I wonder if I might just give you a vignette and get your thoughts about, kind of, acute management, right? I just took care of a patient who had a longitudinally extensive myelitis and she was essentially paraplegic and actually came in progressing fairly rapidly, and we, of course, started her on IV methylprednisolone, sent off the proper diagnostic testing - the question I have is, how quickly do you advance therapy and go to IVIG or plasma exchange when you're encountering these, right? It takes, you know, I think the turnaround time is, you know, often about a week to get these tests back (at least several days) - I mean, should we be going very quickly to plasma exchange in someone who has a severe phenotype? Is it okay to do three to five days of IV methylprednisolone and wait for the results to come back? What's the right approach?

Dr Sechi: I think this is a great question, actually. You know, management of the acute attacks probably is the most important thing, you know, to allow a good recovery, and I think timing of PLEX administration should be very short - so, the threshold for PLEX should be low, especially when the attack is severe, and this has to be done regardless of antibody testing results, which is typically not available before one or two weeks (at least a year in Italy), I think, in many hospitals. So, I think the risk-benefit ratio of administering PLEX is in favor of treatment in these patients, because the side effects (the potential side effects) are very rare and can be prevented. Some diseases, they can mimic NMO or MOGAD - they're very rare, and they can really worsen with PLEX. As an example, we can say spinal cord infarction can worsen, maybe, because of hypotension due to PLEX. Or some very rare infections, like one case, a bad case of intramedullary spinal cord abscess that looked really similar to an AQP-4 IgG-related LTM - and it was bad, because the patient had no fever, no signs of infection, the CSF culture was negative initially, so we ended up doing a biopsy after failure of PLEX and steroids. So, it is recommended to start within the first three to five days, preferentially, in severe cases, and this is great for the outcome of the patient, so, I do recommend PLEX as a second treatment option. And I'm not sure about IVIG acutely. There is some data on MOG, but it's still controversial - it works a lot when PLEX fails, but it can be considered after PLEX, of course. And there are some very rare patients that do not improve, even after IV methylprednisolone, PLEX, or IVIG, and so, you need to consider some rescue therapies. In those patients, it's kind of complicated, because there are some options, like IL-6 inhibitors seem to be quite effective and quite fast-acting for MOGAD attacks, and also eculizumab and complement inhibitors can be an option in patients with AQP-4 - but maybe less in patients with MOG. So, these are the possibilities (very quickly).

Dr Smith: So, you mentioned FcRn inhibitors a moment ago, and I wonder, do you see a future where - and I think you were mentioning them as maybe more chronic therapy? Correct me if I'm wrong.

Dr Sechi: Yeah, yeah.

Dr Smith: Do you foresee a role for these agents in acute management? I mean, there are some that, you know, very quickly lower immunoglobulin levels, though just looking out in the future, you think that these sort of infusion therapies that we think about chronic therapy (you mentioned, you know, complement inhibitors) are going to be useful in acute management?

Dr Sechi: Yeah, it depends. It's a good option to try. I'm not sure about the time to action. It's very dependent on that, because IL-6 inhibitors and complement inhibitors are very fast-acting (I think they can be effective already within twelve hours, 24 hours, which is good), but it's reasonable that, also, Fc inhibitors can be an alternative in the future. As far as I know, there is not much in the literature, but it's good to try in the future in case, acutely.

Dr Smith: Well, exciting times indeed. Elia, thank you so much for a great discussion. I thoroughly enjoyed this. I look forward to visiting you soon, and I want to congratulate you on a really great article that's very interesting and very clinically useful.

Dr Sechi: Well, thank you, Dr Smith. This is my pleasure, and thank you for great questions. I had a great time and hope the readers of Continuum will like the article and the nice figures we have put together. So, thank you, thank you very much.

Dr Smith: Well, again, congratulations. And for our listeners today, I've been interviewing Dr Elia Sechi, whose article on aquaporin-4 antibody-positive NMOSD and MOGAD appears in the most recent issue of Continuum, which is on autoimmune neurology. It's a very exciting issue. Please check out Continuum Audio episodes from this and other issues of Continuum. And thanks to you all for joining us today.

Dr Monteith: This is Dr Teshamae Monteith, Associate Editor of Continuum Audio. If you've enjoyed this episode, you'll love the journal, which is full of in-depth and clinically relevant information important for neurology practitioners. Use this link in the episode notes to learn more and subscribe. AAN members, you can get CME for listening to this interview by completing the evaluation at Continpub.com/AudioCME. Thank you for listening to Continuum Audio.

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

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Host: @headacheMD

Guest: @RebeccaCBurch

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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 medicine relies heavily on the patient's history, perhaps more than any other field in neurology. A systematic approach to history taking is critical in evaluating patients with headache.

In this episode, Katie Grouse, MD, FAAN, speaks with Deborah Friedman, MD, MPH, FAAN author of the article "Approach to the Patient With Headache," in the Continuum April 2024 Headache issue.

Dr. Grouse is Dr. Grouse is a Continuum® Audio interviewer and a clinical assistant professor at the University of California San Francisco in San Francisco, California.

Dr. Friedman is a neuro-Ophthalmologist and headache specialist in Dallas, Texas.

Additional Resources

Read the article: Approach to the Patient with Headache

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

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 tuned after the episode to hear how you can get CME for listening.

Dr Grouse: This is Dr. Katie Grouse. Today, I'm interviewing Dr Deborah Friedman on approach to the clinic patient with headache, which is part of an issue on headache. Dr. Friedman is a neuro-ophthalmologist and headache specialist in Dallas, Texas. Deborah, I'd love if we could just start by you telling us more about you. How did you become interested in the diagnosis and treatment of headache?

Dr Friedman: I guess one of the lessons in life that I have learned regarding this question is, "never say never." I started as a neuro-ophthalmologist - that's what I did my fellowship in. My very first job was in Syracuse, New York, at Upstate Medical University, and there was no headache specialist in Syracuse at the time. And I started seeing neuro-ophthalmology patients and specifically told the person who did my scheduling for me, "Do not schedule headache patients. I am not a headache doctor; I'm a neuro-ophthalmologist." Well, these people just snuck in the door. They got referred in for their visual disturbances, right - we know what that was - or for their, you know, transient loss of vision or some type of visual manifestation of migraine or eye pain, right? So, I started seeing the patients and I figure, "Well, I did a neurology residency; I can treat headache as well as anybody else." And so I started treating their headaches. and they would come back to see me in follow-up and say, "You gave me my life back," and I was pretty blown away by that. This was a few decades ago, and we didn't give very many people "their lives back" at the time in neurology, so I decided I should go learn more about headache medicine. And I started attending national meetings of what is now the American Headache Society. I found that I really, really loved treating headache, and it has a natural marriage with neuro-ophthalmology. As my career progressed, I ended up doing more headache medicine and less neuro-ophthalmology, but I still love both.

Dr Grouse: Yeah, absolutely. I think the treatment of headache can be so satisfying and I'm so happy to hear that you were able to discover that love of treating headache in your own career. Why do you think it's important for neurology clinicians to read your article?

Dr Friedman: Well, headache is the most common disorder seen in general neurology. It is actually the most common neurological disorder overall, by a factor of ten. And it is one of the most common causes of neurologic disability worldwide - like it's in (routinely in) the top five. So, it's an important problem, and patients are going to come see us, and we need to know how to effectively interview them so we can effectively manage them. I think, in a nutshell, that's why.

Dr Grouse: You mentioned in your article the importance of making time to discuss the headache - so much so that, actually, you said that if they mentioned it offhand at the end of the visit that they have a headache, you really should be scheduling time for them to come back, to prepare and organize the information, and to have the time to really talk with them. I find this is such an important point and, in my mind, really gets to the heart of what you're trying to tell us in your article - that the way you take the history can make or break your ability to diagnose and treat the problem. Can you talk more about that?

Dr Friedman: Sure. The history is absolutely the most important part of the office visit with headache medicine. I mean, they always say, "In medicine and in neurology, ninety percent of the diagnosis is made by history." And that is more than true in headache medicine. So, you have to really get a good history. And it's a skill, but there's also kind of an art to it. So, there are certain questions you want to have answers to, but there's also this art of how to relate to the patient and how to really get them to tell you what you need to know, right? When I wrote the article, I really tried to convey that, because I think a lot of it can be learned. But there are a lot of nuances to taking a headache history, and I think that, for many people, it's helpful to have a guide to do that.

Dr Grouse: Following up on what you just said - you mentioned, of course, the art of taking the good history for headache, which I completely agree is absolutely true. However, in your article, you also mentioned that things like various questionnaire tools, AI, can also be really helpful for diagnosis, which seems to be the opposite of the art of medicine. Tell me more about how you can incorporate that into taking your history.

Dr Friedman: I find that questionnaires are incredibly helpful. I devised my own - it is one of the questionnaires that's available in the article (there's a link for it). It's not that I just read the questionnaire and I walk in the room knowing exactly what's going on - sometimes that's true - but at least I have a good idea of what I'm going to be facing when I walk into the room and start talking to the patient. The other reason (perhaps more importantly) that I think it's so helpful is because it gets the patient thinking about the details of their headaches and the details of their life and, you know, like, what medications they've taken in the past. And it really prepares the patient for the interview. In a lot of ways, I think that's more important than the information it gives me. But I do look at all the questionnaires, and I'll say, "Well, you know, you checked off this, and what did you mean by that? And you said this or that on your questionnaire." And I kind of refer to it so they at least know that I looked at it - there's nothing more irritating than filling out a long questionnaire and then nobody ever looks at it - so, I do look at it and I do acknowledge in front of them that I have looked at it and am looking at it. But I think that they help in many ways. There are programs in AI that the patient will just enter information into online and the program will just spit out a narrative, as well as a diagnosis or a differential diagnosis. For clinicians that are really under a lot of time constraints, I think these can help considerably as well.

Dr Grouse: That's really interesting, and that actually brings me to the next question I wanted to ask, which was - do you have any tips for the many busy neurologists out there (many listening to this podcast right now) who really want to do a good job gathering information and taking a careful history but are really limited on time to be able to do this? What other tools out there would you recommend for them, or tips?

Dr Friedman: Yeah, I think that probably the questionnaires and the AI-based programs are very helpful. There is - I have no financial relationship with this company; I just happen to know about it and I know the people that developed it - but it's called BonTriage (as opposed to bon voyage), and it was developed by headache specialists. And I've seen the product and I've seen the output that can be used, and I think that one is incredibly helpful. It was really made for primary care, so that people could do this thing online and then just walk in with a piece of paper, hand it to their primary care doctor, and they'd have the whole history and the differential diagnosis. But it's equally as useful for neurologists.

Dr Grouse: How about in history taking - any tricks to get the history you need and let the patient feel heard without necessarily taking lots of time going down the wrong pathway?

Dr Friedman: Yeah, that can be really hard, and sometimes patients just want to bring you down what you would consider the wrong pathway (obviously, they consider it the right pathway). People have different styles of interviewing and people have different styles of answering the question. I find that it's often very obvious early on whether the patient is going to do better by asking closed-ended questions or asking open-ended questions. I always start with open-ended questions because the research says that that's more helpful, and that getting the patient to describe their headache disability is one of the most important things that you can do, so you should ask it right up front. But some people - when you ask them the questions (as you probably know), they just go on and on and on, and it's really not the way that you might process information. So sometimes I just have to take it back and ask them very specific questions – "Do you have this symptom? Do you have that symptom? How long does this last? What triggers your headache?" - that kind of stuff. It's very, I think, specific to an individual patient.

Dr Grouse: Yeah, that absolutely makes sense. Your article highlights some important and frequently missed causes of headache, including hemicrania continua and intracranial hypotension, and specifically, you have some example cases that you talk about. I have to say, reading those certainly triggers my own latent fear of misdiagnosis of these important causes of secondary headache. Can you highlight some of the important questions to ask or situations to keep in mind in order not to miss these?

Dr Friedman: Sure. You know, those examples in the article came from my practice. I had to alter them a little bit because they're not supposed to sound like real people, but the patient with hemicrania continua was a real - I wouldn't say necessarily "eye opener" - but it really hit home with me. I spent all this time taking the history from the patient. She'd seen numerous doctors beforehand; they all thought she had chronic migraine. I take her history and I think she's got chronic migraine too, but she's trialed several medications; they haven't really worked, so, you know, we kind of ended it. I said, "Well, I think you have chronic migraine." She came back for her follow-up visit and looked at me and said, "Could I have hemicrania continua?" At which point, I panicked. It's like, "Oh my god - I think I take a pretty good history, but what did I miss?" I'm like, looking through the note from the last visit and trying to figure out where I went wrong. And where I went wrong was, I never asked her, "Are you ever completely headache free?" And that is such an important question to ask because most often, when people come in and they start talking about their headaches, they talk about their worst headaches, right? Those are the ones that are really interfering with their lives. They often will just totally neglect to tell you that they have a headache almost every single day, but it's just mild and they don't pay attention to it. That was like a big lesson for me, and I try - it's even on my questionnaire – "Are you ever headache free?," because it's just so important to know that. Intracranial hypotension is also one that you really have to be a detective for. A lot of times, the imaging will help us, but about ten, fifteen, twenty percent of people with intracranial hypotension have normal imaging. Then it becomes like this whole quest of making a diagnosis based on your clinical impression, right? So, there are just a lot of different things that you can ask and there are a lot of different symptoms people can have. One of the important lessons I learned in there was asking about orthostatic headache; the common way to ask that is, "Does it get better when you lie down?" Well, with few exceptions, most people with headache prefer to lie down, right? People with migraine prefer to lie down. But their headache doesn't get better just because they were lying down. It gets better because they took medicine and maybe they went to sleep. So, it's not just, "Is it better when you're lying down?" Is not going to sleep is part of it? And conversely, we want to know like what they feel like when they first wake up in the morning before they get out of bed, right? So just asking about, "Well, what's your headache like in the morning?" - that's not going to necessarily get the answer you want. So there are, again, kind of fine points about asking some of these questions to really find out what you need to know.

Dr Grouse: Absolutely - that makes sense, that the intracranial hypotension case was another one that really, you know, makes me go back and think, "Gosh, how many of these might I have missed in my own career?" You know, such an easy-to-miss case based on what was described.

Dr Friedman: I go through the same thing. I think that, early in my career, I could think back to patients that I probably missed that diagnosis. One of them I even sent to (may he rest in peace) Dr Mokri, who described it, and I sent him the imaging. He said, "No, this patient doesn't have it." But knowing what we know now, I think she probably did.

Dr Grouse: Wow. Transition to some other types of questions - what's the most common misconception you've encountered in treating patients with migraine?

Dr Friedman: I would say that a lot of people think that migraine has to be (as the name implies) hemicranial. A substantial proportion of adults and even a higher proportion of children have migraine headaches that affect both sides of the head. I think that's really the most common misconception.

Dr Grouse: What's the easiest mistake to make (and potentially avoid) when treating patients with migraine, or headache in general?

Dr Friedman: Studies have been done looking at this question in migraine. The first mistake is not giving the patient a correct diagnosis. And it is surprising in real life how many people walk out of the doctor's office and nobody's ever told them, "You have migraine with aura," or "You have chronic migraine," right, and giving them a very specific diagnosis. Second most common mistake in treatment is not offering them an acute treatment. So, many people are using over-the-counter medications that are not very effective, or even prescription medications that are not very effective. We have a lot of good treatments out now, and basically every patient with migraine should be offered an acute treatment. We also know that preventive treatment is massively underutilized. Again, studies (mostly by Richard Lipton and his group) have interviewed patients and done population studies, and people who clearly meet contemporary guidelines for offering preventive treatment are never offered it. So, I guess those would be my top three.

Dr Grouse: Going on the theme of patients maybe not being offered the optimal treatments, what's the greatest inequity or disparity you see in treating patients with headache disorders?

Dr Friedman: The first thing that contributes to that is - there is a shortage of headache specialists. There's also a shortage of neurologists, so that's a problem. There are certain groups that are less likely to seek care for headache. If people don't seek care, it makes it harder for us to treat them. African American males, in particular; Hispanics. I think that some of this might be stigma; some of this just might be cultural - I'm not sure. Women are more likely to seek care for migraine than men are. But there are what they refer to as, like, "islands of health-care disparity" throughout our country, where there are just not enough physicians, or even advanced practice providers working with physicians, to be able to take care of all these people. So, it's estimated that there are well over forty million people with migraine alone in the United States (not to mention all the other kinds of headaches), and there are really not enough of us to go around, and there are very long waiting times to get in to see us. So, some people will end up using the emergency room to treat their headaches, which is totally suboptimal and not a good experience for the patient, either. So, I think there are a lot of aspects to disparities in migraine care, and there is a group in the American Headache Society that actively focuses on this issue and has written papers about it. But I think it's multifaceted and it's going to take a lot of effort on both the part of us, as clinicians, as well as patients, recognizing that there is good treatment out there and people shouldn't have to live with these kinds of disorders.

Dr. Grouse: Absolutely. This has been such an interesting article. I just wanted to end with one last question, which is, what do you think is the most important clinical message of your article that you hope our listeners take away from this podcast?

Dr Friedman: I was really happy to be asked to write this article for Continuum. And I'm glad it is the lead article in Continuum because I think that taking the headache history is by far and away the most important part of the headache medicine evaluation. When I was asked to write it, I was specifically requested to write it from the perspective of a clinician seeing adult patients. And I just want to let the audience know that I did not neglect the pediatric patients - that there is a different chapter in Continuum that addresses the specifics of taking a history and what's important to ask from pediatric patients. It was really a joy to write the article. I hope that people read it and learn from it and enjoy it.

Dr Grouse: I really thoroughly enjoyed this article - it was so interesting. Even as someone who does a lot of headache diagnosis and treatment myself, I learned a lot. I think it's such a rich source of information and I hope everyone takes advantage of the opportunity to read it and learn a little bit more about headache treatment and diagnosis. Thanks so much for coming to talk with us today.

Dr Friedman: Thank you so much for inviting me. It was a pleasure.

Dr Grouse: Again, today I've been interviewing Dr. Deborah Friedman whose article on Approach to the Patient with Headache appears in the most recent issue of Continuum on Headache. Be sure to check out Continuum Audio episodes from this and other issues, and thank you to our listeners for joining today.

Dr. Monteith: This is Dr Teshamae Monteith, Associate Editor of Continuum Audio. If you've enjoyed this episode, you'll love the journal, which is full of in-depth and clinically relevant information important for neurology 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 is among the most common neurologic disorders worldwide. The differential diagnosis for primary and secondary headache disorders is broad and making an accurate diagnosis is essential for effective management.

In this episode, Lyell K. Jones Jr, MD, FAAN, speaks with Amy Gelfand, MD, who served as the guest editor of the Continuum® April 2024 Headache issue. They provide a preview of the issue, which publishes on April 3, 2024.

Dr. Jones is the editor-in-chief of Continuum: Lifelong Learning in Neurology® and is a professor of neurology at Mayo Clinic in Rochester, Minnesota.

Dr. Gelfand is an associate professor at Benioff Children's Hospitals, University of California San Francisco in San Francisco, California.

Additional Resources

Continuum website: ContinuumJournal.com

Subscribe to Continuum and save 15%: continpub.com/Spring2024

More about the American Academy of Neurology: aan.com

Social Media

facebook.com/continuumcme

@ContinuumAAN

Host: @LyellJ

Guest: @aagelfand

Full transcript available here

Dr Jones: This is Dr Lyell Jones, Editor-in-Chief of Continuum, the premier topic-based neurology clinical review and CME journal from the American Academy of Neurology. Thank you for joining us on Continuum Audio, a companion podcast to the journal. Continuum Audio features conversations with the guest editors and authors of Continuum, who are the leading experts in their fields. Subscribers to the Continuum journal 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 Show Notes.

Dr Jones: This is Dr Lyell Jones, Editor-in-Chief of Continuum Lifelong Learning in Neurology. Today, I'm interviewing Dr Amy Gelfand, who recently served as Continuum's guest editor for our latest issue on headache disorders. Dr. Gelfand is a child neurologist at the University of California, San Francisco, where she is an associate professor of neurology, and she also happens to be Editor-in-Chief of the journal Headache. Dr Gelfand, welcome, and thank you for joining us today.

Dr Gelfand: Thank you so much for having me.

Dr Jones: Dr Gelfand, this issue is full of extremely helpful clinical descriptions and treatment strategies for headache disorders. With your perspective as the editor for this issue - and you've just read all these wonderful articles and edited these articles - what were you most surprised to learn?

Dr Gelfand: I would say that the medication overuse headache article I think is where you'll find the most surprising content. This is an area in headache medicine that has been controversial. I think what we've got is new data - relatively new data, published in Neurology (in the Green Journal) in 2022 - the MOTS trial, showing that what we all thought was not necessarily true. In headache medicine, there was this mantra that, if somebody is overusing (too frequently using) a certain kind of headache acute medication, you've got to stop them; you've got to have them stop it completely before you can get them on a preventive treatment if you expect it to work. Turns out, in this trial, that's not the case. People were randomized to either stopping the overused acute medicine and starting a preventive versus continuing it and starting a new preventive, and they did equally well. I think that's really taught us that that dogma was not based in evidence (was not true), and what really matters is getting a patient started on an effective migraine preventive treatment.

Dr Jones: Wow, that is really – that is kind of ground shaking, isn't it? That's going to change a lot of practices for a lot of neurologists out there. Do you think that's going to be well received, or has it been well received so far?

Dr Gelfand: I think it has. I want it to get out there further, so I hope everybody will read in that chapter and really pick up on that piece. I think it's helpful for patients, too - that we don't necessarily need to disrupt what makes them feel like they're getting some acute, in-the-moment relief. We just need to make sure we're getting a good-quality migraine preventive therapy started. That's the most important thing. We don't necessarily need to ask them to change something about their acute treatment.

Dr Jones: That's fantastic, and it certainly could make things a little more straightforward, I think for people who are helping patients manage this. To be honest with you, the term, "medication overuse" almost sounds like it's putting the onus on the patient a little bit.

Dr Gelfand: It very much does sound that way. It is a very challenging term for a lot of reasons. And I agree with you that that's a problematic part of this whole terminology.

Dr Jones: Well, just three minutes into the interview here and, Dr Gelfand, you've already changed people's practice. I think that's wonderful, and we'll look forward to reading that specific article in the issue. Again, from your view as a headache specialist and a leader in the field, what do you think the biggest debate or controversy is in headache medicine right now?

Dr Gelfand: I think where we're really a little bit stuck in trying to figure out how to move forward is how to take care of patients who have continuous headache. It's not even really a fully defined term, but if you imagine a person who - they wake up, headache is present; it continues to be present throughout the entire day; they go to bed- it's still present; if they happen to wake up in the middle of the night to go to the bathroom, it's there then - it's just there all the time. It can be hard to imagine that situation is real - that somebody could have a headache that is continuously present for weeks, months - but this is true of some of our patients who have chronic migraine, our patients who have new, daily, persistent headache, certain other headache disorders. This entire group of patients who have continuous headache have historically been excluded from treatment trials, so our existing data don't necessarily generalize to how to treat their condition. And we need to change that, because this is a group that is arguably most in need of research, most in need of effective therapies. The question is how? Who exactly should be included in the inclusion criteria? And then, what are your outcome measures? Historically, in migraine treatment trials, we use headache days per month or migraine days per month. Days of headache per month may or may not be the right primary outcome measure for somebody who's starting from a point of continuous headache. Maybe more appropriate is, how many severe headache days you're having in a month, or how much disability you have from your headache disease. It's an area that's evolving and really does need to evolve, because this is a patient population that has been underserved in research thus far.

Dr Jones: I learned that, I think, in reading one of the articles talking about continuous headache at onset – so, the headaches that are continuous from day one, which is, as I understand it, pretty uncommon. But really very little of the clinical trial data speak to how to care for those patients - is that right?

Dr Gelfand: That is exactly right. And, epidemiologically, maybe not as common. But in a headache clinic, we certainly see patients who have had these headache disorders where it starts on one particular day, it becomes continuous within twenty-four hours of onset and has now been going for at least three months, and we would call that new, daily, persistent headache. Or equally commonly, people with chronic migraine where it ramped up over maybe a short to medium-long period to daily and continuous. And now they have been experiencing continuous headache for some number of months, if not longer.

Dr Jones: This question may be a little bit of an unfair question. One of the challenges with headache is that, unlike some other areas of a diverse specialty of neurology, there aren't as many biomarkers as you might have for dealing with patients who have cerebral ischemia or neuromuscular disease. Do you find that that leads to more differences of opinion or more variability in diagnosis and management than you might see in other areas?

Dr Gelfand: I'm so glad you asked that question. What I find that leads to is more stigma. Many of our patients are not believed, including by medical professionals who they've met before. People might think they are faking their symptoms, or that there's some sort of secondary gain, or this is something related to - they just don't know how to manage stress. This is a real problem for patients with migraine to be encountering so much stigma. As a headache medicine clinician, when I'm meeting a patient, oftentimes I need to make sure to acknowledge that, almost certainly, they've encountered that before. I need to reassure them that they're not going to be experiencing that in our headache clinic, and really try to undo some of that harm to be able to build trust that we're going to have a collaborative relationship moving forward - we're going to be a team; we're going to be determining the next steps in treatment together - and that I 100% believe them that the symptoms they are experiencing are real, are very challenging. Because migraine and other primary headache disorders are real neurologic diseases that can be quite severe. But because we have a paucity of biomarkers, it's hard for some people outside the field to recognize that. And that, I think, has been really difficult for patients historically.

Dr Jones: So, a challenge for clinicians has become really more of a burden for patients.

Dr Gelfand: Yes - well said.

Dr Jones: Yeah. That's too bad, and maybe someday that will change, and probably can be approached from a couple of different directions, right? - from educating clinicians' perspective and also pursuing the science. This might be a related question, Dr Gelfand - what do you think the biggest misconception you've encountered in - I'm thinking mostly from the provider of the clinician community - what do you think the biggest misperception or misconception there is about patients who have headache and the management of those patients?

Dr Gelfand: Well, I think it is tied in, in some way, to this notion that the patients are somehow causing their problem; that it's something about - well, I'm a child neurologist; I see adolescents and children – so, their parent is causing their problem because they're a helicopter mom or whatever it is, or they're just not managing stress in an appropriate way. I think that that is really an issue that patients are sort of handed from the medical community. Whereas if I step back and think about it, before 2018, no migraine-specific preventive therapies existed. We were borrowing from all other corners of medicine. We were borrowing from antihypertensives, antiseizure medicines, antidepressant medicines, but there was no actual migraine-specific therapy. Then came the monoclonal antibodies targeting CGRP (calcitonin gene-related peptide) - they're targeting either the ligand or the receptor. We now also have the oral forms that target the receptor, the gepants. So, we do have this one or two classes, depending on how you break that out, that are migraine-specific preventive therapies. But that's not enough for a complex disease like migraine - we need twenty of them. Look at epilepsy; there are probably twenty-plus antiseizure medicines, and yet, some patients still seize. Is that because they're anxious or stressed, or their mothers are too stressed? No - it's because some people have terrible epilepsy. And yet that same explanation has not been afforded to people with difficult migraine disease, that with just one class of migraine-specific preventive (or two, if you break out the monoclonals and the gepants) - that, somehow, they're supposed to have magically stopped with this treatment. That really doesn't make any sense. It's because we don't have enough effective therapies that they're still having difficult migraine - it's not because they're causing their disease.

Dr Jones: Thank you - that's a great example. That is important to understand - that misconception about causation. And we may come back to causation here in a moment. It really doesn't make any sense that there are few specific, disease-modifying therapies for migraine, which affects tens of millions of people in the United States alone, right? Why is that? Why are there so few?

Dr Gelfand: First of all, Dr Jones, I love it that you called it disease-modifying therapy, because that's how I think about it, too. The term, "preventive migraine therapy," which is the more commonly used therapy, is not always really useful because - some people who have continuous headache will say, "Well, what are you trying to prevent? I've got headache all the time." But this is really just treatments that are designed to dampen down disease activity in any form - how frequent, how long of duration, how intense - and I think it is really better conceptualized as disease-modifying therapy, so I love that you use that term. Why have there been so few? I think that it comes down to a paucity of research. Historically, NIH has underfunded migraine and other primary headache disorder research quite a bit, compared to how much disability those diseases cause in Americans each year. Hopefully, that will be getting better soon; I think there are some positive signs that that could be moving in a more positive direction. But I think, because migraine and other primary headache disorders are "invisible" illnesses - can't show you an x-ray with a broken bone; can't show you a lab readout with what your disease activity is; like you said, there's not a lot of biomarkers. Because of that, it's been hard for funders to really get behind it, and I think that's put us a little bit behind where we need to be. More research will lead to more therapies.

Dr Jones: Let's hope so. It certainly is very common and affects, again, millions upon millions of people and leads to impaired quality of life and disability, as you point out. You are also the editor-in-chief of a leading journal in your field, Headache. I know many of our listeners who are neurologists and perhaps interested in editorial work as a career path might be curious - what led you to that, and how has it helped you as a clinician (being in that role)?

Dr Gelfand: Yeah - I love being the editor of Headache. It's the journal of the American Headache Society. I think it's where the most interesting new science and work in headache medicine is coming out of. I have always found that reading helps me learn. If I want to learn about a topic, I need to read about it and I need to synthesize everything I read about. Being an editor makes that so accessible and fun. I really enjoy reading all of the articles that are coming in. It really helps me to think about everything I know, and thought I knew, in the field. And keeps my mind really questioning – do I really know that that's true or did I just think that's true? - and now this new data shows me that, actually, it's something else. And I really enjoy being challenged that way, on a daily basis, by new science that's coming in. So for anybody out there who has an interest in editing and playing an editorial role, I definitely encourage you to pursue that. There are programs - I know that the Green Journal has a resident and fellow section; that's where I started out, and I really had a wonderful experience in that. And then in our journal, in Headache, we have an assistant editor program for junior people - residents, fellows, postdocs - people who want to learn more about how to be an editor. I think that you learn so much about how to be a better writer, how to be a better scientist, how to communicate your findings in the most effective way. It's just invaluable and it's very fun.

Dr Jones: It is kind of selfishly fun, isn't it?

Dr Gelfand: Right, right.

Dr Jones: Yeah, and it's important work, obviously - to put good information out into the world. At Continuum, we also have - on our editorial board, we have two residents and fellow positions, again, for that career development. I have to ask you a really hard question here, Dr Gelfand. You mentioned you read to learn; if you had to make a choice - electronic or print - what would it be?

Dr Gelfand: Electronic. I know that many journals, including ours, are having to make some of these decisions right now. But I read my PDFs and I store them so that I can come back to them and search for them, and make sure, when I'm citing them, that they actually say what I thought they said because sometimes I need to look back at that. So, I am an electronic person. How about you?

Dr Jones: I think I'm print.

Dr Gelfand: Uh huh.

Dr Jones: And I'm just sitting here thinking, there are so many people listening to this interview, and they're screaming at their device, saying, "Electronic is the answer," or "Print is the answer." Like you, we want to meet our subscribers where they are, and I think neurologists are very clear in their preferences. Let's just say we'll agree to disagree, and no one is right and no one is wrong – how about that?

Dr Gelfand: Fair enough - I can respect that.

Dr Jones: All right. I have one more question for you. This might sound like a strange question in an interview between two neurologists talking about headache - what can you tell us about chicken farming?

Dr Gelfand: Well, I'd be delighted to tell you about chicken farming. As you know, because they were squawking earlier in our chat, I've got a little flock of chickens in our backyard and they are an absolute joy in my life. One thing I can tell you is that chickens respond to the photo period (how long the daylight is in a year). Now that it's November, it's the time of year when they don't get a lot of light, so they stop laying very much. I find that between Thanksgiving and about Valentine's Day, we actually start to need to buy eggs, which makes me very sad because I love having our egg supply come completely from our chickens. But we want them to rest and so that's what they're doing. Chickens will not lay very much at this time of year. During the summer and the spring and the fall (in the earlier part of the fall), they will lay almost daily, depending on which breed and how old they are. But at this time of year, it's really quiet - really, just one or two a week, I would say, right now.

Dr Jones: It sounds like a fun hobby. Hopefully the chickens don't mind that you're buying chickens in the winter, and they don't feel offended by that or jealous.

Dr. Gelfand: I worry that they do. I try not to show them the grocery bags.

Dr Jones: Well, Dr Gelfand, thank you so much for joining us today, and thank you for such a thorough and fascinating discussion on headache disorders from your unique position as a guest editor for Continuum, I do encourage all of our listeners to check out that issue. It's really full of phenomenal pointers on practice-changing tips and tricks for managing patients who have headache disorders. I'm really grateful for your time today. And thank you for telling me a little bit about chicken farming.

Dr Gelfand: Thank you so much for having me. It was really fun. And thank you for your interest.

Dr Jones: Again, we've been speaking with Dr Amy Gelfand, guest editor for Continuum's most recent issue, on headache. Please check it out and thank you to our listeners for joining today.

Dr. Monteith: This is Dr Teshamae Monteith, Associate Editor of Continuum Audio. If you've enjoyed this episode, you'll love the journal, which is full of in-depth and clinically relevant information important for neurology 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.

Regardless of the underlying cause of spinal cord disease, we have many tools at our disposal to improve symptoms and function in these patients. Even better, technology in this area is advancing rapidly.

In this episode, Lyell Jones, MD, FAAN, speaks with Kathy Chuang, MD, author of the article "Symptomatic Treatment of Myelopathy," in the Continuum February 2024 Spinal Cord Disorders issue.

Dr. Jones is the editor-in-chief of Continuum: Lifelong Learning in Neurology® and is a professor of neurology at Mayo Clinic in Rochester, Minnesota.

Dr. Chuang is an instructor in neurology at Harvard Medical School and assistant in neurology co-director at Paralysis Center, Massachusetts General Hospital and Spaulding Rehabilitation Hospital in Boston, Massachusetts.

Additional Resources

Read the article: Symptomatic Treatment of Myelopathy

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: @LyellJ

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 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 Jones: This is Dr Lyell Jones, Editor-in-Chief of Continuum Lifelong Learning in Neurology. Today, I'm interviewing Dr Kathy Chuang, who has recently authored an article on symptomatic management of myelopathy in the latest issue of Continuum, on spinal cord disorders. Dr. Chuang is a neurologist and physical medicine and rehabilitation specialist at Mass General, where she serves as Co-Director of the MGH Paralysis Program and Chief of the Neuromuscular Rehabilitation Program. Dr Chuang, welcome, and thank you for joining us today. Would you introduce yourself to our listeners?

Dr Chuang: Hi, my name is Kathy Chuang. As you said, I'm a neurologist at Mass General Hospital specializing in neuromuscular medicine, also physiatry, physical medicine, and rehab. And I'm glad to be here.

Dr Jones: Thank you for joining us. Basically, if we want to know more about managing spinal cord disorders, we have come to the right person, right?

Dr Chuang: I try to do my best with all patients - yep.

Dr Jones: For our listeners who are new to Continuum, Continuum is a journal dedicated to helping clinicians deliver the highest quality neurologic care to their patients, and we do this with high-quality and current clinical reviews. For our long-time Continuum Audio listeners, you'll notice a few different things with our latest issue and series of author interviews. For many years, Continuum Audio has been a great way to learn about our Continuum articles. Starting with our issue on spinal cord disorders (this issue), I'm happy to announce that our Continuum Audio interviews will now be available to all on your favorite open podcast platform, with some exciting new content in our interviews. Dr. Chuang, your article is absolutely full of extremely helpful and clinically relevant recommendations for the treatment of myelopathy, regardless of the cause. If there were one single most important practice-changing recommendation that you'd like our listeners to take away, what would that be?

Dr Chuang: I think the most important thing to take away is that spinal cord injury of any type spans so many organ systems, it is good to get people - or multidisciplinary care - involved early on. There's eighteen model systems for spinal cord injuries scattered across the US. Those can be great avenues of resources for patients and for practitioners, for people around. Physical medicine and rehab specialists (our physiatrists or spinal cord injury specialists) can be very useful. And then, also for each individual organ system, there are specialists involved. And so, having that multidisciplinary care is probably the most important thing for a patient that's suffering from myelopathy because every patient is different and coordinating that care is so important to them.

Dr Jones: So, teamwork is probably the most important thing, and I think most of our listeners who have taken care of patients with spinal cord disorders realize that that's really key. Your article - it leads off with such a great review of one of the big problems with myelopathy, which is spasticity management. From a medication perspective, I think many of us struggle with the balance between controlling the spasticity and some of the side effects of those medications, like sedation. How do you walk that fine line, Dr. Chuang?

Dr Chuang: Spasticity management, like everything else, is patient directed. It depends on what the patient is most complaining of. If a patient has spasticity but they're not actually having any complaints from it, we don't need to treat, because of fear of side effects. I tend to try to use focal procedures (like botulinum toxin injections) earlier on, in order to try and spare side effects of antispasticity medications. Use of other conservative therapies, like bracing, stretching, is very essential. Another thing to consider is that dantrolene doesn't usually have side effects - cognitive side effects, at least - and actually can be monitored pretty closely for hepatotoxicity, which is its major side effect. Other possibilities are the baclofen pumps, which can be very useful in patients with spinal cord injury because their spasticity is often more in their lower limbs than in their upper limbs. By using multimodality approaches, we can definitely limit the amount of cognitive side effects of medications.

Dr Jones: That's fantastic. Do you start with that multimodal at the beginning, or do you step into it with one, then the other, then the other?

Dr Chuang: I usually start off with a low-dose baclofen because they usually have generalized tone - first, in order to see if they have cognitive side effects with it and if so, at what dose. Also, so that insurers have a trial of some medication before we proceed to something as expensive as botulinum toxin injection. But yes, if there's significant focal spasticity, especially, I try to bring in botulinum toxin injections as early as possible, just because of the possibility of minimizing the effect.

Dr Jones: That's a great point - that you can start these from multiple angles and start them early. And great point about dantrolene - I think the hepatotoxicity makes many of us nervous. But it's a key point there - that it can spare some of the cognitive side effects.

Dr Chuang: Yes, and actually, it can be monitored pretty closely. As long as a patient has access to labs, we can check liver function tests weekly or every two weeks until you're on a stable dose, and after that, only at intervals. And it can be weaned off just as quickly.

Dr Jones: Fantastic. Another issue that you cover really nicely in the article, that I think is an underrecognized complication of spinal cord diseases - neuropathic pain. What's your approach to that problem, Dr. Chuang?

Dr Chuang: Neuropathic pain is very, very tough to treat a lot of times. I usually give the chance of gabapentin, pregabalin, and duloxetine early, just to see if we can start managing their pain early and to try to prevent potentiation of pain. But I also tend to try to get pain management specialists on early, and also keep in mind that there can be other causes of pain other than just the actual spinal cord injury itself. Because of deafferentation and reafferentation, patients may think of neuropathic pain, and it could be something as simple as appendicitis. If there's a change in pain, there always needs to be a workup for acute causes. Again, multidisciplinary treatment, especially with pain specialists, can be really helpful.

Dr Jones: Great point about thinking of other causes, including appendicitis or the musculoskeletal things that I'm sure can be pain generators in this pain population, right?

Dr Chuang: Yeah, it's very common. Patients can often fracture themselves just with a simple transfer and that can cause a huge flare-up of pain. So, not all pain should be just dismissed as being neuropathic or just from the spinal cord injury itself.

Dr Jones: Great point - thank you. Another topic that you cover - that I think is mystifying to many of us - is the neurogenic bladder problems that occur in patients with myelopathy. You talk about the different types - how do you tell them apart?

Dr Chuang: It's hard to tell them apart from a patient perspective because a patient will just say that they have difficulty with urination. With a spastic bladder or detrusor sphincter dyssynergia, oftentimes, patients will complain of a short stream and having to force things out. And with an atonic bladder or flaccid bladder, they have difficulty initiating a stream. What can be useful are postvoid residuals - where, if a patient is in the hospital, or if you have access to an ultrasound, or if they see a urologist - after they void, you measure the amount of urine left in their bladder. You can see whether it's a smaller amount, which is suggestive of a spastic bladder, versus a large amount, or an atonic or flaccid bladder. The standard procedure that's done to measure these are also urodynamic studies that are done, oftentimes, by urologists, where they can actually measure pressure volumes and oftentimes get EMG recordings of the actual bladder - the sphincters.

Dr Jones: Perfect. When you do those postvoid residuals (easiest done with ultrasound), what's the general cutoff you use to say - that's a small amount that might be suggestive of a spastic bladder?

Dr Chuang: I would say, probably less than a hundred. And then, if it was flaccid, more than five hundred. If there's in between, it may fall into either category.

Dr Jones: Got it. When you think about neurogenic bladder, what are the treatment options? How do they vary between the different types that patients may have?

Dr Chuang: If you have an atonic or flaccid bladder, the main possibilities for patients just are, oftentimes, Credé maneuvers (or pressure on the bladder) in order to try and help with the bladder to squeeze urine out. But a lot of times they need clean intermittent catheterization or maybe placement of a suprapubic catheter long term. For patients who have a spastic bladder or detrusor sphincter dyssynergia, we can use anticholinergic medications, like bethanechol, tolterodine - those medications - in order to try to relax the sphincter a little bit and then allow the urine to pass through. You can also have BOTOX injections to these sphincters of the bladder as well, which can be useful to relax them so that they can allow the urine to pass through. But a lot of times, a mainstay of treatment is intermittent catheterization, also for patients with severe detrusor sphincter dyssynergia, so that we can maintain small bladder volumes and not develop hydronephrosis, urinary tract infections, and complications of holding urine in the bladder.

Dr Jones: Thanks for that, Dr. Chuang. Another part of your article that I thought was really fascinating, and probably will cover some new ground for our readers and listeners, is the use of nerve transfers or surgical treatment of weakness, basically. Tell us about that and how it's used in patients with myelopathy.

Dr Chuang: For patients with myelopathy, it's used often in the upper extremities. If a patient has voluntary control of either elbow flexion or elbow extension (usually, elbow flexion), you can oftentimes have the ability to transfer nerves into the finger flexors and allow voluntary hand closure. If there's supination or wrist extension, you can oftentimes allow transfers of branches of the nerve - for example, from the supinator, or from the branch to the extensor carpi radialis brevis, into the finger extensor - so that, over a period of nine to twelve months, we'll be able to slowly regrow the nerve back in and allow the denervated muscle to become reinnervated with a voluntary controlled muscle and then restore voluntary finger extension, which can be extremely beneficial - just being able to voluntarily open and close their hands.

Dr Jones: Right. And it sounds like the goal is really that functional use of grip and use of the upper limb. Not really so much for transfers, I imagine - is that not so much the goal?

Dr Chuang: If there's less than antigravity strength of elbow extension and reasonable external rotation strength, you may be able to get elbow extension strong enough antigravity, and at that point a patient may be able to transfer independently - with a lot of training.

Dr Jones: Wow, that's fantastic - thank you. There's lots of therapeutic options, really, for many of these complications, which I think is an important point for our readers and our listeners to take home. When you look into the future, Dr. Chuang, what do you see on the horizon as the next generation of care for patients with spinal cord disorders?

Dr Chuang: I see a huge, expanding field, both of therapeutics - there are stem cell trials all over the world; there are neurorestorative hormones that are being tried. I'm very excited about the advent of robotics, with motors being basically shrunk down to the size of millimeters, and exoskeletons becoming lighter and lighter. I suspect that, long term, we'll be able to have robotic exoskeletons to be able to help patients walk and move their limbs normally. I know there are clinical trials right now involving orthoses that are controlled with brain interfaces that will hopefully help restore function in patients who need it.

Dr Jones: It sounds like science fiction, but a lot of that technology exists now, right?

Dr Chuang: Yes, it does. We definitely have prototypes of multigear hands with multiple directions. Now, the problem is trying to find the way to control these motors and to control these robotic hands and legs.

Dr Jones: Caring for patients with myelopathy I imagine can be challenging, but I imagine it can also be quite rewarding. Tell us, Dr. Chuang, what drew you to this work specifically, and what do you find most exciting about it?

Dr Chuang: I want to help people move better. I'm a physiatrist by training, and our job as physiatrist is to try to get people back to their activities of daily living as soon as possible; to try to remove any barriers to becoming active, independent people in their society. And so, I think that spinal patients that suffer from myelopathies or other spinal cord injuries have a lot of potential in the amount of activities that they can do and the way that they can contribute. I've seen patients who have been paralyzed and unable to move their hands at all develop tenodesis scripts, initially in order to just pick up things and then later obtain voluntary control of opening and closing their fingers. And it's huge in terms of what they can do in their everyday lives. Just being able to see that is just really rewarding. And even being able to help patients navigate society around them is just a hugely rewarding experience.

Dr Jones: I imagine that must be really fantastic to see folks regain those milestones.

Dr Chuang: Yes.

Dr Jones: It's pretty unusual for someone to have done a neurology and a physiatry residency. So, between me and you and all of our listeners, which residency was better?

Dr Chuang: Wouldn't trade one without the other. Probably wouldn't have done the one without the other, either!

Dr Jones: What a great, diplomatic answer. Okay, good.

Dr Chuang: It's true.

Dr Jones: Yeah. You avoided offending all the neurologists and physiatrists out there. And really fascinating discussion, Dr. Chuang. It's an outstanding article. I think it's a must-read for anyone who takes care of patients with spinal cord disorders. I want to thank you Dr. Wang for joining us and for such a thoughtful, fascinating discussion on symptomatic management of spinal cord disorders.

Dr Chuang: Thank you, Dr. Jones for having me today.

Dr Jones: Again, we've been speaking with Dr. Kathy Chuang, author of an article on symptomatic treatment of myelopathy in Continuum's most recent issue on spinal cord disease - please check it out. And thank you to our listeners for joining today.

Dr. Monteith: This is Dr Teshamae Monteith, Associate Editor of Continuum Audio. If you've enjoyed this episode, 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.

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.

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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.

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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.

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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

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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.

Compressive myelopathy caused by degenerative spine disease is common, but the pathophysiology is surprisingly complex and there are potential surprises in the evaluation of these patients.

In this episode, Katie Grouse, MD, FAAN, speaks with Ligia Onofrei, MD, author of the article "Structural Myelopathies," in the Continuum February 2024 Spinal Cord Disorders issue.

Dr. Grouse is a Continuum® Audio interviewer and a clinical assistant professor at the University of California San Francisco in San Francisco, California.

Dr. Onofrei is an associate professor of neurology and neuromuscular medicine at the University of Utah in Salt Lake City, Utah.

Additional Resources

Read the article: Structural Myelopathies

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American Academy of Neurology website: aan.com

Social Media

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Guest: @Ligia_OnofreiMD

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 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 Grouse: This is Dr. Katie Grouse. Today, I'm interviewing Dr. Ligia Onofrei about our article on structural myelopathies in the February 2024 Continuum issue on spinal cord disorders. Dr Onofrei is an Associate Professor of Neurology in neuromuscular medicine at the University of Utah, in Salt Lake City, Utah. Welcome to the podcast. Just to kind of get started, I wanted to ask you, the topic of your Continuum article is cervical and thoracic structural myelopathies - what are these and how common are they?

Dr Onofrei: So actually, structural myelopathies are the most common myelopathies that we encounter clinically. I know in neurology we tend to focus on things like MS or NMO or transverse myelitis as the myelopathies that we talk about most commonly, but we actually see them a fair bit. As you will see in my article, it's really hard to actually give you a precise number as to how common they are. We know they're common because we encounter them a lot, but there are also a lot of patients out there who have them who are undiagnosed. Structural myelopathies really refer to both the symptoms of myelopathy but also having compression of the spinal cord. That's what you have to have in order to have a structural myelopathy.

Dr Grouse: How did you become interested in this area of neurology?

Dr. Onofrei: It's a bit of a different kind of story in neurology than the usual career trajectory. Actually, when I was a resident, there was a patient at the VA who had Parkinson's disease and myelopathy, and he went undiagnosed for months because people kept blaming his dexterity issues and day changes on his Parkinson's. But, in fact, he really had a cervical myopathy that was actually quite severe. When we got him diagnosed. I remember thinking to myself, "I really want to learn more about it." And I was asking around and what I saw, even though my attendance at the time were super smart and very well versed in neurological issues, they just weren't comfortable with degenerative disorders of the spine. I wanted to learn more. I read what was available and I actually went to the AAN Spine Course, which at the time was a full day. I met Dr JD Bartleson, who was my mentor - who became my mentor, I should say. He gave me some really terrific advice about how to learn more. When I finished my residency at the University of Utah, I went on to do a neuromuscular fellowship, also at the University of Utah. But during that fellowship, I actually had two months to spend as additional training time outside of neurology, and I chose to spend it with the spine and musculoskeletal physical medicine and rehabilitation specialists at the University of Utah. They taught me a lot about degenerative spine issues, musculoskeletal issues, and I felt I really, for the first time, had a really good grasp of the diagnosis, and also the interplay between degenerative spine issues and neurological disorders. And then after that, I did something even less typical for neurologists. After I graduated fellowship, I actually went on to have a clinic embedded within the neurosurgery department at our institution. I evaluated patients – like, a day a week - patients who had spine issues and were referred for surgical evaluation. I would evaluate the patients in conjunction with one of the neurosurgeons, and then we would decide together if they needed surgery. It was a really great education to understand the interplay between degenerative spine issues and neurological disorders.

Dr Grouse: That sounds like a circuitous but very interesting path, and very fruitful in the end. You mentioned that even very adept clinicians can miss this important and actually common diagnosis. What are some early signs that are easily missed?

Dr. Onofrei: I think, with myelopathy, the most important part is actually just thinking about it as a diagnostic possibility. If you think about it, then you will essentially ask the questions that are really important diagnosis. I think it can be especially difficult if it's a patient who has a preexisting neurological disorder because we get stuck in asking the kind of things we usually ask our patients with MS or Parkinson's, or whatever else they may have. But it's really important to understand the trajectory of symptoms always. If they're having dexterity changes, "Did that happen all of a sudden? Was there something else happening?" Asking about dexterity changes to start with is a super helpful, important part of the diagnosis. And then also asking about gait changes. Again, if they have a preexisting neurological diagnosis, asking them if they've had a big change, a rapid progression, if something else happened in their disease - that's the beginning step. It's actually very, very basic information, but asking about these changes is super important. Then, once people have identified those changes, then you can delve into the more specific questions that are really unique to myelopathy, like manipulating small objects, manipulating utensils - for example, zippers or buttons. That's a really sensitive way to ask for dexterity changes for myelopathy. For gait abnormalities, it's a little bit less unique to myelopathy. A lot of the symptoms overlap phenotypically with, like, peripheral neuropathies. For example, having difficulty on uneven ground or getting your toes caught on something. But identifying a shift in your gait is usually that key initial diagnostic clue.

Dr Grouse: Really, really helpful. And, I think, always a great reminder with almost anything - you don't think of it, you won't diagnose it. Sounds like for myelopathies - structural myopathies – this could be especially true. Thinking about this article, what do you think would come as the biggest surprise to our listeners who read the article?

Dr. Onofrei: It's a really great question. I think there can be a lot of different surprises in each little section. But, to me, the thing that stands out is how complex the pathophysiology of myelopathy actually really is. There's so much more than just direct compression of the spinal cord. When you have compression of the spinal cord, you are stretching the spinal cord; you are inducing changes to the gray matter, the white matter. But you're also changing the actual biology of the cells. When you're causing compression of the spinal cord, you're inducing hypoxic or ischemic injury, and that triggers a neuroinflammatory cascade and it causes apoptosis of the neurons and the oligodendroglia. I think what was really interesting to learn is that, when you're decompressing the spinal cord with surgery, that reduces that cascade of neuroinflammation but it doesn't eliminate it. You will still have some residual apoptosis of the cells even after decompression. This actually is probably one of the pieces of information that supports the idea that we really should be intervening at an earlier stage for these patients.

Dr Grouse: Does this mean that, even after decompression, patients can continue to deteriorate or do worse as a result of that apoptosis and those changes?

Dr Onofrei: I think that the way I would interpret that, more in practice, is that those patients might not improve. They might not have any improvement post surgery. In fact, any surgeon who is an ethical surgeon will tell you that they cannot promise improvement with decompressive surgery, but we do notice improvement in a significant proportion of patients. While you can never promise that there's actual hope for these patients, it's just that some patients may not improve and we don't have a great way to predict who will improve and who will not improve.

Dr Grouse: I was also curious, when you mentioned about what chronic compression looks like, why does chronic compression look so different from acute compression of the cord, both how it presents and how the patients can look?

Dr Onofrei: That's a really fantastic question. I think part of it is that, just like with other degenerative disorders of the spine – like, for example, lumbar stenosis with neurogenic claudication and cauda equina, there's an element of time and adaptation. When you have acute compression, you do not have those adaptive mechanisms in place, and you will have to deal with just acute loss of function. That's how I would think about it. The time component allows for some adaptive changes, and also for specifically degenerative myelopathies. When you have chronic compression, you usually have less compression than with an acute traumatic myelopathy.

Dr Grouse: I want to ask, as well, what do you think is the biggest debate or controversy in this particular area - whether it comes to the underlying pathophysiology of what's going on, or else the management or treatment of it?

Dr Onofrei: I would say, without a doubt, the biggest controversy is when to intervene. Obviously, that is a hugely important question for patients and physicians alike. There's a lot of debate because there are patients who remain stable with mild myelopathy for many years, and then there are people who decline. There is a yearly rate of decline for these patients. But right now, we don't have good ways to predict who will decline and who will remain stable. I think there's a huge potential for more research, especially in the field of imaging - and especially with diffusion tensor imaging - to see if that can be used as a way to predict who will be declining or who might respond better to treatment.

Dr Grouse: That makes a lot of sense, and certainly, I think, something that a lot of our listeners grapple with as they try to counsel patients with these types of conditions. I was struck by another point you made in your article - which I thought was really interesting - which was that a common misconception is that pain is a significant manifestation of spinal cord dysfunction. And this made me think that this could definitely fall in the category of an easy mistake that you could make in this diagnosis. Tell us more about that.

Dr Onofrei: Yeah, so we are very used to using pain as an alarm signal. I think it's important, again, at a provider level, to remind ourselves that, actually, function is a better proxy for dysfunction than pain for a lot of patients. But pain, again, continues to be a really important reason why patients come to us. From one perspective, even though pain is something that we worry about and patients think potentially has really bad consequences, pain can actually be reassuring in some ways. But for myelopathy, pain is usually an incidental finding, in the sense that, usually, pain with myelopathy will happen because you have axial pain – you know, pain because your posture is poor, or you might have a superimposed radiculopathy. Pain will be sometimes the symptom that will bring the patient to attention, but it's very unlikely to be a symptom of how bad the problem is or to actually tell you if there is underlying myelopathy.

Dr Grouse: Thank you - that's a really important review, I think for all of us. Often we'll ask that as almost one of the first questions, when we're thinking about it. Tell us a little bit more. I was reviewing some of the common signs of cervical myelopathy and - it's funny - a lot of them, especially the early signs, may not even be the ones you first think of. I think you've mentioned it before - the gait dysfunction and slight loss of dexterity. I also was interested in (and this maybe may not be quite as an early one) myelopathic hand - if you wouldn't mind telling us a little bit more about that as well.

Dr. Onofrei: Of course. Assessing function is very important, just by asking the patient what they do that requires dexterity. So, starting there and then moving on to trying to understand if there's any particular issues that would confound the patient's ability to perform these activities. Like, if they have arthritis of their hands or a painful finger (like a trigger finger, or something like that), that will change the way they can handle the types of activities that require them to be dexterous. That's the initial phase. Once they have had progression of their myelopathy, they will usually have more frank weakness. I think a lot of people will say they drop more objects, but that's probably the least helpful, from a clinical perspective, just because it happens with so many different pathologies. But really paying attention to loss of actual strength and then visually examining the hand – so, looking for loss of muscle for the hand and looking for loss of strength on exam. So, finger abduction is your most sensitive exam maneuver that you can do to assess for that. And even very subtle weakness can be a really good indication of myelopathy. And then, in patients who have more advanced pathologies, you'll see more significant atrophy of the hand - actual frank, like, muscle wasting and potentially fasciculations in the hand. I talk about the myelopathic hand from a pathophysiology perspective. I thought it was really interesting that you can see this myelopathic hand with compression at any level in the spinal cord. So, even if it's high cervical compression, you can still see the hand atrophy and weakness. So, it is important to visually inspect the hand, do the strength examination, and like I said, really ask the patient about their function.

Dr Grouse: Thank you. That was really helpful. Being a neurologist, of course, I think, like many of our listeners, I'm a big fan of checking reflexes, and in your article, you mention some really interesting, different ones that we don't check every day. Do you have favorite or a few favorites that you'd like to call out for us to pay attention to?

Dr. Onofrei: As I mentioned my article, hyperreflexia is a really common manifestation of myelopathy. While it's not always present, if you can elicit hyperreflexia, it's really helpful. I think you can do whatever reflexes are your favorites, as long as they're a measure of hyperreflexia. I do like the finger flexor reflex, and I included that in the paper. It's just one that people use less often, but it's super easy to do. And if it's asymmetric, in particular, it's a really helpful tool. But, again, I don't think it matters which ones you do as long as you do a complete exam and then you look at the presence of hyperreflexia.

Dr Grouse: That's great, and I encourage everyone to check out the article and take a look at some of those reflexes that she referenced are very interesting. What role does DTI play for imaging of degenerative myelopathies, and what promise do they hold going forward?

Dr Onofrei: Diffusion tensor imaging is a really interesting imaging modality for the spine. It's not as commonly used for the spine as it is for things like stroke, right? We all are super familiar with its amazing role in stroke and early diagnosis of stroke. In the spine, it's much more complicated. The spine is a much more difficult structure to image, in general. So, while it's not being used right now on a clinical basis routinely, there's a lot of active research in that arena to try to understand what the best protocol might be, and how to use it to either predict which patients might deteriorate or which patients might need to have earlier surgical intervention. I think the promise of it is really tremendous, but to date, there hasn't been a unified protocol. But I think that, as we have more sensitive imaging modalities, better software algorithms to analyze the images, we might actually be really able to have excellent sensitivity.

Dr Grouse: Well, very interested to see how that develops over time. Just to finish up, is there any last sort of important key points you hope that our listeners will take away as they go forward into the world and look for patients with structural myelopathies?

Dr. Onofrei: I think the most important things that I want people to remember from this article, number one, is that diagnosing myelopathy starts by thinking about myelopathy, first of all. If you're thinking about myelopathy, you're more likely to ask the questions to elicit myelopathies. And then, I do want people to think about the phenotypic overlap between myelopathies and other neurological disorders. Third, I think people just need to remember that they are already doing the work of discovering myelopathy, which is asking the questions, doing a really good history and a really good exam. Really, the key for the diagnosis is having a really good history, is understanding the function of the patient, and is doing a really good neurologic exam, especially in patients who have a preexisting neurological diagnosis. Having those serial neurologic exams is really, really important to understand if the patient has a new myelopathy or to give the patient a better understanding of how they might respond to surgery, or what proportion of their symptoms is really attributed to a neurological disorder versus a myelopathy.

Dr Grouse: Thank you so much for coming to talk with us about this really important topic. Again, I can't encourage everyone enough to read this article. I think it was so helpful, so interesting, and just gets back to all the things I think we all love about neurology.

Dr. Onofrei: Thank you for having me.

Dr. Grouse: Again, today I've been interviewing Dr. Ligia Onofrei, whose article on structural myelopathies appears in the most recent issue of Continuum, on spinal cord disorders. Be sure to check out Continuum Audio episodes from this and other issues. And thank you to our listeners for joining today.

Dr Monteith: This is Dr. Teshamae Monteith, Associate Editor of Continuum Audio. If you've enjoyed this episode, 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.

Paraneoplastic neurologic syndromes can present with manifestations at any level of the neuraxis. In patients with high clinical suspicion of a paraneoplastic neurologic syndrome, cancer screening and treatment should be undertaken, regardless of the presence of a neural antibody.

In this episode, Katie Grouse, MD, FAAN, speaks with Anastasia Zekeridou, MD, PhD, author of the article "Paraneoplastic Neurologic Disorders," in the Continuum August 2024 Autoimmune Neurology issue.

Dr. Grouse is a Continuum® Audio interviewer and a clinical assistant professor at the University of California San Francisco in San Francisco, California.

Dr. Zekeridou a senior associate consultant in the departments of neurology, laboratory medicine, and pathology, and for the Center for Multiple Sclerosis and Autoimmune Neurology at Mayo Clinic in Rochester, Minnesota.

Additional Resources

Read the article: Paraneoplastic Neurologic Disorders

Subscribe to Continuum: shop.lww.com/Continuum

Earn CME (available only to AAN members): continpub.com/AudioCME

Continuum® Aloud (verbatim audio-book style recordings of articles available only to Continuum® subscribers): continpub.com/Aloud

More about the American Academy of Neurology: aan.com

Social Media

facebook.com/continuumcme

@ContinuumAAN

Guest: @ANASTASIA_ZEK

Transcript

Full transcript available here

  Dr Jones: This is Dr Lyell Jones, Editor-in-Chief of Continuum, the premier topic-based neurology clinical review and CME journal from the American Academy of Neurology. Thank you for joining us on Continuum Audio, which features conversations with Continuum's guest editors and authors who are the leading experts in their fields. Subscribers to the Continuum journal can read the full article or listen to verbatim recordings of the article and have access to exclusive interviews not featured on the podcast. Please visit the link in the episode notes for more information on the article, subscribing to the journal, and how to get CME.

Dr Grouse: This is Dr Katie Grouse. Today, I'm interviewing Dr Anastasia Zekeridou about her article on classical paraneoplastic neurologic disorders, which is part of the August 2024 Continuum issue on autoimmune neurology. Welcome to the podcast, and please introduce yourself to our audience.

Dr Zekeridou: Hi. Thank you, Dr Grouse. I'm always excited to talk about paraneoplastic neurological diseases. So, I'm an autoimmune neurologist at Mayo Clinic in Rochester, and I spend my time between the lab and seeing patients in the autoimmune neurology clinic.

Dr Grouse: Thank you so much for joining us, and we're really excited to talk about this really important topic. So, to start, I'd like to ask what, in your opinion, is the key message from this article.

Dr Zekeridou: That's a good question - there are a lot of messages, but maybe if I can distill it down. For me, one of the first things is that paraneoplastic neurological diseases can actually affect any level of the neuraxis. It can manifest with different types of presentations. If we do suspect a paraneoplastic neurological syndrome, then we need to look for the cancer, and then if we're not certain, even do an immunotherapy trial. A negative antibody does not make for an absence of a paraneoplastic neurological disease (because, often, we depend a lot on them), but you can see patients with paraneoplastic disease that do not have neural antibodies. And then, we always need to be thinking that if we have a paraneoplastic neurological disease, we actually need to be thinking of both the cancer and the immune response together - so, we need to be treating the cancer, we need to be treating the immune response – because, essentially, paraneoplastic neurological syndrome is evidence of this antitumor immune response. So, the main (if I can distill this down in one) is probably that we need to be discussing all of these patients with the treating oncologist, because they have complicated care.

Dr Grouse: Great. Thank you so much for that summary. It's very helpful. While many of our listeners are likely familiar with paraneoplastic disorders in their workup (which you've mentioned just now), the concept of neurologic autoimmunity in the context of immune checkpoint inhibitor therapy has more recently become widely recognized. Can you summarize this briefly for our listeners who may be less familiar with this?

Dr Zekeridou: I think that we learn more and more about this and we see more and more patients with immune checkpoint inhibitor-related neurological immunity, so, I always think about it in a very straightforward way. So, I think the way we think about immune responses is a balance between tolerance and regulation and immune activations. And then, immune checkpoints are the molecules that help us maintain self-tolerance. So, our immune system - it's probably the best tool that we have to fight against cancer. So, essentially, when we inhibit the immune checkpoints, we actually use our own immune system to fight cancer, but taking the breaks of the immune system essentially can lead to a lot of complications that are immune-mediated. Some of them are neurological - the neurological complications are rare, especially the ones that we need to do something about (so, it's 1% to 4%, in some cases up to 14%), and they do increase when you use multiple immune checkpoint inhibitors together. The main thing for me with the neurological complications is that, sometimes, they are difficult to recognize, they can (again) affect every level of the neuraxis - like, it can be the neuromuscular or the central nervous system (even though neuromuscular complications are much more common than central nervous system complications) - and then a lot of them (the vast majority) will happen within the first three months, but they can also happen even after you stop the immune checkpoint inhibitor. But this three-month interval, it's sometimes useful when you're in a diagnostic silence - it kind of helps you make the decision more towards an immune-related adverse event affecting the nervous system. And then, I think that, practically, once we have diagnosed this patients, we still are not very certain how to treat. All of them will get steroids upfront, but some of them will be difficult to treat, so then, we have to decide on the next treatment depending on evolution. And then, I will just say that (I mentioned it previously, but) these are the patients that the coordination with other subspecialties is one of the main things that we need to do (eg, oncologists) - they often have immune-related adverse events from other systems, so, there is a lot of coordination of care. And, always, the question at the end comes up, Should we be putting these patients back to their immune checkpoint inhibitor cancer immunotherapy that might help them with the cancer? And I think that this is difficult sometimes, and it needs to be decided - most cases - in a case-by-case basis, even though there are some recommendations that I've been discussing in the Continuum article.

