Neurologic Manifestations of Rheumatologic Disorders With Dr. Jennifer McCombe

18 Sep · Continuum Audio

00:25:14

Basic knowledge of the common CNS manifestations of rheumatologic diseases and sarcoidosis is important. In the context of many systemic inflammatory diseases, CNS disease may be a presenting feature or occur without systemic manifestations of the disease, making familiarity with these diseases even more important.

In this episode, Kait Nevel, MD speaks with Jennifer A. McCombe, MD, author of the article “Neurologic Manifestations of Rheumatologic Disorders,” in the Continuum® August 2024 Autoimmune Neurology issue.

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

Dr. McCombe is an associate professor in the Division of Neurology, Department of Medicine at the University of Alberta, Edmonton in Alberta, Canada.

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Transcript

Full episode transcript available here

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

Dr Nevel: Hello. This is Dr Kait Nevel. Today, I'm interviewing Dr Jennifer McCombe about her article on neurosarcoidosis and neurologic involvement of rheumatological disorders, which appears in the August 2024 Continuum issue on autoimmune neurology. Welcome to the podcast, and I would love to have you introduce yourself to the audience.

Dr McCombe: Well, thank you, and thank you for having me. As you said, my name is Jen McCombe. I'm a neurologist in Edmonton, Alberta, Canada, where I spend kind of a third of my time in teaching roles (I coordinate the undergraduate block for our medical school there), I spend about a third of my time in a neuroinflammatory clinic in Edmonton, Alberta, and then about a third of my time doing clinical research.

Dr Nevel: Wonderful. Well, thank you so much for being here today and for chatting with me about your article on this topic.

Dr McCombe: Thank you for having me.

Dr Nevel: To start off, can you share with the listeners a little bit about your career path?

Dr McCombe: Absolutely. Yeah. So, I've had, uh, a bit of a circuitous career path. I did my medical school in Queens (which is in Eastern Canada, in Kingston, Ontario) and then went back to Edmonton, Alberta, for my residency (in Canada, we have a five-year residency program, so a little bit different than the US), but finished my residency and then did a master's degree in Public Health at Johns Hopkins while completing clinical research in HIV, actually, and did this thing we call the Clinical Scholar Training Program – so, kind of like a fellowship, but a little bit more, you know, research and academic-based. So, when I first started, I was focused more on neuroinfectious diseases, and that's kind of what my career path looked like at the time - but, actually, shortly after I finished my residency program, I also had my first child, and he, unfortunately, developed opsoclonus-myoclonus syndrome, and at the time (this was in 2010), it was a rather rare condition, so, I ended up finding myself having to become a bit of a neuroinflammatory disease specialist at the same time. So, at that point, I transitioned into working in the neuroinflammatory clinic with some mentorship but was getting all of the kind of weird and wonderful referrals and diagnostic dilemmas from my colleagues who recognized I kind of developed some expertise, and so decided (actually, mid-career) to take a sabbatical, and in 2021, completed a fellowship in autoimmune neurology at the Mayo Clinic. So, I finished that quite recently and then went back, and now I'm feeling much more, I guess, confident, too. Sometimes, you wonder about, you know, the choices you're making. I recognize most of the conditions I'm dealing with don't have, in fact, any evidence for their treatment, and that was confirmed when I went to the Mayo Clinic and found that, really, it was just trying to gain an understanding of the disease process to make a rational choice to medications and treatments. So, now, I'm back and kind of trying to focus a little bit more on some clinical research in that area since I've kind of solidified that expertise.

Dr Nevel: Wow. Well, thank you for sharing with us your career path and how, you know, unexpected life events kind of changed your interests or molded your interests (changed kind of the things that you became expert in, you know), and being fluid in your career path and willing to kind of take a break and reassess and get additional training. That's really inspiring to, I think, to me, and probably to a lot of listeners, that you can always, you know, develop more expertise in the more niche area or additional area no matter where you are in your stage of life or career path.

Dr McCombe: Yeah.

Dr Nevel: So, can you tell us a little bit more about - you know, you shared with us kind of autoimmune inflammatory disorders and how you became interested in that, neurosarcoidosis, specifically (you know the article focuses on that), and what's your background in neurosarcoidosis, how you became interested in that specifically and in neurologic manifestations of rheumatologic disorders?

Dr McCombe: I started in our neuroinflammatory clinic over a decade ago, and, you know, at the time, a lot of the expertise in any of these neuroinflammatory disorders was quite spread out over the country, and so, as I kind to alluded to before, often some of the more complicated patients where there wasn't necessarily clear-cut evidence or even, you know, a fellowship path to get there, I would end up getting referrals for - and so, I developed quite a cohort of patients with central nervous system primarily, but other types of neuroinflammatory and autoimmune neurologic diseases, and part of that cohort was a rather large (and still growing) group of patients with neurosarcoidosis. And so, I kind of developed some practical expertise, although, as you can see in the article (and as I'm sure you all know), the approach to the treatment is extremely variable. One of the most telling things is when we were at the Mayo Clinic, one of my co-fellows actually pulled all of the neurologists in neuroinflammation at all of the Mayo Clinic sites and asked them, you know, what is your treatment approach to a patient with neurosarcoidosis, and I think got twelve completely different responses as to the medications chosen and the length of time for the tapers and things like that. So, you know, it is very much a part of neurologic disease treatment that we still really don't have great evidence for, and although we do have some kind of rational choices that we can make based on other types of evidence, so -

Dr Nevel: Yeah.

Dr McCombe: And I enjoy working with patients with these types of diseases where we can kind of work together to come up with a treatment plan that makes sense for them and also makes sense based on whatever evidence we do have at this time.

Dr Nevel: Yeah. So, moving on to the article a little bit, knowing that this is a area of neurology where there's a lot of, you know, maybe personal expertise and experience but not a ton of data or evidence to necessarily guide our standardization to our treatments and approach, what do you think is the most important clinical takeaway from your article for our listeners?

Dr McCombe: Well, I mentioned before I coordinate the neuro block for our undergraduate program here, so I've developed over the years (I've been doing that for a number of years) a curriculum that's all based on, kind of, that approach to - and I like to do it that way because it's very practical. I like the students to be able to basically take their class notes and then go to the emergency department on their first shift as a clerk and, you know, use their approach to headache that I've developed for them to kind of take a clinical history and examine a patient with that sort of problem. And so, similar to that, I tried to do an approach to, you know, a couple of the more common presentations that would make you think of a rheumatologic condition or neurosarcoidosis in looking at the approach to CNS vasculitis and the approach to, uh, pachymeningitis - and these are difficult differentials for lots of neurologists, because it really relies on a lot of medicine knowledge, and we graduate from our residencies slightly more confident in our medicine knowledge, because we get a lot of that in our residencies. But as neurologists, as we go through our careers, we get much more confident in our areas of specialty, and at least for myself and many of my colleagues, much less confident in other things like general medicine. And so, it's difficult, because you have to face your areas of potentially less confident knowledge and really think about that in the differential - and so, I think, you know, I put those two big “approach to” sections in there, because they're the most relevant for the conditions that I was covering. But, I think also what I would say to a learner or a more experienced neurologist who might be reading the article, kind of pick out the little things that you might add to your own kind of approach to - you know, when you see that person with an ataxia, remember that Sjogren syndrome is one of the things you might consider that could be a treatable cause, or you want to see a sensory neuronopathy, don't just think paraneoplastic – again, Sjogren syndrome. So, kind of pick out those little pearls and add them to your approach to that patient that we all see, and I think that would be my biggest takeaway.

Dr Nevel: Yeah. Thank you. So, kind of like, keep this information from the article in mind so that you keep rheumatologic disorders in mind as a possibility when you're approaching a patient with whatever neurologic symptoms they're presenting with. So, what do you think is challenging? You kind of already mentioned a little bit, you know, just that it stretches us maybe into the medicine arena and so maybe stretches our medical knowledge, especially as we become more subspecialized or focused in neurology - but what is challenging about identifying, diagnosing neurologic symptoms as being related or due to an underlying rheumatologic disorder?

Dr McCombe: Absolutely. Yeah. Well, as you said, you know, it forces us to kind of face that medicine stuff that we might not be as comfortable with, but I think what else is challenging is that, sometimes, those medical clues aren't there. For the rheumatologic disorders for the most part, they are. Sjogren’s is potentially a little bit different in that, potentially, the symptoms are less obvious or a little bit more subtle. But, in particular, with neurosarcoidosis, there's a distinct proportion of the patients that won't, in fact, have any systemic complications of their underlying disease, and so, you have to think about it even when the clues aren't there. That's why you have to add it to those kind of differential diagnoses where it might be considered, because those systemic clues that we all rely on when we do our review of systems and we ask about rashes and joint pain and lung issues, and these sorts of things may not be there - and so, you still have to think about it even when it might be completely isolated to the central nervous system.

Dr Nevel: What is our understanding of why some patients with rheumatologic disorders develop neurologic involvement? Do we have an understanding? Do we know why some patients do and some patients don't? I know that's, you know, kind of, uh - that's a tough question, but that was something that I thought of as I was reading your article, like, why does this happen to some people?

Dr McCombe: Absolutely. I mean, I think, potentially, it's a little bit more clear for some of them, like rheumatoid arthritis, because, typically, if you develop a CNS complication of this, it's, in fact, just because you've had the disease for a very long time, and often, it's uncontrolled, and so you think about the disease “spreading” now to the central nervous system - but for other conditions, like neurosarcoidosis, it is much less clear, and even if you look at the epidemiologic patterns for that, it makes it even more muddied in that in some populations, it appears that they develop more central nervous system disease, whereas in others, less. And so, why that is the case and why certain individuals might develop this complication of these diseases I think is yet to be seen.

Dr Nevel: Yeah, that's always the crux of things if we can figure out the why, then maybe we could prevent it, right?

Dr McCombe: Million-dollar question always.

Dr Nevel: Always. So, what do you find the most intriguing about neurologic involvement of rheumatologic disorders?

Dr McCombe: Well, I think one of the things that, really, I mean, for neurosarcoidosis in particular, so many patients do so well, and that's what I really like about it. You know, you see patients who present with an incredible burden of disease radiologically, and yet, don't look nearly as sick as they should when they're sitting in front of you. And then, you start them on therapies and some of them do so well, and even those with relatively devastating deficits, or moderate disease who do have neurologic symptoms, have a remarkable improvement in their neurologic symptoms with treatment. And so, that's always something that's quite rewarding when you get to see these patients in follow-up, and they're generally quite thankful because they're doing so well. And it's different from many of the neurologic diseases that we treat. I mean, in autoimmune neurology, we're lucky because we do have a number of diseases that are quite treatable and patients can have wonderful outcomes. But, you know, it's always scary when we see patients with devastating neurologic signs and it's great to see improvement with treatment. And so, that really draws me to it.

Dr Nevel: Yeah, absolutely. That's really rewarding when you're able to help somebody get better in such a profound way.

Dr McCombe: Mm hmm.

Dr Nevel: What is one common misconception about neurologic manifestations of rheumatologic disorders? Or what do you think is not well understood by treating clinicians?

Dr McCombe: I think probably one of the things I see the most is, sometimes, an undertreatment of the patient. And so, I see patients who, you know, other clinicians may have seen and have made the diagnosis, and perhaps it's a lack of confidence in the diagnosis and so they kind of want somebody else with a subspecialty to kind of confirm the diagnosis, but that treatment hasn't been initiated despite pathological confirmation on biopsy of another tissue. And these patients, like I alluded to before, they do well, but you need to treat them and you need to treat them adequately, and when their symptoms are quite impairing, you need to treat them adequately now. And so I think, sometimes, that delay in starting a second-line therapy and relying on steroids for too long - those sorts of things can really expose a patient to a lot of different side effects and to a lot of different complications that they may not have had, too. So, that's why I spent some time focusing on the treatment, because I think just gaining a little bit of comfort with some of these more common second-line medications is a good thing, because starting those early, I think, makes sense because you can really save the patient a lot. And then, the other thing, too, is that when you're using steroids, think about all of the systemic things that you're causing - think about the increased risk of infection and the fact that you need to prophylax for certain infections, think about bone health, think about protecting the lining of someone's stomach - so not only kind of thinking about your disease in isolation and what you need to do for treatment, but that you need to ensure that you're appropriately prescribing the patient all of the things they need to do to protect themselves during these times.

Dr Nevel: Yeah. I think that's so important. And I'm glad that you brought that up, because I think, unfortunately, many of us have seen a patient who ended up having PJP pneumonia (or something like that) because they weren't put on antibiotic coverage for prolonged steroid use or, you know, bone health - all of that is really important to think about. So, this may be entering a territory where there's no, you know, great evidence, but you mentioned, you know, starting kind of that maintenance or second-line agent - when do you decide to do that in patients? And maybe we can focus (since it gets a little broad), but, you know, in a patient with neurosarcoidosis, let's say - when you're starting the steroids, when do you decide, okay, this person is also going to need a maintenance therapy? Is that something that you do at the beginning when you're starting the steroids, or is that something that you think about later on depending on how their course goes?

Dr McCombe: Yeah. In my practice, I do it at the outset - again, because I'm quite focused on, you know, as soon as I get them on it, getting people off steroids - and so I start essentially almost all of my patients on it unless there's some other contraindication or complication to their disease. And because I deal with central nervous system complications in the vast majority of my patients, I'm starting a TNF-a inhibitor as well as methotrexate, and that's because I see a lot of patients with cord disease and significant brain disease, and so I want to treat them kind of more aggressively from the outset. And so, typically, they'll be on steroids, um, a TNF-a inhibitor, as well as methotrexate, and then I just back off, actually, as they do well. And so, I try to taper the steroids quite quickly over the course of just a number of weeks, or kind of two to three months at most. I maintain the TNF-a inhibitor, and then in some patients, depending on how they're doing, I might eventually stop the methotrexate. Some patients tolerate it so well that we don't for a number of months - other patients want to try to minimize their medications as quick as they can. So, that's my personal practice. In the province where I live, we don't have to worry about access to these medications, and so I understand that that might be an issue in some centers where people practice and have different access and different funding. Of course, I live in a country where we have universal healthcare, and in our province, I have very good access to these medications and they're funded from my patients regardless of socioeconomic status, and so I have the luxury of making these choices and I understand that other people might not, but that's my personal practice and I find it works quite well in the vast majority of patients.

Dr Nevel: Yeah. And you bring up a really good point that, you know, access to some of these medications for patients with CNS manifestations of sarcoidosis, neurosarcoidosis, sometimes can be challenging to treating the patient with medications that you feel like would be best for them. But that's wonderful that you don't have those access issues where you live. How long do you typically continue the TNF-a inhibitor in patients, since you mentioned, you know, tapering off the steroids, tapering off the methotrexate, potentially depending on patient tolerance and course. What's your approach to the TNF-a inhibitor?

Dr McCombe: Yeah, so, of course I follow them clinically, and then radiologically as well, and it's really satisfying if you can see the resolution of their symptoms as well as resolution of the abnormalities and the MRI, so I let that guide me a little bit. But, in most patients, I keep them on therapy for about one to two years, and then at that point, see if I can cease it in some patients. And I, again, continue to follow them radiologically and clinically after I cease it so that I can ensure that I'm catching their disease more quickly if it does come back and then can just reinitiate therapy, but in lots of patients you're able to stop the medication and they have persisting, kind of, disease freedom after that, and so they don't need to be on anything.

Dr Nevel: Yeah, great. And I'm almost hesitant to focus so much on neurosarcoidosis. (It was the rheumatologic manifestation that you talked about the most in your article.) I'm going to put in a plug for everybody to read your article so that they can read about neurologic manifestations of rheumatoid arthritis, Sjogren’s, lupus, Behcet’s - many more things. But focusing on neurosarcoidosis, it can be difficult in my experience to definitively diagnose, and people who have neurosarcoidosis particularly, and people who don't seem to have any systemic manifestations or, you know, imaging findings consistent with sarcoidosis - can you share your approach with us? And you outlined this in your article nicely, too, but your personal approach to patients with suspected neurosarcoidosis, and how you make that clinical decision to treat somebody with possible neurosarcoidosis, somebody who maybe you're not able to get pathologic evidence on?

Dr McCombe: Absolutely. Yeah, those ones are difficult. And, you know, whenever possible (as I mentioned in my article), I think pathological evidence of a diagnosis is important, because then when you find yourself a year down the road and a treatment path and you have uncertainty, it's much more difficult to consider continuing medications that can have quite a number of side effects when you're not absolutely certain about that diagnosis. But, in some patients, you know, I've had patients who might have nondiagnostic biopsies (if you attempt to do a biopsy), or they have disease in a site that really just isn't amenable to biopsy, or they have some other reason they can't have a biopsy. So, how I approach that is that, you know, if you think about possible neurosarcoidosis similar to any other nondiagnosed, you know, blow out-like lesion (for lack of a better term) in the CNS, if it's steroid-responsive, I think that kind of going down a path of treating it as a steroid-responsive lesion is kind of the approach that I take - so the diagnosis in the chart might be possible neurosarcoidosis, but in the back of my mind, I'm just thinking of kind of a steroid-responsive nondiagnostic or idiopathic lesion. So, I then follow that up typically with something like methotrexate (so, a more broader- spectrum immunosuppressant-type medication), and if the methotrexate is able to maintain the response that the steroids initiated, then eventually get them off the steroids. And so, you know, if I think about my patients that I've treated in the past, if they have a diagnosis of possible neurosarcoidosis, I probably don't start a TNF-a inhibitor as quickly in them, because in the back of my mind, I'm always wondering what type of inflammatory lesion this is, but that steroid responsiveness really helps me decide to start a second-line or maintenance therapy and then, typically, in those patients, as I mentioned, I'll start something like methotrexate a little bit more soon.

Dr Nevel: Yeah, great. Thanks for sharing that with us. So, what do you think comes next in this field? What excites you? Where do you think our next kind of development or understanding or breakthrough, whether it's diagnostic or treatment-wise?

Dr McCombe: I think, in the field, you know, any immunologic diseases, we've been really gaining a much better understanding of pathophysiology, and that's honestly what excites me the most, when you can know precisely what part of the immune system is at play here (whether it's, you know, complement-mediated or antibody-mediated) and then being able to then rationally choose medications based on a really clear understanding of the disease is something that I think is kind of novel in a way. For so many years, we would use kind of big broad-spectrum immunosuppression - even in multiple sclerosis, still, we use medications that, historically, we've found to be helpful - but we don't have a great understanding sometimes of why the medicines work. So, kind of going at it from the other way, where we're actually determining what is the exact pathophysiology of disease and then making a rational approach to a therapy, or choosing a therapy based on that, I think is what excites me the most, and I think we'll gain a better understanding of even a broader swath of diseases and be able to make those choices more often. That's what I like about this field.

Dr Nevel: Great. Well, thank you so much for sharing that - and looking forward to the future in this area of neurology. And thanks so much for talking with me today and sharing your story and your expertise and knowledge.

Dr McCombe: Well, thank you for having me. It's been fun.

Dr Nevel: And I encourage all the listeners to read your article. Again, today, I've been interviewing Dr Jennifer McCombe, whose article on neurosarcoidosis and neurologic involvement of rheumatologic disorders appears in the most recent issue of Continuum on autoimmune neurology. Be sure to check out Continuum Audio episodes from this and other issues, and thank you to our listeners for joining today.

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

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Episodes

December 2024 Dementia Issue With Dr. Lisa Silbert
27 Nov· Continuum Audio
In this episode, Lyell K. Jones Jr, MD, FAAN, speaks with Lisa C. Silbert, MD, MCR, FAAN, who served as a guest editor of the Continuum® December 2024 Dementia issue. They provide a preview of the issue, which publishes on December 2, 2024.

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

Dr. Silbert is co-director at Oregon Alzheimer's Disease Research Center, a Gibbs Family Endowed professor of neurology, a professor of neurology at Oregon Health & Science University, a staff neurologist, director of Cognitive Care Clinic, and director of the Geriatric Neurology Fellowship Program at Portland Veterans Affairs Health Care System in Portland, Oregon.

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Continuum website: ContinuumJournal.com

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Host: @LyellJ

Full episode transcript available here

Dr Jones: This is Dr Lyell Jones, Editor-in-Chief of Continuum, the premier topic-based neurology, clinical review and CME journal from the American Academy of Neurology.

Thank you for joining us on Continuum Audio, a companion podcast to the journal.

Continuum Audio features conversations with the guest editors and authors of Continuum who are the leading experts in their fields. Subscribers to the Continuum Journal have access to exclusive audio content not featured on the podcast. If you're not already a subscriber, we encourage you to become one. For more information, please visit the link in the show notes.

Dr Jones: This is Dr Lyell Jones, Editor-in-Chief of Continuum: Lifelong Learning in Neurology. Today I'm interviewing Dr Lisa Silbert, who recently served as Continuum's co-guest editor for our latest issue on dementia alongside Dr Lianna Apostolova. Dr Silbert is a professor in the Department of Neurology at Oregon Health and Science University of the School of Medicine in Portland, Oregon, where she's also the director of the Neuroimaging Core and now the co-director of the Alzheimer's Disease Research Center. She also serves as director of the dementia clinic at the VA Portland Healthcare System. Which, Dr Silbert, sounds like a lot of work? Anyway, welcome. I really appreciate you taking the time to join us today and co-guest editing this issue. Why don't you introduce yourself a little bit to our listeners?

Dr Silbert: Well, thank you so much for interviewing with me today and for inviting me to be the guest, co-guest editor of this issue. It's a really exciting time for dementia care and dementia research. As you already said, my name is Lisa Silbert. I'm in Oregon Health and Science University in Portland, Oregon. I've been involved in caring for dementia patients and their families for over twenty years now and been involved in a lot of really exciting research during that time. But I would say now is probably the most dynamic time in dementia research and care that I've seen. So, it's really, really exciting to be here.

Dr Jones: It really is an interesting time. So, I look back in our last issue of Continuum focusing on dementia came out in 2022, which doesn't sound like that long ago, but a lot has changed, right? With the anti-amyloid monoclonals for Alzheimer's disease, new biomarkers and so on. And as the guest editor, you have this unique view, Dr Silbert, of the issue and the whole topic of dementia. As you were reading these really outstanding articles, what was the biggest “aha” moment for you or the biggest change in practice that you saw that's come up over the last couple of years?

Dr Silbert: I think, you know, in reading through the different manuscripts or chapters in this issue, it really struck home the advances that have been made throughout all the different areas of dementia. Not just- so, we hear a lot about Alzheimer's biomarkers and Alzheimer's treatments on the horizon, which is really exciting, but this is happening across other dementias as well. There's biomarkers on the horizon for a Lewy body disease and potentially for some of the frontaotemporal dementias. And so that to me really struck home as this is really, across the board, a change in the entire field that we're looking at.

Dr Jones: That is exciting. And I'd like to come back to some of those biomarker developments because I think that's an area where we've really been lacking in neurology as a specific way to diagnose those disorders. I think a topic which you just alluded to that a lot of our listeners and readers are thinking about are those antiamyloid monoclonal therapies for Alzheimer's disease. So, addicanumab, lecanumab and most recently the approval of donanemab. For these drugs specifically, how are you using them in your practice and how should our listeners be thinking about these drugs?

Dr Silbert: These are, you know, relatively new, really exciting new and emerging therapies for Alzheimer's disease. They are shown to remove amyloid from the brain. Patients who have clinical manifestations of Alzheimer's disease, and that is those in the stages of mild cognitive impairment or mild dementia. We are using lecanemab at Oregon Health and Science University through our therapeutics and clinical units. It's a really exciting time and it's a time where we have to be, also, cautious about who undergoes these therapies. So being really informed about the use, who's appropriate to undergo these therapies, what kind of safety tests need to be undergone, how do you assess risk in individual patients so that you can counsel them. So, all of these factors need to be weighed in when you're making a decision about whether or not to treat a patient with a monoclonal antibody therapy. And specifically, we do neuroimaging to assess whether there are already the presence of microhemorrhages in the brain. We do genetic testing to look for APOE 4 genotypes that can increase the risk of Aria, which is amyloid-related imaging abnormalities. And all of these factors go into how we counsel patients and discuss whether or not to pursue treatment with monoclonal antibodies.

Dr Jones: So certainly a complex patient selection process and drug administration and monitoring of therapy for those patients. And that- it brings to mind for me how we already have too few neurologists in the US. And now for a really prevalent disorder, Alzheimer's disease, we're making it a lot more complicated to deliver these new disease-modifying therapies. What do you think or what do you see as the role of the neurologists in caring for patients with dementia? And do these developments change that role?

Dr Silbert: For now, I think these developments make it even more important in a way that neurologists are involved in making a very specific clinical diagnosis of which dementia is playing a factor in the patient 's clinical presentation. I think one thing to note is with these emerging biomarkers, a lot of them can be positive before there are clinical symptoms and multiple etiologies are also very prevalent. And so just having one positive biomarker, it doesn't necessarily tell you what's going on with an individual patient. You need to take the whole picture into consideration. So, I think a really detailed evaluation by the neurologist, especially with these emerging therapies that have potential risks, is extremely important right now. Just getting a test is really not sufficient. You really have to take the entire clinical picture into account and know the ins and outs of the risks involved in these disease-modifying therapies.

Dr Jones: Which brings us back to something you mentioned earlier, right? Which is good news. We have on the horizon new potential biomarkers for other neurodegenerative causes of dementia. I can foresee and maybe I'm, you know, being an alarmist here, Dr Silbert, but if we have sensitive biomarkers for other neurodegenerative conditions, we know patients often have copathologies. Is that going to help clarify things? Is it going to confuse us? How is that going to work?

Dr Silbert: Well, I think ultimately, it's going to help clarify things. Because there are multiple pathologies that are common in age related cognitive impairment, any kind of additional specific input that we can get with different biomarkers is going to be helpful in putting the pieces together to come up with what's happening clinically with each individual patient. Ultimately, I think these biomarkers, they're not- any one biomarker isn't going to be a solution to diagnosis, but putting them together to help improve early and accurate diagnosis is really the goal here. Having a very early diagnosis, having a very accurate diagnosis will improve our ability to give prognosis and also improve effective treatment strategies moving forward. I think that these biomarkers have the promise in facilitating that for us.

Dr Jones: And progress is always a good thing. We just have to learn how to adapt and use the evidence appropriately. There have been and I think most of our listeners will be familiar with some of the controversies related to these, these new disease-modifying drugs for Alzheimer's disease. Do you want to walk us through a couple of those, and what are your thoughts about those controversies?

Dr Silbert: Yeah, these new therapies, they're very exciting for everyone in the field, but they, like you mentioned, they're not without their controversies. I think one controversy or one potential downside to these therapies is access to them. Like you already mentioned there, there's really not enough neurologists out there. There's not enough behavioral neurologists out there. There's limitations to infusion centers, sites and prescribers. Access to these therapies is is significantly limited. They are requiring infusions quite frequently. So, if you're not living near specialty care, you're not really able to feasibly undergo these kinds of treatments. Another controversy is the fact that the treatment effects are considered by some to be fairly modest when looking at the clinical data and in association with that, there are risks involved. Like I already mentioned, there's the amyloid-related imaging abnormalities, which sounds kind of like a benign thing, but they really consist of microhemorrhages that can lead to bigger hemorrhages and edema in the brain. These risks are relatively small - they are seeing more commonly in those who have a specific genotype, an APOE E 4 genotype - but they're risks nonetheless.

And so, there's controversy about the risk-benefit ratio and access to care with these new therapies.

Dr Jones: It's very exciting, but we should be cautious, right? I recall a few years ago as a program director, a neurology residency program director, interest in different areas of neurology would often follow developments in those areas, right? Lots of interest in autoimmune neurology when those developments would proceed in neuro oncology, etc. And I wonder if the therapeutic advances in in behavioral neurology and neurodegenerative cognitive disorders, I wonder if that's going to stimulate interest among our trainees to pursue behavioral neurology? Do you have a view on that or have you seen much change in interest in in this field?

Dr Silbert: You know, we are seeing a lot more interest in our trainees. The residents are very interested in these new therapies and how to apply them. And I'm really excited about that.

I'm hopeful that this will stimulate interest in the field. And we need those specialists, we need those sub specialists to undergo fellowship training in behavioral neurology and geriatric neurology so that we have more access to the subspecialty care and delivering these new therapies. So, I agree with you, I'm hopeful about it and I am seeing new interest in our trainees about these new therapies.

