Episodes
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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
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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
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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 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.
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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.
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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
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: @gordonsmithMD
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.
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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.
Additional Resources
Read the article: NMOSD and MOGAD
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More about the American Academy of Neurology: aan.com
Social Media
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@ContinuumAAN
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.
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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
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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 professor of neurology at the University of California San Francisco, Department of Neurology and a neurohospitalist, general neurologist, and a clinician educator at the San Francisco VA Medical Center and San Francisco General Hospital in San Francisco, California.
Dr. Pittock is the director for the Center for Multiple Sclerosis and Autoimmune Neurology at Mayo Clinic in Rochester, Minnesota.
Additional Resources
Read the article: Overview and Diagnostic Approach in Autoimmune Neurology
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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
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.
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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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More about the American Academy of Neurology: aan.com
Social Media
facebook.com/continuumcme
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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.
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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
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: @SMuehlschMD
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 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.
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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
Subscribe to Continuum: shop.lww.com/Continuum
Earn CME (available only to AAN members): continpub.com/AudioCME
Continuum® Aloud (verbatim audio-book style recordings of articles available only to Continuum® subscribers): continpub.com/Aloud
More about the American Academy of Neurology: aan.com
Social Media
facebook.com/continuumcme
@ContinuumAAN
Host: @gordonsmithMD
Guest: @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.
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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 professor of neurology at the University of California San Francisco, Department of Neurology and a neurohospitalist, general neurologist, and a clinician educator at the San Francisco VA Medical Center and San Francisco General Hospital in San Francisco, California.
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.
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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, 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.
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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
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Social Media
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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.
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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
Subscribe to Continuum: shop.lww.com/Continuum
Earn CME (available only to AAN members): continpub.com/AudioCME
Continuum® Aloud (verbatim audio-book style recordings of articles available only to Continuum® subscribers): continpub.com/Aloud
More about the American Academy of Neurology: aan.com
Social Media
facebook.com/continuumcme
@ContinuumAAN
Host: @IUneurodocmom
Guest: @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.
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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.
Additional Resources
Read the article: Neurocritical Care for Patients With Ischemic Stroke
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Transcript
Full transcript available
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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 professor of neurology at the University of California San Francisco, Department of Neurology and a neurohospitalist, general neurologist, and a clinician educator at the San Francisco VA Medical Center and San Francisco General Hospital in San Francisco, California.
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
Continuum® Aloud (verbatim audio-book style recordings of articles available only to Continuum® subscribers): continpub.com/Aloud
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Social Media
facebook.com/continuumcme
@ContinuumAAN
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.
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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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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.
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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
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Continuum® Aloud (verbatim audio-book style recordings of articles available only to Continuum® subscribers): continpub.com/Aloud
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Host: @gordonsmithMD
Guest: @petergoadsbyTranscript
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.
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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
facebook.com/continuumcme
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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.
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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
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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.
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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 professor of neurology at the University of California San Francisco, Department of Neurology and a neurohospitalist, general neurologist, and a clinician educator at the San Francisco VA Medical Center and San Francisco General Hospital in San Francisco, California.
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.
Additional Resources
Read the article: New Daily Persistent Headache
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Host: @https://twitter.com/AaronLBerkowitz
Guest: @ @mrobbinsmd
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 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.
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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 professor of neurology at the University of California San Francisco, Department of Neurology and a neurohospitalist, general neurologist, and a clinician educator at the San Francisco VA Medical Center and San Francisco General Hospital in San Francisco, California.
Dr. Schwedt is a professor of neurology at Mayo Clinic in Phoenix, Arizona.
Additional Resources
Read the article: Posttraumatic Headache
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Social Media
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@ContinuumAAN
Host: @AaronLBerkowitz
Guest: @schwedtt
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 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.
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