Dr Grose: That's great, and I encourage everyone to read more about this, because it is a very complex and fascinating topic. On the note of the immune checkpoint inhibitor neurologic dysfunction - I would imagine these are pretty rare - how common are these? And I would suspect they're getting missed a lot - is that correct?

Dr Zekeridou: I think it's a very good question. Essentially, what we say for the neurological immune-related adverse events (the ones that we need intervention) - so, they are at least of grade two. (I think that there are less than 4%, mostly, probably close to 1.5%.) There was a study where they used double immune checkpoint inhibitors (so CTLA-4 and PD-1, PD-L1) - they were up to 14%, but this was any grade (so, a little bit of tingling, a little bit of headache), while the ones that we actually need to act upon and we need to actually do something about, they are probably closer to 1.5%. So, are they being missed? I am certain that some of them never make it to the neurologist. So, the ones that we know that we are underestimating is definitely the meningitis - because I think it's more common – but, often, when the patients present, they have something else as well. So, the oncologists will put them on steroids and then they will get better - so, we don't really see them in the neurology clinic (the ones with the very mild side effects). And then, also, these patients are often very sick, and they have a lot of things going for them, so they sometimes do not make it to the diagnosis.

Dr Grouse: So then, I want to just take a step back and ask you, what's the most challenging aspect of paraneoplastic neurologic disorders in your opinion?

Dr Zekeridou: I think, for me, one of the main things, the classic paraneoplastic disorders - and when I say "classic paraneoplastic disorders", they are the ones that we think more of with antibodies that are mostly biomarkers of the immune response, and they suggest a cytotoxic T-cell mediated disorder (so, like PCA1 [or anti-Yo] or ANNA-1 [or anti-Hu]) - these patients are very sick often, and we don't have a lot of good treatments for them. And then, even if we treat them, we actually sometimes do not manage to reverse their course - the best that we can do is stabilize. So, I think that this is part of the discussion that we have upfront with these patients - but it is quite challenging, because most of them, we will be giving them a cancer diagnosis ourselves, because we recognize the paraneoplastic neurological syndrome, and we look for the cancer, and then we'll be giving them a cancer diagnosis. And even if we treat their cancer and we treat the immune system, sometimes, then, we don't make a real improvement – like, we stabilize their disease and we sometimes get improvement, but there are cases that we do not and they continue to progress – so, that has been the most challenging aspect of this, and I think that's kind of where we really need more things coming – like, we need more treatments, we need to better understand these diseases and get more straightforward.

Dr Grouse: I agree. I think that's absolutely, uh, what we all hope for these types of disorders, and I can imagine we all can remember at least one case just like this where someone had this type of problem and just didn't respond to treatment. So, strong hopes that there will be improvement with this in the years coming. Another question I have for you is, what in your article do you think would come as the biggest surprise to our listeners?

Dr Zekeridou: I think that, because we discussed that immune checkpoint inhibitors (maybe we don't know as well), so one of the main things for me is when we first started thinking of neurological complications of immune checkpoint inhibitors, there was a lot of myasthenia gravis mentioned (patients presenting with myasthenia gravis), and then some of them antibody-positive, some of them antibody-negative. Now, with the time that has passed by, we recognize that myasthenia gravis is very rare. Like, I've seen tons of patients (probably more than that, actually) – and then, maybe I've seen one patient with de novo myasthenia gravis. We realize that the immune checkpoint inhibitor myasthenia gravis that we were thinking of are – they're mostly the immune checkpoint inhibitor myocytes cases - so, then, this is one of these myopathies that looks like no other. So, it really has a very predominant oculobulbar involvement (that's why everybody was thinking that this is myasthenia gravis), but, practically, the EMGs are negative, the patients do not respond to pyridostigmine - so, practically, these are really myopathy cases. And why is that important? Because 30% to 40% of these cases might also have a cardiomyopathy, for example, and then we're putting all these patients on pyridostigmine and medications that they do not necessarily need. So, I think one of the chains in concepts that we have in the later years is that, really (and this is one of the most common immune-related adverse events that we see in our clinic), that these patients with ICI myositis really present with the oculobulbar involvement and proximal involvement that we can see in myasthenia, but they do not have a neuromuscular junction problem.

Dr Grouse: Now, we've all struggled with identifying a primary malignancy in patients where a paraneoplastic syndrome was strongly suspected. Do you have any tips on how to make this workup as high yield as possible?

Dr Zekeridou: Yeah, I think that's a difficult question. I think it depends a little bit on your patient as well. So, if you have an antibody that makes things easier (and we can discuss about that, but), practically, for me, a patient that I have a high suspicion, that we get a CT chest, abdomen, and pelvis upfront - and often, we don't get PET scans, right, directly, because we have insurance companies maybe playing a role in what we would do. So, I would get this for a woman - she has to have a mammogram. For a man, they have to have a testicular ultrasound. That's the basics for me. And then, when we see more younger women or when we suspect an MDA, then they will need to have the ultrasound to look for the ovarian teratomas or an MRI of the abdomen - so, the PET scan for me, if I have a high suspicion, it will always be the next step. Like, we have increased diagnostic yield with PET scans, but we also need to remember, what are the tumors that you will not find on a PET scan? Teratomas are not PET-avid, and, often we say, "Oh, we found the lesion in the ovary and the PET scan was negative." That doesn't matter. In an NMDA-receptor antibody patient, if you find the lesion in the ovary, you need to make certain it's not a teratoma, because PET scans will not necessarily pick up a teratoma - it's not an avid malignancy. So, if the patient is a smoker and I suspect small-cell lung cancer, so I would always get the PET scan. If I have a patient with a high-risk antibody like PCA1 (or anti-Yo) and I didn't really find the tumor with the CT chest, abdomen, and pelvis and the mammogram, I will always get the PET scan. Same for the patients with the smoking history. I will also say that, sometimes, we forget other malignancies. So, for example, we have neuronal intermediate filament antibodies (so, ANNA-3 antibodies), and some of them will have Merkel cell. So, depending on the patient, on the antibody, and if we didn't find anything else, I would do a skin check. If they have GI symptoms, I would look for the GI tumor as well. So, even though the basics are what I mentioned, I will adapt depending on the patient symptoms. And all of these patients should have age-appropriate cancer screening, so if they didn't have a colonoscopy, they will have to have a colonoscopy. So, this is part of the main things. And then, the question for me that always comes up is, "Who is the person that you're going to keep on repeating the screen?" And then, practically, if you have a low-risk paraneoplastic antibody that comes (let's say LGI1), we know it's a low risk, so I would actually do the cancer screening - I will look for the thymoma once, and then that would be it. But if you have a patient with a high-risk paraneoplastic antibody (let's say ANNA-1 [or anti-Hu] or anti-Yo [anti-PCA1]), these are the patients that I will keep on screening - and then I will do every four to six months for two years (that's the current recommendation), but I will probably continue yearly after. And then, we need to also remember that whenever you have a neurological relapse, that's exactly when you need to be looking for the cancer as well - so, you must be thinking that the idea is that maybe you have the immunological relapse because there is cancer somewhere. So, these are the types of things that I kind of adapt to specific patients. But I think when we're not certain, broad screening is what we need. And then, again, the PET scan - for me, it's a great test, but we need to know its limitations. So, that's the other thing that comes up a lot in the phone calls or in the patients that I see that we do a PET scan - but practically, it's not good for some of the malignancies that we're looking for.

Dr Grouse: That's really great to point out, and I'm glad you brought up the risk level of the particular syndrome. You have a great table in your article that summarizes the risk level of some of the various syndromes - so, you know, just a reminder for everyone to check that out if you want to have more information about this and how this applies to the screening - so very helpful. What is the easiest mistake to make, and also maybe to avoid, when treating patients with paraneoplastic neurologic disorders?

Dr Zekeridou: That's a great question, actually. So, there are two things here. One is that we need to be thinking about paraneoplastic neurological syndromes, because if you don't think about them, then you don't look for them. So that's the one thing. So, patients that come with a subacute onset of neurological dysfunction - they have systemic features, or they are smokers, they have autoimmunity in the family (all those things) – like, we need to be thinking about paraneoplastic neurological syndromes. On the other side, we also see a little bit more of overdiagnosis that's coming in the later years. So, one of the things that we see a lot is that we kind of have difficulties with the interpretation of the neural antibodies - so, sometimes, we will get a neural antibody, and then it will not fit, but we will base our diagnosis on the neural antibody presence. And then, some neural antibodies are great - we don't really see false-positives - but some of them are not great and we do see false-positives. So, for me, the main thing that I would say is that we need to have a clinical suspicion - we're treating the patient and the clinical syndrome if it is compatible with a paraneoplastic neurological disorder, and then the neural antibodies are the ones that are going to help us, like, diagnose or point to a cancer - but we are really treating the patient. And then, if we give a treatment and it doesn't make sense how the patient evolves, we actually need to reassess the diagnosis, because we do have both overdiagnosis, but also we have underdiagnosed in patients that it's not suspected - so I think it's kind of the increased awareness that helps, but we also need to be going back always to the clinical manifestations of the patient.

Dr Grouse: Really great points to make, and thank you so much for that. What is the most common misconception you've encountered in treating patients with paraneoplastic disorders?

Dr Zekeridou: So, one of the things that we see a lot is that patients wait to be treated - even with high suspicion of paraneoplastic neurological syndromes - until we have the neural antibodies, and sometimes, if the neural antibodies are negative, we have patients that are not given a paraneoplastic neurological syndrome or autoimmune neurological syndrome diagnosis because of the negativity of the antibodies. So, for me, one of the main things is that the patients actually fit clinically with a paraneoplastic neurological syndrome - and there are scores that can help us, clinical manifestations that can actually help us make this diagnosis. We need to be looking for the cancer and treating them, regardless of the presence of the antibody. Some patients will not have the antibodies for weeks. The second aspect to this is that, often, we want to say, "Oh, it's a paraneoplastic neurological syndrome. They will treat the cancer and, like, that's the oncologist's job." But, practically, I think that the neurologist will really need to be involved with this. I think the patients need treatment of the immune response and treatment of the tumor. So, I think we are part of the treatment team for these patients and it's not only the oncologists that are treating the tumor.

Dr Grouse: Where do you think the next big breakthrough in this area will be?

Dr Zekeridou: Where I hope it would be - and I'm hoping that it's actually what it is going to be – is, really, better understanding and treating the classic paraneoplastic neurological diseases, that they are T-cell mediated disorders that lead to neural cell distraction, and we don't have good treatments for these patients and we cannot get any improvement. So, there is a lot of research going on there. How can we prevent? How can we treat? But, I think that would be the next big milestone for us, because the antibody-mediated diseases - so we now have a lot of good treatments. Like NMDA-receptor encephalitis, AMPAR encephalitides - these antibody-mediated disorders, we have good treatments. The disorders that the antibodies are biomarkers  - and they are the cytotoxic diseases, the effectors of the autoimmunity - we don't. So, that's where I hope and think our breakthrough will be.

Dr Grouse: Definitely hoping to see more advancements in this area and already, I think, very quickly developing field. So, I wanted to talk a little bit more about you and what brought you to this area of neurology I think which most of us find to be a very fascinating field  that would love to hear more about what brought you to it. How did you become interested in this area of neurology?

Dr Zekeridou: I did my medical school in Greece. So, in Greece, towards the end of the sixth year, you need to decide what your specialty would be, and for the life of me, I could not decide between oncology and neurology - I was changing my mind all the time. And then, I decided that the diagnosis is more important to me in terms of a physician - that's why I went more with neurology and I was clear on my choice. So, practically, then, I went and did my residence in Switzerland, and something happened and I found myself in the outpatient autoimmune neurology multiple sclerosis clinic for a year, and it was evident to me that this is my passion. Like, the multiple sclerosis, I thought was a great disease, but it was the cases that they were not multiple sclerosis, that they were the ones that they were the most fascinating for me. So, then, I did my peripheral nerve year - so even more, it was clear for me that this is the immune system interactions, the cancer, and the neurological symptoms - that's what I wanted to do. And practically, I pursued a fellowship in Lyon in the French Reference Center for Paraneoplastic Diseases, and I was sold. There was nothing else for me. So, eventually I came here at Mayo (and then I stayed) - but it was very clear, even since the beginning - and I really found something that combined both of my passions even from medical school.

Dr Grouse: What are you most excited about in this field? And, specifically, you know, what might you impart to other trainees who are thinking about choosing this field for themselves?

Dr Zekeridou: So, I think that there are many things. So, autoimmune neurology or paraneoplastic neurological syndromes, they can affect every level of the neuraxis, so, practically, your clinician, that we see everything - we'll see central nervous system, peripheral nervous system, neuromuscular junction – so, that's actually very fascinating for me. The second part of it is that we have diseases that we can actually treat. We see differences in patients that we will intervene and we will really change their disease course. And the other thing for me is all the research that is ongoing. So, practically, the research in paraneoplastic syndromes or neurological immunity is directly translational to the patient - like, we have kind of a bed-to-bedside type of research that is going on. And basic research is important and there is a lot of advances, but you can see them directly, like, being translated in patients - so, essentially, the research is directly translational to clinic, and that makes it very exciting.

Dr Grouse: I think that your excitement about this field is very inspirational and will hopefully inspire many future trainees who are interested in this field. So, when you're not learning more about paraneoplastic syndromes and their treatment and diagnosis, what else do you like to do? Tell us something about your outside interests.

Dr Zekeridou: So, again, I come from a very diverse background and the way that I arrived in the states, but, I really like traveling. So, we would travel a lot lately. We travel more in Greece, because when you're coming from Greece and you're not living there, your summers are always there - but we try to explore different places there. And one of my main things and passions that I like is, essentially, cooking. So that relaxes me, that helps me - cooking and having friends over – so, that's my favorite thing of doing outside of work.

Dr Grouse: Well, I have to say it's hard right now to imagine anything more fun than traveling and enjoying good food and Greece. So, I think your hobby seems like one we can all get behind.

Dr Zekeridou: It's relaxing the mind.

Dr Grouse: Yes, yes. This has been a really great discussion on what I think is a very interesting area of neurology, and we really appreciate you taking the time to talk with us today.

Dr Zekeridou: Thank you so much for having me. It was great talking to you.

Dr Grouse: Again, today, I've been interviewing Dr Anastasia Zekeridou, whose article on classical paraneoplastic neurologic disorders appears in our most recent issue of Continuum on autoimmune neurology. Be sure to check out Continuum Audio episodes from this and other issues. And thank you to our listeners so much for joining us today.

Dr Monteith: This is Dr Teshamae Monteith, Associate Editor of Continuum Audio. If you've enjoyed this episode, you'll love the journal, which is full of in-depth and clinically relevant information important for neurology practitioners. Use this link in the episode notes to learn more and subscribe. AAN members, you can get CME for listening to this interview by completing the evaluation at Continpub.com/audioCME. Thank you for listening to Continuum Audio.

Full transcript available at URL to come

Traumatic spinal cord injury is a potentially devastating disorder. Best practices in clinical care for these patients has evolved, with implications for long term outcomes.

In this episode, Aaron Berkowitz, MD, PhD, FAAN, speaks with Saef Izzy, MD, author of the article "Traumatic Spinal Cord Injury," in the Continuum February 2024 Spinal Cord Disorders issue.

Dr. Berkowitz is a Continuum® Audio interviewer and a professor of clinical neurology at the University of California, San Francisco

Dr. Izzy is an assistant professor of neurology at Harvard Medical School and an associate neurologist in the Department of Neurology, Divisions of Neurocritical Care and Cerebrovascular Diseases at Brigham and Women's Hospital in Boston, Massachusetts.

Additional Resources

Read the article: Traumatic Spinal Cord Injury

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

American Academy of Neurology website: aan.com

Social Media

facebook.com/continuumcme

@ContinuumAAN

Host: @AaronLBerkowitz

Guest: @SaefIzzy

Full transcript available here

Dr Jones: This is Dr. Lyell Jones, editor-in-chief of Continuum, the premier topic-based neurology clinical review and CME journal from the American Academy of Neurology. Thank you for joining us on Continuum Audio, a companion podcast 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 Berkowitz: This is Dr. Aaron Berkowitz. Today, I'm interviewing Dr. Saef Izzy about his article on traumatic spinal cord disorders from the February 2024 Continuum issue on spinal cord disorders. Dr. Izzy is an Assistant Professor of Neurology at Harvard Medical School and an associate neurologist at Brigham and Women's Hospital in Boston, Massachusetts. Welcome to the podcast, Dr. Izzy. So, let's say a patient comes to the emergency room with an acute spinal cord injury due to a car accident. Walk us through your approach. What's going through your mind when you hear this pager go off and you're walking down to the emergency room; what are you thinking?

Dr Izzy: Yeah, great question. So, one of the first question is, what's the medical status of the patient? And, starting from, "How sick is the patient? (looking at the ABCD - basically, airway, breathing, circulation), make sure the patient is stable from that perspective, with the specific focus then going to be the injury level and the injury severity. And with that, once the patient is clinically stable, we try to pay very close attention to that aspect, especially since we know the patient is coming with a spinal cord injury from the prefield assessment. So, having a very close assessment to the spinal cord using a standardized tool (such as the ASIA, which is the American Spinal Injury Association Impairment Scale) will be very helpful to communicate the level of injury to the rest of the team, which usually is going to be a multidisciplinary team approach from the emergency room into neurosurgery, neurology and other disciplines where we'll be involved. So, having a standardized tool will be a key. ASIA, as a scale - it starts with a letter "A" - and to be A when there is a complete injury, with loss of motor and sensory, and E is basically normal exam (a neuro exam with normal motor and sensory examination). And between B to D, they have some preserved voluntary anal contraction and some of the reflexes, such as the bulbocavernosus reflexes, with a various degree of motor and sensory. Having an early introduction into this scale will be super helpful to communicate with other services. Then will be the decision about who I should image, and also, whether I should clear the C-collar or not. And this is also another sort of decision making, comes into the patient mental status, the injury severity, the level of injury, as well as ability to perform a reliable neurological examination - all plays a role into this decision. In this article, we have elaborated on the clinical decision making - an approach in the acute setting - and we provided, in Figure 1, a comprehensive approach about patient we should think about imaging and what modality of imaging, as well.

Dr Berkowitz: Perfect, that's so helpful. So, you're thinking through the ABCDs, as you mentioned. And then a detailed neurologic exam to get a sense of the degree of injury. And then you mentioned the decisions about imaging. Tell us a little bit about how you think about who to image, what to image, how to image, after you've done your neurologic exam.

Dr Izzy: So, the imaging in general, as we know, that previously used to be an x-ray. But the recent literature really focus on utilizing the utility of high-quality CAT scans as it's provide more comprehensive characterization of vertebral fractures. And that will be very helpful to identify the level and severity of radiographic injury. However, MRI will always be superior, as it also provides the extent of the cord compression, signs of cord injury, as well as could help us rule out ligamentous injury within, especially, the first 48 hours post the event. In addition to that, we have to pay attention to a patient at risk of having vascular injuries, as many spinal cord, especially the cervical and skull-based injuries, can associate with blunt cerebrovascular injuries, which often missed in the emergency room, and even in the acute stay, as no one would have thought about that aspect. That's why, in this article, we have highlighted the role of Memphis criteria, which is a very valuable tool to identify patients at risk to be scanned. And also the Biffl Scale, which used to be known at the Denver, and modified Denver Scale, to assist classifying the level of vascular injury.

Dr Berkowitz: Great. So, I want to pick up on a number of the things you mentioned there. So, let's talk about injury to the bony structures that could result in impingement on neurologic structures, such as the nerve roots or cord or cauda equina. So, Often, neurology and neurosurgery are consulted together in these patients, right? And both arrive at the bedside in the emergency room. Tell us a little bit about working with our neurosurgical colleagues to figure out who should go for surgery, what type of surgery they should go for, and the neurologist's role in helping in that decision making.

Dr Izzy: I believe the neurologists have a significant role in the acute setting, especially with performing a very thorough, refined neurological examination when it comes into assessing the cranial nerve, because often traumatic spinal cord injury could associate with traumatic head injury. In addition to that, perform a very thorough motor and sensory exam, with a specific look into reflexes, as well as anal reflexes. And documenting that, in conjuncture with the neurosurgery colleague, will be super helpful. We have to know that doing neurological assessment, or also relying on them, the ASIA scale is a key, but also could be confounded in the acute setting with other multisystemic events, including respiratory failure, using some pain medication, traumatic brain injury, hypotension, which all could confound the initial exam. That's why having a repeated exam for this patient throughout the hospital stay will be a key, especially when we are using some of these examination in the acute setting to guide our prognostication. Also, when it comes into the neurological assessment, looking into, not only the level of injury, but paying attention into the levels below. And documenting this exam is also a very critical aspect of assessment. One of the early decisions we share - many times when we, as neurologists, get consulted on these patients who should go to surgery, and that's a whole topic by itself discussed thoroughly in this article about the literature on a patient who should basically pursue surgery. And, one of the main highlight of the literature that, pursuing surgery in less than 24 hours has been associated with improved outcomes. Yet the literature on that still need further evaluation, especially now the most common practice that patients with worsening exam, mass effect, and epidural mass takes priority. But further studies on this area definitely require further exploration.

Dr Berkowitz: Another aspect you mentioned is blunt cerebrovascular injury - so, injury to the carotid or vertebral arteries in the neck or in the skull base. So, are CT angiograms part of the standard neuroimaging now for patients with spine injury, or on a case-by-case basis, or perhaps should they be?

Dr Izzy: Great question. It's not. That's why paying specific attention for a patient at risk, and that's where the Memphis screening protocol takes place. And we encourage our colleagues from neurology and neurosurgery, as well as emergency department, to try to keep this sort of screening, helpful protocol handy when approach traumatic spinal cord injury. More specifically patients, who have basilar skull fracture with involvement of the carotid canal; the one with a basilar fracture with involvement of the petrous bone; the cervical spine fracture with neurological exam that doesn't necessarily explained by imaging; having a Horner syndrome on neurological exam; fractures pattern involve LeFort II or III fractures; as well as neck soft injury; the seatbelt sign - these are all signs that could really raise the red flag that there is a possible underlying vascular injury that require evaluation by CT angiogram in the emergency room to further identify. Once we identify the vascular injury, there is another helpful and valuable score, which is the Biffl Scale, or the - what also well known to be Denver or the modified Denver. And that one will further characterize the injury from level 1 to 5, 1 involving the luminal irregularity and dissection with less than 25% luminal narrowing - that's the 1. And 2, more than 25% narrowing. The 1 and 2 carries different prognostication and management, because these two we can always think about starting antiplatelet or anticoagulation on the first two, while 3 is aneurysm or pseudoaneurysm in the artery, while 4 is occlusion or thrombosis, and 5, usually transection of the vessel, the free extravasation. Grade 3 and above, usually, medical treatment has not much of a big role and discussion with the vascular neurosurgery or neuroendovascular colleague will be super helpful.

Dr Berkowitz: You started alluding to the next question I was going to ask you related to these. As neurologists are often consulted when there's vascular injury, traumatic vascular injury, about the questions of the risks and benefits of starting antiplatelets or anticoagulation. You mentioned that, in extreme cases - obviously if the vessel is transected or there's extravasation - there'll probably be great danger in starting those types of agents. But often we're consulted for the lower grades, such as a dissection or a luminal irregularity. And the question comes up, what is the extent of the benefit of antiplatelet and anticoagulation when balanced with the risk? – that these are often patients with polytrauma, not just affecting the nervous system, but often systemic organs as well. How do you balance the risk and benefit of treating these traumatic vascular injuries with antiplatelets or anticoagulation, to wanting to reduce the stroke risk related to these, on the one hand, and taking into account the extensive injuries that often accompany these?

Dr Izzy: Yeah, absolutely. Very clinical relevant question. The short answer: there is no randomized clinical trials that compared antiplatelet therapy with anticoagulation, whether it's unfractionated or low-molecular-weight heparin, for the treatment of blunt cerebrovascular injury- not even compare the timing to start. That's why it comes into the clinical judgment when it comes to answer this question. As far as level of injury defined by Biffl Scale, Grade 1 and 2, when there is a dissection less than or more than 25%, it's reasonable to start either or. And that comes into the context of the patient. In general, most of these patient comes with other multisystemic event. Could be having a traumatic brain injury with contusion, and the size of the contusion maybe also play a role in this decision where there is risk of contusion expansion or bleeding in other parts of the body, which makes anticoagulation very critical and dangerous with these patients. Maybe starting aspirin could be reasonable and safe, as that comes into a multidisciplinary discussion with our colleague from neurosurgery, ortho (if they are involved), as well as the primary ICU team. Having a thorough discussion about the pros and cons of this decision is a key. Most specifically, it's about balancing the risks and benefits in management. When it comes into high grade (3 and above) involving pseudoaneurysm, we know that antiplatelet or anticoagulation might play a lesser role; might be beneficial to some extent (not very well studied in this cohort of patients). But having a discussion when it comes into vascular malformation involving arteriovenous fistula or near occlusion of a vessel with our neuroendovascular colleague and vascular neurosurgeon will be always a key. Just one more point to make - that if it's too risky to start in the acute setting because of other multisystemic involvement, having a repeat imaging in a few days might be also helpful in assessing the progression of the vascular injury - could also be helpful from that setting. If the patient start developing new neurological symptoms, rather than just blaming it on the cervical or thoracic spine, thinking about new-onset strokes that happen would be a key to elaborate there, as we know the duration - for how long. If we end up starting patients on anticoagulation, or antiplatelets such as aspirin, for how long we should keep it for? It's still controversial, but the common approach is to start when it's safe from clinical standpoint and consider keeping it for three to six months. And repeat follow up imaging in the outpatient setting to assess that vascular injury and determine the duration of treatment will also be a key.

Dr Berkowitz: Shifting gears again here - you're involved in the acute setting here, diagnosing and managing these patients, often otherwise healthy patients who've suffered a devastating accident. How do you begin the conversation about communicating the prognosis, often probably the first question from the patient's family, "Are they going to walk again?" Obviously, a lot of factors go into this and it can be hard to prognosticate from the first moments of injury. But how do you begin to have that conversation when that question is asked for the first time, often in the emergency room?

Dr Izzy: As a neural intensivist, commonly involved in the acute management of traumatic spinal cord injury patients, we try to focus on the acute management of patient, try to inform families that it's too early to provide an accurate prognostication of the long-term outcome. Especially, that the acute course of the disease could associate with so many other clinically relevant variables that could have an impact on the long-term outcome, such as respiratory failure, hypotension, in terms of neurogenic or spinal shock, in addition to rate of infections. In such acute, early, or superacute stage of the disease, there's still not much known about the correlation with the very-long-term outcomes. As I mentioned earlier, even the very first ASIA scale, the first neurological assessment could be easily confounded by many of these factors. Once we address the hypotension, treat the infection, or even try to control the respiratory failure, we have seen that might improve the neurological assessment - could be in the acute setting. That's why we try to provide the families with the clinical status of the patient and postpone any discussion on neuroprognostication until the patient in a stable clinical state and when we have a better assessment of the neurological and hemodynamic state.

Dr Berkowitz: Tell us now, in closing, what does the future hold for the treatment of these patients with acute spinal cord injury?

Dr Izzy: Despite all the unknowns about the course of the disease, when it comes into the long-term outcomes and the increasing rate of early and delayed mortality in this disease and poor outcome, there are many ongoing attempts to test various pharmacological and nonpharmacological interventions to achieve neuroprotection and enhanced functional outcome after traumatic spinal cord injury. There are many promising attempts for transplantation of neuronal embryonic mesenteric stem cells, as well as oligodendrocyte precursor cells. Two or three clinical trials now ongoing, trying to assess the benefit for long-term outcome. The future is still optimistic that some of these initiatives might eventually transition to the bedside application and potentially leading to significant improvement in the long-term outcomes of our patient. However, many of these initiatives are still investigational but carries the hope. Our role as a clinical team - always satisfying taking care of traumatic spinal cord injury patients and their family and guide them through the journey to recovery.

Dr Berkowitz: Dr. Izzy, thanks so much for taking the time to speak with us today. I encourage all of our listeners to read your phenomenal article. We could only scratch the surface today in our discussion on this very complicated, challenging area of neurologic practice, but your article lays out a lot of very helpful, practical clinical elements in the diagnosis, treatment, and prognostication in patients with spinal cord injury.

Dr Izzy: Absolutely. My pleasure.

Dr Berkowitz:  Again, for our listeners, I've been interviewing Dr. Saef Izzy, whose article on traumatic spinal cord disorders appears in the most recent issue of Continuum on spinal cord disorders. Be sure to check out other Continuum Audio episodes from this and other issues. And thank you to our listeners for joining today.

Dr Monteith: This is Dr. Teshamae Monteith, Associate Editor of Continuum Audio. If you've enjoyed this episode, 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 article. Thank you for listening to Continuum Audio.

The spinal cord is a fragile network containing hundreds of millions of neurons, all passing through a conduit about the size of a dime. A consistent, organized approach to the diagnosis of spinal cord disease is necessary to give patients the best possible care.

In this episode, Teshamae Monteith, MD, FAAN, speaks with Carlos Pardo, MD, author of the article "Clinical Approach to Myelopathy Diagnosis," 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. Pardo is a professor of neurology and pathology at Johns Hopkins University School of Medicine and director of the Johns Hopkins Myelitis and Myelopathy Center in Baltimore, Maryland.

Additional Resources

Read the article: Clinical Approach to Myelopathy Diagnosis

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Host: @headacheMD

Transcript

Full Transcript Available Here

Dr Jones: This is Dr. Lyell Jones, Editor-in-Chief of Continuum, the premier topic-based neurology clinical review and CME journal, from the American Academy of Neurology. Thank you for joining us on Continuum Audio, a companion podcast 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 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 Carlos Pardo about his article on an Integrative Clinical Approach to Myelopathy Diagnosis, which is found in the February 2024 Continuum issue on spinal cord disorders. Dr Pardo is a professor of neurology and pathology at Johns Hopkins University School of Medicine in Baltimore, Maryland. Welcome to the podcast. Carlos, thank you so much for this wonderful article. I think it was great!

Dr Pardo: Thank you very much for the invitation and, particularly, to continue to write about myelitis and myelopathy - that is one of my passions in my activities as a clinical neurologist. And I think that this is basically one of the areas in which I thought, after finishing my residency training here, to focus, because there was absolutely no good understanding of the biology, clinical profile – particularly, understanding of the pathophysiology of myelitis and myelopathies, and what was called (at that time) transverse myelitis. So, that is what I have spent the past 25 years is try to understand that concept and apply what I was trained, as a neurologist and neuropathologist, to be translated in the clinical practice.

Dr Monteith: Great. Well, I definitely want to know - how did you get into this area?

Dr Pardo: That's a very nice question.

Dr Monteith: I'm going to give you an easy one.

Dr Pardo: I was trained as a clinical neurologist, but at the same time was trained as a clinical and experimental neuropathologist. When I finished my residency training, along with some of my co-residents and colleagues in my residency training, we took the challenge to take a neurological disorder that was called at that time transverse myelitis, to investigate diagnosis, clinical neurology of those patients, and investigate the etiological factors contributing to that. Very soon, we discovered that that group of patients that we call transverse myelitis was a very heterogeneous group of patients. And that basically put us in the situation to expand our approach to investigate what were those etiological factors contributing to those pathologies that we call, at that time, transverse myelitis. Since then, we have been focused on that. We have been focusing on characterizing patients with inflammatory myelopathies, with vascular myelopathies, with patients with infection disorders associated myelopathies. That is one of the main messages of the paper, and is - we need to think in a very etiological approach, because the variety of etiological factors that may contribute to spinal cord disorders is quite broad - it's very extensive. We need to be extremely careful when we approach those patients. There are very common myelopathies, there are very rare myelopathies. So, obviously, we always look for the commonalities and common pathologies, but we shouldn't basically forget about those myelopathies that may be rare but are present. I will say, frequently, we ignore the possibility of metabolic-associated myelopathies because we don't see those too much. But after we do an analysis of that equation - the clinical profile, temporal evolution, lesion topography, and biomarkers in imaging, blood, spinal fluid - and we don't find a clear explanation, we need to stop a little bit and think more about other things that we are missing. And frequently, metabolical disorders of the spinal cord are missed, or other type of pathology. That the reason the clinician need to have open mind and, occasionally, need to think out of the box, particularly when there is no clear answer to the search for etiological factors.

Dr Monteith: I mean, when we think about spinal cord lesions, they can obviously be devastating because they affect patient's ability to ambulate. Why don't you tell us the most important takeaways from your article?

Dr Pardo: Yeah, so this is a very important aspect of the article. The first thing is, if we are going to treat the patient, if we are going to focus in the management of a clinical problem, we need to understand first, what is the clinical diagnosis? What is the cause of the problem? Importantly, what is the etiology or the etiological factors contributing to that problem? The first thing that I always emphasize is, we are not able to treat a patient with a neurological condition if we don't have a very precise diagnosis, regardless what we are investigating in that patient. Specifically, for spinal cord disorders, there is a multitude of etiologies and pathogenic factors and other causes of the disease that may be involved. For that reason, the clinician, the health care provider, need to be aware about how to approach that question; is, we need to answer first the cause and the profile of the spinal cord disorder. And when we need to answer the cause, we need to focus first in evaluating clearly what has been the evolution of the symptoms, how is the neurological exam, how the evolution of the symptoms are going to help us to identify those etiological factors that we are looking for. For that reason, in the approach that I am suggesting to take in patient with the spinal cord disorder, the first critical element of that approach is to sit down and talk very well with the patient about what is going on - what are the main symptoms that are present, what has been the temporal evolution of those symptoms, and what has been basically the pattern of progression of those symptoms - because those are the clinical elements that will facilitate the clinician a much better understanding for the clinical diagnosis. Evaluating the clinical profile of symptoms and evaluating the temporal profile of symptoms is probably the first step for solving that critical equation about the diagnosis of spinal cord disorders. The main target is to establish a diagnosis.

Dr Monteith: And that's really the bread and butter of neurology, because we have a global audience and we have some neurologists that practice in areas with very limited resources. But you do speak of some very cool things that I want to also touch on, such as precision medicine, the advances in biomarker development and neuroimaging, as well as investigating different viral etiologies in the pathology of spinal cord disease. So, can you just speak to some of that? You've been in this field now - you said, 25 years - how that evolution has helped you better treat patients.

Dr Pardo: That's a very important question, because in 25 years we have learned tons about myelopathies, myelitis, and noninflammatory myelopathies - and it's quite amazing. I think that one of the most important aspects of spinal cord disorders is that, in the past 25 years, we have learned about mechanism of the disease in spinal cord disorders. Back in the 20th century we used the term transverse myelitis, and one of the main messages that I have for the clinicians who are reading the article is, please stop using that terminology. We have now capability to establish a more precise diagnosis, a more etiologically oriented diagnosis. If you can take a look at what happened in the past 25 years, understanding spinal cord disorders is quite amazing. We have a better understanding of the immunological factors that contribute to myelopathies. We are able to diagnose myelopathies associated with aquaporin 4 disorders, or MOG-associated disorders, or demyelinating diseases, or infectious disorders. So, in the past 25 years, with a combination of different tools in laboratory studies, studies of spinal fluid analysis, studies of the blood, we have basically able to identify biological markers that may guide us to treat more precisely those patients that are suffering from immune-related disorders. In the same way, imaging has contributed dramatically to improve our understanding of myelopathy. We are able to use neuroimaging studies to differentiate in better way, what are the myelopathies that are associated with vascular etiology, versus myelopathies that are associated with inflammatory etiology. In other words, the 25 years have provided all set of tools (assays, imaging techniques) that allow us to establish a better and precise diagnosis that facilitate etiological diagnosis. And in that way, we avoid the use of the term, transverse myelitis, that I frequently say is a basket diagnosis that is not taking us anywhere, because we are not using properly the etiological diagnostic approach.

Dr Monteith: In the setting of all of this evolution, what do you still find challenging, and as well, rewarding in treating these types of patients?

Dr Pardo: The best reward that we obtain when we establish this type of diagnosis is that we are able to facilitate better recovery, we are able to identify the factors associated with the problem, and eventually, to target, in a better way, those factors that are contributing to the problem and identify potential avenues for full recovery of the spinal cord. If we are dealing, for example, with patients with suspected inflammatory myelopathies, and we are able to identify an antibody that is contributing to that inflammatory myelopathy - like in the case of neuromyelitis optica - I think that the reward is that we are going to avoid a very long process that is going to decrease our ability to rescue that spinal cord and facilitate improvement of that patient. If we identify a vascular myelopathy and we are able to establish promptly a precise diagnosis of a stroke of the spinal cord, that will avoid that the patient goes in a very long road of treatments that even may be more harmful for that patient. And in that way, we are able to contribute the recovery and facilitate improvement of those patients with vascular spinal cord disorders. This is the reward: the reward is that we are able to facilitate a much better recovery of those patients and, in that way, to improve outcomes in those patients that are suffering myelopathies.

Dr Monteith: What's been some of the more surprising cases in your practice, in terms of patient presentations, surprise recoveries, or whatever?

Dr Pardo: One of the best rewards that we have seen in our research (clinical research) in the past several years is to be able to provide a much better framework for evaluating patients. The other aspect is to be able to identify patients that have very specific pathologies, like strokes of the spinal cord - ischemic pathology of the spinal cord that may be acute ischemic pathology or even chronic evolving pathology. In that way, actually, we have been able to establish much better protocol for assessment of those patients. That is actually one of the major aspects of our progression in terms of understanding the spinal cord disorders. And that is the reason - once again, I emphasize that when we use the term transverse myelitis and we erroneously diagnose patients with transverse myelitis when they are experiencing vascular pathologies of the spinal cord, we are basically not serving well those patients. That is one of the emphasis that I always include in the manuscript is, it is much better to spend time establishing a diagnosis (etiological diagnosis) rather than treating empirically diagnosis that probably are not going to be very well served by using treatments that probably are not going to benefit the patient. For example, when we deal with patients that have vascular myelopathies associated with chronic venous abnormalities, like happen in dural arteriovenous fistula, we are deserting those patients by treating them with IV methylprednisolone or treating them with IVIG, or treating them with immunosuppressive treatments. This is a critical element of the precision approach to establish a better diagnosis in patients with myelopathy.

Dr Monteith: And then, your article spoke a little bit about recent outbreaks of infectious etiologies - viral etiologies. Can you talk a little bit about that? Because sometimes we send off these tests and they come back nonspecific or negative, and we have a sense that this was an infectious process. Maybe there was a prodromal phase, or something like that. Can you speak about your excitement in the area of advances in these methodologies?

Dr Pardo: Yeah - this is an important aspect of the clinical conversation. Our patients may provide initial clues for identification of potential risk factors, such as infections, as etiological factors contributing to spinal cord disorder. When you are discussing with patients about specific symptoms that emerge after they have experienced either illnesses or systemic symptoms (like fever, chills, rash, or anything that look like an infection disorder) it's extremely important for the clinician to try to characterize that in much better way so we can use those elements of the investigation to determine if infection disorders may be involved as etiological factors in those myelopathies. We were trained to think about transverse myelitis as either an immunological-mediated disorder or an infection-mediated disorder. That's the reason I think that the clinician need to be open-minded when he's interviewing the patients to acquire, as much as possible, elements of the clinical history that may focus  or avoid that the clinician pay too much attention to things that are not involved as etiological factor. Infection disorders frequently may produce neurological problems, and, obviously, spinal cord inflammation is one of those neurological problems. However, it's very important that the clinician be critical in the assessment of those potential risk factors. I frequently discuss with the students and residents in our ward that it's okay to think about West Nile myelitis when we are in the summer, but we are not able to discuss specifically about West Nile myelitis in middle of the winter, and particularly because those are etiological factors that are associated with seasonality and those are etiological factors that are associated with some risk factors that include, for example, mosquito transmission of a virus. When we talk about acute flaccid myelitis with our pediatric patient population, we need to think about circulation of viruses, and we need to think about if that is the right period of circulation of the virus that we are suspicious that is producing that spinal cord disorder. Again, the clinician need to be aware about the particularities of some infection disorder - seasonality, modes of transmission - to think about what is going on in terms of etiological factors, particularly infections, as part of causes of spinal cord inflammation.

Dr Monteith: Let's talk a little bit about some controversies - things that maybe lead to overdiagnosis or underdiagnosis.

Dr Pardo: It's a very good question, and I appreciate the controversy, always. One thing that is going back to the basis of the article is the precise diagnosis is strictly dependent of equation that involves different factors. We are not able to diagnose spinal cord disorders just using one factor of that equation. This is something that is extremely important for the clinician and health care provider. We are not able to establish a precise diagnosis just when we use only neuroimaging studies. We need to bring the clinical profile of that patient, the neurological examination, the neuroimaging studies, the spinal fluid analysis to the same equation. That is one of the controversies, because in the past, we relied heavily on neuroimaging studies for establishing a diagnosis of myelopathies. But I believe that has been a little bit of a mistake because we have been ignoring major elements of the clinical history and neurological examination. And probably the best example of that is the example of spinal cord strokes. When patients show up in the emergency department with acute onset of weakness and sensory problems, and an MRI show a lesion in the spinal cord, that is not automatically a myelitis. That is an acute spinal cord disorder in which the clinician has the responsibility to establish the precise diagnosis. This is one of the major messages that I want to give to our colleagues in the clinical setting is, we need to interview the patient; we need to characterize the clinical profile and make sure that what we see in the spinal cord MRI fits the clinical profile, the neurological examination, and even the spinal fluid analysis of that patient. One of the controversies that we have frequently is to diagnose patients with spinal cord strokes, because there is no gold standard for those diagnosis, unfortunately. It's a diagnosis that is comprised by several layers of assessment. In that way, we need to reach, basically, a consensus how to deal with those patients and how to manage those patients correctly.

Dr Monteith: So, of course, we have a broad, I guess, "background" of listeners - from residents, medical students, even lay audience, as well as, of course, from neurologists. But why should a resident go into spinal cord disease as a subspecialty?

Dr Pardo: It's a very important aspect of the central nervous system function. I always equate the spinal cord as the major avenue for the neurological function in the human body. If there is a very good connectivity in our brain and brain hemispheres, that connectivity is not going to be effective if there is not a healthy and very good function in the spinal cord. The spinal cord is the best avenue for execution of many of the function of the central nervous system. And in that way, a clinician who is working in neurology need to be aware about the spinal cord - need to be aware about the pathophysiology of the spinal cord. Because even if there is not any element of cognitive function in the spinal cord, we have all of the major avenues that facilitate the human function in the spinal cord - motor function, autonomical function, sensory function – so, most of the central nervous system function needs to go through the spinal cord. And the clinician (neurologists and residents) need to be aware - fully aware - about how to approach disorders of the spinal cord, how to identify correctly disorders of the spinal cord, and how to evaluate and treat those disorders.

Dr Monteith: Well, thank you - I really appreciate this talk. I really appreciate your article. It was very thorough, including "the bread and the butter," the approach to a patient clinically, but also all the new innovation in your field and all of the excitement. And of course, your story, too. So, thank you so much.

Dr Pardo: Thank you, Tesha, for inviting me to this interview, and I hope that at least the main message is very well taken. Remember, the main goal of my proposal in this article: number one, is to get rid of the diagnosis of transverse myelitis; number two, that the clinician and health care providers establish a better etiological diagnosis that facilitate better recovery of patients, better management, and better outcomes in patients with spinal cord disorders.

Dr Monteith: Thank you, Dr Pardo for joining me on Continuum Audio. Again, today we've been interviewing Dr Carlos Pardo, whose article on an integrative clinical approach to myelopathy diagnosis appears in the most recent issue of Continuum on Spinal Cord Disorders. 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 the episode notes and complete the evaluation to get CME for this episode. Thank you for listening to Continuum Audio. 

Spinal cord disorders are common and frequently disabling. Despite advances in our ability to diagnose and treat patients with spinal cord disease, many are underserved by their health care systems due to gaps in knowledge and care.

In this episode, Lyell K. Jones Jr, MD, FAAN, speaks with Shamik Bhattacharyya, MD, FAAN, who served as the guest editor of the Continuum® February 2024 Spinal Cord Disorders issue. They provide a preview of the issue, which publishes on February 8, 2024.

Dr. Jones is the editor-in-chief of Continuum: Lifelong Learning in Neurology® and is a professor of neurology at Mayo Clinic in Rochester, Minnesota.

Dr. Bhattacharyya is the Anne M. Finucane Distinguished Chair in Neurology and chief of the division of spinal cord disorders at Brigham Women's Hospital and an assistant professor of neurology at Harvard Medical School in Boston, Massachusetts.

Additional Resources

Continuum website: ContinuumJournal.com

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American Academy of Neurology website: aan.com

Social Media

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@ContinuumAAN

Host: @LyellJ

Guest: @shamik_b

Full transcript available here

Transcript 

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.

Dr Jones: This is Dr. Lyell Jones, Editor-in-Chief of Continuum: Lifelong Learning in Neurology. Today I'm interviewing Dr. Shamik Bhattacharyya, who recently served as Continuum's Guest Editor for our latest issue, on spinal cord disorders. Dr. Bhattacharyya is a neurologist at Brigham and Women's Hospital, where he serves as Chief of the Division of Spinal Cord Disorders and as an Assistant Professor of Neurology at Harvard Medical School, in Boston, Massachusetts. Dr.  Bhattacharyya, it's great to see you - welcome. Thank you for joining us today.

Dr Bhattacharyya: Good to see you, Dr. Jones. I look forward to speaking.

Dr Jones: So, for our listeners who are new to Continuum, Continuum is a journal dedicated to helping clinicians deliver the highest neurologic care to their patients. We do so with high-quality clinical reviews and content in our journal and in our audio format. For our long-time listeners to Continuum Audio, you'll notice a few different things with our latest issue and our latest author interviews. For many years, Continuum Audio has been a great way to learn about Continuum articles. Starting with this issue on spinal cord disorders, I'm happy to announce that our Continuum Audio interviews will now be available to all on your favorite open podcast platforms. We'll hear some exciting new content in our interviews, and we're also going to introduce interviews with our guest editors, like Dr Bhattacharyya, who are really indispensable in putting these issues together. In this issue, specifically, Dr. Bhattacharyya is full of extremely helpful clinical descriptions and treatment strategies for patients with spinal cord disorders. As the editor, you got really a broad view of the whole range of spinal cord disease. What was the most surprising thing when you were reviewing these articles?

Dr Bhattacharyya: I think as a field, neurology - the knowledge base in neurology - grows bigger and bigger and bigger each day and in fields hard to keep up and how to integrate all of it together, right? I think all of us deal with it. And that's the hope of Continuum, is that you can provide these periodic refreshers. I got refreshed myself! Even though I see the patients day in and day out, when you actually read about the advances, for example, in hereditary spastic paraplegias, or the nuances of how neoplasms in the spinal cord are now classified- you say "wow", I didn't actually know that. The knowledge spreads and grows, and I think that's the beauty of being an editor of some of these issues - is that you get to learn yourself and maybe perhaps even apply them in the clinical situation.

Dr Jones: You and I are both educators. And that's, I think, one of the secret joys of teaching is that you end up learning a lot, sometimes from the people you're teaching, right? I guess maybe that's not a surprise - that you learn something by reading it. I guess it was probably pretty nice, huh?

Dr Bhattacharyya: It was very good. I think the authors all come from different geographic backgrounds, even from different training backgrounds. In spinal cord disorders, there are trials in some aspects, but in other aspects it's really opinion-based practice, right? So, it was good to also see how other institutions do it. And I imagine it's the same for readers when they see how they do it at their institution and also get a viewpoint of how it's done at other places. That's the valuable perspective piece for putting together a different of authors and see how people do it at different places.

Dr Jones: Always nice to learn from others. And speaking of learning - for our clinicians who are listening to our interview today, Shamik, tell us a little bit about the basics of how spinal cord disorders present. I know as an educator, sometimes for, especially junior learners, it's a little mysterious and I'm not really sure why that is, but what are some of the basic clinical tenets of how spinal cord disorders present?

Dr Bhattacharyya: I'm glad you brought this up, because in some ways, spinal cord is the orphan child of neurology, right? I think for most neurology trainees, the nervous system stops at the brainstem and then progresses again at the nerves. The spinal cord is really just viewed as this conduit of tracts up and down, and that's all it does is a big set of wires, which is not true, right? A lot of primary neurological processing happens at the level of the spinal cord, and it really is a continuation of the central nervous system. And I hope, with this issue, people get a sense of that. For spinal cord disorders (also called myelopathy; the name goes, synonymously, hand in hand), I think one of the principal functions of the spinal cord is balance. A lot of the program - the neural programming of balance on postural reflexes are hard wired into the spinal cord. I think one of the key aspects of spinal cord disorders is imbalance. I think that people should think of this as a core feature of myelopathy. If you take an example for cervical spondylotic disease, people think, is it going to be off your hands? Well, I think most patients with cervical spondylotic myelopathy actually complain of gait imbalance as one of the early features of the disease. So, imbalance, bilateral weakness, and/or bilateral numbness, tingling, paresthesia - those aspects are suggestive of spinal cord disorder. Bowel and bladder dysfunction can be, but it's not universally true. Now, there's some specific symptoms that I think are especially suggestive of spinal cord disorders I think that are kind of fun to ask about, and if true, can help you localize. One is the Lhermitte sign; you ask people to flex their neck and say, like, "Do you feel sharp, shooting thing, like, down your hands or your back?" In your legs? If true, you have something, right? That's a spinal cord disorder. The other sign that I think is clinically helpful is weakness on one leg and numbness on the other, like Brown-Séquard syndrome or hemicord syndrome. If you find that to be true - and you often see that with multiple sclerosis lesions or other traumatic lesions - that is a spinal cord disorder. I think those clues can come out in history and on exam, and can help you localize it better.

Dr Jones: It's nice to know those specific features - in other words, those things that, when you do see or hear them, really should make us think about spinal cord disorders, right? Again, they might not be the most common way they present, but it's good to have those in your pocket, right?

Dr Bhattacharyya: Right.

Dr Jones: You mentioned this - spinal cord pathology occupies kind of an interesting place in the neurological world, right? There really aren't "myelopathists," but you direct a division on spinal cord disorders, which is - I think is pretty uncommon. Tell us a little about that. How does that work at your institution?

Dr Bhattacharyya: Maybe I can start with the history of this, right - of how this actually came about. I was graduating as a fellow and entering as a faculty in our neurology department. Initially, my interest was in autoimmune neurological disorder - it still is in autoimmune neurological disorders. And yet, when they saw patients who came in for myelitis and turned out they didn't have an inflammatory myelopathy, there really was no home for them, right? - it's a strange space. And that includes even for garden-variety, cervical spondylotic disease that's causing myelopathy - there is no good neurology home for those patients. After the first year of seeing patients, I felt that we need to do better for that. That's why we ended up opening the spinal cord disorders clinic, which was actually the only neurology-based one in our system. There are plenty run by physiatry, surgery, pain management, and other services. But the only neurology one in our system focused specifically on neurologic management of patients with any type of spinal cord pathology.

Dr Jones: That's a distinctive way that it came about at your institution and in your own career. It sounds like this does need to be a team effort. Who are the other disciplines or specialists who need to be involved in the care of these patients?

Dr Bhattacharyya:  Our spinal cord clinic itself is a part of the comprehensive spine center in our hospital. In that center are pain management doctors, physiatry, as well as different spine specialties, including orthopedics and neurosurgeons and interventional radiologists. So, it's kind of a multidisciplinary group effort to take care of these patients.

Dr Jones: I know it'll vary according to the problem with the spinal cord, right? There's dozens or hundreds of different diseases that can affect the spinal cord. So, treatments are different for different diseases, right? But what do you see, therapeutically, as being some of the next big things on the horizon for patients with spinal cord disease?

Dr Bhattacharyya: I think one of the common, unifying aspects is pain from spinal cord injury. Especially if there's interruption in the spinothalamic tracts, the pain can be a very severe thing that ranges all the way from neuromyelitis optica, the tonic spasms, to spinal cord infarcts, chronic sequelae of pain, to trauma (spinal cord trauma) - pain is such a big aspect. And our both interventional and oral neuropathic pain medicines don't do a good job with it. I think there's a wave of new medications that are in trials for neuropathic pain and I'm hopeful that they will be helpful and that they will improve pain control and quality of life for our patients. The medication approaches to pain also come with side effects that all of the medicines have. Some of our patients are on high doses of multiple medicines and have cognitive impairment, right? I think that was also the motivation behind our getting a specific section in this issue on symptomatic management of spinal cord injury. Because I think no matter where you are in the spectrum of spinal cord disorders, whether you're a vascular doctor or a family doctor, you will be prescribing gabapentin and baclofen, right - as for helping the patient, and it's good to know how to do it. The other aspect that I'm really hopeful about are sort of second-generation prosthetic devices. These are some of the electrostimulation devices where there's intelligence built into the device that detects you moving your leg and then artificially stimulates a peroneal nerve. This is much better than foot braces, for example, for foot drops. And there are now multiple companies who make these devices, and for some of our patients who have had spinal cord disorders and had difficulty walking or tripping, these have actually made a big difference. I think prosthetic and electric stimulation also has potential of helping a broad range of patients with spinal cord disorders.

Dr Jones: And I'm glad you mentioned that article on the symptomatic management of the problems with spinal cord disease, regardless of the cause. And it's a wonderful article that will encourage our listeners to seek out. To go back to the pain, this is something that - many of us who care for patients with spinal cord problems - we encounter is this. And I think it's underrecognized (the pain complications of spinal cord disease). Medications on the horizon - what about devices and neuromodulation? This is another thing I get asked about a lot.

Dr Bhattacharyya: Exactly. I think the - for example, spinal cord stimulators for pain management - I think it's been controversial in the sense of who are the best people for it. The history of neuromodulation in spinal pain in some senses has been unfortunate because it was first approved for so-called "failed back syndrome," right? And the name is terrible. The patient population is heterogeneous. And it has come to a point where it was unclear who it was helping and what the right indications were. I think for neuropathic pain and, in particular, for spinal cord injury pain, I think there is now a renewed push to study neuromodulation, both implantable devices and external devices, to see if those aspects can help. I think they're part of the new wave of things. I think the question patients often ask me is, "Can you regrow my spinal cord?" - right? "Is there something on the horizon yet?" As far as I know, right at this moment, there is not, that's clinically applicable, but perhaps in the future that might be true. But I think, short of regrowing the spinal cord, we can help function and help pain in meaningful ways.

Dr Jones: We'll be hopeful about cell therapies and other regenerative therapies down the road. I don't think it's in our immediate future, but we maintain hope. You know, I know this is an area that, again - spinal cord problems are common, spine disease is common - but it does kind of fall between the cracks clinically. If there were one point, Dr Bhattacharyya, that you would want to make to our listeners about the one thing not to miss, or the thing that you most commonly see being missed in the clinical evaluation and/or care of these patients, what would that one thing be?

Dr Bhattacharyya: I think the time to clinical evolution of myelopathy probably has the biggest value in determining the cause of it. I think this was beautifully brought out by the article by Dr. Pardo, where he talks about an integrative approach to myelopathy, and in contrast to prior conceptions of whether it's inflammatory based on your CSF cell count or your MRI features, it's actually based on time - time from onset of symptom to nadir of symptom. Is it a few hours, is it days, is it months, right? And having that diagnostic framework is, I think - I go back to it time and time again - is key in trying to figure out, because none of the measures we use, both on imaging or CSF or laboratories, are very sensitive or specific, and actually do not outperform just categorizing by time alone, right? So, I think the one take-home message is, if you have sudden, rapid-onset myelopathy that evolves over minutes, it's probably a vascular process. Even if you find ten cells in the CSF, it's still vascular, right? If it's something that evolves over days, maybe 7, 8, 9 days, and then you find diffusion restriction in the spinal cord on imaging, it's probably still an inflammatory process rather than a sudden spinal cord infarct, right? So, I think that the time aspect cannot be ignored and should play a central role in decision making.

Dr Jones: That's very helpful. And I think maybe the corollary to that is - there are chronic spinal cord disorders, right? And I think clinicians, especially if you're not familiar with spinal cord disease, it's terrifying, right? As soon as you start to think, "Wow, this patient's telling me a story and I'm worried this could be a spinal cord problem - should I send them to the emergency department?" - right? They have some bladder dysfunction; they have some gait disorder. But if it has been going on for years, the emergency department is probably not the best place to evaluate that, is it?

Dr Bhattacharyya: I'm glad you mentioned it because we see that in the emergency room, right? Someone clearly has a myelopathy; you asked him how long it's going on – it going for months or even years sometimes, right? And it was first noticed and sent out. So, yes - there are multiple causes of chronic myelopathies. They range all the way from structural causes, where you can have things like, for instance, webs, of arachnoid webs, that cause slow progressive myelopathies, to vascular malformations of myelopathies, to nutritional causes (even that can cause a slow, progressive myelopathy), Not to speak of infections; I think we often think of infections as causing fast myelopathies, but especially with HTLV-1-associated myelopathy, the usual clinical progression is slow and progressive. I think across all categories of disease, there are instances of slow, progressive myelopathies that really require thoughtful workup but doesn't require an emergency workup.

Dr Jones: Yeah, it's good to know that not every spinal cord problem is an emergency. I think it does terrify clinicians, right? I mean, this is the broadband connection between the brain and the body, and it's fragile, and it's unforgiving, and it's every command sent to the body - every piece of information sent back to the brain, all traveling through a billion neurons with a maximum diameter slightly larger than a dime, right? I think that's why it creates consternation. But I imagine it's also - on the clinical side - it's probably in part challenging and in part rewarding to care for these patients. When you think about what's most rewarding about the care of patients with spinal cord disorders, what comes to mind for you?

Dr Bhattacharyya: I think, a couple of aspects. And just thinking back to my last clinic - I put it on Fridays, just because I get the most joy out of this clinic, right? The first is that there's no single piece of test that gives you the answer totally, right? It's usually about putting the history together, the labs, the imaging, and talking about it together, right? And I think it's that integrated piece that, as clinicians, I think that brings us joy; it's that figuring something out, that's more than saying, "Is there diffusion restriction or not on the brain MRI?" – right? The second piece that I think is helpful is that, that patients really want to learn, and for spinal cord disorders in particular, there's easy anatomic things that you can point to patients and say, like, "This is why you are weak in the arm and maybe numb in the leg, and that's causing your problem, and this is what we're going to do about it." And I think, the ability to communicate that with the patient through images is, I think, unique in the sense that patients understand it - that this is the connection and there's something wrong here and that's why I'm having these symptoms. I think those are aspects of spinal cord disorders that I think are really neat. I will say that I also hope that, for our trainees, right, - I think their comfort with imaging stops at the brainstem, right? The moment it gets below the spine, whether looking at foraminal narrowing or canal stenosis, it's about, "Do they have a T2-hyperintense lesion or not?" And beyond that, people are hesitant. I hope that if this issue can give a different categories of spinal cord disorders, our trainees also become a little bit more facile with different aspects of spinal pathology.

Dr Jones: I think a lot of neurologists are drawn to our field because of the problem-solving nature, right? Which is what you have to do before you start helping the patient. And you clearly have a lot of enthusiasm for this - I mean, it's contagious, right? There aren't a lot of myelopathists right now, but maybe after listening to your interview, Dr Bhattacharyya, reading your issue in Continuum, maybe you've created some myelopathists.

Dr Bhattacharyya: And just remind, there's an AAN spine section that exists in the American Academy of Neurology, and it's very small and can use more members. Certainly, you're welcome to join.

Dr Jones: Well, that's a great plug and, Dr Bhattacharyya, once again, I want to thank you for joining us and thank you for such a thorough, fascinating, engaging discussion on spinal cord disorders. Thank you for guest editing a really phenomenally well-done issue that I think is going to be really informative to our readers and our listeners. Again, we've been speaking with Dr Shamik Bhattacharyya, Guest Editor for Continuum's most recent issue, on spinal cord disease. Please check it out, and thank you to our listeners for joining today.

Dr. Monteith: This is Dr. Teshamae Monteith, Associate Editor of Continuum Audio. If you've enjoyed this episode, 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. Thank you for listening to Continuum Audio.

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

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Autoimmune neurology is a rapidly evolving subspecialty that focuses on neurologic disorders with atypical immune responses.

In this episode, Aaron Berkowitz, MD, PhD FAAN, speaks with Sean J. Pittock, MD, an author of the article "Overview and Diagnostic Approach in Autoimmune Neurology," in the Continuum August 2024 Autoimmune Neurology issue.

Dr. Berkowitz is a Continuum® Audio interviewer and a professor of clinical neurology at the University of California, San Francisco

Dr. Pittock is the director for the Center for Multiple Sclerosis and Autoimmune Neurology at Mayo Clinic in Rochester, Minnesota.

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Host: @AaronLBerkowitz

Transcript

Full transcript available here

Dr Jones: This is Dr Lyell Jones, Editor-in-Chief of Continuum, the premier topic-based neurology clinical review and CME journal from the American Academy of Neurology. Thank you for joining us on Continuum Audio, which features conversations with Continuum's guest editors and authors who are the leading experts in their fields. Subscribers to the Continuum journal can read the full article or listen to verbatim recordings of the article and have access to exclusive interviews not featured on the podcast. Please visit the link in the episode notes for more information on the article, subscribing to the journal, and how to get CME. 

Dr Berkowitz: This is Dr Aaron Berkowitz, and today, I'm interviewing Dr Sean Pittock about his article, "Introduction to Autoimmune Neurology and Diagnostic Approach", which he wrote with his colleague, Dr Andrew McKeon. This article is a part of the August 2024 Continuum issue on autoimmune neurology. Welcome to the podcast, Dr Pittock. Could you introduce yourself to our audience? 

Dr Pittock: Well, thank you very much, Dr Berkowitz. So, yeah, I'm a neurologist at the Mayo Clinic. I direct the neuroimmunology laboratory with Dr McKeon and Dr Mills here, and I have also been very much involved in the autoimmune neurology section at the American Academy of Neurology. 

Dr Berkowitz: So, many of you probably know Dr Pittock - or if you don't know, you've certainly diagnosed diseases that he has described and written about, and so it's a real honor to get to talk to you today and pick your brain a little bit about some of these complex diseases. So, autoimmune neurology is certainly one of the most exciting subspecialties of our field. I feel like when I talk to students and they ask me to make a case for why they should consider neurology as a career, I tell them, "Of course, I have many reasons I love neurology", but one thing I mention is that, although many other fields of medicine may have made incredible advances as far as treatments, I can't think of too many other fields outside neurology where entirely new diseases have been described since I've been in training and come out of training - and many of those have been in your field of autoimmune neurology. I can think of cases where I've heard you or one of your colleagues on a neurology podcast describing a new antibody, new disease, and a few weeks later, we see that disease and give a patient a diagnosis that had been elusive from other physicians and hospitals. It's a very exciting, gratifying area. It's also daunting, like, every time I go to the AAN and hear one of your colleagues, there's a new disease, and we realize, "Oops! Was I missing that?" or, "Am I going to see this?" And so, hoping to pick your brain a bit today about some of the key concepts and how to keep them in mind so our listeners can recognize, diagnose, and treat these conditions, even if they can't remember every single antibody in your article and all the new ones you and your colleagues will probably discover between now and when this, um, podcast is released. So, before we get into some of the important clinical aspects of these conditions, could you just lay out sort of the broad breaststrokes, the lay of the land of cell-mediated versus antibody-mediated paraneoplastic versus nonparaneoplastic cell surface versus intracellular - how can we sort of organize this area in our minds? 