Dr Jones: We can hope so. And all the other fellowship directors will be anxious if neurology residents start leaving to go into behavioral neurology. But there’s certainly demand. And I know that under the best of circumstances, dementia is so common. It's something that we have to care for in partnership with primary care and community resources. And these disease-modifying therapies capture a lot of attention, but it's really a small part of the continuum of care of these patients. And Dr Silbert as an expert, you know, if we put that disease-modifying therapy to the side for a second and just said, well, what are the biggest gaps in the care for patients with dementia? What do you see as those biggest gaps and, and what can we do to fix them at not just a neurology level, but at a societal level?

Dr Silbert: That's a big question. And you know, what I see almost every day are gaps in the support mechanisms for families who are caring for patients with dementia. These caregivers are under a lot of stress and oftentimes they just don't have the resources to take care of somebody who at some point will often need twenty-four hour care and supervision. Caregivers are older, usually of older age themselves and have their medical issues as well. And then we're just not doing a good job as a nation in in supporting patients and their families with like supportive care and respite care that's really needed. So, you know, I'm not just seeing and treating patients with dementia, but I'm seeing and I'm really trying to support and care for those who are taking care of patients with dementia. To me, that's the biggest gap in our system.

Dr Jones: Yeah. And as I look through this issue of Continuum, we touched on not only the conventional topics in dementia and behavioral neurology. I'm really happy in hindsight that we have invited some discussion of the psychiatric symptoms in dementia, which I think are really important and often underrecognized and maybe undermanaged or mismanaged, and really also focusing on the caregiver burden and support services. We do have an article dedicated to that as well, and I think that'll be useful to our readers and listeners when we when we publish those podcasts. We we've heard this year especially a lot of public conversation about cognitive impairment and dementia. I sometimes wonder if that public attention is helpful and constructive for the population of patients with dementia. Sometimes I wonder if that conversation is counterproductive. What's your take on that?

Dr Silbert: You know, I think it's- it can be a mixed bag, but ultimately, it's in the conversation. We're talking about it. And I think that's only a good thing. There's more public awareness of it.

There is more interest in therapies. So, I think at the end of the day, talking about it, making it more prevalent in the ether, it stimulates the conversation and discussion. And even if there's controversies about it, we're talking about it. And I think that's kind of the first step in acknowledging that we need more support, we need more therapies.

Dr Jones: Yeah, I agree. And I think often patients with neurologic disorders and their caregivers and families often appreciate being seen.

Dr Silbert: Yeah, no, absolutely true. So, I'd say in regards to the monoclonal antibody treatments, you know, despite the controversies with these new treatments, I think there's a real promise and a real hope and a real excitement across a lot of behavioral neurologists, including myself, that this is just the beginning. That even if these first line, first generation therapies maybe have downsides, that there'll be second generation and third generation variations on these kinds of treatments that are going to be more accessible, have less side effects and hopefully be more clinically effective. And, and down the line, the other real hope for the field is that these maybe second generation therapies will actually delay the onset or prevent clinical manifestation of the disease. And that's the real goal here.

Dr Jones: And that's a great segue to the to the next thing I wanted to ask you about and you, you may have already answered the question. We talked about how we have and will have new biomarkers which will help us with diagnosis. We have hopefully the first phase in increasingly effective disease modifying therapies for Alzheimer, maybe prevent Alzheimer's disease. Wouldn't that be great? Are there any other things on the horizon that you see maybe for other neurodegenerative disorders from a therapeutic perspective? What do you, what do you think the next big thing will be in that area?

Dr Silbert: Well, that's a great question. I think, you know, there's a lot of exciting research in Lewy body dementia and targeting alpha synuclein pathologies. We really need biomarkers.

So, we're ways off from therapeutics, but I think there's a lot of exciting progress in that area.

Dr Jones: So, like many areas of neurology, there are rewarding and challenging aspects to the care of these patients. What do you- what's the most rewarding aspect of your practice, Dr Silbert?

Dr Silbert: You know, a lot of… I hear from trainees over the years that, you know, they can't imagine or it's difficult for them to think about caring for patients who have a neurodegenerative disease that has no cure. But I feel like that's a lot of what neurologists do. We don't necessarily cure all diseases, but we treat the patient throughout their disease process. And to me that is extremely satisfying. You know, I enjoy listening to patients’ stories and hearing about what they have been through over the years. And I really feel, like, appreciated for the care that I provide in giving not just an accurate diagnosis, which a lot of people come in lacking, but talking about future planning and, really, treatment throughout the course of the disease. And I was in clinic yesterday and talking to one of my patients’ caregivers, and we were talking about a particularly difficult behavioral manifestation that her husband was going through. And we were talking through how to manage it. And she said to me, you know, Dr Silbert, I really feel like I have a partner in going through this disease. And you know, that's kind of what it's all about for me. So, to me, it's extremely rewarding field. It's also a very exciting field, especially right now with all these new biomarkers and treatments. So, I just think there isn't a better area of neurology to be involved in right now.

Dr Jones: What a great place to land and end the interview. And I hope our listeners and our readers really do enjoy this issue. It's really a fantastic, not just an update, but a survey of a very dynamic aspect of the field of neurology. And Dr Silbert, I want to thank you for joining us and thank you for such a thorough and fascinating discussion on caring for patients with dementia.

Dr Silbert: It was my pleasure. Thank you.

Dr Jones: Again, we’ve been speaking with Dr Lisa Silbert, co-guest editor, alongside Dr Leanna Apostolova for Continuum 's most recent issue on dementia. Please check it out, and thank you to our listeners for joining us today.

Dr Monteith: This is Dr Teshamae Monteith, associate editor of Continuum Audio. If you've enjoyed this episode, you'll love the journal, which is full of in-depth and clinically relevant information important for neurology practitioners. Use this link in the episode notes to learn more and subscribe. Thank you for listening to Continuum Audio.
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Neuromodulation for Neuropathic Pain Syndromes With Dr. Prasad Shirvalkar
20 Nov· Continuum Audio
For certain diagnoses and patients who meet clinical criteria, neuromodulation can provide profound, long-lasting relief that significantly improves quality of life.

In this episode, Aaron Berkowitz, MD, PhD, FAAN speaks with Prasad Shirvalkar, MD, PhD, author of the article “Neuromodulation for Neuropathic Pain Syndromes,” in the Continuum® October 2024 Pain Management in Neurology issue.

Dr. Berkowitz is a Continuum® Audio interviewer and a professor of neurology at the University of California San Francisco in the Department of Neurology and a neurohospitalist, general neurologist, and clinician educator at the San Francisco VA Medical Center at the San Francisco General Hospital in San Francisco, California.

Dr. Shirvalkar is an associate professor in the Departments of Anesthesia and Perioperative Care, Neurological Surgery, and Neurology at Weill Institute for Neurosciences at the University of California, San Francisco in San Francisco, California.

Additional Resources

Read the article: Neuromodulation for Neuropathic Pain Syndromes

Subscribe to Continuum: shop.lww.com/Continuum

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Host: @AaronLBerkowitz

Guest: @PrasadShirvalka

Full episode transcript available here

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

Dr Berkowitz: This is Dr Aaron Berkowitz, and today I'm interviewing Dr Prasad Shirvalkar about his article on neuromodulation for painful neuropathic diseases, which appears in the October 2024 Continuum issue on pain management in neurology. Welcome to the podcast, and if you wouldn't mind, please introducing yourself to our listeners.

Dr Shirvalkar: Thanks, Aaron. Yes, of course. So, my name is Prasad Shirvalkar. I'm an associate professor in anesthesiology, neurology and neurological surgery at UCSF. I am one of those rare neurologists that's actually a pain physician.

Dr Berkowitz: Fantastic. And we're excited to have you here and talk to you more about being a neurologist in in the field of pain. So, you wrote a fascinating article here about current and emerging neuromodulation devices and techniques being used to treat chronic pain. And in our interview today, I'm hoping to learn and for our listeners to learn about these devices and techniques and how to determine which patients may benefit from them. But before we get into some of the clinical aspects here, can you first just give our listeners an overview of the basic principles of how neuromodulation of various regions of the nervous system is thought to reduce pain?

Dr Shirvalkar: Yeah, I would love to try. But I will promise you that I will not succeed because I think to a large extent, we don't understand how neuromodulation works to treat pain, to describe or to define neuromodulation. Neuromodulation is often described as using electrical stimuli or a chemical stimuli to alter nervous system activity to really influence local activity, but also kind of distant network activity that might be producing pain. On one level, we don't fully understand how pain arises, specifically how chronic pain arises in the nervous system. It's a huge focus of study from the NIH Heal Initiative and many labs around the world. But acute pain, which is kind of when you stub your toe or you burn your finger, is thought to be quite different from the changes over time and the kind of plasticity that produces emotional, cognitive and sensory dimensions. Really what I think is its own disease, chronic pain, of which there are multiple syndromes when we use neuromodulation, either peripheral nerve stimulation or electrical spinal cord stimulation. One common or predominant theory actually comes from a paper in science from 1967 and people still use it, foundational theory and it's called the gate control theory. Two authors, Melzack and Wall, postulated that at the spinal level, there are, there's a local inhibitory circuit or, you know, there's a local circuit where if you provide input to either peripheral nerves or either spinal cord ascending fibers that to kind of summarize it, there's only so much bandwidth, you know, that nerves can carry. And so that if you literally pass through artificial signals electrically, that you will help gate out or block natural pathological but natural pain signals that might be arising from the periphery or spinal cord. So, you know, one idea is that you are kind of interfering with activity that's arising for chemical neuromodulation. The most common is something known as intrathecal drug infusion drug delivery ITTD for that we quite literally put a catheter in the spinal fluid, you know, at the level of the dorsal horn neurons that we think are responsible for perpetuating or creating the pain.

Where's the pain generator? And you really, you can infuse local anesthetic, you can infuse opioids. And what's nice is you avoid a lot of systemic side effects and toxicity because it goes right to the spinal cord, you know, by infusing in the fluid. So there's a couple of modalities, but I will say just, like maybe all of our living experience, pain is in the brain. And so, we don't really understand, I would say, what neuromodulation is doing to the higher spinal or brain levels.

Dr Berkowitz: Fascinating topic. And yeah, very interesting to hear both what our current understanding is that some of our current understanding is based on data that's 60 years old and that we're actually probably learning about pain by using these modulation techniques, even though we don't really understand how they might be working. So interesting feedback loop there as well as in as in the as in this land. So, your article very nicely organizes the neuromodulation techniques from peripheral to central. So, encourage our listeners to check out your article. And first before we get into some of the clinical applications, just to give the listeners the lay of the land, can you sort of lay out the devices and techniques available for treating pain at each level of the neuroaxis? We'll get into some of the indications in patient selection in a moment, but just sort of to lay out the landscape. What's available that you and your colleagues can use or implant at different levels when we're thinking of referring patients too?

Dr Shirvalkar: Absolutely. So, starting from the least invasive or you know, over the counter patients can purchase themselves a TENS machine. Many folks listening to this have probably tried a TENS machine in the past. And the idea is that you put a couple of pads, at least two. So you have like a dipole or you have a positive and a negative lead and you basically inject some current. So, the pads are attached to a battery and you can put these pads over muscle. If you have areas where myofascial pain or sore muscles, you can put them, frankly, over nerves as well and stimulate nerves that are deeper. Most TENS machines kind of use electrical pulses that occur at different rates. You change the rates, you can change the amplitude and patient can kind of have control for what works best. Then getting slightly more invasive, we can often stimulate electrically peripheral nerves. To do this we implant through a needle, a small wire that consists of anywhere from one electrical contact to four or even eight electrical contact. What I think is particularly cool, like TENS, which is transcutaneous electrical nerve stimulation that goes through the skin. Peripheral nerve stimulation aims to stimulate nerves, but you don't have to be right up against the nerve. So, yeah. We typically do this under an ultrasound and you can visualize a nerve like the sciatic nerve, peroneal nerve, or you know, even if someone has an ulnar or a neuropathy, you know, that's the compression. There's a role obviously for surgery and release, but if they have predominantly pain, it's not related to a mechanical problem per se, you could prevent a wire from a peripheral nerve stimulator as far as one centimeter from a nerve and it'll actually stimulate that that modulated and then, you know, kind of progressing even more deeply. The spinal cord stimulation, SCS, it's probably the most ubiquitous or popular form of neuromodulation for pain. People use it for all kinds of diseases. But what it roughly involves is a trial period, which is a placement of either two cylindrical wires, not directly over the spinal cord, but actually in the epidural space, right? So, it's kind of like when you get an epidural injection or doing labor and delivery, when women get epidural catheters, placing spinal cord stimulator leads in that same potential space outside the dura, and you're stimulating through the dura to actually target the ascending dorsal column fibers. And so, you do a trial period or a test drive where the patients get these wires put in. They're coming out of the skin, they're connected to a battery, and they walk around at home for about a week, take careful notes, check in with them, and they keep a diary or a log about how much it helps. Separately. I will say it's hard to distinguish this, the placebo effect often, but you know, sometimes we want to use the placebo effect in clinical practice, but it is a concern, you know, with such invasive things. But you know, if the trial works well, right, you basically can either keep the leads where they are and place a battery internally. And it's for neurologists. You're familiar with deep brain stimulation. These devices are very similar to DVS devices, but they're specifically made for spinal cord stimulation. And there's now like seven companies that offer manufacturers that offer it, each with their own proprietary algorithm or workflow. But going yet more invasive, there is intrathecal drug delivery, which I mentioned, which involves placement of the spinal catheter and infusion of drug into spinal fluid. You could do a trial for that as well.

Keep a patient in the hospital for a few days. You've all probably had experience with lumbar drains. It's something real similar. It just goes the other way. You know, you're infusing drugs, and it could also target peripheral nerves or nerve roots with catheters, and that's often done.

And last but not least, there's brain stimulation. Right now, it's all experimental except for some forms of TMS or transcranial magnetic stimulation, which is FDA approved for migraine with aura. There are tens machine type devices, cutaneous like stimulators where you can wear on your head like a crown or with stickers for various sorts of migraines. I don't really talk about them too much in in the article, but if there's a fast field out there for adjunctive therapy as well,

Dr Berkowitz: Fantastic. That's a phenomenal overview. Just so we have the lay on the land of these devices. So, from peripheral essentially have peripheral nerve stimulators, spinal cord stimulators, intrathecal drug delivery devices and then techniques we use in other areas of neurology emerging for pain DBS deep brain stimulation and TMS transcranial magnetic stimulation. OK let's get into some clinical applications now. Let's start with spinal cord stimulators, which - correct me if I'm wrong - seem to be probably the most commonly seen in practice. Which patients can benefit from spinal cord stimulators? When should we think about referring a patient to you and your colleagues for consideration of implantation of one of these spinal cord stimulator devices?

Dr Shirvalkar: So, you know, it's a great question. I would say it's interesting how to define which patients or diagnosis might be appropriate. Technically, spinal cord stimulators are approved for the treatment of most recently diabetic peripheral neuropathy. And so, I think that's a really great category if you have patients who have been failed by more conservative treatments, physical therapy, etcetera, but more commonly even going back, neuropathic low back pain and neuropathic leg pain. And so, you think about it and it's like, how do you define neuropathic pain. Neuropathic pain is kind of broadly defined as any pain that's caused by injury or some kind of lesion in the somatosensory nervous system. We now broaden that to be more than just somatosensory nervous system, but still, what if you can't find a lesion, but the pain still feels or seems neuropathic. Clinically, if something is neuropathic, we often use certain qualitative descriptors to describe that type of pain burning, stabbing, electric light, shooting radiates. There's often hyperpathia, like it lingers and spreads in space and time as opposed to, you know, arthritis, throbbing dull pain or as opposed to muscle pain might be myofascial pain, but sometimes it's hard to tell. So, there aren't great decision tools, I would say to help decide. One of the most common syndromes that we use spinal cord stimulation for is what used to be called failed back surgery syndrome. We never like to, we now try to shy away from explicitly saying something is someone has failed in their clinical treatment. So, the euphemism is now, you know, post-laminectomy syndrome. But in any case, if someone has had back surgery and they still have a nervy or neuropathic type pain, either shooting down their legs and often there's no evidence on MRI or even EMG that that something is wrong, they might be a good candidate, especially if they're relying on long term medications that have side effects or things like full agonist opioids, you know that that might have side effects or contraindication. So, I would say one, it's not a first line treatment. It's usually after you've gone through physical therapy for sure. So, you've gone through tried some medications. Basically, if chronic pain is still impacting your life and your function in a meaningful way that's restricting the things you want to do, then it it's totally appropriate, I think, to think about spinal cord stimulation. And importantly, I will add a huge predictor of final court stimulation success is psychological composition, you know, making sure the person doesn't have any untreated psychological illness and, and actually making sure their expectations going in are realistic. You're not going to cure anyone's pain. You may and that's, you know, a win, but it's very unlikely. And so, give folks the expectation that we hope to reduce your pain by 50% or we want you to list personally, I like functional goals where you say what is your pain preventing you from doing? We want to see if you can do X,Y, and Z during the trial period. Pharmacostimulation right now. Yeah. Biggest indication low back leg pain, Diabetic peripheral neuropathy. There is also an indication for CRPS, complex regional pain syndrome, a lesser, I'd say less common but also very debilitating pain condition. For better or worse. Tertiary quaternary care centers. You often will see spinal cord stem used off label for neuropathic type pain syndromes that are not explicitly better. That may be for example, like a nerve injury that's peripheral, you know, it's not responding. A lot of this off label use is highly variable and, you know, on the whole at a population level not very successful. And so, I think there's been a lot of mixed evidence. So, it's something to be aware about.

Dr Berkowitz: That's a very helpful framework. So, thinking about referring patients to who have most commonly probably the patients with chronic low back pain have undergone surgery, have undergone physical therapy, are on medications, have undergone treatment for any potential psychological psychiatric comorbidities, and yet remain disabled by this pain and have a reasonable expectation and goals that you think would make them a good candidate for the procedure. Are those similar principles to peripheral nerve stimulation I wasn't familiar with that technique, I'm reading your article, so are the principles similar and if so, which particular conditions would potentially benefit from referral for a trial peripheral nerve stimulation as opposed to spinal cord stimulation?

Dr Shirvalkar: Yeah, the principles are similar overall. The peripheral nerve stimulation, you know, neuropathic pain with all the characteristics you listed. Interestingly enough, just like spinal cord stim, most insurances require a psychological evaluation for peripheral nerve stim as well. And we want to make sure again that their expectations are reside, they have good social support and they understand the kind of risks of an invasive device. But also, for peripheral nerve stem, specifically, if someone has a traumatic injury of an individual peripheral nerve, often we will consider it seeing kind of super scapular stimulation. Often with folks who've had shoulder injuries or even sciatic nerve stimulation. I have done a few peroneal nerve stimulations as well as occipital nerve stimulation from migraine, so oxygen nerve stimulation has been studied a lot. So, it's still somewhat controversial, but in the right patient it can actually be really helpful.

Dr Berkowitz: Very helpful. So, these are patients who have neuropathic pain, but limited to one peripheral nerve distribution as opposed to the more widespread back associated pains, spine associated pains.

Dr Shirvalkar: Yeah, Yeah, that's right. And maybe there's one exception actually to this, which is brachial plexopathy. So, you know, folks who've had something like a brachial plexus avulsion or some kind of traumatic injury to their plexus, there is I think good Class 2 evidence that peripheral nerve stem can work. It falls under the indication. No one is as far as to my knowledge, No one's done an explicit trial, you know PNS randomized controlled trial. Yeah, that's, you know, another area one area where PNS or peripheral nerve stems emerging is actually, believe it or not in myofascial low back pain to actually provide muscle stimulation. There are some, there's a company or two out there that seeks to alter the physiology of the multifidus muscle, one of your spinal stabilizer muscles to really see if that can help low back pain. And they've had some interesting results.

Dr Berkowitz: Very interesting. You mentioned TENS units earlier, transcutaneous electrical nerve stimulation as something a patient could get over the counter. When would you encourage a patient to try TENS and when would you consider TENS inadequate and really be thinking about a peripheral nerve stimulator?

Dr Shirvalkar: Yeah, you know TENS we think of as really appropriate for myofascial pain. Folks who have muscular pain, have clear trigger points or taught muscle bands can often get relief from TENS If you turn a TENS machine up too high, you'll actually see muscle infection. So, there's an optimal level where you actually can turn it up to induce, like, a gentle vibration.

And so folks will feel paresthesia and vibrations, and that's kind of the sweet spot. However, I would say if folks have pain that's limited or temporary in time or after a particular activity, TENS can be really helpful. The unfortunate reality is TENS often has very time-limited benefits - just while you're wearing it, you know? So, it's often not enduring. And so that's one of the limitations.

Dr Berkowitz: That's helpful to understand. We've talked about the present landscape in your article, also talk a little bit about the future and you alluded to this earlier. Tell us a little bit about some off label emerging techniques that we may see in future use. Who, which types of patients, which conditions might we be referring to you and your colleagues for deep brain stimulation or transcranial magnetic stimulation or motor cortex stimulation? What's coming down the pipeline here?

Dr Shirvalkar: That's a great question. You know, one of my favorite topics is deep brain stimulation. I run the laboratory that studies intracranial signals trying to understand how pain is processed in the brain. But, believe it or not, chronic pain is probably the oldest indication for which DBS has been studied. the first paper came out in 1960, I believe, in France. And you know, the, the original pivotal trials occurred even before the Parkinson's trial and so fell out of favor because in my opinion, I think it was just too hard or too difficult or a problem or too heterogeneous. You know, many things, but there are many central pain syndromes, you know, poststroke pains, there's often pains associated with Parkinson's disease, epilepsy, or other brain disorders for which we just don't have good circuit understanding or good targets.

So, I think what's coming down the pipeline is a better personalized target identification, understanding where can we stimulate to actually alleviate pain. The other big trend I think in neuromodulation is using closed loop stimulation which means in contrast to traditional electrical stimulation which is on all the time, you know it's 24/7, set it and forget it. Actually, having stimulation respond or adapt to ongoing physiological signals. So that's something that we're seeing in spinal cord stem, but also trying to develop in deep brain stimulation and noninvasive stimulation. TMS is interestingly approved for neuropathic pain in Europe, but not approved by the FDA in the US. And so I think we may see that coming out of pipeline broader indication. And finally, MR guided focused ultrasound is, is a kind of a brand new technique now. You know, focused ultrasound lesions are being used for essential tremor without even making an incision in the skull or drilling in skull. But there are ways to modulate the brain without lesioning. And, you know, I think a lot of research will be emerging on that in the next five years for, for pain and many other neuronal disorders.

Dr Berkowitz: That's fascinating. I didn't know that history that DBS was first studied for pain and now we think of it mostly for Parkinson's and other movement disorders. And now the cycle is coming back around to look at it for pain again. What are some of the targets that are being studied that are thought to have benefit or are being shown by your work and that of others to have benefit as far as DBS targets for, for chronic pain?

Dr Shirvalkar: You know, that's a great question. And so, the hard part is finding one target that works for all patients. So, it may actually require personalization and actually understanding what brain circuit phenotypes do you have with regards to your chronic pain and then based on that, what target might we use? But I will say the older targets. Classical targets were periaqueductal gray, which is kind of the opioid center in your brain. You know, it's thought to just release large amounts of endogenous opioids when you stimulate there and then the ventral pusher thalamus, right. So, the sensory ascending system may be through gait control theory interferes with pain, but newer targets the answer singlet there's some interest in in stimulating there again, it doesn't work for everybody. We found some interesting findings with the medial thalamus as well as aspects of the caudate and other basal ganglion nuclei that we hopefully will be publishing soon in a data science paper.

Dr Berkowitz: Fantastic. That's exciting to hear and encourage all of our listeners to check out your article. That goes into a lot more depth than we had time to do in this short interview, both about the science and about the clinical indications, pros and cons, risks and benefits of some of these techniques. So again, today I've been interviewing Dr Prasad Shirvalkar, whose article on neuromodulation for painful neuropathic diseases appears in the most recent issue of Continuum on pain management in neurology. Be sure to check out Continuum Audio episodes from this and other issues. And thank you again to our listeners for joining today.

Dr Shirvalkar: Thank you for having me. It was an honor.

Dr Monteith: This is Dr Teshamae Monteith, associate editor of Continuum Audio. If you've enjoyed this episode, you'll love the journal, which is full of in depth and clinically relevant information important for neurology practitioners. Use this link in the episode notes to learn more and subscribe. AAN members, you can get CME for listening to this interview by completing the evaluation at continpub.com/AudioCME. Thank you for listening to Continuum Audio.
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Opioids and Cannabinoids in Neurology Practice With Dr. Friedhelm Sandbrink
13 Nov· Continuum Audio
Opioids may be considered for temporary use in patients with severe pain related to selected neuropathic pain conditions and only as part of a multimodal treatment regimen. Close follow-up when initiating or adjusting opioid therapy and frequent reevaluation during long-term opioid therapy is required.

In this episode, Allison Weathers, MD, FAAN speaks with Friedhelm Sandbrink, MD, FAAN, an author of the article “Opioids and Cannabinoids in Neurology Practice,” in the Continuum® October 2024 Pain Management in Neurology issue.

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

Dr. Sandbrink is the national program director of Pain Management, Opioid Safety and Prescription Drug Monitoring Programs at the Veterans Health Administration, Uniformed Services University in Bethesda, Maryland.

Additional Resources

Read the article: Opioids and Cannabinoids in Neurology Practice

Subscribe to Continuum: shop.lww.com/Continuum

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

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

More about the American Academy of Neurology: aan.com

Social Media

@ContinuumAAN

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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: I'm Dr Allison Weathers. Today I'm interviewing Dr Friedhelm Sandbrink, who is one of the authors of the article Opioids and Cannabinoids for the Practicing Neurologist from the October 2024 Continuum issue on pain management Neurology. Welcome to the podcast and please introduce yourself to our audience.

Dr Sandbrink: Yeah, hi. So, I'm Friedhelm Sandbrink. I'm a neurologist and pain physician. I work at the Washington DC VA Medical Center, where I lead our intercessory pain management team, and I have a role also in the VA central office for pain management. I'm also associate professor, clinical associate professor at George Washington University and at the Uniformed Services University in Bethesda.

Dr Weathers: A lot of expertise, which you obviously brought to this article. And I do want to emphasize before we get started, although the article discusses both opioids and cannabinoids, as I said in the introduction, you worked in specifically on opioids. And so that's the part of the article where we'll focus our conversation today. Of course, I think all of our Continuum Audio topics are really fascinating. I know that some may not resonate as much, especially with our non-neurology listeners as others. Clearly not the case with your articles. I was reading it and preparing for a conversation today. I was really struck by how broadly applicable this topic is, not only to all neurologists but, really, all physicians, and even it should be to all of our listeners. Especially with what happened been going on over the last several years, what's been in the news about the opioid epidemic. And while usually like to start with this question, it feels even more pertinent in your case, what is the most important clinical message of your article?

Dr Sandbrink: So, the role of the opioid, the role of opioid therapy, really, for pain care has changed dramatically over the last many years right? I mean, it's we, we still consider opioids like the most potent analgesic medication for treatment of acute pain. The benefit for chronic pain really has changed right I mean, you know, we- the understanding in that regard and they're controversial. So, they're generally not recommended for chronic treatment for neuropathic pain conditions or for headache, but there are probably situations when opioids are still indicated and may be considered especially for temporary use. So, one example is probably the patient who has severe acute post hepatic neuralgia and we know that we use other medications for that, you know, the gabapentinoids and duloxetine and but they may take several days or weeks to work, right? And we have to titrate them up. And when more acute pain relief is needed, the opioid medication may be may be an option for temporary use. But I think what we need to keep in mind is that when we use it, we need to be informed about how to mitigate the risks, right? What, what are our best ways to reduce harms? And we need to also know the regulatory, you know, situation right I mean, what is that that we have to do nowadays to stay within the frameworks, right? And so, one of the main emphasis on this article is really go through what the clinical that the CDC has now established as the standards for opiate therapy when we use opioids I think we all need to know the rules right I mean, we know what to do to mitigate risks. What is expected from us in regard to use it as safely as possible, right? And that's important for the patient. That's also important for us in our practice.

Dr Weathers: I think very important advice. And this seems so obvious, but at the same time, I think it's worth very clearly stating why is it so important for neurology clinicians and again, really all clinicians, to read this article?