Dr Pittock: Yeah. It's complex, and it's really an evolving story. But the importance, really, from the perspective of the reader and the perspective of the clinician is that we're talking about disorders where we can actually do something - we can actually impact patients.  And we think about the concept of stopping and restoring in neurology now. We're talking about disorders where we have the potential to stop these inflammatory immune-mediated disorders and, potentially, by stopping early, we may be able to restore function - so, a really important new and evolving field in neurology, because you don't want to miss these conditions. Trying to get your head around the complexity of these entities is difficult, but what we've done in this chapter is, really, to try and lay the groundwork for the following chapters, but provide somewhat of a simplistic approach, but a practical approach that really, I think, can help clinicians. So, the way I think of it, a lot of autoimmune neurology really has stemmed from the discovery of antibodies that cause neurological disease, and the examples of those would be going back to myasthenia gravis (with antibodies to the acetylcholine receptor), going back to Lambert-Eaton syndrome. And then, you know, even if you go back to the older traditional paraneoplastic disorders (the Hu, the Ri, the Yo), at the end of the day, you really have two essential entities, if you want to be very simple. The first is disorders that are caused by an antibody, and the second are disorders where the antibodies you detect are not causing the disorder, but they're telling you that there's predominantly a cellular or T-cell mediated attack of the nervous system. And I think thinking about the diseases in those kind of simple terms helps us when we think about what would be the best treatment to use in these types of cases.

Dr Berkowitz: Fantastic. I think that's very helpful. And just to make sure it's clear in the minds of our listeners when we're dividing into these sort of causative antibodies versus antibodies that might be, uh (I don't know if I'm using the word properly), but, sort of epiphenomena (or they're present, but they're not causative) as you said, can you just give some examples of the ones on either side and how making this distinction helps us in practice? 

Dr Pittock: Yes. So, antibodies that are causative of disease - I think, you know, the one that I've done a lot of work on is in neuromyelitis optica, where you have antibodies that are targeting a water channel that sits on an astrocyte, and so it causes NMOSD, or what we consider an autoimmune astrocytopathy. And we know that when the antibody binds to the target, many things can happen. So, when aquaporin-4 antibodies bind to aquaporin-4, they can do a lot of things. They can cause internalization, they can activate complement that results in the killing of the cell - but there can be other situations. For example, when NMDA-receptor antibodies bind to the NMDA receptor, then a variety of different things can occur different to water channel autoimmunity - where, for example, the receptor (the NMDA receptor) is downregulated off the cell surface, and that results, to some extent, in the neuropsychiatric phenomenon that we see in NMDA-receptor autoimmunity. And, obviously, when you have a situation where the antibodies are causing the disease, removal of those antibodies, or the reduction in the production of those antibodies, is going to help patients. Now, on the other side, we have antibodies that we detect in the blood or in the spinal fluid, and those antibodies are targeting proteins that are inside the cell - so those antibodies we don't consider as being pathogenic. Now, remember, there are sometimes situations where proteins that are inside the cell occasionally can be available for antibodies to bind at certain situations. So, for example, in the synapse, amphiphysin or the septins, may at times become available. And so, sometimes, there are targets or antibodies that are somewhat in between those two simplistic concepts. But when we're talking about antibodies that are targeting proteins on the inside of the cell, remember that antibodies don't just suddenly occur. There's a whole process of presentation of target antigen at the lymph node, and then both a T- and a B-cell response. The B-cell response potentially produces the antibodies but also triggers and stimulates T-cells, and those T-cells then go on to cause the disease. And those T-cells are very problematic, because those classical paraneoplastic and the newer ones we've described (and many have described) - these are associated with quite severe neurological disability, and they're very, very difficult to treat. And if you ask me, "Where is the holy grail of autoimmune neurology therapeutic research?" It's in trying to actually figure out ways of treating the predominantly T-cell mediated paraneoplastic and autoimmune neurological disorders. We're making great headway in terms of the treatments of the antibody-mediated neurological disorders.

Dr Berkowitz: That's a helpful overview. So, sticking with this framework, you mentioned as sort of the "causative antibody" category and the antibodies that are predominantly for intracellular antigens, but not believed to be causative - I want to make sure I'm understanding this correctly and we can convey it to our listeners - I believe you said in your paper, then, that the antibodies that are predominantly causative are more likely to be associated with conditions that are very treatable, as compared to the intracellular antibodies that are not thought to be causative, as you just said the disability can be irrecoverable or very hard to treat. And I believe another theme in your paper that you brought out is the antibodies that tend to be causative tend to be cell surface and tend to be less likely to be associated with underlying cancer (although not a perfect rule), and the intracellular antigens more commonly associated with cancer in those cases to look very hard for a cancer before giving up. Are those themes that I understand them from your paper properly, or anything else to add there? 

Dr Pittock: Yes, I think that that's exactly the message that we were trying to get across, so that's good news that you've picked up on the themes. I think, yeah, in simple terms, remember that when a cytotoxic T-cell identifies the peptide that its T-cell receptor will target, the ultimate outcome is poor, all right? T-cells are like the marines - they don't mess around. Once they find their target, they eliminate that target, and so, it's really difficult to treat those types of diseases if you get them late. And most patients with cytotoxic T-cell mediated paraneoplastic neurological disorders, oftentimes, by the time they get to a center of excellence, the boat has left the dock in many respects - in other words, it's too late. So, you know, I will often see patients, for example, with progressive cerebellar degeneration (say, in the context of Purkinje cell autoantibody type 1 antibodies and a breast cancer), and if those patients are in a wheelchair at the time that I see them, there's very, very little that we can do. So, you really want to try and get that patient into the office, you know, when they're using a cane (or not), and then, potentially, you have the opportunity - using very aggressive immunosuppressive medications - to make a difference. And that is quite different to other scenarios, where, for example, if you have NMDA-receptor encephalitis - as many of the readers will know, this is a condition that is very treatable, and most patients do very well, because the antibodies, they're disrupting function, but they're not killing the neuron, as we see in those more aggressive, paraneoplastic cytotoxic T-cell mediated diseases.

Dr Berkowitz: Also, in terms of searching for an underlying cancer, another theme in your paper as I understood (but want to make sure I'm understanding and conveying to our listeners and hear your thoughts), that the cell surface and treatable antibody-mediated syndromes, as you mentioned (NMO, NMDA) tend to be less associated with underlying cancers (although can be), whereas the intracellular antigens, um, a much higher percentage of those patients are going to end up having underlying cancers. Is that correct, or any notable exceptions to be aware of in that framework? 

Dr Pittock: Yeah, I think the major exception to the rule for the antibodies that are targeting intracellular antigens is the GAD65 antibody story. We generally don't consider the stiff person syndrome, cerebellar ataxia, or other autoimmune neurological disorders associated with very high levels of GAD65 antibodies - those are generally not paraneoplastic. And then there are always exceptions on both sides. You know, one of the benefits of understanding the implications of certain antibodies is trying to understand, you know, what is the likelihood of identifying a malignancy, which antibodies are high-risk antibodies (in other words, high-risk paraneoplastological disorders), and which are low risk in terms of cancer? And, you know, age and the demographic of the individual is often important, because we know, for example, with NMDA-receptor antibodies, the frequency of ovarian teratoma varies with the age of the patient.

Dr Berkowitz: Fantastic. And we encourage our listeners to read your articles – certainly, some very helpful tables and figures that help to elucidate some of these broad distinctions Dr Pittock is making - but just to summarize for the antibody-related part of autoimmune neurology, we have one category of cell-surface antibodies and another of intracellular antibodies. Both can cause very severe and varied neurologic presentations, but the cell surface tend to be more treatable, less likely to be associated with the underlying cancer, and the intracellular less treatable, more likely to be associated with the underlying cancer - but, as with everything in neurology and medicine, exceptions on both sides. Is that a fair aerial view of some of the details we've discussed so far, Dr Pittock? 

Dr Pittock: Yeah, I think so. I mean, I also think that, you know, not only, at least, for the antibody-mediated disorders (you know, as we discussed) we have drugs that will reduce the production of those antibodies, but we're also learning a lot more about the cytokine and chemokine signatures of these disorders. For example, NMO, water-channel antibody-mediated diseases are associated with elevated levels of IL-6. We know, for example, in LGI1 encephalitis and other encephalitides, that IL-6 also is elevated at the time of that encephalitic process. And so, the potential to target IL-6 with, you know, drugs that inhibit IL-6 and the IL-6 receptor, these potentially have, you know, a role to play in the management of these types of patients - whereas in the T-cell mediated disorders, you know, no advance has been made in the treatment of those conditions, I would say, in over 50 years. So, for example, the standard of treatment is steroids and then drugs that impact the bone marrow, and so we really haven't moved forward in that respect. And that, I think, is an area that really needs drive and enthusiastic out-of-the-box thinking so that we can try to get better treatments for those patients.

Dr Berkowitz: This has been a helpful overview. I look to dive into some of the scenarios that frontline practitioners will be facing thinking about these diseases. An important point you make in your article is that autoimmune and antibody-mediated neurologic syndromes can affect any level of the neuraxis. Even just our discussion so far, you've talked about anti-NMDA receptor encephalitis, you've talked about myasthenia gravis (that's at the neuromuscular junction), you've talked about paraneoplastic cerebellar degeneration - there can be an "itis" of any of our neurologic structures and that "itis" can be antibody-mediated. So, one of the key messages you give us is, one, that these are sort of in the differential diagnosis for any presenting neurologic syndrome, and, two, sort of one of the key features of the history, really, to keep in mind (since we could be anywhere along the neuraxis) is the subacute presentation when this should really sort of be top of mind in our differential diagnosis - so, many of these patients are going to be mystery cases at the outset. And one striking element you bring out in the paper is that, sometimes, the MRI, CSF, electrophysiology studies may be normal or nonspecifically abnormal, and although it's very helpful when we can send these antibody panels out, in some cases, resources are limited or institutions have certain thresholds before you can send these out (because neurologists love to send them in). Sometimes, they are not necessarily appropriate. So, love to hear your thoughts on when we should be sending these panels. What are some clues? Um we have a subacute neurologic presentation at any level of the neuraxis, and when it's not anti-NMDA receptor encephalitis, that is sort of a clear phenotype in many cases. How you would approach a patient, maybe, where the MRI is either normal or borderline abnormal (or people are squinting at the medial temporal lobe and saying, "Maybe they're a little brighter than normal"), CSF is maybe normal or nonspecifically, um, and the protein is a little high, but no cells? What clues do you use to say, you know, "These are the patients where we should be digging deep into antibody panels and making sure these are sent and not miss this diagnosis?" 

Dr Pittock: Well, thank you. That's a good question. So, I think, you know, first of all, these are complex cases. So, the patient is sitting in front of you and you're trying to figure out, first of all, Is this a hardware or a software problem? Are we definitively dealing with an encephalitis or an organic neurological entity that's immune-mediated? And, you know, the way I think of it is, for me, you see a patient, it's a twenty-five-piece jigsaw puzzle and you've got two pieces, and you're trying to say, "Well, if I step back and look at those two pieces, do I have any sense of where we're going with this patient?" So, the first thing you need to do is to collect data, both the clinical story that the patient tells you (and I think you make the good point that that subacute onset is really a big clue), but subacute onset, also fluctuating course, sometimes, can be important. The history of the patient - you know, Is the patient somebody who has a known history of autoimmune disease? Because we know that patients that have thyroid autoimmunity are more likely to have diabetes, they're more likely to have gastrointestinal motility or dysmotility, they're more likely to have a variety of different immune-mediated conditions. So, is there a family history or a personal history of autoimmunity? Is the patient at high risk for malignancy? Are there clues that this potentially could be a tumor-initiated immune process affecting the nervous system? The neurological exam also is extremely important because, again, that helps you, first of all, kind of define and get some objectivity around what you're dealing with. So, does the patient have hyperreflexia? Are there signs that there is neurological involvement? And then, really, what I think we need to do is to try and frame the predominant neurological presentation. So, what is the major issue? Because a lot of these patients will have multiple complaints, multiple symptoms, and it's very important to try and identify the major presentation. And that's important, because the neural autoantibody tests are now presentation-defined - in other words, they're built around the neurological presentation, because the old approach of just doing, apparently, a plastic evaluation is gone, because we've got to a stage where we have now so many neural antibodies, you can't test every single neural antibody. So, if you're suspecting that there may be an autoimmune neurological component, then you really need to think about what would be the most appropriate comprehensive evaluation I need to do for this patient. So, for example, if a patient comes in with a subacute-onset encephalopathy, you're probably going to want the autoimmune encephalitis evaluation, and then you have to pick whether it's going to be serum or spinal fluid - and as we outlined in the paper, there are certain antibodies that are better detected in serum versus spinal fluid. So, for example, in adults over the age of 50, LGI1 is much more accurately detected in serum than spinal fluid, and the absolute opposite is true for NMDA-receptor antibody detection. One of the most important components of the neurological evaluation is the spinal fluid, but actually looking at the white cell count - and in fact, sometimes, it's quite interesting to me that I'll often see patients referred with a diagnosis of encephalitis and autoimmune encephalitis, and yet they haven't had a spinal fluid examination. So, the presence of a white cell count, you know, greater than five is hugely helpful - it's like two pieces of that twenty-five-piece jigsaw, because that really tells you that there is something inflammatory going on. And now, in terms of imaging, you're right - some patients will have normal MRI. And if you really do think that there's evidence of - you know, for example, you do an MRI, but you're getting a good sense that there's a temporal lobe seizure occurring, MRI looks normal, the EEG shows some abnormalities in the mesial temporal area - you know, considering additional imaging modalities (like PET scan of the brain), I think, is reasonable. We know that in NMDA-receptor encephalitis cases, 30% of patients will have normal MRI but they'll often have abnormalities on the PET scans. So, I think, what we do is we try to gather data and gather information that allows us to add in pieces of that jigsaw so that, eventually, after we've done this evaluation, we can see now we have ten pieces. If we step back, we say, "Yes, now we know what this condition is", and then we essentially plan out the therapeutic approach dependent on what we've found. In terms of identification of underlying malignancy, you know, different people have different approaches. Our approach generally has been to try to get a PET-CT scan of the body as our first go-to test, because, actually, we found that CT chest abdomen and pelvis really actually delivers the same amount of radiation - and from a cost perspective, it's about the same - and we have found that PET-CTs really do provide a higher sensitivity for cancer detection.

Dr Berkowitz: Perfect. A lot of very helpful clinical pearls there. So, in closing, Dr Pittock, I've learned a lot from you today. I'm sure our listeners will as well. What does the future hold in this field? What's coming down the pipeline? What are we going to be learning from you and your colleagues that are going to help us take care of patients with these diseases going forward? 

Dr Pittock: Well, thank you, Dr Berkowitz, for that question. I think the future is very bright and very exciting, and, hopefully, some of the more junior members will be enthused by this Continuum series, and, hopefully, we'll go into this area. So, let's talk about the future. The future, I think, is going to be of great interest. Firstly, there's going to be continued discovery of novel biomarkers, and the reasons for that is because of the technical and technological advances we've seen. So, for example, there have been many, many antibodies discovered by us and others that have been discovered on the basis of, for example, phage technology. In fact, the Kelch 11 biomarker discovery in collaboration with UCSF and our group was done on the basis of Joe DeRisi and Michael Wilson's phage approach. And we're actually using that now at Mayo Clinic, and we've discovered about three or four new antibodies just in the last couple of years using this technology (and that here is led by John Mills and Div Dubey). And then, we're also going to see, I think, the evolution of protoarrays much more in biomarker discovery, so, we'll have more antibodies, and again, I think, generally, those antibodies will fall into the two categories we kind of described - so, you know, in terms of the approach to those conditions, maybe not so much change. I do think, though, that the introduction and the utility of comprehensive cytokine and chemokine analysis in the future will assist us in making diagnoses of seronegative encephalitis, but also potentially will direct therapy. So, for example, cytokine A is elevated - maybe that would be a potential target for therapy that's available for these patients with rare and potentially very disabling disorders. Then, when we look at the cytotoxic T-cell mediated disorders, I think the major areas of advance are going to be in better understanding the immunophenotype of cytotoxic T-cell mediated diseases, and then the potential development of tolerization strategies using the specific targets, those specific epitope targets that are involved in paraneoplastic and nonparaneoplastic diseases, and seeing if we can vaccinate patients, but move that immune response into more of a tolerogenic immune response rather than a cytotoxic killing response. And then I think, lastly, we're going to see a dramatic revolution in CAR-T therapeutic approaches to these types of disorders moving forward - and not just, you know, CAR-T therapies that are targeting, you know, CD19 or CD20, but CAR-Ts that are actually personalized and developed so that they can target the specific B- and T-cells in an individual patient and actually do a very fine removal of that autoimmune pathologic process that I think would have significant benefit for patients not only in stopping progression, but also in significantly reducing the potential of side effects - so, a much more targeted approach. So, that's where I think the next ten years is going to be. I think it's very exciting. It's going to require the collaboration of neurologists with, you know, immunologists, hematologists, you know, across the board. So, a very exciting future, I think, for this field. 

Dr Berkowitz: Exciting, indeed. And we have learned so much from you and your colleagues at the Mayo Clinic about these conditions, and I definitely encourage our listeners to read your article on this phenomenal issue that really gives us a modern, up-to-date overview of this field and what's coming down the pipeline. So, a real honor to get to speak with you, pick your brain about some of the clinical elements, pitfalls and challenges, and also hear about some of the exciting signs. Thank you so much, Dr Pittock, for joining me today on Continuum Audio.

Dr Pittock: Thank you very much. 

Dr Berkowitz: Again, today, I've been interviewing Dr Sean Pittock, whose article with Dr Andrew McKeon on an introduction to autoimmune neurology and diagnostic approach appears in the most recent issue of Continuum on autoimmune neurology. Be sure to check out Continuum Audio episodes from this and other issues. And thank you so much to our listeners for joining us today. 

Dr Monteith: This is Dr Teshamae Monteith, Associate Editor of Continuum Audio. If you've enjoyed this episode, you'll love the journal, which is full of in-depth and clinically relevant information important for neurology practitioners. Use this link in the episode notes to learn more and subscribe. AAN members, you can get CME for listening to this interview by completing the evaluation at Continpub.com/audioCME. Thank you for listening to Continuum Audio.

In this episode, Lyell K. Jones Jr, MD, FAAN, speaks with Eoin P. Flanagan, MBBCh, FAAN who served as the guest editor of the Continuum® August 2024 Autoimmune Neurology issue. They provide a preview of the issue, which publishes on August 1, 2024.

Dr. Jones is the editor-in-chief of Continuum: Lifelong Learning in Neurology® and is a professor of neurology at Mayo Clinic in Rochester, Minnesota.

Dr. Flanagan is a professor of neurology at Mayo Clinic in Rochester, Minnesota.

Additional Resources

Continuum website: ContinuumJournal.com

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@ContinuumAAN

Host: @LyellJ

Guest: @EoinFlanagan14

Transcript

Full episode transcript available here

Dr Jones: This is Dr Lyell Jones, Editor-in-Chief of Continuum, the premier topic-based  neurology clinical review and CME journal from the American Academy of Neurology. Thank you for joining us on Continuum Audio, a companion podcast to the journal. Continuum Audio features conversations with the guest editors and authors of Continuum, who are the leading experts in their fields. Subscribers to the Continuum journal have access to exclusive audio content not featured on the podcast. If you're not already a subscriber, we encourage you to become one. For more information, please visit the link in the show notes. 

Dr Jones: This is Dr Lyell Jones, Editor-in-Chief of Continuum: Lifelong Learning in Neurology. Today, I'm interviewing Dr Eoin Flanagan, who recently served as Continuum's guest editor for our latest issue on autoimmune neurology. Dr Flanagan is a neurologist at Mayo Clinic in Rochester, Minnesota, where he's a professor of neurology. Eoin, why don't you introduce yourself to our listeners?

Dr Flanagan: Yeah, it's a great pleasure to be here today. I'm a neurologist. I'm originally from Ireland – I did my medical school training over there, and then came over to the Mayo Clinic to train in neurology and in neuroimmunology. And delighted to be able to edit this exciting issue of autoimmune neurology of Continuum. I think, um, it's a really fascinating area that's moving very quickly, and I'm hoping that we can educate listeners to be able to feel comfortable when they come to see these patients and to realize how much of a growing specialty it is and how we're getting treatments, and we can really help these patients.  

Dr Jones: Yeah, it's a pretty exciting area. And, so, not only are you the Guest Editor for our latest issue of Continuum, this is the first-ever Continuum issue dedicated to autoimmune neurology, so I want to thank you for taking it on. This is something that our readers have been asking for for many years. I hope the topic wasn't too daunting.  

Dr Flanagan: No, absolutely, it's a pleasure to be able to do it, and it's just great when you read all the articles to kind of feel where the field is going and how much of  a benefit we can now make for our patients. So, that's been a real joy to do.

Dr Jones: Well, congratulations, and it's a magnificent issue. You have a lot to be proud of putting this group of authors together. So, for a few of our issues now, we've had the opportunity on the Continuum Audio podcast to interview the Guest Editor, which is really fun for me. I have to confess it's really a joy to talk to someone who is up to the minute not only in their narrow area of expertise at the article level, but, really, across the entire breadth of the subspecialty. And so, you've had an opportunity to delve into all relevant topics in autoimmune neurology. When you look at the issue as a whole, or the field as a whole, what do you think the biggest debate or controversy in the world of autoimmune neurology is right now?  

Dr Flanagan: Yeah, I think there's some changes happening. You know, initially, people used to recognize a disease called Hashimoto's encephalitis, where patients would have a presentation of encephalitis in the setting of thyroid antibodies. And what we're now realizing is that many of these patients actually have antibodies to neural-specific targets, because we know that the antibodies that target the thyroid don't really impact the brain. And what we're now realizing is that there's many antibodies out there that bind to different receptors in the brain (the NMDA receptor, for example, AMPA receptor), so we're really trying to refine the field towards these different antibody-associated disorders - and each different disorder may behave very differently. A patient with NMDA receptor encephalitis, for example, may be in the ICU, in hospital, may take them six, nine months to recover. On the other hand, a patient with LGI1-antibody encephalitis may get five days of steroids and be almost back to normal within a few weeks. So, it's a really broad spectrum. And, I think, what we're now learning is that each antibody has a role in helping define the disease, guide your treatment, guide your search for cancer - but, also, they behave differently - so these neural-specific antibodies are really important, while the older antibodies (like the thyroid antibodies) may just be a bystander and something that's happening in the background in a patient who's more prone to autoimmune disease.

Dr Jones: Very helpful, and I think that resonates with our listeners who have taken care of patients with autoimmune neurologic disorders, and it really is, I think, a great prototype in our specialty, maybe (for lack of a better word) of how observations start at the bedside, and then discoveries are made at the bench, and those benefits are brought back to patients. You know, there's been a recognition of autoimmunity in neurology for a long time, right - responsiveness to immunosuppression, even before the biomarkers were discovered - tell us a little story about how that works for our listeners. 

Dr Flanagan: Yeah, so, I think one of the first steps is defining a clinical syndrome. So what you'll find is that some of these syndromes (for example, neuromyelitis optica spectrum disorder, where they have longitudinally extensive lesions within a spinal cord) provoked people to be interested that these looked different to MS, and then that went to the lab, and the aquaporin-4 antibodies were discovered - or, more recently, MOG antibodies were discovered. The aquaporin-4 antibody-associated neuromyelitis optica spectrum disorder is a good prototype, because that went to the laboratory. Initially, they saw complement deposition on the pathology of these patients, they saw antibody deposition - the antibody was then discovered to aquaporin-4. And then, many labs around the world went to their own labs and they tried to delve in to determine what the pathogenesis was, and they found that complement was important in cell killing, that interleukin-6 elevation was important, and that complement appeared to be important. So, then, what they did was they tried to find treatments that would target those pathways. So, and now, we have treatments that are successful for this disease that can target complement, target interleukin-6, and target B cells (be it CD19 or CD20). So, we now have many different treatments, and this disease used to be very severe (so, had a 33% mortality at five years), and now these patients can live a long life with these treatments. So, I think that gives you an example of how you can follow the immunology of the disease and use targeted treatments to help our patients, and I think we can use that as a good prototype for many of   the other antibodies, because every year we discover two to three new antibodies, and each disease is a bit different in its mechanism. So, there are now clinical trials in NMDA receptor encephalitis starting up. There's clinical trials in MOG antibody-associated disease. And I think we're going to see that as we move forward, that these treatment trials will come and we'll be able to help our patients better with proven treatments that we know work, rather than a history of we would just use five days of steroids and then we didn't know exactly what to do in the long term - and we could manage some of the relapse as well, but we couldn't really take care of the disease in the background - so, I think the NMO is a good model for moving forward, and the pharmaceutical companies are supporting moving forward with different trials for the disease.

Dr Jones: So, a key message there is understanding the biology so we can be a little more targeted and less indiscriminate in the immunomodulation we're going to use. And we have parallels to that in the neuromuscular world, right, like using B-cell depletion for MuSK-associated neuromuscular junction disorders, as opposed to the trial-and-error approach, right? That's got to be a little more patient-centric and you get to a therapeutic response faster, right?

Dr Flanagan: I think so. Yeah, and I think, in the future, that might be something where, you know, a different patient, if they had elevated cytokines that pointed more to an IL-6 elevation, then maybe, in that patient, you would target IL-6, while the next patient with the same disease has more prominent complement activation, maybe you would target complement, or another patient has more prominent B-cell markers elevated, that you would target B cells. So, I think, we're really moving towards a more individualized treatment in some of these disorders. So, it's a very exciting time, but we've only really made that breakthrough in one of the antibodies, and we have probably sixty, seventy antibody-mediated disorders now. So, it's going to get complicated, but it's also going to be, really, an exciting time for our patients, and I think an exciting time for neurology trainees and people who see patients in practice that we can now make diagnoses and guide their treatment that, previously, you know, these patients were told they might have presumed infectious encephalitis or we didn't know the exact cause.

Dr Jones: So targeted not only to the diagnosis, but to the individual.

Dr Flanagan: Yeah.

Dr Jones: So, that's a level of complexity that I think is going to blow a lot of our minds, right? And it's exciting, but I think it also is a little daunting, right?

Dr Flanagan: Absolutely. Yeah. Yeah, it's going to be complicated, and these are rare diseases, so they're difficult to do clinical trials in. But I think we can be guided, and our experience tells us that if you follow the mechanisms, that you can find targeted treatments. Now, you can also find targeted treatments in MS - you know, it took us a longer time to find successful high-efficacy treatments, but now we're doing much better with many high-efficacy treatments available. But, I think in these autoantibody-mediated diseases, really looking at the mechanisms and trying to figure out that and then targeting the treatment in that direction makes the most sense and is the most likely to be successful.

Dr Jones: So, one of the purposes of Continuum is to educate our readers and our listeners, and because neurology is so broad, because it is evolving so quickly,   it's really hard to stay current. And so, again, that's part of the purpose of the journal. I think one of the challenging areas is autoimmune neurology, because it changes fast, and it's complicated, and the treatments are high stakes and complicated to administer - so, I think this is an important topic. I know from my own experience in clinical practice, one of the challenging scenarios is you see   a patient who may have an autoimmune neurological disorder, you obtain some serum or CSF markers of neurologic autoimmunity, right? And of the ten antibodies you check, one of them comes back, and it's a low titer-positive antibody. I know that's something that you get a lot of questions about. How do you approach that?  

Dr Flanagan: Yeah, I think, you know, we're all neurologists, and, you know, it's immediately back to the history, the examination, and the investigations, and what do they support - so, are you really dealing with an antibody-mediated disorder? And I think, from a neuroimmunology laboratory standpoint, we're always trying to get better tests, remove those less-specific tests (so, move away from the thyroid peroxidase antibodies) and really hone in on the exact targets and their mechanisms. So, I suppose, when you find a low-positive result, it's really important to go back to that clinical. And, I think, you know, that is job security for neurologists, right? Because you really have to interpret these in context. And, I think when you're seeing autoimmune cases, you need to have a good, broad understanding of differential diagnosis, because there are many different disorders that can present in a similar way, and you don't want to get distracted by that low-positive antibody and then put a patient on long-term immunosuppression that has many different risks. So, there is a potential for misdiagnosis, and I think that's an emerging area that we're recognizing that we always have to put the antibodies into clinical context. And, you know, there are more and more studies coming out that will help guide you, and I think the issue in Continuum will help guide you in terms of your understanding of, you know, what does a positive antibody mean? And it'll give a little bit on the methodology of how the antibodies are tested and how that can help you – or, sometimes, be it the titer may be very high that can help you. So, different aspects of the antibody test results can also help guide you in the likelihood of that being kind of a true positive versus a false positive. But I think always back to the history, exam, and the investigations, too.

Dr Jones: You're being very gracious there, and I'm glad you bring it up that it's really not just about the laboratory performance of the test, right? It's about the pretest probability of the clinical syndrome if it doesn't clinically resemble an autoimmune neurological disorder. So, I'm not going to pretend to be an expert in Bayesian statistics, but I think we should recognize that if we obtain any test when there's a low likelihood of the syndrome or the diagnosis being present, we're more likely to have false positives than in other scenarios or other settings. So, I think that is a charge to the clinician, where if we are obtaining these tests, we do really need to think about the likelihood of there being a clinical autoimmune neurology syndrome, right?

Dr Flanagan: That's exactly right. You know, one of the teachings that I sometimes give to the trainees is that, you know, if you have a ninety-year-old patient with mild cognitive impairment who comes into the emergency department with some worsened altered mental status, you know, you want to check for a urinary tract infection, you want to check a chest x-ray - you don't want to test neural antibodies upfront. So, you always have to consider the setting and avoid overtesting, because like any test, they're not perfect, and you can run into trouble if you order it too frequently - so, that's another thing that we try to educate people. And then if you do order the test, we like to educate people on, you know, what the positive test results mean, and is there any potential for false positives like we talked about?

Dr Jones: And I think, keeping in mind - obviously, there are exceptions - but the subacute onset of multifocal neurological disorder is really suggestive of autoimmunity. It doesn't mean that it can't happen in other contexts. And it has been exciting not only on the diagnostic side, but on the therapeutic side. There are so many exciting new treatments. What do you think is on the horizon beyond what we've seen in the last few years with small- and large-molecule therapies for these disorders?  

Dr Flanagan: Yeah, I think there's new things. You know, people are always looking at different approaches. So, for example, there's a lot of interest in tolerance, and is there a way you could tolerize yourself out of some of these autoimmune conditions? There's a lot of work on CAR-T treatments, looking particularly in the field of lupus and other systemic autoimmune diseases, and I suspect that they will also be applied to autoimmune neurologic conditions. And then the other thing to mention is that we're seeing the more frequent use of immune checkpoint inhibitors in patients with lots of different types of cancers, including neuroendocrine tumor. So I think, in the future, everybody's going to have to learn about autoimmune neurology, because we're going to be seeing these patients more often, because there's going to be more neurologic immune-related adverse effects related to those immune checkpoint inhibitor treatments – so, I think we're going to continue to see autoimmune neurologic disorders pop up. And, you know, the immune checkpoint inhibitors are almost real-world laboratory experiments, because you're ramping up the immune system, and you can trigger many different types of autoimmune conditions. We're actually learning a lot from these patients that can help us in the way we diagnose and the way we treat these patients in the future, but I will say that, sometimes, they can cause a challenge, because some of these patients have difficult-to-control cancer - you need to up their immune system, but then they get autoimmune complications. We try and dampen down the immune system, and then we need to kind of ramp it back up to treat the cancer. And we've had some challenges where managing such cases can be difficult with that balance of cancer-directed immunotherapy versus immune-related adverse events, and, sometimes, that can pose a challenge for autoimmune neurologists when we see these patients.

Dr Jones: So, those are challenges, and I imagine it's a challenging and often rewarding field. What is the most rewarding thing about caring for patients with autoimmune neurological disorders?  

Dr Flanagan: I think it's a few things. You know, one is that it's a multidisciplinary area,   so many of these patients will have different subspecialties of neurology involved. So, we'll get to work with our colleagues, and we may work with our oncology colleagues, we work with our ophthalmologist, and we work with our physical medicine and rehab team – so, it's a real team approach to help the patient. So, that's one aspect that's very enjoyable, because everybody needs to work together. And then, you know, these are treatable conditions. So we can have patients who are in the intensive care unit - you know, quadriplegic, in a coma - and then we treat them, we see them back, and they can be back close to normal. So, particularly, with some of these antibodies that target the cell-surface receptors (like NMDA receptor encephalitis, MOG antibodies), these patients can really go from being really, really sick in the ICU to coming back to normal – so, that's very satisfying, and much of that is related to the improvements we have in treatments, and then we can manage them in the long term with some of these newer treatments that are coming along for these diseases. So, I think it's a very exciting area and exciting time for our patients with these disorders, and we're getting more and more clinical trials, so we're hoping that we'll have more and more treatments available into the future.

Dr Jones: I think that has to be part of why the interest in autoimmune neurology has grown so much. I know as an educator - I hear this a lot from trainees - you know, the level of interest in MS and autoimmune neurology has really only grown over time. It must be because of better understanding of the pathobiology of disease, better treatment options, and something that our listeners may not know. Not only is Dr Flanagan an expert in autoimmune neurology - he's very well trained, he did fellowship in MS and autoimmune neurology, and behavioral neurology, right?

Dr Flanagan: That's correct. Yeah. Yeah.

Dr Jones: And, you know, it's going to sound like I'm trying to flatter Eoin here, but I'm really not (this is going to lead to a question). Eoin is, you know, very well recognized for his work in autoimmune neurology and discovery in this area. Uh, he happens to be one of the best doctors I know. And Eoin, you've won the Teacher of the Year Award several times. So, for our listeners who are looking into their careers and trying to manage multiple areas of interest, how do you do it? You do so many different things so well.

Dr Flanagan: Well, you know, I'm lucky to have had the opportunity to work here at the Mayo Clinic and in the neuroimmunology lab. So, we have a lot of resources, and it's an exciting area, you know? We need to bring up the next generation of leaders, so we need to be enthusiastic about these conditions, and we really can do a lot for these patients. So I think when I cover on the hospital service - you work with the residents or work with the fellows and clinic - you know, these cases (when they come around) are really enjoyable to see you can get an answer, we can figure out what type of treatment to do, and we can really help these patients. So, I think that makes it a very exciting area and an easy area to teach residents and to convey some of the excitement that's happening in the field. So, it's just a great honor to be able to work with trainees to kind of let them know the field. And, you know, there's more and more fellowship opportunities in different centers in neuroimmunology, and I think more residents are becoming interested in the field of autoimmune neurology because of so much happening. But, in saying that, with these challenges, it's very hard to keep up with all these antibodies - I find it hard. There's 70 different antibodies - it's hard to know every single thing about every single one. So, we need to continue to educate, to try and simplify, to try and help our younger people be able to manage these patients, because no matter who it is in neurology, you're going to encounter these patients - if you cover the hospital, if you see regular patients in clinic, if you do consult service, you'll come across these patients - and we're going to see them more and more with immune checkpoint inhibitors and other treatments coming along. So, I think it's an exciting area, and it's an important area for everyone to be aware of. So, it's just a great pleasure to be able to be involved in the field and see such enthusiasm in junior people.

Dr Jones: So, in addition to doing all those things well, you're also very humble. So, that's a great answer, and I think it is important - even though these are collectively rare - the opportunity to treat these patients and have wonderful outcomes is great, and I think the ability to recognize and feel comfortable. And, hopefully, Continuum has a place in that. I think your issue, Dr Flanagan, is a stellar issue and, uh, will be a benchmark for a generation of neurologists and how to approach these disorders. So, I want to thank you for being our Guest Editor for that topic and joining us today for such a thorough and fascinating discussion on autoimmune neurology.

Dr Flanagan: Thanks so much. And thank you to the Continuum team for highlighting autoimmune neurology. It's an exciting field, and I think, really, there is a great group of authors that cover neuroimmunology comprehensively, and I think, hopefully, people will enjoy the edition.

Dr Jones: Again, we've been speaking with Dr Eoin Flanagan, Guest Editor for Continuum's most recent issue on autoimmune neurology. Please check it out. And thank you to our listeners for joining today.  

Dr Monteith: This is doctor Teshamae Monteith, Associate Editor of Continuum Audio.   If you've enjoyed this episode, you'll love the journal, which is full of in-depth   and clinically relevant information important for neurology practitioners. Use this link in the episode notes to learn more and subscribe. Thank you for listening to Continuum Audio.

Patients with severe acute brain injury often lack the capacity to make their own medical decisions, leaving surrogate decision makers responsible for life-or-death choices. Patient-centered approaches and scientific methodologies can guide clinicians' prognostications.

In this episode, Teshamae Monteith, MD, FAAN, speaks with Susanne Muehlschlegel, MD, MPH, FNCS, FCCM, FAAN, author of the article "Prognostication in Neurocritical Care," in the Continuum® June 2024 Neurocritical Care issue.

Dr. Monteith is the associate editor of Continuum® Audio and an associate professor of clinical neurology at the University of Miami Miller School of Medicine in Miami, Florida.

Dr. Muehlschlegel is a professor (PAR) in the departments of neurology, anesthesiology/critical care medicine and neurosurgery, division of neurosciences critical care at Johns Hopkins University School of Medicine in Baltimore, Maryland.

Additional Resources

Read the article: Prognostication in Neurocritical Care

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Host: @headacheMD

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Full transcript available here

Dr Jones: This is Dr Lyell Jones, Editor-in-Chief of Continuum, the premier topic- based neurology clinical review and CME journal from the American Academy of Neurology. Thank you for joining us on Continuum Audio, a companion podcast to the Journal. Continuum Audio features conversations with the guest editors and authors of Continuum, who are the leading experts in their fields. Subscribers to the Continuum journal 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 Tesha Monteith, Associate Editor of Continuum Audio. Today, I'm interviewing doctor Susanne Muehlschlegel about her article on prognostication in neurocritical care, which is part of the June 2024 Continuum issue on neurocritical care. Well, Susanne, thank you so much for coming on the podcast, and thank you for writing that beautiful article.

Dr Muehlschlegel: Thank you so much for having me. Excited to be here.

Dr Monteith: Why don't we start with you just introducing yourself?

Dr Muehlschlegel: Yeah, sure. My name is Susanne Muehlschlegel. I'm a neurointensivist at Johns Hopkins in Baltimore, Maryland. I have been a neurointensivist for about eighteen years or so. I worked previously at the University of Massachusetts and recently arrived here at Hopkins.

Dr Monteith: Cool. So, what were you thinking about - What information did you want to convey - when you set out to write your article?

Dr Muehlschlegel: Yeah. So, the article about neuroprognostication is really near and dear to my heart and my research focus, and I'm very passionate about that part. And as neurologist and neurointensivist, prognostication, you know, might be considered the bread and butter of what we're asked to do by families and other services, but as the article states, is that we don't usually do a great job (or physicians sometimes believe they do). But when you actually do research and look at data, it's probably not as good as we think, and there's a lot of room for improvement. And, so, the reason for this article really was to shine the light at the fact that I think we need to really make neuroprognostication a science, just like we make prediction models a science - and, so, that is the main topic of my research, as well as the article.

Dr Monteith: So, we know about your interest in research in this area, but what got you into critical care to begin with?

Dr Muehlschlegel: Yeah. It's, pretty much, a story of always being drawn to what's exciting and what others may want to avoid. So, in medical school, people were afraid of neurology and learning all the anatomy, and I just loved that and loved interacting with these patients. And then, in neurology residency, I was drawn to not just treating the brain and the spinal cord, but also the entire patient (so the lung and the heart and the interaction of all the organs). And then, naturally, I'm a little bit of an impatient person, and so I like the environment of the ICU of rapid change and always having to be on my toes. And so that's what drew me into neurocritical care. It was a very new field when I was training, and so, I was probably, you know, one of the, maybe, first- or second-generation neurointensivists.

Dr Monteith: And it sounds like you're maybe okay with uncertainty and a lot of variability?

Dr Muehlschlegel: Well, you know, neuroprognostication - I think everyone has to acknowledge that we cannot take away uncertainty, right? So, folks who pretend that they know for sure what's going to happen - I think the only time we can say that is in a patient who's braindead. But everyone else, we really don't know for sure, and all we can do is do the best to our ability to give a rough outlook - but we need to acknowledge uncertainty, that's for sure.

Dr Monteith: So, can you just give us a few of the biggest causes of variability when it comes to withdrawing life-sustaining therapies in patients with severe acute brain injuries?

Dr Muehlschlegel: So, that's the focus of quite some research. And, of course, there are many epidemiological factors, patient severity of disease, and, you know, how fast someone might arrive to the hospital, ethnic, racial, social demographic factors (and there's research on that), but when you adjust and control for all of those factors, variability remains. And so, what I've observed in my practice and what I also describe in the article is that maybe it's the way physicians describe prognostication or communicate with families, meaning there is potentially the chance for physician bias - that may also drive prognostication. And I can tell you from my own experience, what really drove me into this area is anecdotal experience that probably we've all had of other physicians kind of nihilistically prognosticating, thinking, you know, "This is going to be bad no matter what", and not even wanting to try to provide aggressive care to patients. So, I think these what we call "self-fulfilling prophecies" we need to be very aware of. So, I think some of the variability may be driven by other factors other than family, patient, or health system factors.

Dr Monteith: And you outline that really nicely in the article, so thank you for that. Why don't you just give us an example of a challenging case that maybe you're still thinking about today, that maybe happened years ago, that helps us understand what you go through?

Dr Muehlschlegel: Yeah, I'll rephrase the case. I still have, you know, very vivid memories about this, but I tell my residents about this case. When I was a fellow, there was a young patient in his early forties, a father of several children, a young family man who had a big right MCA stroke and really was progressing to the point that it was clear that he needed a hemicraniectomy or he was going to die. Discussed this with my attending, who said I should consult neurosurgery. At the time, the neurosurgical service had a transition to practice service for these emergencies - and so, these were fairly young, chief residents or early-year attendings. And the person came in, went into the patient's room, and I didn't even know about it, and came out and then just said, "Family decided for CMO". I was very surprised and shocked and was trying to understand how this happened, and this provider, all he said was, "Well, it's all how you put it to the family. I told him that he probably shouldn't be a vegetable. They didn't want him to be a vegetable, and so this was the only option." And, so, I was very shocked, and the patient did progress to die within a few days. And, so, that was a dire example of how biased prognostication can drive families to maybe an unnecessary outcome.

Dr Monteith: And what's CMO?

Dr Muehlschlegel: I'm sorry. Comfort measures only - so, essentially, a withdrawal of life-sustaining therapies.

Dr Monteith: Yeah. That is a good example of that and how our bias can inform families and maybe not with the exact amount of data to support that, as you outlined so nicely in your article.

Dr Muehlschlegel: And I do want to emphasize, I don't want to generalize that all providers are like that, but it is an example that really still sticks in the back of my mind, and I think, you know, we need to shine a light at how we do this and how we do it right or wrong.

Dr Monteith: And wouldn't it be nice to just have more objective measures (right?) to guide us? So why don't we talk about existing tools that are used to help guide neuroprognostication?

Dr Muehlschlegel: Yeah, so I think, in general, we can break down prognostication to two pieces (and I outline that in the article as well). So, one is, kind of, a derivation of prognostication in the head of a physician or, you know, clinician – and what may go into that is how the patient presented, examination, radiology or other diagnostics, biomarkers, you name it. But, then the second part of it (that also is really important) is how we put it to the family, right? Because we can influence families in a way that we may not even be aware of, and I think we all have unconscious biases, and how we talk to families is really important and may drive what happens to the patient as well. So, I always say there's two pieces to that – so, first of all, how we come up with a prognosis, and then how we disclose that to the family.

Dr Monteith: So how can we better handle uncertainty?

Dr Muehlschlegel: So, we actually did some research on that and we asked stakeholders, "How do you want physicians to handle uncertainty?". People are aware that no physician can be certain (again, other than in the case of brain death), and so families are very aware of that. And there's quite some data out there to suggest that if physicians have very absolute statements - you know, want to close the door by saying something very absolute - is that the optimistic bias in families goes up. So, the mistrust in what the physician is saying, coming up with their own (you know, "This is a fighter, and he or she is going to do better than what you're saying") - and, so, I think, you know, there's no true answer to what's the absolute right way to do it, but some have suggested to maybe fully acknowledge that there is uncertainty. That's actually what families want you to do, based on some qualitative research we've done – is to say, "I do not have a crystal ball. There will be uncertainty", but then to potentially go into a best/ worst-case scenario. But again, there, all we can do is give a best gross estimate and guess. And so, the work is not really clear at this point. There's research ongoing as to what should be the best way of doing it, but currently, that's what is suggested.

Dr Monteith: And in your article, you spoke about some pretty innovative approaches, such as modeling, to help guide shared decision-making. And, so, you know, how reliable is that?

Dr Muehlschlegel: That's a good point, right? So, that is up to statisticians or those who are inventing these new models. So, you know, in the old days we used logistic regression, maybe linear regression. Now, there are fancy machine-learning modeling and other Bayesian models that people use, and they certainly have some advantages that I outlined in the article. Bayesian models, for example, may use serial data as it comes in throughout the patient's hospital course - and that's kind of how we do it in real life. But, I think what's really important before we apply models is that we know that there's always outliers, and we don't know if this one patient might be the outlier, and that we need to validate these models, and most importantly, look at calibration. So, I talk in the article about how, you know, all models always report the what's called "area under the receiver-operating curve (the AUC)", which is discrimination. But, what's actually more important for a model to be applied to a patient at the bedside is calibration, meaning how well does it actually predict a potential outcome. And, you know, there's a lot of research into that, that only maybe half of the papers that report on a new model actually report calibration - so, I think it's really important to pay attention to that (has the model been validated and calibrated before we actually use these models?). I think prediction models have definitely a important role. But, then again, as the article says, we also have to think about how we then apply that to the patient and how we do it in individual patients.

Dr Monteith: And then, of course, there's some variability between institutions.

Dr Muehlschlegel: That's for sure. You know, there's these systematic approaches or system-based cultures in certain institutions. And then, of course, you know, there's still this model of learning from a role model or a mentor or an attending - meaning you look at how this person does it and then you may adapt it to your own practice. I think we need to critically examine whether we need to continue with that kind of apprenticeship model of learning how to neuroprognosticate, or whether we need to have other educational ways of doing that. So, especially in the field of palliative care, there's a lot of education now around communication - and I think med students get that exposure, and residents may get that exposure, too - but I think we need to practice it and study it systematically, whether having a standardized approach to do this leads to more patient-congruent decisions.

Dr Monteith: And, you know, we do have a lot of trainees, residents, and fellows that listen in. So, what are some key messages that you want to make sure gets conveyed?

Dr Muehlschlegel: Key messages is that, I think, we need to move away from looking at a patient the first one or two weeks and then concluding that we will know what will happen to this patient in six months or a year or further down the line. I think there's not a lot of longitudinal studies out there now that show that patients actually probably do better than expected if they're allowed to live. And what I mean by that is many studies allow early withdrawal of life-sustaining therapies within the first three days or maybe two weeks - but if we actually allow these patients to live, people wake up more than we thought, people may do better than we thought. So, referring to the article, I discuss in detail some twelve-month data from the TRACK-TBI study or very interesting results from South Korea where withdrawal of life-sustaining therapies is forbidden by law. And, so, you can actually do a true natural-history study of what happens with these patients if you allow them to live. And, surprisingly, a lot of people that, you know, within the first two weeks were still comatose actually ended up waking up. And, I think it's really important to look at those studies and to continue to conduct those studies so that we know better what might happen. I always shudder a little bit when I hear, "We need an MRI in the first few days or first week for neuroprognostication". And then I always question, "Well, what is it really going to tell you about that patient who clearly isn't brain dead and still has certain, you know, exam findings?" and "Shouldn't we just give those patients time?". I think some of those were a bit too quick to provide poor prognostication if we really don't know.

Dr Monteith: And, so, I want to know how did you get into research? You know, it can be competitive to get funding, grant funding - so, tell us about that in terms of, you know, your day-to-day, what's it like? And then, also, what makes you most excited about research happening in this area?

Dr Muehlschlegel: Yeah, I mean, there's a lot of research happening in that area. I think there's a huge focus on biomarkers and models and all sorts of new diagnostic tools to predict outcome, big push over decades now to do large longitudinal epidemiological studies - and all of those are very, very important, you know. I just mentioned as an example, the TRACK-TBI study is one of many other examples. I'm also excited about doing research in the second part of neuroprognostication that I mentioned - the communication and disclosure part - and the potential of bias as we speak to families. So, I get very excited about that part. It's not easy to get funding, but I think what's important is to focus on the potential impact. And, of course, then you try to convince funders that this is important research that has to be done in addition to funding model development and large epidemiological studies. What my day-to-day looks like? Well, you know, we have several ongoing projects (I won't get into details on that), but to get involved would probably be the best time as a trainee - so, I have medical students working with us, residents and fellows (although their time can be limited). And then to continue to just be curious and ask questions.

Dr Monteith: And what do you find most exciting about the work that you do? Just, kind of, overall?

Dr Muehlschlegel: I mean, without a doubt, the potential impact, right? So, changing the field a little bit. I'm not claiming that my research is doing that - I hope it might. But, most importantly, it's the potential impact on families and patients. I think our goal is not to have less withdrawal of care (although, sometimes, I just think we need to give people more time), but I think it's important to focus and ask about what patients might want, and then really focus families onto that. I think that can be difficult, because patients don't always tell families what they would want or families want something different than what they know the patient might want - and so, we spend quite some time on that when we speak to families. And then, I also talk about the disability paradox. So, you know, at one point, the family might say, "Well, he would not want to live if he can't walk", but then, patients, as they learn to live with this new normal, may actually later say, "Well, it's not as bad as I expected it to be, and I'm actually very happy to be alive, even if I'm not able to walk". And so, that's something that others are doing research on, and that's also important to consider.

Dr Monteith: Yeah, that's cool. Thinking about outside of the ICU, right?

Dr Muehlschlegel: For sure. Yes.

Dr Monteith: Great. Thank you so much for being on our podcast. I know that our listeners are going to really enjoy reading your article and all the thought that you put into that.

Dr Muehlschlegel: Thank you so much for having me.

Dr Monteith: Again, today, we've been interviewing Dr Susanne Muehlschlegel whose article on prognostication in neurocritical care appears in the most recent issue of Continuum on neurocritical care. Be sure to check out Continuum Audio episodes from this and other issues. And thank you to our listeners for joining today.

Dr Monteith: This is doctor 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.

In this episode, Gordon Smith, MD, FAAN speaks with Casey S.W. Albin, MD, author of the article "Neuromuscular Emergencies," in the Continuum® June 2024 Neurocritical Care issue.

Dr. Smith is a Continuum® Audio interviewer and professor and chair of neurology at Kenneth and Dianne Wright Distinguished Chair in Clinical and Translational Research at Virginia Commonwealth University in Richmond, Virginia.

Dr. Albin is an assistant professor of neurology and neurosurgery in the departments of neurology and neurosurgery, division of neurocritical care at Emory University School of Medicine in Atlanta, Georgia.

Additional Resources

Read the article: Neuromuscular Emergencies

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Host: @gordonsmithMD

Guest: @caseyalbin

Transcript

 Full transcript available here 

Dr Jones: This is Dr Lyell Jones, Editor-in-Chief of Continuum, the premier topic-based neurology clinical review and CME journal from the American Academy of Neurology. Thank you for joining us on Continuum Audio, a companion podcast to the journal. Continuum Audio features conversations with the guest editors and authors of Continuum, who are the leading experts in their fields. Subscribers to the Continuum journal 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 Smith: Hi. This is Dr Gordon Smith. I'm super excited today to be able to have the opportunity to talk to Dr Casey Albin, who will introduce herself in a second. She's well known to Continuum Nation as the Associate Editor for Media Engagement for Continuum. She's also a Neurointensivist at Emory University and wrote a really outstanding article for the neurocritical care issue of Continuum on neuromuscular emergencies. Casey, thanks for joining us. Tell us about yourself.

Dr Albin: Sure. Thank you so much, Dr Smith. So, yes, I'm Casey Albin. I am a Neurointensivist. I practice at Emory. We have a really busy and diverse care that we provide at the Emory neuro ICUs. Just at the Clifton campus, there's over forty beds. So, although neuromuscular emergencies certainly do not make up the bread and butter of our practice - I mean, like many intensivists, I spend most of my time primarily caring for patients with cerebrovascular disease - this is a really interesting and just kind of a fun group of patients to take care of because of the ability we have to improve their outcomes and that some of these patients really do get better. And that's a really exciting thing to bear witness to.

Dr Smith: I love finding neurointensivists that are interested in neuromuscular medicine because I share your interest in these patients and the fact that there's a lot that we can do for them. You know, how did you get interested in neurocritical care, Casey?

Dr Albin: You know, I was always interested in critical care. It was really actually the neurology part that I came late to the party. I was actually, like, gearing up to apply into emergency medicine and was doing my emergency medicine sub-I (like, that was the route I was going to take), and during that sub-I, I just kept encountering patients with neurologic emergencies - so, you know, leptomeningeal carcinomatosis and obstructive hydrocephalus, and then a patient with stroke - and I realized I was just gravitating towards the neuroemergencies more so than just any general emergencies. And I had really enjoyed my neurology rotation. I did not foresee that as the path I was going to take, but after kind of spending some time and taking care of so many neurologic emergencies from the lens of an emergency department, sort of realized, like, "You know, I should go back and do a neurology sub-I." And so, kind of, actually, late in the game is when I did that rotation and, like, dramatically changed my whole life trajectory. So, I have known since sort of that fourth year of medical school that I really wanted to focus on neurocritical care and neurologic emergencies, and I love the blend of critical care medicine and the procedural aspect of my job while doing it with the most interesting of all the organ systems. So, it's really a great blend of medicine.

Dr Smith: Did you ever think about neuromuscular medicine?

Dr Albin: Uh, no.

Dr Smith: I had to ask. I had to ask.

Dr Albin: No, I mean, I do really love neuromuscular emergencies, but I've known for forever that like, really wanted to be in an acute care setting.

Dr Smith: You know, I think it's such a great story, Casey, and I know you're an educator, too, right? And, um, we hear this from learners all the time about how they come to neurology relatively late in medical school, and it's been really great to see the trajectory in terms of fellowship determination dates and giving our students opportunities to make their choice, you know, later during their medical school career. And I wonder whether your journey is an example of what we're seeing now (which is more and more students going into neurology because we're giving them the free space to do that), and then also in terms of fellowship decisions as well (which was what I was alluding to earlier)?

Dr Albin: Yeah, absolutely. I think having more exposure to neurology and getting a chance to be in that clinical environment - you know, when you are doing the "brain and behaviors" (or whatever your medical school calls the neurology curriculum) - it is so hard and it's so dense, and I think that that's really overwhelming for students. And then you get into the clinical aspect of neurology, and sure, you have to know neurolocalization - and that is fundamentally important to everything we do - but the clinical application is just so beautiful and so much fun and it's so challenging, but in a good way. So, I totally agree. I think that more students need more exposure.

Dr Smith: Well, I mean, that's a perfect segue to something I wanted to talk to you about, which is you brought up the beauty of neurology - which is, I think, you know, neurologic formulation, really – and we talk a lot about the elegance of the neurologic examination. But one of the things I really liked about your article was its old-school formulation – you talk about the importance of history, examination, localization, pattern recognition – I wonder if, maybe, you could give us some pearls from that approach and how you think about acute neuromuscular problems and the ICU?

Dr Albin: Absolutely. I really do think that this is the cornerstone of making a good diagnosis, right? I will tell you what's really challenging about some of these patients when they are admitted to the ICU is that we are often faced with sort of a confounded exam. The patient may have been rapidly deteriorating, and they may not be able to provide a good history. They may be intubated by the time that we meet them. And so not only are they not able to provide a history themselves, but their exam may be confounded by the fact that they're on a little bit of sedation, or they were aspirating and now they have a little bit of pneumonia. I mean, it can be really challenging to get a good neurologic exam in these patients. But I do think the history and the physical are really where the money is in terms of being able to send the appropriate test. And so, when I think about these patients who get admitted to the neuro ICU, the first thing that we have to have is someone who can provide a really good collateral history, because so much of what we're trying to determine is, "Is this the first presentation, and this is a de novo (new) neuromuscular problem?" or "Had the patient actually had sort of a subacute or chronic (even) decline and they've been undiagnosed for something that was maybe a little bit more indolent, but (you know, they had an abrupt decline because, you know, they got pneumonia, or they have bloodstream infection, or whatever it was allowing them to sort of compensate) they have no longer been able to compensate?". And so, I really do think that that's key. And when I am hearing the story the first time, that's really one of the focuses of my history – is, "Was this truly a new problem?". And then, when we think about, you know, "Where do we localize this within the nervous system?", it's actually quite challenging because, you know, patients with acute spinal cord pathology may also not present with the upper motor neuron findings that are classic for spinal cord pathology. And so I think, again, it's a little bit recognizing that you can be confounded and we have to keep a broad differential, but I am sort of examining for whether or not there's proximal versus distal (like, the gradient of where they're weakest), is there symmetry or asymmetry, and then, are there other, sort of, features that go along with helping us localize to something to the nerves (such as sensory symptoms or autonomic symptoms)? So when I think about, you know, where we're putting this, you can put anything in sort of the anterior horn cells or to the nerves themselves, to the neuromuscular junction, and then to the muscles. And teasing that out, I put in some figures and tables within the article to help kind of help the reader think about what are features of my patient's exam, my patient's history, that might help me to put it into one of those four categories.

Dr Smith: Yeah, I was actually going to comment on the figures in your article, Casey. They're really fantastic, and I encourage all of our listeners to check it out. There's, you know, figures showing muscle group involvement and different diseases and different muscle disorders and different forms of Guillain-Barré syndrome - it's a really beautiful way of visualizing things. I wonder if we could go back, though, because I wanted to delve down a little bit in this concept of patients who have chronic neuromuscular diseases presenting into the ICU. I mean, this happens surprisingly frequently with ALS patients or, like, myotonic dystrophy. I've seen this a number of times where folks are, just, they're not diagnosed and they're kind of slowly progressing and they tipped over the edge. Can you tell us more about how you recognize this? You talked a little bit about collateral history - other words of wisdom there?

Dr Albin: I would say this is one of the hardest things that we encounter in critical care medicine, because quite frequently - and I see this more with ALS than myotonic dystrophies - but, I would say, like, I don't know, once every six months, we have a patient who's undiagnosed ALS present. And I think it can be extremely difficult to tease this out because there's something that's tipped them over the edge. And as an intensivist, you were always focused on resuscitating the patient and saving them from that life-threatening thing that pushed them over the edge, and then trying to tease out, "Well, were they hypercarbic and did they have respiratory failure because, you know, they've got a little bit of COPD, and is that what's going on here?" or, "Have they been declining and has there been sort of this increase in inability to ventilate actually because of diaphragmatic weakness and because of neuromuscular weakness?" Again, the collateral history is really important. One of the things that I think we are challenged by is how difficult - and I'm sure you can comment on this, as someone who is a neuromuscular guy - is how difficult it is to get a good EMG and nerve conduction study in the ICU in patients who may have been there for a little bit, you know? I think about this, sort of, the electrical interference, the fact that the patient's body temperature has fluctuated, the fact that they are, usually, by this time, like, they're a little volume overloaded – they're puffy. You know, it can be very frustrating. I think, actually, you probably would know more about, like, what it's like to do that exam on our ICU patients.

Dr Smith: Sometimes, it's really challenging, I agree. And it's the whole list of things that you raised - and I think it goes back to the first question, really. You put a premium on old-school formulation, pattern recognition, localization, and taking a good history - you know, thinking of that ALS patient, right? I mean, one of the challenges, of course, that you have to deal with in that situation is prognostication and decisions regarding intubation, right? And that's very different from (I'll give another scenario that sometimes we run into, which is the other extreme) a patient with myasthenia gravis who, maybe we expect to be able to get off a ventilator very quickly, but sometimes they're reluctant to be ventilated because of their age or advanced directives and whatnot. I wonder if you could talk a little bit about how you approach counseling patients regarding prognosis related to their underlying neuromuscular disease and the need for intubation in a period of mechanical ventilation?

Dr Albin: Just like you said, it really ranges from what the underlying diagnosis is. So, one of the things that, you know, like you said, myasthenia - these patients, when they're coming in in crisis, we know that there is a good chance that they're going to respond pretty quickly to immunotherapy. I mean, I think we've all seen these patients get plasma exchange, and within a day or two, they are so much stronger (they're lifting their head off the bed, they're clearing their secretions), and every now and then, we're able to temporize those patients with just noninvasive ventilation. You know, when we're having a discussion about that with the patient and with the care team, we really have to look at the amount of secretions and how well they're clearing them, because, again, we certainly don't want them to aspirate - that really sets people back. But, you know, I think, often in those cases, we can kind of use shared decision-making of, you know, "Can we help you get through this with noninvasive?" or, you know, "Looking at you, would you be all right with a short term of intubation?" Knowing that, usually, these patients stabilize not all the time, but quite frequently, with plasma exchange, which we use preferentially. The middle of that is, then, Guillain-Barré - those patients, because of the neuropathy features (the fact that it's going to take their nerves quite some time to heal, you know) - when those patients need to be intubated, a good 70% or more are going to require longer-term ventilation. And, so, again, it's working with a family, it's working with a patient to let them know, "We suspect that you're going to need to be on the ventilator for a long time. And we suspect, actually, you would probably benefit from early tracheostomy". And there was a really nice guidance that was just presented in the Journal of Neurocritical Care about prognosticating in patients with specifically Guillain-Barré (so that's helpful). And then, we get to the, really, very difficult (I would say the most difficult thing that we deal with in neuromuscular emergencies) - is the patient who we think might have ALS (we are not positive), and then we are faced with this diagnosis of, "Would you like to be intubated, knowing that we very likely will never extubate you?" - and that, I think, is a very difficult conversation, especially given that there is a lot of uncertainty often in the diagnosis. I would say, even more frequently, what happens is they have been intubated at an outside hospital and then transferred to us for failure to wean from the ventilator and, "Can you work it up and say whether or not this is ALS?" – and that, I think, is one of the most difficult conundrums that we face in the ICU.

Dr Smith: Yeah. I mean, that's often very, very difficult. And even when the patient wants to be intubated and ultimately receive a tracheostomy, getting them out of the hospital can sometimes be a real challenge. There's so much I want to talk to you about, and, you know, you talked about prognostication - really great discussion about tools to prognosticate in GBS, both strengths of things like EGRIS and the modified EGOS, and so forth – but, I wonder (given that I'm told time is limited for us) if you could talk a little bit about bedside guidance in terms of assessing when patients need to be intubated? You provide really great definitions of different respiratory parameters and the 20/30/40 rule that I'll refer listeners to, but I wonder if you could share, what's your favorite, kind of, bedside test - or couple of bedside tests - that we can use to assess the need for ventilatory support? And this could be particularly helpful in patients who have, let's say, bifacial weakness and can't get a good seal. So, what do you recommend? Is it breath count? Is it cough? Something else?

Dr Albin: I think for me, anecdotally (and I really looked for is there any evidence to support this), but for me, anecdotally - and knowing that there is not really good evidence to support this - whether or not the patient could lift their head off the bed, to me, is a very good marker of their diaphragmatic strength. You know, if they've got good neck flexion, I feel a lot better about it. The single breath count test is another thing that I kind of went down a rabbit hole of, like, "Where did this come from?" because I think, you know, it was one of the first things I was taught in residency - like, "Oh, patient with neuromuscular weakness, have them take a deep breath and count for as many breaths as they can." We have probably all done that bedside test. It's really important to recognize that the initial literature about it was done in myasthenia patients who were in clinic (so, these were not patients who are, like, abruptly going to need intubation), and it does correlate fairly well with their forced vital capacity (meaning how much they're able to exhale on bedside perimetry), but it is not perfect. And I put that nice graph in the article, and you can see, there's a lot of patients who are able to count quite high but actually have a very low FVC, and patients who count only to ten but have a very good FVC. So, I do like the test and I continue to use it, but I, you know, put an asterisk by it. It's also really important - and I would encourage any sort of neurology trainees, or trainees in any specialty - if you're taking care of these patients, watch the respiratory therapist come and do these at the bedside with them. You'll get a much greater sense of (a) what they're doing, but (b) how well the patient tried. And it is really, I mean, we have to interpret this number in the context of, "Did they give a really good effort?" So, I'll often go to the bedside with the RT and be the one coaching the patient - saying, like, you know, "Try again", "Practice taking this", "Do the best you can", "Go, go, go! Go, go, go!" (you know, like, really coaching the patient) - and you would be surprised at how much better that makes their number. And when you're really appropriately counseling them, that we actually get numbers that are much better predicting what they're doing. Then, you also have a gestalt just from being at the bedside of what they looked like during this.