Dr Sandbrink: Yeah. We need to know the words regarding opiate prescribing right in the clinic. You know, the CDC has now issued their opiate practice guide, the Opiate Therapy Guideline. Really, it's a guideline for pain care in 2022. It's an update from 2016 that made some major changes in that regard. And I think we need to know really where we are nowadays in regard to expectations. I think we need to place the opiate therapy appropriately in our armamentarium regarding the many options that we have for pain care. But then when we use them, we need to know what we need to do to make it safe. Right? So, I'm thinking about the prescription drug monitoring programs and the patient education that's expected. We use in our practice an informed consent process even for patients on chronic pain, When and how to interpret urine drug screens, right? And how to issue, and maybe when to issue a naloxone comedication in order to have a rescue medication in case the patient is in a terrible situation. So, these are just things that have become nowadays standards of care and part of our practice. And we need to be familiar with it and use them as we take care of the patients. And for instance, in regard to opiate medication, we need to know about the specific rules regarding telehealth, prescribing of controlled substances, controlled Substances Act and the Ryan Hate Act that mandates in person evaluations for patients when we prescribe controlled substances. That obviously has been somewhat amended or changed or temporarily put on hold during the COVID crisis. And many states now have started developing their own guidance in regard to what's available and what's possible during telehealth. And we need to be familiar about that also.

Dr Weathers: I think those are such important and thoughtful points. I, I've mentioned it several times on this podcast before. I am a clinical informaticist and this is a topic that really lends itself to the EHR being able to help support. So, a lot of the things that you just mentioned, the consents for patients, the prescribing of naloxone, some of the support, clinical decision support can really be done in the electronic health record to help support providers. However, it's also one of those things where if people don't understand what's behind it, it can become a little bit of a crutch. And so, as I was reading the article, I was really struck by how helpful it is to really have that background. I think people can become very dependent and it becomes almost just doing it all for them and, and they lose the- then you can make this argument about probably a lot of the other clinical decision supports in there, but really understanding the why behind a lot of the support that's there around all of the, the tools that are in there to, to support safe opioid prescribing. I think it's so important for that people have that background that the article provides.

Dr Sandbrink: I think often it feels like you're going through a checklist of things to do right and, and, and you do right. But at the same time, as you said, you need to know why you're doing it right And, and I think it's very important for us to know what the rules are and the expectations in regard to standards of care. So, we also know what is the framework that we have to follow, but where can we make modifications? Where can we individualize based on the patient's need? What is really that that is still within our ability to do and how to modify that? Because in the very end, it really is about good care of the patient. We need to know what we are allowed to do, but we also need to know where the limits are right And I hope that that article provides really some information about that, especially as it outlines what the CDC expects. But then also, I think it gives - hopefully, and this is a message that the CDC also has – it really emphasizes that it's about good communication with the patient, truly informing them and about what are the range of options and the limits that we have, but also at the same time never to abandon the patient. You know, I think this is something that we need to understand. It's not really about us. The rules are there to make the care of the patients safer. The rules are not the primary goal itself. It is still patient care. So, in that regard, we need to make sure to never abandon the patient, even if the patient for instance, may come to us and maybe they took more opiates and prescribed or you know, and they ran out early and figure out what exactly was that drove the patient for that, right? I mean, you know, so that we know maybe it is actually worse than pain. Maybe there was something that happened that caused the patient to have a significant increase of it. You know, I think one of the biggest misconceptions is really also that patients who make sure some misuse of medication, that everybody has opioid abuse disorder, addiction. Common, far too common, right? And I think we've learned over the years how common it is. Clearly pain itself, intractable pain is a very strong driver of behavior. If you're in pain, if a patient is in pain, they are desperate often to seek some kind of relief. And taking extra medication in itself, while it's not at all something that we can endorse and tolerate, obviously in many ways, right, we have to still take it as a possible sign of pain control rather than opiate use disorder in itself. So, we need to be very careful of how to assess such a patient and that we guide them into the right direction in regard to the next.

Dr Weathers: That, again, is very important advice, and thinking about how chronic pain on a very different level than acute pain, right? Understanding how these patients are processing pain in a very different way than patients with acute pain. And again, also, I think a very important point that the pendulum has swung kind of back and forth over the years. You know, that they were in pain was another vital sign and it was make sure you're asking your patient about pain. And then all of a sudden it was, oh, we have to be really careful and people should not, nobody should be on these medications, which you- to your point, led to sudden abandonment. And that's not the point. That's not what we should be doing as providers. I know, though, there's very sensitive and challenging situations when you find out a patient though, perhaps taking more than expected because of chronic pain, but perhaps diversion. How have you handled those challenging cases?

Dr Sandbrink: I think diversion needs to be taken obviously very, very seriously. And you know, if a patient is truly diverting medication and there are obviously multiple variations of that, right? I mean, it's like giving it to a family member, for instance. That's one thing. It's on the other hand actually selling it. I think a patient who diverts is such a situation where opioid prescribing has to stop immediately, right? I mean, this is not a patient that we would take off at this point. I mean, so I think it's one of the very, very few occasions where you'd say that you have to just stop it immediately. I think there are other situations really in general, I think the patients who have been on opioids long term, especially in higher doses, I mean the majority of patients are not different. We have to be aware of it. We have to always look out for it. That's part of our risk mitigation. But we also have to make sure that patients on long term opioid therapy, right, that we guide them appropriately. I think the guidance probably in many ways is that we want to make sure whether opioids, the opioid medications still have helps them to achieve their functional goal. Are they truly helpful for the patients in achieving what they aspire to do in regard to their work life, in regard to the family situation. I think a lot of times for patients who have been on opioids long term, it's probably not that it really helps them that much for pain anymore, but they've often made that experience and they try to stop it. Pain gets worse, which is the effect obviously, that that happens with opiates right I mean, the moment you stop them, the opposite of the effect happens right I mean, they become irritable, right? The sleep gets worse, the pain gets worse, right? And it's a temporary phenomenon. And so, when we try to talk to a patient about possibly reducing the medication, I think this is one of the most challenging aspects that we have, that we really look at the patient and try to motivate them to be part of that plan. It's not something that we want to impose on the patient, but rather that we motivate the patient to look towards in the long term, probably more efficient pain care, which is really much more comprehensive pain care using all modalities. And I think one of the things that we learned over the last years is that when we make opiate medication reductions, we have to go very slowly. I think in the past we've talked about a matter of weeks and now the guidance including from the CDC guideline is probably more- closer to 10% per month to reducing it. So, you make reductions that may take many months to a year even, right. And the patient is allowed to help us, guide us how fast we can go. And you're allowed to make pauses if needed for the patient to adjust physiologically to reduction. And we want to go slowly enough that we don't run into an acute withdrawal situation right If you do it very gradually, it's much more manageable for the patient to do that. Then they'll be much more motivated to work with you.

But still, it's a challenge right I think that we do. And I think at the very end, it's really providing good patient care that allows us to build that rapport with the patient that they trust us and that they say, Hey, you know, yes, I'm, I'm willing to work with you, doc, to maybe reduce my reliance on the medication, right? So that that I don't end up on this. You know, one of the things that I sometimes do is asking patients when they come to us this first time and there are a lot of opiate medication maybe is like, what's your goal in this regard? Where do you see yourself in, in five or ten years? Are you thinking you will still be on this medication or would you want to come off? And how can we help you then if that's your goal? So, I think this is all part of our important conversation that we have to have in order to motivate the patient.

Dr Weathers: What I heard you say repeatedly through that. And what I really want to emphasize for our listeners is that the therapeutic relationship with that patient that no matter what that scenario, really keeping them and their goals at the focus and really making it a partnership, not a paternalistic relationship, not dictating to them what the plan will be, but really emphasizing shared decision-making. And I think again, that's such a key take home point for our listeners. And also, even going back to my original question about diversion, what really struck me in your response is even though you said yes, then that was one of the few cases or perhaps even the only case where you said, all right, this is where we have to cut it off immediately. It still wasn't abandoning them as a patient, although you said we have to stop the medication. It wasn't about ending that relationship with that patient necessarily, but ending that therapy option. So really critical in how we think about opioids therapy and our relationship overall with patients.

Dr Sandbrink: So, Allison, maybe I can add on, you know, I think the patient with diversion is the one aspect where we have to look at the population as a whole and the opioid that makes it to somebody else, potentially a vulnerable child, right, even you know, who could die from it, right? Another aspect of probably the patients we mentioned them earlier who have opioid use disorder, who maybe take more than prescribed and where we as a neurologist feel often quite uncomfortable dealing with that. And I think that's so important that at that point we don't abandoned the patient, right. I mean, you know, maybe we want to continue, we don't want to continue the opiate medication for the treatment of the pain. But as we diagnose and initially suspect opiate use disorder and have a conversation about it with a patient, we need to guide them to therapy. It's a treatable condition, right? It's an untreated, it's, it's actually rather lethal in many situations, right? So, we have to make sure that we provide an integrated access to the treatment or we have a warm hand off to somebody who will continue that and not abandon the patient in regard to that pain care, as we said earlier also, right? I mean, because that second condition really doesn't obviously I mean in any way that the pain is any better. No, I mean it's a common concurrent situation and we need to make sure that they still have the better pain care possible.

Dr Weathers: Again, it's a really key point for our listeners as and as I emphasized at the beginning, regardless of their subspecialty or specialty or even if they're physicians, I hope for everybody listening they can take away something from this. How did you become interested in pain management? I know that this was something that that you became interested in even when still in training. What struck you about this?

Dr Sandbrink: So, yeah, so my initial fellowship actually after residence was clinical neurophysiology. So, you know, a lot of the spine and different nerve conditions really was, was, but then when I began practice, clearly longitudinal care, chronic disease management, I think many of us in neurology do that right That, that became an emphasis. And I think building that accord with the patients right and, and, and that having that ability to provide pain care is something that really worked out very well. I think I love teamwork and part of teamwork pain care in in our setting is a collaborative approach right You have other disciplines, physical therapist, psychologist, right? You know, you have intervention and nonintervention provider. I think nowadays we even have integrative modalities available to us. So, I'm working together on a team, trying to optimize it here with many team members that we have with everybody bringing that personal expertise is something that I really cherish.

Dr Weathers: I feel like that's such a great example and I feel like a lot of people don't necessarily think about this specialty as one that is, that is collaborative in that way. And it really is. So, I, I think that's a wonderful way to highlight it. I always like to end on a hopeful note. And I know that there hasn't been necessarily a lot of hope or positive news in regards to, to opioid use, opioid therapy in the last several years. But are there developments that give you hope that you're excited about?

Dr Sandbrink: So, you know, I think there are probably two things I would mention. On one hand, I think patients are so much more aware now about the risk of opioids. So that is actually much easier to look and get them motivated about comprehensive pain care. There's much more interest in integrative modalities. Patients nowadays would be much more willing to maybe try acupuncture or mindfulness or yoga or Tai chi. So, I think that's actually a really nice development in that regard. But if I think about opioids specifically, I think the availability of buprenorphine as a medication, it's certainly something we should mention in this interview here, right? I mean, buprenorphine is now increasingly used for pain as well, not just in the higher dosage for opiate use disorder. It really is a good choice for patients who have.

pain conditions, chronic pain conditions, severe pain and to require a daily opioid, especially in regard to safety aspect when the patient has medical conditions or mental health conditions that may put them at higher risk and they have to be on an opiate anyway. This is really something that I think has changed our practice. As you know, we don't have to rely on the X waiver anymore. Anybody with a DA license can prescribe buprenorphine. Even for opiate disuse disorder, it really has become something that I think many of us integrate much more into our practice and I want to encourage the listener to really look into that direction.

Dr Weathers: Excellent advice and I'll actually refer our listeners who are subscribers of Continuum to reference, specifically, Table 4 where you dive into the buprenorphine.

It's just a fantastic table, as are all the tables. It really goes into detail of the commonly prescribed opioids for pain with the special characteristics and the conversion of morphine equivalent, but especially for this one about how to prescribe the details of us. Again, when I was preparing for this, I said wow. Like for me as a neurohospitalist and thinking about when I'm on service, how to use it, when to use it, I thought it was incredibly useful for that management of patients, especially as a powerful point of care tool. Well, thank you so much for being here with me today for this great conversation.

Dr Sandbrink: Yeah, thank you. That was my pleasure.

Dr Weathers: Again, today I've been interviewing Dr Friedhelm Sandbrink, whose article on opioids and cannabinoids for the practicing neurologist, written with Dr Nathaniel Schuster, appears in the most recent issue of Continuum on Pain Management and Neurology. To learn more about the topics of opioids and cannabinoids, be sure to read the full article. And don't forget to listen to Continuum audio episodes from this and other issues. Thank you to our listeners for joining today.

Dr Monteith: This is Dr Teshamae Monteith, associate editor of Continuum Audio. If you've enjoyed this episode, you'll love the journal, which is full of in-depth and clinically relevant information important for neurology practitioners. Use this link in the episode notes to learn more and subscribe. AAN members, you can get CME for listening to this interview by completing the evaluation at continpub.com/AudioCME. Thank you for listening to Continuum Audio.
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Orofacial Pain With Drs. Meredith Barad and Marcela Romero-Reyes
6 Nov· Continuum Audio
Orofacial pain comprises many disorders with different etiologies and pathophysiologies. A multidisciplinary approach combining medication, physical therapy, and procedural and psychological strategies is essential in treating patients with orofacial pain.

In this episode, Teshamae Monteith, MD, FAAN, speaks with Meredith Barad, MD; Marcela Romero-Reyes, DDS, PhD, authors of the article “Orofacial Pain,” in the Continuum® October 2024 Pain Management in Neurology issue.

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

Dr. Barad is a clinical associate professor of anesthesiology, perioperative and pain medicine, and neurology and neurological sciences and codirector of the Stanford Facial Pain Program at Stanford Medicine in Stanford, California.

Dr. Romero-Reyes is a clinical professor and director of the Brotman Facial Pain Clinic and Department of Neural and Pain Sciences at the University of Maryland in Baltimore, Maryland.

Additional Resources

Read the article: Orofacial Pain

Subscribe to Continuum: shop.lww.com/Continuum

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

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

More about the American Academy of Neurology: aan.com

Social Media

@ContinuumAAN

Host: @headacheMD

Guest: @meredith_barad

facebook.com/continuumcme

Full episode transcript available here

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

Dr Monteith: This is Dr Teshamae Monteith, associate editor of Continuum Audio.

Today I'm interviewing Drs Meredith Barad and Marcela Romero-Reyes about their article on oralfacial pain, which appears in the October 2024 Continuum issue on pain management and neurology. Welcome to the podcast, ladies. How are you?

Dr Barad: Excellent.

Dr Romero-Reyes: Fine, happy to be here.

Dr Monteith: I am so happy to see you. I mean, I think both of you I've known for like ten years.

Dr Romero-Reyes: Yeah.

Dr Barad: Yes.

Dr Monteith: So why don't you introduce yourselves? While I know you, our audience, some of them, may not know you.

Dr Romero-Reyes: I'm Dr Marcella Romero Reyes. I am a neuropathial pain specialist, clinical professor, and director of the Provident Special Pain Clinic here in the University of Maryland School of Dentist.

Dr Monteith: Excellent.

Dr Barad: My name is Meredith Barad. I'm a clinical associate professor at Stanford and I work- I'm the codirector of our headache and facial pain clinic in the Stanford pain management clinic.

Dr Monteith: Well, first of all, thank you for writing this article. It is extremely detailed and up-to-date and very informative. And in neurology, I think we don't get enough pain management.

I'm interested in both of your backgrounds and, you know, what led you even to become an expert in this area? And both of you have complementary areas. I think we can see in the quality of this article. But why don't we start with you, Dr Romero-Reyes?

Dr Romero-Reyes: Well, for me to get interested in orofacial pain, I will say more than an interest was like a calling that I wanted to take care of this patient population. So, as you know, my background is dentistry and at that time I was very interested in patients with complex medical issues. And was the time I was- I started to be interested in temporomandibular disorders. But what really picked completely my attention was the first time I saw a patient with trigeminal neuralgia. This was my last year in dental school. This patient already had, like, almost a full upper quadrant of teeth extracted where pain was not resolved. So when the patient came to us and I did my exam and, you know, and I triggered the pain, the sharp shoot electrical pain, that really broke my heart. And I took an x-ray and I didn't find anything that will explain it was something wrong until I talked to my professor and he said, no, this is medical. There's nothing wrong with it, with that tooth and needs to be, you know, followed with proper management and medication. And for me, that was like, wow, what a proper diagnosis and proper management can take care of these of these patients. And when the patient got better, that really said, oh, you know, I want to do this.

Dr Monteith: That's a crazy story. It's always that last patient of the day.

Dr Romero-Reyes: And you know, think about it, at least in dentistry at that time, I learned about trigeminal neuralgia from a book, right, my classes. But when you see the patient, this is it. That completely, you know, made me say yes, I want to study this.

Dr Monteith: Yeah. And unfortunately, that's not an uncommon scenario where patients with trigeminal neuralgia get, you know, their extractions and pain can sometimes be more complicated. What about you, Dr Barad?

Dr Barad: Well, I guess I'm sort of like the opposite. So as a neurologist and a trained pain physician, I saw a lot of patients with neuralgic pain and headache pain, but I also saw many patients who would say, I have TMJ. And as, as Dr Romero has educated us, that's like saying I have shoulder or I have knee. But I quickly realized that I needed to work with a multidisciplinary team to really understand more about orofacial pain. It's not just neuralgic. There are other ideologies. And so that's how we started working together and that's how we practice in our clinic at Stanford.

Dr Monteith: So, why don't you tell us about the objectives of this article?

Dr Barad: I think our objectives were to help the neurologist broaden the differential diagnosis on facial pain to encompass below the nose, the oral cavity, the temporal mandibular joint. And to just think more broadly about facial pain and to understand some of the more recent diagnostic criteria that have been developed for facial pain and to- how to diagnose properly and how to begin treatment for some of the other conditions that are non-neurologic.

Dr Romero-Reyes: And I think I will ask about what Dr Barad say that also to bring awareness to the neurologist about the vast classification of oral facial pain disorder, craniofacial and orofacial. I think that was also a key thing too. And also, to show how well we can work together, you know, the multi-disciplinary management that is indicated for these cases.

Dr Monteith: Cool. And you mentioned some of the new diagnostic criteria. I want to talk just briefly about the new international classification of orofacial pain, ICOP. When did that come out and what was the process there in really fine-tuning the diagnosis of orofacial pain disorders?

Dr Romero-Reyes: So, in 2019 the orofacial head pain especially interest group of the International Association for the Study of Pain, the International Network for Orofacial Pain and Related Disorders methodology and the American Academy of Orofacial Pain and the International Headache Society. They partnered together to develop to develop this international classification of orofacial pain. And these, I think- it's such a great effort, you know, all the main people doing pain about this area, and goes very well together with the international classification of headache disorders. So, for example, you know, some disorders that International Classification of Headache Disorders doesn't present such as and the ICOP, International Classification of Orofacial Pain, presents, like the persistent idiopathic dental Viola pain. You have it in the ICOP. It's not, you know, mentioned in the in the International Classification of Headache Disorders, as well as, also we have the- I think it’s item number five, the orofacial representations headache disorder or primary headache disorder. The ICOP gives you a nice, clean diagnostic criteria.

Dr Monteith: So, I guess I would ask Dr Barad with this classification in mind, how useful is it in neurology practice? And I know obviously you see patients with pain, but how useful even in managing patients with headache?

Dr Barad: I think it's great because I've had a lot of dentists and ENT doctors who have started referring patients to me because they've realized that they've increased their awareness about orofacial pain and realized that pain in the sinuses, for example, accompanied by light sensitivity and sound sensitivity and rhinorrhea, may not be a recurrent monthly sinus infection.

And so that kind of broadens our awareness of these of these disorders. And it's been, it's brought new patients into my clinic that we can help and treat. So that's been exciting.

Dr Monteith: And what about in the world of dentistry? Obviously, I think people in orofacial pain worlds are highly attuned to this, but I would hope this would hopefully have been disseminated into dentists and regular practice at C patients with trigeminal neuralgia.

Dr Romero-Reyes: Going back for the, what you were discussing about the ICOP. So, it's what we're trying now as a new specialty. Well that we have been for the last four years, but finally in 2020 we have been recognized by the American Mental Association to disseminate this knowledge. But also, you know, can you imagine in in the realm in orofacial pain or dentistry have a patient with this recurrent pain, phonophobia, photophobia, throbbing dental pain is throbbing, but it's nothing wrong with your tooth. And that did they tell you that actually you have an orofacial or facial migraine or a neurovascular or facial pain. How crazy, right? And that is managed with migraines therapy. So it really, you know, to make you think like that. Wow, so these weird tooth things that used to come every week or these with facial pain, it's nothing to deal with, you know, with my teeth or any structure, you know, inside my mouth.

Dr Barad: It sounds to me like what you're saying is that we've, this has encouraged patient education as well, not only interdisciplinary education, but really helping provide an explanation for the patient about what is going on with them. So rather than just getting sent away to another tertiary specialist, the patient is getting a more robust understanding of what's going on.

Dr Romero-Reyes: And going back to what you were saying about trigeminal neuralgia, you know, at least in dentistry also we're teaching now a new awareness like for two things, right? What about from the neurology setting? The patient has captured electrical pain. The trigger is intraoral. If it's pain inside your mouth, the first practitioner you're going to see who will be maybe the dentist that the dentist knows that could be a possibility of a disorder that doesn't deal with teeth, but also, it's important and we discussed that in our paper. What about that actually that weird trigger actually, it's not a general. What about if it's a cracked tooth has that singing sensation too. So, you see, it's two ways; one, to teach dentist to learn about this disorder and you know, we have learned, but you know, it's much more awareness now that this is great that, you know, these disorders you're not going to treat with dental procedures. Right? It's medical and vice versa, that the neurologist also has the awareness that oh, central trigger. Have you gone to the to the dentist? Have you checked that out?

Dr Monteith: So what should neurologist know about dental sources of pain?

Dr Barad: Well, maybe they should read the paper?

Dr Romero-Reyes: Yeah. Yeah, you need to read the paper. Yeah.

Dr Monteith: Top three, don't treat this with gabapentin.

Dr Romero-Reyes: Like well, dental pain is not going to be resolved with gabapentin. That would need to make a diagnosis if and you know it's that examination that come comes with a radiographic evidence that shows that maybe could be a cavity or could be a problem. You know in the in the practical tissues of the tooth that is given a symptomatology. Not only dental could be a lot of different disorders inside there now that can produce pain that also the readers can check our paper and learn about and see the wonderful interesting pictures that we have added there.

Dr Monteith: Yeah. And so why don't we talk a little bit about TMD disorders and what is the new thinking around these conditions?

Dr Romero-Reyes: Well, I will say for the last decade, maybe a little bit more has been a change in the evidence. They evidence based understanding of the theologia pathophysiologist and for mandibular disorders. Imagine that what's the shift in the in the paradigm that in dentistry prevails for a long, long time. That is that really focus and I will call it the pathological mechanistic point of view. What I mean by that I was focusing your bite, your occlusion, how the relation between in your maxilla mandible. That was the only issues that would create in temporomandibular disorders. So now we know that temporomandibular disorders are complex, are multifactorial and you need to understand them and see them within a biopsychosocial framework. And this dictate the main way to management for the primary way that we start will be conservative, reversible and basing evidence that the best evidence available that we have.

Dr Monteith: And what about for trigeminal neuralgia? Is there newer kind of classification around trigeminal neuralgia? and what are some key points that we should consider when diagnosing these patients and treating these patients, Dr Barad?

Dr Barad: There haven't been any new diagnostic criteria, but I would say that there's been an increased awareness that classical trigeminal neuralgia is more likely than not related to neurovascular compression or we should say, maybe I should say neurovascular contact or compression. There is a developing grading system of that. That's an evolution as we speak. I think it's an exciting time for facial neuralgia because it's opened the door for us to look at other neuralgia also as vascular compressions and to think about how we can treat them with decompression or possibly with peripheral nerve stimulation or medicine or Botox. Or who knows what's the future is going to hold? But it is I think a change in the way we are thinking about the definition of neuralgia of, of trigeminal neuralgia in that is caused by a compression which is different than other neuralgia in other parts of the body. I should, I just want to classify there's about maybe ten twelve percent of people who present with classical trigeminal neuralgia who there is not evidence on imaging of a vascular contact or compression. But the majority of cases do seem to have some somewhere in the spectrum from contact to compression.

Dr Monteith: Even contact I find to be a bit vague sometimes say, well, thanks for letting me know that they're touching. But and then some of the neurosurgeons have different perspective when you open the patient up. So, I didn't know about the grading.

Dr Barad: Yeah, I think you've hit on it exactly like that is a big problem in the field right now. How do we understand what patients will be the best patients for surgery? And it used to be that you have the classical trigeminal neurologist symptomology plus some imaging that shows something versus nothing. And now we're getting into parsing out the imaging and trying to understand who's the best candidate for that with the imaging.

Dr Monteith: Dr Romero, anything to add?

Dr Romero-Reyes: No, that I agree about that, you know, and I think now maybe for the patients that I have seen with that, because under partial pain settings, sometimes we're the ones that, oh, actually what you have is trigeminal neuralgia idea, you know, so we start to have our small disciplinary management, but you know, when they come out, I already have an MRI doctor, but, and they say that these are compression, but what degree? And some patients that they don't have symptoms can have a compression. And I'm thinking maybe right that later on when we have more time and maybe nicer imaging, we're going to really find out or if it's the development angle is the measurement has some other characteristics, who knows. So, I think for trigeminal neuralgia, the things is still evolving, right? For our understanding. I have to help us to make a more- I will not say definitive diagnosis, but maybe some parameters will change in the future.

Dr Monteith: So now we have a lot of people listening, international folks listening, and they always want some treatment, a tip, some clinical tips. So, can you give us a little bit of clinical insight to how to treat patients with trigeminal neuralgia and when you're seeing patients for second and third opinions, what might you see that may explain why their pain is not well controlled? We all get into interdisciplinary care, but in terms of pharmacology?

Dr Barad: I think people are a little reluctant to use some of these medications that neuromodulating medications because, in general, it's an older population and they're rightly worried about falls and dizziness and confusion and low sodium. And so, I think they hesitate to go to the doses that are needed to help with pain control. So, a lot of our, my initial management is gingerly and gently titrating that to try to get to see if we can get control of the pain.

Dr Monteith: Dr Romero?

Dr Romero-Reyes: I could add, for example, one thing that I in the realm of facial pain addition to pharmacology. Let's say that we have a patient with that intraoral trigger and we were able to localize that intraoral trigger. Sometimes we can even also use topical medication. And in the topical medication we can use, for example, an anticonvulsant, let's say gabapentin, oxcarbazepine for example, to add in the cream. And we use, we call it a neurosensory stent in my looks like a Nygard, but it's not a Nygard that can cover that area. So, the patient can add that cream very delimited in that area. And that helps, you know, can help with the pain sometimes. What we can find is that, at least in my, in my experience, and that when we add a topical, maybe we don't need to increase as much. The systemic medication, of course, depends from case to case.

Dr Monteith: So those are two great tips. Not being afraid to push those doses up in a safe manner and maybe with monitoring as well as of maybe utilizing more topicals. And I think we could probably hear a lot more from you on topicals at some other point. But thank you also for the table. I think it's, it's really nice the way all the treatments are laid out. So what other cranial neuralgia advances have there been?

Dr Barad: I would say the main advancements have been in applying the knowledge that neurosurgeons have learned from microvascular decompression of the trigeminal nerve, to the glossopharyngeal nerve, to the geniculate nerve, and really trying to optimize imaging and optimize neurosurgical techniques to try to treat these neuralgias. If the patient has failed medicine, if the patient is a good candidate for surgery and if the patient desires that.

Dr Monteith: Great. So now let's talk about multidisciplinary approaches. I know both of you are big fans of that, and you may do things a little bit differently at your institution, especially with your background. So maybe Dr Romero, do you want to tell us about your experience? And then we'll have Dr Brad.

Dr Romero-Reyes: But in my experience from study management, let's say depend, of course, also the started we're talking about. But let's say for example about temporomandibular disorders, you know that for TMD is one of these overlapping pain conditions and we know that TMD is common with primary headache disorders, especially migraine. So, if we're able to utilize, you know, the expertise of neurologist specializing headache. With me, for example, or a facial pain person that is that is helping you manage a patient with this comorbidity. This is super effective because we know the presence of TMD in a migraineur can help the disorder to, to progress some more chronic form. So, you see, this is super important and effective to provide, you know, optimal care for the patient. For example, in the patients that I do see with neuralgias, like in addition to trigeminal neuralgia, let's say nervous intermediates neuralgia, that sometimes they can come to me like, oh, the pain is in my ear and my EMT or, or I think maybe it's my TMJ and for the pain is charged shooting inside the ear doesn't follow the for the diagnosis of temporomandibular disorders. And I can maybe help the patient to get a proper imaging or already penalize it with a neurologist to make sure. And maybe at least my way will be maybe I'm the one that can catch those disorders and help, you know, the patient to go for the next step.

Dr Barad: I think Marcella, Dr Romero-Reyes, hit on a nice point that maybe this group is not as familiar with and that is that temporal mandibular dysfunction TMD is a, is one of the disorders that we call chronic overlapping pain conditions or COCPs. And those include headache. it's not, it's not specified fibromyalgia, irritable bowel syndrome, chronic pelvic pain and several other chronic pain syndromes. And they suggest a central sensitization to one's pain. And the way that we treat centrally sensitized pain is not just through medications, it's in a biopsychosocial framework because we see much higher rates of depression and anxiety in this group. And so, using a pain psychologist to help the patient develop coping strategies to help them manage their pain, using a physical therapist to help them learn this, the stretching exercises and using medications to help with not only with their pain syndrome, but also sometimes with their psych comorbidities. And then additionally, procedures sometimes play a role in the process to help usually turn down the pain. Interestingly, when we look at trigeminal neuralgia, we see much less overlapping pain disorders. It's much rarer to see somebody with TN who has other COCPs or the kind of chronic levels of depression and anxiety that we see in these patients. So, the approach is very different, and I think it requires the use of a multidisciplinary team to help guide the treatment pathways for these patients.

Dr Monteith: Today, I've been interviewing Drs Meredith Barad and Marcelo Romero-Reyes, whose article on orofacial pain appears in the most recent issue of Continuum on pain management and neurology. Be sure to check out Continuum Audio episodes from this and other issues. And thank you to our listeners for joining today.

Dr Monteith: This is Dr Teshamae Monteith, associate editor of Continuum Audio. If you've enjoyed this episode, you'll love the journal, which is full of in-depth and clinically relevant information important for neurology practitioners. Use this link in the episode notes to learn more and subscribe. AAN members, you can get CME for listening to this interview by completing the evaluation at continpub.com/AudioCME. Thank you for listening to Continuum Audio.
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Central Neuropathic Pain With Dr. Charles Argoff
30 Oct· Continuum Audio
In the patient populations treated by neurologists, central neuropathic pain develops most frequently following spinal cord injury, multiple sclerosis, or stroke. To optimize pain relief, neurologists should have a multimodal and individualized approach to manage central neuropathic pain.

In this episode, Lyell K. Jones Jr, MD, FAAN, speaks with Charles E. Argoff, MD, author of the article “Central Neuropathic Pain,” in the Continuum October 2024 Pain Management in Neurology issue.

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

Dr. Argoff is a professor of neurology and vice chair of the department of neurology, director of the Comprehensive Pain Management Center, and director of the Pain Management Fellowship at Albany Medical College in Albany, New York.

Additional Resources

Read the article: Central Neuropathic Pain

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Host: @LyellJ

Full episode transcript available here

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

Dr Jones: This is Doctor Lyell Jones, Editor-in-Chief of Continuum: Lifelong Learning in Neurology. Today I'm interviewing Dr Charles Argoff, who recently authored an article on central neuropathic pain in the latest issue of Continuum covering pain management. Dr Argoff is a neurologist at Albany Medical College where he's a professor of Neurology, and he serves as vice chair of the Department of Neurology and program director of the Pain Medicine Fellowship Program there. Dr Argoff, welcome. Thank you for joining us today. Why don't you introduce yourself to our listeners?

Dr Argoff: I'm Charles Argoff. It's a pleasure to be here and thank you so much for that kind introduction.

Dr Jones: I've read your article. Many of our listeners are going to read your article. Wonderful article, extremely helpful. Closes a lot of gaps, I think, that exist in our field about understanding central neuropathic pain, treating central neuropathic pain. You now, Doctor Argoff, you have the attention of a huge audience of mostly neurologists. What's the biggest point you would like to make to them, or the most important practice-changing advice that you would give to them?

Dr Argoff: I think it's at least twofold. One is that central neuropathic pain is not as uncommon as you think it might be, and it occurs in a variety of settings that are near and dear to a neurologist's heart, so to speak. And secondly, although we live in an evidence-based world and we want to practice evidence-based medicine - and I'm proud to have formerly been a member of the Quality Standard subcommittee, which I think has changed its name over time. And so, I understand the importance of, you know, treatment based upon evidence - the true definition of evidence-based medicine is using the best available evidence in making decisions about individual patients. And so, I would urge those who are listening that, although there might not be as robust evidence currently as you’d like, please don't not take the time to try to treat the patient in front of you o r at least acknowledge the need for treatment and work with your colleagues to address the significant neuropathic pain associated with that central neurological disorder. Because it can be life-changing in a positive way to make even a dent and to really work with somebody, even though not clear-cut always what's going to work for an individual patient.

Dr Jones: Well said. I'm glad you brought that up. So, to put it a different way, absence of evidence is not an excuse for absence of treatment. Right?

Dr Argoff: Exactly. And I think that, I hope that we would agree that especially in neurology, what we do is about as far from, ‘Yep, you've got strep throat, here’s that antibiotic that's going to work for you and all you have to do is take the medicine.’ I mean, most of what we do is nowhere near that.

Dr Jones: It's complicated stuff. And this is a complicated topic. And I'll tell you, I learned a lot reading your article. I think most of us in neurology and medicine, when we hear the term neuropathic pain, it feels roughly synonymous with peripheral generators of that pain, such as diabetic neuropathy or posttraumatic neuralgia. But as you mentioned, there's central mechanisms for pain generation. How is it defined? What is central neuropathic pain?

Dr Argoff: It's defined as pain caused by a lesion or disease of the central somatosensory system . Though neuropathic pain in general is pain associated with the lesion of the somatosensory system; and to your point, that can be peripheral, which of course is outside the spinal cord, or brain or central, which is within the spinal cord or brain. And central neuropathic pain is defined specifically as pain caused by a lesion or disease of the central somatosensory system. That's either brain or spinal cord. But there's an interesting follow-up, and I'm going to ask if you could remind me because I know we're talking about definitions now, but I'll just bring something up and we can come back to it. What's interesting about that is that my - whoever 's listening, that's not to say that they're not connected. And in fact, they are very much connected.

And there's very new work, which I included in the article, down at Washington University in Saint Louis, that suggests you can actually affect central neuropathic pain by addressing peripheral input to the central nervous system. If you remember Ken Casey at the University of Michigan at the World Pain Congress in Vancouver, British Columbia many years ago, he ended his talk on pain with a limerick, of which the last line was, Remember, there ain't no such thing as pain without a brain. And so that kind of summarizes that.

Dr Jones: Well, and it goes both ways too, right? We know that there's some central sensitization that can happen with peripheral generators, right? So we really have to think about the whole circuit.

Dr Argoff: Yes. And that's been sometimes the bane of my existence as a colleague of others and a sometimes debater. Is the pain central? Is it peripheral? Well, it's everything. And it's important to know as many of the mechanisms and many of the targets that you could use for treatment so that you can affect the best outcome for your patients.

Dr Jones: Yeah, so - and you mentioned in your article what some of the common causes of central neuropathic pain are. What are the big ones in your experience?

Dr Argoff: So, the biggest ones are spinal cord injury-related pain, MS-related pain - and I'd like to come back to a point and just if I do the third one - and central poststroke pain. And what struck me, I think Tim Vollmer published a survey about the incidence, the prevalence of ongoing pain in patients with multiple sclerosis. And it blew my mind several years ago because it was incredibly high. Like in this survey of MS patients who, you never hear about pain, you hear about these modifying treatments, all the wonderful expanses that have been made. I mean, like seventy something percent of people say they have moderate to severe pain. And when you think about how sensory processing occurs, it makes perfect sense that a demyelinating disorder is going to interrupt the flow of information for a person to feel normal.

Dr Jones: Yeah, I think it's a good example of, there are things that we tend to focus on as clinicians where we worry about deficit and function and capacity. But if we're patient-centered and we ask patients what they care about, pain usually moves up higher on the list. And so, I think that's why we, it's maybe underrecognized with some of those central disorders, right?

Dr Argoff: I think so, and I and I think you hit the nail on the head that - and we're also trained that way. I tell this to my patients very often so that they are reassured when I examine them and I say, and I tell them that everything looked pretty OK. It's not a medical term, I understand that. Because what we do in a typical neurological exam, even if it's detailed, doesn't really address all the intricacies of the nervous system. So it's really a big picture and sensory processing and especially picking up sensory deficits; you know, we use quantitative sensory testing and research studies and things like that, but bedside testing may not reveal the subtle changes. And when we don't see overt changes, we often think - that can lead someone to think that everything is OK and it's not.

Dr Jones: So, when you when you see a patient who you've diagnosed with a central mechanism, so central neuropathic pain, how do you approach the management of those patients, Dr Argoff?

Dr Argoff: I always review what treatments and what approaches have been addressed already. And I see if - a handful of time, we actually just submitted a paper for publication regarding this in a group of patients with pelvic pain who had untreated, difficult-to-treat chronic pelvic pain, seen all the urological kinds, gynecological things. Look, we picked up two patients who had unknown MS. So, it's just interesting when it comes down to that level.

And we also picked up some patients who had subacute combined degeneration. So that's another central kind of disorder as well. Again, the neurologist in us says to make sure that we have specific diagnosis that underlies the central neuropathic pain. And so interestingly, of course, for somebody with MS - or even though it's uncommon, it could be more than one. Somebody with MS might have a stroke, somebody with MS might have a cord injury due to cervical, you know, joint disc disease. Not to overcomplicate things. Know the lay of the land, know the conditions, know what you're battling and lay out so that you can treat the treatable; you want to treat whatever you can correct? So, for MS you simply want to have the best disease-modifying treatment on board, tolerable and appropriate for that person, and so on. And then you really want to take a history of past treatments - and your treatments can be everything and anything, including behavioral modification, physical rehabilitative approaches, as well as pharmacologic management. That's - as I think I put in my article, we concentrated in the article on pharmacologic management because honestly, that's what most patients are looking for, is ‘what can we, what can you do to help me now, in addition to what I can do myself.’ And that's what we typically think of. There are also some more interventional approaches, invasive options, that have developed over time. And of course, those are the ones, some of them, especially in neuromodulation, that we have the least information about, but it appears somewhat promising.

Dr Jones: No, that's exactly what we need to hear. And you also mentioned something that I think is important. This is a common theme throughout the issue because I think it's true for the management of many different types of pain and interdisciplinary approach. In other words, not just honing in on pharmacotherapy or neuromodulation as a one-size-fits-all magic pill, right? So, that - tell us a little bit more about that interdisciplinary approach and how that's important for these patients.

Dr Argoff: So, let me back up and give an example. Let's look at Botox for chronic migraine.

So, the pre-M studies that led to the approval of Botox for chronic migraine: two treatment sessions versus two random, two placebo session in different patients. The mean headache frequency was, let's say, fifteen to twenty in each group. It was like seventeen, eighteen, something like that. But the mean pain headache day reduction was somewhere between four and five after two treatments compared to a lesser, a lower number in the placebo group.

So, if you think about that, that means that you went from nineteen, let's say, to fourteen, thirteen, or twelve. Want to be generous, eleven or ten. But that means that person, everyone 's happy. We use treatment. We have better data than that because the longer you use it, the better it gets in general, but it means that people are still going to be symptomatic. So that drives home in a different painful disorder the importance of yes, treatment can be effective, but it's not the only treatment that a person is going to likely need. And so, I think that's what's so important about multidisciplinary approach. I- we may affect positive changes, reduction in pain intensity with a particular pharmacologic agent, but we don't anticipate it's like taking an antibiotic or a strep throat, not curative. And so, we want to, early on, to explain that logically, methodically, step by step. There are many options for you and we're going to, you know, systematically go through them. And I may need to call in some colleagues to help because I don't do everything. No one does everything, right? But don't feel as if there isn't any hope because there is. If we were to use intraspinal Baclofen for someone who has painful spasticity following a stroke or a spinal cord injury, combining that with physical therapy might give more effect, maybe synergistic. Some targeted muscles, some local muscles may not respond as well to the intraspinal Baclofen, so is that - what can we do? Well, we could use oral agents or we might be able to target that with botulinum toxin, and so on and so forth. So it's limitless, virtually, in what you can do.

Dr Jones: There's kind of setting expectations and letting people know that you, you're going to need a lot of different approaches, right? To sort of get them the best possible outcome.

Dr Argoff: Yeah, I think that's so important. And of course, no matter what we try to set out, there are going to be individuals - for those of you who are listening, we all know - who expect to be cured yesterday. That might be challenging for us not only to actually complete, but also, it's challenging for some individuals to appreciate that we're with them, we're going to work with them. It’ll be a process, but we've got your back.

Dr Jones: Great. And you know, this is a question that I get all the time from patients and from other clinicians is, you know, what about cannabinoids? What's the role of cannabinoids for the management of central neuropathic pain?

Dr Argoff: First, I'll say that the short answer to that is we don't know. The second part of my response would be, there is new evidence that it might be helpful in the acute treatment of migraine. And I'm happy to say that the editor of this edition of Continuum is the person who developed that evidence, and it's been recently presented at the American Headache Society.

But the challenge and the conundrum that we all face is, everywhere within our nervous system where there's pain being processed, there are endocannabinoid receptors. There also happen to be opioid receptors, but that's a separate issue. And the endocannabinoid system, the peripheral or central, you know, CB1, CB2, is very, very important, but we haven't figured out a way of harnessing that knowledge in developing an analgesic, an effective analgesic. And part of that is that there are so many chemical agents that have cannabinoid properties and there are different… the right balance has not yet been found. But even the legalization, the available of medical cannabis, hasn't led to a standardized approach to evaluating if a preparation does help. And that's part of the conundrum. It's like saying, ‘does medicine work?’Well, yeah, sometimes. But which medicine? Which receptor? How do you harness the right ratio between TBD, THC, other active agents, et cetera? And I think maybe as we go forward in the future, we’ll be able to do that with - more precise.

I mentioned Dr Schuster's study in which he had defined ratios of THC effect and CBD and was able to clearly show effect based upon that. But the average person going into a dispensary doesn't really get that. We don't get to study that. Each person's an NF1 and it's not very helpful to understand how to do that. I would say, as I'm sure you remember, there was a practice parameter that was published probably over a decade ago about using cannabis symptomatically in different neurological disorders. And I believe that it was what they studied or what they reviewed was helpful in MS-related urinary discomfort and spasticity, but not necessarily pain.

Dr Jones: And we're still in the early days of studying it, right?

Dr Argoff: Yes.

Dr Jones: That's part of the point, as we got started late and we're still waiting for high-quality evidence. And I guess, if you look at the horizon, Dr Argoff, or the future of management of central neuropathic pain, what's going to be the next big thing?

Dr Argoff: One of the joys of being asked to get involved in a project like this is that inevitably we learn so many new things because, you know, that's when anyone says, oh, you must be an expert, I say, I don't know anything because I'm always learning something new. One of the reasons why I moved to Albany Medical College about seventeen years ago was to be able to further my interest in studying why people benefit from topical analgesics by working with a scientist at Albany Med who studied keratinocyte neurochemistry and its impact on pain transmission. And that's a separate issue, but it indicates my love for the peripheral nervous system. And one of my thoughts historically, that is, what the central nervous system processes is what it processes and it might get input, as you mentioned earlier, from the peripheral nervous system, so that topical agents could be dampening central mechanisms. And lo and behold, as I was doing research for this article, I learned that people doing peripheral nerve blocks - so blocking peripheral input at the into the spinal cord - at Washington University, Simon Guterian and colleagues, demonstrate that they could give prolonged benefit from central pain by blocking peripheral input. And that's wild because certainly the nervous system is a two-way street. It's an understatement. What I really found amazing was that, again, blocking input helped the injured central nervous system to behave better.

Dr Jones: That is kind of cool to think about. And I'll tell you, as editor of the journal, one of the funnest things is getting to learn all about neurology, including pain and including central neuropathic pain, when in the end you're doing all the work, I just get to sit here and enjoy it.

And you're a program director of a pain fellowship. What's the pipeline look like? Are neurologists more interested in pain than they used to be?

Dr Argoff: I'm happy for this. We are seeing more and more applicants from neurology into our pain management programs. I would say… I was going to say tragically. If I say tragically, it's because what specialty better understands how to diagnose, figure out, assess, come to a conclusion? You can't have pain without your brain. It's always amazed me that more neurologists weren't interested, and I understand the background and such. Just like in migraine, it's only advances in understanding mechanisms of migraine that allow neuroscientific advances that are leading to great therapeutics - that's happening and increasing in ‘pain.’ Today, as program director, we had our fellowship interviews earlier today and three of the nine applicants that we interviewed were neurologists. Last week, I think we interviewed two or three also. That would not have happened five years ago or six years ago. And if you think about it, we can not only diagnose, quote-unquote figure out what's happening, but we now, with pain management training, we can offer people a variety of both invasive and noninvasive options, all while understanding what we're doing with respect to the nervous system in a way that's different than the other specialties that typically go into pain med. And that's such - for me, it's a beautiful experience and something I really enjoy doing. There isn't a neurological condition in the most part that either doesn't have pain associated with it or doesn't have mechanisms that overlap. If you think about epilepsy, and please don't think I'm crazy, but epilepsy is associated with disinhibited hyper-excitatory behavior, just to put it loosely, among certain neurons. That's what pain and neuropathic pain is about too. And you, in fact, we know that several mechanisms since now what medicines are used for both. But what was interesting since, if I may just go back to another point, one of the advances since I brought up the migraine that's very exciting is the whole story about sodium channels. Dr Harouthounian at WashU and his group used lidocaine injection. Lidocaine's a more generalized sodium channel blocker, but some of the newest treatments for treating neuropathic pain. Our NAV specific sodium channel blocker’s trying to match up mechanism to treatment. Not exactly the way that we do with migraine, but still a step forward to not just generally treat but really target different neuronal mechanisms. It's an exciting time.

Dr Jones: So, the pipeline is doing better because we're getting better understanding of disease, and hopefully that pulls in more interest because obviously there are big gaps in caring for patients with pain. And again, thank you, Dr Argoff, for an amazing article.

Thank you for joining us and thank you for such a fascinating discussion. I enjoyed the article.

I read the article, I learned from our conversation today. So, thank you for joining us to talk about central neuropathic pain.

Dr Argoff: Thank you for having me.

Dr Jones: Again, we've been speaking with Dr Charles Argoff, author of an article on central neuropathic pain in Continuum 's most recent issue on pain management. Please check it out, and thank you to our listeners for joining today.

Dr Monteith: This is Doctor Teshamae Monteith, associate editor of Continuum Audio. If you've enjoyed this episode, you'll love the journal, which is full of in-depth and clinically relevant information important for neurology practitioners. Use the link in the episode notes to learn more and subscribe. AAN members, you can get CME for listening to this interview by completing the evaluation at Continpub.com/AudioCME. Thank you for listening to Continuum Audio.
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Peripheral Neuropathic Pain With Dr. Miroslav Bačkonja
23 Oct· Continuum Audio
Peripheral neuropathic pain is primarily influenced by the biology and pathophysiology of the underlying structures, peripheral sensory nerves, and their central pathways.

In this episode, Kait Nevel, MD speaks with Miroslav Bačkonja, MD, an author of the article “Peripheral Neuropathic Pain,” in the Continuum October 2024 Pain Management in Neurology issue.

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

Dr. Bačkonja is the clinical director in the Division of Intramural Research at the National Institutes of Health in Bethesda, Maryland.

Additional Resources

Read the article: Peripheral Neuropathic Pain

Subscribe to Continuum: shop.lww.com/Continuum

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

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

More about the American Academy of Neurology: aan.com

Social Media

facebook.com/continuumcme

@ContinuumAAN

Host: @IUneurodocmom

Full episode transcript available here

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

Dr Nevel: Hello, this is Dr Kait Nevel. Today I'm interviewing Dr Miroslav Backonja about his article on peripheral neuropathic pain, which appears in the October 2024 Continuum issue on pain management and neurology. Welcome to the podcast.

Dr Backonja: Thank you.

Dr Nevel: Misha, can you please introduce yourself to the audience?

Dr Backonja: Yes, I’m Miroslav Backonja, but everybody calls me Misha. So everybody knows me by that. I'm a training neurologist, and I also have training as well as certification in pain management. And most of my practice has been where neurology meets the pain, which is neuropathic pain. I spend some time basic science lab and then transition into clinical research. And I was in academia for a couple of decades and was most recently recruited by NCCIH National Center for Complementary and Integrated Health and have been there for two and a half years now.

Dr Nevel: That's wonderful. I would love to hear more about your career at the NCCIH, a little bit and what you do in your role now, and how that came to be.

Dr Backonja: Yeah, I was recruited to help and provide clinical support to efforts at NCCIH in the phenotyping of pain and neurologists who've done research in quantitative sensory assessment and other quantitative means of assessment of pain. Coming to NIH was very rewarding and quite of a learning experience. After six months being there, I've discovered that NIH is the biggest secret in plain sight. They say in the plain sight because it's public institution and everything is open to public and it's a secret because we don't think about it. This is in particular in reference to biomedical research training, including clinical trainings. So, I would encourage everybody to think of NIH as a place to spend some time and learn. There are wonderful research opportunities as well as educational opportunities. Vast library of presentations, green rounds and different other types of courses - some of them open to public, and some of them are up to FAS, which is a foundation of advances in science education by discovering. I feel like being back in school and having fun.

Dr Nevel: That's wonderful. Can you share with us a little bit about how you became interested in peripheral neuropathy and pain management of peripheral neuropathic pain?

Dr Backonja: It actually goes back to my residency and fellowship. And actually, you know, I had the luck of being exposed to a couple of clinicians who actually became my mentors. First was Jose Ochoa, who was one of the first people to quote from a small fiber, C fiber specifically, and he also was pioneered in quantitative sensory testing. And the other one was Charles Cleland, who was a psychologist and who pioneered assessment of patient symptoms, developing the Brief Pain Inventory is one of the tools. That actually peaked my interest in the topic of pain and once when I started learning about pain, what is the kind of mysterious experience of humans’ pain, turns out that we have learned a lot of science about the pain and can make the pain very accessible. And I hope some of this will come to the chapter that we've provided.

Dr Nevel: Thank you for sharing that. I think of peripheral neuropathy and I think most neurologists think of peripheral neuropathy as one of the bread-and-butter diagnosis within our field. For the practicing neurologist out there who might be listening, what do you think is the most important takeaway from your article that maybe they don't already know about peripheral neuropathic pain?

Dr Backonja: When it comes to peripheral neuropathy and peripheral neuropathic pain, it goes back to my early experience and still holds the truth. Neuropathies don't kill people, they just maim them. They create- cause lots of disability and if you add a pain to it, it can be quite disabling. In some regards, it has been neglected the area of development in neurology in terms of scientific discoveries, although things are changing quite rapidly as of recently. Main take home messages, and especially when it comes to a sensory neuropathies and painful neuropathies, is that it's one of the skills that has not been well researched and then not well communicated to the vaccine neurologist in terms of what to do with it. But most neurologist sensory symptoms are just like a noise because, especially when it comes to pain and prosthesias and allodynia and hyperalgesias, like, what is that like? It's just not knowing what to make of it. Frequently associated also with emotional components in terms of the people are either depressed because of persistence of pain or anxious, not knowing what's going on. And that really can create quite a bit of a challenge in terms of what to do with it. But once anybody who's interested learns the fact that sensory neuropathies and fever neuropathies as well could be as well and is easily diagnosed by a neurologist who pays a little bit of attention and gains some skills in assessing not only negative sensory phenomena, because that's what he as a neurologist get trained to detect and quantify sensory deficits as well as motor deficits and loss reflexes. Also, if you pay attention to positive sensory phenomena, which is part of the repertoire of symptoms that patients with neuropathic pain experience, it's not whether patients would have either positive sensory phenomena like prosthesia and pain or negative sensory phenomena. Actually, they have all of them. And that's kind of puzzling for many patients. And lots of times, very patients say, like, how can I hurt when I don't feel like, let's say, like most commonly it's lower extremities. Like I don't feel my feet, but it hurts. I mean, how come? Oh, that's a cardinal feature of neuropathic pain, neuropathic painful neuropathy.

Dr Nevel: Yeah, thanks for that. You know, I really thought that your Table 3-1 was really nice. It kind of lists through the common causes of peripheral neuropathic pain and just demonstrates the diversity of the different etiologies or other conditions that can cause neuropathic pain. And so, I encourage the listeners to review that table. But, on that topic, can you share with us what you think are the most important components of evaluating patients with neuropathic pain to maybe come to a diagnosis, to find what the underlying etiology or driver is?

Dr Backonja: When it comes to painful neuropathies, there are actually two problems you have to solve. So, don't forget that part. The first one is finding a pathological theology. Why a person has a neuropathy, what kind of neuropathy. And then second is, what's the nature of the sensory problems? What's the nature of the sensory symptoms, specifically pain, levodenia and hypogesia. So, figuring out the theology of the B12 deficiency or diabetic painful neuropathy, you can relatively quickly or hopefully one would relatively quickly come to that at theological diagnosis. But then the second part is the diagnosis of symptoms. What's the underlying metaphysiology of that. And again, just reminding colleagues that the specific sensory phenomena such as thermal hyperalgesia is now well established to be due to what's called peripheral sensitization of C fibers, which are the small unmyelinated fibers, expressed TP 1 receptors. So, patients who will report that taking a hot shower is very painful. An example of that or when conducting sensory exam and applying if you come to the point of examining the perception of warm and hot and patient affords the pain. That's just the hallmark of the C hurtful sensitizations to C fibrous sensitization. On the other hand, if somebody has mechanical ordinia like putting the shirt on hurts, putting the socks hurts. Well, that's evident to central sensitization. These are the simple, relatively simple but symptoms or signs that could have implication if those patients with central sensitization are more than likely to benefit from medications that restore descending inhibition, such as tricyclic antidepressants or SNRI’s. And so just paying attention to that, it gives a clinician being a clinician or a neurologist, like, let me consider prescribing medication that have central A acting properties. Or if it's purpose sensitization, something we have like a sodium channel blocking property, things of that sort. Actually, there are some other strategies such as antagonist TRPV1receptors, the capsaicin base. Those are the kind of things that can help a neurologist kind of take the evaluation of painful neuropathies to the next level.

Dr Nevel: Yeah, the- by getting a careful history and exam, that can influence what treatment you prescribe to patients. Understanding whether it's central or peripheral. On the topic of treating patients and talking with patients and evaluating them, what do you think is most important to counsel our patients about who we are treating for neuropathic pain?

Dr Backonja: Number one: by getting good history and exam. Well, really in the coming to specific diagnosis is huge relief to the patients who thinks many themselves that they're just going nuts are crazy because nobody else understands these symptoms. So, validation in terms they have a real problem. Second important step is that for the most patients, there is probably reasonable degree of therapeutic interventions that can lead to relief of pain. And also, with applying the integrative approaches with complementary medicine is that patients are given tools to deal with what is otherwise underlying problem. Those two steps make a huge difference.

Dr Nevel: Absolutely. What's the most challenging aspect about managing patients with peripheral neuropathic pain?