Dr Smith: Yeah. I used to work with a neuromuscular nurse who was truly outstanding who was the loudest and most successful vital capacity coach ever. But, you know, she'd be doing it in one room, and you'd be in the next room with a patient. They'd be like, "What are they doing next door?" She was shouting and exhorting the patient to go harder and breathe better. So, it was always, "Wow, that sounds exciting over there". All right, this is all in a prelude. What I really want to ask you, Casey, is, you know, whenever we do Continuum Audio interviews, we, like, look up people, and it's not hard to look you up because you're everywhere on the Internet. And come to find out, you're a fully credential neuro Twitter star - and that's the term I saw, a star. So, what's it like being a Twitter star? I guess it's an X star. I don't even know what we call it anymore.

Dr Albin: I guess it's that. I don't know. I don't know, either. It's so funny, um, that that has become so much of my, like, academic work. I got on Twitter, or X (whatever it is) during the pandemic because, really, my interest is in, you know, innovatives and medical education, and I really had been trained to do simulation. So, I really wanted to develop simulation curriculum. I love doing sims with our medical students to our fellows. So, I was, like, developing this whole curriculum, and then the pandemic came along, and the sim lab at Emory was like, "Mm, yeah, we're not going to let people go in the sim lab. Like, that's not exposure that we want (people in a room together)". So one of our fellows at the time was doing a lot on Twitter and he was like, "You would love this. You have cases that you want to teach about. You should really get on board". And I, sort of, reluctantly agreed and have found the NeuroTwitter community to be, like, just a fantastic exchange of, you know, cases, wisdom, new studies - I mean, it's the way that I keep up with what is being published in the many fields that are adjacent to neurocritical care. So, it's very funny that that has ended up being sort of something that is a really big part of my academic time. But now that we're talking about it, I will give a plug for any of the listeners who are not on X. Dr Jones and I post cases, usually twice a week, that come directly from the Continuum articles or from our files (because, you know, sometimes we can spin them a little bit), but it's an amazing, sort of case-based, way to do some, like, microteaching from all of the beautiful Continuum articles, all the cases - and because there are free articles released from the issue, you know we'll link directly to those. So, for any of the listeners who have not, kind of, joined X for all the reasons that many people cite of not joining, I would say that there's so much learning that happens - but Dr Jones and I are people to follow because of our involvement with Continuum and the great cases that we're able to showcase on that platform.

Dr Smith: I think that's a great point. And, you know, there are certainly organizations that are questioning their engagement with X, and I'm on a board of an organization that's talked about not actually participating, and I brought up this point that I think the NeuroTwitter (NeuroX) community is really amazing. You'll have to give me some tips, though, I'm at, like, 498 followers or something like that. Do you know how many followers you have? I looked it up yesterday. I've got it for you if you don't know.

Dr Albin: I don't know recently.

Dr Smith: Yeah, 18,200 as of yesterday. That's amazing!

Dr Albin: Yeah, it's worldwide. We're spreading knowledge of Continuum across the globe. It's fantastic.

Dr Smith: That's crazy. Yeah, that's great work. It's really great to see the academic, kind of, productivity that comes of that. And I agree with you - Continuum has a really great presence there, and it's a great example of why you're the Associate Editor for Media Engagement. I think we're going to have to, I guess, gamify would be the right thing? Maybe we should, uh, see what the Las Vegas book is on the number of followers between you and Lyell Jones, I think.

Dr Albin: Totally.

Dr Smith: Yeah. Hey, Casey, this has been awesome. I've been so excited to talk to you - and I could keep talking to you for hours about your NeuroTwitter stardom – but in particular, neuromuscular weakness. I really encourage all of our listeners to check out the article. It's really, really, really, great - really enjoyed it. I learned a lot, and it reminded me a lot of things that I had forgotten. So thank you for the great article, and thanks for a really fun discussion.

Dr Albin: Thank you, Dr Smith. It was truly a pleasure.

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 article. Thank you for listening to Continuum Audio.

Neurologic infections become emergencies when they lead to a rapid decline in a patient's function; however, neurologic infections are often challenging to recognize.

In this episode, Aaron Berkowitz, MD, PhD, FAAN, speaks with Alexandra S. Reynolds, MD, author of the article "Neuroinfectious Emergencies," in the Continuum® June 2024 Neurocritical Care issue.

Dr. Berkowitz is a Continuum® Audio interviewer and a professor of clinical neurology at the University of California, San Francisco

Dr. Reynolds is an associate professor in the departments of neurosurgery and neurology at Icahn School of Medicine at Mount Sinai Health System in New York, New York.

Additional Resources

Read the article: Neuroinfectious Emergencies

Subscribe to Continuum: shop.lww.com/Continuum

Earn CME (available only to AAN members): continpub.com/AudioCME

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More about the American Academy of Neurology: aan.com

Social Media

facebook.com/continuumcme

@ContinuumAAN

Host: @AaronLBerkowitz

Transcript

Full transcript available here

Dr Jones: This is Dr Lyell Jones, Editor-in-Chief of Continuum, the premier topic-based neurology clinical review and CME journal from the American Academy of Neurology. Thank you for joining us on Continuum Audio, a companion podcast to the Journal. Continuum Audio features conversations with the guest editors and authors of Continuum, who are the leading experts in their fields. Subscribers to the Continuum journal 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 Berkowitz: This is Dr Aaron Berkowitz, and today, I'm interviewing Dr Alexandra Reynolds about her article on neuroinfectious emergencies, which is part of the June 2024 Continuum issue on neurocritical care. Welcome to the podcast, Dr Reynolds. Um, would you mind, please, introducing yourself to our audience?

Dr Reynolds: Sure. Thank you for the invitation. I'm Alex Reynolds, and I am a neurointensivist at Mount Sinai Hospital in New York City.

Dr Berkowitz: Fantastic. Thanks for joining us. Dr Reynolds has written a really comprehensive article with lots of clinical pearls for the evaluation of patients with neurologic infections. So, to start off, when should we consider a neurologic infection as the cause of a patient's neurologic symptoms?

Dr Reynolds: That is a, really, much more complicated question than I think you recognize. I feel like a lot of it has to do with the risk factors of the patient. So, certainly, you know, a lot of times, we think about a patient who comes in with fever and altered mental status, and that's sort of the patient we're thinking about as having an intracranial infection – but, I do think there are a lot of risk factors that, sort of, may push us in that direction even if the patient doesn't have a fever or even if the patient doesn't seem like meningitis (for example). So, you know, a lot of patients nowadays are immunosuppressed, either because of infections or because of the therapies that we're using as immunosuppressants (so, autoimmune diseases, transplants, bone marrow patients). And then, I think, any patient who has had an intracranial procedure or a spinal procedure, we sort of just have to have in the back of our mind that surgical procedures come, by definition, with risk of infection (and so, that's always something to think about). And then, certainly, anything in terms of endemic risk factors (so a patient who has come from a country that has an endemic infection), we need to just be a little bit more broad about what we're thinking about in that patient population.

Dr Berkowitz: That's very helpful. You mentioned something I wanted to pick up on. We always think fever, of course we're going to be thinking about a neurologic infection, but some types of neurologic infections and in some patient populations, it's possible to have an infection of the nervous system with no fever, sometimes even no white count. What other clues should be considered, or when would you think about pursuing infection even in patients who don't have a fever or an elevated white count?

Dr Reynolds: So, certainly, in patients who have imaging that's a little abnormal. I think, oftentimes, the patients that I've seen with sort of indolent infections have a subdural collection that just doesn't look quite right or doesn't make sense with the clinical history (you know, you can have P. acnes infections that go on for months that people really don't necessarily notice) - so any imaging, oftentimes on MRI, you'll see, sort of, diffusion restriction where you don't really expect to see it. So, those sorts of patients might be ones where if the story is just not really fitting, you might want to think about infection. So, I think it's also important to remember that patients who have procedures elsewhere in the body can sort of seed themselves, and either by direct spread or by hematogenous spread, those infections can kind of seed the CNS - so, patients with valve procedures in the heart, patients who have intraabdominal procedures, there really is no reason that those infections can't travel to the CNS as well. And so, I was sort of always taught, you know, if the story doesn't make sense, then you have to consider infection, even if the patient doesn't have a white count or fever. So, I think just having, sort of, that suspicion in the back of your mind that if you can't really make sense of the story, then consider an infection.

Dr Berkowitz: Yeah. So, obviously, fever, white count, those would clue us in that a patient with new neurologic symptoms (signs) may have an infection as a cause. But, as you said, they may not be present in patients who have had any type of neurosurgical procedure (or you've just taught us even non-neurosurgical procedures elsewhere in the body) that could have led to bacteremia. And then, you mentioned earlier, also patients who are immunocompromised may develop a neurologic infection without fever or white count, and our threshold is certainly lower to pursue that possibility in that population as well. Other points on that before we move on?

Dr Reynolds: I had an attending that told me if you're thinking about a lumbar puncture, you better just do it – so, I think those are wise words to sort of live by. If you're thinking about an infection, you better just work it up.

Dr Berkowitz: Yeah. I think that's right. I heard something similar that if you're standing around on rounds debating whether the patient should get a lumbar puncture, probably, if you've talked about it that much, you should probably do it. I think we've heard the same things in different places. Along those lines of who needs a lumbar puncture, many patients with systemic infections can develop a headache, even if it's just from systemic infection (you don't necessarily have meningitis and cephalitis), and many patients, particularly older patients, develop confusion in the course of systemic infections, like pneumonia and urinary tract infections. And as neurologists, we are often consulted on these patients because they are confused, they are febrile, they may have an elevated white count, and people start to wonder, Could this patient have meningitis? Could this patient have encephalitis? In many cases, at least in my experience (I'm curious to hear your experience), it turns out that these patients have a systemic infection and the confusion and/or headache are related to that systemic infection, not a primary neurologic infection - but based on that topic we just discussed about, if you've talked about lumbar puncture enough, probably best to do it. How do you think about these patients who are, for example, admitted to a medical service for fever and confusion, may or may not have had a systemic source identified, but the suspicion is there? How do you think about which of those patients need a lumbar puncture, or what clues you into thinking to have a higher concern for meningitis, encephalitis, abscess, other neurologic infections in this context?

Dr Reynolds: It's such a good question, because I think, especially as we get older, you know, even things like nuchal rigidity might be hard to assess in a patient who's sort of started to fuse their spine - so, I think it can be really challenging. I think, you know, always go back to basics. Is there any new laterality that doesn't really make sense? Is there a sort of disconnect between imaging and how the patient looks? And it can be so confounded, because these are patients who are also on antibiotics (which themselves can be neurotoxic), and so, it can be really hard to sort of parse that out. But, I do think that there are some less invasive things you can try to do first to sort of help risk stratify your patient. So, you know, certainly, getting a CAT scan and just making sure that everything looks as you would expect it to look - there's no, sort of, hydro out of proportion to what you might expect. I've definitely seen patients who have meningitis that we caught because they have just a little bit of pus in the ventricles that was interpreted as intraventricular hemorrhage. And you sort of just have to sit there and think, like, Does that make sense, or is it an infection? EEG can be helpful, too, if it's lateralizing. You know, I think we don't think as much about HSV in the hospital. But, certainly, if you have something lateralizing on your EEG that just doesn't make sense, I think that could sort of push you in that direction as well. But, again, I think in most cases, unless the patient's very thrombocytopenic or coagulopathic, the risk of an LP sort of doesn't really outweigh the benefit of feeling confident that you haven't missed something, because I think, you know, one of the big points of this article is that if you catch these CNS infections early, people can actually do really well, and, really, most of the morbidity and mortality is from missing the infection - so we've been trying to move away from LP-ing everybody on admission, but I do think that you should be tapping some people that are not infected, because then you're probably catching everyone who is.

Dr Berkowitz: It's great to hear your approach, and I think that aligns with my thinking as well. I do want to ask as a follow-up to that question (I've asked this of internists I work with and other neurologists) - I totally agree with everything you said in the sense that, you know, we are consulted by our internists, we presume that they haven't found a reason that the patient is febrile and confused from a systemic standpoint, and that's why we're being consulted. There are, obviously, many patients who are febrile and confused in the hospital where neurology has not been called because there's other obvious reasons, as you have mentioned. However, as you said, if the patient has some immunocompromise, maybe there's some features that are suggestive in the history or nuchal rigidity - as you said, harder in older patients - but there's something there that you sort of think, maybe we should just do a lumbar puncture just to make sure we sort of settle this because we keep thinking about it. The question is, in your experience, when you've gotten a lumbar puncture more as a rule-out, or you think, I think this is the patient's pneumonia and they're confused because they're delirious in the hospital (sort of toxic metabolic encephalopathy), have you ever been surprised? Talking to an internist colleague, I've said, I feel like I haven't actually seen that much bacterial meningitis in the U.S., fortunately, thanks to vaccination. And, usually, the patient is coming in with a pretty profound syndrome of meningitis or encephalitis. But, as far as patients in the hospital with a fever, where you're thinking, "This is kind of a rule-out, so just make sure, even though I don't think I'm going to find meningitis in a patient who is immunocompetent", have you ever been surprised and found meningitis encephalitis when you didn't expect to find it? Or, what's been your experience when you, as you said, tap these patients because you'd rather get a few normal ones in there to make sure you never missed the abnormal?

Dr Reynolds: I would say the few times that I've been surprised were not with fully immunocompetent patients. You know, someone with a splenectomy who otherwise looks immunocompetent, someone with pretty advanced cancer - those are examples where you wouldn't necessarily have thought about it as being immunocompromised, but they are. Certainly, I think patients with advanced cancer can, really - they're much higher risk than I used to think about. The more I've taken care of them, the more I've realized how sensitive they are to infections and how quickly that can spread, even if they're not actively getting chemotherapy. But, I would say in general, for the truly immunocompetent patient, I would say I haven't really diagnosed anything super exciting.

Dr Berkowitz: Yeah, that's good to hear. I love to, on these Continuum Audio interviews, poll experts in other institutions who trained other places and, you know, learn from different patient populations if your experience resonates with mine and others I've spoken to. Yeah, that sounds similar to my experience as well, yeah, if the patient is immunocompromised - and as you said, we maybe need to broaden that from being truly profoundly immunocompromised by congenital immunodeficiency or HIV or immunomodulatory therapy to have a slightly broader perspective on what could constitute immunocompromise - and, of course, we'd have an extremely low threshold to perform a lumbar puncture in such patients, as you said. You reminded me of a case I was trying to remember the details (which I don't) – it was a patient, actually, with a temporal lobe glioblastoma that had been resected and had some recurrence and was worsening, and it looked like it was tumor recurrence/progression. And I don't - wasn't my patient, I just sort of heard about it - but I don't know which attending or resident or fellow decided that the patient should get a lumbar puncture, and the patient actually developed HSV encephalitis of the temporal lobe, where the glioblastoma was.

Dr Reynolds: Wow.

Dr Berkowitz: Patients with cancer, especially with all the new immunotherapies - and even without them, as you said - this is a state in which people may be vulnerable to infections and ones you might not immediately think of. So, those are some great pearls. Speaking of pearls, you have a really fantastic section in your article on neurologic complications of CNS infections. In other words, you've already diagnosed the meningitis, encephalitis, abscess, or otherwise, and all the other neurologic complications that can occur in the course of this illness. So, it'd be great to talk with you a little bit about that here. So, if a patient is diagnosed with infectious meningitis or encephalitis (we've made that diagnosis by the clinical picture, the lumbar puncture findings, and/or the neuroimaging), we're following them along, we think we have them on appropriate therapy, (antimicrobial therapy), and their neurologic status worsens - what's the differential diagnosis for this worsening? What are some things we can think about? How do we look for them on exam? How do we work them up?

Dr Reynolds: Yeah. It's funny, because, you know, the topic of this is neuroinfectious emergencies, and when I first heard about it, I was like, "Every neuroinfection is an emergency", and I think part of the reason I felt that way is because as a neuro ICU physician, I see the complications a lot more. You know, I think, from a meningitis and encephalitis standpoint, certainly cerebral edema (whether it be focal or global) is sort of your biggest concern. If you've used your adjunctive steroid therapy at the beginning before you've started antibiotics, you know the idea is that might help – and, certainly, it should help with potential hearing loss as a result of meningitis - but I would say cerebral edema or development of abscesses because of delayed antibiotic initiation is certainly a concern. If a patient's getting lethargic, hydrocephalus can often be a concern - and that may be obstructive hydrocephalus or communicating hydrocephalus – either way, that is a situation where, really, the patient may need, depending on the etiology of the hydrocephalus, either another lumbar puncture (for example, in the case of cryptococcal meningitis) or an external ventricular drain placement (which would bring them to the ICU in cases where there is an obstructive component). So, I do think hydrocephalus is hard to diagnose. My go-to is to sort of check tone in the legs every day, because a lot of times, patients with developing hydro will start to have really high tone in their legs - so, that's sort of my go-to physical exam finding, although, obviously, hydrocephalus can present as just sort of generalized lethargy or even, you know, worsening nausea and vomiting, for example. And then, I think, you know, if someone starts to be localizing on exam, I think that can be concerning not only for abscess, but potentially for ischemic stroke related to a vasculopathy, for example, or hemorrhage in the context of mycotic aneurysm formation, for example - and, so, I do think there is a role, if a patient starts to become lateralizing, for emergent imaging. And generally, we should be able to see most of the stuff on just a plain CAT scan to start. You know, certainly, localizing stuff can also be as a result of seizures, but I think that that's sort of a diagnosis of exclusion, and rapidly imaging a patient with new focal signs is probably the way to go before putting them on EEG.

Dr Berkowitz: Very helpful pearls. So, um, shifting gears a little bit, right before we began our conversation, you were telling me you had done some work in Malawi, and you were reflecting on some of the differences in epidemiology of neuroinfectious disease and resources available to diagnose neuroinfectious disease. So, I'm sure it would be very interesting for our listeners to hear a little bit about the perspective you bring to the diagnosis and treatment of patients with neurologic infections from your experience in Malawi.

Dr Reynolds: Yeah. So, I was lucky enough as a trainee to be able to go to Malawi for a few weeks with my neuroinfectious disease attending, and I think that it's pretty striking (the difference that we see in lower income countries, compared to the U.S.). I think a lot of the disease processes that we sort of take for granted as being easily treatable are not necessarily easily treatable, not only because of lack of access to medications and antibiotics, but also because of sort of a stigma that might be associated with the workup. So, for example, a lot of people were very hesitant to consent to lumbar puncture, because they had seen that their friends and family members who had gotten lumbar punctures ultimately died, and it didn't seem necessarily clear that the reason that they had died was from the primary infection itself. So, I think that really being attuned to disparities not only abroad, but even - you know, working in New York City, I can say that there are definitely disparities in terms of access to care and health equity, and, certainly, the timing of your presentation almost necessarily will change the outcome, and people who are presenting to the hospital later because of infections that were sort of ignored or because of lack of access to healthcare, those patients, really, by definition, end up doing worse - and so, I think that that is really a big thing to think about in our resource-rich areas, think about these infections.

Dr Berkowitz: Well, thank you for sharing those valuable and important perspectives both from Malawi and from your work in New York City.

Dr Reynolds: Thank you.

Dr Berkowitz: Well, thank you so much, Dr Reynolds, for joining me today on Continuum Audio. I've enjoyed our discussion and learned a lot from it. Again, today, we've been interviewing Dr Alexandra Reynolds, whose article on neuroinfectious emergencies appears in the most recent issue of Continuum on neurocritical care. Be sure to check out Continuum Audio episodes from this and other issues. And thank you to all of 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.

Despite validated models, predicting outcomes after traumatic brain injury remains challenging, requiring prognostic humility and a model of shared decision making with surrogate decision makers to establish care goals.

In this episode, Lyell Jones, MD, FAAN, speaks with Jamie E. Podell, MD, an author of the article "Traumatic Brain Injury and Traumatic Spinal Cord Injury," in the Continuum June 2024 Neurocritical Care issue.

Dr. Jones is the editor-in-chief of Continuum: Lifelong Learning in Neurology® and is a professor of neurology at Mayo Clinic in Rochester, Minnesota.

Dr. Podell is an assistant professor in the department of neurology, program in trauma at the University of Maryland School of Medicine in Baltimore, Maryland.

Additional Resources

Read the article: Traumatic Brain Injury and Traumatic Spinal Cord Injury

Subscribe to Continuum: shop.lww.com/Continuum

Earn CME (available only to AAN members): continpub.com/AudioCME

Continuum® Aloud (verbatim audio-book style recordings of articles available only to Continuum® subscribers): continpub.com/Aloud

More about the Academy of Neurology: aan.com

Social Media

facebook.com/continuumcme

@ContinuumAAN

Host: @LyellJ

Guest: @jepodell

Transcript

Full transcript available here

Dr Jones: This is Dr Lyell Jones, Editor-in-Chief of Continuum, the premier, topic-based neurology clinical review and CME journal from the American Academy of Neurology. Thank you for joining us on Continuum Audio, a companion podcast to the journal. Continuum Audio features conversations with the guest editors and authors of Continuum, who are the leading experts in their fields. Subscribers to the Continuum journal 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 Jones: This is Dr Lyell Jones, Editor-in-Chief of Continuum: Lifelong Learning in Neurology. Today, I'm interviewing Dr Jamie Podell, who has recently authored an article on traumatic brain injury and traumatic spinal cord injury in the latest issue of Continuum on neurocritical care. Dr Podell, welcome. Thank you for joining us today. Why don't you introduce yourself to our audience and tell us a little bit about yourself?

Dr Podell: Thanks, Dr Jones. It's great to be here. As you mentioned, I'm Dr Podell. I'm neurocritical care faculty at University of Maryland Shock Trauma. I have a primary interest in traumatic brain injury, both from a research and clinical perspective. I previously have more of a cognitive neuroscience background, but I think it kind of ties into how I think about TBI and outcomes from traumatic brain injury. But what I really like doing is managing acutely ill patients in the ICU, and I think TBI really affords those kinds of interventions, and it's a really rewarding kind of setting to take care of patients.

Dr Jones: Yeah, and I really can't wait to talk to you about your article here, which is fantastic. For our listeners who might be new to Continuum, Continuum is a journal dedicated to helping clinicians deliver the best possible neurologic care to their patients, just like Dr Podell was talking about. We do that with high quality and current clinical reviews, and Dr Podell's article - it's a massive topic - traumatic brain injury and traumatic spinal cord injury. And, you know, as we start off here, Dr Podell, we have the attention now of a massive audience of neurologists. If you had one most important practice change that you would like to see in the care of these patients who have trauma, what would that practice change be? And, I think, maybe, we'll give you two answers, because you cover TBI and you cover spinal cord injury. What would be the most important practice changes you'd like to see?

Dr Podell: So, this isn't that specific, but I think it's really important. I think we need more neurologists, and specifically neurointensivists, managing these patients. I think there's a lot of variability across institutions and how acute severe TBI and spinal cord injury patients are managed. They're often in surgical ICUs, and neurology may be involved in consultation but not in the day-to-day management. But I think what we're seeing is that, you know, there's a lot of multisystem organ dysfunction that happens in these patients, and that has a really strong interplay with neurologic recovery and brain function. And I think, you know, neurointensivists are very well equipped to think about the whole body and how we can kind of manipulate and really aggressively support the body to help heal the brain with special attention to, kind of, the nuance of any individual patient's brain injury. Because TBI is extremely heterogeneous and there's not just a cookie-cutter script for how these patients can be managed, I think, you know, people like neurologists, neurointensivists who have a lot of attention to the nuance - that's really helpful in their management.

Dr Jones: I'm so glad you said that, and not just because I'm a neurologist who's a fan of neurologists, but I do think there are some corners of neuroscience care where neurologists could be a little more present - and trauma definitely seems like one of those, doesn't it?

Dr Podell: Yeah, I think it's tough, because some patients with severe TBI and spinal cord injury can have a lot of multisystemic trauma with, you know, pulmonary contusions, intraabdominal pathology - you need to go to the OR for their other injuries, and so I think it really makes sense to have kind of a collaborative multidisciplinary approach to these patients, but I think neurologists should play a very big role in that approach, however that's done (there are lots of different ways that it's done). But I think having a primary neurology-trained neurointensivist – I know I'm biased, but I think that's where I'd like to see the field moving.

Dr Jones: And, obviously, neurocritical care is an intuitive place for neurological trauma care to start, and even with the sequelae of downstream things, I think neurologists could be more engaged. I wonder if neurology hasn't historically been as involved because it's sort of gravitated to surgical specialists. And I think part of it is, you know, trauma is not usually a diagnostic mystery, right? The neurologist can't pretend to be Sherlock Holmes and try to figure out what's going on when it was pretty clear what the event was, right?

Dr Podell: Right. Yeah, I agree with both of those points. I think, for one, I think postacute care is also a big area where neurologists can be involved more - and patients kind of fall through the cracks. A lot of times, these patients will just follow up with a neurosurgeon and get a repeat head CT and it'll look stable. We started implementing post-TBI neural recovery clinics, which I think other places are starting to do as well, and I think that's kind of a good model for getting neurologists involved - but also, rehab specialists are involved in that. But in terms of, yeah, the diagnostic mysteries and stuff, I think there still can be some, though, with TBI. Yes, obviously, the initial primary insult is obvious, but the secondary pathology that can happen in patients is really nuanced, and it is so variable, and, sometimes, it does take that detective eye to see, "Oh, this patient has one cerebrovascular injury, their risk of stroke to this territory? How are we going to manage it? and thinking about all the kind of sources of secondary decline that are possible. I think it takes that neurology detective sometimes to think about, too.

Dr Jones: Yeah. We never stop pretending to be detectives, right?

Dr Podell: Yeah.

Dr Jones: And on a related note, you know, in your article, you mentioned some of the novel serum and electrophysiologic and imaging biomarkers that are being used to care for these patients. How are you using those in your practice, Dr Podell?

Dr Podell: That's a good question. I think, unfortunately, as with a lot of clinical care, the clinical care does kind of lag behind the research and what we know what we can learn about these patients and their outcomes through retrospective studies. So, to be completely honest, you know, even the serum studies that I mentioned in the article (like GFAP, UCH-L1) - those kind of things, that's not clinically available at our institution. We don't use those. I think a lot of the imaging biomarkers that we see, some of them are coming from more advanced imaging – like, we're talking about FMRI - that requires a lot of post processing (so, again, we're not necessarily using that clinically). But what I would say is that we use imaging to kind of try to predict what complications patients might be at risk of and to try to predict their clinical course. And I think it comes down to trying to break down the heterogeneity of these patients and to try to kind of lump them into different bins of, "What's this patient at risk for?", "What's their trajectory going to be like?", "When can I start peeling back how aggressive I am with this patient?". And, so far, I don't think any of the markers that we have are really clear black-white prescriptive indicators of what to do (I don't think we're quite there yet). So, again, I think we just kind of use all of the data in combination to come up with a management plan for these patients. I think some of the markers, (like some of the electrophysiologic markers), looking at EEG for things like background can provide prognostic information, especially in patients who are comatose that you're wondering about if they're going to wake up (so a lot of this can inform family discussions). But, you know, we used to think that grade three diffuse axonal injury on MRI portended a very poor prognosis (and in the past, some surgeons and ICUs might use that to limit care in patients), but more and more, we're finding that even that is quite nuanced and we're detecting more and more diffuse axonal injury on images in patients who then wake up, or have already woken up and they have the MRI later, and you're like, "Hmm, they had DAI. It's a good thing you didn't get the MRI early and decide not to move forward with aggressive care". But, I think, in a patient who's comatose and you don't have a good explanation, sometimes, looking for those additional biomarkers to explain what kind of injury pathology you have can just provide more information for families.

Dr Jones: Yeah, and that's a great point that comes up in a lot of our articles and interviews (that the biomarkers really do have to be in a clinical context). So, if I understand you correctly, really, no individual biomarker that has emerged as a precise predictor or prognosticator for outcomes - but you do talk a lot about recent advances in the care of these patients. What would you want to point out to our listeners that's come up recently in the care of trauma?

Dr Podell: Yeah. I think the evidence basis for severe TBI is limited because, again, there's so much heterogeneity and different things going on with different patients, but some of the evidence that has come out more recently involves, kind of, indications for surgical procedures and the timing of those procedures. Some of that is still kind of expert consensus-based. But, for example, doing a secondary decompression for elevated ICP with the DECRA and RESCUEicp trials. We do have better high-quality evidence that doing a secondary decompression for more refractory, elevated ICP can improve both mortality and functional outcomes in patients, so that has kind of become more standard of care. Additionally, I think timing for spinal cord injury, neurosurgical procedures - that's been a topic that's been studied in more evidence-based to perform earlier decompressive surgeries. And then, I think, you know, more and more is emerging just about the pathophysiology of secondary injury - and some of those things haven't necessarily translated to what to do about it - but we've learned about things like cortical spreading depolarizations being associated with worse outcomes in traumatic brain injury, and we've also identified that ketamine or memantine can both actually stop those cortical spreading depolarizations. But the overall impact of managing them is still unknown, and the way that we detect those, it requires an invasive electrocorticography monitor which not all centers have. So, I think, one of the important things as we move forward in TBI care is, as we get this better mechanistic understanding of some of the pathophysiology that's happening in these TBI patients, figuring out a way to be able to translate that across all clinical settings where you can actually do the monitoring invasively - that's also an issue we see. Even intracranial pressure monitoring is pretty standard of care, but not all centers do that, and we have to be able to apply practice recommendations to centers where there isn't necessarily access to the same things that we have at large academic trauma centers. 

Dr Jones: Got it. Obviously, there's a lot of research in this area, a lot of clinical research, and I'm glad you mentioned the secondary injury - things that are happening at the tissue level are important for us to think about. As the care of patients with trauma has evolved (and I'm thinking now of patients with spinal cord injury), we still see patients who receive high-dose corticosteroids in the setting of acute spinal cord injury - and obviously, that's something that's evolved. Can you tell our listeners a little bit more about what they should be doing when they're seeing a patient with a traumatic spinal cord injury?

Dr Podell: Yes. So, the steroids story for spinal cord injury is kind of interesting. There were a series of trials called the NASCIS trials that looked at corticosteroids and spinal cord injury, and they were initially interpreted that high-dose steroids had a beneficial effect on spinal cord injury recovery - but then, kind of in relooking at the data and recognizing that these were kind of unplanned subgroup analyses that showed benefit, and then looking at kind of pooled reanalysis and meta-analysis of all the data out there, it was determined that there actually was no clear benefit from steroids and that there was a clear incidence of more complications from high-dose steroids. So, in general, corticosteroids are not recommended for spinal cord injury. Same for traumatic brain injury, too (even though some people will still give steroids for that) - there was a CRASH study that looked at corticosteroids in TBI and found worse outcomes in TBI (so there actually is high-level evidence not to use steroids in that case). That's not to say that there's not an inflammatory process that's going on that could be causing secondary injury - I think that's still, really, you know, an area of active research is to try to figure out what is the balance between potential adaptive mechanisms of inflammation that are happening versus more maladaptive sources of secondary injury from inflammation and how and when do we target that inflammation to improve outcomes. So, there's still, I think, more to come on that.

Dr Jones: And, you know, we are guided by evidence, obviously, but also, we learn from our experience as clinicians. You work in the neurocritical care unit. You take care of all patients with critical neurologic problems. When it comes to TBI and spinal cord injury, what kind of management tips or tricks have you learned that would be good for our audience to hear?

Dr Podell: I think the way that I would sum it up is that you should be very aggressive - supportive care early on, and then thoughtfully pull back and let the brain and spinal cord heal itself. And, you know, the patients come in with TBI (for example) very sympathetically aroused. They do need sedation, they need blood pressure support, they need mechanical ventilation - they need help kind of maintaining homeostasis. And other autonomic effects with spinal cord injury happen, too - you get neurogenic shock (you need very aggressive management of blood pressure, volume assessments), you know, in both cases in trauma patients, managing things like coagulopathy - but, you know, over time, usually, these things start to, kind of, heal themselves to some degree. And then, kind of thoughtfully figuring out when you can peel back on the different measures that you're doing to support them through their acute injuries. Different protocols have been developed, and the Brain Trauma Foundation has developed evidence-based guidelines that have improved (just having a protocol, we know, improves) trauma outcomes overall at centers - but I think those protocols are just guidelines, and you really have to pay attention to the individual patient in front of you. For TBI, for example, our guideline will say to aggressively manage fever within the first seven days with surface cooling. But in a patient that, for example, developed kind of a stroke or progressive cerebral edema even on day five (or something) you're looking at them, and on day seven, they're still having a lot of swelling in their brain, I'm not going to peel off the temperature management. So, there is nuance - you can't just kind follow a rule book in these patients.

Dr Jones: Got it. And I think that point about aggressive support early is a good takeaway for any listeners who might be engaged in the care of these patients. You know, I imagine working in that setting and taking care of patients who are in the midst of a devastating injury - I imagine that can be pretty challenging, but I imagine it could be pretty rewarding as well. What drew you to this particular area of interest, Dr Podell, and what do you find most exciting about it?

Dr Podell: A lot kind of converged for me in this area. I went into neurology thinking I would be a cognitive neurologist. I had more of a neuroimaging background and an interest in neural network pathology that certainly happens to patients with TBI (and patients with TBI often will have neuropsychiatric and neurocognitive problems after injury). But then, during residency, I found myself. My personality clicked in the ICU, and I just liked managing sick patients - I liked the pace of it, I also really liked it. It's kind of a team sport in the ICU with multiple people involved - the bedside nurses, respiratory therapists, neurosurgeons, trauma surgeons - all working together to figure out the best management plan for these patients, so you don't feel alone in managing them. And not all outcomes are good, obviously, but you can see people get better even during their course of their ICU stay - and that's really, really rewarding. And I think what we're seeing even in the literature following patients out longer and longer, the recovery trajectory for TBI is different than what we see in other neurologic injuries (like stroke, where the longer you go - up to ten, twenty years, even - people are still improving). I think the idea that you can keep hope alive for a lot of these patients and try to combat any kind of nihilism - obviously, there's a time and place for that after a really devastating injury, but I've seen a lot of patients who are really, really sick, needing therapeutic hypothermia, barbiturate coma, decompression, still then recovering and being able to come back into the ICU and talk to us.

Dr Jones: We might have some junior listeners who are thinking about behavioral neurology or neurocritical care, and it's probably - I don't know if it's reassuring, or maybe concerning, to them to know that they might swing completely to the other end of the spectrum of acuity, which is kind of what you did.

Dr Podell: Yeah, and what I'm trying to do now is, I'm very interested in autonomic dysfunction that happens in these patients. It's related a lot to multisystem organ dysfunction and, I think, may contribute to secondary injury, too, with changes in cerebral perfusion, especially in patients who have storming or even just the early autonomic dysregulation that happens early on. I think it's induced by neural network dysfunction from the brain injury, kind of similar to the way that there are other phenotypes that would be induced by neural network dysfunction (like coma).  So, we're trying to look at MRIs of acute TBI patients and trying to identify what structural imaging pathology then gives rise to these different kinds of clinical phenotypes - trying to bring it back to this neuroscience focus.

Dr Jones: Well, that gives us and our listeners something to look forward to, Dr Podell. And again, I just want to thank you for joining us, and thank you for such a great discussion on the care of patients with TBI, and spinal cord disorders and thank you for such a wonderful article.

Dr Podell: Thank you very much. It is my pleasure.

Dr Jones: Again, we've been speaking with Dr Jamie Podell, author of an article on traumatic brain injury and traumatic spinal cord injury in Continuum's latest issue on neurocritical care. Please check it out. And thank you to our listeners for joining today.

Dr Monteith: This is Dr Teshamae Monteith, Associate Editor of Continuum Audio. If you've enjoyed this episode, 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 article. Thank you for listening to Continuum Audio.  

Stiff Person Syndrome (SPS) is treatable if managed correctly from the outset. It is essential to distinguish SPS spectrum disorders from disease mimics to avoid both overdiagnoses and misdiagnoses.

In this episode, Allison Weathers, MD, FAAN, speaks with Marinos C. Dalakas, MD, FAAN, author of the article "Stiff Person Syndrome and GAD Antibody–Spectrum Disorders," in the Continuum® August 2024 Autoimmune Neurology issue.

Dr. Weathers is a Continuum® Audio interviewer and associate chief medical information officer at the Cleveland Clinic in Cleveland, Ohio.

Dr. Dalakas is a professor of neurology and director of the neuromuscular division at Thomas Jefferson University in Philadelphia, Pennsylvania; a professor of neurology and chief of the neuroimmunology unit and the National and Kapodistrian at the University of Athens in Athens, Greece.

Additional Resources

Read the article: Stiff Person Syndrome and GAD Antibody–Spectrum Disorders

Subscribe to Continuum: shop.lww.com/Continuum

Earn CME (available only to AAN members): continpub.com/AudioCME

Continuum® Aloud (verbatim audio-book style recordings of articles available only to Continuum® subscribers): continpub.com/Aloud

More about the American Academy of Neurology: aan.com

Social Media

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facebook.com/continuumcme

Full episode transcript available here

Dr Jones: This is Dr Lyell Jones, Editor-in-Chief of Continuum, the premier topic-based neurology clinical review and CME journal from the American Academy of Neurology.  Thank you for joining us on Continuum Audio, which features conversations with Continuum's guest editors and authors who are the leading experts in their fields. Subscribers to the Continuum journal can read the full article or listen to verbatim recordings of the article and have access to exclusive interviews not featured on the podcast. Please visit the link in the episode notes for more information on the article, subscribing to the journal, and how to get CME.

Dr Weathers: This is Dr Allison Weathers. Today, I'm interviewing Dr Marinos Dalakas about his article on stiff-person syndrome and GAD antibody-spectrum disorders, which is part of the August 2024 Continuum issue on autoimmune neurology. Dr Dalakas is a world- renowned expert in neuromuscular diseases and, really, the first name any neurologist thinks of when they hear the diagnosis of stiff-person syndrome. Dr Dalakas, this is such an honor to be able to speak to you today. Welcome to the podcast, and would you please introduce yourself to our audience?

Dr Dalakas: Yes, thank you very much. I'm so happy to participate in this interview. I'm the Chief of the Neuromuscular Division at Thomas Jefferson University in Philadelphia, and I am interested in autoimmune neuromuscular diseases for many years and also on disease mechanisms and immunotherapy.

Dr Weathers: Thank you again for talking with me today. So, given how very rare stiff-person syndrome and the GAD antibody-spectrum disorders are, prior to December 2022, I would have started our time together by asking you to explain this collection of diagnoses to our listeners and by also talking about how often they occur. It feels like that's a bit unnecessary ever since Celine Dion went public with her diagnosis - that moment really changed the public awareness of what was previously outside of neurology and almost unheard-of disease. So, instead, I'll start with, what is the key message of your article? If our listeners are going to walk away remembering one thing from our discussion, what would you like it to be?

Dr Dalakas: Well, I think the publicity has been very good for the disease, this disease spectrum. On the other hand, there have been some misleading messages, like, it's extremely rare, it's untreatable, it's disabling – which, they are partially correct, so, my message is, first, to make sure the neurologists make the correct diagnosis, because there are a lot of diseases similar to stiff-person, but they are not stiff-person. So, to make sure the diagnosis is correct and to make the patients aware of what to expect when they have this disease and what therapies we have and what we may have in the future. So, the number one message is the correct diagnosis and then to avoid overdiagnosis or misdiagnosis, because now we see both - we see overdiagnosis and misdiagnosis.

Dr Weathers: I think that's such a critically important point, and one you really delve into really beautifully in the article, so I encourage our listeners who do have access to it to really read through it. As I said, you do a great job really explaining that - and, actually, to go into that further, could you explain how you approach the diagnosis of a patient with possible stiff-person syndrome or one of the other GAD antibody-spectrum disorders? And I know you probably get asked that on a daily basis. As I was telling you before we actually formally started recording, I remember back when I was a resident and saw my first case of a suspected patient with stiff-person syndrome, my mentor advised me to look up your case series, your articles at the time, and really use that to guide my diagnosis. What do you feel is the most challenging aspect of diagnosing a patient with one of these conditions?

Dr Dalakas: Well, the first is the clinical symptomatology. We say the patients present with spasms and stiffness, but also, there are phobias. They are very hyperexcitable to sudden stimulations, to sudden noises, to unexpected touches, and all of them can cause spasms, and then when you examine the patients, they have stiffness. Now, the stiffness (if there is a true stiffness) results in gait abnormalities (the patients are falling because they're so stiff), and also, the hyperexcitability causes a lot of anxiety and a lot of phobias (they're afraid to cross the street, they're afraid to make a destination promptly) – so, all these things are sort of suggestive of stiff-person. So, these are the symptoms that you hear, you listen, and you ask the patients, and then, when you examine the patient, you look for certain signs that there are, specifically, like stiffness of what we call agonist muscles and antagonist muscles, which means there is stiffness of the abdominal muscles and at the same time, stiffness of the back muscles - so, this concurrent stiffness of these opposing muscles is very specific, very characteristic of the stiff person, so if you see that, and then you listen to the history, you're very close to the diagnosis, and then you do the antibodies. And the antibodies (the specific antibodies, the GAD antibody), but it is specific as we say in the article, and we tried to make this very clear to the neurologists, that it's the high titers that matter, because low titers are not necessarily specific. So high titers of antibodies in the serum, above 10,000 by ELISA (or whatever method they use; but it has to be this many times above normal), and then if you have high serum titers and all the symptoms they mentioned, it is stiff-person. On the other hand, if the titers are low, then you may want to do a spinal tap to see if there is synthesis of antibodies in the spinal fluid. That helps you. Now if the GAD antibodies are negative, then you start wondering, is this seronegative SPS? And how do you confirm the seronegative SPS? You do electrophysiology, and the electrophysiology is, again, to see if there is activity (muscle activity) concurrently from the agonist and antagonist muscles - in other words, from the, let's say the tibialis anterior and the gastrocnemius (so, it's two opposing muscles, eg, biceps and triceps) - and if you see activity in both of these opposing muscle groups, and you see also hyperexcitability (you touch the patient, you stimulate just a little, and you see activity in other muscle groups). So, the electrophysiology is very important if the patient's antibody negative, but they have the other symptoms that I mentioned before.

Dr Weathers: I can imagine how challenging those must be (those seronegative cases) to try to really make sure you're identifying and carefully determining that you have the right disease as you alluded to at the beginning. I know how hard it must be for patients to want to at least have some answers to have a diagnosis.

Dr Dalakas: And this is the main thing today, because the publicity, as I mentioned, the beginning, increased the receipt of some information, so they overdiagnose it, like, "Oh, you have this and this and this, so it may be stiff-person". And so, in fact, recently, we had a series of patients together with the Mayo Clinic Group of out of 173 patients referred to the Mayo Clinic for stiff-person – that's referred to them - only 28% had stiff-person. It's a low percentage, but it is an indication that the neurologists now refer patients to us for stiff-person, but we need to be very careful to correctly make a diagnosis.

Dr Weathers: On one hand, it's good that people are aware and considering the diagnosis, but it does highlight that risk of overdiagnosing.

Dr Dalakas: Yeah. It's the opposite of when I started this stiff-person syndrome (was close to 30 years ago at NIH) - at that time was underdiagnosed. This was the most rare disease, and I collected patients because at the NIH, I was also the Chief of the neuromuscular division there, and I was doing a study, so it was easy to collect patients (I collected more than 100 patients), but at that time, it was misdiagnosed. So, we had patients that I was seeing and they're really disabled, because they have been having the disease for many years, but they had been diagnosed either for Parkinson disease, for anxiety disorder, for psychiatric diseases, or for MS, or for myelopathies, or for myelitis - so many different things, and of course, they didn't have the correct diagnosis and they were disabled.

Dr Weathers: The side effect of having one of the most famous celebrities in the world having this rare disease - you know, the downside of the increased awareness, as we've said. So, moving on from the diagnosis to treatment - again, you do a, obviously, you know, an incredible job in the article, really going through the treatment options and your algorithms - what would you say is the most common misconception you've encountered in treating patients with this disease?

Dr Dalakas: The most common is now (with the publicity) is that it is a disabling disease. Well, it is disabling, but if you treat the disease correctly and early on, I'm not saying we're curing the disease - many diseases (autoimmune diseases), we help a lot, so there are some we make the patient feel normal, but the disease is there - so, if we start the correct therapy early, a good number of patients respond very well. But by the time the patients come to us, they are so stiff, they walk like a statue, or they come in a wheelchair - of course, it's difficult to reverse this, although we have been very happy to see patients with immunotherapies to get out of the wheelchair, to walk, to enjoy normal activities. So, we have made enough progress with the therapists to help a good number of patients. Now, what is the first therapy we do? Well, is what we call the antispasmodics - these are drugs that relax the stiffness that patients have, sort of a symptomatic therapy. It's not going to address the disease itself, but we address the symptoms. And of course, the symptomatic therapy in SPS is not just to relax the patients - it is related to the so-called GABAergic inhibition. So, the drugs that we use (like the benzodiazepines, or the baclofen, et cetera), these are the drugs that work on the GABAergic pathways. So, it is symptomatic therapy, but it works also on the mechanism, so it's not just a relaxing basis - but since the patients have a lot of phobias, the benzodiazepines also help the phobias. The anxiety and the phobias make the patients worse - they make them more stiff. And in the beginning, they go to psychiatrists because they are so phobic - they're phobic to walk. They hear something, they get so stiff. And I have patients coming at the National Airport in Washington to come to there needing aids in getting out of the plane - some of them get so stiff, they have to get an ambulance to come to the hospital because they're stiff everywhere. So, these phobias and anxiety have triggered a lot of my interest to the point of asking the investigators at the National Institute of Mental Health to see if there is any such thing like autoimmune phobias, because these patients have an autoimmune disease, so, well, maybe we can treat the phobias of immunology - well, we did not find anything, but I just sort of brought the idea maybe we have an autoimmune phobia. But on the other hand, when the patients get better, the phobias are reduced and they're more comfortable to walk. So, it's a very interesting complexity of the symptoms altogether.

Dr Weathers: That is – and, actually, that leads into my next question somewhat, that, as I mentioned in your introduction, you are the world expert in this rare disease. How did that happen? You talked about it a little bit just now. But how did you develop this particular interest and expertise? What drew you to this particular disease?

Dr Dalakas: Yes. It's interesting. I was interested in autoimmune neuromuscular diseases (many of them) and neuropathies and myopathies, and one day, I had a good friend of mine who was the clinical director of NINDS at that time, Dr Hallett. So, he saw patients in the movement disorder clinic and they had stiff-person (I don't know why they went to the movement disorder, but they went there), and Dr Hallett said, "Well, this is an autoimmune disease. You should work on this." And then, I started seeing one or two patients, and I was very impressed. Really, the symptomatology is so interesting. The patients are suffering, and they sort of give the impression that they're neurotic. So, it's just a combination of when you listen to the symptoms, I was very impressed with the depth of the discomfort that they have and without seeing anything - but, when you examine the patient, you see the stiffness and nothing else. They're not weak, like, we see patients with MS, with myopathies, with neuropathies - they have weakness. They may use a cane, they may use two canes, they may use a walker, because they're stiff. So, it's a different disability than you see in patients who are weak. So, this really made me so interested to understand the mechanism - what's going on here - and that's the reason I started and I put the protocol. And then, we did a lot of immunological studies to understand the mechanism, electrophysiological studies to look at these agonist and antagonist muscles - and of course, we named it also. You know, in the beginning, the syndrome was described as stiff man (stiff-man syndrome), and they're all women. They are most of them, women. In fact, there is an article in a major journal, three women with stiff-man syndrome - and this was many years ago. So, stiff-person will be a more proper term. And then we're seeing a lot of patients or more women, but also we have enough men.

Dr Weathers: So, we've talked a lot about the change with this disease in public awareness. How has that changed your day-to-day life - has it (with the change in public awareness)? Are you bombarded with media requests?

Dr Dalakas: Well, it has stimulated me to write more about the disease and more articles, but also to highlight certain things that were not known before. For example, I had recently a paper on late-onset stiff-person. So, people, we see now patients who develop stiff-person at the age of seventy - they are above sixty or so, overall - and they have more severe disease. These patients also have not good tolerance to the medications we use - so, it's a more challenging group, so it is important to make the diagnosis even in patients with late-onset. These people do less well, because, first of all, they're all misdiagnosed, because if you're a little stiff at the age of sixty-five or seventy - well, you have a bad back, so you all have degenerative disc disease, so you don't think of stiff- person in that age. So, the stimulus was to identify some other issues with the stiff-person. The other is to think of new trials - and I have been working on two new trials. They're not out yet. I'm working to see how best to apply the new therapies. And also, it came up the idea of what are the best ways to assess, objectively, to assess the response, because this is an issue from the beginning. When I did controlled trials at the NIH, and we had established the so-called stiffness index to see how stiff they are measurably, but it is still subjective. It's not really objective, it's not (weakness to measure). So, we have gait analysis, we have the time to walk. So, I think establishing objective criterion to assess response to therapy, it's an important one - and so, I have been working on this how to make it more objective or as subjective as we can.

Dr Weathers: I think that's fantastic. And you actually, I think, have already answered my question - which is, what is the next breakthrough coming in the diagnosis and management of patients with stiff-person syndrome and the GAD antibody-spectrum disorders - and I think it's going to be the outcomes of these trials. Is there anything else that you're really excited about coming along in this field?

Dr Dalakas: Well, I think that the hope is, then, better immunotherapy, because the patients respond to IVIG based on the controlled study. We did one with anti-B-cell therapy - it was not statistically positive, but we had some placebo effects, because that second trial included some patients who did not have severe disease, so it was difficult to assess mild response. So, I'm interested in other similar immunotherapies, and we were approaching companies to see if they can sponsor such a trial. I think the publicity helps a lot, because if I was going to approach a company before the publicity, nobody would be interested in - there's no, you know - it's money-driven, so they will not do it. But at the NIH, I did it, because NIH had the grants there to sponsor the trials. So, I think the publicity will help us. And I know talking to companies, there are one or two companies that they have expressed a lot of interest, and, hopefully, we can do some new trials and go work on it, but I don't have any clear drug at the moment. I cannot discuss a real drug.

Dr Weathers: Of course, of course, more to come, but still very exciting. And so, still to learn more about you - again, you're so well known, obviously, for what you've done for the field of neurology. What do you like to do outside of seeing neuromuscular patients in your research career? What do you do for fun for your hobbies?

Dr Dalakas: Well, I have two hobbies. One is I'm an art collector of abstract expressionism. So, I go to a lot of auction houses, and I bid often for certain artists that I'm very interested, some French artists, some at the New York School of Modern Art. The eras of the forties and fifties of the abstract expressionism - so that's my collection and my interest in not missing auctions. And the other was I have a interest in wine collection – but, so, most of the time, I read art and I collect art.

Dr Weathers: That is a great answer. I appreciate art. I am not (fortunately) at the auction and collecting stage yet, but that I will have to learn from you. That's wonderful.

Dr Dalakas: Yeah. I'm originally from Greece, and I have also a professorship at the University of Athens, and also I go there. I also have some European artists in my collection.

Dr Weathers: That's wonderful. We have one more modern piece that we've been lucky enough to have.

Dr Dalakas: Yeah, I started with the impression impressionistic art, but I evolved into abstract.

Dr Weathers: Who is your favorite artist?

Dr Dalakas: Well, it's, you know, Rothko and Newman. So, these are very expensive artists, of course, so I can, but in that school, so these artists are not alive now, but people who are working with Rothko and Newman in the other group - so, there are four or five of them that I collect.

Dr Weathers: I feel like we need a whole separate interview just to talk about that.

Dr Dalakas: But, they are very stimulating, because the colors talk to you, and it's not like an impressionistic piece that, sort of, their flowers are nice, et cetera - so the colors talk to you differently.

Dr Weathers: They do. I love Rothko. Well, thank you, Dr Dalakas, for joining me on Continuum Audio. This has been a wonderful conversation. Again, today, I've been interviewing Dr Marinos Dalakas, whose article on stiff-person syndrome and GAD antibody-spectrum disorders appears in the most recent issue of Continuum on autoimmune neurology. Be sure to check out Continuum Audio episodes from this and other issues, and thank you to our listeners for joining us today.

Dr Monteith: This is Dr Teshamae Monteith, Associate Editor of Continuum Audio. If you've enjoyed this episode, you'll love the journal, which is full of in-depth and clinically relevant information important for neurology practitioners. Use this link in the episode notes to learn more and subscribe. AAN members, you can get CME for listening to this interview by completing the evaluation at Continpub.com/AudioCME. Thank you for listening to Continuum Audio.

Many autoimmune neuromuscular disorders are reversible with prompt diagnosis and early treatment. Understanding the potential utility and limitations of antibody testing in each clinical setting is critical for practicing neurologists.

In this episode, Teshamae Monteith, MD, FAAN speaks with Divyanshu Dubey, MD, FAAN, author of the article "Autoimmune Neuromuscular Disorders Associated With Neural Antibodies," in the Continuum® August 2024 Autoimmune Neurology issue.

Dr. Monteith is the associate editor of Continuum® Audio and an associate professor of clinical neurology at the University of Miami Miller School of Medicine in Miami, Florida.

Dr. Dubey is an associate professor in the departments of neurology and laboratory medicine and pathology at the Mayo Clinic in Rochester, Minnesota.

Additional Resources

Read the article: Autoimmune Neuromuscular Disorders Associated With Neural Antibodies

Subscribe to Continuum: shop.lww.com/Continuum

Earn CME (available only to AAN members): continpub.com/AudioCME

Continuum® Aloud (verbatim audio-book style recordings of articles available only to Continuum® subscribers): continpub.com/Aloud

More about the American Academy of Neurology: aan.com

Social Media

facebook.com/continuumcme

@ContinuumAAN

Host: @headacheMD

Guest: @Div_Dubey

Transcript

Full episode transcript available here

Dr Jones: This is Dr Lyell Jones, Editor-in-Chief of Continuum, the premier topic-based neurology clinical review and CME journal from the American Academy of Neurology. Thank you for joining us on Continuum Audio, which features conversations with Continuum's guest editors and authors who are the leading experts in their fields. Subscribers to the Continuum journal can read the full article or listen to verbatim recordings of the article and have access to exclusive interviews not featured on the podcast. Please visit the link in the episode notes for more information on the article, subscribing to the journal, and how to get CME.

Dr Monteith: This is Dr Teshamae Monteith, Associate Editor of Continuum Audio. Today, I'm interviewing Dr Divyanshu Dubey about his article on autoimmune neuromuscular disorders associated with neural autoantibodies, which is part of the August 2024 Continuum issue on autoimmune neurology. Welcome to the podcast. How are you?

Dr Dubey: Hi, Dr Monteith. Thank you for inviting me to be a part of this podcast. I'm doing well.

Dr Monteith: Well, why don't you introduce yourself to the audience? And, call me Tesha.

Dr Dubey: I'm Divyanshu Dubey (please, call me Div). I'm one of the autoimmune neurology consultants here at Mayo Clinic Rochester. I'm an Associate Professor of neurology, as well as lab medicine and pathology. My responsibilities here are split - partly seeing patients (primarily patients with autoimmune disorders, including neuromuscular disorders), and then 50% of my time (or, actually, more than 50%), I spend in the lab, either doing research on these autoimmune disorders or reporting antibodies in a clinical setting for various antibody panels which Mayo's neuroimmunology lab offers.

Dr Monteith: That's a nice overlap of subspecialty area. How did you get into this work?

Dr Dubey: I think a lot of it was, sort of, by chance. Meeting the right people at the right time was the main, sort of, motivation for me. Initially, I trained in India for my medical school and didn't really got much exposed to autoimmune neurology in India. I think our primary concern in my training was sort of treating TB meningitis and cerebral malaria - that was my exposure to neurology, including stroke and some epilepsy cases. As a part of application for USMLEs and coming here to residency, I did some externships, and one of the externships was at Memorial Sloan Kettering Cancer Center, and that's when I worked a few weeks with Dr Posner and got introduced to the idea of paraneoplastic neurological syndrome working with him. And that sort of started - I wouldn't call it vicious cycle - but my interest in the area of autoimmune neurology and paraneoplastic neurological disorders, which subsequently was refined further through residency and fellowships.

Dr Monteith: That's interesting. I actually rotated through - I did a externship also at Sloan Kettering, and I had a clinic with Dr Posner. And I thought, at the time, he was such a rock star, and, like, I took a picture with him, and I think he thought it was insane. And I didn't go into autoimmune neurology. So, you know, interesting pathways, right?

Dr Dubey: Yes. And I think he's inspired many, many people, and sort of trained a lot of them as well.

Dr Monteith: So, why don't you tell us what you set out to do when writing this article?

Dr Dubey: So, I think, given my background and training in various subspecialties in neurology, I was, sort of, formally did fellowships in autoimmune neurology, as well as neuromuscular medicine. One of the areas in these areas that I focus on is in my clinical practice, as well as in my sort of lab work, is autoimmune muscular disorders - and that to, specifically, autoantibodies and their clinical utility for autoimmune muscular disorders. So, that's what I wanted to focus on in an article. When I was invited to write an article on autoimmune muscular conditions in general, I thought it was very difficult to pack it all in one chapter or one article, so I narrowed my focus (or tilted my focus) towards antibody-positive disorders and trying to understand how we as neurologists can firstly sort of identify these conditions (which may end up being antibody-positive) – and then, on the other hand, once we get these antibody results, how we can find the utility in them or find them useful in taking care of our patients. At the same time, I also wanted to kind of highlight that these antibodies are not perfect, they do have certain limitations – so, that's another thing I sort of highlighted in the article.

Dr Monteith: So, why don't we just start with a very broad question - what do you believe the role of autoantibodies is in the workup of neuropathies and then neuromuscular disorders? Obviously, when we think of myasthenia gravis, but there are some presentations that you may not necessarily think to first order autoantibody tests. So, what is the role, and where does it fit in the paradigm?

Dr Dubey: I think it's extremely crucial, and it's evolving as time goes on, and it's becoming more and more clinically relevant. Let's say three, four decades ago, the number of biomarkers which were available were very limited and only a handful - and there has been a significant increase in these biomarkers with growing utilization of newer techniques for discovery of antibodies, and more and more people jumping into this field trying to not only discover, but try and understand and validate these biomarkers (what they truly, clinically mean). These antibodies, like you pointed out, ones for myasthenia (such as acetylcholine receptor-binding antibodies, or MuSK antibodies), they can be extremely helpful in clinical diagnosis of these patients. We all know the importance of EMG in managing our patients with neuromuscular disorders. But, oftentimes, EMG nerve conduction studies are often not available at every center. In those scenarios, if you have antibodies with very high clinical specificity, and you're seeing a patient on examination whom you're seeing ptosis (fatigable ptosis), double vision, you're suspecting myasthenia, you send antibodies, and they come back positive. It brings you closer to the answer that may, in turn, require you to refer to a patient to a place where you can get high-quality EMGs or high-quality care. In addition to getting to the diagnosis, it also, sometimes, leads you in directions to search for what is the trigger. A good example is all these paraneoplastic neurological syndromes (which we started our conversation with), where once you find a biomarker (such as anti-Hu antibodies or CRMP5 antibodies) in a patient with paraneoplastic neuropathies, it can direct the search for cancer. These are the patients where, specifically, these two antibodies, small-cell lung cancer is an important cancer to rule out - they require CT scans, and if those are negative, consider doing PET scan – so, we can remove the inciting factor in these cases. And then, lastly, it can guide treatment. Depending upon subtypes of antibodies or particular antibodies, it can give us some idea what is going to be the most effective treatment for these patients.

Dr Monteith: I think paraneoplastic syndromes are a very good example of how autoantibodies can help guide treatment. But, what other examples can you provide for us?

Dr Dubey: Yeah, so I think one of the relatively recent antibody tests which our lab started offering is biomarkers of autoimmune neuropathies - these are neurofascin and contactin, and those are great examples which can target or guide your treatment. I personally, in the past, have had many CIDP patients before we were offering these testings, where we used to kind of start these patients on IVIG. They had the typical electrodiagnostic features, which would qualify them for CIDP. They did not show any response. In many of these cases, we tried to do sort of clinical testing or sort of research-based testing for neurofascin and contactin back in the day, but we didn't have this resource where we can sort of send the blood, hopefully, and within a week, get an answer, whether these patients have autoimmune neuropathy or not. Having this resource now, in some of these cases, even before starting them on IVIG, knowing that test result can guide treatments, such as considering plasma exchange up front as a first-line therapy, followed by rituximab or B-cell depleting therapies, which have been shown to be extremely beneficial in these conditions. And it is not just limited to neurofascin or contactin (which are predominantly IgG4-mediated condition), but the same concept applies to other IgG4-mediated diseases, such as MuSK myasthenia, where having an antibody result can guide your treatment towards B-cell depleting therapies instead of sort of trying the typical regimen that you try for other myasthenia gravis patients.

Dr Monteith: And you mentioned where I was reading that, sometimes, nerve conduction studies and EMG can be useful to then narrow the autoantibody profiles. Oftentimes, in the inpatient service, we order the autoantibodies much faster, because it's sometimes harder to access EMG nerve conduction studies - but talk about that narrowing process.

Dr Dubey: Yeah. And it goes back to the point you just made where we end up sending, sort of, sometimes (and I'm guilty of this as well), where we just send antibodies incessantly, even knowing that this particular patient is not necessarily likely to be an autoimmune neurological disorder, and that can be a challenge, even if the false-positive rate for a particular test is, let's say 1% - if you send enough panels, you will get that false-positive result for a particular patient. And that can have significant effects on the patient - not only unnecessary testing or imaging (depending on what type of antibody it is), but also exposure to various immunotherapies or immunosuppressive therapies. It's important to recognize red flags – and that's one of the things I've focused on in this article, is talking about clinical, as well as electrodiagnostic, factors, which make us think that this might be an autoimmune condition, and then, subsequently, we should consider autoantibody testing. Otherwise, we can be in a situation - that 1% situation - where we may be sort of dealing with a false-positive result, rather than a true-positive result. In terms of EMGs, I think I find them extremely useful, specifically for neuropathies, distinguishing between demyelinating versus exonal, and then catering our antibody-ordering practices toward specific groups of antibodies which are associated with demyelinating neuropathies (if that's what the electrophysiology showed) versus if it's an exonal pathology (considering a different subset of antibodies) - and that's going to be extremely important.

Dr Monteith: You're already getting to my next question, which is what are some of the limitations of autoantibody testing? You mentioned the false-positivity rate - what other limitations are there?

Dr Dubey: So, I think the limitations are both for seropositive, as well as seronegative, patients. As a neurologist, when we see patients and send panels, we can be in a challenging situation in both of those scenarios. Firstly, thinking about seropositives - despite the growing literature about neurology and antibodies, we have to be aware, at least to some extent, about what methodologies are being utilized for these antibody tests. And what I mean by that is knowing when you're sending a sample to a particular lab, the methodology that they're utilizing - is that the most sensitive, specific way to test for certain antibodies? We've learned about this through some of the literature published regarding MOG and aquaporin-4, which has demonstrated that these antibodies, which we suspect are cell surface antibodies, not only generate false-positive, but also false-negative results if they are tested by Western blots or ELISAs. Similar can be applied to some of the cell surface antibodies we are investigating on the autoimmune neuromuscular side (we have some sort of unpublished data regarding that for neurofascin-155). Secondly, it's also kind of critical when you're getting these reports to kind of have a look at what type of secondary antibodies are being utilized, an example being we talked about neurofascin-155, and I mentioned these are IgG4-predominant diseases, so testing for neurofascin IgG4 and knowing that particular patient is positive IgG4 rather than neurofascin pan-IgG. That's an important discrimination, and important information for you to know, because we have seen, at least in my clinical practice, that patients who are positive for neurofascin IgG4 follow the typical story of autoimmune neuropathies - the ones who are not (who are just neurofascin-155 IgG-positive), oftentimes can have wide-ranging phenotypes. The same applies to neurofascin-155 IgMs. And then (not for all antibodies, but for some antibodies), titers are important. A good example of that is a3 ganglionic receptor antibodies, which we utilize for when we're taking care of patients who have autoimmune dysautonomia - and in these cases, if the titers of the antibodies are below .2 nmol/L, usually, those don't have a high specificity for AAG diagnosis. So, I get referred a lot of patients with very low titers of a3 ganglionic receptor antibodies, where the clinical picture does not at all look like autoimmune autonomic ganglionopathy. So, that's another thing to potentially keep in mind. And then, on the seronegative front, it's important to recognize that we are still sort of seeing the tip of the iceberg as far as these antibodies or biomarkers are concerned, specifically for certain phenotypes, such as CIDP. If you look at the literature, depending upon what demographics we're looking at or sort of racial profiles we're looking at, the frequency of these autoimmune neuropathy biomarkers range from 5% to 20%, with much higher frequency in Asian patients - so, a good chunk of these diseases are still seronegative. In the scenario where you have a very high suspicion for an autoimmune neuromuscular disorder (specifically, we'll talk about neuropathies, because that's why we utilize tissue immunofluorescence staining on neural tissues), I recommend people to potentially touch base with that tertiary care lab or that referral lab to see if they have come across some research-based antibodies which are not clinically validated, which can give you some idea, some additional supportive idea, that what you're dealing with is an autoimmune neuromuscular disorder. So, we have to keep the limitations of some of these antibody panels and antibody tests in mind for both positive, as well as negative, results.

Dr Monteith: So, you've already given us a lot of good stuff, um, about titer seronegativity and false-positive rates. And, you know, also looking at the clinical picture when ordering these tests, utilizing EMG nerve conduction studies, give us a major key point that we can't not get when reading your article.

Dr Dubey: I think the major key point is we are neurologists first and serologists later. Most of these patients, we have to kind of evaluate them clinically and convince ourselves at least partly that this might be an autoimmune neuromuscular disorder before sending off these panels. Also, I find it useful to narrow down the phenotype, let's say, in a particular neuropathy or a muscle disease or a hyperexcitability syndrome. So, I have a core group of antigens, autoantigens, or autoantibodies, which I'm expecting and making myself aware of - things beyond that will raise my antenna - potentially, is this truly relevant? Could this be potentially false-positive? So, clinical characterization up front, phenotypic characterization upfront, and then utilizing those antibody results to support our clinical decision-making and therapeutic decision-making is what I've tried to express in this article.

Dr Monteith: And what is something that you wish you knew much earlier in your career?

Dr Dubey: It's a very challenging field, and it's a rapidly evolving field where we learn many things nearly every year, and, sometimes, we learn things that were previously said were incorrect, and we need to kind of work on them. A good example of that is initial reports of voltage-gated potassium-channel antibodies. So, back in the day when I was actually in my medical school and (subsequently) in my residency, voltage-gated potassium-channel antibodies were closely associated with autoimmune neuromyotonia, or autoimmune peripheral hyperexcitability syndromes. Now, over time, we've recognized that only the patients who are positive for LGI1 or CASPR2 are the ones who truly have autoimmune neuromuscular disorders or even CNS disorders. The voltage-gated potassium-channel antibody by itself, without LGI1 or CASPR2, truly doesn't have a very high specificity for neurological autoimmunity. So, that's one example of how even things which were published were considered critical thinking or critical knowledge in our field of autoimmune neuromuscular disorders has evolved and has sort of changed over time. And, again, the new antibodies are another area where nearly every year, something new pops up - not everything truly stands a test of time, but this keeps us on our toes.

Dr Monteith: And what's something that a patient taught you?

Dr Dubey: I think one of the things with every patient interaction I recognize is being an autoimmune neurologist, we tend to focus a lot on firstly, diagnosis, and secondly, immunotherapy - but what I've realized is symptomatic and functional care beyond immunotherapy in these patients who have autoimmune neurological disorders is as important, if not more important. That includes care of patients, involving our colleagues from physical medicine and rehab in terms of exercise regimen for these patients as we do immunotherapies, potentially getting a plan for management of associated pain, and many other factors and many other symptoms that these patients have to deal with secondary to these autoimmune neurological conditions.

Dr Monteith: I think that's really well said, because we get excited about getting the diagnosis and then getting the treatment, but that long-term trajectory and quality of life is really what patients are seeking.

Dr Dubey: Yeah, and as you pointed out, most of the time, especially when we are in inpatient service, or even when we're seeing the patients upfront outpatient, we are seeing them, sometimes, in their acute phase or at their disease not there. What we also have to realize is, what are the implications of these autoimmune neurological conditions in the long term or five years down the line? And that's one of the questions patients often ask me and how this can impact them even when the active immune phase has subsided - and that's something we are actively trying to learn about.

Dr Monteith: So, tell me something you're really excited about in your field.

Dr Dubey: I think, firstly (which is pretty much the topic of my entire article), is novel antibodies and new biomarker discoveries. That's very exciting - we are actively, ourselves, involved in the space. The second thing is better mechanistic understanding of how these antibodies cause diseases, so we can not only understand diseases, we can also try and understand how to target and treat these diseases - this is being actively done for various disorders. One of the disorders which continue to remain a challenge are T-cell mediated diseases, where these antibodies are just red flags or biomarkers are not causing the disease, but it's potentially the T-cells possibly attacking the same antigen which are causing disease process, and those are often the more refractory and harder-to-treat conditions. I'm hoping that with some of the work done in other fields (such as rheumatology or endocrinology for type one diabetes), we're able to learn and apply the same in the field of autoimmune neurology and autoimmune neuromuscular medicine. And then, the final frontier is developing therapies which are antigen specific, where you have discovered that somebody has a particular antibody, and if that antibody is pathogenic, can I just deplete that antibody, not necessarily pan-depleting the immune system. And there is some translational data, there's some animal model data in that area, which I find very exciting, will be extremely helpful for many of my patients.

Dr Monteith: So, very personalized targeted therapies?

Dr Dubey: Correct. Without having all the side effects we all have to kind of take care of in our patients when we start them on, let's say, cyclophosphamide, or some of these really, really, significantly suppressive immunosuppressive medications.

Dr Monteith: Well, thank you so much. I learned a lot from reading your article to prepare for this interview, but also just from talking to you. And it's clear that you're very passionate about what you do and very knowledgeable as well, so, thank you so much.

Dr Dubey: Thank you so much. Thank you for inviting me to do this. And thank you for inviting me to contribute the article.

Dr Monteith: Today, I've been interviewing Dr Divyanshu Dubey, whose article on autoimmune neuromuscular disorders associated with neural autoantibodies appears in the most recent issue of Continuum on autoimmune neurology. Be sure to check out Continuum Audio episodes from this and other issues. And thank you to our listeners for joining us today.

Dr Monteith: This is Dr Teshamae Monteith, Associate Editor of Continuum Audio. If you've enjoyed this episode, you'll love the journal, which is full of in-depth and clinically relevant information, important for neurology practitioners. Use this link in the episode notes to learn more and subscribe. AAN members, you can get CME for listening to this interview by completing the evaluation at Continpub.com/AudioCME. Thank you for listening to Continuum Audio.

Basic knowledge of the common CNS manifestations of rheumatologic diseases and sarcoidosis is important. In the context of many systemic inflammatory diseases, CNS disease may be a presenting feature or occur without systemic manifestations of the disease, making familiarity with these diseases even more important.

In this episode, Kait Nevel, MD speaks with Jennifer A. McCombe, MD, author of the article "Neurologic Manifestations of Rheumatologic Disorders," in the Continuum® August 2024 Autoimmune Neurology issue.

Dr. Nevel is a Continuum® Audio interviewer and a neurologist and neuro-oncologist at Indiana University School of Medicine in Indianapolis, Indiana.

Dr. McCombe is an associate professor in the Division of Neurology, Department of Medicine at the University of Alberta, Edmonton in Alberta, Canada.

Additional Resources

Read the article: Neurologic Manifestations of Rheumatologic Disorders

Subscribe to Continuum: shop.lww.com/Continuum

Earn CME (available only to AAN members): continpub.com/AudioCME

Continuum® Aloud (verbatim audio-book style recordings of articles available only to Continuum® subscribers): continpub.com/Aloud

More about the American Academy of Neurology: aan.com

Social Media

facebook.com/continuumcme

@ContinuumAAN

Host: @headacheMD

Guest: @Div_Dubey

Transcript

Full episode transcript available here

Dr Jones: This is Dr Lyell Jones, Editor-in-Chief of Continuum, the premier topic-based neurology clinical review and CME journal from the American Academy of Neurology.  Thank you for joining us on Continuum Audio, which features conversations with Continuum's guest editors and authors who are the leading experts in their fields. Subscribers to the Continuum journal can read the full article or listen to verbatim recordings of the article and have access to exclusive interviews not featured on the podcast. Please visit the link in the episode notes for more information on the article, subscribing to the journal, and how to get CME.

Dr Nevel: Hello. This is Dr Kait Nevel. Today, I'm interviewing Dr Jennifer McCombe about her article on neurosarcoidosis and neurologic involvement of rheumatological disorders, which appears in the August 2024 Continuum issue on autoimmune neurology. Welcome to the podcast, and I would love to have you introduce yourself to the audience.

Dr McCombe: Well, thank you, and thank you for having me. As you said, my name is Jen McCombe. I'm a neurologist in Edmonton, Alberta, Canada, where I spend kind of a third of my time in teaching roles (I coordinate the undergraduate block for our medical school there), I spend about a third of my time in a neuroinflammatory clinic in Edmonton, Alberta, and then about a third of my time doing clinical research.

Dr Nevel: Wonderful. Well, thank you so much for being here today and for chatting with me about your article on this topic.

Dr McCombe: Thank you for having me.

Dr Nevel: To start off, can you share with the listeners a little bit about your career path?

Dr McCombe: Absolutely. Yeah. So, I've had, uh, a bit of a circuitous career path. I did my medical school in Queens (which is in Eastern Canada, in Kingston, Ontario) and then went back to Edmonton, Alberta, for my residency (in Canada, we have a five-year residency program, so a little bit different than the US), but finished my residency and then did a master's degree in Public Health at Johns Hopkins while completing clinical research in HIV, actually, and did this thing we call the Clinical Scholar Training Program – so, kind of like a fellowship, but a little bit more, you know, research and academic-based. So, when I first started, I was focused more on neuroinfectious diseases, and that's kind of what my career path looked like at the time - but, actually, shortly after I finished my residency program, I also had my first child, and he, unfortunately, developed opsoclonus-myoclonus syndrome, and at the time (this was in 2010), it was a rather rare condition, so, I ended up finding myself having to become a bit of a neuroinflammatory disease specialist at the same time. So, at that point, I transitioned into working in the neuroinflammatory clinic with some mentorship but was getting all of the kind of weird and wonderful referrals and diagnostic dilemmas from my colleagues who recognized I kind of developed some expertise, and so decided (actually, mid-career) to take a sabbatical, and in 2021, completed a fellowship in autoimmune neurology at the Mayo Clinic. So, I finished that quite recently and then went back, and now I'm feeling much more, I guess, confident, too. Sometimes, you wonder about, you know, the choices you're making. I recognize most of the conditions I'm dealing with don't have, in fact, any evidence for their treatment, and that was confirmed when I went to the Mayo Clinic and found that, really, it was just trying to gain an understanding of the disease process to make a rational choice to medications and treatments. So, now, I'm back and kind of trying to focus a little bit more on some clinical research in that area since I've kind of solidified that expertise.

Dr Nevel: Wow. Well, thank you for sharing with us your career path and how, you know, unexpected life events kind of changed your interests or molded your interests (changed kind of the things that you became expert in, you know), and being fluid in your career path and willing to kind of take a break and reassess and get additional training. That's really inspiring to, I think, to me, and probably to a lot of listeners, that you can always, you know, develop more expertise in the more niche area or additional area no matter where you are in your stage of life or career path.

Dr McCombe: Yeah.

Dr Nevel: So, can you tell us a little bit more about - you know, you shared with us kind of autoimmune inflammatory disorders and how you became interested in that, neurosarcoidosis, specifically (you know the article focuses on that), and what's your background in neurosarcoidosis, how you became interested in that specifically and in neurologic manifestations of rheumatologic disorders?

Dr McCombe: I started in our neuroinflammatory clinic over a decade ago, and, you know, at the time, a lot of the expertise in any of these neuroinflammatory disorders was quite spread out over the country, and so, as I kind to alluded to before, often some of the more complicated patients where there wasn't necessarily clear-cut evidence or even, you know, a fellowship path to get there, I would end up getting referrals for - and so, I developed quite a cohort of patients with central nervous system primarily, but other types of neuroinflammatory and autoimmune neurologic diseases, and part of that cohort was a rather large (and still growing) group of patients with neurosarcoidosis. And so, I kind of developed some practical expertise, although, as you can see in the article (and as I'm sure you all know), the approach to the treatment is extremely variable. One of the most telling things is when we were at the Mayo Clinic, one of my co-fellows actually pulled all of the neurologists in neuroinflammation at all of the Mayo Clinic sites and asked them, you know, what is your treatment approach to a patient with neurosarcoidosis, and I think got twelve completely different responses as to the medications chosen and the length of time for the tapers and things like that. So, you know, it is very much a part of neurologic disease treatment that we still really don't have great evidence for, and although we do have some kind of rational choices that we can make based on other types of evidence, so -

Dr Nevel: Yeah.

Dr McCombe: And I enjoy working with patients with these types of diseases where we can kind of work together to come up with a treatment plan that makes sense for them and also makes sense based on whatever evidence we do have at this time.

Dr Nevel: Yeah. So, moving on to the article a little bit, knowing that this is a area of neurology where there's a lot of, you know, maybe personal expertise and experience but not a ton of data or evidence to necessarily guide our standardization to our treatments and approach, what do you think is the most important clinical takeaway from your article for our listeners?

Dr McCombe: Well, I mentioned before I coordinate the neuro block for our undergraduate program here, so I've developed over the years (I've been doing that for a number of years) a curriculum that's all based on, kind of, that approach to - and I like to do it that way because it's very practical. I like the students to be able to basically take their class notes and then go to the emergency department on their first shift as a clerk and, you know, use their approach to headache that I've developed for them to kind of take a clinical history and examine a patient with that sort of problem. And so, similar to that, I tried to do an approach to, you know, a couple of the more common presentations that would make you think of a rheumatologic condition or neurosarcoidosis in looking at the approach to CNS vasculitis and the approach to, uh, pachymeningitis - and these are difficult differentials for lots of neurologists, because it really relies on a lot of medicine knowledge, and we graduate from our residencies slightly more confident in our medicine knowledge, because we get a lot of that in our residencies. But as neurologists, as we go through our careers, we get much more confident in our areas of specialty, and at least for myself and many of my colleagues, much less confident in other things like general medicine. And so, it's difficult, because you have to face your areas of potentially less confident knowledge and really think about that in the differential - and so, I think, you know, I put those two big "approach to" sections in there, because they're the most relevant for the conditions that I was covering. But, I think also what I would say to a learner or a more experienced neurologist who might be reading the article, kind of pick out the little things that you might add to your own kind of approach to - you know, when you see that person with an ataxia, remember that Sjogren syndrome is one of the things you might consider that could be a treatable cause, or you want to see a sensory neuronopathy, don't just think paraneoplastic – again, Sjogren syndrome. So, kind of pick out those little pearls and add them to your approach to that patient that we all see, and I think that would be my biggest takeaway.

Dr Nevel: Yeah. Thank you. So, kind of like, keep this information from the article in mind so that you keep rheumatologic disorders in mind as a possibility when you're approaching a patient with whatever neurologic symptoms they're presenting with. So, what do you think is challenging? You kind of already mentioned a little bit, you know, just that it stretches us maybe into the medicine arena and so maybe stretches our medical knowledge, especially as we become more subspecialized or focused in neurology - but what is challenging about identifying, diagnosing neurologic symptoms as being related or due to an underlying rheumatologic disorder?

Dr McCombe: Absolutely. Yeah. Well, as you said, you know, it forces us to kind of face that medicine stuff that we might not be as comfortable with, but I think what else is challenging is that, sometimes, those medical clues aren't there. For the rheumatologic disorders for the most part, they are. Sjogren's is potentially a little bit different in that, potentially, the symptoms are less obvious or a little bit more subtle. But, in particular, with neurosarcoidosis, there's a distinct proportion of the patients that won't, in fact, have any systemic complications of their underlying disease, and so, you have to think about it even when the clues aren't there. That's why you have to add it to those kind of differential diagnoses where it might be considered, because those systemic clues that we all rely on when we do our review of systems and we ask about rashes and joint pain and lung issues, and these sorts of things may not be there - and so, you still have to think about it even when it might be completely isolated to the central nervous system.

Dr Nevel: What is our understanding of why some patients with rheumatologic disorders develop neurologic involvement? Do we have an understanding? Do we know why some patients do and some patients don't? I know that's, you know, kind of, uh - that's a tough question, but that was something that I thought of as I was reading your article, like, why does this happen to some people?

Dr McCombe: Absolutely. I mean, I think, potentially, it's a little bit more clear for some of them, like rheumatoid arthritis, because, typically, if you develop a CNS complication of this, it's, in fact, just because you've had the disease for a very long time, and often, it's uncontrolled, and so you think about the disease "spreading" now to the central nervous system - but for other conditions, like neurosarcoidosis, it is much less clear, and even if you look at the epidemiologic patterns for that, it makes it even more muddied in that in some populations, it appears that they develop more central nervous system disease, whereas in others, less. And so, why that is the case and why certain individuals might develop this complication of these diseases I think is yet to be seen.

Dr Nevel: Yeah, that's always the crux of things if we can figure out the why, then maybe we could prevent it, right?

Dr McCombe: Million-dollar question always.

Dr Nevel: Always. So, what do you find the most intriguing about neurologic involvement of rheumatologic disorders?

Dr McCombe: Well, I think one of the things that, really, I mean, for neurosarcoidosis in particular, so many patients do so well, and that's what I really like about it. You know, you see patients who present with an incredible burden of disease radiologically, and yet, don't look nearly as sick as they should when they're sitting in front of you. And then, you start them on therapies and some of them do so well, and even those with relatively devastating deficits, or moderate disease who do have neurologic symptoms, have a remarkable improvement in their neurologic symptoms with treatment. And so, that's always something that's quite rewarding when you get to see these patients in follow-up, and they're generally quite thankful because they're doing so well. And it's different from many of the neurologic diseases that we treat. I mean, in autoimmune neurology, we're lucky because we do have a number of diseases that are quite treatable and patients can have wonderful outcomes. But, you know, it's always scary when we see patients with devastating neurologic signs and it's great to see improvement with treatment. And so, that really draws me to it.

Dr Nevel: Yeah, absolutely. That's really rewarding when you're able to help somebody get better in such a profound way.

Dr McCombe: Mm hmm.

Dr Nevel: What is one common misconception about neurologic manifestations of rheumatologic disorders? Or what do you think is not well understood by treating clinicians?

Dr McCombe: I think probably one of the things I see the most is, sometimes, an undertreatment of the patient. And so, I see patients who, you know, other clinicians may have seen and have made the diagnosis, and perhaps it's a lack of confidence in the diagnosis and so they kind of want somebody else with a subspecialty to kind of confirm the diagnosis, but that treatment hasn't been initiated despite pathological confirmation on biopsy of another tissue. And these patients, like I alluded to before, they do well, but you need to treat them and you need to treat them adequately, and when their symptoms are quite impairing, you need to treat them adequately now. And so I think, sometimes, that delay in starting a second-line therapy and relying on steroids for too long - those sorts of things can really expose a patient to a lot of different side effects and to a lot of different complications that they may not have had, too. So, that's why I spent some time focusing on the treatment, because I think just gaining a little bit of comfort with some of these more common second-line medications is a good thing, because starting those early, I think, makes sense because you can really save the patient a lot. And then, the other thing, too, is that when you're using steroids, think about all of the systemic things that you're causing - think about the increased risk of infection and the fact that you need to prophylax for certain infections, think about bone health, think about protecting the lining of someone's stomach - so not only kind of thinking about your disease in isolation and what you need to do for treatment, but that you need to ensure that you're appropriately prescribing the patient all of the things they need to do to protect themselves during these times.

Dr Nevel: Yeah. I think that's so important. And I'm glad that you brought that up, because I think, unfortunately, many of us have seen a patient who ended up having PJP pneumonia (or something like that) because they weren't put on antibiotic coverage for prolonged steroid use or, you know, bone health - all of that is really important to think about. So, this may be entering a territory where there's no, you know, great evidence, but you mentioned, you know, starting kind of that maintenance or second-line agent - when do you decide to do that in patients? And maybe we can focus (since it gets a little broad), but, you know, in a patient with neurosarcoidosis, let's say - when you're starting the steroids, when do you decide, okay, this person is also going to need a maintenance therapy? Is that something that you do at the beginning when you're starting the steroids, or is that something that you think about later on depending on how their course goes?

Dr McCombe: Yeah. In my practice, I do it at the outset - again, because I'm quite focused on, you know, as soon as I get them on it, getting people off steroids - and so I start essentially almost all of my patients on it unless there's some other contraindication or complication to their disease. And because I deal with central nervous system complications in the vast majority of my patients, I'm starting a TNF-a inhibitor as well as methotrexate, and that's because I see a lot of patients with cord disease and significant brain disease, and so I want to treat them kind of more aggressively from the outset. And so, typically, they'll be on steroids, um, a TNF-a inhibitor, as well as methotrexate, and then I just back off, actually, as they do well. And so, I try to taper the steroids quite quickly over the course of just a number of weeks, or kind of two to three months at most. I maintain the TNF-a inhibitor, and then in some patients, depending on how they're doing, I might eventually stop the methotrexate. Some patients tolerate it so well that we don't for a number of months - other patients want to try to minimize their medications as quick as they can. So, that's my personal practice. In the province where I live, we don't have to worry about access to these medications, and so I understand that that might be an issue in some centers where people practice and have different access and different funding. Of course, I live in a country where we have universal healthcare, and in our province, I have very good access to these medications and they're funded from my patients regardless of socioeconomic status, and so I have the luxury of making these choices and I understand that other people might not, but that's my personal practice and I find it works quite well in the vast majority of patients.

Dr Nevel: Yeah. And you bring up a really good point that, you know, access to some of these medications for patients with CNS manifestations of sarcoidosis, neurosarcoidosis, sometimes can be challenging to treating the patient with medications that you feel like would be best for them. But that's wonderful that you don't have those access issues where you live. How long do you typically continue the TNF-a inhibitor in patients, since you mentioned, you know, tapering off the steroids, tapering off the methotrexate, potentially depending on patient tolerance and course. What's your approach to the TNF-a inhibitor?

Dr McCombe: Yeah, so, of course I follow them clinically, and then radiologically as well, and it's really satisfying if you can see the resolution of their symptoms as well as resolution of the abnormalities and the MRI, so I let that guide me a little bit. But, in most patients, I keep them on therapy for about one to two years, and then at that point, see if I can cease it in some patients. And I, again, continue to follow them radiologically and clinically after I cease it so that I can ensure that I'm catching their disease more quickly if it does come back and then can just reinitiate therapy, but in lots of patients you're able to stop the medication and they have persisting, kind of, disease freedom after that, and so they don't need to be on anything.

Dr Nevel: Yeah, great. And I'm almost hesitant to focus so much on neurosarcoidosis. (It was the rheumatologic manifestation that you talked about the most in your article.) I'm going to put in a plug for everybody to read your article so that they can read about neurologic manifestations of rheumatoid arthritis, Sjogren's, lupus, Behcet's - many more things. But focusing on neurosarcoidosis, it can be difficult in my experience to definitively diagnose, and people who have neurosarcoidosis particularly, and people who don't seem to have any systemic manifestations or, you know, imaging findings consistent with sarcoidosis - can you share your approach with us? And you outlined this in your article nicely, too, but your personal approach to patients with suspected neurosarcoidosis, and how you make that clinical decision to treat somebody with possible neurosarcoidosis, somebody who maybe you're not able to get pathologic evidence on?

Dr McCombe: Absolutely. Yeah, those ones are difficult. And, you know, whenever possible (as I mentioned in my article), I think pathological evidence of a diagnosis is important, because then when you find yourself a year down the road and a treatment path and you have uncertainty, it's much more difficult to consider continuing medications that can have quite a number of side effects when you're not absolutely certain about that diagnosis. But, in some patients, you know, I've had patients who might have nondiagnostic biopsies (if you attempt to do a biopsy), or they have disease in a site that really just isn't amenable to biopsy, or they have some other reason they can't have a biopsy. So, how I approach that is that, you know, if you think about possible neurosarcoidosis similar to any other nondiagnosed, you know, blow out-like lesion (for lack of a better term) in the CNS, if it's steroid-responsive, I think that kind of going down a path of treating it as a steroid-responsive lesion is kind of the approach that I take - so the diagnosis in the chart might be possible neurosarcoidosis, but in the back of my mind, I'm just thinking of kind of a steroid-responsive nondiagnostic or idiopathic lesion. So, I then follow that up typically with something like methotrexate (so, a more broader- spectrum immunosuppressant-type medication), and if the methotrexate is able to maintain the response that the steroids initiated, then eventually get them off the steroids. And so, you know, if I think about my patients that I've treated in the past, if they have a diagnosis of possible neurosarcoidosis, I probably don't start a TNF-a inhibitor as quickly in them, because in the back of my mind, I'm always wondering what type of inflammatory lesion this is, but that steroid responsiveness really helps me decide to start a second-line or maintenance therapy and then, typically, in those patients, as I mentioned, I'll start something like methotrexate a little bit more soon.

Dr Nevel: Yeah, great. Thanks for sharing that with us. So, what do you think comes next in this field? What excites you? Where do you think our next kind of development or understanding or breakthrough, whether it's diagnostic or treatment-wise?

Dr McCombe: I think, in the field, you know, any immunologic diseases, we've been really gaining a much better understanding of pathophysiology, and that's honestly what excites me the most, when you can know precisely what part of the immune system is at play here (whether it's, you know, complement-mediated or antibody-mediated) and then being able to then rationally choose medications based on a really clear understanding of the disease is something that I think is kind of novel in a way. For so many years, we would use kind of big broad-spectrum immunosuppression - even in multiple sclerosis, still, we use medications that, historically, we've found to be helpful - but we don't have a great understanding sometimes of why the medicines work. So, kind of going at it from the other way, where we're actually determining what is the exact pathophysiology of disease and then making a rational approach to a therapy, or choosing a therapy based on that, I think is what excites me the most, and I think we'll gain a better understanding of even a broader swath of diseases and be able to make those choices more often. That's what I like about this field.

Dr Nevel: Great. Well, thank you so much for sharing that - and looking forward to the future in this area of neurology. And thanks so much for talking with me today and sharing your story and your expertise and knowledge.

Dr McCombe: Well, thank you for having me. It's been fun.

Dr Nevel: And I encourage all the listeners to read your article. Again, today, I've been interviewing Dr Jennifer McCombe, whose article on neurosarcoidosis and neurologic involvement of rheumatologic disorders appears in the most recent issue of Continuum on autoimmune neurology. Be sure to check out Continuum Audio episodes from this and other issues, and thank you to our listeners for joining today.

Dr Monteith: This is Dr Teshamae Monteith, Associate Editor of Continuum Audio. If you've enjoyed this episode, you'll love the journal, which is full of in-depth and clinically relevant information important for neurology practitioners. Use this link in the episode notes to learn more and subscribe. AAN members, you can get CME for listening to this interview by completing the evaluation at Continpub.com/AudioCME. Thank you for listening to Continuum Audio.

Over the past 20 years, more than 50 antibodies have been identified and associated with autoimmune neurologic disorders. Although advances in diagnostic testing have allowed for more rapid diagnosis, the therapeutic approach to these disorders has largely continued to rely on expert opinion, case series, and case reports.

In this episode, Allison Weathers, MD, FAAN, speaks with Tammy L. Smith, MD, PhD, an author of the article "Therapeutic Approach to Autoimmune Neurologic Disorders," in the Continuum® August 2024 Autoimmune Neurology issue.

Dr. Weathers is a Continuum® Audio interviewer and associate chief medical information officer at the Cleveland Clinic in Cleveland, Ohio.

Dr. Smith is a GRECC investigator and staff neurologist at George E. Wahlen Veteran Affairs Medical Center and an assistant professor of neurology, at the University of Utah in Salt Lake City, Utah.

Additional Resources

Read the article: Therapeutic Approach to Autoimmune Neurologic Disorders

Subscribe to Continuum: shop.lww.com/Continuum

Earn CME (available only to AAN members): continpub.com/AudioCME

Continuum® Aloud (verbatim audio-book style recordings of articles available only to Continuum® subscribers): continpub.com/Aloud

More about the American Academy of Neurology: aan.com

Social Media

facebook.com/continuumcme

@ContinuumAAN

Transcript

Full episode transcript available here

Dr Jones: This is Dr Lyell Jones, Editor-in-Chief of Continuum, the premier topic-based neurology clinical review and CME journal from the American Academy of Neurology.  Thank you for joining us on Continuum Audio, which features conversations with Continuum's guest editors and authors who are the leading experts in their fields. Subscribers to the Continuum journal can read the full article or listen to verbatim recordings of the article and have access to exclusive interviews not featured on the podcast. Please visit the link in the episode notes for more information on the article, subscribing to the journal, and how to get CME.

Dr Weathers: This is Dr Allison Weathers. Today, I'm interviewing Dr Tammy Smith about her article on therapeutic approach to autoimmune neurologic disorders, which she wrote with Dr Stacey Clardy. This article is a part of the August 2024 Continuum issue on autoimmune neurology. Although, one of the things I love most about being an interviewer for Continuum is getting the opportunity to meet new neurologists and learn all about their areas of expertise, there's something really special when I get the chance to interview and catch up with old colleagues - and today, I'm fortunate to do just that. I had the privilege of working with Dr Smith when she was a resident at Rush, and I'm so excited to be able to speak to her today about her fantastic and really comprehensive article on this very timely topic. Welcome to the podcast, Dr Smith, and please introduce yourself to our audience.

Dr Smith: Hi. Yeah, thank you for inviting me to participate in the podcast and to write this article. So, I'm Tammy Smith. I am a neurologist who practices in Salt Lake City. I primarily work at the Salt Lake City VA Medical Center where I get to treat veterans with all sorts of neurologic diseases. I'm also an assistant professor of neurology at the University of Utah in the division of Neuroimmunology and Autoimmune Neurology, and I serve as a Clinical Consultant for ARUP Laboratories to help improve diagnostic testing for immune-mediated neurologic diseases.

Dr Weathers: Wow. That is a lot of different roles and things that you have on your plate. I want to start, actually, by talking about the article. Again, you cover so much ground (you and Dr Clardy) in this really comprehensive article, but if you had to choose the one most important message - if you wanted our listeners to walk away remembering one key point, what would it be?

Dr Smith: I think the key point I want our listeners to think about is just to use the resources that are available to you. Nobody can have all of these drugs (as we're talking about treatment of autoimmune neurologic diseases in this article) - no one can have all of those drugs memorized, all of the mechanisms of action, all of the approved treatments and off-label treatments, and all of the symptomatic therapies. But that's why resources like the Continuum exist - so that we can provide those resources to clinicians who are busy at that touch of, er, hopefully - or when they open their issue - to get the information they need to make decisions to take good care of their patients.

Dr Weathers: I think that is so reassuring. As I was reading this article, that was, like, one of the things that really struck me is that, you know, thinking about even being a resident and studying for something like the rate exam, you know, how much easier it used to be when there was such a limited number of drugs thinking about the autoimmune diseases or epilepsy, where just the number of drugs has just, kind of, multiplied so manyfold since I was in training, that it's really overwhelming. And I think you make a great (and as I said, a very reassuring) point that we don't have to memorize these, that there are these incredible resources (like Continuum) where it's not any longer about kind of memorization and keeping it in our heads, that it's more about knowing where to look and thinking about what's the right thing for the patient - knowing how to go and get the information is the more important knowledge there. And, actually, thinking about that and moving on, given your expertise, how do you personally approach the management of a patient with an autoimmune neurologic disorder? Again, in the article, you speak about all the different things to keep in mind, both from a therapeutic (really, treatment) standpoint, as well as a symptomatic standpoint - but what is your personal approach?

Dr Smith: My personal approach really involves considering whether the diagnosis of an autoimmune neurologic disorder is correct, first and foremost, and gathering the information to help support that diagnosis - and I think that's something that often gets overlooked in the excitement of a patient coming in with a rare-looking syndrome. Someone sends off diagnostic testing, rules out a few things, decides it's autoimmune, and starts down a pathway and keeps pushing forward. And I understand that inclination on a busy neurology service or in a busy clinic to just decide on one path and move forward, but I'm always questioning the diagnosis, even in the presence of positive antibody results sometimes. If my patient doesn't respond to the treatment that I'm giving them based on their presentation and the antibody results, I reassess and wonder if there's something else going on, are there two syndromes going on, or was that antibody result really not the right answer for some reason. So, I think my approach, really, is to always have a healthy amount of skepticism around the diagnosis, and even when I'm fairly confident in the diagnosis, to continually reassess that patient and their unique response to treatment. And then, also, their unique circumstances - so, everyone will need different symptomatic management, as well as different rehabilitation resources and other resources mobilized to help them maximize their recovery. And so, there's just not a "one size fits all" approach, but always keep talking to the patient, keep re-evaluating, stay curious, and don't be afraid to change paths when things aren't making sense.

Dr Weathers: I think that is incredibly sound, really thoughtful advice. So, I can imagine how incredibly challenging those cases must be when you think you have the right answer, it looks like it's lining up, the antibodies are pointing you in the right direction, and then, they're not responding. What else do you feel is the most challenging aspect of the management of these conditions? Is there some other kind of aspect that you also feel is really challenging in the treatment of these patients?

Dr Smith: Yeah, I think other challenges are really access to state-of-the-art therapies due to financial barriers - I think that's a pretty significant challenge for a lot of these patients, and I think we need to continue to work on advocacy efforts to make sure all patients have access to the medications they need to treat the disorders they are diagnosed with. And it's a real challenge, even when there's FDA-approved therapeutics - a lot of them are quite expensive, and then we end up playing the insurance game, and we learned that AI is automatically denying people's insurance claims, and so, we're battling computers as well as insurance companies. And I think that's a really significant challenge for a lot of these patients. And then, really, just the fact that a lot of immune-mediated neurologic disorders have a long tale. So, we don't treat a patient the same way we do for an infection and expect a dramatic and rapid recovery - a lot of the recovery for these patients happens over months to years. It's a process, and I think it's really important to be counseling patients and caregivers and other providers and educating them about this that we continue to mobilize resources to help our patients long past their inpatient hospitalization and the most dramatic part of their recovery.

Dr Weathers: Again, you raised some really insightful points there. No, I think they're really key. And I think, to your point, that even for some of these patients, that even if we can get over the economic barriers of the medications themselves and get them authorized, get them covered, you're left with, for a lot of patients, all of the other limitations of some of their social determinants of health challenges, right? So, the transportation challenges to even kind of get them to the appointments, and some of the other challenges they face, which makes some of these treatments very, very hard for them to be able to accomplish. So, it is very challenging - I think that's a very important call-out. What do you think is the easiest mistake to make when treating patients with autoimmune neurologic disorders, and how should our listeners avoid it?

Dr Smith: Yeah, that's an excellent question. One of the most common mistakes I see is either overvaluing diagnostic testing or not ordering the appropriate diagnostic testing for the clinical syndrome in any given patient. And where this comes into play, really, is the fact that when we order diagnostic testing in the United States for immune-mediated neurologic disorders, these autoantibody panels are available to us that test for a multitude of autoantibodies all at the same time, and if we don't choose the appropriate test for the clinical syndrome that the patient is there with, we run the risk of getting a positive result for an antibody that's unrelated to the syndrome we're seeing in the patient – and no test is 100% specific (or 100% sensitive, for that matter), but these low-specificity issues when you indiscriminately test really can cloud the clinical picture and delay getting the appropriate diagnosis. And so, I really think that one of the biggest mistakes is seeing maybe a low-positive result for an antibody that does not match the clinical syndrome if you go back to the books and use your resources to figure out if that result is meaningful - overvaluing that antibody result and maybe plowing forward with a treatment plan that involves a long course of immunomodulatory therapy is a pretty significant mistake. And then, on the flip side is that because these panel tests, you order them as a block, and you think that you ordered the right thing - or you think that whoever you asked to order the order for you ordered the right thing – and so often, people say the panel was negative, and they don't look at the individual results of the antibodies that were tested in the panel, and because different antibody panels are designed to test for different clinical phenotypes. I see the error where a clinician thinks that all of the antibodies necessary to test for were tested for and negative, and now they feel like their hands are tied. And so, it's both this overvaluing the diagnostic testing and forgetting to question the testing results if they're not what you expect once you get more clinical data - I think both of those are pretty big mistakes. And continuing, again, always be curious, always recheck results, and don't take laboratory values in an EMR that are in black and white as the stone-cold truth that tells you your answer - you have to stay curious about the patient, their history, their neurologic presentation, their response to treatment over time, and really keep assessing. My other soap box here about diagnostic testing is that, historically, a lot of the antibodies that we test for were called paraneoplastic (and that's because they were some of the first antibodies discovered, so, they were some of the earliest ones that we developed tests for), and clinical reference laboratories continue to offer paraneoplastic panels for historical reasons and because a lot of people think that that's what they want. But, paraneoplastic panels, in and of themselves, are not representative of a specific clinical phenotype - they just diagnose patients who have a high risk of malignancy associated with an antineural antibody. And so, most of the clinical reference labs I know of - certainly at ARUP, we have a notice on our testing page, I know Mayo Clinical Laboratories also has a notice that says, "Paraneoplastic panels are not generally the recommended panel to test for antineural antibodies. Consider ordering the phenotype-specific panel that fits the patient's clinical syndrome". And I think that's super important – we still have paraneoplastic stuck in our head for historical reasons, and it is almost never the right answer.

Dr Weathers: It's really interesting. At my organization, you know, we actually have had some really thoughtful conversations about, do we really restrict it (you know, as part of lab stewardship efforts) - and, you know, these are expensive, and to your point, they can be frankly, really dangerous, you know, to really send somebody down this wrong path with a lot of surveillance, committing them to immunomodulatory therapies, and take you in completely the wrong direction when, actually, your low test probability was very low. So, I think that is an excellent one to really call out and for people to be very thoughtful of - and the way, again, to avoid it is to be very thoughtful about the panels. And for people, certainly, they are very convenient, but people need to be really aware of what's in them and what they are ordering and how to interpret them. And I love that advice about not just thinking about the wholesale as negative - really, you know, for many of us, they are still coming in as scan documents, you know, click into them, read every line, really understand what those results mean.

Dr Smith: And I would also say that I think people don't realize, but clinical reference laboratories would love for you to reach out when there are questions. So, if you don't understand the diagnostic testing that was performed or result, you pretty much all have hotlines. You can call and reach out to an expert in the testing and ask them some questions, and don't be afraid to reach out to your colleagues who might have more experience. We love hearing from people with questions and helping to direct them to the right testing and help them get the answers that they really want to for their patients.

Dr Weathers: I think that is a great plug. Before you order, preferably, before you send in.

Dr Smith: I do like when I hear from people before mistakes were made. Yes. That's nice.

Dr Weathers: It's a great point.

Dr Smith: When you order these panels, you do run the risk of having these low positive results that may or may not be clinically meaningful. And we do recommend that most of the diagnostic testing be ordered in both serum and CSF. And so, a good example of a mistake that can be made is a very low-positive NMDA-receptor antibody in serum - maybe it was ordered for a patient with cognitive decline or confusion (maybe not under the ideal clinical scenario for ordering), and then it's negative in the CSF. So, an NMDA-receptor positive, negative in the CSF, not the right clinical picture, people can get really jazzed and want to treat an NMDA-receptor encephalitis, that in that case, really isn't meeting diagnostic criteria, and there are excellent diagnostic criteria that have been developed and published for that disorder and for several other autoimmune neurologic disorders, and I think going back to those criteria and really questioning yourself before you start blindly down a path based on a lab result is really important.

Dr Weathers: I think that's excellent advice, too, always keeping that in mind that just because you have gone down this path and gotten that result doesn't mean that you are stuck and committed to it. Always keeping that criteria in mind, always going back, always checking it is really important as well. Moving on from mistakes to kind of an adjacent question, what do you think is the biggest controversy right now when it comes to the treatment of patients with autoimmune neurologic disorders?

Dr Smith: You know, one of the big controversies that I see and I'm concerned about is that we've gotten into a habit of treating the way we've always treated based on expert opinion, and while experts have their opinions based on a lot of experience, they don't take the place of well-designed randomized controlled clinical trials - and in rare diseases (like autoimmune neurologic diseases), it can be really challenging to conduct those trials, especially in the face of people who have a pathway that they always do with their patients. If they have a NMDA-receptor encephalitis patient, they feel very comfortable doing their standard of care with IV steroids and then either plasma exchange or IVIG, and then possibly (and very often), I see following with a B-cell inhibitor, like rituximab, as sort of just a "kitchen-sink" approach to treatment. And while I understand the passion and the desire to make a really sick patient sitting in front of us better as fast as possible, I don't think we have adequate evidence to support that being the "one-size-fits-all kitchen-sick" approach for treatment. And I really am passionate about all clinicians all over the world, supporting randomized controlled clinical trials that are well-designed with the backing of experts in the community, so that when we look at a patient and tell them that we recommend a course of treatment, we're recommending it based on the best quality evidence available, not just what everyone's always done before. I think we can do better than that. And I think there's some controversy in this. Some people think that it doesn't make sense, we already know the answer, but I would say we haven't asked the right question and thoroughly investigated enough. And this is especially important with children, right? We know pediatric patients often don't have well-designed clinical trials to guide their treatments - but in NMDA-receptor encephalitis, many of the patients are children, and I think that they deserve to be involved in well-designed clinical trials in order to support the recommendations that we make for treatment.

Dr Weathers: And in addition to children, think about all of the other patient populations that have traditionally not been well represented in trials, right - pregnant patients, patients of color (historically very underrepresented in trials) - many, many other patient populations that have not been adequately represented.

Dr Smith: Absolutely. Yeah. I think we need to really care about that and face that problem head on and speak to it. We can't just say this is the way we've always done things, so we're going to keep doing it that way. I think we owe it to our patients and ourselves, when we look our patients in the eye, to say that we have good evidence to support the recommendations we're making.

Dr Weathers: I think we have already answered this question in many ways with each of the questions we've already talked about, but is there any other strong arguments that you can make for why it's important for neurology clinicians to read your article?

Dr Smith: Dr Clardy and I spent a lot of time working on this article, trying to put together a piece that will be a resource that people could turn to again and again. I don't think that this article is something that you should read from top to bottom and think that you've absorbed and digested everything, right? So, what we work to do was to really provide a structure and a framework to think about the treatment of immune-mediated neurologic diseases. So, rather than memorizing specific drugs for specific conditions, we developed sort of a space where you could talk about B-cell targeting therapies and the different ways we can target B-cells, we talked about complement inhibitors, neonatal FC receptors, and, really, just at a high level, how these drugs work and how they're targeted, so that going forward in three, four, five years, what I believe we'll know more about each of the individual diseases mediated by antineural antibodies. When we understand what causes that disease, we'll be able to go to a resource like this and choose rationally based on mechanism of action, a drug to treat our patient - even if it's in a patient with such a rare disease that we don't have the luxury of a clinical trial to guide our choices.

Dr Weathers: That's a really excellent point - and I know I've said it a few times, but I think you guys did such a really excellent job at really laying it out in a way that makes it this really comprehensive, really easy-to-use resource at that point of care for providers to be able to do exactly that. Well, I always like to end on a hopeful note, so, this is always my favorite last question – but, what do you think is the next breakthrough coming in the treatment of patients with autoimmune neurologic diseases?

Dr Smith: Yeah, I think in the near future (I certainly hope, at least) that the next breakthrough is going to be in really being able to deliver personalized care based on what we understand about the mechanisms of a patient's rare disease. So, again, right now, I find we're kind of left with the "kitchen-sink" approach because we know so little about the mechanisms that drive each of these unique neurologic diseases and we don't have enough information from clinical trials to inform rational treatment decisions, so we go with these broad approaches - and I really think that in the near future, with work being done by a lot of people (dedicated people over the world) on biomarkers and things that predict either onset of disease or relapse or disease severity or really looking at basic fundamental mechanisms that drive disease, we're going to be able to make more rational choices in the treatment of these patients and mobilize the resources that are expensive, but valuable for the right patient at the right time.

Dr Weathers: That is a very exciting and hopeful future to look towards. Thank you, Dr Smith, for joining me on Continuum Audio. It was wonderful to get to spend this time with you again. Again, today, I've been interviewing Dr Tammy Smith, whose article on therapeutic approach to autoimmune neurologic disorders, written with Dr Stacey Clardy, appears in the most recent issue of Continuum on autoimmune neurology. Be sure to check out Continuum Audio episodes from this and other issues. And thank you to our listeners for joining today.

Dr Monteith: This is Dr Teshamae Monteith, Associate Editor of Continuum Audio. If you've enjoyed this episode, you'll love the journal, which is full of in-depth and clinically relevant information important for neurology practitioners. Use this link in the episode notes to learn more and subscribe. AAN members, you can get CME for listening to this interview by completing the evaluation at Continpub.com/AudioCME. Thank you for listening to Continuum Audio.

In this episode, Lyell K. Jones Jr, MD, FAAN, speaks with Nathaniel M. Schuster, MD who served as the guest editor of the Continuum® October 2024 Pain Management in Neurology issue. They provide a preview of the issue, which publishes on October 2, 2024. 

Dr. Jones is the editor-in-chief of Continuum: Lifelong Learning in Neurology® and is a professor of neurology at Mayo Clinic in Rochester, Minnesota.

Dr. Schuster is an associate professor and associate clinic director in the Center for Pain Medicine and Department of Anesthesiology at the University of California, San Diego in La Jolla, California.

Additional Resources

Continuum website: ContinuumJournal.com

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More about the American Academy of Neurology: aan.com

Social Media

facebook.com/continuumcme

@ContinuumAAN

Host: @LyellJ

Guest: @NatSchuster

Full episode transcript available here

Dr Jones: This is Dr Lyell Jones, Editor-in-Chief of Continuum, the premier topic-based neurology clinical review and CME Journal from the American Academy of Neurology. Thank you for joining us on Continuum Audio, a companion podcast to the journal. Continuum Audio features conversations with the guest editors and authors of Continuum, who are the leading experts in their fields. Subscribers to the Continuum journal have access to exclusive audio content not featured on the podcast. If you're not already a subscriber, we encourage you to become one. For more information, please visit the link in the show notes.

Dr Jones: This is Dr Lyell Jones, Editor-in-Chief of Continuum: Lifelong Learning in Neurology. Today, I'm interviewing Dr Nathaniel Schuster, who recently served as Continuum's guest editor for our latest issue on pain management and neurology. Dr Schuster is a pain neurologist at the University of California, San Diego, where he is an Associate Professor of Anesthesia. Dr Schuster, welcome. Thank you for joining us today. Why don't you introduce yourself to our listeners?

Dr Schuster: Thank you so much, Dr Jones, for having me. My name is Nat Schuster. I am a pain and headache neurologist at UC San Diego, in the Department of Anesthesiology. I do research, clinical practice, and of course, education of med students through pain fellows, and it's been a pleasure to be the guest editor for this forthcoming issue of Continuum.

Dr Jones: Well, I want to thank you for editing the issue. I want to thank you for putting together, really, an incredible list of topics and, really, expert authors. It's been a long time since Continuum has dedicated significant space in an issue to pain management, which is obviously a hugely prevalent, major problem in society, and I think a big gap for many of us – I know it is for me in my practice, so I've enjoyed learning about it – so I want to congratulate you on the issue and thank you for doing it.

Dr Schuster: Yeah. I was just at AAN a few weeks ago. I was chatting with the person who edited one nearly 20 years ago, a prior pain Continuum issue - so, really glad that for another generation of neurologists that we're going to have this as a reference, and hopefully, it'll serve them in their care of so many patients, because this is just such a ubiquitous problem facing Americans and people around the world.

Dr Jones: Yeah, and a lot's changed in 20 years, so let's get into it. And I will say, you know, now that with our open podcast model, we're interviewing the guest editors, you have, really, an incredible view of the entire field at the moment. And with your reading of the issue and your experience as a pain expert, Dr Schuster, what do you think is the biggest controversy in pain medicine right now?

Dr Schuster: Yes, certainly. I think the most controversial thing facing our practicing neurologists is the opioid issue and how things have been changing with national guidelines since 2016, and, fortunately, we are going to have an article by Dr Friedhelm Sandbrink - who is not only a neurologist, but he is the national director for the VA system - on pain management, opioid safety, and prescription drug monitoring programs. So, it's really wonderful that we have him as an author, and I hope that all the neurologists take an opportunity to read his really important manuscript, because it's dizzying, and, you know, if you're not reading the latest things from people like Dr Sandbrink pretty much every couple of years, you're probably falling behind when it comes to what are current attitudes, what is necessary to be, you know, most responsibly continuing your patients who have been on opioids for so long (many of whom have really debilitating neurologic conditions, nothing else is helpful for them), how are you able to best treat them, best monitor them in the appropriate ways to be doing things in compliance with guidelines.

Dr Jones: And I think monitoring is one of the things that, for neurologists who are uncomfortable with pain management, uncomfortable with the modern role of opioids, I think part of it is, well, what are my accountabilities? What are my responsibilities for doing that? That article will have great insights for our readers. Cannabinoids - that's another one I hear a lot of questions about, and it's obviously evolving. The science is relatively less mature there. From your perspective, what's the role of cannabinoids in a modern pain practice?

Dr Schuster: Yeah. Once again, so much controversy there and so much variability across the US, of course, between institutions, between states - hugely different. And as we speak, it's looking like cannabis will very likely be recategorized as being schedule III, so things are changing, you know, even between right now, probably, and when people are going to be reading the forthcoming Continuum and listening to this podcast. At UC San Diego, we certainly have been on the forefront of doing clinical trials, looking at these clinical trials. They're academic studies using the NIDA drug supply. So, they're not the size and scope of so many of the things that we use that have had industry-funded, large, multicenter studies done, but the research that we've done has shown promise for quite a few different neurologic conditions, ranging from my most recent research was in the migraine space, looking at acute migraine (and I just had the pleasure of presenting that data at AAN a few weeks ago), looking at other things over the years, looking at spasticity pain and multiple sclerosis, spinal cord injury pain, diabetic peripheral neuropathy, other peripheral neuropathies. So, in the conditions that we as neurologists so often do treat, that does seem like there is a lot of promise. It's something that in our practice, some of our doctors are more comfortable with it, others are less comfortable. I know, myself, I'm very conservative when I discuss it with patients, because there is, you know, addiction concerns, misuse concerns, abuse concerns - I don't believe that it's to the degree of opioids, and I don't think that the risks are anywhere close to what they are with opioids - and while it's less in opioids, we have other things, fortunately, in this field that don't carry those concerns, and so, I certainly try to use those other options as much as possible before having the discussions about cannabinoids. That said, so many people are using them, and so I'm able to guide them towards, you know, telling that very often, doses that are lower than what they might need to get intoxicated might actually be the doses that are therapeutic, and recommending using high CBD and low THC is probably going to have less side effects, and there's some evidence towards, hopefully, having more therapeutic benefit, especially in our most recent study looking at acute migraine that you want to have that CBD component with the THC.

Dr Jones: That's outstanding. So, we know more than we used to. It still feels like a relatively understudied area (and that's partly been the regulatory barriers to doing science on cannabinoids), so we'll look forward to hearing the latest and greatest in the issue. When we think about in neurology - and I'm thinking here as a clinician - when we think about pain and neurology, we often think about neuropathic pain. And, personally, you know, I see a lot of patients who have peripheral generators for those symptoms of neuropathic pain, but central neuropathic pain is an issue, too - and we have articles on both of those, one on peripheral neuropathic pain, one on central neuropathic pain. For our listeners, what should they know about the differences between those two and the treatment approaches to those?

Dr Schuster: Yeah. So, we fortunately have two wonderful articles - one of them from Dr Charles Argoff looking at central neuropathic pain, another one looking at peripheral neuropathic pain from Drs Misha Bačkonja and Victor Wang. And one thing that I think is really interesting about central neuropathic pain is that for these same patients, we don't need to only be thinking about the central neuropathic pain alone, and not everything that they're experiencing is going to be central neuropathic pain, because they can have "frozen shoulder" - post-stroke shoulder pain is actually a really big deal. Of course, you need to be concerned about things like sacral decubitus ulcers in so many of these patients. And so, they can have nociceptive components in those same patients, and us as neurologists, taking care of these very complicated patients, need to have our eyes open for the central neuropathic components, but also in those same patients, the other pain generators that we can do a lot for.

Dr Jones: So, the musculoskeletal and other generators of pain are relevant. I think that's something that many of us have experienced. Certainly, when I trained, Dr Schuster, the general construct around pain was that it was a really biological phenomenon, and it's an adaptive phenomenon, but it becomes a clinical problem when the pain is unmanageable or out of proportion to the patient's coping skills, and it seems to have evolved - at least in terms of our understanding of it, how it impacts people's lives. It's not just a physical or biological process, right? There are psychological factors here, there are social factors here. How does that inform your thinking about management of pain?

Dr Schuster: Yeah, so, I think that that's one of the most important running themes throughout this issue of Continuum that readers will find, is that there's a movement away from the biomedical model towards the biopsychosocial model in thinking about patients. And, at least for myself, when I was coming out of neurology residency, my training was much more on the biomedical model and on medication treatments. And throughout this issue, what you'll find is discussions of the importance of the biopsychosocial model, having pain psychology as being a component of the treatment for so many of these patients. That medications alone (for many of our most challenging patients) won't be the answer by themselves - that you'll need to have involvement of physical therapy, of pain psychology. And we have an article written by the pain psychologist who I work with at UCSD, Dr Mirsad Serdarevic, which I think will be very interesting for so many neurologists. It's also wonderful that we have an article on facial pain that's written by a neurologist, Dr Meredith Barad, together with a dentist, Dr Marcela Romero-Reyes. So, it really takes a team to treat so many of these very challenging patients who we are treating in our neurological practices.

Dr Jones: Yeah, thanks for that. I realize that with a complex problem, a lot of times you need more than one area of expertise, right? It's a team process and a team effort. When you think about your own practice, Dr Schuster, when do you bring in other specialists or other perspectives in the management of patients with pain?

Dr Schuster: So, one of the articles that I really enjoyed reading in this forthcoming issue of Continuum is the one from Dr Narayan Kissoon on widespread pain syndromes. These patients who have widespread pain syndromes very often are the patients that I'm referring to our pain psychologist. Neurologists can do so much for these patients by making the right diagnosis. So often, these patients might be treated by one specialist for one organ system, another specialist for another organ system, and they can have so many different specialists, and they can be going from institution to institution. And a neurologist is in a really good position to be able to take the full history, put everything together and say, "I think you have a chronic overlapping pain condition. I think you have central sensitivity syndromes" - to be able to talk to them about their central nervous system being amped up, and that there are treatments that we can give them to help to treat these conditions, fibromyalgia and others, that affect so many of our patients who we encounter in neurologic practice. So, the International Association for the Study of Pain now has this term, nociplastic, and some people use the term neuroplastic to talk about these central sensitivity syndromes, and while not all neurologists maybe are hearing those terms used yet in clinical practice, I think it gives us a good framework - and between Dr Kissoon's article, as well as Dr Beth Hogans' article on general principles of pain, I think that those will give the practicing neurologist a lot of good updates as to how our thinking about these patients has evolved.

Dr Jones: I know, as clinicians, we have a very cause-and-effect kind of component to our training, right? Here is the problem, here is the lesion, here is the result, and what do I do about it. I think patients also want to know what is the cause of the pain, and I think it's, maybe, historically been frustrating when someone clearly has pain and there's not a single factor, especially a removable factor, that causes it. So, I think, hopefully, having this language that we can use to communicate it with our better understanding of pain, hopefully that will help. Does that help you in your practice when you're talking to patients, when you explain what's going on? Is that well-received in general?

Dr Schuster: Yeah, you know, I think a lot of doctors are afraid to talk about fibromyalgia, for example, with patients. And what I'm finding in my practice, actually, is that a lot of patients are liberated when they can receive a diagnosis, such as fibromyalgia, that they can read about, they can learn about treatments for it, they can join support groups online and find that they're not alone - indeed, this condition affects 2 to 4% of people, and that very well could be a underdiagnosis. It keeps them from looking to different specialists for each painful body part and potentially having unneeded surgeries - and surgeries that might make things worse. So, I think physicians are understandably concerned because there is stigma - there's stigma around a lot of painful conditions, and there's stigma around some of the treatments that we use to treat these patients - and I think that physicians who are sensitive to that can sometimes be hesitant, but I'm really surprised how often patients are just really appreciative to get the right diagnosis.

Dr Jones: And you mentioned a minute ago that things have changed even since you came out of training, and, obviously, training is really important to know how to manage these problems. In my own world, I've seen, I think, an increase in the interest in pain management as a subspecialty among neurology trainees. There's obviously something that grabbed you, something that pulled you into this field. What's been your path to being a pain specialist?

Dr Schuster: Yeah, so I was a neurology resident at Ronald Reagan UCLA Medical Center, and fortunately, there, they have a few pain neurologists - and also, in the community, we have a few other pain neurologists as well that I had the great fortune to work with. And I was so impressed, especially those who are doing both pain and headache treatment, that you were able to help so many people treating very high-prevalence conditions - very often, younger patients, people who are going through school, building families - and being able to really reduce their disability, improve their quality of life and the quality of lives of their families is very gratifying. So, I encountered that as a neurology resident. I had their mentorship. And then, I applied for both headache and pain fellowships, and I did both a headache fellowship and a pain fellowship - and I think that that's been a wonderful combination for my career. To have that mix of patients has been really wonderful for preventing burnout. I think having a combination of slightly different patient populations between the headache population and the pain population, as well as, of course, those who have comorbid headache and pain conditions, has been very gratifying to treat people with these conditions. Not that many neurology residents think about doing a pain fellowship, and I wrote, together with my good friend and colleague Jacob Hascalovici, back in 2018 (that was published in the Green Journal), an article on pain neurology as an emerging subspecialty within neurology - and certainly, I would encourage any neurology residents who are interested in potentially pursuing a pain fellowship to read this article. There's such a need for neurologists in the pain field.

Dr Jones: It can be a little bit of a self-fulfilling prophecy, right? So, obviously, role modeling was important to you, right? You could see the practice when you were in training, when you could still make the decision, and if there aren't enough pain neurologists (which I think we can agree that there aren't), there are probably a lot of trainees who don't have that window into what that practice can be like, which, again, makes it kind of a barrier to folks entering the field - so, hopefully, being more comfortable with it will help our listeners and our readers, you know, integrate this into their practice and see it as a path forward for their own careers if they're interested. One last question for you, Dr Schuster, is - you know, looking into the future, obviously, when we have more options to treat these patients, it's rewarding and engaging and exciting - what do you think the next big thing in pain management is going to be? What should our listeners know that's coming down the road for these patients?

Dr Schuster: Yeah, so the interventional segment and the neuromodulation treatments are really changing a lot these last few years, and I believe are going to keep on evolving with new treatments coming down the pathway. And so, we have two wonderful and really nicely balanced articles on these topics: one of them from one of my former mentors from my UCLA days, Dr Vernon Williams, wrote one on spine pain, and he talks about the interventional pain treatments; and another from Dr Prasad Shirvalkar on neuromodulation for painful neuropathic diseases. And these are really wonderful articles for the neurologist who wants to learn about what treatments are available that, they might not personally be doing these, but that they can refer to colleagues - and these are changing a lot. Epidural steroid injections, for example: helpful for a lot of patients, but there's so much more to the interventional pain field than just that, and I think our practicing neurologists will learn a lot about, "Oh, what can neuromodulation be useful for within the pain field?" And, of course, because there's industry involvement in neuromodulation research, you need somebody who's really good at being very balanced, and I think Dr Shirvalkar did an incredible job about writing a really balanced article about the neuromodulation options that we have for patients with neuropathic pain disorders.

Dr Jones: It's exciting stuff. I think there's a lot to look forward to. I think the update that our readers and listeners will have from this issue will be extremely helpful for themselves in their practice and for their patients. For people who are audiophiles, each of these articles will have a corresponding podcast, so we'll refer people to that. And with that, Dr Schuster, I want to thank you for joining us for a really thorough, fascinating discussion on the field of pain neurology and our brand-new issue on pain neurology. And again, we've been speaking with Dr Nat Schuster, Guest Editor for Continuum's most recent issue on pain neurology. Please check it out. And thank you to our listeners for joining today.

Dr Monteith: This is Dr Teshamae Monteith, Associate Editor of Continuum Audio. If you've enjoyed this episode, you'll love the journal, which is full of in-depth and clinically relevant information, important for neurology practitioners. Use this link in the episode notes to learn more and subscribe. Thank you for listening to Continuum Audio.

Neurologists bring special skills to pain evaluation and management and are well equipped to appreciate both the focal and diffuse nature of pain. By using expert knowledge of the nervous system and implementing relevant therapies, neurologists can succeed at and find meaning in optimizing patient outcomes.

In this episode, Allison Weathers, MD, FAAN, speaks with Beth B. Hogans, MD, PhD, author of the article "Principles of Pain Management," in the Continuum October 2024 Pain Management in Neurology issue.

Dr. Weathers is a Continuum® Audio interviewer associate chief medical information officer at the Cleveland Clinic in Cleveland, Ohio.

Dr. Hogans is an associate professor in the department of neurology at Johns Hopkins School of Medicine and an associate director for education and evaluation at the Geriatric Research Education and Clinical Center at the VA Maryland Health Care System in Baltimore, Maryland.

Additional Resources

Read the article: Principles of Pain Management

Subscribe to Continuum: shop.lww.com/Continuum

Earn CME (available only to AAN members): continpub.com/AudioCME

Continuum® Aloud (verbatim audio-book style recordings of articles available only to Continuum® subscribers): continpub.com/Aloud

More about the American Academy of Neurology: aan.com

Social Media

facebook.com/continuumcme

@ContinuumAAN

Full episode transcript available here

Dr Jones: This is Dr Lyell Jones, Editor-in-Chief of Continuum, the premier topic-based neurology clinical review and CME journal from the American Academy of Neurology. Thank you for joining us on Continuum Audio, which features conversations with Continuum's guest editors and authors who are the leading experts in their fields. Subscribers to the Continuum Journal can read the full article or listen to verbatim recordings of the article and have access to exclusive interviews not featured on the podcast. Please visit the link in the episode notes for more information on the article, subscribing to the journal, and how to get CME.

Dr Weathers: This is Dr Allison Weathers. Today I'm interviewing Dr Beth Hogans, author of Principles of Pain Assessment, Diagnosis, and Management from the October 2024 Continuum issue on pain management and neurology. Welcome to the podcast, and please introduce yourself to our audience.

Dr Hogans: Good afternoon. My name is Beth Hogans. I'm a neurologist. My faculty appointment is at Johns Hopkins School of Medicine in the Department of Neurology, where I'm an assistant professor. I also serve at the Baltimore VA Medical Center, where I'm the Associate Director of Education and Evaluation for the Geriatric Research, Education and Clinical Center, as well as a neurologist.

Dr Weathers: Thank you so much for, again, being with us today and taking the time to speak with me. I was really struck by how broadly applicable this topic is, not only to all neurologists, but to all physicians and even to all of our listeners, given how prevalent these conditions are.

Nearly all physicians involved in direct patient care treat some type of pain disorders, and we all experience pain at some point, though hopefully not chronic pain. Well, usually like to start with a question - again, it feels especially pertinent here in getting to speak with you - what is the most important clinical message of your article?

Dr Hogans: So, I'm going to say there's two key messages. The first one is that all pain has a differential diagnosis, and the second one is that all meds work better with non-pharmacological and whole-health comprehensive management incorporated. So that's why I structured the article around the ideas of assessment, diagnosis and management. It's a pretty sort of traditional, basic approach to how we look at clinical problems, but we definitely want to start with proper assessment, go on to a thoughtful differential diagnosis, and then move towards a management plan that is not just, you know, one stop shop, but actually kind of brings several aspects together. Because pain is so multidimensional; you know, it's represented in multiple places in the brain as well as other levels of the nervous system. And so, I think we're still in an era, and we may stay in an era, of, you know, needing something to go along with medication in many cases.