Dr Backonja: Actually, there are a couple. Number one thus far: we do not have a cure for any other neuropathies or painful neuropathies. So that's one of the big disappointing things one would need to communicate to the patient. The second challenge is actually the therapies that actually for neuropathic pain. There's a half a dozen- yeah, half a dozen FDA approved treatment. One thing that's interesting characteristic that all of them prove proven efficacy in clinical trials. If you scratch the surface, you find out that only 40% of patients obtain 30% pain relief. So, it's a rare patient that gets 100% pain relief, and even those, too, get what we call clinically significant, and then in studies, basically significant benefit. It's only partial penalty. But for the most those who do get the benefit, pain goes down probably enough for them to get some a semblance of normality in terms of having some control over the symptoms and their function. It's then the third challenge is really working through those available therapies to find what works for individual patients because we're not at the point yet where for example, other fields like oncology, you can quickly through the means of biomedical and other evaluation come to the patient specific therapy. So, at this point in time you're far from that. What we end up doing with when it comes to management for painful neuropathies is a trial. Sometimes patients say, well, trial and error. I would say, well, it's a treatment trials. We try one thing at a time, assess the risks and benefits and then there was many treatments that carry the benefit. If you carry it on when once, when they don't or if there's adverse events, side effects, we discontinue them. And then most of the patients end up with a combination of pharmacological and now pharmacological treatments and most of them can get some semblance of symptoms control.

Dr Nevel: I really appreciate your point on preparing our patients and you know, expectations and things like that and working with them and looking for things that may help. But also having an understanding that the likelihood of complete pain relief is maybe not a super high chance of complete pain relief.

Dr Backonja: But if you're going back to the kind of preparing patients, it's a good to acknowledge or give a chance to express themselves because many times they patients are confused because they have symptoms that are confusing to them. And so just to have them express it. And for example, my alma mater, we developed the color paint drawing where the different sensory qualities are presented by different colors. And then on the body diagram, patients draw where they have symptoms. And this is probably one of the rare examples where you can literally see a pain because these neurologists can recognize the patterns. You can see the pattern of the motor, right, is multiplex or radiculopathy or the list goes on and on. So, this is one of the kind of tools that's very simple, but gives the patients another way to communicate because lots of times they really have difficulties expressing themselves.

Dr Nevel: Right. So, the opposite of the most challenging, can you share with the listeners what you find the most rewarding about taking care of patients with peripheral neuropathic pain?

Dr Backonja: What is rewarding is that with some work- and again, it's not easy work because it does require multiple visits and multiple assessments and the reassessments, most patients can get control over their symptoms to the point of coming to beginning some of the functional improvement and aspects of quality of life like sleep and work, they are definitely rewarding and most of the time it's fairly obvious. And again, pain management is definitely a team sport where really, it's important to gauge colleagues. Most of the places don't have what I have had when I was in academic institutions, easy access to health psychologist or physical therapist. Most communities do have those specialties. And many patients actually benefit from things that are what's considered a complementary medicine, such as Tai chi or yoga. And actually, in my practice, Tai chi was probably most common prescription for my patients because, as I tell them, there are multiple benefits. Number one: one of the risks of patients, especially prophyl neuropathies and lower extremities, is a loss of proprioception. Again, even those who have a reasonable preserved proprioception over welding, noise of pain actually makes the problem walking the at risk of falling. Actually, Tai chi one gets improvement in balance. There's also medicating component to it. So, mindfulness medication is kind of built in it and that all kind of gives the patients a better control of symptoms. So, some of those interventions are easily accessible in community. So, it's, again, it's a patient education that really takes important part.

Dr Nevel: Yeah. And that Tai chi is maybe one of the answers to the next question that I have for you. But as the clinical director of the Division of Intramural Research at the National Center for Complementary and Integrative Health, I have to ask you, Misha, what sort of integrative and complementary type interventions do you counsel your patients about, maybe beyond Tai chi, and which ones do you think are the most helpful?

Dr Backonja: To clarify, the NIH patients I see are all admitted per protocol. Actually, NIH has the largest research hospitals called clinical NIH Clinical Centre, which has a hospital and clinics. All the patients that come to our program, they come per protocol for the most part.

They come for specific investigations. At the moment, we do not have intramural treatment protocols, although in near future one of my goals is to establish that. The NIH funds- 90% of funding from NIH goes extramurally to academic institutions and other healthcare organizations and so on, and only 10% goes for intermural research. So, what we do is much smaller in scope, much more focused. So, what do we support NCCIH actually support extramurally full range of anything from probiotics, research in microbiome related to health and pain all the way to interventions such as mindfulness meditation? Intramurally, once when patients come for protocol, we evaluated and it's unavoidable to be a question. So, what do we do now? What recommendations do we make? Again, we don't- with the present time, we have treatment protocols and then, most of the time, what I can do is provide recommendations to the patients when they go back to the treating community, to the treating providers. It's usually a fairly comprehensive list including pharmacological and non-pharmacological accommodations for those who have had experience with pharmacology. Sometimes I can just say yes, continue or change or whatever. But then when it comes to additional complementary accommodations, they always provide information. For example, why do I recommend Tai chi? Or, what's the benefit of yoga and why would one want to try to learn trying to behavioral therapy or mindfulness meditation? What's the benefit of turmeric and some other components of what's called anti-inflammatory diet and what's the rationale behind all of that? So rather than just giving a list of recommendations and leaving it that, I try to engage patients in terms of having to understand why something is recommended, whether the fits with their expectations and what fits with their lifestyle and so on.

Dr Nevel: Yeah. So, what's coming up, what's next in painful peripheral neuropathy? What do you think is exciting? Where do you foresee some breakthroughs in this field?

Dr Backonja: Probably what will make the most difference is application of some of the really molecular biology tools that are being applied to peripheral neuropathy. So hopefully one of these days you'll have a cure for neuropathy and pain and anything would come to that will be probably interaction between a nervous system and an immune system, in particular neuroinflammation. That's kind of my bias. They're probably that's- well, the answer will be, but many painful neuropathies - actually every painful neuropathy, because they come from, as a result, specific pathologies - are different in a sense of trajectory natural course that will have to be first addressed. And again, depending on the underlying disease and molecular biology of that and genetics of it will determine that. But on the other hand, there are some common denominators, as we talked, when it comes to painful neuropathies, which is drivers of peripheral and central sensitization. And maybe one of these days, we'll find what are those drivers and how to change the system so it does not produce pain and other associated symptoms.

Dr Nevel: So once again, today I've been interviewing Dr Miroslav Misha Backonja, whose article on peripheral neuropathic pain appears in the most recent issue of Continuum on pain management in neurology. Be sure to check out Continuum Audio episodes from this and other issues. And thank you to our listeners for joining us today. And thank you, Misha, so much for talking with me today about your article. I encourage all of the listeners to read it. It was very comprehensive and just really wonderful to read.

Dr Backonja: Thank you. Enjoyed it.

Dr Monteith: This is Dr Teshamae Monteith, associate editor of Continuum Audio. If you've enjoyed this episode, you'll love the journal, which is full of in-depth and clinically relevant information important for neurology practitioners. Use this link in the episode notes to learn more and subscribe. AAN members, you can get CME for listening to this interview by completing the evaluation at continpub.com/AudioCME. Thank you for listening to Continuum Audio.
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Spine Pain With Dr. Vernon Williams
16 Oct· Continuum Audio
Spine pain is one of the most common presenting concerns in health care settings. It is important for neurologists to understand strategies for evaluating and managing patients with spine pain.

In this episode, Katie Grouse, MD, FAAN, speaks with Vernon B. Williams, MD, FAAN, author of the article “Spine Pain,” in the Continuum October 2024 Pain Management in Neurology issue.

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

Dr. Williams is the director of the Center for Sports Neurology and Pain Medicine at Cedars-Sinai Kerlan-Jobe Institute in Los Angeles, California.

Additional Resources

Read the article: Spine Pain

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More about the American Academy of Neurology: aan.com

Social Media

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@ContinuumAAN

Guest: @VernWilliamsMD

Transcript

Full episode transcript available here

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

Dr Grouse: This is Dr Katie Grouse. Today I'm interviewing Dr Vernon Williams about his article on spine pain, which appears in the October 2024 Continuum issue on pain management in neurology. Welcome to the podcast, and please introduce yourself to our audience.

Dr Williams: Oh, well, thanks for having me. My name is Vernon Williams and I'm a neurologist here in Southern California.

Dr Grouse: So, I want to start off today by asking, what do you feel is the key message from your article?

Dr Williams: So, I think the key message is that we want to make sure people understand that there's really a distinction between abnormal imaging, tissue damage, nociception, and this experience of spine pain. So, the concept is that nociception is different from the clinical experience of pain; nociception, meaning the electrical signaling from these, quote unquote, pain generators and that kind of thing. But it's really an incomplete framing. We really want people to understand that the experience of pain is colored by a number of other things, things like genetics, biochemical factors, behavior and psychological factors, social factors, those kinds of things. So that's one of the big messages, this distinction between nociception and this clinical experience of pain.

Dr Grouse: Why do you think it's important for neurology clinicians to read this article?

Dr Williams: Well, I think, you know, for one thing, spine pain is very common. So, it is likely that neurologists will encounter patients who come to see them because of that chief complaint.

But I think that if we want to really be successful at treating spine-related pain, then we really have to know all of that basic information, the basic knowledge that we came to learn as residents and medical students or what have you. But it's also important to know that that knowledge is necessary, but it's insufficient. You really also have to confront pain from the standpoint of these other things, these other behavioral factors, psychological factors, social factors, and you got to kind of combine those things to be the most successful in treating this very common condition.

Dr Grouse: You know, you mentioned earlier about the difference between tissue damage pain and nociception. I find this to be, you know, a really great lens thinking about these concepts to view this topic and your article specifically. Can you go a little more into what the difference between, specifically, pain and nociception really is?

Dr Williams: Yeah. I mean, so when we talk about nociception, in many ways we're talking about the electrical activity. And so, there's the stimulation of these nerves, in the periphery typically, and that electrical signal is transmitted, you know, from those nociceptive fibers into the spinal cord. And it's headed from the first-order neuron to the second-order neuron and axons in the spinal cord and eventually reaches the brain. But essentially the concept is that it's not pain at that point. It's not pain until those signals reach the cortex and they are experienced in some context. And that context really colors whether or not, and to what extent, people experience pain or suffer pain as a result. So, when we think about nociception, we tend to think about kind of tissue damage or the threat of tissue damage. And in clinic, we tend to kind of focus on that and we look for relationships between abnormalities on imaging studies that could be causing those kinds of electrical signals. And we tend to focus less on that second but critical aspect of things, and that's that individual 's personal experience, which is colored by a number of different things: their attention, their expectation, colored by how we interact with them, our verbal and non-verbal communication with them. And again, like we talked about: their history, who are they, their genetics, their behavioral history, their psychological history and those kinds of things. So, it's really this combination of things that we have to be aware of when we're treating spine pain. And I think the tendency is for us to focus on the first half and less on the second half.

Dr Grouse: Absolutely. I certainly think our training and our focus on localizing the lesion may in some ways hurt us in that sense because we really focus so much on the first and not so much the second. Would you say that's probably right?

Dr Williams: Yeah, I mean, that's part of our heritage as clinicians, particularly neurologists. It's, where's the lesion? And so, what happens when there is no, quote unquote, lesion? What happens if there are multiple potential lesions? And so, these kinds of concepts, I think, become really important, and the context in which you're examining and evaluating that patient becomes important. And I think they are at least as important as the potential pain generator or the nociceptive signal.

Dr Grouse: Now, you mentioned earlier something about sort of how we approach the patient and the language we're putting out, the body language. I found the concept of nocebo and maladaptive pain-related neuroplasticity to be absolutely fascinating when I was reading your article, and I was really surprised to learn that clinicians can really contribute to this effect unknowingly through their body language, verbal language, nonverbal messaging, and even how they're interpreting the test results? When a patient comes to see you with chronic back pain, how do you approach the whole process to minimize this effect and, really, to set the stage for more constructive and therapeutic evaluation?

Dr Williams: Yeah, Katie, I think that's… it's tough because our culture is so, you know, it's so ingrained in our culture to look for a structural abnormality as an explanation for an individual 's symptoms. And so, I find myself struggling with that all the time, not only discussing why we're ordering an imaging study, but, if that person comes back and I'm describing to them the abnormalities on that imaging study, I've got to be very careful about describing them in the context of what we expect. And so, I'll typically try to use words like, well, you've got some wear-and-tear changes that we all get, as compared to saying, well, you've got a disc herniation abnormality at L five S one that's causing your pain. That statement could have a negative effect on that individual's framing of what's going on. Maybe that L five S one disc is contributing to their symptoms and maybe it isn't. Maybe it's been there or for years and maybe it's new. And even if it is new, does that mean, in that patient's mind, that now they've got an abnormality that has to be fixed or else they will continue to have pain? And so, kind of trying to keep all of those things in mind is why we want to kind of color that interaction. And I mentioned both verbal and nonverbal interaction and communication with the patient, because I think that they are picking up on all of these signals. Some of them are very obvious and some of them are very subtle. But keep in mind their brains, their nervous systems are primed to interpret all of these signals, both verbal and nonverbal. And that's going to have a downstream - or upstream, I would say - effect on their framing and how they interpret the interaction and what they think it means for them and their future. So, you know, it's kind of a big thing to think about when you- every time you walk in a room, but it's an important thing to think about when we're communicating with patients.

Dr Grouse: It's absolutely fascinating and has really made me go back and think about, gosh, are there ways that I could have done things better to really message this in a more helpful way? And on that note, do you have any tips or tricks on how to put out that that messaging, both verbal and nonverbal; to be, you know, to avoid those pitfalls of kind of reinforcing the wrong message about tissue damage?

Dr Williams: Yeah. I mean, so one of the main things is trying to be very purposeful about educating people on the difference between tissue damage or potential tissue damage and pain. And so being careful not to use statements like, well, I think your pain is coming from this disc or this structural abnormality because again, we want to try to separate those things.

They are different. I think that, you know, how we discuss imaging studies is very important because you want people to understand that an imaging study is just that. It's anatomy and it doesn't equal function, it doesn't equal what they experience in terms of sensory symptoms and pain. But I think the goal is to try to be very purposeful and maybe even reexamine how we discuss those things or when we discuss those things. One of the things I've found helpful is kind of the order in which I perform my clinical assessment. So traditionally, I was taught, like many, take the history, do the physical examination, and then start to discuss and educate patients. Right? Here's the test I want to order, here's what I think may be going on, so on and so forth. I think in some cases it's more beneficial to take the history and, before the physical examination, discuss what I'm thinking, taking that opportunity to discuss the differences between nociception, tissue damage, the experience of pain, the importance of movement, so on and so forth. And then do the physical examination so that that person has some idea of what is it that he's looking for. How is this going to inform his opinions and recommendations and so on and so forth. But also provide them with the concept that movement, for instance, is safe unless they have certain kinds of red flags on their history. I'm encouraging movement and I'm encouraging them to recognize that some of these movements they may have predicted would have been painful for them actually aren't painful, and they may start to internalize the concept that they can do it once without paying, that probably means that they're not damaging themselves every time they perform that movement. And if they can do one pain-free rep, that's important, and that may counteract the concept that they are damaging themselves every time they move and every time they feel pain, that means that there's tissue damage. So, what we talk about, how we talk about it and even when we talk about it during the course of that evaluation may have some negative or positive effects. And it may be beneficial to kind of think about those things and whether or not our typical approach might be the best or maybe we can improve on that or adjust that, particularly in certain situations and with certain patients.

Dr Grouse: That’s absolutely fascinating, and great tips I think that all of our listeners will want to incorporate as we're approaching this patient population. You know, in your article, I also wanted to talk about, you mentioned some really interesting treatments for pain is that I think would include, or would, fall under the category of neuromodulation. Can you summarize some of these options for us?

Dr Williams: Yeah. I mean, so I think that the concept of neuromodulation, I tend to think of it in a very holistic sense. And so not only focusing on the application of external stimuli and that could be, you know, electrical stimuli, magnetic stimuli, cryo, analgesia, those kinds of things in order to turn up or down nervous system activity, electrical signals, what have you.

I think of neuromodulation in a global sense. I think in a way, cognitive restructuring and education, in a way, is a form of neuromodulation. It's affecting how that individual frames the concept of their pain, structural changes versus experience, so on and so forth.

But generally, I'm talking about these kinds of things. So, there are some very interesting approaches with electrical stimulation and it doesn't necessarily have to be permanent implantation of a stimulator as we tend to think about with spinal cord stimulation, but there are some interesting temporary peripheral nerve stimulators that that can be very helpful for various kinds of spinal pain. And then there's also these technologies that I find fascinating. Some of them are in the wearables category. So, combining the education and framing and cognitive restructuring with things like virtual reality, there are some interesting programs that combine some predictive modeling with virtual reality, such that an individual has goggles on,

they are participating in some activity that requires them to move in a certain direction and move to a certain extent that may or may not match what they are seeing visually in the goggles.

So, you can kind of begin to kind of dissociate their expectation of when they may experience pain as a function of their movement from what actually happens. So, these kinds of things, I think, are really interesting ways to augment our traditional approaches to pain, physical therapy, rehabilitation, medications, some kinds of injections, with these additional approaches that really have an effect on the nervous system as opposed to just focusing on what I would call kind of the mechanical anatomy, the joints and the discs and what have you, with traditional approaches.

Dr Grouse: It's really exciting to hear about some of these new options that can be tried to help with this neuromodulation and sort of cognitive restructuring. Of course, understanding that there's some things that we do ourselves that do this in the clinic encounter, which I think is a great reminder. I wanted to touch on, in your article, you had mentioned that we really have to be aware as clinicians, that health inequities and disparities and even the social determinants of health have inevitable effects on spine pain. How can our listeners better recognize and ensure equitable care for this patient population, particularly in light of the fact that many of these therapies that we've just been talking about can be difficult to access even in the best circumstances?

Dr Williams: Well, you know, thanks for asking that question. I think that's a great question. I think from the standpoint of, you know, health equity and addressing, you know, disparities and that kind of thing, the first thing is to just acknowledge and recognize that these things are present. And even, you know, though we may have the best intentions, there may be scenarios where our practices are affected and our patients are affected by these kinds of things.

So, I think the first thing is the acknowledgement. And then the second thing is kind of trying to figure out if there are things that we can do as individual practitioners, or our offices can do or the entities that we interact with, maybe that's a hospital system or what have you to address these kinds of things. So, we know, for instance, from the standpoint of race and ethnicity, there's disparities with respect to African Americans, with Hispanics and other ethnic minorities and the kind of care they receive. We know that access resulting from insurance coverage and geographical limitations, that kind of thing can be significant. And interestingly, it doesn't necessarily mean that the person is uninsured. So, for instance, we will often see individuals who've had work injuries and who are covered by the workers’ compensation system have certain limitations placed on what they have access to, often resulting in lots of frustration from those patients. And that's a reality that we sometimes have to work really hard to overcome. Socioeconomic status, provider bias. And again, this is something that we have to kind of do some internal searching to say, hey, am I approaching these individuals on a on a more equal and equitable basis, or am I also subject to some of the biases that that I've been exposed to and trying to overcome that? So, I think that's a huge part of the context. And when we talk about how we learn, whether we're talking about spine pain or anything else, I'm a believer in that kind of cycle of pedagogy that includes content-based information, which is kind of the very basic foundational information, that includes things we can memorize and definitions we can memorize. And that may include things like what we've talked about relative to kind of the nociception and pain pathways, so on and so forth. But then there are concepts, and we've talked about the concept of verbal communication and nonverbal communication, the concept of cognitive restructuring and neuromodulation as an approach. But then context is kind of that last level, probably the most significant level in terms of how we can integrate all this information and really master information. And that context has to do with things like social determinants and disparities and the reality that these things have an effect on how we evaluate and manage patients and the success with which patients can be managed. And so, I appreciate that question, I think it’s a great question, because it gets that kind of the reality of what does this look like in real life as opposed to just on the page or just in a textbook.

Dr Grouse: Well, that's really helpful and certainly something that we can all keep in mind as we try to be more aware of this, and I like the idea of just acknowledging it and just having it there, knowing that this exists and helping that inform how we approach these patients.

I wanted to ask you, what do you think the biggest controversy is currently in the evaluation and management of spine pain?

Dr Williams: You know, I think that there's a couple of controversies that are interesting. Nowadays, one of them has to do with the utility of some of the things that have been performed and done most frequently for spine pain, and that's things like epidural injections, facet injections, some of the interventional procedures. There's some controversy among some as to whether or not these things are effective, you know, what role they have in treatment because some people will say, oh, is there any long-term effect from these kinds of procedures? Even patients will sometimes say, hey, listen, I'm not sure if I want an injection because isn't that just temporary, or, isn't that just a band aid? But I think that when we talk about pain from the perspective of it potentially being a progressive disorder and trying to be aggressive with managing pain so that we are less likely to see some of the chronic manifestations that occur with maladaptive neuroplasticity it's important to be aggressive with stopping no subceptive signals, reducing an individual 's experience of pain, optimizing their function, and having a positive effect on the ability to treat and eliminate pain, even if that means with epidural injections or blocks or what have you, as long as they're safe and effective. I think that there are some controversies evolving related to some of the regenerative procedures that have been done for other kinds of musculoskeletal pain. So, for instance, PRP and stem cells, you know, people have been doing those for knees and muscle tears and what have you. And of course, that technology has kind of evolved into potential approaches for spine pain. People are often interested in whether PRP or stem cells may help their spine pain. And so, I think that's another area of potential controversy because there hasn't been a ton of, you know, high-level evidence, although there are some, you know, there's some studies out there and there's some evidence that they may be of benefit. And I think the role of stimulators and implants for axial pain is another area of potential controversy. Those are probably the biggest things in this area of spine pain that are topics of controversy. There are things that have people talked about for years in terms of chiropractic care versus traditional medical care. But I think right now it's the utility of these kinds of interventional procedures, the role of regenerative procedures and injections, and then the role of more aggressive interventions like permanent implantation of stimulators and that kind.

Dr Grouse: Is there anything coming on the horizon in the field of managing spine pain that we should be looking out for?

Dr Williams: Well, you know, I am still bullish on the concept of neuromodulation and we've talked about that peripheral nerve stimulation, spinal cord stimulation, and then other wearables, VR, so on and so forth. I think that those things will continue to evolve, and I think that technologies continue to evolve that are likely to help with spine related pain. Some of them are very interestingly related to the ability to strengthen multifidus muscles and improve muscular function in individuals with spine pain. But I think that's one area - neuromodulation - that we'll continue to see evolution. I think that- I'm interested to see what the role of regenerative injections and regenerative procedures may play. And then just like every other field of human endeavor, artificial intelligence, machine learning, those kinds of things are likely to have a significant effect on how we diagnose an individuals, on treatment options for various individuals, and even a predicting outcome from various treatment. So those, I think, are examples of areas that we'll see continued growth and evolution with respect to spine pain.

Dr Grouse: Well, I'm very excited to see what comes down the pipeline and both vastly more to come, I'm sure. So, thank you so much, Vernon, for joining us. I really enjoyed reading your article. I really enjoyed talking about this topic. I think I've learned a lot and I hope that our listeners will take the time to read this article. It's really, really helpful.

Dr Williams: Well, I appreciate the opportunity. I really enjoy participating in this process. The interview was fun, so thanks a lot for having me. I really appreciate it.

Dr Grouse: Again, today I've been interviewing Dr Vernon Williams, whose article on spine pain appears in the most recent issue of Continuum on pain management in neurology. Be sure to check out Continuum Audio episodes from this and other issues. And thank you to our listeners for joining today.

Dr Monteith: This is Dr Teshamae Monteith, associate editor of Continuum Audio. If you've enjoyed this episode, you'll love the journal, which is full of in-depth and clinically relevant information important for neurology practitioners. Use this link in the episode notes to learn more and subscribe. AAN members, you can get CME for listening to this interview by completing the evaluation at Continnpub.com/AudioCME. Thank you for listening to Continuum Audio.
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Principles of Pain Management With Dr. Beth Hogans
9 Oct· Continuum Audio
Neurologists bring special skills to pain evaluation and management and are well equipped to appreciate both the focal and diffuse nature of pain. By using expert knowledge of the nervous system and implementing relevant therapies, neurologists can succeed at and find meaning in optimizing patient outcomes.

In this episode, Allison Weathers, MD, FAAN, speaks with Beth B. Hogans, MD, PhD, author of the article “Principles of Pain Management,” in the Continuum October 2024 Pain Management in Neurology issue.

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

Dr. Hogans is an associate professor in the department of neurology at Johns Hopkins School of Medicine and an associate director for education and evaluation at the Geriatric Research Education and Clinical Center at the VA Maryland Health Care System in Baltimore, Maryland.

Additional Resources

Read the article: Principles of Pain Management

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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

Full episode transcript available here

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

Dr Weathers: This is Dr Allison Weathers. Today I'm interviewing Dr Beth Hogans, author of Principles of Pain Assessment, Diagnosis, and Management from the October 2024 Continuum issue on pain management and neurology. Welcome to the podcast, and please introduce yourself to our audience.

Dr Hogans: Good afternoon. My name is Beth Hogans. I'm a neurologist. My faculty appointment is at Johns Hopkins School of Medicine in the Department of Neurology, where I'm an assistant professor. I also serve at the Baltimore VA Medical Center, where I'm the Associate Director of Education and Evaluation for the Geriatric Research, Education and Clinical Center, as well as a neurologist.

Dr Weathers: Thank you so much for, again, being with us today and taking the time to speak with me. I was really struck by how broadly applicable this topic is, not only to all neurologists, but to all physicians and even to all of our listeners, given how prevalent these conditions are.

Nearly all physicians involved in direct patient care treat some type of pain disorders, and we all experience pain at some point, though hopefully not chronic pain. Well, usually like to start with a question - again, it feels especially pertinent here in getting to speak with you - what is the most important clinical message of your article?

Dr Hogans: So, I'm going to say there's two key messages. The first one is that all pain has a differential diagnosis, and the second one is that all meds work better with non-pharmacological and whole-health comprehensive management incorporated. So that's why I structured the article around the ideas of assessment, diagnosis and management. It's a pretty sort of traditional, basic approach to how we look at clinical problems, but we definitely want to start with proper assessment, go on to a thoughtful differential diagnosis, and then move towards a management plan that is not just, you know, one stop shop, but actually kind of brings several aspects together. Because pain is so multidimensional; you know, it's represented in multiple places in the brain as well as other levels of the nervous system. And so, I think we're still in an era, and we may stay in an era, of, you know, needing something to go along with medication in many cases.

Dr Weathers: I think those are two absolutely critical points for our listeners to keep in mind, both, again, keeping that broad differential, and - we'll get more into management in a bit, but again - that dual strategy of both the pharmacologic and the non-pharmacologic. And again, going down a little bit more there on that management track, a really recurring theme that I picked up in your article is the importance of interprofessional collaboration in the assessment and the management of patients with pain. In the abstract, you actually use the phrase “remarkable” for the diversity of health professions, which I really loved. What other clinicians do you work with in diagnosing and managing pain conditions, and what are their roles in the care of these patients?

Dr Hogans: So, something you hear over and over again at pain meetings is, “there is no I in team.” They say that all the time. And it's one of the things I really love about pain, is that we get to work with great colleagues who have their own perspectives, approaches and therapies for pain. So, in my particular practice, which I do focus kind of more at the interface between neurological and musculoskeletal pain because of my passion and interest for spinal pain, you know, ranging from neck to tailbone, but most especially in the lower back. Physical therapy, clinical psychology, sleep sedicine, nursing, pharmacy, rehab… Podiatry is something that people don't often think of, but is really important for getting spine mechanics correct… Ergonomics. But I want to just say something about clinical psychology because there may not be enough clinical psychologists in the United States, but we as neurologists are also brain doctors. You know, we have to stay within our scope of practice. But there's a move now to talk about psychologically informed physical therapy. So why don't we talk about psychologically informed neurology? I think we could do an even better job of kind of leveraging our knowledge of the brain and how it works to kind of bring that into our practice. And so, people with pain often need a lot of empathetic support, for example, as well as knowledge about their condition.

So, I would encourage people to build local networks of folks that they refer to and work with. Because when I was a younger doctor, physical therapists taught me a lot of what I know now - because I didn't get it at med school, although by the time I got to residency, I had some really great teachers. But clinical psychology, PT, sleep medicine, those are, like, almost all-the-time collaborators for me. And then like I said, nursing, pharmacy, rehab, podiatry, et cetera, et cetera, prosthetics… those things are all important for pain.

Dr Weathers: I was struck by the quote, “one of the things I really love about pain.” That's a great line, and understand how it was meant, but I think - again, a really great quote, but I think you make such important points and, really, it is such a critical team approach. And I love all of those roles you called out. And I was struck in listening to your really thoughtful answer about how I've spoken with several other authors of actually very different topics, but about how we're thinking now about a trauma-informed care approach to many neurological conditions and the similarities with this patient population, how it likely informs very much the approach to this patient population as well and probably the significant potential.