Dr Weathers: I think those are two absolutely critical points for our listeners to keep in mind, both, again, keeping that broad differential, and - we'll get more into management in a bit, but again - that dual strategy of both the pharmacologic and the non-pharmacologic. And again, going down a little bit more there on that management track, a really recurring theme that I picked up in your article is the importance of interprofessional collaboration in the assessment and the management of patients with pain. In the abstract, you actually use the phrase "remarkable" for the diversity of health professions, which I really loved. What other clinicians do you work with in diagnosing and managing pain conditions, and what are their roles in the care of these patients?

Dr Hogans: So, something you hear over and over again at pain meetings is, "there is no I in team." They say that all the time. And it's one of the things I really love about pain, is that we get to work with great colleagues who have their own perspectives, approaches and therapies for pain. So, in my particular practice, which I do focus kind of more at the interface between neurological and musculoskeletal pain because of my passion and interest for spinal pain, you know, ranging from neck to tailbone, but most especially in the lower back. Physical therapy, clinical psychology, sleep sedicine, nursing, pharmacy, rehab… Podiatry is something that people don't often think of, but is really important for getting spine mechanics correct… Ergonomics. But I want to just say something about clinical psychology because there may not be enough clinical psychologists in the United States, but we as neurologists are also brain doctors. You know, we have to stay within our scope of practice. But there's a move now to talk about psychologically informed physical therapy. So why don't we talk about psychologically informed neurology? I think we could do an even better job of kind of leveraging our knowledge of the brain and how it works to kind of bring that into our practice. And so, people with pain often need a lot of empathetic support, for example, as well as knowledge about their condition.

So, I would encourage people to build local networks of folks that they refer to and work with. Because when I was a younger doctor, physical therapists taught me a lot of what I know now - because I didn't get it at med school, although by the time I got to residency, I had some really great teachers. But clinical psychology, PT, sleep medicine, those are, like, almost all-the-time collaborators for me. And then like I said, nursing, pharmacy, rehab, podiatry, et cetera, et cetera, prosthetics… those things are all important for pain.

Dr Weathers: I was struck by the quote, "one of the things I really love about pain." That's a great line, and understand how it was meant, but I think - again, a really great quote, but I think you make such important points and, really, it is such a critical team approach. And I love all of those roles you called out. And I was struck in listening to your really thoughtful answer about how I've spoken with several other authors of actually very different topics, but about how we're thinking now about a trauma-informed care approach to many neurological conditions and the similarities with this patient population, how it likely informs very much the approach to this patient population as well and probably the significant potential.

Dr Hogans: A hundred percent! And so, for example, one of the things that probably does factor in for chronic pain - not in everyone, but in, let's say, many cases - is a prior exposure to trauma, whether it's PTSD or adverse childhood events. And so that's why, you know, clinical psychology is, like, very high up on my list of collaborators. And one of the things that I really like - you could say love - about working in the BA system is the ready availability of mental health co-management. So, I would say about a third of my patients in neurology are co-managed by mental health. And what it does is it sort of defuses a lot of what would otherwise come into the visit and be my job as a neurologist to manage, if not treat, right? I still have to manage, you know, someone who comes in with untreated mental trauma or mental health conditions if they're coming into that visit, and I'm trying to open the topic of whether mental health co-management could be helpful. That can sometimes, strangely enough, antagonize people. We're still in an era of substantial stigma. But I can just say the practice of neurology, together with appropriate mental health co-management, is far superior than going alone.

Dr Weathers: Absolutely. And how fortunate that for a lot of your practice, your patients do have those resources available to them. And I think it speaks to the importance of those resources, that all of our patients should really have that availability, and the importance of access.

Dr Hogans: Right. So, at Johns Hopkins, we also have exceptional access to, you know, some of the world 's best clinical psychologists. And I've been really privileged to work with my colleagues in clinical psychology. The challenges that - in some of my roles, I interact with trainees and learners who are in clinics that are not as well resourced. And therein lies just tremendous heartache and difficulty. We've been trying to build some resources. There are federal resources that can help to open those conversations and maybe take some of the initial steps towards things like cognitive behavioral therapy, acceptance commitment therapy, mindfulness-based stress reduction. There's many of these psychological therapies that are proven to be effective for pain and chronic pain, and yet we haven't really had that conversation as a society about, how do we get people connected with those therapies? Many of them can be delivered on a larger scale. And I think we just need to think a lot more thoughtfully about, how can we have more of a public health approach to chronic pain and wellness?

Dr Weathers: Absolutely. Such really important points. So, we've talked about the really kind of important, obvious points for what we very much kind of know to be accurate. I want to talk now about, what are the most common misconceptions that you've encountered in treating patients with pain disorders?

Dr Hogans: Yeah. So, this is where, you know, physician as advocate for the patient really comes into play. So, I think the number one misconception that I and many of my colleagues encounter: that pain is the patient 's problem, or that that pain reflects an excessive sensitivity.

I think one analogy that I use with students that helps to kind of piece this apart is the immune system, right? There are people who have immunodeficiencies that they're not sufficiently protected from the environment, and then there are - lots of people have allergies where their immune system is sort of hyper-alerted to things that are not a true threat. And the pain system is exquisitely regulated. The neurology of the pain system is fascinating and compelling, and once you learn a little bit about it, you can apply it at the bedside, time after time after time.

So, number one: pain is real. And there is an association between strong pain and increased risk for chronic pain. And then sort of the flip side of that is that malingering or, you know, fictitious pain is probably a lot like other functional disorders in that it's part of a complex. So, I think we need to do a lot more work to discover, you know, quote, what is pain that people think is amplified or manufactured and how can we frame that in a clinical context rather than just casting blame or- we already mentioned stigma. You know, stigmatizing people does not help. And there are people who have real pain problems that are really severe and disabling, and neurologists can actually help support those people as they encounter their environment.

Dr Weathers: I really love that response. And I think you're right in that we do so often, in the medical system, tend to stigmatize these patients, even as we say the right things and we, I think, talk about it and we recognize… and yet, still, it's almost these unconscious biases. I think, as good as we've gotten in some areas, it's still hard to separate them. It's almost kind of one of the last unspoken, still-acceptable ones in some ways that oh, they must be drug-seeking or, you know, to your point, you use the word, kind of malingering, that they're somehow, you know, either at fault or that there's some nefarious behavior going on there. And I think you made such really important points that we have to change our way of thinking that it is such a common and, frankly, wrong misconception that a lot of us really carry around and it's really hard to break. We have to kind of recognize these biases in ourself and really fight against them when we encounter these patients.

Dr Hogans: I think part of how we got there is the opioid crisis.

Dr Weathers: Yes.

Dr Hogans: You know, unfortunately we still do not have a fantastic understanding of opioid durability. Like, how long does opioid analgesia last? Not from, like, hour to hour, but, like, from month to month. Roger Cho has done some awesome work looking at long-term efficacy of opioids, and it's surprisingly modest. And yet, opioids have this profound kind of behavioral impact, that they really are highly reinforcing. And so, once they're in the conversation, you find yourself in, like, almost this life-or-death struggle between, you know, am I going to get opioids at this visit? How many? You know, if not, why not; are you going to decrease? And so those of us who are working today, you know, and have been working for the last five years, have been through this terrible struggle. And that struggle is not yet resolved. But once opioids are kind of off the table or neutralized, then we actually have a conversation that is really, you know, A: how good of a clinician are we? Do we really understand what our patient is going through? And how can we bring, like Hippocrates said, you know, get the system to bear on the problem and not just, you know, try to throw drugs at it. So I think that, really, pain challenges us to be our best selves and to, you know, really be clever and kind and helpful. And it is a really great opportunity to help. And as I said, the mechanisms of pain are fascinating neurologically. So, it kind of satisfies some of what we come to work for, but I think it's not all done yet. One of my challenges has been, I wrote an article in 2011 with one of my trainees where we counted up the number of hours documented in the double AMC database for med schools, and we found that the modal value for US medical schools at that time was four. So out of four thousand curricular hours, there were four pain hours. And when you think about the prevalence of pain, that's just a drop in the bucket. So, you know, it's getting better, but we need to come up with some new strategies. So I wrote, I've written three books now. The latest one is really designed to give that intro-level knowledge of pain. But also, obviously, the Continuum article, I wanted to kind of set the table, lay the foundation, and give people some core knowledge to get started with.

Dr Weathers: And again, a fantastic article. If our listeners haven't read it, I strongly encourage them to go back because I think you did just that. And as you were just talking, I was thinking about that, especially for those of us who, you know, depending on when in your training was, you know, mine started in the early 2000s. We've kind of lived through that era with the pendulum swinging. Where was, you know, the signs were posted in each clinic room. You know, don't forget to ask, you know, your provider about your pain meds, and it was the sixth vital sign, and all of that. And then the pendulum swung very quickly and very severely the other way, where it was, you have now created this problem, right? We have all caused this epidemic and we're supposed to immediately take these meds away, right?

And now to your point, you know, we've all been in these situations with opioids where that was all that was talked about, right? So, you know, we've all been on call and now you're getting the call overnight from people trying to get their opioids filled when, you know, not their prescriber because they knew if they called - or family members, as soon as you got prescribing rights, were now calling and asking. And we've all been in these very hard situations.

Dr Hogans: Just because you have a hammer doesn't mean that everything is a nail.

Dr Weathers: I know. So, in trying to negotiate and navigate, you know, these very rough situations… And I think now we're reaching kind of this new era where, to your excellent point, realizing that there are a lot of other solutions. And I love how you framed it, that this is really where we can be our best selves as providers. And actually, to that point, so - as I've mentioned on this podcast many times, clinically, I'm a neuro-hospitalist and I actually wanted to get your opinion as one of the foremost experts. So, a challenging situation I'm also often faced with in my clinical role is when a patient with a chronic pain condition such as diabetic neuropathy or lumbar radiculopathy is admitted to the hospital, often with a totally unrelated condition that either results in a new acute pain, but often also exacerbates their underlying chronic pain, what's your approach to the assessment and management of similar cases? I know our listeners will return again and again to that fantastic approach you laid out in Figure 1.1 with the coordination of the pharmacologic and non-pharmacologic therapies, as we've talked about several times just throughout our conversation, how important both of those approaches are. But a lot of those options are unfortunately limited in the in-patient setting. So how do you balance those?

Dr Hogans: So, there's a whole other toolkit that comes into play for acute pain or sort of pain palliation. And you actually have some important allies in the hospital. It turns out that nurses, generally speaking, have some more education than do most physicians about pain.

And the nurses that I encounter really see themselves as genuine, sincere advocates for the patient 's interest. They're at the bedside, they're working very closely, and their training actually does, I think, give them a number of tools and a set of inspirational ideas that build towards patient comfort. So, if you communicate with nursing staff about your desire to provide more comfort for the patient, whether it's padding, positioning, activities such as, you know, having them participate in something, you know, whether it's just having a family member, you know, take them for a walk, whether it's in a wheelchair or having an older adult sit by the nurse's station just to give some form of distraction. Ice, you know, cool packs and hot packs, you know, supportive toweling or pillows, all of that can really help. Years ago, nurses used to actually be trained in giving massages, and that can provide some comfort. You know, supportive touch is kind of how we frame that nowadays. But the other piece that you have is, in many cases, PT is getting involved much earlier in the patient, you know, rehabilitation course. And remember that motion is lotion. So, our endogenous analgesia system, which actually involves both endogenous opioids and endogenous cannabinoids, can be activated through many forms of motion, as well as immobility is actually a cause of pain itself. So, you just, you break out your in-patient tool kit and, you know, there are other tools and there's other allies that you want to think about in that context.

Dr Weathers: Those are all really great tips, many of which, I know, as you said, a lot of us tend in our thinking to go right to pharmacologic strategy, so wouldn't even be considered, but I think really thoughtful, and that we do have at our fingertips. So-

Dr Hogans: I wish I had thought to put them in the article.

Dr Weathers: No, they were fantas- but again, why we podcast, agree for complimenting the article… we encourage people to take advantage of both. Well, this has been wonderful, and I know I have learned so much, even more than was in the article. I always like to end on a hopeful note, so I would love to hear what developments in the field of pain that you're most excited about. What do you think is coming down the pipe?

Dr Hogans: Well, I think, like a lot of people, I've been waiting for the opportunity that's happening right now, which is, there's a massive investment in pain science being made by the NIH. Finally. You know, we've moved from, you know, just like, little things here or there, commercial kind of entities, to, we now have large NIH dollars flowing into pain. I'd like to see not only a focus on small molecule development, which will ultimately lead to better pharmacological agents, but I'd also like to see a thoughtful approach to non-pharmacological therapies, whole health approaches. Things like healthy communities, safe exercise spaces for all ages, more nutritious food, yoga, Tai chi. We know from Skelly and Cho's article in 2020 that there are many, many non-pharmacological therapies that actually work for chronic pain. There're some things we still don't know. Like, do older adults respond as well as middle-aged adults? And how can we get NPTs - non-pharmacological therapies - more accessible to people who are subject to disparities? I think part of what happened during the opioid era is that you could get, you know, a bottle of pills for a four-to-ten dollar co-pay and physical therapy was twenty dollars a shot. And we know PT will get you to a better place, but that person that you're talking to may not have three hundred dollars to go to a course of PT. And we need to figure out, you know, how do we do this better, safer, more healthfully.

Dr Weathers: And, I think, forgetting even the co-pay; it's the coordination, the time off work, all of it, right? So it's, I think, all of those challenges, but I think all of that are such important points about - and I think, that's really where I'm hopeful. Right? The emphasis, we talked a little bit about trauma-informed care earlier in our conversation, but the focus now on addressing the underlying social disparities of health and overall healthcare disparities, I think, is so promising.

Dr Hogans: We need to think about the long-term consequences for human health; and pain has a terrible impact on human health for many reasons, and, I hope, will continue to be the focus of effort for years to come.

Dr Weathers: Absolutely. Well, that is such an important statement to end on. Thank you again, Dr Hogans, for such a fantastic conversation and again, such an overall excellent article.

Dr Hogans: Thank you, Dr Weathers, it was great to speak with you today again.

Dr Weathers: Today I've been interviewing Dr Beth Hogans, whose article on principles of pain assessment, diagnosis, and management appears in the most recent issue of Continuum on pain management and neurology. To learn more about the topics of pain assessment and other topics of pain management, don't forget to listen to Continuum Audio episodes from this and other issues. Thank you to our listeners for joining today.

Dr Monteith: This is Dr Teshamae Monteith, associate editor of Continuum Audio. If you've enjoyed this episode, you'll love the journal, which is full of in depth and clinically relevant information important for neurology practitioners. Use this link in the episode notes to learn more and subscribe. AAN members, you can get CME for listening to this interview by completing the evaluation at Continpub.com/AudioCME. Thank you for listening to Continuum Audio.

Spine pain is one of the most common presenting concerns in health care settings. It is important for neurologists to understand strategies for evaluating and managing patients with spine pain.

In this episode, Katie Grouse, MD, FAAN, speaks with Vernon B. Williams, MD, FAAN, author of the article "Spine Pain," in the Continuum October 2024 Pain Management in Neurology issue.

Dr. Grouse is a Continuum® Audio interviewer and a clinical assistant professor at the University of California San Francisco in San Francisco, California.

Dr. Williams is the director of the Center for Sports Neurology and Pain Medicine at Cedars-Sinai Kerlan-Jobe Institute in Los Angeles, California.

Additional Resources

Read the article: Spine Pain

Subscribe to Continuum: shop.lww.com/Continuum

Earn CME (available only to AAN members): continpub.com/AudioCME

Continuum® Aloud (verbatim audio-book style recordings of articles available only to Continuum® subscribers): continpub.com/Aloud

More about the American Academy of Neurology: aan.com

Social Media

facebook.com/continuumcme

@ContinuumAAN

Guest: @VernWilliamsMD

Transcript

Full episode transcript available here

Dr Jones: This is Dr Lyell Jones, Editor-in-Chief of Continuum, the premier topic-based neurology clinical review and CME journal from the American Academy of Neurology. Thank you for joining us on Continuum Audio, which features conversations with Continuum's guest editors and authors who are the leading experts in their fields. Subscribers to the Continuum Journal can read the full article or listen to verbatim recordings of the article and have access to exclusive interviews not featured on the podcast. Please visit the link in the episode notes for more information on the article, subscribing to the journal, and how to get CME.

Dr Grouse: This is Dr Katie Grouse. Today I'm interviewing Dr Vernon Williams about his article on spine pain, which appears in the October 2024 Continuum issue on pain management in neurology. Welcome to the podcast, and please introduce yourself to our audience. 

Dr Williams: Oh, well, thanks for having me. My name is Vernon Williams and I'm a neurologist here in Southern California.

Dr Grouse: So, I want to start off today by asking, what do you feel is the key message from your article?

Dr Williams: So, I think the key message is that we want to make sure people understand that there's really a distinction between abnormal imaging, tissue damage, nociception, and this experience of spine pain. So, the concept is that nociception is different from the clinical experience of pain; nociception, meaning the electrical signaling from these, quote unquote, pain generators and that kind of thing. But it's really an incomplete framing. We really want people to understand that the experience of pain is colored by a number of other things, things like genetics, biochemical factors, behavior and psychological factors, social factors, those kinds of things. So that's one of the big messages, this distinction between nociception and this clinical experience of pain. 

Dr Grouse: Why do you think it's important for neurology clinicians to read this article?

Dr Williams: Well, I think, you know, for one thing, spine pain is very common. So, it is likely that neurologists will encounter patients who come to see them because of that chief complaint.

But I think that if we want to really be successful at treating spine-related pain, then we really have to know all of that basic information, the basic knowledge that we came to learn as residents and medical students or what have you. But it's also important to know that that knowledge is necessary, but it's insufficient. You really also have to confront pain from the standpoint of these other things, these other behavioral factors, psychological factors, social factors, and you got to kind of combine those things to be the most successful in treating this very common condition. 

Dr Grouse: You know, you mentioned earlier about the difference between tissue damage pain and nociception. I find this to be, you know, a really great lens thinking about these concepts to view this topic and your article specifically. Can you go a little more into what the difference between, specifically, pain and nociception really is?

Dr Williams: Yeah. I mean, so when we talk about nociception, in many ways we're talking about the electrical activity. And so, there's the stimulation of these nerves, in the periphery typically, and that electrical signal is transmitted, you know, from those nociceptive fibers into the spinal cord. And it's headed from the first-order neuron to the second-order neuron and axons in the spinal cord and eventually reaches the brain. But essentially the concept is that it's not pain at that point. It's not pain until those signals reach the cortex and they are experienced in some context. And that context really colors whether or not, and to what extent, people experience pain or suffer pain as a result. So, when we think about nociception, we tend to think about kind of tissue damage or the threat of tissue damage. And in clinic, we tend to kind of focus on that and we look for relationships between abnormalities on imaging studies that could be causing those kinds of electrical signals. And we tend to focus less on that second but critical aspect of things, and that's that individual 's personal experience, which is colored by a number of different things: their attention, their expectation, colored by how we interact with them, our verbal and non-verbal communication with them. And again, like we talked about: their history, who are they, their genetics, their behavioral history, their psychological history and those kinds of things. So, it's really this combination of things that we have to be aware of when we're treating spine pain. And I think the tendency is for us to focus on the first half and less on the second half.

Dr Grouse: Absolutely. I certainly think our training and our focus on localizing the lesion may in some ways hurt us in that sense because we really focus so much on the first and not so much the second. Would you say that's probably right?

Dr Williams: Yeah, I mean, that's part of our heritage as clinicians, particularly neurologists. It's, where's the lesion? And so, what happens when there is no, quote unquote, lesion? What happens if there are multiple potential lesions? And so, these kinds of concepts, I think, become really important, and the context in which you're examining and evaluating that patient becomes important. And I think they are at least as important as the potential pain generator or the nociceptive signal.

Dr Grouse: Now, you mentioned earlier something about sort of how we approach the patient and the language we're putting out, the body language. I found the concept of nocebo and maladaptive pain-related neuroplasticity to be absolutely fascinating when I was reading your article, and I was really surprised to learn that clinicians can really contribute to this effect unknowingly through their body language, verbal language, nonverbal messaging, and even how they're interpreting the test results? When a patient comes to see you with chronic back pain, how do you approach the whole process to minimize this effect and, really, to set the stage for more constructive and therapeutic evaluation?

Dr Williams: Yeah, Katie, I think that's… it's tough because our culture is so, you know, it's so ingrained in our culture to look for a structural abnormality as an explanation for an individual 's symptoms. And so, I find myself struggling with that all the time, not only discussing why we're ordering an imaging study, but, if that person comes back and I'm describing to them the abnormalities on that imaging study, I've got to be very careful about describing them in the context of what we expect. And so, I'll typically try to use words like, well, you've got some wear-and-tear changes that we all get, as compared to saying, well, you've got a disc herniation abnormality at L five S one that's causing your pain. That statement could have a negative effect on that individual's framing of what's going on. Maybe that L five S one disc is contributing to their symptoms and maybe it isn't. Maybe it's been there or for years and maybe it's new. And even if it is new, does that mean, in that patient's mind, that now they've got an abnormality that has to be fixed or else they will continue to have pain? And so, kind of trying to keep all of those things in mind is why we want to kind of color that interaction. And I mentioned both verbal and nonverbal interaction and communication with the patient, because I think that they are picking up on all of these signals. Some of them are very obvious and some of them are very subtle. But keep in mind their brains, their nervous systems are primed to interpret all of these signals, both verbal and nonverbal. And that's going to have a downstream - or upstream, I would say - effect on their framing and how they interpret the interaction and what they think it means for them and their future. So, you know, it's kind of a big thing to think about when you- every time you walk in a room, but it's an important thing to think about when we're communicating with patients. 

Dr Grouse: It's absolutely fascinating and has really made me go back and think about, gosh, are there ways that I could have done things better to really message this in a more helpful way? And on that note, do you have any tips or tricks on how to put out that that messaging, both verbal and nonverbal; to be, you know, to avoid those pitfalls of kind of reinforcing the wrong message about tissue damage?

Dr Williams: Yeah. I mean, so one of the main things is trying to be very purposeful about educating people on the difference between tissue damage or potential tissue damage and pain. And so being careful not to use statements like, well, I think your pain is coming from this disc or this structural abnormality because again, we want to try to separate those things.

They are different. I think that, you know, how we discuss imaging studies is very important because you want people to understand that an imaging study is just that. It's anatomy and it doesn't equal function, it doesn't equal what they experience in terms of sensory symptoms and pain. But I think the goal is to try to be very purposeful and maybe even reexamine how we discuss those things or when we discuss those things. One of the things I've found helpful is kind of the order in which I perform my clinical assessment. So traditionally, I was taught, like many, take the history, do the physical examination, and then start to discuss and educate patients. Right? Here's the test I want to order, here's what I think may be going on, so on and so forth. I think in some cases it's more beneficial to take the history and, before the physical examination, discuss what I'm thinking, taking that opportunity to discuss the differences between nociception, tissue damage, the experience of pain, the importance of movement, so on and so forth. And then do the physical examination so that that person has some idea of what is it that he's looking for. How is this going to inform his opinions and recommendations and so on and so forth. But also provide them with the concept that movement, for instance, is safe unless they have certain kinds of red flags on their history. I'm encouraging movement and I'm encouraging them to recognize that some of these movements they may have predicted would have been painful for them actually aren't painful, and they may start to internalize the concept that they can do it once without paying, that probably means that they're not damaging themselves every time they perform that movement. And if they can do one pain-free rep, that's important, and that may counteract the concept that they are damaging themselves every time they move and every time they feel pain, that means that there's tissue damage. So, what we talk about, how we talk about it and even when we talk about it during the course of that evaluation may have some negative or positive effects. And it may be beneficial to kind of think about those things and whether or not our typical approach might be the best or maybe we can improve on that or adjust that, particularly in certain situations and with certain patients.

Dr Grouse: That's absolutely fascinating, and great tips I think that all of our listeners will want to incorporate as we're approaching this patient population. You know, in your article, I also wanted to talk about, you mentioned some really interesting treatments for pain is that I think would include, or would, fall under the category of neuromodulation. Can you summarize some of these options for us?

Dr Williams: Yeah. I mean, so I think that the concept of neuromodulation, I tend to think of it in a very holistic sense. And so not only focusing on the application of external stimuli and that could be, you know, electrical stimuli, magnetic stimuli, cryo, analgesia, those kinds of things in order to turn up or down nervous system activity, electrical signals, what have you.

I think of neuromodulation in a global sense. I think in a way, cognitive restructuring and education, in a way, is a form of neuromodulation. It's affecting how that individual frames the concept of their pain, structural changes versus experience, so on and so forth.

But generally, I'm talking about these kinds of things. So, there are some very interesting approaches with electrical stimulation and it doesn't necessarily have to be permanent implantation of a stimulator as we tend to think about with spinal cord stimulation, but there are some interesting temporary peripheral nerve stimulators that that can be very helpful for various kinds of spinal pain. And then there's also these technologies that I find fascinating. Some of them are in the wearables category. So, combining the education and framing and cognitive restructuring with things like virtual reality, there are some interesting programs that combine some predictive modeling with virtual reality, such that an individual has goggles on,

they are participating in some activity that requires them to move in a certain direction and move to a certain extent that may or may not match what they are seeing visually in the goggles.

So, you can kind of begin to kind of dissociate their expectation of when they may experience pain as a function of their movement from what actually happens. So, these kinds of things, I think, are really interesting ways to augment our traditional approaches to pain, physical therapy, rehabilitation, medications, some kinds of injections, with these additional approaches that really have an effect on the nervous system as opposed to just focusing on what I would call kind of the mechanical anatomy, the joints and the discs and what have you, with traditional approaches.

Dr Grouse: It's really exciting to hear about some of these new options that can be tried to help with this neuromodulation and sort of cognitive restructuring. Of course, understanding that there's some things that we do ourselves that do this in the clinic encounter, which I think is a great reminder. I wanted to touch on, in your article, you had mentioned that we really have to be aware as clinicians, that health inequities and disparities and even the social determinants of health have inevitable effects on spine pain. How can our listeners better recognize and ensure equitable care for this patient population, particularly in light of the fact that many of these therapies that we've just been talking about can be difficult to access even in the best circumstances?

Dr Williams: Well, you know, thanks for asking that question. I think that's a great question. I think from the standpoint of, you know, health equity and addressing, you know, disparities and that kind of thing, the first thing is to just acknowledge and recognize that these things are present. And even, you know, though we may have the best intentions, there may be scenarios where our practices are affected and our patients are affected by these kinds of things.

So, I think the first thing is the acknowledgement. And then the second thing is kind of trying to figure out if there are things that we can do as individual practitioners, or our offices can do or the entities that we interact with, maybe that's a hospital system or what have you to address these kinds of things. So, we know, for instance, from the standpoint of race and ethnicity, there's disparities with respect to African Americans, with Hispanics and other ethnic minorities and the kind of care they receive. We know that access resulting from insurance coverage and geographical limitations, that kind of thing can be significant. And interestingly, it doesn't necessarily mean that the person is uninsured. So, for instance, we will often see individuals who've had work injuries and who are covered by the workers' compensation system have certain limitations placed on what they have access to, often resulting in lots of frustration from those patients. And that's a reality that we sometimes have to work really hard to overcome. Socioeconomic status, provider bias. And again, this is something that we have to kind of do some internal searching to say, hey, am I approaching these individuals on a on a more equal and equitable basis, or am I also subject to some of the biases that that I've been exposed to and trying to overcome that? So, I think that's a huge part of the context. And when we talk about how we learn, whether we're talking about spine pain or anything else, I'm a believer in that kind of cycle of pedagogy that includes content-based information, which is kind of the very basic foundational information, that includes things we can memorize and definitions we can memorize. And that may include things like what we've talked about relative to kind of the nociception and pain pathways, so on and so forth. But then there are concepts, and we've talked about the concept of verbal communication and nonverbal communication, the concept of cognitive restructuring and neuromodulation as an approach. But then context is kind of that last level, probably the most significant level in terms of how we can integrate all this information and really master information. And that context has to do with things like social determinants and disparities and the reality that these things have an effect on how we evaluate and manage patients and the success with which patients can be managed. And so, I appreciate that question, I think it's a great question, because it gets that kind of the reality of what does this look like in real life as opposed to just on the page or just in a textbook.

Dr Grouse: Well, that's really helpful and certainly something that we can all keep in mind as we try to be more aware of this, and I like the idea of just acknowledging it and just having it there, knowing that this exists and helping that inform how we approach these patients.

I wanted to ask you, what do you think the biggest controversy is currently in the evaluation and management of spine pain?

Dr Williams: You know, I think that there's a couple of controversies that are interesting. Nowadays, one of them has to do with the utility of some of the things that have been performed and done most frequently for spine pain, and that's things like epidural injections, facet injections, some of the interventional procedures. There's some controversy among some as to whether or not these things are effective, you know, what role they have in treatment because some people will say, oh, is there any long-term effect from these kinds of procedures? Even patients will sometimes say, hey, listen, I'm not sure if I want an injection because isn't that just temporary, or, isn't that just a band aid? But I think that when we talk about pain from the perspective of it potentially being a progressive disorder and trying to be aggressive with managing pain so that we are less likely to see some of the chronic manifestations that occur with maladaptive neuroplasticity it's important to be aggressive with stopping no subceptive signals, reducing an individual 's experience of pain, optimizing their function, and having a positive effect on the ability to treat and eliminate pain, even if that means with epidural injections or blocks or what have you, as long as they're safe and effective. I think that there are some controversies evolving related to some of the regenerative procedures that have been done for other kinds of musculoskeletal pain. So, for instance, PRP and stem cells, you know, people have been doing those for knees and muscle tears and what have you. And of course, that technology has kind of evolved into potential approaches for spine pain. People are often interested in whether PRP or stem cells may help their spine pain. And so, I think that's another area of potential controversy because there hasn't been a ton of, you know, high-level evidence, although there are some, you know, there's some studies out there and there's some evidence that they may be of benefit. And I think the role of stimulators and implants for axial pain is another area of potential controversy. Those are probably the biggest things in this area of spine pain that are topics of controversy. There are things that have people talked about for years in terms of chiropractic care versus traditional medical care. But I think right now it's the utility of these kinds of interventional procedures, the role of regenerative procedures and injections, and then the role of more aggressive interventions like permanent implantation of stimulators and that kind.

Dr Grouse: Is there anything coming on the horizon in the field of managing spine pain that we should be looking out for?

Dr Williams: Well, you know, I am still bullish on the concept of neuromodulation and we've talked about that peripheral nerve stimulation, spinal cord stimulation, and then other wearables, VR, so on and so forth. I think that those things will continue to evolve, and I think that technologies continue to evolve that are likely to help with spine related pain. Some of them are very interestingly related to the ability to strengthen multifidus muscles and improve muscular function in individuals with spine pain. But I think that's one area - neuromodulation - that we'll continue to see evolution. I think that- I'm interested to see what the role of regenerative injections and regenerative procedures may play. And then just like every other field of human endeavor, artificial intelligence, machine learning, those kinds of things are likely to have a significant effect on how we diagnose an individuals, on treatment options for various individuals, and even a predicting outcome from various treatment. So those, I think, are examples of areas that we'll see continued growth and evolution with respect to spine pain.

Dr Grouse: Well, I'm very excited to see what comes down the pipeline and both vastly more to come, I'm sure. So, thank you so much, Vernon, for joining us. I really enjoyed reading your article. I really enjoyed talking about this topic. I think I've learned a lot and I hope that our listeners will take the time to read this article. It's really, really helpful.

Dr Williams: Well, I appreciate the opportunity. I really enjoy participating in this process. The interview was fun, so thanks a lot for having me. I really appreciate it.

Dr Grouse: Again, today I've been interviewing Dr Vernon Williams, whose article on spine pain appears in the most recent issue of Continuum on pain management in neurology. Be sure to check out Continuum Audio episodes from this and other issues. And thank you to our listeners for joining today.

Dr Monteith: This is Dr Teshamae Monteith, associate editor of Continuum Audio. If you've enjoyed this episode, you'll love the journal, which is full of in-depth and clinically relevant information important for neurology practitioners. Use this link in the episode notes to learn more and subscribe. AAN members, you can get CME for listening to this interview by completing the evaluation at Continnpub.com/AudioCME. Thank you for listening to Continuum Audio.

Peripheral neuropathic pain is primarily influenced by the biology and pathophysiology of the underlying structures, peripheral sensory nerves, and their central pathways.

In this episode, Kait Nevel, MD speaks with Miroslav Bačkonja, MD, an author of the article "Peripheral Neuropathic Pain," in the Continuum October 2024 Pain Management in Neurology issue.

Dr. Nevel is a Continuum® Audio interviewer and a neurologist and neuro-oncologist at Indiana University School of Medicine in Indianapolis, Indiana.

Dr. Bačkonja is the clinical director in the Division of Intramural Research at the National Institutes of Health in Bethesda, Maryland.

Additional Resources

Read the article: Peripheral Neuropathic Pain

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Full episode transcript available here

Dr Jones: This is Dr Lyell Jones, Editor in Chief of Continuum, the premier topic-based neurology clinical review and CME journal from the American Academy of Neurology. Thank you for joining us on Continuum Audio, which features conversations with Continuum's guest editors and authors who are the leading experts in their fields. Subscribers to the Continuum Journal can read the full article or listen to verbatim recordings of the article and have access to exclusive interviews not featured on the podcast. Please visit the link in the episode notes for more information on the article, subscribing to the journal, and how to get CME.

Dr Nevel: Hello, this is Dr Kait Nevel. Today I'm interviewing Dr Miroslav Backonja about his article on peripheral neuropathic pain, which appears in the October 2024 Continuum issue on pain management and neurology. Welcome to the podcast. 

Dr Backonja: Thank you. 

Dr Nevel: Misha, can you please introduce yourself to the audience?

Dr Backonja: Yes, I'm Miroslav Backonja, but everybody calls me Misha. So everybody knows me by that. I'm a training neurologist, and I also have training as well as certification in pain management. And most of my practice has been where neurology meets the pain, which is neuropathic pain. I spend some time basic science lab and then transition into clinical research. And I was in academia for a couple of decades and was most recently recruited by NCCIH National Center for Complementary and Integrated Health and have been there for two and a half years now. 

Dr Nevel: That's wonderful. I would love to hear more about your career at the NCCIH, a little bit and what you do in your role now, and how that came to be.

Dr Backonja: Yeah, I was recruited to help and provide clinical support to efforts at NCCIH in the phenotyping of pain and neurologists who've done research in quantitative sensory assessment and other quantitative means of assessment of pain. Coming to NIH was very rewarding and quite of a learning experience. After six months being there, I've discovered that NIH is the biggest secret in plain sight. They say in the plain sight because it's public institution and everything is open to public and it's a secret because we don't think about it. This is in particular in reference to biomedical research training, including clinical trainings. So, I would encourage everybody to think of NIH as a place to spend some time and learn. There are wonderful research opportunities as well as educational opportunities. Vast library of presentations, green rounds and different other types of courses - some of them open to public, and some of them are up to FAS, which is a foundation of advances in science education by discovering. I feel like being back in school and having fun. 

Dr Nevel: That's wonderful. Can you share with us a little bit about how you became interested in peripheral neuropathy and pain management of peripheral neuropathic pain? 

Dr Backonja: It actually goes back to my residency and fellowship. And actually, you know, I had the luck of being exposed to a couple of clinicians who actually became my mentors. First was Jose Ochoa, who was one of the first people to quote from a small fiber, C fiber specifically, and he also was pioneered in quantitative sensory testing. And the other one was Charles Cleland, who was a psychologist and who pioneered assessment of patient symptoms, developing the Brief Pain Inventory is one of the tools. That actually peaked my interest in the topic of pain and once when I started learning about pain, what is the kind of mysterious experience of humans' pain, turns out that we have learned a lot of science about the pain and can make the pain very accessible. And I hope some of this will come to the chapter that we've provided. 

Dr Nevel: Thank you for sharing that. I think of peripheral neuropathy and I think most neurologists think of peripheral neuropathy as one of the bread-and-butter diagnosis within our field. For the practicing neurologist out there who might be listening, what do you think is the most important takeaway from your article that maybe they don't already know about peripheral neuropathic pain?

Dr Backonja: When it comes to peripheral neuropathy and peripheral neuropathic pain, it goes back to my early experience and still holds the truth. Neuropathies don't kill people, they just maim them. They create- cause lots of disability and if you add a pain to it, it can be quite disabling. In some regards, it has been neglected the area of development in neurology in terms of scientific discoveries, although things are changing quite rapidly as of recently. Main take home messages, and especially when it comes to a sensory neuropathies and painful neuropathies, is that it's one of the skills that has not been well researched and then not well communicated to the vaccine neurologist in terms of what to do with it. But most neurologist sensory symptoms are just like a noise because, especially when it comes to pain and prosthesias and allodynia and hyperalgesias, like, what is that like? It's just not knowing what to make of it. Frequently associated also with emotional components in terms of the people are either depressed because of persistence of pain or anxious, not knowing what's going on. And that really can create quite a bit of a challenge in terms of what to do with it. But once anybody who's interested learns the fact that sensory neuropathies and fever neuropathies as well could be as well and is easily diagnosed by a neurologist who pays a little bit of attention and gains some skills in assessing not only negative sensory phenomena, because that's what he as a neurologist get trained to detect and quantify sensory deficits as well as motor deficits and loss reflexes. Also, if you pay attention to positive sensory phenomena, which is part of the repertoire of symptoms that patients with neuropathic pain experience, it's not whether patients would have either positive sensory phenomena like prosthesia and pain or negative sensory phenomena. Actually, they have all of them. And that's kind of puzzling for many patients. And lots of times, very patients say, like, how can I hurt when I don't feel like, let's say, like most commonly it's lower extremities. Like I don't feel my feet, but it hurts. I mean, how come? Oh, that's a cardinal feature of neuropathic pain, neuropathic painful neuropathy.

Dr Nevel: Yeah, thanks for that. You know, I really thought that your Table 3-1 was really nice. It kind of lists through the common causes of peripheral neuropathic pain and just demonstrates the diversity of the different etiologies or other conditions that can cause neuropathic pain. And so, I encourage the listeners to review that table. But, on that topic, can you share with us what you think are the most important components of evaluating patients with neuropathic pain to maybe come to a diagnosis, to find what the underlying etiology or driver is? 

Dr Backonja: When it comes to painful neuropathies, there are actually two problems you have to solve. So, don't forget that part. The first one is finding a pathological theology. Why a person has a neuropathy, what kind of neuropathy. And then second is, what's the nature of the sensory problems? What's the nature of the sensory symptoms, specifically pain, levodenia and hypogesia. So, figuring out the theology of the B12 deficiency or diabetic painful neuropathy, you can relatively quickly or hopefully one would relatively quickly come to that at theological diagnosis. But then the second part is the diagnosis of symptoms. What's the underlying metaphysiology of that. And again, just reminding colleagues that the specific sensory phenomena such as thermal hyperalgesia is now well established to be due to what's called peripheral sensitization of C fibers, which are the small unmyelinated fibers, expressed TP 1 receptors. So, patients who will report that taking a hot shower is very painful. An example of that or when conducting sensory exam and applying if you come to the point of examining the perception of warm and hot and patient affords the pain. That's just the hallmark of the C hurtful sensitizations to C fibrous sensitization. On the other hand, if somebody has mechanical ordinia like putting the shirt on hurts, putting the socks hurts. Well, that's evident to central sensitization. These are the simple, relatively simple but symptoms or signs that could have implication if those patients with central sensitization are more than likely to benefit from medications that restore descending inhibition, such as tricyclic antidepressants or SNRI's. And so just paying attention to that, it gives a clinician being a clinician or a neurologist, like, let me consider prescribing medication that have central A acting properties. Or if it's purpose sensitization, something we have like a sodium channel blocking property, things of that sort. Actually, there are some other strategies such as antagonist TRPV1receptors, the capsaicin base. Those are the kind of things that can help a neurologist kind of take the evaluation of painful neuropathies to the next level.

Dr Nevel: Yeah, the- by getting a careful history and exam, that can influence what treatment you prescribe to patients. Understanding whether it's central or peripheral. On the topic of treating patients and talking with patients and evaluating them, what do you think is most important to counsel our patients about who we are treating for neuropathic pain?

Dr Backonja: Number one: by getting good history and exam. Well, really in the coming to specific diagnosis is huge relief to the patients who thinks many themselves that they're just going nuts are crazy because nobody else understands these symptoms. So, validation in terms they have a real problem. Second important step is that for the most patients, there is probably reasonable degree of therapeutic interventions that can lead to relief of pain. And also, with applying the integrative approaches with complementary medicine is that patients are given tools to deal with what is otherwise underlying problem. Those two steps make a huge difference. 

Dr Nevel: Absolutely. What's the most challenging aspect about managing patients with peripheral neuropathic pain?

Dr Backonja: Actually, there are a couple. Number one thus far: we do not have a cure for any other neuropathies or painful neuropathies. So that's one of the big disappointing things one would need to communicate to the patient. The second challenge is actually the therapies that actually for neuropathic pain. There's a half a dozen- yeah, half a dozen FDA approved treatment. One thing that's interesting characteristic that all of them prove proven efficacy in clinical trials. If you scratch the surface, you find out that only 40% of patients obtain 30% pain relief. So, it's a rare patient that gets 100% pain relief, and even those, too, get what we call clinically significant, and then in studies, basically significant benefit. It's only partial penalty. But for the most those who do get the benefit, pain goes down probably enough for them to get some a semblance of normality in terms of having some control over the symptoms and their function. It's then the third challenge is really working through those available therapies to find what works for individual patients because we're not at the point yet where for example, other fields like oncology, you can quickly through the means of biomedical and other evaluation come to the patient specific therapy. So, at this point in time you're far from that. What we end up doing with when it comes to management for painful neuropathies is a trial. Sometimes patients say, well, trial and error. I would say, well, it's a treatment trials. We try one thing at a time, assess the risks and benefits and then there was many treatments that carry the benefit. If you carry it on when once, when they don't or if there's adverse events, side effects, we discontinue them. And then most of the patients end up with a combination of pharmacological and now pharmacological treatments and most of them can get some semblance of symptoms control.

Dr Nevel: I really appreciate your point on preparing our patients and you know, expectations and things like that and working with them and looking for things that may help. But also having an understanding that the likelihood of complete pain relief is maybe not a super high chance of complete pain relief. 

Dr Backonja: But if you're going back to the kind of preparing patients, it's a good to acknowledge or give a chance to express themselves because many times they patients are confused because they have symptoms that are confusing to them. And so just to have them express it. And for example, my alma mater, we developed the color paint drawing where the different sensory qualities are presented by different colors. And then on the body diagram, patients draw where they have symptoms. And this is probably one of the rare examples where you can literally see a pain because these neurologists can recognize the patterns. You can see the pattern of the motor, right, is multiplex or radiculopathy or the list goes on and on. So, this is one of the kind of tools that's very simple, but gives the patients another way to communicate because lots of times they really have difficulties expressing themselves.

Dr Nevel: Right. So, the opposite of the most challenging, can you share with the listeners what you find the most rewarding about taking care of patients with peripheral neuropathic pain?

Dr Backonja: What is rewarding is that with some work- and again, it's not easy work because it does require multiple visits and multiple assessments and the reassessments, most patients can get control over their symptoms to the point of coming to beginning some of the functional improvement and aspects of quality of life like sleep and work, they are definitely rewarding and most of the time it's fairly obvious. And again, pain management is definitely a team sport where really, it's important to gauge colleagues. Most of the places don't have what I have had when I was in academic institutions, easy access to health psychologist or physical therapist. Most communities do have those specialties. And many patients actually benefit from things that are what's considered a complementary medicine, such as Tai chi or yoga. And actually, in my practice, Tai chi was probably most common prescription for my patients because, as I tell them, there are multiple benefits. Number one: one of the risks of patients, especially prophyl neuropathies and lower extremities, is a loss of proprioception. Again, even those who have a reasonable preserved proprioception over welding, noise of pain actually makes the problem walking the at risk of falling. Actually, Tai chi one gets improvement in balance. There's also medicating component to it. So, mindfulness medication is kind of built in it and that all kind of gives the patients a better control of symptoms. So, some of those interventions are easily accessible in community. So, it's, again, it's a patient education that really takes important part.

Dr Nevel: Yeah. And that Tai chi is maybe one of the answers to the next question that I have for you. But as the clinical director of the Division of Intramural Research at the National Center for Complementary and Integrative Health, I have to ask you, Misha, what sort of integrative and complementary type interventions do you counsel your patients about, maybe beyond Tai chi, and which ones do you think are the most helpful?

Dr Backonja: To clarify, the NIH patients I see are all admitted per protocol. Actually, NIH has the largest research hospitals called clinical NIH Clinical Centre, which has a hospital and clinics. All the patients that come to our program, they come per protocol for the most part.

They come for specific investigations. At the moment, we do not have intramural treatment protocols, although in near future one of my goals is to establish that. The NIH funds- 90% of funding from NIH goes extramurally to academic institutions and other healthcare organizations and so on, and only 10% goes for intermural research. So, what we do is much smaller in scope, much more focused. So, what do we support NCCIH actually support extramurally full range of anything from probiotics, research in microbiome related to health and pain all the way to interventions such as mindfulness meditation? Intramurally, once when patients come for protocol, we evaluated and it's unavoidable to be a question. So, what do we do now? What recommendations do we make? Again, we don't- with the present time, we have treatment protocols and then, most of the time, what I can do is provide recommendations to the patients when they go back to the treating community, to the treating providers. It's usually a fairly comprehensive list including pharmacological and non-pharmacological accommodations for those who have had experience with pharmacology. Sometimes I can just say yes, continue or change or whatever. But then when it comes to additional complementary accommodations, they always provide information. For example, why do I recommend Tai chi? Or, what's the benefit of yoga and why would one want to try to learn trying to behavioral therapy or mindfulness meditation? What's the benefit of turmeric and some other components of what's called anti-inflammatory diet and what's the rationale behind all of that? So rather than just giving a list of recommendations and leaving it that, I try to engage patients in terms of having to understand why something is recommended, whether the fits with their expectations and what fits with their lifestyle and so on.

Dr Nevel: Yeah. So, what's coming up, what's next in painful peripheral neuropathy? What do you think is exciting? Where do you foresee some breakthroughs in this field?

Dr Backonja: Probably what will make the most difference is application of some of the really molecular biology tools that are being applied to peripheral neuropathy. So hopefully one of these days you'll have a cure for neuropathy and pain and anything would come to that will be probably interaction between a nervous system and an immune system, in particular neuroinflammation. That's kind of my bias. They're probably that's- well, the answer will be, but many painful neuropathies - actually every painful neuropathy, because they come from, as a result, specific pathologies - are different in a sense of trajectory natural course that will have to be first addressed. And again, depending on the underlying disease and molecular biology of that and genetics of it will determine that. But on the other hand, there are some common denominators, as we talked, when it comes to painful neuropathies, which is drivers of peripheral and central sensitization. And maybe one of these days, we'll find what are those drivers and how to change the system so it does not produce pain and other associated symptoms.

Dr Nevel: So once again, today I've been interviewing Dr Miroslav Misha Backonja, whose article on peripheral neuropathic pain appears in the most recent issue of Continuum on pain management in neurology. Be sure to check out Continuum Audio episodes from this and other issues. And thank you to our listeners for joining us today. And thank you, Misha, so much for talking with me today about your article. I encourage all of the listeners to read it. It was very comprehensive and just really wonderful to read.

Dr Backonja: Thank you. Enjoyed it.

Dr Monteith: This is Dr Teshamae Monteith, associate editor of Continuum Audio. If you've enjoyed this episode, you'll love the journal, which is full of in-depth and clinically relevant information important for neurology practitioners. Use this link in the episode notes to learn more and subscribe. AAN members, you can get CME for listening to this interview by completing the evaluation at continpub.com/AudioCME. Thank you for listening to Continuum Audio.

In the patient populations treated by neurologists, central neuropathic pain develops most frequently following spinal cord injury, multiple sclerosis, or stroke. To optimize pain relief, neurologists should have a multimodal and individualized approach to manage central neuropathic pain.

In this episode, Lyell K. Jones Jr, MD, FAAN, speaks with Charles E. Argoff, MD, author of the article "Central Neuropathic Pain," in the Continuum October 2024 Pain Management in Neurology issue.

Dr. Jones is the editor-in-chief of Continuum: Lifelong Learning in Neurology® and is a professor of neurology at Mayo Clinic in Rochester, Minnesota.

Dr. Argoff is a professor of neurology and vice chair of the department of neurology, director of the Comprehensive Pain Management Center, and director of the Pain Management Fellowship at Albany Medical College in Albany, New York.

Additional Resources

Read the article: Central Neuropathic Pain

Subscribe to Continuum: shop.lww.com/Continuum

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Host: @LyellJ

Full episode transcript available here

Dr Jones: This is Doctor Lyell Jones, Editor-in-Chief of Continuum, the premier topic-based neurology clinical review and CME journal from the American Academy of Neurology. Thank you for joining us on Continuum Audio, which features conversations with Continuum's guest editors and authors who are the leading experts in their fields. Subscribers to the Continuum Journal can read the full article or listen to verbatim recordings of the article and have access to exclusive interviews not featured on the podcast. Please visit the link in the episode notes for more information on the article, subscribing to the journal, and how to get CME.

Dr Jones: This is Doctor Lyell Jones, Editor-in-Chief of Continuum: Lifelong Learning in Neurology. Today I'm interviewing Dr Charles Argoff, who recently authored an article on central neuropathic pain in the latest issue of Continuum covering pain management. Dr Argoff is a neurologist at Albany Medical College where he's a professor of Neurology, and he serves as vice chair of the Department of Neurology and program director of the Pain Medicine Fellowship Program there. Dr Argoff, welcome. Thank you for joining us today. Why don't you introduce yourself to our listeners? 

Dr Argoff: I'm Charles Argoff. It's a pleasure to be here and thank you so much for that kind introduction.

Dr Jones: I've read your article. Many of our listeners are going to read your article. Wonderful article, extremely helpful. Closes a lot of gaps, I think, that exist in our field about understanding central neuropathic pain, treating central neuropathic pain. You now, Doctor Argoff, you have the attention of a huge audience of mostly neurologists. What's the biggest point you would like to make to them, or the most important practice-changing advice that you would give to them?

Dr Argoff: I think it's at least twofold. One is that central neuropathic pain is not as uncommon as you think it might be, and it occurs in a variety of settings that are near and dear to a neurologist's heart, so to speak. And secondly, although we live in an evidence-based world and we want to practice evidence-based medicine - and I'm proud to have formerly been a member of the Quality Standard subcommittee, which I think has changed its name over time. And so, I understand the importance of, you know, treatment based upon evidence - the true definition of evidence-based medicine is using the best available evidence in making decisions about individual patients. And so, I would urge those who are listening that, although there might not be as robust evidence currently as you'd like, please don't not take the time to try to treat the patient in front of you o r at least acknowledge the need for treatment and work with your colleagues to address the significant neuropathic pain associated with that central neurological disorder. Because it can be life-changing in a positive way to make even a dent and to really work with somebody, even though not clear-cut always what's going to work for an individual patient.

Dr Jones: Well said. I'm glad you brought that up. So, to put it a different way, absence of evidence is not an excuse for absence of treatment. Right?

Dr Argoff: Exactly. And I think that, I hope that we would agree that especially in neurology, what we do is about as far from, 'Yep, you've got strep throat, here's that antibiotic that's going to work for you and all you have to do is take the medicine.' I mean, most of what we do is nowhere near that. 

Dr Jones: It's complicated stuff. And this is a complicated topic. And I'll tell you, I learned a lot reading your article. I think most of us in neurology and medicine, when we hear the term neuropathic pain, it feels roughly synonymous with peripheral generators of that pain, such as diabetic neuropathy or posttraumatic neuralgia. But as you mentioned, there's central mechanisms for pain generation. How is it defined? What is central neuropathic pain?

Dr Argoff: It's defined as pain caused by a lesion or disease of the central somatosensory system . Though neuropathic pain in general is pain associated with the lesion of the somatosensory system; and to your point, that can be peripheral, which of course is outside the spinal cord, or brain or central, which is within the spinal cord or brain. And central neuropathic pain is defined specifically as pain caused by a lesion or disease of the central somatosensory system. That's either brain or spinal cord. But there's an interesting follow-up, and I'm going to ask if you could remind me because I know we're talking about definitions now, but I'll just bring something up and we can come back to it. What's interesting about that is that my - whoever 's listening, that's not to say that they're not connected. And in fact, they are very much connected.

And there's very new work, which I included in the article, down at Washington University in Saint Louis, that suggests you can actually affect central neuropathic pain by addressing peripheral input to the central nervous system. If you remember Ken Casey at the University of Michigan at the World Pain Congress in Vancouver, British Columbia many years ago, he ended his talk on pain with a limerick, of which the last line was, Remember, there ain't no such thing as pain without a brain. And so that kind of summarizes that.

Dr Jones: Well, and it goes both ways too, right? We know that there's some central sensitization that can happen with peripheral generators, right? So we really have to think about the whole circuit.

Dr Argoff: Yes. And that's been sometimes the bane of my existence as a colleague of others and a sometimes debater. Is the pain central? Is it peripheral? Well, it's everything. And it's important to know as many of the mechanisms and many of the targets that you could use for treatment so that you can affect the best outcome for your patients.

Dr Jones: Yeah, so - and you mentioned in your article what some of the common causes of central neuropathic pain are. What are the big ones in your experience? 

Dr Argoff: So, the biggest ones are spinal cord injury-related pain, MS-related pain - and I'd like to come back to a point and just if I do the third one - and central poststroke pain. And what struck me, I think Tim Vollmer published a survey about the incidence, the prevalence of ongoing pain in patients with multiple sclerosis. And it blew my mind several years ago because it was incredibly high. Like in this survey of MS patients who, you never hear about pain, you hear about these modifying treatments, all the wonderful expanses that have been made. I mean, like seventy something percent of people say they have moderate to severe pain. And when you think about how sensory processing occurs, it makes perfect sense that a demyelinating disorder is going to interrupt the flow of information for a person to feel normal. 

Dr Jones: Yeah, I think it's a good example of, there are things that we tend to focus on as clinicians where we worry about deficit and function and capacity. But if we're patient-centered and we ask patients what they care about, pain usually moves up higher on the list. And so, I think that's why we, it's maybe underrecognized with some of those central disorders, right?

Dr Argoff: I think so, and I and I think you hit the nail on the head that - and we're also trained that way. I tell this to my patients very often so that they are reassured when I examine them and I say, and I tell them that everything looked pretty OK. It's not a medical term, I understand that. Because what we do in a typical neurological exam, even if it's detailed, doesn't really address all the intricacies of the nervous system. So it's really a big picture and sensory processing and especially picking up sensory deficits; you know, we use quantitative sensory testing and research studies and things like that, but bedside testing may not reveal the subtle changes. And when we don't see overt changes, we often think - that can lead someone to think that everything is OK and it's not.

Dr Jones: So, when you when you see a patient who you've diagnosed with a central mechanism, so central neuropathic pain, how do you approach the management of those patients, Dr Argoff?

Dr Argoff: I always review what treatments and what approaches have been addressed already. And I see if - a handful of time, we actually just submitted a paper for publication regarding this in a group of patients with pelvic pain who had untreated, difficult-to-treat chronic pelvic pain, seen all the urological kinds, gynecological things. Look, we picked up two patients who had unknown MS. So, it's just interesting when it comes down to that level.

And we also picked up some patients who had subacute combined degeneration. So that's another central kind of disorder as well. Again, the neurologist in us says to make sure that we have specific diagnosis that underlies the central neuropathic pain. And so interestingly, of course, for somebody with MS - or even though it's uncommon, it could be more than one. Somebody with MS might have a stroke, somebody with MS might have a cord injury due to cervical, you know, joint disc disease. Not to overcomplicate things. Know the lay of the land, know the conditions, know what you're battling and lay out so that you can treat the treatable; you want to treat whatever you can correct? So, for MS you simply want to have the best disease-modifying treatment on board, tolerable and appropriate for that person, and so on. And then you really want to take a history of past treatments - and your treatments can be everything and anything, including behavioral modification, physical rehabilitative approaches, as well as pharmacologic management. That's - as I think I put in my article, we concentrated in the article on pharmacologic management because honestly, that's what most patients are looking for, is 'what can we, what can you do to help me now, in addition to what I can do myself.' And that's what we typically think of. There are also some more interventional approaches, invasive options, that have developed over time. And of course, those are the ones, some of them, especially in neuromodulation, that we have the least information about, but it appears somewhat promising. 

Dr Jones: No, that's exactly what we need to hear. And you also mentioned something that I think is important. This is a common theme throughout the issue because I think it's true for the management of many different types of pain and interdisciplinary approach. In other words, not just honing in on pharmacotherapy or neuromodulation as a one-size-fits-all magic pill, right? So, that - tell us a little bit more about that interdisciplinary approach and how that's important for these patients.

Dr Argoff: So, let me back up and give an example. Let's look at Botox for chronic migraine.

So, the pre-M studies that led to the approval of Botox for chronic migraine: two treatment sessions versus two random, two placebo session in different patients. The mean headache frequency was, let's say, fifteen to twenty in each group. It was like seventeen, eighteen, something like that. But the mean pain headache day reduction was somewhere between four and five after two treatments compared to a lesser, a lower number in the placebo group.

So, if you think about that, that means that you went from nineteen, let's say, to fourteen, thirteen, or twelve. Want to be generous, eleven or ten. But that means that person, everyone 's happy. We use treatment. We have better data than that because the longer you use it, the better it gets in general, but it means that people are still going to be symptomatic. So that drives home in a different painful disorder the importance of yes, treatment can be effective, but it's not the only treatment that a person is going to likely need. And so, I think that's what's so important about multidisciplinary approach. I- we may affect positive changes, reduction in pain intensity with a particular pharmacologic agent, but we don't anticipate it's like taking an antibiotic or a strep throat, not curative. And so, we want to, early on, to explain that logically, methodically, step by step. There are many options for you and we're going to, you know, systematically go through them. And I may need to call in some colleagues to help because I don't do everything. No one does everything, right? But don't feel as if there isn't any hope because there is. If we were to use intraspinal Baclofen for someone who has painful spasticity following a stroke or a spinal cord injury, combining that with physical therapy might give more effect, maybe synergistic. Some targeted muscles, some local muscles may not respond as well to the intraspinal Baclofen, so is that - what can we do? Well, we could use oral agents or we might be able to target that with botulinum toxin, and so on and so forth. So it's limitless, virtually, in what you can do.

Dr Jones: There's kind of setting expectations and letting people know that you, you're going to need a lot of different approaches, right? To sort of get them the best possible outcome.

Dr Argoff: Yeah, I think that's so important. And of course, no matter what we try to set out, there are going to be individuals - for those of you who are listening, we all know - who expect to be cured yesterday. That might be challenging for us not only to actually complete, but also, it's challenging for some individuals to appreciate that we're with them, we're going to work with them. It'll be a process, but we've got your back.

Dr Jones: Great. And you know, this is a question that I get all the time from patients and from other clinicians is, you know, what about cannabinoids? What's the role of cannabinoids for the management of central neuropathic pain?

Dr Argoff: First, I'll say that the short answer to that is we don't know. The second part of my response would be, there is new evidence that it might be helpful in the acute treatment of migraine. And I'm happy to say that the editor of this edition of Continuum is the person who developed that evidence, and it's been recently presented at the American Headache Society.

But the challenge and the conundrum that we all face is, everywhere within our nervous system where there's pain being processed, there are endocannabinoid receptors. There also happen to be opioid receptors, but that's a separate issue. And the endocannabinoid system, the peripheral or central, you know, CB1, CB2, is very, very important, but we haven't figured out a way of harnessing that knowledge in developing an analgesic, an effective analgesic. And part of that is that there are so many chemical agents that have cannabinoid properties and there are different… the right balance has not yet been found. But even the legalization, the available of medical cannabis, hasn't led to a standardized approach to evaluating if a preparation does help. And that's part of the conundrum. It's like saying, 'does medicine work?'Well, yeah, sometimes. But which medicine? Which receptor? How do you harness the right ratio between TBD, THC, other active agents, et cetera? And I think maybe as we go forward in the future, we'll be able to do that with - more precise.

I mentioned Dr Schuster's study in which he had defined ratios of THC effect and CBD and was able to clearly show effect based upon that. But the average person going into a dispensary doesn't really get that. We don't get to study that. Each person's an NF1  and it's not very helpful to understand how to do that. I would say, as I'm sure you remember, there was a practice parameter that was published probably over a decade ago about using cannabis symptomatically in different neurological disorders. And I believe that it was what they studied or what they reviewed was helpful in MS-related urinary discomfort and spasticity, but not necessarily pain. 

Dr Jones: And we're still in the early days of studying it, right?

Dr Argoff: Yes. 

Dr Jones: That's part of the point, as we got started late and we're still waiting for high-quality evidence. And I guess, if you look at the horizon, Dr Argoff, or the future of management of central neuropathic pain, what's going to be the next big thing? 

Dr Argoff: One of the joys of being asked to get involved in a project like this is that inevitably we learn so many new things because, you know, that's when anyone says, oh, you must be an expert, I say, I don't know anything because I'm always learning something new. One of the reasons why I moved to Albany Medical College about seventeen years ago was to be able to further my interest in studying why people benefit from topical analgesics by working with a scientist at Albany Med who studied keratinocyte neurochemistry and its impact on pain transmission. And that's a separate issue, but it indicates my love for the peripheral nervous system. And one of my thoughts historically, that is, what the central nervous system processes is what it processes and it might get input, as you mentioned earlier, from the peripheral nervous system, so that topical agents could be dampening central mechanisms. And lo and behold, as I was doing research for this article, I learned that people doing peripheral nerve blocks - so blocking peripheral input at the into the spinal cord - at Washington University, Simon Guterian and colleagues, demonstrate that they could give prolonged benefit from central pain by blocking peripheral input. And that's wild because certainly the nervous system is a two-way street. It's an understatement. What I really found amazing was that, again, blocking input helped the injured central nervous system to behave better. 

Dr Jones: That is kind of cool to think about. And I'll tell you, as editor of the journal, one of the funnest things is getting to learn all about neurology, including pain and including central neuropathic pain, when in the end you're doing all the work, I just get to sit here and enjoy it.

And you're a program director of a pain fellowship. What's the pipeline look like? Are neurologists more interested in pain than they used to be? 

Dr Argoff: I'm happy for this. We are seeing more and more applicants from neurology into our pain management programs. I would say… I was going to say tragically. If I say tragically, it's because what specialty better understands how to diagnose, figure out, assess, come to a conclusion? You can't have pain without your brain. It's always amazed me that more neurologists weren't interested, and I understand the background and such. Just like in migraine, it's only advances in understanding mechanisms of migraine that allow neuroscientific advances that are leading to great therapeutics - that's happening and increasing in 'pain.' Today, as program director, we had our fellowship interviews earlier today and three of the nine applicants that we interviewed were neurologists. Last week, I think we interviewed two or three also. That would not have happened five years ago or six years ago. And if you think about it, we can not only diagnose, quote-unquote figure out what's happening, but we now, with pain management training, we can offer people a variety of both invasive and noninvasive options, all while understanding what we're doing with respect to the nervous system in a way that's different than the other specialties that typically go into pain med. And that's such - for me, it's a beautiful experience and something I really enjoy doing. There isn't a neurological condition in the most part that either doesn't have pain associated with it or doesn't have mechanisms that overlap. If you think about epilepsy, and please don't think I'm crazy, but epilepsy is associated with disinhibited hyper-excitatory behavior, just to put it loosely, among certain neurons. That's what pain and neuropathic pain is about too. And you, in fact, we know that several mechanisms since now what medicines are used for both. But what was interesting since, if I may just go back to another point, one of the advances since I brought up the migraine that's very exciting is the whole story about sodium channels. Dr Harouthounian at WashU and his group used lidocaine injection. Lidocaine's a more generalized sodium channel blocker, but some of the newest treatments for treating neuropathic pain. Our NAV specific sodium channel blocker's trying to match up mechanism to treatment. Not exactly the way that we do with migraine, but still a step forward to not just generally treat but really target different neuronal mechanisms. It's an exciting time. 

Dr Jones: So, the pipeline is doing better because we're getting better understanding of disease, and hopefully that pulls in more interest because obviously there are big gaps in caring for patients with pain. And again, thank you, Dr Argoff, for an amazing article.