Dr Hogans: A hundred percent! And so, for example, one of the things that probably does factor in for chronic pain - not in everyone, but in, let's say, many cases - is a prior exposure to trauma, whether it's PTSD or adverse childhood events. And so that's why, you know, clinical psychology is, like, very high up on my list of collaborators. And one of the things that I really like - you could say love - about working in the BA system is the ready availability of mental health co-management. So, I would say about a third of my patients in neurology are co-managed by mental health. And what it does is it sort of defuses a lot of what would otherwise come into the visit and be my job as a neurologist to manage, if not treat, right? I still have to manage, you know, someone who comes in with untreated mental trauma or mental health conditions if they're coming into that visit, and I'm trying to open the topic of whether mental health co-management could be helpful. That can sometimes, strangely enough, antagonize people. We’re still in an era of substantial stigma. But I can just say the practice of neurology, together with appropriate mental health co-management, is far superior than going alone.

Dr Weathers: Absolutely. And how fortunate that for a lot of your practice, your patients do have those resources available to them. And I think it speaks to the importance of those resources, that all of our patients should really have that availability, and the importance of access.

Dr Hogans: Right. So, at Johns Hopkins, we also have exceptional access to, you know, some of the world 's best clinical psychologists. And I've been really privileged to work with my colleagues in clinical psychology. The challenges that - in some of my roles, I interact with trainees and learners who are in clinics that are not as well resourced. And therein lies just tremendous heartache and difficulty. We've been trying to build some resources. There are federal resources that can help to open those conversations and maybe take some of the initial steps towards things like cognitive behavioral therapy, acceptance commitment therapy, mindfulness-based stress reduction. There's many of these psychological therapies that are proven to be effective for pain and chronic pain, and yet we haven't really had that conversation as a society about, how do we get people connected with those therapies? Many of them can be delivered on a larger scale. And I think we just need to think a lot more thoughtfully about, how can we have more of a public health approach to chronic pain and wellness?

Dr Weathers: Absolutely. Such really important points. So, we've talked about the really kind of important, obvious points for what we very much kind of know to be accurate. I want to talk now about, what are the most common misconceptions that you've encountered in treating patients with pain disorders?

Dr Hogans: Yeah. So, this is where, you know, physician as advocate for the patient really comes into play. So, I think the number one misconception that I and many of my colleagues encounter: that pain is the patient 's problem, or that that pain reflects an excessive sensitivity.

I think one analogy that I use with students that helps to kind of piece this apart is the immune system, right? There are people who have immunodeficiencies that they're not sufficiently protected from the environment, and then there are - lots of people have allergies where their immune system is sort of hyper-alerted to things that are not a true threat. And the pain system is exquisitely regulated. The neurology of the pain system is fascinating and compelling, and once you learn a little bit about it, you can apply it at the bedside, time after time after time.

So, number one: pain is real. And there is an association between strong pain and increased risk for chronic pain. And then sort of the flip side of that is that malingering or, you know, fictitious pain is probably a lot like other functional disorders in that it's part of a complex. So, I think we need to do a lot more work to discover, you know, quote, what is pain that people think is amplified or manufactured and how can we frame that in a clinical context rather than just casting blame or- we already mentioned stigma. You know, stigmatizing people does not help. And there are people who have real pain problems that are really severe and disabling, and neurologists can actually help support those people as they encounter their environment.

Dr Weathers: I really love that response. And I think you're right in that we do so often, in the medical system, tend to stigmatize these patients, even as we say the right things and we, I think, talk about it and we recognize… and yet, still, it's almost these unconscious biases. I think, as good as we've gotten in some areas, it's still hard to separate them. It's almost kind of one of the last unspoken, still-acceptable ones in some ways that oh, they must be drug-seeking or, you know, to your point, you use the word, kind of malingering, that they’re somehow, you know, either at fault or that there's some nefarious behavior going on there. And I think you made such really important points that we have to change our way of thinking that it is such a common and, frankly, wrong misconception that a lot of us really carry around and it's really hard to break. We have to kind of recognize these biases in ourself and really fight against them when we encounter these patients.

Dr Hogans: I think part of how we got there is the opioid crisis.

Dr Weathers: Yes.

Dr Hogans: You know, unfortunately we still do not have a fantastic understanding of opioid durability. Like, how long does opioid analgesia last? Not from, like, hour to hour, but, like, from month to month. Roger Cho has done some awesome work looking at long-term efficacy of opioids, and it's surprisingly modest. And yet, opioids have this profound kind of behavioral impact, that they really are highly reinforcing. And so, once they're in the conversation, you find yourself in, like, almost this life-or-death struggle between, you know, am I going to get opioids at this visit? How many? You know, if not, why not; are you going to decrease? And so those of us who are working today, you know, and have been working for the last five years, have been through this terrible struggle. And that struggle is not yet resolved. But once opioids are kind of off the table or neutralized, then we actually have a conversation that is really, you know, A: how good of a clinician are we? Do we really understand what our patient is going through? And how can we bring, like Hippocrates said, you know, get the system to bear on the problem and not just, you know, try to throw drugs at it. So I think that, really, pain challenges us to be our best selves and to, you know, really be clever and kind and helpful. And it is a really great opportunity to help. And as I said, the mechanisms of pain are fascinating neurologically. So, it kind of satisfies some of what we come to work for, but I think it's not all done yet. One of my challenges has been, I wrote an article in 2011 with one of my trainees where we counted up the number of hours documented in the double AMC database for med schools, and we found that the modal value for US medical schools at that time was four. So out of four thousand curricular hours, there were four pain hours. And when you think about the prevalence of pain, that's just a drop in the bucket. So, you know, it's getting better, but we need to come up with some new strategies. So I wrote, I've written three books now. The latest one is really designed to give that intro-level knowledge of pain. But also, obviously, the Continuum article, I wanted to kind of set the table, lay the foundation, and give people some core knowledge to get started with.

Dr Weathers: And again, a fantastic article. If our listeners haven't read it, I strongly encourage them to go back because I think you did just that. And as you were just talking, I was thinking about that, especially for those of us who, you know, depending on when in your training was, you know, mine started in the early 2000s. We've kind of lived through that era with the pendulum swinging. Where was, you know, the signs were posted in each clinic room. You know, don't forget to ask, you know, your provider about your pain meds, and it was the sixth vital sign, and all of that. And then the pendulum swung very quickly and very severely the other way, where it was, you have now created this problem, right? We have all caused this epidemic and we're supposed to immediately take these meds away, right?

And now to your point, you know, we've all been in these situations with opioids where that was all that was talked about, right? So, you know, we've all been on call and now you're getting the call overnight from people trying to get their opioids filled when, you know, not their prescriber because they knew if they called - or family members, as soon as you got prescribing rights, were now calling and asking. And we've all been in these very hard situations.

Dr Hogans: Just because you have a hammer doesn’t mean that everything is a nail.

Dr Weathers: I know. So, in trying to negotiate and navigate, you know, these very rough situations… And I think now we're reaching kind of this new era where, to your excellent point, realizing that there are a lot of other solutions. And I love how you framed it, that this is really where we can be our best selves as providers. And actually, to that point, so - as I've mentioned on this podcast many times, clinically, I'm a neuro-hospitalist and I actually wanted to get your opinion as one of the foremost experts. So, a challenging situation I'm also often faced with in my clinical role is when a patient with a chronic pain condition such as diabetic neuropathy or lumbar radiculopathy is admitted to the hospital, often with a totally unrelated condition that either results in a new acute pain, but often also exacerbates their underlying chronic pain, what's your approach to the assessment and management of similar cases? I know our listeners will return again and again to that fantastic approach you laid out in Figure 1.1 with the coordination of the pharmacologic and non-pharmacologic therapies, as we've talked about several times just throughout our conversation, how important both of those approaches are. But a lot of those options are unfortunately limited in the in-patient setting. So how do you balance those?

Dr Hogans: So, there's a whole other toolkit that comes into play for acute pain or sort of pain palliation. And you actually have some important allies in the hospital. It turns out that nurses, generally speaking, have some more education than do most physicians about pain.

And the nurses that I encounter really see themselves as genuine, sincere advocates for the patient 's interest. They're at the bedside, they're working very closely, and their training actually does, I think, give them a number of tools and a set of inspirational ideas that build towards patient comfort. So, if you communicate with nursing staff about your desire to provide more comfort for the patient, whether it's padding, positioning, activities such as, you know, having them participate in something, you know, whether it's just having a family member, you know, take them for a walk, whether it's in a wheelchair or having an older adult sit by the nurse's station just to give some form of distraction. Ice, you know, cool packs and hot packs, you know, supportive toweling or pillows, all of that can really help. Years ago, nurses used to actually be trained in giving massages, and that can provide some comfort. You know, supportive touch is kind of how we frame that nowadays. But the other piece that you have is, in many cases, PT is getting involved much earlier in the patient, you know, rehabilitation course. And remember that motion is lotion. So, our endogenous analgesia system, which actually involves both endogenous opioids and endogenous cannabinoids, can be activated through many forms of motion, as well as immobility is actually a cause of pain itself. So, you just, you break out your in-patient tool kit and, you know, there are other tools and there's other allies that you want to think about in that context.

Dr Weathers: Those are all really great tips, many of which, I know, as you said, a lot of us tend in our thinking to go right to pharmacologic strategy, so wouldn't even be considered, but I think really thoughtful, and that we do have at our fingertips. So-

Dr Hogans: I wish I had thought to put them in the article.

Dr Weathers: No, they were fantas- but again, why we podcast, agree for complimenting the article… we encourage people to take advantage of both. Well, this has been wonderful, and I know I have learned so much, even more than was in the article. I always like to end on a hopeful note, so I would love to hear what developments in the field of pain that you're most excited about. What do you think is coming down the pipe?

Dr Hogans: Well, I think, like a lot of people, I've been waiting for the opportunity that's happening right now, which is, there's a massive investment in pain science being made by the NIH. Finally. You know, we've moved from, you know, just like, little things here or there, commercial kind of entities, to, we now have large NIH dollars flowing into pain. I'd like to see not only a focus on small molecule development, which will ultimately lead to better pharmacological agents, but I'd also like to see a thoughtful approach to non-pharmacological therapies, whole health approaches. Things like healthy communities, safe exercise spaces for all ages, more nutritious food, yoga, Tai chi. We know from Skelly and Cho's article in 2020 that there are many, many non-pharmacological therapies that actually work for chronic pain. There’re some things we still don't know. Like, do older adults respond as well as middle-aged adults? And how can we get NPTs - non-pharmacological therapies - more accessible to people who are subject to disparities? I think part of what happened during the opioid era is that you could get, you know, a bottle of pills for a four-to-ten dollar co-pay and physical therapy was twenty dollars a shot. And we know PT will get you to a better place, but that person that you're talking to may not have three hundred dollars to go to a course of PT. And we need to figure out, you know, how do we do this better, safer, more healthfully.

Dr Weathers: And, I think, forgetting even the co-pay; it's the coordination, the time off work, all of it, right? So it's, I think, all of those challenges, but I think all of that are such important points about - and I think, that's really where I'm hopeful. Right? The emphasis, we talked a little bit about trauma-informed care earlier in our conversation, but the focus now on addressing the underlying social disparities of health and overall healthcare disparities, I think, is so promising.

Dr Hogans: We need to think about the long-term consequences for human health; and pain has a terrible impact on human health for many reasons, and, I hope, will continue to be the focus of effort for years to come.

Dr Weathers: Absolutely. Well, that is such an important statement to end on. Thank you again, Dr Hogans, for such a fantastic conversation and again, such an overall excellent article.

Dr Hogans: Thank you, Dr Weathers, it was great to speak with you today again.

Dr Weathers: Today I've been interviewing Dr Beth Hogans, whose article on principles of pain assessment, diagnosis, and management appears in the most recent issue of Continuum on pain management and neurology. To learn more about the topics of pain assessment and other topics of pain management, don't forget to listen to Continuum Audio episodes from this and other issues. Thank you to our listeners for joining today.

Dr Monteith: This is Dr Teshamae Monteith, associate editor of Continuum Audio. If you've enjoyed this episode, you'll love the journal, which is full of in depth and clinically relevant information important for neurology practitioners. Use this link in the episode notes to learn more and subscribe. AAN members, you can get CME for listening to this interview by completing the evaluation at Continpub.com/AudioCME. Thank you for listening to Continuum Audio.
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October 2024 Pain Management in Neurology Issue With Dr. Nathaniel Schuster
2 Oct· Continuum Audio
In this episode, Lyell K. Jones Jr, MD, FAAN, speaks with Nathaniel M. Schuster, MD who served as the guest editor of the Continuum® October 2024 Pain Management in Neurology issue. They provide a preview of the issue, which publishes on October 2, 2024.

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

Dr. Schuster is an associate professor and associate clinic director in the Center for Pain Medicine and Department of Anesthesiology at the University of California, San Diego in La Jolla, California.

Additional Resources

Continuum website: ContinuumJournal.com

Subscribe to Continuum: shop.lww.com/Continuum

More about the American Academy of Neurology: aan.com

Social Media

facebook.com/continuumcme

@ContinuumAAN

Host: @LyellJ

Guest: @NatSchuster

Full episode transcript available here

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

Dr Jones: This is Dr Lyell Jones, Editor-in-Chief of Continuum: Lifelong Learning in Neurology. Today, I'm interviewing Dr Nathaniel Schuster, who recently served as Continuum’s guest editor for our latest issue on pain management and neurology. Dr Schuster is a pain neurologist at the University of California, San Diego, where he is an Associate Professor of Anesthesia. Dr Schuster, welcome. Thank you for joining us today. Why don't you introduce yourself to our listeners?

Dr Schuster: Thank you so much, Dr Jones, for having me. My name is Nat Schuster. I am a pain and headache neurologist at UC San Diego, in the Department of Anesthesiology. I do research, clinical practice, and of course, education of med students through pain fellows, and it's been a pleasure to be the guest editor for this forthcoming issue of Continuum.

Dr Jones: Well, I want to thank you for editing the issue. I want to thank you for putting together, really, an incredible list of topics and, really, expert authors. It's been a long time since Continuum has dedicated significant space in an issue to pain management, which is obviously a hugely prevalent, major problem in society, and I think a big gap for many of us – I know it is for me in my practice, so I've enjoyed learning about it – so I want to congratulate you on the issue and thank you for doing it.

Dr Schuster: Yeah. I was just at AAN a few weeks ago. I was chatting with the person who edited one nearly 20 years ago, a prior pain Continuum issue - so, really glad that for another generation of neurologists that we're going to have this as a reference, and hopefully, it'll serve them in their care of so many patients, because this is just such a ubiquitous problem facing Americans and people around the world.

Dr Jones: Yeah, and a lot's changed in 20 years, so let's get into it. And I will say, you know, now that with our open podcast model, we're interviewing the guest editors, you have, really, an incredible view of the entire field at the moment. And with your reading of the issue and your experience as a pain expert, Dr Schuster, what do you think is the biggest controversy in pain medicine right now?

Dr Schuster: Yes, certainly. I think the most controversial thing facing our practicing neurologists is the opioid issue and how things have been changing with national guidelines since 2016, and, fortunately, we are going to have an article by Dr Friedhelm Sandbrink - who is not only a neurologist, but he is the national director for the VA system - on pain management, opioid safety, and prescription drug monitoring programs. So, it's really wonderful that we have him as an author, and I hope that all the neurologists take an opportunity to read his really important manuscript, because it's dizzying, and, you know, if you're not reading the latest things from people like Dr Sandbrink pretty much every couple of years, you're probably falling behind when it comes to what are current attitudes, what is necessary to be, you know, most responsibly continuing your patients who have been on opioids for so long (many of whom have really debilitating neurologic conditions, nothing else is helpful for them), how are you able to best treat them, best monitor them in the appropriate ways to be doing things in compliance with guidelines.

Dr Jones: And I think monitoring is one of the things that, for neurologists who are uncomfortable with pain management, uncomfortable with the modern role of opioids, I think part of it is, well, what are my accountabilities? What are my responsibilities for doing that? That article will have great insights for our readers. Cannabinoids - that's another one I hear a lot of questions about, and it's obviously evolving. The science is relatively less mature there. From your perspective, what's the role of cannabinoids in a modern pain practice?

Dr Schuster: Yeah. Once again, so much controversy there and so much variability across the US, of course, between institutions, between states - hugely different. And as we speak, it's looking like cannabis will very likely be recategorized as being schedule III, so things are changing, you know, even between right now, probably, and when people are going to be reading the forthcoming Continuum and listening to this podcast. At UC San Diego, we certainly have been on the forefront of doing clinical trials, looking at these clinical trials. They're academic studies using the NIDA drug supply. So, they're not the size and scope of so many of the things that we use that have had industry-funded, large, multicenter studies done, but the research that we've done has shown promise for quite a few different neurologic conditions, ranging from my most recent research was in the migraine space, looking at acute migraine (and I just had the pleasure of presenting that data at AAN a few weeks ago), looking at other things over the years, looking at spasticity pain and multiple sclerosis, spinal cord injury pain, diabetic peripheral neuropathy, other peripheral neuropathies. So, in the conditions that we as neurologists so often do treat, that does seem like there is a lot of promise. It's something that in our practice, some of our doctors are more comfortable with it, others are less comfortable. I know, myself, I'm very conservative when I discuss it with patients, because there is, you know, addiction concerns, misuse concerns, abuse concerns - I don't believe that it's to the degree of opioids, and I don't think that the risks are anywhere close to what they are with opioids - and while it's less in opioids, we have other things, fortunately, in this field that don't carry those concerns, and so, I certainly try to use those other options as much as possible before having the discussions about cannabinoids. That said, so many people are using them, and so I'm able to guide them towards, you know, telling that very often, doses that are lower than what they might need to get intoxicated might actually be the doses that are therapeutic, and recommending using high CBD and low THC is probably going to have less side effects, and there's some evidence towards, hopefully, having more therapeutic benefit, especially in our most recent study looking at acute migraine that you want to have that CBD component with the THC.

Dr Jones: That's outstanding. So, we know more than we used to. It still feels like a relatively understudied area (and that's partly been the regulatory barriers to doing science on cannabinoids), so we'll look forward to hearing the latest and greatest in the issue. When we think about in neurology - and I'm thinking here as a clinician - when we think about pain and neurology, we often think about neuropathic pain. And, personally, you know, I see a lot of patients who have peripheral generators for those symptoms of neuropathic pain, but central neuropathic pain is an issue, too - and we have articles on both of those, one on peripheral neuropathic pain, one on central neuropathic pain. For our listeners, what should they know about the differences between those two and the treatment approaches to those?

Dr Schuster: Yeah. So, we fortunately have two wonderful articles - one of them from Dr Charles Argoff looking at central neuropathic pain, another one looking at peripheral neuropathic pain from Drs Misha Bačkonja and Victor Wang. And one thing that I think is really interesting about central neuropathic pain is that for these same patients, we don't need to only be thinking about the central neuropathic pain alone, and not everything that they're experiencing is going to be central neuropathic pain, because they can have “frozen shoulder” - post-stroke shoulder pain is actually a really big deal. Of course, you need to be concerned about things like sacral decubitus ulcers in so many of these patients. And so, they can have nociceptive components in those same patients, and us as neurologists, taking care of these very complicated patients, need to have our eyes open for the central neuropathic components, but also in those same patients, the other pain generators that we can do a lot for.

Dr Jones: So, the musculoskeletal and other generators of pain are relevant. I think that's something that many of us have experienced. Certainly, when I trained, Dr Schuster, the general construct around pain was that it was a really biological phenomenon, and it's an adaptive phenomenon, but it becomes a clinical problem when the pain is unmanageable or out of proportion to the patient's coping skills, and it seems to have evolved - at least in terms of our understanding of it, how it impacts people's lives. It's not just a physical or biological process, right? There are psychological factors here, there are social factors here. How does that inform your thinking about management of pain?

Dr Schuster: Yeah, so, I think that that's one of the most important running themes throughout this issue of Continuum that readers will find, is that there's a movement away from the biomedical model towards the biopsychosocial model in thinking about patients. And, at least for myself, when I was coming out of neurology residency, my training was much more on the biomedical model and on medication treatments. And throughout this issue, what you'll find is discussions of the importance of the biopsychosocial model, having pain psychology as being a component of the treatment for so many of these patients. That medications alone (for many of our most challenging patients) won't be the answer by themselves - that you'll need to have involvement of physical therapy, of pain psychology. And we have an article written by the pain psychologist who I work with at UCSD, Dr Mirsad Serdarevic, which I think will be very interesting for so many neurologists. It's also wonderful that we have an article on facial pain that's written by a neurologist, Dr Meredith Barad, together with a dentist, Dr Marcela Romero-Reyes. So, it really takes a team to treat so many of these very challenging patients who we are treating in our neurological practices.

Dr Jones: Yeah, thanks for that. I realize that with a complex problem, a lot of times you need more than one area of expertise, right? It's a team process and a team effort. When you think about your own practice, Dr Schuster, when do you bring in other specialists or other perspectives in the management of patients with pain?

Dr Schuster: So, one of the articles that I really enjoyed reading in this forthcoming issue of Continuum is the one from Dr Narayan Kissoon on widespread pain syndromes. These patients who have widespread pain syndromes very often are the patients that I'm referring to our pain psychologist. Neurologists can do so much for these patients by making the right diagnosis. So often, these patients might be treated by one specialist for one organ system, another specialist for another organ system, and they can have so many different specialists, and they can be going from institution to institution. And a neurologist is in a really good position to be able to take the full history, put everything together and say, “I think you have a chronic overlapping pain condition. I think you have central sensitivity syndromes” - to be able to talk to them about their central nervous system being amped up, and that there are treatments that we can give them to help to treat these conditions, fibromyalgia and others, that affect so many of our patients who we encounter in neurologic practice. So, the International Association for the Study of Pain now has this term, nociplastic, and some people use the term neuroplastic to talk about these central sensitivity syndromes, and while not all neurologists maybe are hearing those terms used yet in clinical practice, I think it gives us a good framework - and between Dr Kissoon's article, as well as Dr Beth Hogans’ article on general principles of pain, I think that those will give the practicing neurologist a lot of good updates as to how our thinking about these patients has evolved.

Dr Jones: I know, as clinicians, we have a very cause-and-effect kind of component to our training, right? Here is the problem, here is the lesion, here is the result, and what do I do about it. I think patients also want to know what is the cause of the pain, and I think it's, maybe, historically been frustrating when someone clearly has pain and there's not a single factor, especially a removable factor, that causes it. So, I think, hopefully, having this language that we can use to communicate it with our better understanding of pain, hopefully that will help. Does that help you in your practice when you're talking to patients, when you explain what's going on? Is that well-received in general?

Dr Schuster: Yeah, you know, I think a lot of doctors are afraid to talk about fibromyalgia, for example, with patients. And what I'm finding in my practice, actually, is that a lot of patients are liberated when they can receive a diagnosis, such as fibromyalgia, that they can read about, they can learn about treatments for it, they can join support groups online and find that they're not alone - indeed, this condition affects 2 to 4% of people, and that very well could be a underdiagnosis. It keeps them from looking to different specialists for each painful body part and potentially having unneeded surgeries - and surgeries that might make things worse. So, I think physicians are understandably concerned because there is stigma - there's stigma around a lot of painful conditions, and there's stigma around some of the treatments that we use to treat these patients - and I think that physicians who are sensitive to that can sometimes be hesitant, but I'm really surprised how often patients are just really appreciative to get the right diagnosis.

Dr Jones: And you mentioned a minute ago that things have changed even since you came out of training, and, obviously, training is really important to know how to manage these problems. In my own world, I've seen, I think, an increase in the interest in pain management as a subspecialty among neurology trainees. There's obviously something that grabbed you, something that pulled you into this field. What's been your path to being a pain specialist?

Dr Schuster: Yeah, so I was a neurology resident at Ronald Reagan UCLA Medical Center, and fortunately, there, they have a few pain neurologists - and also, in the community, we have a few other pain neurologists as well that I had the great fortune to work with. And I was so impressed, especially those who are doing both pain and headache treatment, that you were able to help so many people treating very high-prevalence conditions - very often, younger patients, people who are going through school, building families - and being able to really reduce their disability, improve their quality of life and the quality of lives of their families is very gratifying. So, I encountered that as a neurology resident. I had their mentorship. And then, I applied for both headache and pain fellowships, and I did both a headache fellowship and a pain fellowship - and I think that that's been a wonderful combination for my career. To have that mix of patients has been really wonderful for preventing burnout. I think having a combination of slightly different patient populations between the headache population and the pain population, as well as, of course, those who have comorbid headache and pain conditions, has been very gratifying to treat people with these conditions. Not that many neurology residents think about doing a pain fellowship, and I wrote, together with my good friend and colleague Jacob Hascalovici, back in 2018 (that was published in the Green Journal), an article on pain neurology as an emerging subspecialty within neurology - and certainly, I would encourage any neurology residents who are interested in potentially pursuing a pain fellowship to read this article. There's such a need for neurologists in the pain field.

Dr Jones: It can be a little bit of a self-fulfilling prophecy, right? So, obviously, role modeling was important to you, right? You could see the practice when you were in training, when you could still make the decision, and if there aren't enough pain neurologists (which I think we can agree that there aren't), there are probably a lot of trainees who don't have that window into what that practice can be like, which, again, makes it kind of a barrier to folks entering the field - so, hopefully, being more comfortable with it will help our listeners and our readers, you know, integrate this into their practice and see it as a path forward for their own careers if they're interested. One last question for you, Dr Schuster, is - you know, looking into the future, obviously, when we have more options to treat these patients, it's rewarding and engaging and exciting - what do you think the next big thing in pain management is going to be? What should our listeners know that's coming down the road for these patients?

Dr Schuster: Yeah, so the interventional segment and the neuromodulation treatments are really changing a lot these last few years, and I believe are going to keep on evolving with new treatments coming down the pathway. And so, we have two wonderful and really nicely balanced articles on these topics: one of them from one of my former mentors from my UCLA days, Dr Vernon Williams, wrote one on spine pain, and he talks about the interventional pain treatments; and another from Dr Prasad Shirvalkar on neuromodulation for painful neuropathic diseases. And these are really wonderful articles for the neurologist who wants to learn about what treatments are available that, they might not personally be doing these, but that they can refer to colleagues - and these are changing a lot. Epidural steroid injections, for example: helpful for a lot of patients, but there's so much more to the interventional pain field than just that, and I think our practicing neurologists will learn a lot about, “Oh, what can neuromodulation be useful for within the pain field?” And, of course, because there's industry involvement in neuromodulation research, you need somebody who's really good at being very balanced, and I think Dr Shirvalkar did an incredible job about writing a really balanced article about the neuromodulation options that we have for patients with neuropathic pain disorders.

Dr Jones: It's exciting stuff. I think there's a lot to look forward to. I think the update that our readers and listeners will have from this issue will be extremely helpful for themselves in their practice and for their patients. For people who are audiophiles, each of these articles will have a corresponding podcast, so we'll refer people to that. And with that, Dr Schuster, I want to thank you for joining us for a really thorough, fascinating discussion on the field of pain neurology and our brand-new issue on pain neurology. And again, we've been speaking with Dr Nat Schuster, Guest Editor for Continuum’s most recent issue on pain neurology. Please check it out. And thank you to our listeners for joining today.

Dr Monteith: This is Dr Teshamae Monteith, Associate Editor of Continuum Audio. If you've enjoyed this episode, you'll love the journal, which is full of in-depth and clinically relevant information, important for neurology practitioners. Use this link in the episode notes to learn more and subscribe. Thank you for listening to Continuum Audio.
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Therapeutic Approach to Autoimmune Neurologic Disorders With Dr. Tammy Smith
25 Sep· Continuum Audio
Over the past 20 years, more than 50 antibodies have been identified and associated with autoimmune neurologic disorders. Although advances in diagnostic testing have allowed for more rapid diagnosis, the therapeutic approach to these disorders has largely continued to rely on expert opinion, case series, and case reports.

In this episode, Allison Weathers, MD, FAAN, speaks with Tammy L. Smith, MD, PhD, an author of the article “Therapeutic Approach to Autoimmune Neurologic Disorders,” in the Continuum® August 2024 Autoimmune Neurology issue.

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

Dr. Smith is a GRECC investigator and staff neurologist at George E. Wahlen Veteran Affairs Medical Center and an assistant professor of neurology, at the University of Utah in Salt Lake City, Utah.

Additional Resources

Read the article: Therapeutic Approach to Autoimmune Neurologic Disorders

Subscribe to Continuum: shop.lww.com/Continuum

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

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

More about the American Academy of Neurology: aan.com

Social Media

facebook.com/continuumcme

@ContinuumAAN

Transcript

Full episode transcript available here

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

Dr Weathers: This is Dr Allison Weathers. Today, I'm interviewing Dr Tammy Smith about her article on therapeutic approach to autoimmune neurologic disorders, which she wrote with Dr Stacey Clardy. This article is a part of the August 2024 Continuum issue on autoimmune neurology. Although, one of the things I love most about being an interviewer for Continuum is getting the opportunity to meet new neurologists and learn all about their areas of expertise, there's something really special when I get the chance to interview and catch up with old colleagues - and today, I'm fortunate to do just that. I had the privilege of working with Dr Smith when she was a resident at Rush, and I'm so excited to be able to speak to her today about her fantastic and really comprehensive article on this very timely topic. Welcome to the podcast, Dr Smith, and please introduce yourself to our audience.

Dr Smith: Hi. Yeah, thank you for inviting me to participate in the podcast and to write this article. So, I'm Tammy Smith. I am a neurologist who practices in Salt Lake City. I primarily work at the Salt Lake City VA Medical Center where I get to treat veterans with all sorts of neurologic diseases. I'm also an assistant professor of neurology at the University of Utah in the division of Neuroimmunology and Autoimmune Neurology, and I serve as a Clinical Consultant for ARUP Laboratories to help improve diagnostic testing for immune-mediated neurologic diseases.

Dr Weathers: Wow. That is a lot of different roles and things that you have on your plate. I want to start, actually, by talking about the article. Again, you cover so much ground (you and Dr Clardy) in this really comprehensive article, but if you had to choose the one most important message - if you wanted our listeners to walk away remembering one key point, what would it be?

Dr Smith: I think the key point I want our listeners to think about is just to use the resources that are available to you. Nobody can have all of these drugs (as we're talking about treatment of autoimmune neurologic diseases in this article) - no one can have all of those drugs memorized, all of the mechanisms of action, all of the approved treatments and off-label treatments, and all of the symptomatic therapies. But that's why resources like the Continuum exist - so that we can provide those resources to clinicians who are busy at that touch of, er, hopefully - or when they open their issue - to get the information they need to make decisions to take good care of their patients.

Dr Weathers: I think that is so reassuring. As I was reading this article, that was, like, one of the things that really struck me is that, you know, thinking about even being a resident and studying for something like the rate exam, you know, how much easier it used to be when there was such a limited number of drugs thinking about the autoimmune diseases or epilepsy, where just the number of drugs has just, kind of, multiplied so manyfold since I was in training, that it's really overwhelming. And I think you make a great (and as I said, a very reassuring) point that we don't have to memorize these, that there are these incredible resources (like Continuum) where it's not any longer about kind of memorization and keeping it in our heads, that it's more about knowing where to look and thinking about what's the right thing for the patient - knowing how to go and get the information is the more important knowledge there. And, actually, thinking about that and moving on, given your expertise, how do you personally approach the management of a patient with an autoimmune neurologic disorder? Again, in the article, you speak about all the different things to keep in mind, both from a therapeutic (really, treatment) standpoint, as well as a symptomatic standpoint - but what is your personal approach?

Dr Smith: My personal approach really involves considering whether the diagnosis of an autoimmune neurologic disorder is correct, first and foremost, and gathering the information to help support that diagnosis - and I think that's something that often gets overlooked in the excitement of a patient coming in with a rare-looking syndrome. Someone sends off diagnostic testing, rules out a few things, decides it's autoimmune, and starts down a pathway and keeps pushing forward. And I understand that inclination on a busy neurology service or in a busy clinic to just decide on one path and move forward, but I'm always questioning the diagnosis, even in the presence of positive antibody results sometimes. If my patient doesn't respond to the treatment that I'm giving them based on their presentation and the antibody results, I reassess and wonder if there's something else going on, are there two syndromes going on, or was that antibody result really not the right answer for some reason. So, I think my approach, really, is to always have a healthy amount of skepticism around the diagnosis, and even when I'm fairly confident in the diagnosis, to continually reassess that patient and their unique response to treatment. And then, also, their unique circumstances - so, everyone will need different symptomatic management, as well as different rehabilitation resources and other resources mobilized to help them maximize their recovery. And so, there's just not a “one size fits all” approach, but always keep talking to the patient, keep re-evaluating, stay curious, and don't be afraid to change paths when things aren't making sense.

Dr Weathers: I think that is incredibly sound, really thoughtful advice. So, I can imagine how incredibly challenging those cases must be when you think you have the right answer, it looks like it's lining up, the antibodies are pointing you in the right direction, and then, they're not responding. What else do you feel is the most challenging aspect of the management of these conditions? Is there some other kind of aspect that you also feel is really challenging in the treatment of these patients?

Dr Smith: Yeah, I think other challenges are really access to state-of-the-art therapies due to financial barriers - I think that's a pretty significant challenge for a lot of these patients, and I think we need to continue to work on advocacy efforts to make sure all patients have access to the medications they need to treat the disorders they are diagnosed with. And it's a real challenge, even when there's FDA-approved therapeutics - a lot of them are quite expensive, and then we end up playing the insurance game, and we learned that AI is automatically denying people's insurance claims, and so, we're battling computers as well as insurance companies. And I think that's a really significant challenge for a lot of these patients. And then, really, just the fact that a lot of immune-mediated neurologic disorders have a long tale. So, we don't treat a patient the same way we do for an infection and expect a dramatic and rapid recovery - a lot of the recovery for these patients happens over months to years. It's a process, and I think it's really important to be counseling patients and caregivers and other providers and educating them about this that we continue to mobilize resources to help our patients long past their inpatient hospitalization and the most dramatic part of their recovery.

Dr Weathers: Again, you raised some really insightful points there. No, I think they're really key. And I think, to your point, that even for some of these patients, that even if we can get over the economic barriers of the medications themselves and get them authorized, get them covered, you're left with, for a lot of patients, all of the other limitations of some of their social determinants of health challenges, right? So, the transportation challenges to even kind of get them to the appointments, and some of the other challenges they face, which makes some of these treatments very, very hard for them to be able to accomplish. So, it is very challenging - I think that's a very important call-out. What do you think is the easiest mistake to make when treating patients with autoimmune neurologic disorders, and how should our listeners avoid it?

Dr Smith: Yeah, that's an excellent question. One of the most common mistakes I see is either overvaluing diagnostic testing or not ordering the appropriate diagnostic testing for the clinical syndrome in any given patient. And where this comes into play, really, is the fact that when we order diagnostic testing in the United States for immune-mediated neurologic disorders, these autoantibody panels are available to us that test for a multitude of autoantibodies all at the same time, and if we don't choose the appropriate test for the clinical syndrome that the patient is there with, we run the risk of getting a positive result for an antibody that's unrelated to the syndrome we're seeing in the patient – and no test is 100% specific (or 100% sensitive, for that matter), but these low-specificity issues when you indiscriminately test really can cloud the clinical picture and delay getting the appropriate diagnosis. And so, I really think that one of the biggest mistakes is seeing maybe a low-positive result for an antibody that does not match the clinical syndrome if you go back to the books and use your resources to figure out if that result is meaningful - overvaluing that antibody result and maybe plowing forward with a treatment plan that involves a long course of immunomodulatory therapy is a pretty significant mistake. And then, on the flip side is that because these panel tests, you order them as a block, and you think that you ordered the right thing - or you think that whoever you asked to order the order for you ordered the right thing – and so often, people say the panel was negative, and they don't look at the individual results of the antibodies that were tested in the panel, and because different antibody panels are designed to test for different clinical phenotypes. I see the error where a clinician thinks that all of the antibodies necessary to test for were tested for and negative, and now they feel like their hands are tied. And so, it's both this overvaluing the diagnostic testing and forgetting to question the testing results if they're not what you expect once you get more clinical data - I think both of those are pretty big mistakes. And continuing, again, always be curious, always recheck results, and don't take laboratory values in an EMR that are in black and white as the stone-cold truth that tells you your answer - you have to stay curious about the patient, their history, their neurologic presentation, their response to treatment over time, and really keep assessing. My other soap box here about diagnostic testing is that, historically, a lot of the antibodies that we test for were called paraneoplastic (and that's because they were some of the first antibodies discovered, so, they were some of the earliest ones that we developed tests for), and clinical reference laboratories continue to offer paraneoplastic panels for historical reasons and because a lot of people think that that's what they want. But, paraneoplastic panels, in and of themselves, are not representative of a specific clinical phenotype - they just diagnose patients who have a high risk of malignancy associated with an antineural antibody. And so, most of the clinical reference labs I know of - certainly at ARUP, we have a notice on our testing page, I know Mayo Clinical Laboratories also has a notice that says, “Paraneoplastic panels are not generally the recommended panel to test for antineural antibodies. Consider ordering the phenotype-specific panel that fits the patient's clinical syndrome”. And I think that's super important – we still have paraneoplastic stuck in our head for historical reasons, and it is almost never the right answer.

Dr Weathers: It's really interesting. At my organization, you know, we actually have had some really thoughtful conversations about, do we really restrict it (you know, as part of lab stewardship efforts) - and, you know, these are expensive, and to your point, they can be frankly, really dangerous, you know, to really send somebody down this wrong path with a lot of surveillance, committing them to immunomodulatory therapies, and take you in completely the wrong direction when, actually, your low test probability was very low. So, I think that is an excellent one to really call out and for people to be very thoughtful of - and the way, again, to avoid it is to be very thoughtful about the panels. And for people, certainly, they are very convenient, but people need to be really aware of what's in them and what they are ordering and how to interpret them. And I love that advice about not just thinking about the wholesale as negative - really, you know, for many of us, they are still coming in as scan documents, you know, click into them, read every line, really understand what those results mean.

Dr Smith: And I would also say that I think people don't realize, but clinical reference laboratories would love for you to reach out when there are questions. So, if you don't understand the diagnostic testing that was performed or result, you pretty much all have hotlines. You can call and reach out to an expert in the testing and ask them some questions, and don't be afraid to reach out to your colleagues who might have more experience. We love hearing from people with questions and helping to direct them to the right testing and help them get the answers that they really want to for their patients.

Dr Weathers: I think that is a great plug. Before you order, preferably, before you send in.

Dr Smith: I do like when I hear from people before mistakes were made. Yes. That's nice.

Dr Weathers: It’s a great point.

Dr Smith: When you order these panels, you do run the risk of having these low positive results that may or may not be clinically meaningful. And we do recommend that most of the diagnostic testing be ordered in both serum and CSF. And so, a good example of a mistake that can be made is a very low-positive NMDA-receptor antibody in serum - maybe it was ordered for a patient with cognitive decline or confusion (maybe not under the ideal clinical scenario for ordering), and then it's negative in the CSF. So, an NMDA-receptor positive, negative in the CSF, not the right clinical picture, people can get really jazzed and want to treat an NMDA-receptor encephalitis, that in that case, really isn't meeting diagnostic criteria, and there are excellent diagnostic criteria that have been developed and published for that disorder and for several other autoimmune neurologic disorders, and I think going back to those criteria and really questioning yourself before you start blindly down a path based on a lab result is really important.

Dr Weathers: I think that's excellent advice, too, always keeping that in mind that just because you have gone down this path and gotten that result doesn't mean that you are stuck and committed to it. Always keeping that criteria in mind, always going back, always checking it is really important as well. Moving on from mistakes to kind of an adjacent question, what do you think is the biggest controversy right now when it comes to the treatment of patients with autoimmune neurologic disorders?

Dr Smith: You know, one of the big controversies that I see and I'm concerned about is that we've gotten into a habit of treating the way we've always treated based on expert opinion, and while experts have their opinions based on a lot of experience, they don't take the place of well-designed randomized controlled clinical trials - and in rare diseases (like autoimmune neurologic diseases), it can be really challenging to conduct those trials, especially in the face of people who have a pathway that they always do with their patients. If they have a NMDA-receptor encephalitis patient, they feel very comfortable doing their standard of care with IV steroids and then either plasma exchange or IVIG, and then possibly (and very often), I see following with a B-cell inhibitor, like rituximab, as sort of just a “kitchen-sink” approach to treatment. And while I understand the passion and the desire to make a really sick patient sitting in front of us better as fast as possible, I don't think we have adequate evidence to support that being the “one-size-fits-all kitchen-sick” approach for treatment. And I really am passionate about all clinicians all over the world, supporting randomized controlled clinical trials that are well-designed with the backing of experts in the community, so that when we look at a patient and tell them that we recommend a course of treatment, we're recommending it based on the best quality evidence available, not just what everyone's always done before. I think we can do better than that. And I think there's some controversy in this. Some people think that it doesn't make sense, we already know the answer, but I would say we haven't asked the right question and thoroughly investigated enough. And this is especially important with children, right? We know pediatric patients often don't have well-designed clinical trials to guide their treatments - but in NMDA-receptor encephalitis, many of the patients are children, and I think that they deserve to be involved in well-designed clinical trials in order to support the recommendations that we make for treatment.

Dr Weathers: And in addition to children, think about all of the other patient populations that have traditionally not been well represented in trials, right - pregnant patients, patients of color (historically very underrepresented in trials) - many, many other patient populations that have not been adequately represented.

Dr Smith: Absolutely. Yeah. I think we need to really care about that and face that problem head on and speak to it. We can't just say this is the way we've always done things, so we're going to keep doing it that way. I think we owe it to our patients and ourselves, when we look our patients in the eye, to say that we have good evidence to support the recommendations we're making.

Dr Weathers: I think we have already answered this question in many ways with each of the questions we've already talked about, but is there any other strong arguments that you can make for why it's important for neurology clinicians to read your article?

Dr Smith: Dr Clardy and I spent a lot of time working on this article, trying to put together a piece that will be a resource that people could turn to again and again. I don't think that this article is something that you should read from top to bottom and think that you've absorbed and digested everything, right? So, what we work to do was to really provide a structure and a framework to think about the treatment of immune-mediated neurologic diseases. So, rather than memorizing specific drugs for specific conditions, we developed sort of a space where you could talk about B-cell targeting therapies and the different ways we can target B-cells, we talked about complement inhibitors, neonatal FC receptors, and, really, just at a high level, how these drugs work and how they're targeted, so that going forward in three, four, five years, what I believe we'll know more about each of the individual diseases mediated by antineural antibodies. When we understand what causes that disease, we'll be able to go to a resource like this and choose rationally based on mechanism of action, a drug to treat our patient - even if it's in a patient with such a rare disease that we don't have the luxury of a clinical trial to guide our choices.

Dr Weathers: That's a really excellent point - and I know I've said it a few times, but I think you guys did such a really excellent job at really laying it out in a way that makes it this really comprehensive, really easy-to-use resource at that point of care for providers to be able to do exactly that. Well, I always like to end on a hopeful note, so, this is always my favorite last question – but, what do you think is the next breakthrough coming in the treatment of patients with autoimmune neurologic diseases?

Dr Smith: Yeah, I think in the near future (I certainly hope, at least) that the next breakthrough is going to be in really being able to deliver personalized care based on what we understand about the mechanisms of a patient's rare disease. So, again, right now, I find we're kind of left with the “kitchen-sink” approach because we know so little about the mechanisms that drive each of these unique neurologic diseases and we don't have enough information from clinical trials to inform rational treatment decisions, so we go with these broad approaches - and I really think that in the near future, with work being done by a lot of people (dedicated people over the world) on biomarkers and things that predict either onset of disease or relapse or disease severity or really looking at basic fundamental mechanisms that drive disease, we're going to be able to make more rational choices in the treatment of these patients and mobilize the resources that are expensive, but valuable for the right patient at the right time.

Dr Weathers: That is a very exciting and hopeful future to look towards. Thank you, Dr Smith, for joining me on Continuum Audio. It was wonderful to get to spend this time with you again. Again, today, I've been interviewing Dr Tammy Smith, whose article on therapeutic approach to autoimmune neurologic disorders, written with Dr Stacey Clardy, appears in the most recent issue of Continuum on autoimmune neurology. Be sure to check out Continuum Audio episodes from this and other issues. And thank you to our listeners for joining today.

Dr Monteith: This is Dr Teshamae Monteith, Associate Editor of Continuum Audio. If you've enjoyed this episode, you'll love the journal, which is full of in-depth and clinically relevant information important for neurology practitioners. Use this link in the episode notes to learn more and subscribe. AAN members, you can get CME for listening to this interview by completing the evaluation at Continpub.com/AudioCME. Thank you for listening to Continuum Audio.
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Neurologic Manifestations of Rheumatologic Disorders With Dr. Jennifer McCombe
18 Sep· Continuum Audio
Basic knowledge of the common CNS manifestations of rheumatologic diseases and sarcoidosis is important. In the context of many systemic inflammatory diseases, CNS disease may be a presenting feature or occur without systemic manifestations of the disease, making familiarity with these diseases even more important.

In this episode, Kait Nevel, MD speaks with Jennifer A. McCombe, MD, author of the article “Neurologic Manifestations of Rheumatologic Disorders,” in the Continuum® August 2024 Autoimmune Neurology issue.

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

Dr. McCombe is an associate professor in the Division of Neurology, Department of Medicine at the University of Alberta, Edmonton in Alberta, Canada.

Additional Resources

Read the article: Neurologic Manifestations of Rheumatologic Disorders

Subscribe to Continuum: shop.lww.com/Continuum

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

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

More about the American Academy of Neurology: aan.com

Social Media

facebook.com/continuumcme

@ContinuumAAN

Host: @headacheMD

Guest: @Div_Dubey

Transcript

Full episode transcript available here

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

Dr Nevel: Hello. This is Dr Kait Nevel. Today, I'm interviewing Dr Jennifer McCombe about her article on neurosarcoidosis and neurologic involvement of rheumatological disorders, which appears in the August 2024 Continuum issue on autoimmune neurology. Welcome to the podcast, and I would love to have you introduce yourself to the audience.

Dr McCombe: Well, thank you, and thank you for having me. As you said, my name is Jen McCombe. I'm a neurologist in Edmonton, Alberta, Canada, where I spend kind of a third of my time in teaching roles (I coordinate the undergraduate block for our medical school there), I spend about a third of my time in a neuroinflammatory clinic in Edmonton, Alberta, and then about a third of my time doing clinical research.

Dr Nevel: Wonderful. Well, thank you so much for being here today and for chatting with me about your article on this topic.

Dr McCombe: Thank you for having me.

Dr Nevel: To start off, can you share with the listeners a little bit about your career path?

Dr McCombe: Absolutely. Yeah. So, I've had, uh, a bit of a circuitous career path. I did my medical school in Queens (which is in Eastern Canada, in Kingston, Ontario) and then went back to Edmonton, Alberta, for my residency (in Canada, we have a five-year residency program, so a little bit different than the US), but finished my residency and then did a master's degree in Public Health at Johns Hopkins while completing clinical research in HIV, actually, and did this thing we call the Clinical Scholar Training Program – so, kind of like a fellowship, but a little bit more, you know, research and academic-based. So, when I first started, I was focused more on neuroinfectious diseases, and that's kind of what my career path looked like at the time - but, actually, shortly after I finished my residency program, I also had my first child, and he, unfortunately, developed opsoclonus-myoclonus syndrome, and at the time (this was in 2010), it was a rather rare condition, so, I ended up finding myself having to become a bit of a neuroinflammatory disease specialist at the same time. So, at that point, I transitioned into working in the neuroinflammatory clinic with some mentorship but was getting all of the kind of weird and wonderful referrals and diagnostic dilemmas from my colleagues who recognized I kind of developed some expertise, and so decided (actually, mid-career) to take a sabbatical, and in 2021, completed a fellowship in autoimmune neurology at the Mayo Clinic. So, I finished that quite recently and then went back, and now I'm feeling much more, I guess, confident, too. Sometimes, you wonder about, you know, the choices you're making. I recognize most of the conditions I'm dealing with don't have, in fact, any evidence for their treatment, and that was confirmed when I went to the Mayo Clinic and found that, really, it was just trying to gain an understanding of the disease process to make a rational choice to medications and treatments. So, now, I'm back and kind of trying to focus a little bit more on some clinical research in that area since I've kind of solidified that expertise.

Dr Nevel: Wow. Well, thank you for sharing with us your career path and how, you know, unexpected life events kind of changed your interests or molded your interests (changed kind of the things that you became expert in, you know), and being fluid in your career path and willing to kind of take a break and reassess and get additional training. That's really inspiring to, I think, to me, and probably to a lot of listeners, that you can always, you know, develop more expertise in the more niche area or additional area no matter where you are in your stage of life or career path.

Dr McCombe: Yeah.

Dr Nevel: So, can you tell us a little bit more about - you know, you shared with us kind of autoimmune inflammatory disorders and how you became interested in that, neurosarcoidosis, specifically (you know the article focuses on that), and what's your background in neurosarcoidosis, how you became interested in that specifically and in neurologic manifestations of rheumatologic disorders?

Dr McCombe: I started in our neuroinflammatory clinic over a decade ago, and, you know, at the time, a lot of the expertise in any of these neuroinflammatory disorders was quite spread out over the country, and so, as I kind to alluded to before, often some of the more complicated patients where there wasn't necessarily clear-cut evidence or even, you know, a fellowship path to get there, I would end up getting referrals for - and so, I developed quite a cohort of patients with central nervous system primarily, but other types of neuroinflammatory and autoimmune neurologic diseases, and part of that cohort was a rather large (and still growing) group of patients with neurosarcoidosis. And so, I kind of developed some practical expertise, although, as you can see in the article (and as I'm sure you all know), the approach to the treatment is extremely variable. One of the most telling things is when we were at the Mayo Clinic, one of my co-fellows actually pulled all of the neurologists in neuroinflammation at all of the Mayo Clinic sites and asked them, you know, what is your treatment approach to a patient with neurosarcoidosis, and I think got twelve completely different responses as to the medications chosen and the length of time for the tapers and things like that. So, you know, it is very much a part of neurologic disease treatment that we still really don't have great evidence for, and although we do have some kind of rational choices that we can make based on other types of evidence, so -

Dr Nevel: Yeah.

Dr McCombe: And I enjoy working with patients with these types of diseases where we can kind of work together to come up with a treatment plan that makes sense for them and also makes sense based on whatever evidence we do have at this time.

Dr Nevel: Yeah. So, moving on to the article a little bit, knowing that this is a area of neurology where there's a lot of, you know, maybe personal expertise and experience but not a ton of data or evidence to necessarily guide our standardization to our treatments and approach, what do you think is the most important clinical takeaway from your article for our listeners?

Dr McCombe: Well, I mentioned before I coordinate the neuro block for our undergraduate program here, so I've developed over the years (I've been doing that for a number of years) a curriculum that's all based on, kind of, that approach to - and I like to do it that way because it's very practical. I like the students to be able to basically take their class notes and then go to the emergency department on their first shift as a clerk and, you know, use their approach to headache that I've developed for them to kind of take a clinical history and examine a patient with that sort of problem. And so, similar to that, I tried to do an approach to, you know, a couple of the more common presentations that would make you think of a rheumatologic condition or neurosarcoidosis in looking at the approach to CNS vasculitis and the approach to, uh, pachymeningitis - and these are difficult differentials for lots of neurologists, because it really relies on a lot of medicine knowledge, and we graduate from our residencies slightly more confident in our medicine knowledge, because we get a lot of that in our residencies. But as neurologists, as we go through our careers, we get much more confident in our areas of specialty, and at least for myself and many of my colleagues, much less confident in other things like general medicine. And so, it's difficult, because you have to face your areas of potentially less confident knowledge and really think about that in the differential - and so, I think, you know, I put those two big “approach to” sections in there, because they're the most relevant for the conditions that I was covering. But, I think also what I would say to a learner or a more experienced neurologist who might be reading the article, kind of pick out the little things that you might add to your own kind of approach to - you know, when you see that person with an ataxia, remember that Sjogren syndrome is one of the things you might consider that could be a treatable cause, or you want to see a sensory neuronopathy, don't just think paraneoplastic – again, Sjogren syndrome. So, kind of pick out those little pearls and add them to your approach to that patient that we all see, and I think that would be my biggest takeaway.

Dr Nevel: Yeah. Thank you. So, kind of like, keep this information from the article in mind so that you keep rheumatologic disorders in mind as a possibility when you're approaching a patient with whatever neurologic symptoms they're presenting with. So, what do you think is challenging? You kind of already mentioned a little bit, you know, just that it stretches us maybe into the medicine arena and so maybe stretches our medical knowledge, especially as we become more subspecialized or focused in neurology - but what is challenging about identifying, diagnosing neurologic symptoms as being related or due to an underlying rheumatologic disorder?

Dr McCombe: Absolutely. Yeah. Well, as you said, you know, it forces us to kind of face that medicine stuff that we might not be as comfortable with, but I think what else is challenging is that, sometimes, those medical clues aren't there. For the rheumatologic disorders for the most part, they are. Sjogren’s is potentially a little bit different in that, potentially, the symptoms are less obvious or a little bit more subtle. But, in particular, with neurosarcoidosis, there's a distinct proportion of the patients that won't, in fact, have any systemic complications of their underlying disease, and so, you have to think about it even when the clues aren't there. That's why you have to add it to those kind of differential diagnoses where it might be considered, because those systemic clues that we all rely on when we do our review of systems and we ask about rashes and joint pain and lung issues, and these sorts of things may not be there - and so, you still have to think about it even when it might be completely isolated to the central nervous system.

Dr Nevel: What is our understanding of why some patients with rheumatologic disorders develop neurologic involvement? Do we have an understanding? Do we know why some patients do and some patients don't? I know that's, you know, kind of, uh - that's a tough question, but that was something that I thought of as I was reading your article, like, why does this happen to some people?

Dr McCombe: Absolutely. I mean, I think, potentially, it's a little bit more clear for some of them, like rheumatoid arthritis, because, typically, if you develop a CNS complication of this, it's, in fact, just because you've had the disease for a very long time, and often, it's uncontrolled, and so you think about the disease “spreading” now to the central nervous system - but for other conditions, like neurosarcoidosis, it is much less clear, and even if you look at the epidemiologic patterns for that, it makes it even more muddied in that in some populations, it appears that they develop more central nervous system disease, whereas in others, less. And so, why that is the case and why certain individuals might develop this complication of these diseases I think is yet to be seen.

Dr Nevel: Yeah, that's always the crux of things if we can figure out the why, then maybe we could prevent it, right?

Dr McCombe: Million-dollar question always.

Dr Nevel: Always. So, what do you find the most intriguing about neurologic involvement of rheumatologic disorders?

Dr McCombe: Well, I think one of the things that, really, I mean, for neurosarcoidosis in particular, so many patients do so well, and that's what I really like about it. You know, you see patients who present with an incredible burden of disease radiologically, and yet, don't look nearly as sick as they should when they're sitting in front of you. And then, you start them on therapies and some of them do so well, and even those with relatively devastating deficits, or moderate disease who do have neurologic symptoms, have a remarkable improvement in their neurologic symptoms with treatment. And so, that's always something that's quite rewarding when you get to see these patients in follow-up, and they're generally quite thankful because they're doing so well. And it's different from many of the neurologic diseases that we treat. I mean, in autoimmune neurology, we're lucky because we do have a number of diseases that are quite treatable and patients can have wonderful outcomes. But, you know, it's always scary when we see patients with devastating neurologic signs and it's great to see improvement with treatment. And so, that really draws me to it.

Dr Nevel: Yeah, absolutely. That's really rewarding when you're able to help somebody get better in such a profound way.

Dr McCombe: Mm hmm.

Dr Nevel: What is one common misconception about neurologic manifestations of rheumatologic disorders? Or what do you think is not well understood by treating clinicians?