Thank you for joining us and thank you for such a fascinating discussion. I enjoyed the article.

I read the article, I learned from our conversation today. So, thank you for joining us to talk about central neuropathic pain.

Dr Argoff: Thank you for having me.

Dr Jones: Again, we've been speaking with Dr Charles Argoff, author of an article on central neuropathic pain in Continuum 's most recent issue on pain management. Please check it out, and thank you to our listeners for joining today.

Dr Monteith: This is Doctor Teshamae Monteith, associate editor of Continuum Audio. If you've enjoyed this episode, you'll love the journal, which is full of in-depth and clinically relevant information important for neurology practitioners. Use the link in the episode notes to learn more and subscribe. AAN members, you can get CME for listening to this interview by completing the evaluation at Continpub.com/AudioCME. Thank you for listening to Continuum Audio.

Orofacial pain comprises many disorders with different etiologies and pathophysiologies. A multidisciplinary approach combining medication, physical therapy, and procedural and psychological strategies is essential in treating patients with orofacial pain.

In this episode, Teshamae Monteith, MD, FAAN, speaks with Meredith Barad, MD; Marcela Romero-Reyes, DDS, PhD, authors of the article "Orofacial Pain," in the Continuum® October 2024 Pain Management in Neurology issue.

Dr. Monteith is the associate editor of Continuum® Audio and an associate professor of clinical neurology at the University of Miami Miller School of Medicine in Miami, Florida.

Dr. Barad is a clinical associate professor of anesthesiology, perioperative and pain medicine, and neurology and neurological sciences and codirector of the Stanford Facial Pain Program at Stanford Medicine in Stanford, California.

Dr. Romero-Reyes is a clinical professor and director of the Brotman Facial Pain Clinic and Department of Neural and Pain Sciences at the University of Maryland in Baltimore, Maryland.

Additional Resources

Read the article: Orofacial Pain

Subscribe to Continuum: shop.lww.com/Continuum

Earn CME (available only to AAN members): continpub.com/AudioCME

Continuum® Aloud (verbatim audio-book style recordings of articles available only to Continuum® subscribers): continpub.com/Aloud

More about the American Academy of Neurology: aan.com

Social Media

@ContinuumAAN

Host: @headacheMD

Guest: @meredith_barad

facebook.com/continuumcme

Full episode transcript available here

Dr Jones: This is Dr Lyell Jones, Editor-in-Chief of Continuum, the premier topic-based neurology clinical review and CME journal from the American Academy of Neurology. Thank you for joining us on Continuum Audio, which features conversations with Continuum 's guest editors and authors who are the leading experts in their fields. Subscribers to the Continuum Journal can read the full article or listen to verbatim recordings of the article and have access to exclusive interviews not featured on the podcast. Please visit the link in the episode notes for more information on the article, subscribing to the journal, and how to get CME.

Dr Monteith: This is Dr Teshamae Monteith, associate editor of Continuum Audio.

Today I'm interviewing Drs Meredith Barad and Marcela Romero-Reyes about their article on oralfacial pain, which appears in the October 2024 Continuum issue on pain management and neurology. Welcome to the podcast, ladies. How are you? 

Dr Barad: Excellent. 

Dr Romero-Reyes: Fine, happy to be here. 

Dr Monteith: I am so happy to see you. I mean, I think both of you I've known for like ten years.

Dr Romero-Reyes: Yeah. 

Dr Barad: Yes. 

Dr Monteith: So why don't you introduce yourselves? While I know you, our audience, some of them, may not know you. 

Dr Romero-Reyes: I'm Dr Marcella Romero Reyes. I am a neuropathial pain specialist, clinical professor, and director of the Provident Special Pain Clinic here in the University of Maryland School of Dentist.

Dr Monteith: Excellent. 

Dr Barad: My name is Meredith Barad. I'm a clinical associate professor at Stanford and I work- I'm the codirector of our headache and facial pain clinic in the Stanford pain management clinic.

Dr Monteith: Well, first of all, thank you for writing this article. It is extremely detailed and up-to-date and very informative. And in neurology, I think we don't get enough pain management.

I'm interested in both of your backgrounds and, you know, what led you even to become an expert in this area? And both of you have complementary areas. I think we can see in the quality of this article. But why don't we start with you, Dr Romero-Reyes?

Dr Romero-Reyes: Well, for me to get interested in orofacial pain, I will say more than an interest was like a calling that I wanted to take care of this patient population. So, as you know, my background is dentistry and at that time I was very interested in patients with complex medical issues. And was the time I was- I started to be interested in temporomandibular disorders. But what really picked completely my attention was the first time I saw a patient with trigeminal neuralgia. This was my last year in dental school. This patient already had, like, almost a full upper quadrant of teeth extracted where pain was not resolved. So when the patient came to us and I did my exam and, you know, and I triggered the pain, the sharp shoot electrical pain, that really broke my heart. And I took an x-ray and I didn't find anything that will explain it was something wrong until I talked to my professor and he said, no, this is medical. There's nothing wrong with it, with that tooth and needs to be, you know, followed with proper management and medication. And for me, that was like, wow, what a proper diagnosis and proper management can take care of these of these patients. And when the patient got better, that really said, oh, you know, I want to do this. 

Dr Monteith: That's a crazy story. It's always that last patient of the day. 

Dr Romero-Reyes: And you know, think about it, at least in dentistry at that time, I learned about trigeminal neuralgia from a book, right, my classes. But when you see the patient, this is it. That completely, you know, made me say yes, I want to study this. 

Dr Monteith: Yeah. And unfortunately, that's not an uncommon scenario where patients with trigeminal neuralgia get, you know, their extractions and pain can sometimes be more complicated. What about you, Dr Barad?

Dr Barad: Well, I guess I'm sort of like the opposite. So as a neurologist and a trained pain physician, I saw a lot of patients with neuralgic pain and headache pain, but I also saw many patients who would say, I have TMJ. And as, as Dr Romero has educated us, that's like saying I have shoulder or I have knee. But I quickly realized that I needed to work with a multidisciplinary team to really understand more about orofacial pain. It's not just neuralgic. There are other ideologies. And so that's how we started working together and that's how we practice in our clinic at Stanford.

Dr Monteith: So, why don't you tell us about the objectives of this article?

Dr Barad: I think our objectives were to help the neurologist broaden the differential diagnosis on facial pain to encompass below the nose, the oral cavity, the temporal mandibular joint. And to just think more broadly about facial pain and to understand some of the more recent diagnostic criteria that have been developed for facial pain and to- how to diagnose properly and how to begin treatment for some of the other conditions that are non-neurologic. 

Dr Romero-Reyes: And I think I will ask about what Dr Barad say that also to bring awareness to the neurologist about the vast classification of oral facial pain disorder, craniofacial and orofacial. I think that was also a key thing too. And also, to show how well we can work together, you know, the multi-disciplinary management that is indicated for these cases.

Dr Monteith: Cool. And you mentioned some of the new diagnostic criteria. I want to talk just briefly about the new international classification of orofacial pain, ICOP. When did that come out and what was the process there in really fine-tuning the diagnosis of orofacial pain disorders?

Dr Romero-Reyes: So, in 2019 the orofacial head pain especially interest group of the International Association for the Study of Pain, the International Network for Orofacial Pain and Related Disorders methodology and the American Academy of Orofacial Pain and the International Headache Society. They partnered together to develop to develop this international classification of orofacial pain. And these, I think- it's such a great effort, you know, all the main people doing pain about this area, and goes very well together with the international classification of headache disorders. So, for example, you know, some disorders that International Classification of Headache Disorders doesn't present such as and the ICOP, International Classification of Orofacial Pain, presents, like the persistent idiopathic dental Viola pain. You have it in the ICOP. It's not, you know, mentioned in the in the International Classification of Headache Disorders, as well as, also we have the- I think it's item number five, the orofacial representations headache disorder or primary headache disorder. The ICOP gives you a nice, clean diagnostic criteria. 

Dr Monteith: So, I guess I would ask Dr Barad with this classification in mind, how useful is it in neurology practice? And I know obviously you see patients with pain, but how useful even in managing patients with headache?

Dr Barad: I think it's great because I've had a lot of dentists and ENT doctors who have started referring patients to me because they've realized that they've increased their awareness about orofacial pain and realized that pain in the sinuses, for example, accompanied by light sensitivity and sound sensitivity and rhinorrhea, may not be a recurrent monthly sinus infection.

And so that kind of broadens our awareness of these of these disorders. And it's been, it's brought new patients into my clinic that we can help and treat. So that's been exciting. 

Dr Monteith: And what about in the world of dentistry? Obviously, I think people in orofacial pain worlds are highly attuned to this, but I would hope this would hopefully have been disseminated into dentists and regular practice at C patients with trigeminal neuralgia.

Dr Romero-Reyes: Going back for the, what you were discussing about the ICOP. So, it's what we're trying now as a new specialty. Well that we have been for the last four years, but finally in 2020 we have been recognized by the American Mental Association to disseminate this knowledge. But also, you know, can you imagine in in the realm in orofacial pain or dentistry have a patient with this recurrent pain, phonophobia, photophobia, throbbing dental pain is throbbing, but it's nothing wrong with your tooth. And that did they tell you that actually you have an orofacial or facial migraine or a neurovascular or facial pain. How crazy, right? And that is managed with migraines therapy. So it really, you know, to make you think like that. Wow, so these weird tooth things that used to come every week or these with facial pain, it's nothing to deal with, you know, with my teeth or any structure, you know, inside my mouth.

Dr Barad: It sounds to me like what you're saying is that we've, this has encouraged patient education as well, not only interdisciplinary education, but really helping provide an explanation for the patient about what is going on with them. So rather than just getting sent away to another tertiary specialist, the patient is getting a more robust understanding of what's going on. 

Dr Romero-Reyes: And going back to what you were saying about trigeminal neuralgia, you know, at least in dentistry also we're teaching now a new awareness like for two things, right? What about from the neurology setting? The patient has captured electrical pain. The trigger is intraoral. If it's pain inside your mouth, the first practitioner you're going to see who will be maybe the dentist that the dentist knows that could be a possibility of a disorder that doesn't deal with teeth, but also, it's important and we discussed that in our paper. What about that actually that weird trigger actually, it's not a general. What about if it's a cracked tooth has that singing sensation too. So, you see, it's two ways; one, to teach dentist to learn about this disorder and you know, we have learned, but you know, it's much more awareness now that this is great that, you know, these disorders you're not going to treat with dental procedures. Right? It's medical and vice versa, that the neurologist also has the awareness that oh, central trigger. Have you gone to the to the dentist? Have you checked that out?

Dr Monteith: So what should neurologist know about dental sources of pain?

Dr Barad: Well, maybe they should read the paper? 

Dr Romero-Reyes: Yeah. Yeah, you need to read the paper. Yeah. 

Dr Monteith: Top three, don't treat this with gabapentin. 

Dr Romero-Reyes: Like well, dental pain is not going to be resolved with gabapentin. That would need to make a diagnosis if and you know it's that examination that come comes with a radiographic evidence that shows that maybe could be a cavity or could be a problem. You know in the in the practical tissues of the tooth that is given a symptomatology. Not only dental could be a lot of different disorders inside there now that can produce pain that also the readers can check our paper and learn about and see the wonderful interesting pictures that we have added there.

Dr Monteith: Yeah. And so why don't we talk a little bit about TMD disorders and what is the new thinking around these conditions?

Dr Romero-Reyes: Well, I will say for the last decade, maybe a little bit more has been a change in the evidence. They evidence based understanding of the theologia pathophysiologist and for mandibular disorders. Imagine that what's the shift in the in the paradigm that in dentistry prevails for a long, long time. That is that really focus and I will call it the pathological mechanistic point of view. What I mean by that I was focusing your bite, your occlusion, how the relation between in your maxilla mandible. That was the only issues that would create in temporomandibular disorders. So now we know that temporomandibular disorders are complex, are multifactorial and you need to understand them and see them within a biopsychosocial framework. And this dictate the main way to management for the primary way that we start will be conservative, reversible and basing evidence that the best evidence available that we have.

Dr Monteith: And what about for trigeminal neuralgia? Is there newer kind of classification around trigeminal neuralgia? and what are some key points that we should consider when diagnosing these patients and treating these patients, Dr Barad? 

Dr Barad: There haven't been any new diagnostic criteria, but I would say that there's been an increased awareness that classical trigeminal neuralgia is more likely than not related to neurovascular compression or we should say, maybe I should say neurovascular contact or compression. There is a developing grading system of that. That's an evolution as we speak. I think it's an exciting time for facial neuralgia because it's opened the door for us to look at other neuralgia also as vascular compressions and to think about how we can treat them with decompression or possibly with peripheral nerve stimulation or medicine or Botox. Or who knows what's the future is going to hold? But it is I think a change in the way we are thinking about the definition of neuralgia of, of trigeminal neuralgia in that is caused by a compression which is different than other neuralgia in other parts of the body. I should, I just want to classify there's about maybe ten twelve percent of people who present with classical trigeminal neuralgia who there is not evidence on imaging of a vascular contact or compression. But the majority of cases do seem to have some somewhere in the spectrum from contact to compression. 

Dr Monteith: Even contact I find to be a bit vague sometimes say, well, thanks for letting me know that they're touching. But and then some of the neurosurgeons have different perspective when you open the patient up. So, I didn't know about the grading. 

Dr Barad: Yeah, I think you've hit on it exactly like that is a big problem in the field right now. How do we understand what patients will be the best patients for surgery? And it used to be that you have the classical trigeminal neurologist symptomology plus some imaging that shows something versus nothing. And now we're getting into parsing out the imaging and trying to understand who's the best candidate for that with the imaging. 

Dr Monteith: Dr Romero, anything to add? 

Dr Romero-Reyes: No, that I agree about that, you know, and I think now maybe for the patients that I have seen with that, because under partial pain settings, sometimes we're the ones that, oh, actually what you have is trigeminal neuralgia idea, you know, so we start to have our small disciplinary management, but you know, when they come out, I already have an MRI doctor, but, and they say that these are compression, but what degree? And some patients that they don't have symptoms can have a compression. And I'm thinking maybe right that later on when we have more time and maybe nicer imaging, we're going to really find out or if it's the development angle is the measurement has some other characteristics, who knows. So, I think for trigeminal neuralgia, the things is still evolving, right? For our understanding. I have to help us to make a more- I will not say definitive diagnosis, but maybe some parameters will change in the future.

Dr Monteith: So now we have a lot of people listening, international folks listening, and they always want some treatment, a tip, some clinical tips. So, can you give us a little bit of clinical insight to how to treat patients with trigeminal neuralgia and when you're seeing patients for second and third opinions, what might you see that may explain why their pain is not well controlled? We all get into interdisciplinary care, but in terms of pharmacology?

Dr Barad: I think people are a little reluctant to use some of these medications that neuromodulating medications because, in general, it's an older population and they're rightly worried about falls and dizziness and confusion and low sodium. And so, I think they hesitate to go to the doses that are needed to help with pain control. So, a lot of our, my initial management is gingerly and gently titrating that to try to get to see if we can get control of the pain.

Dr Monteith: Dr Romero? 

Dr Romero-Reyes: I could add, for example, one thing that I in the realm of facial pain addition to pharmacology. Let's say that we have a patient with that intraoral trigger and we were able to localize that intraoral trigger. Sometimes we can even also use topical medication. And in the topical medication we can use, for example, an anticonvulsant, let's say gabapentin, oxcarbazepine for example, to add in the cream. And we use, we call it a neurosensory stent in my looks like a Nygard, but it's not a Nygard that can cover that area. So, the patient can add that cream very delimited in that area. And that helps, you know, can help with the pain sometimes. What we can find is that, at least in my, in my experience, and that when we add a topical, maybe we don't need to increase as much. The systemic medication, of course, depends from case to case. 

Dr Monteith: So those are two great tips. Not being afraid to push those doses up in a safe manner and maybe with monitoring as well as of maybe utilizing more topicals. And I think we could probably hear a lot more from you on topicals at some other point. But thank you also for the table. I think it's, it's really nice the way all the treatments are laid out. So what other cranial neuralgia advances have there been?

Dr Barad: I would say the main advancements have been in applying the knowledge that neurosurgeons have learned from microvascular decompression of the trigeminal nerve, to the glossopharyngeal nerve, to the geniculate nerve, and really trying to optimize imaging and optimize neurosurgical techniques to try to treat these neuralgias. If the patient has failed medicine, if the patient is a good candidate for surgery and if the patient desires that.

Dr Monteith: Great. So now let's talk about multidisciplinary approaches. I know both of you are big fans of that, and you may do things a little bit differently at your institution, especially with your background. So maybe Dr Romero, do you want to tell us about your experience? And then we'll have Dr Brad.

Dr Romero-Reyes: But in my experience from study management, let's say depend, of course, also the started we're talking about. But let's say for example about temporomandibular disorders, you know that for TMD is one of these overlapping pain conditions and we know that TMD is common with primary headache disorders, especially migraine. So, if we're able to utilize, you know, the expertise of neurologist specializing headache. With me, for example, or a facial pain person that is that is helping you manage a patient with this comorbidity. This is super effective because we know the presence of TMD in a migraineur can help the disorder to, to progress some more chronic form. So, you see, this is super important and effective to provide, you know, optimal care for the patient. For example, in the patients that I do see with neuralgias, like in addition to trigeminal neuralgia, let's say nervous intermediates neuralgia, that sometimes they can come to me like, oh, the pain is in my ear and my EMT or, or I think maybe it's my TMJ and for the pain is charged shooting inside the ear doesn't follow the for the diagnosis of temporomandibular disorders. And I can maybe help the patient to get a proper imaging or already penalize it with a neurologist to make sure. And maybe at least my way will be maybe I'm the one that can catch those disorders and help, you know, the patient to go for the next step.

Dr Barad: I think Marcella, Dr Romero-Reyes, hit on a nice point that maybe this group is not as familiar with and that is that temporal mandibular dysfunction TMD is a, is one of the disorders that we call chronic overlapping pain conditions or COCPs. And those include headache. it's not, it's not specified fibromyalgia, irritable bowel syndrome, chronic pelvic pain and several other chronic pain syndromes. And they suggest a central sensitization to one's pain. And the way that we treat centrally sensitized pain is not just through medications, it's in a biopsychosocial framework because we see much higher rates of depression and anxiety in this group. And so, using a pain psychologist to help the patient develop coping strategies to help them manage their pain, using a physical therapist to help them learn this, the stretching exercises and using medications to help with not only with their pain syndrome, but also sometimes with their psych comorbidities. And then additionally, procedures sometimes play a role in the process to help usually turn down the pain. Interestingly, when we look at trigeminal neuralgia, we see much less overlapping pain disorders. It's much rarer to see somebody with TN who has other COCPs or the kind of chronic levels of depression and anxiety that we see in these patients. So, the approach is very different, and I think it requires the use of a multidisciplinary team to help guide the treatment pathways for these patients.

Dr Monteith: Today, I've been interviewing Drs Meredith Barad and Marcelo Romero-Reyes, whose article on orofacial pain appears in the most recent issue of Continuum on pain management and neurology. Be sure to check out Continuum Audio episodes from this and other issues. And thank you to our listeners for joining today.

Dr Monteith: This is Dr Teshamae Monteith, associate editor of Continuum Audio. If you've enjoyed this episode, you'll love the journal, which is full of in-depth and clinically relevant information important for neurology practitioners. Use this link in the episode notes to learn more and subscribe. AAN members, you can get CME for listening to this interview by completing the evaluation at continpub.com/AudioCME. Thank you for listening to Continuum Audio.

Opioids may be considered for temporary use in patients with severe pain related to selected neuropathic pain conditions and only as part of a multimodal treatment regimen. Close follow-up when initiating or adjusting opioid therapy and frequent reevaluation during long-term opioid therapy is required.

In this episode, Allison Weathers, MD, FAAN speaks with Friedhelm Sandbrink, MD, FAAN, an author of the article "Opioids and Cannabinoids in Neurology Practice," in the Continuum® October 2024 Pain Management in Neurology issue.

Dr. Weathers is a Continuum Audio interviewer and the associate chief medical information officer at the Cleveland Clinic in Cleveland, Ohio.

Dr. Sandbrink is the national program director of Pain Management, Opioid Safety and Prescription Drug Monitoring Programs at the Veterans Health Administration, Uniformed Services University in Bethesda, Maryland.

Additional Resources

Read the article: Opioids and Cannabinoids in Neurology Practice

Subscribe to Continuum: shop.lww.com/Continuum

Earn CME (available only to AAN members): continpub.com/AudioCME

Continuum® Aloud (verbatim audio-book style recordings of articles available only to Continuum® subscribers): continpub.com/Aloud

More about the American Academy of Neurology: aan.com

Social Media

@ContinuumAAN

facebook.com/continuumcme

Full episode transcript available here

Dr Jones: This is Dr Lyell Jones, Editor-in-Chief of Continuum, the premier topic-based neurology clinical review and CME journal from the American Academy of Neurology. Thank you for joining us on Continuum Audio, which features conversations with Continuum's guest editors and authors who are the leading experts in their fields. Subscribers to the Continuum Journal can read the full article or listen to verbatim recordings of the article and have access to exclusive interviews not featured on the podcast. Please visit the link in the episode notes for more information on the article, subscribing to the journal and how to get CME.

Dr Weathers: I'm Dr Allison Weathers. Today I'm interviewing Dr Friedhelm Sandbrink, who is one of the authors of the article Opioids and Cannabinoids for the Practicing Neurologist from the October 2024 Continuum issue on pain management Neurology. Welcome to the podcast and please introduce yourself to our audience. 

Dr Sandbrink: Yeah, hi. So, I'm Friedhelm Sandbrink. I'm a neurologist and pain physician. I work at the Washington DC VA Medical Center, where I lead our intercessory pain management team, and I have a role also in the VA central office for pain management. I'm also associate professor, clinical associate professor at George Washington University and at the Uniformed Services University in Bethesda. 

Dr Weathers: A lot of expertise, which you obviously brought to this article. And I do want to emphasize before we get started, although the article discusses both opioids and cannabinoids, as I said in the introduction, you worked in specifically on opioids. And so that's the part of the article where we'll focus our conversation today. Of course, I think all of our Continuum Audio topics are really fascinating. I know that some may not resonate as much, especially with our non-neurology listeners as others. Clearly not the case with your articles. I was reading it and preparing for a conversation today. I was really struck by how broadly applicable this topic is, not only to all neurologists but, really, all physicians, and even it should be to all of our listeners. Especially with what happened been going on over the last several years, what's been in the news about the opioid epidemic. And while usually like to start with this question, it feels even more pertinent in your case, what is the most important clinical message of your article?

Dr Sandbrink: So, the role of the opioid, the role of opioid therapy, really, for pain care has changed dramatically over the last many years right? I mean, it's we, we still consider opioids like the most potent analgesic medication for treatment of acute pain. The benefit for chronic pain really has changed right I mean, you know, we- the understanding in that regard and they're controversial. So, they're generally not recommended for chronic treatment for neuropathic pain conditions or for headache, but there are probably situations when opioids are still indicated and may be considered especially for temporary use. So, one example is probably the patient who has severe acute post hepatic neuralgia and we know that we use other medications for that, you know, the gabapentinoids and duloxetine and but they may take several days or weeks to work, right? And we have to titrate them up. And when more acute pain relief is needed, the opioid medication may be may be an option for temporary use. But I think what we need to keep in mind is that when we use it, we need to be informed about how to mitigate the risks, right? What, what are our best ways to reduce harms? And we need to also know the regulatory, you know, situation right I mean, what is that that we have to do nowadays to stay within the frameworks, right? And so, one of the main emphasis on this article is really go through what the clinical that the CDC has now established as the standards for opiate therapy when we use opioids I think we all need to know the rules right I mean, we know what to do to mitigate risks. What is expected from us in regard to use it as safely as possible, right? And that's important for the patient. That's also important for us in our practice. 

Dr Weathers: I think very important advice. And this seems so obvious, but at the same time, I think it's worth very clearly stating why is it so important for neurology clinicians and again, really all clinicians, to read this article?

Dr Sandbrink: Yeah. We need to know the words regarding opiate prescribing right in the clinic. You know, the CDC has now issued their opiate practice guide, the Opiate Therapy Guideline. Really, it's a guideline for pain care in 2022. It's an update from 2016 that made some major changes in that regard. And I think we need to know really where we are nowadays in regard to expectations. I think we need to place the opiate therapy appropriately in our armamentarium regarding the many options that we have for pain care. But then when we use them, we need to know what we need to do to make it safe. Right? So, I'm thinking about the prescription drug monitoring programs and the patient education that's expected. We use in our practice an informed consent process even for patients on chronic pain, When and how to interpret urine drug screens, right? And how to issue, and maybe when to issue a naloxone comedication in order to have a rescue medication in case the patient is in a terrible situation. So, these are just things that have become nowadays standards of care and part of our practice. And we need to be familiar with it and use them as we take care of the patients. And for instance, in regard to opiate medication, we need to know about the specific rules regarding telehealth, prescribing of controlled substances, controlled Substances Act and the Ryan Hate Act that mandates in person evaluations for patients when we prescribe controlled substances. That obviously has been somewhat amended or changed or temporarily put on hold during the COVID crisis. And many states now have started developing their own guidance in regard to what's available and what's possible during telehealth. And we need to be familiar about that also. 

Dr Weathers: I think those are such important and thoughtful points. I, I've mentioned it several times on this podcast before. I am a clinical informaticist and this is a topic that really lends itself to the EHR being able to help support. So, a lot of the things that you just mentioned, the consents for patients, the prescribing of naloxone, some of the support, clinical decision support can really be done in the electronic health record to help support providers. However, it's also one of those things where if people don't understand what's behind it, it can become a little bit of a crutch. And so, as I was reading the article, I was really struck by how helpful it is to really have that background. I think people can become very dependent and it becomes almost just doing it all for them and, and they lose the- then you can make this argument about probably a lot of the other clinical decision supports in there, but really understanding the why behind a lot of the support that's there around all of the, the tools that are in there to, to support safe opioid prescribing. I think it's so important for that people have that background that the article provides. 

Dr Sandbrink: I think often it feels like you're going through a checklist of things to do right and, and, and you do right. But at the same time, as you said, you need to know why you're doing it right And, and I think it's very important for us to know what the rules are and the expectations in regard to standards of care. So, we also know what is the framework that we have to follow, but where can we make modifications? Where can we individualize based on the patient's need? What is really that that is still within our ability to do and how to modify that? Because in the very end, it really is about good care of the patient. We need to know what we are allowed to do, but we also need to know where the limits are right And I hope that that article provides really some information about that, especially as it outlines what the CDC expects. But then also, I think it gives - hopefully, and this is a message that the CDC also has – it really emphasizes that it's about good communication with the patient, truly informing them and about what are the range of options and the limits that we have, but also at the same time never to abandon the patient. You know, I think this is something that we need to understand. It's not really about us. The rules are there to make the care of the patients safer. The rules are not the primary goal itself. It is still patient care. So, in that regard, we need to make sure to never abandon the patient, even if the patient for instance, may come to us and maybe they took more opiates and prescribed or you know, and they ran out early and figure out what exactly was that drove the patient for that, right? I mean, you know, so that we know maybe it is actually worse than pain. Maybe there was something that happened that caused the patient to have a significant increase of it. You know, I think one of the biggest misconceptions is really also that patients who make sure some misuse of medication, that everybody has opioid abuse disorder, addiction. Common, far too common, right? And I think we've learned over the years how common it is. Clearly pain itself, intractable pain is a very strong driver of behavior. If you're in pain, if a patient is in pain, they are desperate often to seek some kind of relief. And taking extra medication in itself, while it's not at all something that we can endorse and tolerate, obviously in many ways, right, we have to still take it as a possible sign of pain control rather than opiate use disorder in itself. So, we need to be very careful of how to assess such a patient and that we guide them into the right direction in regard to the next. 

Dr Weathers: That, again, is very important advice, and thinking about how chronic pain on a very different level than acute pain, right? Understanding how these patients are processing pain in a very different way than patients with acute pain. And again, also, I think a very important point that the pendulum has swung kind of back and forth over the years. You know, that they were in pain was another vital sign and it was make sure you're asking your patient about pain. And then all of a sudden it was, oh, we have to be really careful and people should not, nobody should be on these medications, which you- to your point, led to sudden abandonment. And that's not the point. That's not what we should be doing as providers. I know, though, there's very sensitive and challenging situations when you find out a patient though, perhaps taking more than expected because of chronic pain, but perhaps diversion. How have you handled those challenging cases?

Dr Sandbrink: I think diversion needs to be taken obviously very, very seriously. And you know, if a patient is truly diverting medication and there are obviously multiple variations of that, right? I mean, it's like giving it to a family member, for instance. That's one thing. It's on the other hand actually selling it. I think a patient who diverts is such a situation where opioid prescribing has to stop immediately, right? I mean, this is not a patient that we would take off at this point. I mean, so I think it's one of the very, very few occasions where you'd say that you have to just stop it immediately. I think there are other situations really in general, I think the patients who have been on opioids long term, especially in higher doses, I mean the majority of patients are not different. We have to be aware of it. We have to always look out for it. That's part of our risk mitigation. But we also have to make sure that patients on long term opioid therapy, right, that we guide them appropriately. I think the guidance probably in many ways is that we want to make sure whether opioids, the opioid medications still have helps them to achieve their functional goal. Are they truly helpful for the patients in achieving what they aspire to do in regard to their work life, in regard to the family situation. I think a lot of times for patients who have been on opioids long term, it's probably not that it really helps them that much for pain anymore, but they've often made that experience and they try to stop it. Pain gets worse, which is the effect obviously, that that happens with opiates right I mean, the moment you stop them, the opposite of the effect happens right I mean, they become irritable, right? The sleep gets worse, the pain gets worse, right? And it's a temporary phenomenon. And so, when we try to talk to a patient about possibly reducing the medication, I think this is one of the most challenging aspects that we have, that we really look at the patient and try to motivate them to be part of that plan. It's not something that we want to impose on the patient, but rather that we motivate the patient to look towards in the long term, probably more efficient pain care, which is really much more comprehensive pain care using all modalities. And I think one of the things that we learned over the last years is that when we make opiate medication reductions, we have to go very slowly. I think in the past we've talked about a matter of weeks and now the guidance including from the CDC guideline is probably more- closer to 10% per month to reducing it. So, you make reductions that may take many months to a year even, right. And the patient is allowed to help us, guide us how fast we can go. And you're allowed to make pauses if needed for the patient to adjust physiologically to reduction. And we want to go slowly enough that we don't run into an acute withdrawal situation right If you do it very gradually, it's much more manageable for the patient to do that. Then they'll be much more motivated to work with you.

But still, it's a challenge right I think that we do. And I think at the very end, it's really providing good patient care that allows us to build that rapport with the patient that they trust us and that they say, Hey, you know, yes, I'm, I'm willing to work with you, doc, to maybe reduce my reliance on the medication, right? So that that I don't end up on this. You know, one of the things that I sometimes do is asking patients when they come to us this first time and there are a lot of opiate medication maybe is like, what's your goal in this regard? Where do you see yourself in, in five or ten years? Are you thinking you will still be on this medication or would you want to come off? And how can we help you then if that's your goal? So, I think this is all part of our important conversation that we have to have in order to motivate the patient. 

Dr Weathers: What I heard you say repeatedly through that. And what I really want to emphasize for our listeners is that the therapeutic relationship with that patient that no matter what that scenario, really keeping them and their goals at the focus and really making it a partnership, not a paternalistic relationship, not dictating to them what the plan will be, but really emphasizing shared decision-making. And I think again, that's such a key take home point for our listeners. And also, even going back to my original question about diversion, what really struck me in your response is even though you said yes, then that was one of the few cases or perhaps even the only case where you said, all right, this is where we have to cut it off immediately. It still wasn't abandoning them as a patient, although you said we have to stop the medication. It wasn't about ending that relationship with that patient necessarily, but ending that therapy option. So really critical in how we think about opioids therapy and our relationship overall with patients. 

Dr Sandbrink: So, Allison, maybe I can add on, you know, I think the patient with diversion is the one aspect where we have to look at the population as a whole and the opioid that makes it to somebody else, potentially a vulnerable child, right, even you know, who could die from it, right? Another aspect of probably the patients we mentioned them earlier who have opioid use disorder, who maybe take more than prescribed and where we as a neurologist feel often quite uncomfortable dealing with that. And I think that's so important that at that point we don't abandoned the patient, right. I mean, you know, maybe we want to continue, we don't want to continue the opiate medication for the treatment of the pain. But as we diagnose and initially suspect opiate use disorder and have a conversation about it with a patient, we need to guide them to therapy. It's a treatable condition, right? It's an untreated, it's, it's actually rather lethal in many situations, right? So, we have to make sure that we provide an integrated access to the treatment or we have a warm hand off to somebody who will continue that and not abandon the patient in regard to that pain care, as we said earlier also, right? I mean, because that second condition really doesn't obviously I mean in any way that the pain is any better. No, I mean it's a common concurrent situation and we need to make sure that they still have the better pain care possible.

Dr Weathers: Again, it's a really key point for our listeners as and as I emphasized at the beginning, regardless of their subspecialty or specialty or even if they're physicians, I hope for everybody listening they can take away something from this. How did you become interested in pain management? I know that this was something that that you became interested in even when still in training. What struck you about this?

Dr Sandbrink: So, yeah, so my initial fellowship actually after residence was clinical neurophysiology. So, you know, a lot of the spine and different nerve conditions really was, was, but then when I began practice, clearly longitudinal care, chronic disease management, I think many of us in neurology do that right That, that became an emphasis. And I think building that accord with the patients right and, and, and that having that ability to provide pain care is something that really worked out very well. I think I love teamwork and part of teamwork pain care in in our setting is a collaborative approach right You have other disciplines, physical therapist, psychologist, right? You know, you have intervention and nonintervention provider. I think nowadays we even have integrative modalities available to us. So, I'm working together on a team, trying to optimize it here with many team members that we have with everybody bringing that personal expertise is something that I really cherish.

Dr Weathers: I feel like that's such a great example and I feel like a lot of people don't necessarily think about this specialty as one that is, that is collaborative in that way. And it really is. So, I, I think that's a wonderful way to highlight it. I always like to end on a hopeful note. And I know that there hasn't been necessarily a lot of hope or positive news in regards to, to opioid use, opioid therapy in the last several years. But are there developments that give you hope that you're excited about? 

Dr Sandbrink: So, you know, I think there are probably two things I would mention. On one hand, I think patients are so much more aware now about the risk of opioids. So that is actually much easier to look and get them motivated about comprehensive pain care. There's much more interest in integrative modalities. Patients nowadays would be much more willing to maybe try acupuncture or mindfulness or yoga or Tai chi. So, I think that's actually a really nice development in that regard. But if I think about opioids specifically, I think the availability of buprenorphine as a medication, it's certainly something we should mention in this interview here, right? I mean, buprenorphine is now increasingly used for pain as well, not just in the higher dosage for opiate use disorder. It really is a good choice for patients who have.

pain conditions, chronic pain conditions, severe pain and to require a daily opioid, especially in regard to safety aspect when the patient has medical conditions or mental health conditions that may put them at higher risk and they have to be on an opiate anyway. This is really something that I think has changed our practice. As you know, we don't have to rely on the X waiver anymore. Anybody with a DA license can prescribe buprenorphine. Even for opiate disuse disorder, it really has become something that I think many of us integrate much more into our practice and I want to encourage the listener to really look into that direction. 

Dr Weathers: Excellent advice and I'll actually refer our listeners who are subscribers of Continuum to reference, specifically, Table 4 where you dive into the buprenorphine.

It's just a fantastic table, as are all the tables. It really goes into detail of the commonly prescribed opioids for pain with the special characteristics and the conversion of morphine equivalent, but especially for this one about how to prescribe the details of us. Again, when I was preparing for this, I said wow. Like for me as a neurohospitalist and thinking about when I'm on service, how to use it, when to use it, I thought it was incredibly useful for that management of patients, especially as a powerful point of care tool. Well, thank you so much for being here with me today for this great conversation. 

Dr Sandbrink: Yeah, thank you. That was my pleasure.

Dr Weathers: Again, today I've been interviewing Dr Friedhelm Sandbrink, whose article on opioids and cannabinoids for the practicing neurologist, written with Dr Nathaniel Schuster, appears in the most recent issue of Continuum on Pain Management and Neurology. To learn more about the topics of opioids and cannabinoids, be sure to read the full article. And don't forget to listen to Continuum audio episodes from this and other issues. Thank you to our listeners for joining today.

Dr Monteith: This is Dr Teshamae Monteith, associate editor of Continuum Audio. If you've enjoyed this episode, you'll love the journal, which is full of in-depth and clinically relevant information important for neurology practitioners. Use this link in the episode notes to learn more and subscribe. AAN members, you can get CME for listening to this interview by completing the evaluation at continpub.com/AudioCME. Thank you for listening to Continuum Audio.

For certain diagnoses and patients who meet clinical criteria, neuromodulation can provide profound, long-lasting relief that significantly improves quality of life.

In this episode, Aaron Berkowitz, MD, PhD, FAAN speaks with Prasad Shirvalkar, MD, PhD, author of the article "Neuromodulation for Neuropathic Pain Syndromes," in the Continuum® October 2024 Pain Management in Neurology issue.

Dr. Berkowitz is a Continuum® Audio interviewer and a professor of clinical neurology at the University of California, San Francisco

Dr. Shirvalkar is an associate professor in the Departments of Anesthesia and Perioperative Care, Neurological Surgery, and Neurology at Weill Institute for Neurosciences at the University of California, San Francisco in San Francisco, California.

Additional Resources

Read the article: Neuromodulation for Neuropathic Pain Syndromes

Subscribe to Continuum: shop.lww.com/Continuum

Earn CME (available only to AAN members): continpub.com/AudioCME

Continuum® Aloud (verbatim audio-book style recordings of articles available only to Continuum® subscribers): continpub.com/Aloud

More about the American Academy of Neurology: aan.com

Social Media

facebook.com/continuumcme

@ContinuumAAN

Host: @AaronLBerkowitz

Guest: @PrasadShirvalka

Full episode transcript available here

Dr Jones: This is Dr Lyell Jones, Editor in Chief of Continuum, the premier topic-based neurology clinical review and CME journal from the American Academy of Neurology. Thank you for joining us on Continuum Audio, which features conversations with Continuum's guest editors and authors, who are the leading experts in their fields. Subscribers to the Continuum Journal can read the full article or listen to verbatim recordings of the article and have access to exclusive interviews not featured on the podcast. Please visit the link in the episode notes for more information on the article, subscribing to the journal, and how to get CME.

Dr Berkowitz: This is Dr Aaron Berkowitz, and today I'm interviewing Dr Prasad Shirvalkar about his article on neuromodulation for painful neuropathic diseases, which appears in the October 2024 Continuum issue on pain management in neurology. Welcome to the podcast, and if you wouldn't mind, please introducing yourself to our listeners. 

Dr Shirvalkar: Thanks, Aaron. Yes, of course. So, my name is Prasad Shirvalkar. I'm an associate professor in anesthesiology, neurology and neurological surgery at UCSF. I am one of those rare neurologists that's actually a pain physician. 

Dr Berkowitz: Fantastic. And we're excited to have you here and talk to you more about being a neurologist in in the field of pain. So, you wrote a fascinating article here about current and emerging neuromodulation devices and techniques being used to treat chronic pain. And in our interview today, I'm hoping to learn and for our listeners to learn about these devices and techniques and how to determine which patients may benefit from them. But before we get into some of the clinical aspects here, can you first just give our listeners an overview of the basic principles of how neuromodulation of various regions of the nervous system is thought to reduce pain?

Dr Shirvalkar: Yeah, I would love to try. But I will promise you that I will not succeed because I think to a large extent, we don't understand how neuromodulation works to treat pain, to describe or to define neuromodulation. Neuromodulation is often described as using electrical stimuli or a chemical stimuli to alter nervous system activity to really influence local activity, but also kind of distant network activity that might be producing pain. On one level, we don't fully understand how pain arises, specifically how chronic pain arises in the nervous system. It's a huge focus of study from the NIH Heal Initiative and many labs around the world. But acute pain, which is kind of when you stub your toe or you burn your finger, is thought to be quite different from the changes over time and the kind of plasticity that produces emotional, cognitive and sensory dimensions. Really what I think is its own disease, chronic pain, of which there are multiple syndromes when we use neuromodulation, either peripheral nerve stimulation or electrical spinal cord stimulation. One common or predominant theory actually comes from a paper in science from 1967 and people still use it, foundational theory and it's called the gate control theory. Two authors, Melzack and Wall, postulated that at the spinal level, there are, there's a local inhibitory circuit or, you know, there's a local circuit where if you provide input to either peripheral nerves or either spinal cord ascending fibers that to kind of summarize it, there's only so much bandwidth, you know, that nerves can carry. And so that if you literally pass through artificial signals electrically, that you will help gate out or block natural pathological but natural pain signals that might be arising from the periphery or spinal cord. So, you know, one idea is that you are kind of interfering with activity that's arising for chemical neuromodulation. The most common is something known as intrathecal drug infusion drug delivery ITTD for that we quite literally put a catheter in the spinal fluid, you know, at the level of the dorsal horn neurons that we think are responsible for perpetuating or creating the pain.

Where's the pain generator? And you really, you can infuse local anesthetic, you can infuse opioids. And what's nice is you avoid a lot of systemic side effects and toxicity because it goes right to the spinal cord, you know, by infusing in the fluid. So there's a couple of modalities, but I will say just, like maybe all of our living experience, pain is in the brain. And so, we don't really understand, I would say, what neuromodulation is doing to the higher spinal or brain levels.

Dr Berkowitz: Fascinating topic. And yeah, very interesting to hear both what our current understanding is that some of our current understanding is based on data that's 60 years old and that we're actually probably learning about pain by using these modulation techniques, even though we don't really understand how they might be working. So interesting feedback loop there as well as in as in the as in this land. So, your article very nicely organizes the neuromodulation techniques from peripheral to central. So, encourage our listeners to check out your article. And first before we get into some of the clinical applications, just to give the listeners the lay of the land, can you sort of lay out the devices and techniques available for treating pain at each level of the neuroaxis? We'll get into some of the indications in patient selection in a moment, but just sort of to lay out the landscape. What's available that you and your colleagues can use or implant at different levels when we're thinking of referring patients too?

Dr Shirvalkar: Absolutely. So, starting from the least invasive or you know, over the counter patients can purchase themselves a TENS machine. Many folks listening to this have probably tried a TENS machine in the past. And the idea is that you put a couple of pads, at least two. So you have like a dipole or you have a positive and a negative lead and you basically inject some current. So, the pads are attached to a battery and you can put these pads over muscle. If you have areas where myofascial pain or sore muscles, you can put them, frankly, over nerves as well and stimulate nerves that are deeper. Most TENS machines kind of use electrical pulses that occur at different rates. You change the rates, you can change the amplitude and patient can kind of have control for what works best. Then getting slightly more invasive, we can often stimulate electrically peripheral nerves. To do this we implant through a needle, a small wire that consists of anywhere from one electrical contact to four or even eight electrical contact. What I think is particularly cool, like TENS, which is transcutaneous electrical nerve stimulation that goes through the skin. Peripheral nerve stimulation aims to stimulate nerves, but you don't have to be right up against the nerve. So, yeah. We typically do this under an ultrasound and you can visualize a nerve like the sciatic nerve, peroneal nerve, or you know, even if someone has an ulnar or a neuropathy, you know, that's the compression. There's a role obviously for surgery and release, but if they have predominantly pain, it's not related to a mechanical problem per se, you could prevent a wire from a peripheral nerve stimulator as far as one centimeter from a nerve and it'll actually stimulate that that modulated and then, you know, kind of progressing even more deeply. The spinal cord stimulation, SCS, it's probably the most ubiquitous or popular form of neuromodulation for pain. People use it for all kinds of diseases. But what it roughly involves is a trial period, which is a placement of either two cylindrical wires, not directly over the spinal cord, but actually in the epidural space, right? So, it's kind of like when you get an epidural injection or doing labor and delivery, when women get epidural catheters, placing spinal cord stimulator leads in that same potential space outside the dura, and you're stimulating through the dura to actually target the ascending dorsal column fibers. And so, you do a trial period or a test drive where the patients get these wires put in. They're coming out of the skin, they're connected to a battery, and they walk around at home for about a week, take careful notes, check in with them, and they keep a diary or a log about how much it helps. Separately. I will say it's hard to distinguish this, the placebo effect often, but you know, sometimes we want to use the placebo effect in clinical practice, but it is a concern, you know, with such invasive things. But you know, if the trial works well, right, you basically can either keep the leads where they are and place a battery internally. And it's for neurologists. You're familiar with deep brain stimulation. These devices are very similar to DVS devices, but they're specifically made for spinal cord stimulation. And there's now like seven companies that offer manufacturers that offer it, each with their own proprietary algorithm or workflow. But going yet more invasive, there is intrathecal drug delivery, which I mentioned, which involves placement of the spinal catheter and infusion of drug into spinal fluid. You could do a trial for that as well.

Keep a patient in the hospital for a few days. You've all probably had experience with lumbar drains. It's something real similar. It just goes the other way. You know, you're infusing drugs, and it could also target peripheral nerves or nerve roots with catheters, and that's often done.

And last but not least, there's brain stimulation. Right now, it's all experimental except for some forms of TMS or transcranial magnetic stimulation, which is FDA approved for migraine with aura. There are tens machine type devices, cutaneous like stimulators where you can wear on your head like a crown or with stickers for various sorts of migraines. I don't really talk about them too much in in the article, but if there's a fast field out there for adjunctive therapy as well, 

Dr Berkowitz: Fantastic. That's a phenomenal overview. Just so we have the lay on the land of these devices. So, from peripheral essentially have peripheral nerve stimulators, spinal cord stimulators, intrathecal drug delivery devices and then techniques we use in other areas of neurology emerging for pain DBS deep brain stimulation and TMS transcranial magnetic stimulation. OK let's get into some clinical applications now. Let's start with spinal cord stimulators, which - correct me if I'm wrong - seem to be probably the most commonly seen in practice. Which patients can benefit from spinal cord stimulators? When should we think about referring a patient to you and your colleagues for consideration of implantation of one of these spinal cord stimulator devices? 

Dr Shirvalkar: So, you know, it's a great question. I would say it's interesting how to define which patients or diagnosis might be appropriate. Technically, spinal cord stimulators are approved for the treatment of most recently diabetic peripheral neuropathy. And so, I think that's a really great category if you have patients who have been failed by more conservative treatments, physical therapy, etcetera, but more commonly even going back, neuropathic low back pain and neuropathic leg pain. And so, you think about it and it's like, how do you define neuropathic pain. Neuropathic pain is kind of broadly defined as any pain that's caused by injury or some kind of lesion in the somatosensory nervous system. We now broaden that to be more than just somatosensory nervous system, but still, what if you can't find a lesion, but the pain still feels or seems neuropathic. Clinically, if something is neuropathic, we often use certain qualitative descriptors to describe that type of pain burning, stabbing, electric light, shooting radiates. There's often hyperpathia, like it lingers and spreads in space and time as opposed to, you know, arthritis, throbbing dull pain or as opposed to muscle pain might be myofascial pain, but sometimes it's hard to tell. So, there aren't great decision tools, I would say to help decide. One of the most common syndromes that we use spinal cord stimulation for is what used to be called failed back surgery syndrome. We never like to, we now try to shy away from explicitly saying something is someone has failed in their clinical treatment. So, the euphemism is now, you know, post-laminectomy syndrome. But in any case, if someone has had back surgery and they still have a nervy or neuropathic type pain, either shooting down their legs and often there's no evidence on MRI or even EMG that that something is wrong, they might be a good candidate, especially if they're relying on long term medications that have side effects or things like full agonist opioids, you know that that might have side effects or contraindication. So, I would say one, it's not a first line treatment. It's usually after you've gone through physical therapy for sure. So, you've gone through tried some medications. Basically, if chronic pain is still impacting your life and your function in a meaningful way that's restricting the things you want to do, then it it's totally appropriate, I think, to think about spinal cord stimulation. And importantly, I will add a huge predictor of final court stimulation success is psychological composition, you know, making sure the person doesn't have any untreated psychological illness and, and actually making sure their expectations going in are realistic. You're not going to cure anyone's pain. You may and that's, you know, a win, but it's very unlikely. And so, give folks the expectation that we hope to reduce your pain by 50% or we want you to list personally, I like functional goals where you say what is your pain preventing you from doing? We want to see if you can do X,Y, and Z during the trial period. Pharmacostimulation right now. Yeah. Biggest indication low back leg pain, Diabetic peripheral neuropathy. There is also an indication for CRPS, complex regional pain syndrome, a lesser, I'd say less common but also very debilitating pain condition. For better or worse. Tertiary quaternary care centers. You often will see spinal cord stem used off label for neuropathic type pain syndromes that are not explicitly better. That may be for example, like a nerve injury that's peripheral, you know, it's not responding. A lot of this off label use is highly variable and, you know, on the whole at a population level not very successful. And so, I think there's been a lot of mixed evidence. So, it's something to be aware about. 

Dr Berkowitz: That's a very helpful framework. So, thinking about referring patients to who have most commonly probably the patients with chronic low back pain have undergone surgery, have undergone physical therapy, are on medications, have undergone treatment for any potential psychological psychiatric comorbidities, and yet remain disabled by this pain and have a reasonable expectation and goals that you think would make them a good candidate for the procedure. Are those similar principles to peripheral nerve stimulation I wasn't familiar with that technique, I'm reading your article, so are the principles similar and if so, which particular conditions would potentially benefit from referral for a trial peripheral nerve stimulation as opposed to spinal cord stimulation? 

Dr Shirvalkar: Yeah, the principles are similar overall. The peripheral nerve stimulation, you know, neuropathic pain with all the characteristics you listed. Interestingly enough, just like spinal cord stim, most insurances require a psychological evaluation for peripheral nerve stim as well. And we want to make sure again that their expectations are reside, they have good social support and they understand the kind of risks of an invasive device. But also, for peripheral nerve stem, specifically, if someone has a traumatic injury of an individual peripheral nerve, often we will consider it seeing kind of super scapular stimulation. Often with folks who've had shoulder injuries or even sciatic nerve stimulation. I have done a few peroneal nerve stimulations as well as occipital nerve stimulation from migraine, so oxygen nerve stimulation has been studied a lot. So, it's still somewhat controversial, but in the right patient it can actually be really helpful.

Dr Berkowitz: Very helpful. So, these are patients who have neuropathic pain, but limited to one peripheral nerve distribution as opposed to the more widespread back associated pains, spine associated pains.

Dr Shirvalkar: Yeah, Yeah, that's right. And maybe there's one exception actually to this, which is brachial plexopathy. So, you know, folks who've had something like a brachial plexus avulsion or some kind of traumatic injury to their plexus, there is I think good Class 2 evidence that peripheral nerve stem can work. It falls under the indication. No one is as far as to my knowledge, No one's done an explicit trial, you know PNS randomized controlled trial. Yeah, that's, you know, another area one area where PNS or peripheral nerve stems emerging is actually, believe it or not in myofascial low back pain to actually provide muscle stimulation. There are some, there's a company or two out there that seeks to alter the physiology of the multifidus muscle, one of your spinal stabilizer muscles to really see if that can help low back pain. And they've had some interesting results. 

Dr Berkowitz: Very interesting. You mentioned TENS units earlier, transcutaneous electrical nerve stimulation as something a patient could get over the counter. When would you encourage a patient to try TENS and when would you consider TENS inadequate and really be thinking about a peripheral nerve stimulator? 

Dr Shirvalkar: Yeah, you know TENS we think of as really appropriate for myofascial pain. Folks who have muscular pain, have clear trigger points or taught muscle bands can often get relief from TENS If you turn a TENS machine up too high, you'll actually see muscle infection. So, there's an optimal level where you actually can turn it up to induce, like, a gentle vibration.

And so folks will feel paresthesia and vibrations, and that's kind of the sweet spot. However, I would say if folks have pain that's limited or temporary in time or after a particular activity, TENS can be really helpful. The unfortunate reality is TENS often has very time-limited benefits - just while you're wearing it, you know? So, it's often not enduring. And so that's one of the limitations.

Dr Berkowitz: That's helpful to understand. We've talked about the present landscape in your article, also talk a little bit about the future and you alluded to this earlier. Tell us a little bit about some off label emerging techniques that we may see in future use. Who, which types of patients, which conditions might we be referring to you and your colleagues for deep brain stimulation or transcranial magnetic stimulation or motor cortex stimulation? What's coming down the pipeline here? 

Dr Shirvalkar: That's a great question. You know, one of my favorite topics is deep brain stimulation. I run the laboratory that studies intracranial signals trying to understand how pain is processed in the brain. But, believe it or not, chronic pain is probably the oldest indication for which DBS has been studied. the first paper came out in 1960, I believe, in France. And you know, the, the original pivotal trials occurred even before the Parkinson's trial and so fell out of favor because in my opinion, I think it was just too hard or too difficult or a problem or too heterogeneous. You know, many things, but there are many central pain syndromes, you know, poststroke pains, there's often pains associated with Parkinson's disease, epilepsy, or other brain disorders for which we just don't have good circuit understanding or good targets.

So, I think what's coming down the pipeline is a better personalized target identification, understanding where can we stimulate to actually alleviate pain. The other big trend I think in neuromodulation is using closed loop stimulation which means in contrast to traditional electrical stimulation which is on all the time, you know it's 24/7, set it and forget it. Actually, having stimulation respond or adapt to ongoing physiological signals. So that's something that we're seeing in spinal cord stem, but also trying to develop in deep brain stimulation and noninvasive stimulation. TMS is interestingly approved for neuropathic pain in Europe, but not approved by the FDA in the US. And so I think we may see that coming out of pipeline broader indication. And finally, MR guided focused ultrasound is, is a kind of a brand new technique now. You know, focused ultrasound lesions are being used for essential tremor without even making an incision in the skull or drilling in skull. But there are ways to modulate the brain without lesioning. And, you know, I think a lot of research will be emerging on that in the next five years for, for pain and many other neuronal disorders.

Dr Berkowitz: That's fascinating. I didn't know that history that DBS was first studied for pain and now we think of it mostly for Parkinson's and other movement disorders. And now the cycle is coming back around to look at it for pain again. What are some of the targets that are being studied that are thought to have benefit or are being shown by your work and that of others to have benefit as far as DBS targets for, for chronic pain?

Dr Shirvalkar: You know, that's a great question. And so, the hard part is finding one target that works for all patients. So, it may actually require personalization and actually understanding what brain circuit phenotypes do you have with regards to your chronic pain and then based on that, what target might we use? But I will say the older targets. Classical targets were periaqueductal gray, which is kind of the opioid center in your brain. You know, it's thought to just release large amounts of endogenous opioids when you stimulate there and then the ventral pusher thalamus, right. So, the sensory ascending system may be through gait control theory interferes with pain, but newer targets the answer singlet there's some interest in in stimulating there again, it doesn't work for everybody. We found some interesting findings with the medial thalamus as well as aspects of the caudate and other basal ganglion nuclei that we hopefully will be publishing soon in a data science paper. 

Dr Berkowitz: Fantastic. That's exciting to hear and encourage all of our listeners to check out your article. That goes into a lot more depth than we had time to do in this short interview, both about the science and about the clinical indications, pros and cons, risks and benefits of some of these techniques. So again, today I've been interviewing Dr Prasad Shirvalkar, whose article on neuromodulation for painful neuropathic diseases appears in the most recent issue of Continuum on pain management in neurology. Be sure to check out Continuum Audio episodes from this and other issues. And thank you again to our listeners for joining today. 

Dr Shirvalkar: Thank you for having me. It was an honor.

Dr Monteith: This is Dr Teshamae Monteith, associate editor of Continuum Audio. If you've enjoyed this episode, you'll love the journal, which is full of in depth and clinically relevant information important for neurology practitioners. Use this link in the episode notes to learn more and subscribe. AAN members, you can get CME for listening to this interview by completing the evaluation at continpub.com/AudioCME. Thank you for listening to Continuum Audio.

A pragmatic and organized approach is needed to recognize patients with symptomatic Alzheimer Disease in clinical practice, stage the level of impairment, confirm the clinical diagnosis, and apply this information to advance therapeutic decision making.

In this episode, Aaron Berkowitz, MD, PhD, FAAN, speaks with Gregory S. Day, MD, MSc, MSCI, FAAN, author of the article "Diagnosing Alzheimer Disease," in the Continuum December 2024 Dementia issue.

Dr. Berkowitz is a Continuum® Audio interviewer and professor of clinical neurology at the University of California, San Francisco 

Dr. Day is an associate professor in the Department of Neurology at Mayo Clinic Florida in Jacksonville, Florida.

Additional Resources

Read the article: Diagnosing Alzheimer Disease

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More about the American Academy of Neurology: aan.com

Social Media

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Host: @AaronLBerkowitz

Guest: @GDay_Neuro

Full episode transcript available here

Dr Jones: This is Doctor Lyell Jones, Editor-in-Chief of Continuum, the premier topic-based neurology clinical review and CME journal from the American Academy of Neurology. Thank you for joining us on Continuum Audio, which features conversations with Continuum's guest editors and authors, who are the leading experts in their fields. Subscribers to the Continuum journal can read the full article or listen to verbatim recordings of the article and have access to exclusive interviews not featured on the podcast. Please visit the link in the episode notes for more information on the article, subscribing to the journal, and how to get CME.

Dr Berkowitz: This is Dr Aaron Berkowitz, and today I have the pleasure of interviewing Dr Gregory Day about his article on Alzheimer disease, which appears in the December 2024 Continuum issue on dementia. Welcome to the podcast, Dr Day. Would you mind introducing yourself to our audience? 

Dr Day: Thanks very much, Aaron. I'm Gregg Day. I'm a behavioral neurologist at Mayo Clinic in Jacksonville, Florida, which means that my primary clinical focus is in the assessment of patients presenting typically with memory concerns and dementia in particular.

Dr Berkowitz: Fantastic. Well, as we were talking about before the interview, I've heard your voice many times over the Neurology podcast and Continuum podcast. I've always learned a lot from you in this rapidly changing field over the past couple of years, and very excited to have the opportunity to talk to you today and pick your brain a little bit on this very common issue of evaluating patients presenting with memory loss who may have concerns that they have dementia and specifically Alzheimer disease. So, in your article, you provide a comprehensive and practical approach to a patient presenting for evaluation for possible dementia and the question of whether they have Alzheimer disease. The article is really packed with clinical pearls, practical advice. I encourage all of our listeners to read it. In our interview today, I'd like to talk through a theoretical clinical encounter and evaluation so that I and our listeners can learn from your approach to a patient like this. Let's say we have a theoretical patient in their seventies who comes in for evaluation of memory loss and they and/or their family are concerned that this could be Alzheimer disease. How do you approach the history in a patient like that?

Dr Day: It's a great way to approach this problem. And if you're reading the article, know that I wrote it really with this question in mind. What would I be doing, what do we typically do, when we're seeing patients coming with new complaints that concern the patient and typically also concern those that know the best? So be that a family member, close friend, adult child. And in your scenario here, this seventy year old individual, we're going to use all the information that we have on hand. First off, really key, if we can, we want to start that visit with someone else in the room. I often say when talking to individuals who come alone that there's a little bit of irony in somebody coming to a memory assessment alone to tell me all the things they forgot. Some patients get the joke, others not so much, but bringing someone with them really enhances the quality of the interview. Very important for us to get reliable information and a collateral source is going to provide that in most scenarios. The other thing that I'm going to start with, I'm going to make sure that I have appropriate time to address this question. We've all had that experience. We're wrapping up a clinical interview, maybe one that's already ran a little bit late and there's that one more thing that's mentioned on the way out the door: I'm really concerned about my memory or I'm concerned about mom 's memory. That's not the opportunity to begin a memory assessment. That's the opportunity to schedule a dedicated visit. So, assuming that we've got someone else in the room with us, we've got our patient of interest, I'm going to approach the history really at the beginning. Seems like an easy thing to say, but so often patients in the room and their caregivers, they've been waiting for this appointment for weeks or months. They want to get it out all out on the table. They're worried we're going to rush them through and not take time to piece it together. And so, they're going to tell you what's going on right now. But the secret to a memory assessment, and particularly getting and arriving at an accurate diagnosis that reflects on and thinks about cause of memory problems, is actually knowing how symptoms began. And so, the usual opening statement for me is going to be: Tell me why you're here, and tell me about the first time or the first symptoms that indicated there was an ongoing problem. And so, going back to the beginning can be very helpful. This article is focused on Alzheimer disease and our clinical approach to the diagnosis of Alzheimer disease. And so, what I'm going to expect in a patient who has a typical presentation of Alzheimer disease is that there may be some disagreement between the patient and the spouse or other partners sitting in the room with me about when symptoms began. If you've got two partners sitting in the room, maybe an adult child and a spouse, there may be disagreement between them. What that tells me is at the onset, those first symptoms, they're hard to pin down. Symptoms typically emerge gradually in patients with symptomatic Alzheimer disease. They may be missed early on, or attributed or contributed to other things going on in the patient's time of life, phase of life. It's okay to let them sort of duke it out a little bit to determine, but really what I'm figuring out here is, are we talking about something that's happened across weeks, months or more likely years? And then I'm going to want to listen to, how did symptoms evolve? What's been the change over time? With Alzheimer disease and most neurodegenerative diseases, we expect gradual onset and gradual progression, things becoming more apparent. And at some point, everyone in the room is going to agree that, well, as of this state, there clearly was a problem. And then we can get into talking about specific symptoms and really begin to pick that apart the way that we traditionally do in any standard neurological assessment.

Dr Berkowitz: Fantastic. And so, what are some of the things you're listening for in that history that would clue you in to thinking this patient may indeed be someone who could have Alzheimer's disease and going to require a workup for that diagnosis?

Dr Day: It's pretty common when I have new trainees that come to clinic, they just head into the exam room and they sort of try to approach it the way that we would any patient in the emergency department or any other clinical scenario. The challenge with that is that, you know, we're taught to let the patient speak and we're going to let the patient speak - open-ended questions are great - but there's only so many questions you need to sort out if someone has a memory problem. And memory is really only one part, one component, of a thorough cognitive evaluation. And so, I'm going to help by asking specific questions about memory. I'm going to make sure that there is memory challenges there. And whenever possible, I'm going to solicit some examples to back that up, add credibility and sort of structure to the deficits. I'm also going to choose examples that help me to understand how does this concern, or this complaint, how does that actually affect the patient in their day-to-day life? Is it simply something that they're aware of but yet hasn't manifested in a way that their partner knows about? Is it to a level where their partner's actually had to take over their responsibility? It's causing some difficulties, disability even, associated with that. That's going to be important for me as I try to understand that. So, I'll ask questions when it comes to memory, not just, you know, do you forget things, but do you manage your own medications? You remember to take those in the morning? Do you need reminders from your partner? What about appointments; health appointments, social appointments? Are you managing that on your own? Sometimes we need a little bit of imagination here. Partnerships, and particularly those who have been together for a long time, it's natural that different people are going to assume different responsibilities. And so, might have to say, Imagine that you went away for the weekend. Would you worry about your partner remembering to take their medications over that time frame? That can help to really solidify how much of an impact are these challenges having on a day-to-day basis. I may ask questions about events, something that they maybe did a couple of weeks ago. Is the patient likely to remember that event? Are they going to forget details? Maybe the most important of all, with each of these, when there's a yes or an affirmation of a problem, we want to be clear that this represents a change from before. We all have forgetfulness. Happens on a day-to-day basis, and we all pay attention to different details, but what we're concerned about and typically the reasons patients want to come and see us as neurologists is because they've noticed a change. And so, I'm going to focus in on the things that represent a change from before. After I've discussed memory, I think it's really important to talk about the other domains. So, how is judgment affected? Decision-making?  In a practical way, we often see that borne out in financial management, paying the bills. Not just paying them on time and consistently, but making wise choices when it comes to decisions that need to be made. You're out at a restaurant. Can you pay the bill? Can you calculate a tip? Can you do that as quickly and as efficiently as before? Are we starting to see a breakdown in decision-making abilities there?

We can sometimes lump in changes in behavior along with judgment as well. The patient that you know, maybe isn't making wise choices, they've picked up the phone and given their social security number out to someone that was calling, seeming to be well-meaning. Or maybe they've made donations to a few more institutions than they would have otherwise? Again, out of- out of order. Again, something that could be atypical for any individual. Looking for behavioral changes along with that as well. And then I'm going to talk about orientation. What's their ability to recognize days of the week, date of the month? Do they get lost? Is there concerns about wayfinding? Thinking about that, which is really a complex integration of some memory, visuospatial processing, judgment, problem solving, as we look to navigate our complex world and find our way from point A to B. And then I like to know, you know, what are they doing outside of the home? What are they doing in the community? How are they maintaining their engagement? Do they go to the store? Do they drive? An important topic that we may need to think about later on in this patient 's assessment. And inside the home? What responsibilities do they maintain there? Are the changes in decision making, memory problems, are they manifesting in any lost abilities inside the home? Cooking being a potentially high-risk activity, but also using typical appliances and interacting with technology, in a way that we are all increasingly, increasingly doing and increasingly reliant on. And last but not least, you know, maybe the one that everyone wants to think about, well, I can still manage all of my own personal care. Well, good news that many of our patients who have early symptoms can manage their own personal care. Their activities of daily living are not the big problem. But we do want to ask about that specifically. And it's not just about getting in the shower, getting clean, getting out, getting your teeth brushed. Do you need reminders to do that? Do you hop in the shower twice because you forgot that you'd already been in there once during the day? And so, asking some more of those probing questions there can give us a little bit more depth to the interview and really does sort of round out the overall comprehensive history taking in a patient with a memory or cognitive concern.

Dr Berkowitz: Fantastic. That was a comprehensive master class on how to both sort of ask the general questions, have you noticed problems in fill in the blank memory, judgment, behavior, orientation, navigation and to sort of drill down on what might be specific examples if they're not offered by the patient or partner to try to say, well, in this domain, tell me how this is going or have you noticed any changes because the everyone's starting from a different level cognitively based on many factors. Right? So, to get a sense of really what the change is in any of these functions and how those have impacted the patient's daily life. So, let's say based on the history, the comprehensive history you've just discussed with us, you do find a number of concerning features in the history that do raise concern for dementia, specifically Alzheimer's disease. How do you approach the examination? We have the MoCA, the mini-mental. We have all of these tools that we use. How do you decide the best way to evaluate based on your history to try to get some objective measure to go along with the more subjective aspects of the history that you've ascertained?

Dr Day: And you're honing in on a really good point here, that the history is one part of the interview or the assessment. We really want to build a story and potentially and hopefully a consistent story. If there are memory complaints, cognitive complaints from history, from reliable- that are supported by reliable collateral sources, we're going to expect to see deficits on tests that measure those same things. And so, I think that question about what neuropsychological measures or particular bedside tests can we integrate in our assessment is a good one. But I'll say that it's not the end-all-be-all. And so, if you've got a spouse, someone that lives with an individual for twenty or thirty years, and they're telling you that they notice a change in daily activity and it's impairing their day to day function, or where there's been some change or some concern at work, that's going to worry me more than a low score on a cognitive test with a spouse saying they haven't noticed any day-to-day impact. And so, we're going to take everything sort of in concert and take it all together. And it's part of our job as clinicians to try to process that information. But often we're going to see corroborating history that comes from a bedside test. He named a few that our listeners are probably pretty familiar with. I think they're the most common ones that are used. The Mini-Mental State Exam, been in practice for a long time. All the points add up to thirty and seems to give a pretty good sample of various different cognitive functions. The Montreal Cognitive Assessment, another favorite; a little bit more challenging of a test, I think, if we're if we're looking at how people tend to perform on it. And like the MMSE, points add up to thirty and gives a pretty good sample. There are others that are out there as well, some that are available without copyright and easy for use in clinical practice. The Saint Louis Mental Status Exam comes to mind. All these tests that we're willing to consider kind of share that same attribute. They can be done relatively quickly. They should sample various different aspects of function. There should be some component for language reading, spoken, spoken word, naming items, something that's going to involve some kind of executive function or decision making, problem solving. Usually a memory task where you're going to remember a set of words and be asked to recall that again later. So, learn it, encode it, and recall it later on. And then a few other features, I mean, some of them, these tests, most of these tests use some sort of drawing tasks so that we can see visuospatial perception and orientation questions about date, time, location, sort of the standard format. Any of these tests can be used aptly in your practice. You're going to use the one that you're most comfortable with, that you can administer in a reasonable amount of time and that seems to fit with your patient population. And that's the nuance behind these tests. There are many factors that we have to take into account when we're picking one and when we're interpreting the test results. These tests all generally assume that patients have some level of traditional sociocultural education that is westernized for the most part. And so, not great tests for people that aren't well into integrated into the community, maybe newcomers to the United States, those that have English as a second, third, or fourth language, as many of our patients do. Statements like no ifs, ands, or buts may not be familiar to them and may not be as easy to repeat, recall and remember. And so, we want to weigh these considerations. We may need to make some adjustments to the score, but ideally, we're going to use these tests and they're going to show us what we expect and we're going to try to interpret that together with the history that we've already ascertained. When I obtain that history and I'm thinking about memory loss, I'm going to look at the specific domain scores. And so, if I'm using the mini mental state examination thirty point test, but three questions that relate to relate to recall. Apple, penny, table. And so, depending on how our patients do on that test, they could have an overall pretty good score. Twenty seven. Oh, that looks good. You're in the normal range according to many different status. But if I look at that and there's zero out of three on recall, they could not remember those three items, that may support the emergence of a memory problem. That may corroborate that same thing on the MoCA, which uses five-item recall, and other tests in those same parameters. I mentioned some other caveat cities testing. Are patients who are presenting with prominent language deficits important part of cognition. They can't get the words out. They can't frame their sentences. They may really struggle with these tests because a lot of them do require you to both understand verbal instructions and convey verbal instructions. People with prominent visual problems, either visual problems that come because of their neurodegenerative disease and so part of cognition, visual perceptual problems, or people who simply have low vision. Are there difficulties for that? These tests require many people to read and execute motor commands, to draw things, to follow lines and connect dots, all very difficult in that setting. And so, we have to be cautious about how we're interpreting test results in patients who may have some atypical features or may arrive with sort of preexisting conditions that limit our ability to interpret and apply the test to clinical practice. 

Dr Berkowitz: Really fantastic overview of these tests, how to use them, how to interpret them. It's not all about the number. As you said, it depends if all the points are lost in one particular domain, that can be salient and then considering, as you said, the patient 's background, their level of education, where English falls in their first language, second, third or fourth, as you said, and then some of the aspects of the MoCA, right, are not always as culturally sensitive since it's a test designed in a particular context. So, let's say your history and exam are now concerning to you, that the patient does indeed have dementia. Tell us a little bit about the next steps in the laboratory neuroimaging evaluation of such a patient? 

Dr Day: I've got a history of memory and thinking problems. I've got some corroborating evidence from bedside cognitive testing, a normal neurological exam. This is where we think about, well, what other tests do we need to send our patients for? Blood testing really can be pretty cursory for most patients with a typical presentation who have typical risk factors, and that can include a thyroid study and vitamin B12. So, measuring those in the blood to make sure that there's no other contributions from potential metabolic factors that can worsen, exacerbate cognitive function. And pretty easy to do for the most part, if patients have other things in their history, maybe they come from a high-risk community, maybe they engage in high risk behaviors, I may think about adding on other tests that associate with cognitive decline. We'll think about the role of syphilis, HIV, other infections. But generally, that's when it's driven by history, not a rule of thumb for me in my typical practice. But beyond the blood tests, neuroimaging, some form of structural brain imaging is important. A CT scan will get you by. So, if you have a patient that can't get in the scanner for one reason or another or won't get in the scanner, or you don't have easy access to an MRI, a CT scan can help us in ruling out the biggest things that we're looking for. That's strokes, hemorrhages, and brain masses. So other things that obviously would take us down a very different path, very different diagnosis and very different treatment approach. An MRI, though, is going to be preferred, not only because it gives us a much higher-resolution view, but also because it helps us to see sort of regional areas of atrophy. It's a sensitive scan to look for small vessel disease, tiny strokes, tiny bleeds, microhemorrhages that again might point towards meteorology for us. Of course, it's better at finding those small masses, whether they be metastasis or primary masses, that could give us something else to consider in our diagnostic evaluation. I get an odd question often from patients, well, can you see Alzheimer's disease on an MRI? And the true answer to that is no, you can't. Can we see the signs of Alzheimer's disease? Sure, in some patients, but really what we see on an MRI is a reflection of neurodegeneration. And so, we see evidence of tissue loss and typically in areas that are most often involved early on in Alzheimer's disease. The hippocampus, the entorhinal areas around the hippocampus, we may see atrophy there. We may see biparietal atrophy, and of course, as the disease progresses, we're going to see atrophy distributed throughout other areas of the brain. But if you're looking for atrophy, you've got to have a pretty good idea what's normal for age and what you expect in that patient population. So, I do encourage clinicians who are assessing patients routinely, look at your own images, look at the images for patients with and without cognitive impairment. So we develop a pretty good sense for what can be normal for age, and of course work with our colleagues in radiology who do this for a living and generally do an excellent job at it as well. 

Dr Berkowitz: Perfect. So, you're going to look for the so-called reversible causes of dementia with serum labs, structural imaging to either rule out or evaluate for potential structural causes that are not related to a neurodegenerative condition or patterns of regional atrophy suggestive of a neurodegenerative condition, and maybe that will point us in an initial direction. But the field is rapidly expanding with access to FDG-PET, amyloid PET, CSF biomarkers, genetic testing for APOE 4, probably soon to be serum biomarkers. So, patients may ask about this or a general neurologist referring to your clinic may ask, who should get these tests? When should we think about these tests? How do you think about when to send patients for advanced imaging, CSF biomarkers, genetic testing for APOE 4?

Dr Day: It's not that patients may ask about this. Patients will ask about this. And you've probably experienced that in your own world as well. They're going to ask about any of these different biomarkers. Certainly, whatever they've recently read or has been covered on television is going to be common fodder for consideration in the clinic environment. It's important to know what tests you can get, what reliable tests that you can get, and to know the differences between some of these tests when making a recommendation or weighing the pros and cons of doing additional testing. I think common practice principles apply here. Let's order tests that are going to change our next steps in some way. And so, if we have a patient, particularly a patient like the one that we've been talking about: seventy something year old, presenting with memory complaints, they're concerned, the family is concerned. We've got that history, physical exam, and now we may need to really hone in on the etiology. Well, I say may need because for that patient it may be enough to know, yeah, I agree, there's a problem here. And I can say it's an amnestic, predominant, gradual-onset progressive cognitive decline. This is probably Alzheimer disease based on your age. And maybe that's all they want to hear. Maybe they're not ready to pursue additional testing or don't see the value or need for additional testing because it's not going to change their perspective on treatment. In that case, it's okay to apply an often underrated test, which is the test of time. Recognizing this is a patient I can follow. I can see them in six months or twelve months, depending on what your clinic schedule allows. If this is Alzheimer disease, I'm going to expect further gradual progression that may affirm the diagnosis. We can think about symptomatic therapies for a patient like that, perhaps Donepezil as an early, early medication that may help with symptoms somewhat and we can leave it at that for the time being. But there's many scenarios where that patient or the family member says, look, I really need to know. We really want this answer. And as you pointed out, there are good tests and increasingly good tests that we have access to. 

Dr Berkowitz: Well, that's a very helpful overview of the landscape of more precise diagnostic testing for Alzheimer disease specifically and how you think about which tests to order and when based on your pretest probability and the patient 's candidacy for some of these new potential therapies. To close here, as you said, treatment is discussed in another podcast. There's another article in this issue. So, we won't get into that today. But let's say you have gotten to the end of the diagnostic journey here. You are now convinced the patient does have Alzheimer's disease. How do you present that diagnosis to the patient and their family?

Dr Day: I think here we're going to recognize that different styles align with different patients and families, and certainly different clinicians are going to have different approaches. I do tend to take a pretty direct approach. By the time that patients are coming to see me, they've probably already seen another neurologist or at least another physician who's maybe started some of the testing, maybe even built the foundation towards this diagnosis and shared some indications. Certainly, when they look up my profile before they come to see me, they know what I specialize in and so, they may even have done their own research, which has ups and downs in terms of the questions that I'll be faced with at that point in time. The way I like to start is first acknowledging the symptoms. And the symptoms that the patients have shared with me, recognizing if those symptoms are impacting daily life, how they impacted daily life, and usually using that information to synthesize or qualify the diagnosis. Is there cognitive impairment, yes or no? And at what level is that cognitive impairment? Is this mild cognitive impairment? Is this mild dementia? Is it maybe more moderate or severe dementia? So, using those terms directly with patients and explaining the meaning of them. But I then transition in relatively quickly to the important point of not leaving it at the syndrome, but actually thinking about the cause. Because it is cause that patients come to talk about. And if they don't say that directly, they say it in their next question, which is what are we going to do about it and how are we going to treat this? And so, I will use the information I have available at that time to suggest that based on your age, based on the history, the normal physical examination, the performance and the bedside testing that we've done. And hey, that's pretty normal structural imaging or imaging that only shows a little bit of atrophy in a few areas. I think that this condition is most consistent with symptomatic Alzheimer's disease, mild cognitive impairment due to Alzheimer's disease, or mild dementia due to Alzheimer's disease. And then I'll discuss the next options in terms of testing and try to get a feel of what our patients are thinking about when it comes to treatment. Do they want to be on the cutting edge with brand-new therapies that offer potential benefits but counterbalance by pretty substantial risks that warrant individualized discussions? Are they interested in symptomatic therapies? Would that be appropriate for them? And I can usually round out the discussion with advice that works for everyone. And that's where we talk about the importance of brain health. What are the other things that I should be doing, you should be doing, and our patients and their partners should be doing as well to maintain our brain in its best possible state as we hope that we all continue to age and look towards the future where we maintain our cognition as best as possible? And that is still the goal. Even when we're talking to patients who have neurodegenerative diseases that are working against our efforts, we still want to do what we can to treat other problems, to evaluate for other problems that may be contributing to decline and may be amenable to our management as well. 

Dr Berkowitz: Well, thank you so much for taking the time to speak with us today. I've learned a lot from your very nuanced and thoughtful approach to taking the history, performing the examination, making sense of cognitive tests and how they fit into the larger picture of the history and examination, and thinking about which patients might be candidates for more advanced imaging as we try to make a precise diagnosis in patients who may be candidates and interested in some of the potential novel therapies, which we both alluded to a few times, but are deferring to another podcast that we'll delve more deeply into that topic in this series. So, thank you so much again, Dr Day. Again, I've been interviewing Dr Gregory Day from the Mayo Clinic, whose article on Alzheimer's disease appears in the most recent issue of Continuum on Dementia. Be sure to check out Continuum Audio episodes from this and other issues. And thank you so much to our listeners for joining today.

Dr Monteith: This is Dr Teshamae Monteith, associate editor of Continuum Audio. If you've enjoyed this episode, you'll love the journal, which is full of in-depth and clinically relevant information important for neurology practitioners. Use this link in the episode notes to learn more and subscribe. AAN members, you can get CME for listening to this interview by completing the evaluation at continpub.com/AudioCME. Thank you for listening to Continuum Audio.

In this episode, Lyell K. Jones Jr, MD, FAAN, speaks with Lisa C. Silbert, MD, MCR, FAAN, who served as a guest editor of the Continuum® December 2024 Dementia issue. They provide a preview of the issue, which publishes on December 2, 2024.

Dr. Jones is the editor-in-chief of Continuum: Lifelong Learning in Neurology® and is a professor of neurology at Mayo Clinic in Rochester, Minnesota.

Dr. Silbert is co-director at Oregon Alzheimer's Disease Research Center, a Gibbs Family Endowed professor of neurology, a professor of neurology at Oregon Health & Science University, a staff neurologist, director of Cognitive Care Clinic, and director of the Geriatric Neurology Fellowship Program at Portland Veterans Affairs Health Care System in Portland, Oregon.

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Host: @LyellJ

Full episode transcript available here

Dr Jones: This is Dr Lyell Jones, Editor-in-Chief of Continuum, the premier topic-based neurology, clinical review and CME journal from the American Academy of Neurology. 

Thank you for joining us on Continuum Audio, a companion podcast to the journal. 

Continuum Audio features conversations with the guest editors and authors of Continuum who are the leading experts in their fields. Subscribers to the Continuum Journal have access to exclusive audio content not featured on the podcast. If you're not already a subscriber, we encourage you to become one. For more information, please visit the link in the show notes. 

Dr Jones: This is Dr Lyell Jones, Editor-in-Chief of Continuum: Lifelong Learning in Neurology. Today I'm interviewing Dr Lisa Silbert, who recently served as Continuum's co-guest editor for our latest issue on dementia alongside Dr Lianna Apostolova. Dr Silbert is a professor in the Department of Neurology at Oregon Health and Science University of the School of Medicine in Portland, Oregon, where she's also the director of the Neuroimaging Core and now the co-director of the Alzheimer's Disease Research Center. She also serves as director of the dementia clinic at the VA Portland Healthcare System. Which, Dr Silbert, sounds like a lot of work? Anyway, welcome. I really appreciate you taking the time to join us today and co-guest editing this issue. Why don't you introduce yourself a little bit to our listeners? 

Dr Silbert: Well, thank you so much for interviewing with me today and for inviting me to be the guest, co-guest editor of this issue. It's a really exciting time for dementia care and dementia research. As you already said, my name is Lisa Silbert. I'm in Oregon Health and Science University in Portland, Oregon. I've been involved in caring for dementia patients and their families for over twenty years now and been involved in a lot of really exciting research during that time. But I would say now is probably the most dynamic time in dementia research and care that I've seen. So, it's really, really exciting to be here.  

Dr Jones: It really is an interesting time. So, I look back  in our last issue of Continuum focusing on dementia came out in 2022, which doesn't sound like that long ago, but a lot has changed, right? With the anti-amyloid monoclonals for Alzheimer's disease, new biomarkers and so on. And as the guest editor, you have this unique view, Dr Silbert, of the issue and the whole topic of dementia. As you were reading these really outstanding articles, what was the biggest "aha" moment for you or the biggest change in practice that you saw that's come up over the last couple of years?  

Dr Silbert: I think, you know, in reading through the different manuscripts or chapters in this issue, it really struck home the advances that have been made throughout all the different areas of dementia. Not just- so, we hear a lot about Alzheimer's biomarkers and Alzheimer's treatments on the horizon, which is really exciting, but this is happening across other dementias as well. There's biomarkers on the horizon for a Lewy body disease and potentially for some of the frontaotemporal dementias. And so that to me really struck home as this is really, across the board, a change in the entire field that we're looking at. 

Dr Jones: That is exciting. And I'd like to come back to some of those biomarker developments because I think that's an area where we've really been lacking in neurology as a specific way to diagnose those disorders. I think a topic which you just alluded to that a lot of our listeners and readers are thinking about are those antiamyloid monoclonal therapies for Alzheimer's disease. So, addicanumab, lecanumab and most recently the approval of donanemab. For these drugs specifically, how are you using them in your practice and how should our listeners be thinking about these drugs? 

Dr Silbert: These are, you know, relatively new, really exciting new and emerging therapies for Alzheimer's disease. They are shown to remove amyloid from the brain. Patients who have clinical manifestations of Alzheimer's disease, and that is those in the stages of mild cognitive impairment or mild dementia. We are using lecanemab at Oregon Health and Science University through our therapeutics and clinical units. It's a really exciting time and it's a time where we have to be, also, cautious about who undergoes these therapies. So being really informed about the use, who's appropriate to undergo these therapies, what kind of safety tests need to be undergone, how do you assess risk in individual patients so that you can counsel them.  So, all of these factors need to be weighed in when you're making a decision about whether or not to treat a patient with a monoclonal antibody therapy. And specifically, we do neuroimaging to assess whether there are already the presence of microhemorrhages in the brain. We do genetic testing to look for APOE 4 genotypes that can increase the risk of Aria, which is amyloid-related imaging abnormalities. And all of these factors go into how we counsel patients and discuss whether or not to pursue treatment with monoclonal antibodies. 

Dr Jones: So certainly a complex patient selection process and drug administration and monitoring of therapy for those patients.  And that- it brings to mind for me how we already have too few neurologists in the US. And now for a really prevalent disorder, Alzheimer's disease, we're making it a lot more complicated to deliver these new disease-modifying therapies. What do you think or what do you see as the role of the neurologists in caring for patients with dementia? And do these developments change that role? 

Dr Silbert: For now, I think these developments make it even more important in a way that neurologists are involved in making a very specific clinical diagnosis of which dementia is playing a factor in the patient 's clinical presentation. I think one thing to note is with these emerging biomarkers, a lot of them can be positive before there are clinical symptoms and multiple etiologies are also very prevalent. And so just having one positive biomarker, it doesn't necessarily tell you what's going on with an individual patient. You need to take the whole picture into consideration. So, I think a really detailed evaluation by the neurologist, especially with these emerging therapies that have potential risks, is extremely important right now. Just getting a test is really not sufficient. You really have to take the entire clinical picture into account and know the ins and outs of the risks involved in these disease-modifying therapies. 

Dr Jones: Which brings us back to something you mentioned earlier, right? Which is good news. We have on the horizon new potential biomarkers for other neurodegenerative causes of dementia. I can foresee and maybe I'm, you know, being an alarmist here, Dr Silbert, but if we have sensitive biomarkers for other neurodegenerative conditions, we know patients often have copathologies. Is that going to help clarify things? Is it going to confuse us? How is that going to work? 

Dr Silbert: Well, I think ultimately, it's going to help clarify things. Because there are multiple pathologies that are common in age related cognitive impairment, any kind of additional specific input that we can get with different biomarkers is going to be helpful in putting the pieces together to come up with what's happening clinically with each individual patient. Ultimately, I think these biomarkers, they're not- any one biomarker isn't going to be a solution to diagnosis, but putting them together to help improve early and accurate diagnosis is really the goal here. Having a very early diagnosis, having a very accurate diagnosis will improve our ability to give prognosis and also improve effective treatment strategies moving forward. I think that these biomarkers have the promise in facilitating that for us. 

Dr Jones: And progress is always a good thing. We just have to learn how to adapt and use the evidence appropriately. There have been and I think most of our listeners will be familiar with some of the controversies related to these, these new disease-modifying drugs for Alzheimer's disease. Do you want to walk us through a couple of those, and what are your thoughts about those controversies? 

Dr Silbert: Yeah, these new therapies, they're very exciting for everyone in the field, but they, like you mentioned, they're not without their controversies. I think one controversy or one potential downside to these therapies is access to them. Like you already mentioned there, there's really not enough neurologists out there. There's not enough behavioral neurologists out there. There's limitations to infusion centers, sites and prescribers. Access to these therapies is is significantly limited. They are requiring infusions quite frequently. So, if you're not living near specialty care, you're not really able to feasibly undergo these kinds of treatments. Another controversy is the fact that the treatment effects are considered by some to be fairly modest when looking at the clinical data and in association with that, there are risks involved. Like I already mentioned, there's the amyloid-related imaging abnormalities, which sounds kind of like a benign thing, but they really consist of microhemorrhages that can lead to bigger hemorrhages and edema in the brain. These risks are relatively small - they are seeing more commonly in those who have a specific genotype, an APOE E 4 genotype - but they're risks nonetheless. 

And so, there's controversy about the risk-benefit ratio and access to care with these new therapies. 

Dr Jones: It's very exciting, but we should be cautious, right? I recall a few years ago as a program director, a neurology residency program director, interest in different areas of neurology would often follow developments in those areas, right? Lots of interest in autoimmune neurology when those developments would proceed in neuro oncology, etc. And I wonder if the therapeutic advances in in behavioral neurology and neurodegenerative cognitive disorders, I wonder if that's going to stimulate interest among our trainees to pursue behavioral neurology? Do you have a view on that or have you seen much change in interest in in this field? 

Dr Silbert: You know, we are seeing a lot more interest in our trainees. The residents are very interested in these new therapies and how to apply them. And I'm really excited about that. 

I'm hopeful that this will stimulate interest in the field. And we need those specialists, we need those sub specialists to undergo fellowship training in behavioral neurology and geriatric neurology so that we have more access to the subspecialty care and delivering these new therapies. So, I agree with you, I'm hopeful about it and I am seeing new interest in our trainees about these new therapies. 

Dr Jones: We can hope so. And all the other fellowship directors will be anxious if neurology residents start leaving to go into behavioral neurology. But there's certainly demand. And I know that under the best of circumstances, dementia is so common. It's something that we have to care for in partnership with primary care and community resources. And these disease-modifying therapies capture a lot of attention, but it's really a small part of the continuum of care of these patients. And Dr Silbert as an expert, you know, if we put that disease-modifying therapy to the side for a second and just said, well, what are the biggest gaps in the care for patients with dementia? What do you see as those biggest gaps and, and what can we do to fix them at not just a neurology level, but at a societal level? 

Dr Silbert: That's a big question. And you know, what I see almost every day are gaps in the support mechanisms for families who are caring for patients with dementia. These caregivers are under a lot of stress and oftentimes they just don't have the resources to take care of somebody who at some point will often need twenty-four hour care and supervision. Caregivers are older, usually of older age themselves and have their medical issues as well. And then we're just not doing a good job as a nation in in supporting patients and their families with like supportive care and respite care that's really needed. So, you know, I'm not just seeing and treating patients with dementia, but I'm seeing and I'm really trying to support and care for those who are taking care of patients with dementia. To me, that's the biggest gap in our system.

Dr Jones: Yeah. And as I look through this issue of Continuum, we touched on not only the conventional topics in dementia and behavioral neurology. I'm really happy in hindsight that we have invited some discussion of the psychiatric symptoms in dementia, which I think are really important and often underrecognized and maybe undermanaged or mismanaged, and really also focusing on the caregiver burden and support services. We do have an article dedicated to that as well, and I think that'll be useful to our readers and listeners when we when we publish those podcasts. We we've heard this year especially a lot of public conversation about cognitive impairment and dementia. I sometimes wonder if that public attention is helpful and constructive for the population of patients with dementia. Sometimes I wonder if that conversation is counterproductive. What's your take on that? 

Dr Silbert: You know, I think it's- it can be a mixed bag, but ultimately, it's in the conversation. We're talking about it. And I think that's only a good thing. There's more public awareness of it. 

There is more interest in therapies. So, I think at the end of the day, talking about it, making it more prevalent in the ether, it stimulates the conversation and discussion. And even if there's controversies about it, we're talking about it. And I think that's kind of the first step in acknowledging that we need more support, we need more therapies. 

Dr Jones: Yeah, I agree. And I think often patients with neurologic disorders and their caregivers and families often appreciate being seen.  

Dr Silbert: Yeah, no, absolutely true. So, I'd say in regards to the monoclonal antibody treatments, you know, despite the controversies with these new treatments, I think there's a real promise and a real hope and a real excitement across a lot of behavioral neurologists, including myself, that this is just the beginning. That even if these first line, first generation therapies maybe have downsides, that there'll be second generation and third generation variations on these kinds of treatments that are going to be more accessible, have less side effects and hopefully be more clinically effective. And, and down the line, the other real hope for the field is that these maybe second generation therapies will actually delay the onset or prevent clinical manifestation of the disease. And that's the real goal here. 

Dr Jones: And that's a great segue to the to the next thing I wanted to ask you about and you, you may have already answered the question. We talked about how we have and will have new biomarkers which will help us with diagnosis. We have hopefully the first phase in increasingly effective disease modifying therapies for Alzheimer, maybe prevent Alzheimer's disease. Wouldn't that be great? Are there any other things on the horizon that you see maybe for other neurodegenerative disorders from a therapeutic perspective? What do you, what do you think the next big thing will be in that area? 

Dr Silbert: Well, that's a great question. I think, you know, there's a lot of exciting research in Lewy body dementia and targeting alpha synuclein pathologies. We really need biomarkers. 

So, we're ways off from therapeutics, but I think there's a lot of exciting progress in that area. 

Dr Jones: So, like many areas of neurology, there are rewarding and challenging aspects to the care of these patients. What  do you- what's the most rewarding aspect of your practice, Dr Silbert?  

Dr Silbert: You know, a lot of… I hear from trainees over the years that, you know, they can't imagine or it's difficult for them to think about caring for patients who have a neurodegenerative disease that has no cure. But I feel like that's a lot of what neurologists do. We don't necessarily cure all diseases, but we treat the patient throughout their disease process. And to me that is extremely satisfying. You know, I enjoy listening to patients' stories and hearing about what they have been through over the years. And I really feel, like, appreciated for the care that I provide in giving not just an accurate diagnosis, which a lot of people come in lacking, but talking about future planning and, really, treatment throughout the course of the disease. And I was in clinic yesterday and talking to one of my patients' caregivers, and we were talking about a particularly difficult behavioral manifestation that her husband was going through. And we were talking through how to manage it. And she said to me, you know, Dr Silbert, I really feel like I have a partner in going through this disease. And you know, that's kind of what it's all about for me. So, to me, it's extremely rewarding field. It's also a very exciting field, especially right now with all these new biomarkers and treatments. So, I just think there isn't a better area of neurology to be involved in right now.  

Dr Jones: What a great place to land and end the interview. And I hope our listeners and our readers really do enjoy this issue. It's really a fantastic, not just an update, but a survey of a very dynamic aspect of the field of neurology. And Dr Silbert, I want to thank you for joining us and thank you for such a thorough and fascinating discussion on caring for patients with dementia. 

Dr Silbert: It was my pleasure. Thank you. 

Dr Jones: Again, we've been speaking with Dr Lisa Silbert, co-guest editor, alongside Dr Leanna Apostolova for Continuum 's most recent issue on dementia. Please check it out, and thank you to our listeners for joining us today. 

Dr Monteith: This is Dr Teshamae Monteith, associate editor of Continuum Audio. If you've enjoyed this episode, you'll love the journal, which is full of in-depth and clinically relevant information important for neurology practitioners. Use this link in the episode notes to learn more and subscribe. Thank you for listening to Continuum Audio. 

Lewy body dementia is a common cause of cognitive impairment in older adults but is often subject to significant delays in diagnosis and treatment, increasing the burden on patients and family caregivers. Understanding key features of the disease and use of biomarkers will improve recognition.

In this episode, Allison Weathers, MD, FAAN, speaks with James E. Galvin, MD, MPH, author of the article "Lewy Body Dementia," in the Continuum December 2024 Dementia issue.

Dr. Weathers is a Continuum® Audio interviewer associate chief medical information officer at the Cleveland Clinic in Cleveland, Ohio.

Dr. Galvin is a professor of neurology at the University of Miami Miller School of Medicine in Miami, Florida.

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Read the article: Lewy Body Dementia

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Full episode transcript available here

Dr Jones: This is Dr Lyell Jones, Editor-in-Chief of Continuum, the premier topic-based neurology clinical review and CME journal from the American Academy of Neurology. Thank you for joining us on Continuum Audio, which features conversations with Continuum's guest editors and authors who are the leading experts in their fields. Subscribers to the Continuum journal can read the full article or listen to verbatim recordings of the article and have access to exclusive interviews not featured on the podcast. Please visit the link in the episode notes for more information on the article, subscribing to the journal, and how to get CME.

Dr Weathers: This is Dr Allison Weathers. Today I'm interviewing Dr James Galvin, author of Lewy body dementias from the December 2024 Continuum issue on dementia. Welcome to the podcast, Dr Galvin. Please introduce yourself to our audience. 

Dr Galvin: Thank you, Allison. My name is Jim Galvin. I'm a neurologist, a professor of neurology at the University of Miami Miller School of Medicine.

Dr Weathers: We're so happy to have you with me today. Thanks, Jim, for your time. And as you highlight right from the start in your really outstanding and comprehensive overview of this really complex topic, even though Lewy body dementia is the second most common cause of neurodegenerative dementia, it often goes unrecognized in clinical practice, resulting in really potentially lengthy diagnostic delays. So, this is a really important article for a neurologist and an important topic for our listeners. So, I'm thrilled we're having this conversation today. While I traditionally start by asking the authors what they feel is the most important clinical message of their article, I would love to actually start a step earlier in this conversation with you. Can you start us off by explaining what's actually meant when we say Lewy body dementia?

Dr Galvin: Great. So, you know, I think this is a, this is an interesting concept. So, we're really talking about two diseases that have a shared common pathology. So, Parkinson's sees dementia and dementia with Lewy bodies. So, their shared pathology is a Lewy body and that's why they're often grouped together as the Lewy body dementias. And then there's arguments back and forth as to whether these are distinct diseases or sort of two ends of the same candle burning in different directions. So, Parkinson's dementia is a lot like what it sounds like. So, if someone has Parkinson's disease, then at some point later they develop a dementia. And so back in the 1800's when Parkinson's disease was like first described as an entity, we basically felt that cognition wasn't affected. But we now know that's not true. And so most patients with Parkinson's do have some cognitive symptoms and a large proportion of them will eventually develop dementia. Perhaps up to 80% of Parkinson's patients will develop a dementia. The flip side is the dementia with Lewy body picture. And these are people who present primarily with a cognitive behavioral syndrome that may or may not have parkinsonism. So, they will sometimes have bradykinesia. They rarely have a rest tremor. And so, these are the people that are very much in the delayed diagnosis group. The Parkinson's dementia is more whether the clinician is checking their cognition as part of their annual visit. The flip side is that the people with DLB are often misdiagnosed early on, but together, this is Lewy body dementia, which is the most common disease that many people have never heard of.

Dr Weathers: That's a great tagline, I think, for the whole article and for this concept. So now that that we're all on the same page about what's meant when we use that the term, what would you want our listeners to walk away with as their one key takeaway from our conversation today?

Dr Galvin: Well, I think the article makes several key points, but I think if I put those all together into a single key point, it would really be that the Lewy body dementias are underrecognized, they're underdiagnosed, yet it is very possible to make the diagnosis using the standardized clinical criteria. They're very, very, very specific. They lack a little bit in sensitivity. So, because other diseases sometimes can look like this, but they're really quite specific. So, if you're confident clinically that the person has Lewy body dementia, you're probably going to be right. And in today's world, we have tests available to help confirm our diagnosis. The world is changing. We can make these diagnosed with much more confidence and we have confirmatory diagnosis laboratory tests that can help us.

Dr Weathers: I want to talk more about the diagnosis in one minute, but first, how common actually are dementia with Lewy bodies and Parkinson's disease dementia?

Dr Galvin: That's a great question. I think one of the challenges, of course, we really don't know how many people have any disease because it's going to largely rely on how well people code the diseases in the medical record. So, if you look at the most common cause of dementia in the United States, it's really dementia not otherwise specified, right? But we believe it to be the second most common cause of dementia. The Lewy Body Dementia Association, about a decade ago, started to try to develop some estimates. So, we have an estimate about how many people roughly have Parkinson's disease and that about 80% of those individuals would go on to develop dementia. And we know from the dementia population that about 40% of those individuals coming to autopsy have Lewy bodies. So, when you start to put that all together, you can get a reasonable estimate of how many people likely have the disease. And then that can be expanded on an annual basis, just like the Alzheimer's Association uses, by extrapolating those estimates onto the census data. So, we estimate right now there are about 1.4 to 1.6 million Americans who are living with Lewy body dementia. That's less than the 6.8 million people who have Alzheimer's disease, but more than a lot of other common diseases. So, if you think about, again, I said before, it's the most common disease no one's ever heard of. You know, there are about a million people who have multiple sclerosis. There are about eight hundred thousand people who have a stroke. There are about seven hundred thousand people who have a brain tumor. There are two hundred and fifty thousand people who have muscular dystrophy. There are twelve thousand people who have ALS. But I think if you stopped clinicians or people in the street and say have you ever heard of ALS or muscular dystrophy, they would say yes. If you ask them if they've heard of Lewy body dementia, they would say no. 

Dr Weathers: That's an excellent point. And I know over the years I think there's been some increased awareness. I think sadly with some of the celebrities that have been impacted, I think that did a lot to raise awareness. But I think you're right that it's still so less commonly recognized by the lay public, by non-neurologists, than so many other diseases that you mentioned. And I think that leads back well into my next question into something that we've already mentioned just a few times already in our short conversation, this unfortunate and very common delay in the diagnosis. Why? And you mentioned earlier that there are these, you know, clinical criteria, these now ancillary tests. So, what makes the diagnosis so challenging? What aspects in particular do you think that neurologists find to be the most challenging in diagnosing patients? What trips us up? 

Dr Galvin: So, there's an old analogy, right, that, you know, if you'll be three blind men to an elephant and each of them are touching a different part of the elephant, they'll each think it's something different. So because Lewy body dementia has so many different diverse kind of symptoms, it would really depend on who's seeing the patient first. So, if a person presents predominantly with a memory cognitive disorder and they go see someone who specializes in memory disorders, they're highly likely to be called Alzheimer's disease. If they present predominantly with the movement problem, they're going to see a movement disorder person and be called Parkinson's disease. If they present with a behavioral disorder, they're going to go see a psychiatrist. Then they'll get diagnoses like, you know, geriatric schizophrenia or bipolar disease or major depressive disorder. If they present with the constitutional symptoms, which are very common and drive patients absolutely batty. So chronic constipation, REM sleep disorder, runny nose, you know, heat intolerance, urinary frequency, obstipation, and you know, they're going to be called all sorts of things. So, if you start thinking about this, who do you show up with first is going to guide how fast you can get a diagnosis. So, we interviewed at point over a thousand caregivers and what we found was there was about an eighteen month delay after seeing five to six doctors for the majority of patients, of which Lewy body dementia was misdiagnosed about 75% of the time for the initial diagnosis. 

Dr Weathers: Wow, what a sobering statistic. And you spoke about the criteria and some of the ancillary tests. What can really help, do you think, kind of mitigate or prevent this misdiagnosis? What is your approach in your own patients? 

Dr Galvin: Well, I think like every good clinician, not starting off with a preconceived notion of what the person has and trying to collect all the valuable information. So, one of the things I highlighted in the article was, while there are diagnostic criteria and people can follow diagnostic criteria, the truth is at your fingertips. You don't always sit and think about whether someone meets diagnostic criteria. So, in the first table in the article, we tried to really then put all the different common symptoms into buckets, right? Because people present like that. They say, well, I have this and I have this and I have this and I have this. Well, then you can start to think about, well, they have a cognitive symptom that's predominantly executive attention or visual perceptual in nature. And gee, they have constipation and heat intolerance and they say they can't smell quite as well as they once did, right, and they're having some disturbance in their sleep with excessive daytime sleepiness. Now you can start to say, well, even though that didn't fit the core and suggestive criteria, the fact is that spectrum of symptoms makes it much easier to begin to make a diagnosis. And so, it's investigative work. A lot of neurology is still investigative work. The old days, they used to say, we knew everything but could do nothing, but now we know everything and can do something about it. And so, I think it's really important that we try to apply this information in clinically useful ways. That was part of the gist of putting this Continuum article together was to try to present it not just as listing the diagnostic criteria, because you can get that anywhere, but how do you actually apply it in clinical practice?

Dr Weathers: That's a great point. And that table that you referenced was really fantastic. And I know I say this a lot, but they're true. So, you know, many of the tables, the reference to Continuum, one I will certainly kind of come back to again, again, as an excellent point of care tool. So, I know in, in preparing for today and reading more about, about you and your areas of research that one of your particular areas of focus and expertise is in healthcare disparities, especially in the early detection of neurodegenerative dementias. What is the greatest inequity or disparity that you see in the diagnosis and treatment of patients with Lewy body dementia? 

Dr Galvin: So, there's a couple things that are that are really interesting. So first, unlike Alzheimer's disease, which tends to be a little bit more female predominant, the Lewy body dementias are male predominant. It's about 1.6 men for everyone woman. So, it's going to be a different presentation. It's going to be largely men and their caregivers are largely going to be their spouses. So, you're going to see sort of a different person looking, you know, staring on the other side of the table to you. It's going to be largely a male. And the other thing that's really interesting is that almost all of the series, case series, case reports, clinical papers are in predominantly white populations. So, this lends to some interesting things. So, you know, is the disease less common in African Americans and other minority populations or are we just really bad at ascertaining the disease? You know, many of the case reports in Alzheimer's disease include African Americans. In fact, we know that African Americans may be at a twofold increased risk of developing Alzheimer's disease compared to nonHispanic whites, probably due to vascular risk factors. But in case series of Lewy body dementia, almost all the patients are non-Hispanic white. There also seems to be a higher risk in Asian populations, and in fact, some of the very earliest case reports were from Japan. Is this a case ascertainment problem or is this really a disparity in how the disease presents? And I think those are really important questions that still need to be asked. I know as researchers, we struggle to try to develop cohorts that could help us understand that. I would say in my twenty five years of seeing these patients, I would say the large percentage of them, and I've seen a lot of them, have been no-Hispanic white. 

Dr Weathers: So, so definitely more research needed in this very important area. So, moving on to somewhat of a personal question, I always, this is such an honor. I always talk about that I get to have this time to sit down with the authors of these outstanding articles and learn not only more about their subjects, but about them as people. I had shared during my last interview that my paternal grandmother had Alzheimer's disease, and unfortunately also my maternal grandmother actually did as well. In preparing for this, I had listened to one of your previous interviews and learned that you also have a personal connection that led you to this subspecialty with several family members impacted. How has this connection inspired your research and your interactions with your patients? 

Dr Galvin: Yeah, I mean, so my personal connection was that my maternal grandfather had Lewy body dementia. So, I grew up in a two family home in New Jersey. My grandparents lived on the second floor. We lived on the first floor. I wass very close to my grandparents. I'm still close to my grandmother, who's a hundred and three years old. But when I was a high junior in high school, my grandfather was driving me home from a swimming practice. I was thinner, fitter and more athletic at that point in my life, and he made the world 's slowest left hand turn and we were broadsided. So luckily no one was hurt. But I remember because I was sixteen at the time and just learning how to drive us, Grandpa, what happened? And he's like, oh, the car didn't react. Or, you know, he was blaming the car. And I didn't think much of it because, you know, I was sixteen years old. Sometime after that he was at work, and he was a greaser. So, he would climb through the machines at Colgate Palmolive and keep them all moving.

And so, he was at work and he fell off a ladder and then broke his ribs. And in the emergency room, when my grandmother went to pick him up, the ER doctor turned to her and said, how long has your husband had Parkinson's disease? And she's like, what are you talking about? And then that was the first time that all of us had noticed his rest tremor. And the reason he turned the wheel so slow is because he was Bradykinetic. And so then over the next few years, he progressed in his motor symptoms. And then as I got into college, he developed the cognitive symptoms. And so, by the time I had finished medical school that was doing my residency, he was no longer oriented to time. So that even though I had finished medical school, I was in my neurology residency, I was married and with children, I was still in college at that time for him. So, he would always ask me, you know, have I heard anything from getting to medical school and the like. So, I got to watch this person who I grew up with go through all of the different stages of disease. And then eventually he developed lots of hallucinations. And although he was relatively immobile, he experienced a hallucination and jumped out of his chair, fell down, and broke his hip. And so, he underwent a hip replacement, being rather severely demented, and then passed away in the rehab hospital. As I was living this with my grandparents, the one thing that my grandfather, while he could still communicate, and that my grandmother continued to say to me, you know, up until fairly recently was, you know, what are you going to do about this? You know, we're counting on you to make a difference. And so, a lot of my research is really focused on how I can make a difference for people. One, to make sure they get diagnosed properly. Two that we would have something to offer the patient and the family. And three, we can provide hope that we are actually going to come away with effective treatments to make a difference in their lives.

Dr Weathers: Well, that is really inspiring. And I think you have really done that in your work. I always like to end these conversations on a hopeful note. So, what are the developments that are on the horizon in terms of diagnosis and treatment of Lewy body dementia that you are most excited about? 

Dr Galvin: Well, I think there are three things that are of great interest right now. I mean, there's lots of things, but I think three things of great interest are, one, on the diagnostic side is that we now have assays that allow us to assess synuclein in body fluids and body tissues. So, we can measure synuclein seeding assays in the spinal fluid and we can visualize Lewy bodies through skin biopsies. And that's a tremendous advance because we were really, really limited otherwise to using indirect evidence, and the only indirect evidence we had was abnormalities on DAT scanning. So, we're looking at dopamine deficiencies. But as I mentioned earlier, that's very abnormal in Parkinson's disease. But in dementia with Lewy bodies, it's a little more subtle. So, the extent of dopamine degeneration in- particularly in early DLB is limited. So, you have to look very carefully. If we're not doing quantitative DAT scan imaging, then you may miss those subtle changes. So, I think that being able to directly visualize either synuclein seeding or synuclein aggregation has really changed the game. Plasma assays, blood-based biomarkers are probably a little farther away because they're- the red blood cells have a lot of synuclein and so it interferes with the ability to get a good sensitive assay. But I do think in the next couple of years we will see PET ligands that also bind  synnuclein. So, I think diagnostically we're going to be able to provide better, earlier, and more precise diagnoses. From a treatment perspective, traditionally we've just borrowed medicines from other fields to treat symptoms, but there are a number of disease-modifying trials that are ongoing. I was fortunate to be the academic PI on two very large NIH grants where we test tested disease modifying medicines. Both of those studies are fully recruited and we should get a readout toward the end of 2024 or the beginning of 2025. So very, very excited about that. I also am fortunate to be MPI an NIH grant where we're just going to be testing the first inhuman synuclein vaccine. So very, very excited about the potential to offer disease-modifying medicines and to fulfill the promise that I made to my grandma and grandpa twenty years ago. And I think the third thing is that right now there's a little bit of like an emerging controversy about developing some integrated staging paradigms between the movement disorder world and the cognitive world. And so, while those paradigms are currently published, you know, not everybody agrees with them. But I think whether I like that staging paradigm now or not, the fact that we're coming together and trying to develop some unified staging paradigms, I think, is going to make a big difference in increasing the ability for clinicians to make early diagnoses that are more precise so that we can either get people into clinical trials or into clinical treatment protocols at the earliest possible time. And that's going to make all the difference in the world for the patients and their families. 

Dr Weathers: I think that was a fantastic answer. Really, all really exciting things that I think are all, I normally, I say on the horizon. I'm thinking, you know, pretty far ahead. And I think the really wonderful thing is that all of these are either here now or very, very close to being here. So, definitely a very positive way to end this discussion. Well, Jim, thank you so much for taking the time to speak with me today.

Dr Galvin: Thank you. This was wonderful. I hope the listeners found this enjoyable and interesting and read the Continuum issue. I think it's going to be the latest and greatest on what we know about the dementias. 

Dr Weathers: Again, thank you again, Dr Galvin, for joining me on Continuum Audio. Again, today I've been reviewing Dr James Galvin, his article on the Lewy body dementias, dementia with Lewy bodies, and Parkinson's disease dementia appears in the December 2024 Continuum issue on dementia. Be sure to check out Continuum Audio episodes from this and other issues. And thank you to our listeners for joining today.

Dr Monteith: This is Dr Teshamae Monteith, associate editor of Continuum Audio. If you've enjoyed this episode, you'll love the journal, which is full of in-depth and clinically relevant information important for neurology practitioners. Use this link in the episode notes to learn more and subscribe. AAN members, you can get CME for listening to this interview by completing the evaluation at continpub.com/AudioCME. Thank you for listening to Continuum Audio.

Although Alzheimer disease (AD) is the most common neurodegenerative cause of dementia, other etiologies can mimic the typical amnestic-predominant syndrome and medial temporal brain involvement. Neurologists should recognize potential mimics of AD for clinical decision-making and patient counseling.

In this episode, Kait Nevel, MD, speaks with Vijay K. Ramanan, MD, PhD, an author of the article "LATE, Hippocampal Sclerosis, and Primary Age-related Tauopathy," in the Continuum December 2024 Dementia issue.

Dr. Nevel is a Continuum® Audio interviewer and a neurologist and neuro-oncologist at Indiana University School of Medicine in Indianapolis, Indiana.

Dr. Ramanan is a consultant and assistant professor of neurology in the Division of Behavioral Neurology at Mayo Clinic College of Medicine and Science in Rochester, Minnesota.

Additional Resources

Read the article: LATE, Hippocampal Sclerosis, and Primary Age-related Tauopathy

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Earn CME (available only to AAN members): continpub.com/AudioCME

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Host: IUneurodocmom

Guest: @vijaykramanan

Full episode transcript available here

Dr Jones: This is Dr Lyle Jones, Editor-in-Chief of Continuum, the premier topic-based neurology clinical review and CME journal from the American Academy of Neurology. Thank you for joining us on Continuum Audio, which features conversations with Continuum 's guest editors and authors who are the leading experts in their fields. Subscribers to the Continuum Journal can read the full article or listen to verbatim recordings of the article and have access to exclusive interviews not featured on the podcast. Please visit the link in the episode notes for more information on the article, subscribing to the journal, and how to get CME.

Dr Nevel: This is Dr Kait Nevel. Today I'm interviewing Dr Vijay Ramanan about his article he wrote with Dr Jonathan Graff-Radford on LATE hippocampal sclerosis and primary age-related tauopathy, which appears in the December 2024 Continuum issue on dementia. Welcome to the podcast. Vijay, can you please introduce yourself to the audience?

Dr Ramanan: Thanks so much, Kait. I'm delighted to be here. So, I am a cognitive neurologist and neuroscientist at the Mayo Clinic in Rochester, Minnesota. I have roles in practice, education and research, but amongst those I see patients with cognitive disorders in the clinic. I help direct our Alzheimer's disease treatment clinic and also do research, including clinical trial involvement and some observational research on genetics and biomarkers related to Alzheimer's and similar disorders.

Dr Nevel: Great, thanks for that. So, I'd like to start off by talking about why is LATE hippocampal sclerosis, why is this important for the neurologist practicing in clinic to know about these things?

Dr Ramanan: That's a great question. So, if we take a step back, we know that degenerative diseases of the brain are really, really common, and they get more and more common as we get older. I think all neurologists, and in fact most clinicians and large swaths of the general public, are well aware of Alzheimer's disease, which is the most common degenerative cause of cognitive impairment in the population. But there are non-Alzheimer's degenerative diseases which can produce cognitive difficulties as well. And it's important to be aware of those disorders, of their specific presentations and their implications, in part because it's always a healthy thing when we can be as precise and confident about diagnosis and expectation with our patients as possible. I'll look to the analogy of a patient presenting with a myelopathy. As neurologists, we would all find it critical to clarify, is that myelopathy the result of a compressive spondylotic change? The result of an inflammatory disorder, of a neoplastic disorder, of an infectious disorder? It's critical to guide the patient and choose appropriate management options based on the cause of their syndrome. It would potentially harm the patient if you treated an infectious myelopathy with steroids or other immune-suppressant drugs. So, a similar principle holds in cognitive neurology. I accept with humility that we can never be 100% crystal clear certain about things in medicine, just because when you think you got it all figured out there's a curveball. But I want to get as close to that 100% as possible. And recognizing that disorders like LATE or PART can mimic the symptoms, sometimes even the imaging features of Alzheimer's disease. I think it's critical to have heightened awareness of those disorders, how they look, to be able to apply appropriate counseling and management options to patients. I think this becomes particularly critical as we move into an era of disease-specific, and sometimes disease-modifying, therapies, where applying a choice of a treatment option could have significant consequences to a patient if the thing you're treating isn't the thing that the drug is trying to accomplish. So, having awareness and spreading awareness about some of these non-AD causes of cognitive difficulty, I think, is a big mission in the field. 

Dr Nevel: Yeah, that makes total sense. And kind of leaning into this, you know, trying to differentiate between these different causes of late-life amnestic cognitive impairment. You know, I'll point out to the listeners today to please read your article, but in addition to reading your article, I'd like to note that there's a really nice table in your article, Table 6-1, where you kind of go through the different causes of amnestic cognitive impairment and the different features that better fit with diagnosis X, Y, or Z, because I think it's a really nice table to reference and really easy to look at and reference back to. But on that note, what is your typical approach when you're seeing a patient in clinic, have a new referral for an older patient presenting with a predominantly progressive amnestic-type features?

Dr Ramanan: Excellent question. And this is one that I think has relevance not just in a subspecialty memory clinic, but to all the clinicians who help to diagnose and manage cognitive disorders, including in primary care and general neurology and others. One principle that I think it's helpful to keep in our minds is that in cognitive neurology, no one data point takes precedence over all the others. We have a variety of information that we can gather from history, from exam, from imaging, from fluid biomarkers. And really the fun, the challenge, the reward is in piercing together that information. It's almost like being a lawyer and compiling the evidence, having possibilities on your list and raising and lowering those possibilities to get as close to the truth as you can. So, for patients with a cognitive syndrome, I think the first plank is in defining that syndrome. As you mentioned, if I'm seeing someone with a progressive amnestic-predominant syndrome, I first want to make sure, are we talking about the same thing, the patient, the care partner, and I?  Can often be helpful to ask them for some examples of what they see, because sometimes what patients may report as memory troubles may in fact reflect cognitive difficult in other parts of our mental functioning. For example, executive functioning or naming of objects. And so helpful to clarify that in the history to get a sense of the intensity and the pace of change over time, and then to pair that with a good general neurologic exam and some type of standardized assessment of their cognitive functioning. At the Mayo Clinic, where partial to the short test of mental status. There are other ways to accomplish that, such as with an MMSE or a MoCA. If I understand that the syndrome is a progressive amnestic disorder, Alzheimer's disease is the most common cause of that presentation in older adults, it deserves to be on my differential diagnosis. But there might be some other features in the story that could raise or lower those mimics on my list. So, in patients who are, say, older than the age of seventy five, disorders like LATE or PART start to rise higher on the likelihood for me, in particular if I know that their clinical course has been more slow brewing, gradually evolving. And again, most degenerative disorders we expect to evolve not over days or weeks, but over many months to many years. But in comparison with Alzheimer's disease, patients with LATE or with PART would be expected to have a little more slow change where maybe year over year they or their care partners really aren't noticing big declines. Their daily function is relatively spare. There might not be as much involvement into other non-memory cognitive domains. So, these are some of the pieces of the story that can help to perhaps isolate those other non-AD disorders on the list as being more likely and then integrating, as a next level, diagnostic testing, which helps you to rule in and rule out or support those different causes. So, for example, with LATE there can be often out of proportion to the clinical picture, out of proportion to what you see on the rest of their imaging or other profiles, very predominant hippocampal and medial temporal volume loss. And so that can be a clue in the right setting that you may not be dealing with Alzheimer's disease or pure Alzheimer's disease, but that this other entity is there. So, in the big picture, I would say being systematic, recognizing that multiple data points being put together helps you get to that confident cause or etiology of the syndrome. And in particular, taking a step back and thinking about big picture factors like age and course to help you order those elements of the differential, whether AD or otherwise.

Dr Nevel: Great, thanks. In your article, you talk about different imaging modalities that can be used, as you mentioned, you know, just another piece of the puzzle, if you will, to try and put together what may be going on with the patient, and recognizing that some of these imaging techniques are imaging is special imaging, not available in a lot of places.  You know, and maybe other diagnostic type tests that could be helpful in differentiating between these different disorders may not be available, you know, for the general neurologist practicing in the community. So, what do you suggest to the general neurologist maybe practicing somewhere where they don't have access to some of these ancillary tests that could assist with a diagnosis? 

Dr Ramanan: Critical question. And here I think there's not likely to be one single answer. As with most things, awareness and recognition is a good place to start. So, some of those clues that I mentioned earlier about the clinical course, about the age, the- we're talking about clinical setting there. So, comfort with and understanding that the clinical setting can help you to be more confident about, for example, LATE or PART being present in contrast to AD. That's important information. It deserves to be part of the discussion. It doesn't necessarily need other tests to have value on its own. A second piece is that tests help, in some cases, to rule in and rule out causes for cognitive difficulty. As part of a standard cognitive evaluation, we would all be interested in getting some blood tests to look for thyroid dysfunction or vitamin deficiencies. Some type of structural head imaging to rule out big strokes, tumors, bleeds. Head CT can accomplish some of that perspective. It's ideal if a brain MRI can be obtained, but again, keeping in mind, what's the primary goal of that assessment? It's to assess structure. Occasionally you can get even deeper clues into a syndrome from the MRI. For example, that very profound hippocampal or medial temporal atrophy. So, increasing awareness amongst clinicians throughout our communities to be able to recognize that change and put it in the context of what they see in other brain regions that can be affected by Alzheimer's or related disorders. For example, the parietal regions can be helpful. And recall that MRI can also be helpful in assessing for chronic cerebrovascular disease changes. This is another mimic that shows up in that table that you mentioned. And so multiple purposes can be satisfied by single tests. Now, you're absolutely right that there are additional test modalities that, perhaps in a subspecialty clinic at an academic medical center, we're very used to relying on and finding great value on; for example, glucose PET scans or sometimes fluid biomarkers from the blood or from the spinal fluid. And these are not always as widely available throughout our communities. Part of the challenge for all of us as a field is therefore to take the expertise that we have gathered in more subspecialty settings and tertiary care settings and translate and disseminate that out into our communities where we need to take care of patients. That's part of the challenge. The other challenge is in continued tool and technological development. There's a lot of optimism in our field that the availability of blood-based biomarkers relevant for Alzheimer's disease may play a part in helping to address some of the disparities in resource and access to care. You can imagine that doing a blood test to give you some high-quality information, there are going to be less barriers to doing that in many settings compared to thinking about a lumbar puncture or a PET scan, both in terms of cost to the patient as well as infrastructure to the clinicians and the care team. So I'm optimistic about a lot of those changes. In the meantime, I think there are, through both clinical evaluation and some basic testing including structural head imaging, there are clues that can help navigate these possibilities.

Dr Nevel: So, let's say you have your patient in clinic, you've done your evaluation, maybe gotten some ancillary testing, and you highly suspect either LATE or PART. How do you counsel those patients and their families? How do you manage those patients moving forward who you really suspect don't have, you know, some sort of co-pathology?

Dr Ramanan: So, it's- I think it's helpful to remember when patients are coming to see us, either they or the people around them have noticed an issue. And very likely it's an issue that's been brewing for a little while. I think it can be very valuable, very helpful for patients to have answers. What's the cause for the issue? Once you have answers, even if sometimes those answers are not the most welcome things or the things that you'd be looking forward to, answers give you an opportunity to grab hold of what's going on, to define a game plan. So, understanding there is a degenerative disease there, it sheds light on why that individual had had memory symptoms over the years. And it gives them a general expectation that over time on an individualized basis, but generally expecting gradually over many months to many years, there may be some worsening in some of those symptoms helps them to plan and helps them to make the adaptations that are a-ok and great to make to just help you to do the things you want to do. As much as I can, I try to put the focus here closer to how we would view things like high blood pressure or high cholesterol. Those are also chronic issues that tend to be more common as we get older, tend to get more troublesome as we get older. The goal is, know what you're dealing with and take the combination of lifestyle modifications, adaptations in your day-to-day and maybe medications to keep them as mild and as slow-changing as possible. With something like LATE, we don't have specific medication therapies to help support cognitive functioning at this time. There's a lot of hope that with additional research we will have those therapies. But even so, I think it's an important moment to emphasize some of those good healthy lifestyle habits. Staying mentally, socially and physically active, getting a good night's sleep, eating a healthy, balanced diet, keeping good control of vascular risk factors, all of that is critical to keeping the brain healthy, keeping the degenerative disease as mild and slow-brewing as possible. And understanding what some of the symptoms to expect could be. So, with LATE the syndrome tends to be very memory-predominant. There may be some trouble with maybe naming of objects or perhaps recall of emotionally salient historical knowledge, world events, but you're not expecting, at least over the short to medium term, huge intervening on other cognitive functioning. And so that can be helpful for patients to understand. So, the hope is once you know what what you're dealing with, you understand that the disease can look different from person to person. Having a general map of what to expect and what you can do to keep it in check, I think, is the goal.

Dr Nevel: I agree with you 100% that it really can be helpful even if we can't, quote unquote, fix it, that for people, family, the patient have a name for what they have and kind of have some sort of idea of what to expect in the future. And they may come in thinking that they have Alzheimer's or something like that. And then, so, to get that information that this is going to be a little different, we expect this to go a little bit differently then it would if you had a diagnosis of Alzheimer's, I can see how that would be really helpful for people. 

Dr Ramanan: I completely agree. And here's another challenge for us in the field when most patients have heard about Alzheimer's disease and many have perhaps even heard of dementia with Lewy bodies or frontotemporal dementia, but may not have heard of things like LATE. And they're not always easy to go online or find books that talk about these things. Having a name for it and being able to pair that with patient-friendly information is really critical. I see our appointments where we're sharing those diagnosis and making initial game plans as an initial foray into that process. 

Dr Nevel: Yeah, absolutely. What is the greatest inequity or disparity that you see in taking care of patients with progressive amnestic cognitive impairment?

Dr Ramanan: Yeah, great question. I think two big things come to mind. The first, you hinted at very well earlier that there are disparities in access to care, access to diagnostic testing, access to specialists and expertise throughout our communities. If we want diagnostics and therapeutics to be broadly applicable, they do need to be broadly available. And that's a big challenge for us as a field to work to address those disparities. There's not going to be one single cause or contributor to those iniquities, but as a field, I'm heartened to see thought and investment into trying to better address those. Another big weakness, and this is not just limited to cognitive neurology, it's a challenge throughout neurology, is that too many of our research studies are lacking in diversity. And that impacts our biological and pathophysiological understanding of these disorders. It also impacts our counseling and management. Again, if we want a new drug treatment to be broadly applicable throughout all of the patients that we take care of, we need to have data which guides how we apply those treatments. And so again, I'm heartened. This is a big challenge. It's a long standing challenge. It will take deep and long standing committed efforts to reverse. But I'm heartened that there are efforts in the field to broaden clinical trial enrollment, broaden observational research enrollment, and again, broaden access to tools and expertise. As a neurologist, I got into this field because I want to help people, use my expertise and my training to help people. These are steps that we can take to make sure that that help is broadly applicable throughout everybody in our communities.

Dr Nevel: Yeah, absolutely. So, kind of segueing from you mentioning research and how we can better include patients in research. What do you think the next breakthrough is going to be? What do you think the next big thing is going to be in these disorders? What do we still need to learn?

Dr Ramanan: There's a lot. I think for LATE and PART, the development of specific biomarkers would be top of the agenda. Now, biomarkers are by their nature imperfect. Even with Alzheimer's disease, where in comparison, we know quite a lot. We have a variety of imaging and fluid biomarkers that we can use to support or rule out a diagnosis. There are nuances in how you interpret those biomarkers. Patients can have signs of amyloid plaques in their brain and have completely normal cognition. They may be at risk for developing cognitive trouble due to Alzheimer's disease in the future, but it's one piece of the puzzle. Patients can have the changes of Alzheimer's disease amyloid plaques and tau tangles in the brain. We can confirm that through biomarkers. But at the end of the day, their cognitive syndrome might be driven by something else. Maybe it's Lewy body disease, maybe it's LATE, maybe it's a combination of factors. So, integrating and interpreting those biomarkers is challenging. But I do think, again, from the standpoint of giving patients answers with a diagnosis, having those biomarkers is really critical to just kind of closing the loop. It will also be critical to have those biomarkers as we're assessing for treatment response. So, for example, patients who may have coexistent Alzheimer's disease and LATE, I don't think we know the answer fully as to how likely they are to benefit from, say, newer antiamyloid monoclonal antibodies for Alzheimer's disease in the setting of that second pathology. So, wouldn't it be great if, similar to an oncologic setting where you engage in a treatment and then you're tracking two or three or four plasma measures and you're tracking tumor size with imaging, if we had this multimodal ability to track neurodegenerative pathology through biomarkers? I think that'll be a critical next step. And so, filling out that for non-Alzheimer's diseases, including LATE and PART, I think is item number one on the agenda.

Dr Nevel: Wonderful, thank you so much. I really appreciate you taking the time to chat with me today about your article. I really enjoyed our conversation, certainly learned a lot.

Dr Ramanan: Thank you so much, Kait. Love talking with you. And again, it was an honor to write this article. I hope it's helpful to many out in the field who take care of patients with cognitive issues. 

Dr Nevel: Yeah, I think it will be. So again, today I'm interviewing Dr Vijay Ramanan about his article that he wrote with Dr Jonathan Graff-Radford on LATE hippocampal sclerosis and primary age-related tauopathy, which appears in the most recent issue of Continuum on dementia. Be sure to check out Continuum audio episodes from this and other issues. And thank you, Vijay, and thank you to our listeners for joining us today.

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