Dr McCombe: I think probably one of the things I see the most is, sometimes, an undertreatment of the patient. And so, I see patients who, you know, other clinicians may have seen and have made the diagnosis, and perhaps it's a lack of confidence in the diagnosis and so they kind of want somebody else with a subspecialty to kind of confirm the diagnosis, but that treatment hasn't been initiated despite pathological confirmation on biopsy of another tissue. And these patients, like I alluded to before, they do well, but you need to treat them and you need to treat them adequately, and when their symptoms are quite impairing, you need to treat them adequately now. And so I think, sometimes, that delay in starting a second-line therapy and relying on steroids for too long - those sorts of things can really expose a patient to a lot of different side effects and to a lot of different complications that they may not have had, too. So, that's why I spent some time focusing on the treatment, because I think just gaining a little bit of comfort with some of these more common second-line medications is a good thing, because starting those early, I think, makes sense because you can really save the patient a lot. And then, the other thing, too, is that when you're using steroids, think about all of the systemic things that you're causing - think about the increased risk of infection and the fact that you need to prophylax for certain infections, think about bone health, think about protecting the lining of someone's stomach - so not only kind of thinking about your disease in isolation and what you need to do for treatment, but that you need to ensure that you're appropriately prescribing the patient all of the things they need to do to protect themselves during these times.

Dr Nevel: Yeah. I think that's so important. And I'm glad that you brought that up, because I think, unfortunately, many of us have seen a patient who ended up having PJP pneumonia (or something like that) because they weren't put on antibiotic coverage for prolonged steroid use or, you know, bone health - all of that is really important to think about. So, this may be entering a territory where there's no, you know, great evidence, but you mentioned, you know, starting kind of that maintenance or second-line agent - when do you decide to do that in patients? And maybe we can focus (since it gets a little broad), but, you know, in a patient with neurosarcoidosis, let's say - when you're starting the steroids, when do you decide, okay, this person is also going to need a maintenance therapy? Is that something that you do at the beginning when you're starting the steroids, or is that something that you think about later on depending on how their course goes?

Dr McCombe: Yeah. In my practice, I do it at the outset - again, because I'm quite focused on, you know, as soon as I get them on it, getting people off steroids - and so I start essentially almost all of my patients on it unless there's some other contraindication or complication to their disease. And because I deal with central nervous system complications in the vast majority of my patients, I'm starting a TNF-a inhibitor as well as methotrexate, and that's because I see a lot of patients with cord disease and significant brain disease, and so I want to treat them kind of more aggressively from the outset. And so, typically, they'll be on steroids, um, a TNF-a inhibitor, as well as methotrexate, and then I just back off, actually, as they do well. And so, I try to taper the steroids quite quickly over the course of just a number of weeks, or kind of two to three months at most. I maintain the TNF-a inhibitor, and then in some patients, depending on how they're doing, I might eventually stop the methotrexate. Some patients tolerate it so well that we don't for a number of months - other patients want to try to minimize their medications as quick as they can. So, that's my personal practice. In the province where I live, we don't have to worry about access to these medications, and so I understand that that might be an issue in some centers where people practice and have different access and different funding. Of course, I live in a country where we have universal healthcare, and in our province, I have very good access to these medications and they're funded from my patients regardless of socioeconomic status, and so I have the luxury of making these choices and I understand that other people might not, but that's my personal practice and I find it works quite well in the vast majority of patients.

Dr Nevel: Yeah. And you bring up a really good point that, you know, access to some of these medications for patients with CNS manifestations of sarcoidosis, neurosarcoidosis, sometimes can be challenging to treating the patient with medications that you feel like would be best for them. But that's wonderful that you don't have those access issues where you live. How long do you typically continue the TNF-a inhibitor in patients, since you mentioned, you know, tapering off the steroids, tapering off the methotrexate, potentially depending on patient tolerance and course. What's your approach to the TNF-a inhibitor?

Dr McCombe: Yeah, so, of course I follow them clinically, and then radiologically as well, and it's really satisfying if you can see the resolution of their symptoms as well as resolution of the abnormalities and the MRI, so I let that guide me a little bit. But, in most patients, I keep them on therapy for about one to two years, and then at that point, see if I can cease it in some patients. And I, again, continue to follow them radiologically and clinically after I cease it so that I can ensure that I'm catching their disease more quickly if it does come back and then can just reinitiate therapy, but in lots of patients you're able to stop the medication and they have persisting, kind of, disease freedom after that, and so they don't need to be on anything.

Dr Nevel: Yeah, great. And I'm almost hesitant to focus so much on neurosarcoidosis. (It was the rheumatologic manifestation that you talked about the most in your article.) I'm going to put in a plug for everybody to read your article so that they can read about neurologic manifestations of rheumatoid arthritis, Sjogren’s, lupus, Behcet’s - many more things. But focusing on neurosarcoidosis, it can be difficult in my experience to definitively diagnose, and people who have neurosarcoidosis particularly, and people who don't seem to have any systemic manifestations or, you know, imaging findings consistent with sarcoidosis - can you share your approach with us? And you outlined this in your article nicely, too, but your personal approach to patients with suspected neurosarcoidosis, and how you make that clinical decision to treat somebody with possible neurosarcoidosis, somebody who maybe you're not able to get pathologic evidence on?

Dr McCombe: Absolutely. Yeah, those ones are difficult. And, you know, whenever possible (as I mentioned in my article), I think pathological evidence of a diagnosis is important, because then when you find yourself a year down the road and a treatment path and you have uncertainty, it's much more difficult to consider continuing medications that can have quite a number of side effects when you're not absolutely certain about that diagnosis. But, in some patients, you know, I've had patients who might have nondiagnostic biopsies (if you attempt to do a biopsy), or they have disease in a site that really just isn't amenable to biopsy, or they have some other reason they can't have a biopsy. So, how I approach that is that, you know, if you think about possible neurosarcoidosis similar to any other nondiagnosed, you know, blow out-like lesion (for lack of a better term) in the CNS, if it's steroid-responsive, I think that kind of going down a path of treating it as a steroid-responsive lesion is kind of the approach that I take - so the diagnosis in the chart might be possible neurosarcoidosis, but in the back of my mind, I'm just thinking of kind of a steroid-responsive nondiagnostic or idiopathic lesion. So, I then follow that up typically with something like methotrexate (so, a more broader- spectrum immunosuppressant-type medication), and if the methotrexate is able to maintain the response that the steroids initiated, then eventually get them off the steroids. And so, you know, if I think about my patients that I've treated in the past, if they have a diagnosis of possible neurosarcoidosis, I probably don't start a TNF-a inhibitor as quickly in them, because in the back of my mind, I'm always wondering what type of inflammatory lesion this is, but that steroid responsiveness really helps me decide to start a second-line or maintenance therapy and then, typically, in those patients, as I mentioned, I'll start something like methotrexate a little bit more soon.

Dr Nevel: Yeah, great. Thanks for sharing that with us. So, what do you think comes next in this field? What excites you? Where do you think our next kind of development or understanding or breakthrough, whether it's diagnostic or treatment-wise?

Dr McCombe: I think, in the field, you know, any immunologic diseases, we've been really gaining a much better understanding of pathophysiology, and that's honestly what excites me the most, when you can know precisely what part of the immune system is at play here (whether it's, you know, complement-mediated or antibody-mediated) and then being able to then rationally choose medications based on a really clear understanding of the disease is something that I think is kind of novel in a way. For so many years, we would use kind of big broad-spectrum immunosuppression - even in multiple sclerosis, still, we use medications that, historically, we've found to be helpful - but we don't have a great understanding sometimes of why the medicines work. So, kind of going at it from the other way, where we're actually determining what is the exact pathophysiology of disease and then making a rational approach to a therapy, or choosing a therapy based on that, I think is what excites me the most, and I think we'll gain a better understanding of even a broader swath of diseases and be able to make those choices more often. That's what I like about this field.

Dr Nevel: Great. Well, thank you so much for sharing that - and looking forward to the future in this area of neurology. And thanks so much for talking with me today and sharing your story and your expertise and knowledge.

Dr McCombe: Well, thank you for having me. It's been fun.

Dr Nevel: And I encourage all the listeners to read your article. Again, today, I've been interviewing Dr Jennifer McCombe, whose article on neurosarcoidosis and neurologic involvement of rheumatologic disorders appears in the most recent issue of Continuum on autoimmune neurology. Be sure to check out Continuum Audio episodes from this and other issues, and thank you to our listeners for joining today.

Dr Monteith: This is Dr Teshamae Monteith, Associate Editor of Continuum Audio. If you've enjoyed this episode, you'll love the journal, which is full of in-depth and clinically relevant information important for neurology practitioners. Use this link in the episode notes to learn more and subscribe. AAN members, you can get CME for listening to this interview by completing the evaluation at Continpub.com/AudioCME. Thank you for listening to Continuum Audio.
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Autoimmune Neuromuscular Disorders Associated With Neural Antibodies With Dr. Divyanshu Dubey
11 Sep· Continuum Audio
Many autoimmune neuromuscular disorders are reversible with prompt diagnosis and early treatment. Understanding the potential utility and limitations of antibody testing in each clinical setting is critical for practicing neurologists.

In this episode, Teshamae Monteith, MD, FAAN speaks with Divyanshu Dubey, MD, FAAN, author of the article “Autoimmune Neuromuscular Disorders Associated With Neural Antibodies,” in the Continuum® August 2024 Autoimmune Neurology issue.

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

Dr. Dubey is an associate professor in the departments of neurology and laboratory medicine and pathology at the Mayo Clinic in Rochester, Minnesota.

Additional Resources

Read the article: Autoimmune Neuromuscular Disorders Associated With Neural Antibodies

Subscribe to Continuum: shop.lww.com/Continuum

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

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

More about the American Academy of Neurology: aan.com

Social Media

facebook.com/continuumcme

@ContinuumAAN

Host: @headacheMD

Guest: @Div_Dubey

Transcript

Full episode transcript available here

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

Dr Monteith: This is Dr Teshamae Monteith, Associate Editor of Continuum Audio. Today, I'm interviewing Dr Divyanshu Dubey about his article on autoimmune neuromuscular disorders associated with neural autoantibodies, which is part of the August 2024 Continuum issue on autoimmune neurology. Welcome to the podcast. How are you?

Dr Dubey: Hi, Dr Monteith. Thank you for inviting me to be a part of this podcast. I'm doing well.

Dr Monteith: Well, why don't you introduce yourself to the audience? And, call me Tesha.

Dr Dubey: I'm Divyanshu Dubey (please, call me Div). I'm one of the autoimmune neurology consultants here at Mayo Clinic Rochester. I'm an Associate Professor of neurology, as well as lab medicine and pathology. My responsibilities here are split - partly seeing patients (primarily patients with autoimmune disorders, including neuromuscular disorders), and then 50% of my time (or, actually, more than 50%), I spend in the lab, either doing research on these autoimmune disorders or reporting antibodies in a clinical setting for various antibody panels which Mayo’s neuroimmunology lab offers.

Dr Monteith: That's a nice overlap of subspecialty area. How did you get into this work?

Dr Dubey: I think a lot of it was, sort of, by chance. Meeting the right people at the right time was the main, sort of, motivation for me. Initially, I trained in India for my medical school and didn't really got much exposed to autoimmune neurology in India. I think our primary concern in my training was sort of treating TB meningitis and cerebral malaria - that was my exposure to neurology, including stroke and some epilepsy cases. As a part of application for USMLEs and coming here to residency, I did some externships, and one of the externships was at Memorial Sloan Kettering Cancer Center, and that's when I worked a few weeks with Dr Posner and got introduced to the idea of paraneoplastic neurological syndrome working with him. And that sort of started - I wouldn't call it vicious cycle - but my interest in the area of autoimmune neurology and paraneoplastic neurological disorders, which subsequently was refined further through residency and fellowships.

Dr Monteith: That's interesting. I actually rotated through - I did a externship also at Sloan Kettering, and I had a clinic with Dr Posner. And I thought, at the time, he was such a rock star, and, like, I took a picture with him, and I think he thought it was insane. And I didn't go into autoimmune neurology. So, you know, interesting pathways, right?

Dr Dubey: Yes. And I think he's inspired many, many people, and sort of trained a lot of them as well.

Dr Monteith: So, why don't you tell us what you set out to do when writing this article?

Dr Dubey: So, I think, given my background and training in various subspecialties in neurology, I was, sort of, formally did fellowships in autoimmune neurology, as well as neuromuscular medicine. One of the areas in these areas that I focus on is in my clinical practice, as well as in my sort of lab work, is autoimmune muscular disorders - and that to, specifically, autoantibodies and their clinical utility for autoimmune muscular disorders. So, that's what I wanted to focus on in an article. When I was invited to write an article on autoimmune muscular conditions in general, I thought it was very difficult to pack it all in one chapter or one article, so I narrowed my focus (or tilted my focus) towards antibody-positive disorders and trying to understand how we as neurologists can firstly sort of identify these conditions (which may end up being antibody-positive) – and then, on the other hand, once we get these antibody results, how we can find the utility in them or find them useful in taking care of our patients. At the same time, I also wanted to kind of highlight that these antibodies are not perfect, they do have certain limitations – so, that's another thing I sort of highlighted in the article.

Dr Monteith: So, why don't we just start with a very broad question - what do you believe the role of autoantibodies is in the workup of neuropathies and then neuromuscular disorders? Obviously, when we think of myasthenia gravis, but there are some presentations that you may not necessarily think to first order autoantibody tests. So, what is the role, and where does it fit in the paradigm?

Dr Dubey: I think it's extremely crucial, and it's evolving as time goes on, and it's becoming more and more clinically relevant. Let's say three, four decades ago, the number of biomarkers which were available were very limited and only a handful - and there has been a significant increase in these biomarkers with growing utilization of newer techniques for discovery of antibodies, and more and more people jumping into this field trying to not only discover, but try and understand and validate these biomarkers (what they truly, clinically mean). These antibodies, like you pointed out, ones for myasthenia (such as acetylcholine receptor-binding antibodies, or MuSK antibodies), they can be extremely helpful in clinical diagnosis of these patients. We all know the importance of EMG in managing our patients with neuromuscular disorders. But, oftentimes, EMG nerve conduction studies are often not available at every center. In those scenarios, if you have antibodies with very high clinical specificity, and you're seeing a patient on examination whom you're seeing ptosis (fatigable ptosis), double vision, you're suspecting myasthenia, you send antibodies, and they come back positive. It brings you closer to the answer that may, in turn, require you to refer to a patient to a place where you can get high-quality EMGs or high-quality care. In addition to getting to the diagnosis, it also, sometimes, leads you in directions to search for what is the trigger. A good example is all these paraneoplastic neurological syndromes (which we started our conversation with), where once you find a biomarker (such as anti-Hu antibodies or CRMP5 antibodies) in a patient with paraneoplastic neuropathies, it can direct the search for cancer. These are the patients where, specifically, these two antibodies, small-cell lung cancer is an important cancer to rule out - they require CT scans, and if those are negative, consider doing PET scan – so, we can remove the inciting factor in these cases. And then, lastly, it can guide treatment. Depending upon subtypes of antibodies or particular antibodies, it can give us some idea what is going to be the most effective treatment for these patients.

Dr Monteith: I think paraneoplastic syndromes are a very good example of how autoantibodies can help guide treatment. But, what other examples can you provide for us?

Dr Dubey: Yeah, so I think one of the relatively recent antibody tests which our lab started offering is biomarkers of autoimmune neuropathies - these are neurofascin and contactin, and those are great examples which can target or guide your treatment. I personally, in the past, have had many CIDP patients before we were offering these testings, where we used to kind of start these patients on IVIG. They had the typical electrodiagnostic features, which would qualify them for CIDP. They did not show any response. In many of these cases, we tried to do sort of clinical testing or sort of research-based testing for neurofascin and contactin back in the day, but we didn't have this resource where we can sort of send the blood, hopefully, and within a week, get an answer, whether these patients have autoimmune neuropathy or not. Having this resource now, in some of these cases, even before starting them on IVIG, knowing that test result can guide treatments, such as considering plasma exchange up front as a first-line therapy, followed by rituximab or B-cell depleting therapies, which have been shown to be extremely beneficial in these conditions. And it is not just limited to neurofascin or contactin (which are predominantly IgG4-mediated condition), but the same concept applies to other IgG4-mediated diseases, such as MuSK myasthenia, where having an antibody result can guide your treatment towards B-cell depleting therapies instead of sort of trying the typical regimen that you try for other myasthenia gravis patients.

Dr Monteith: And you mentioned where I was reading that, sometimes, nerve conduction studies and EMG can be useful to then narrow the autoantibody profiles. Oftentimes, in the inpatient service, we order the autoantibodies much faster, because it's sometimes harder to access EMG nerve conduction studies - but talk about that narrowing process.

Dr Dubey: Yeah. And it goes back to the point you just made where we end up sending, sort of, sometimes (and I'm guilty of this as well), where we just send antibodies incessantly, even knowing that this particular patient is not necessarily likely to be an autoimmune neurological disorder, and that can be a challenge, even if the false-positive rate for a particular test is, let's say 1% - if you send enough panels, you will get that false-positive result for a particular patient. And that can have significant effects on the patient - not only unnecessary testing or imaging (depending on what type of antibody it is), but also exposure to various immunotherapies or immunosuppressive therapies. It's important to recognize red flags – and that's one of the things I've focused on in this article, is talking about clinical, as well as electrodiagnostic, factors, which make us think that this might be an autoimmune condition, and then, subsequently, we should consider autoantibody testing. Otherwise, we can be in a situation - that 1% situation - where we may be sort of dealing with a false-positive result, rather than a true-positive result. In terms of EMGs, I think I find them extremely useful, specifically for neuropathies, distinguishing between demyelinating versus exonal, and then catering our antibody-ordering practices toward specific groups of antibodies which are associated with demyelinating neuropathies (if that’s what the electrophysiology showed) versus if it's an exonal pathology (considering a different subset of antibodies) - and that's going to be extremely important.

Dr Monteith: You're already getting to my next question, which is what are some of the limitations of autoantibody testing? You mentioned the false-positivity rate - what other limitations are there?

Dr Dubey: So, I think the limitations are both for seropositive, as well as seronegative, patients. As a neurologist, when we see patients and send panels, we can be in a challenging situation in both of those scenarios. Firstly, thinking about seropositives - despite the growing literature about neurology and antibodies, we have to be aware, at least to some extent, about what methodologies are being utilized for these antibody tests. And what I mean by that is knowing when you're sending a sample to a particular lab, the methodology that they're utilizing - is that the most sensitive, specific way to test for certain antibodies? We've learned about this through some of the literature published regarding MOG and aquaporin-4, which has demonstrated that these antibodies, which we suspect are cell surface antibodies, not only generate false-positive, but also false-negative results if they are tested by Western blots or ELISAs. Similar can be applied to some of the cell surface antibodies we are investigating on the autoimmune neuromuscular side (we have some sort of unpublished data regarding that for neurofascin-155). Secondly, it's also kind of critical when you're getting these reports to kind of have a look at what type of secondary antibodies are being utilized, an example being we talked about neurofascin-155, and I mentioned these are IgG4-predominant diseases, so testing for neurofascin IgG4 and knowing that particular patient is positive IgG4 rather than neurofascin pan-IgG. That's an important discrimination, and important information for you to know, because we have seen, at least in my clinical practice, that patients who are positive for neurofascin IgG4 follow the typical story of autoimmune neuropathies - the ones who are not (who are just neurofascin-155 IgG-positive), oftentimes can have wide-ranging phenotypes. The same applies to neurofascin-155 IgMs. And then (not for all antibodies, but for some antibodies), titers are important. A good example of that is a3 ganglionic receptor antibodies, which we utilize for when we're taking care of patients who have autoimmune dysautonomia - and in these cases, if the titers of the antibodies are below .2 nmol/L, usually, those don't have a high specificity for AAG diagnosis. So, I get referred a lot of patients with very low titers of a3 ganglionic receptor antibodies, where the clinical picture does not at all look like autoimmune autonomic ganglionopathy. So, that's another thing to potentially keep in mind. And then, on the seronegative front, it's important to recognize that we are still sort of seeing the tip of the iceberg as far as these antibodies or biomarkers are concerned, specifically for certain phenotypes, such as CIDP. If you look at the literature, depending upon what demographics we're looking at or sort of racial profiles we're looking at, the frequency of these autoimmune neuropathy biomarkers range from 5% to 20%, with much higher frequency in Asian patients - so, a good chunk of these diseases are still seronegative. In the scenario where you have a very high suspicion for an autoimmune neuromuscular disorder (specifically, we'll talk about neuropathies, because that's why we utilize tissue immunofluorescence staining on neural tissues), I recommend people to potentially touch base with that tertiary care lab or that referral lab to see if they have come across some research-based antibodies which are not clinically validated, which can give you some idea, some additional supportive idea, that what you're dealing with is an autoimmune neuromuscular disorder. So, we have to keep the limitations of some of these antibody panels and antibody tests in mind for both positive, as well as negative, results.

Dr Monteith: So, you've already given us a lot of good stuff, um, about titer seronegativity and false-positive rates. And, you know, also looking at the clinical picture when ordering these tests, utilizing EMG nerve conduction studies, give us a major key point that we can't not get when reading your article.

Dr Dubey: I think the major key point is we are neurologists first and serologists later. Most of these patients, we have to kind of evaluate them clinically and convince ourselves at least partly that this might be an autoimmune neuromuscular disorder before sending off these panels. Also, I find it useful to narrow down the phenotype, let's say, in a particular neuropathy or a muscle disease or a hyperexcitability syndrome. So, I have a core group of antigens, autoantigens, or autoantibodies, which I'm expecting and making myself aware of - things beyond that will raise my antenna - potentially, is this truly relevant? Could this be potentially false-positive? So, clinical characterization up front, phenotypic characterization upfront, and then utilizing those antibody results to support our clinical decision-making and therapeutic decision-making is what I've tried to express in this article.

Dr Monteith: And what is something that you wish you knew much earlier in your career?

Dr Dubey: It's a very challenging field, and it's a rapidly evolving field where we learn many things nearly every year, and, sometimes, we learn things that were previously said were incorrect, and we need to kind of work on them. A good example of that is initial reports of voltage-gated potassium-channel antibodies. So, back in the day when I was actually in my medical school and (subsequently) in my residency, voltage-gated potassium-channel antibodies were closely associated with autoimmune neuromyotonia, or autoimmune peripheral hyperexcitability syndromes. Now, over time, we've recognized that only the patients who are positive for LGI1 or CASPR2 are the ones who truly have autoimmune neuromuscular disorders or even CNS disorders. The voltage-gated potassium-channel antibody by itself, without LGI1 or CASPR2, truly doesn't have a very high specificity for neurological autoimmunity. So, that's one example of how even things which were published were considered critical thinking or critical knowledge in our field of autoimmune neuromuscular disorders has evolved and has sort of changed over time. And, again, the new antibodies are another area where nearly every year, something new pops up - not everything truly stands a test of time, but this keeps us on our toes.

Dr Monteith: And what's something that a patient taught you?

Dr Dubey: I think one of the things with every patient interaction I recognize is being an autoimmune neurologist, we tend to focus a lot on firstly, diagnosis, and secondly, immunotherapy - but what I've realized is symptomatic and functional care beyond immunotherapy in these patients who have autoimmune neurological disorders is as important, if not more important. That includes care of patients, involving our colleagues from physical medicine and rehab in terms of exercise regimen for these patients as we do immunotherapies, potentially getting a plan for management of associated pain, and many other factors and many other symptoms that these patients have to deal with secondary to these autoimmune neurological conditions.

Dr Monteith: I think that's really well said, because we get excited about getting the diagnosis and then getting the treatment, but that long-term trajectory and quality of life is really what patients are seeking.

Dr Dubey: Yeah, and as you pointed out, most of the time, especially when we are in inpatient service, or even when we're seeing the patients upfront outpatient, we are seeing them, sometimes, in their acute phase or at their disease not there. What we also have to realize is, what are the implications of these autoimmune neurological conditions in the long term or five years down the line? And that's one of the questions patients often ask me and how this can impact them even when the active immune phase has subsided - and that's something we are actively trying to learn about.

Dr Monteith: So, tell me something you're really excited about in your field.

Dr Dubey: I think, firstly (which is pretty much the topic of my entire article), is novel antibodies and new biomarker discoveries. That's very exciting - we are actively, ourselves, involved in the space. The second thing is better mechanistic understanding of how these antibodies cause diseases, so we can not only understand diseases, we can also try and understand how to target and treat these diseases - this is being actively done for various disorders. One of the disorders which continue to remain a challenge are T-cell mediated diseases, where these antibodies are just red flags or biomarkers are not causing the disease, but it's potentially the T-cells possibly attacking the same antigen which are causing disease process, and those are often the more refractory and harder-to-treat conditions. I'm hoping that with some of the work done in other fields (such as rheumatology or endocrinology for type one diabetes), we're able to learn and apply the same in the field of autoimmune neurology and autoimmune neuromuscular medicine. And then, the final frontier is developing therapies which are antigen specific, where you have discovered that somebody has a particular antibody, and if that antibody is pathogenic, can I just deplete that antibody, not necessarily pan-depleting the immune system. And there is some translational data, there's some animal model data in that area, which I find very exciting, will be extremely helpful for many of my patients.

Dr Monteith: So, very personalized targeted therapies?

Dr Dubey: Correct. Without having all the side effects we all have to kind of take care of in our patients when we start them on, let's say, cyclophosphamide, or some of these really, really, significantly suppressive immunosuppressive medications.

Dr Monteith: Well, thank you so much. I learned a lot from reading your article to prepare for this interview, but also just from talking to you. And it's clear that you're very passionate about what you do and very knowledgeable as well, so, thank you so much.

Dr Dubey: Thank you so much. Thank you for inviting me to do this. And thank you for inviting me to contribute the article.

Dr Monteith: Today, I've been interviewing Dr Divyanshu Dubey, whose article on autoimmune neuromuscular disorders associated with neural autoantibodies appears in the most recent issue of Continuum on autoimmune neurology. Be sure to check out Continuum Audio episodes from this and other issues. And thank you to our listeners for joining us today.

Dr Monteith: This is Dr Teshamae Monteith, Associate Editor of Continuum Audio. If you've enjoyed this episode, you'll love the journal, which is full of in-depth and clinically relevant information, important for neurology practitioners. Use this link in the episode notes to learn more and subscribe. AAN members, you can get CME for listening to this interview by completing the evaluation at Continpub.com/AudioCME. Thank you for listening to Continuum Audio.
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Stiff Person Syndrome and GAD Antibody–Spectrum Disorders With Dr. Marinos Dalakas
4 Sep· Continuum Audio
Stiff Person Syndrome (SPS) is treatable if managed correctly from the outset. It is essential to distinguish SPS spectrum disorders from disease mimics to avoid both overdiagnoses and misdiagnoses.

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

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

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

Additional Resources

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

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

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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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BONUS EPISODE: Continuum Aloud NMOSD and MOGAD
31 Aug· Continuum Audio
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 Movement Disorders With Dr. Bettina Balint
28 Aug· Continuum Audio
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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NMOSD and MOGAD With Dr. Elia Sechi
21 Aug· Continuum Audio
Awareness of the specific clinical and MRI features associated with AQP4-NMOSD and MOGAD and the limitations of currently available antibody testing assays is crucial for a correct diagnosis and differentiation from MS. Growing availability of effective treatment options will lead to personalized therapies and improved outcomes.

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

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

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

Additional Resources

Read the article: NMOSD and MOGAD

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: @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 Disorders With Dr. Anastasia Zekeridou
14 Aug· Continuum Audio
Paraneoplastic neurologic syndromes can present with manifestations at any level of the neuraxis. In patients with high clinical suspicion of a paraneoplastic neurologic syndrome, cancer screening and treatment should be undertaken, regardless of the presence of a neural antibody.

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

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

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

Additional Resources

Read the article: Paraneoplastic Neurologic Disorders

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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

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@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.

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Overview and Diagnostic Approach in Autoimmune Neurology With Dr. Sean Pittock
7 Aug· Continuum Audio
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.

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Read the article: Overview and Diagnostic Approach in Autoimmune Neurology

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

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

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

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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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Prognostication in Neurocritical Care With Dr. Susanne Muehlschlegel
24 Jul· Continuum Audio
Patients with severe acute brain injury often lack the capacity to make their own medical decisions, leaving surrogate decision makers responsible for life-or-death choices. Patient-centered approaches and scientific methodologies can guide clinicians’ prognostications.

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

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

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

Additional Resources

Read the article: Prognostication in Neurocritical Care

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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