Continuum Audio

This bonus episode of Continuum Audio features Continuum Aloud with Dr. Michael Kentris narrating the Selected Topics in Neurology Practice article from the February 2024 issue on Spinal Cord Disorders.

Dr. Michael Kentris is a Neurologist at Bon Secours Mercy Health in Youngstown, Ohio and Continuum Aloud program lead.

Continuum Aloud is verbatim, audiobook-style recordings of each Continuum article. It is a Continuum subscriber-only benefit, and audio files are available at ContinuumJournal.com at the article level or on the AAN's Online Learning Center at continpub.com/Aloud.

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Too much, or not enough? A wide range of nutritional deficiencies and toxic exposures may cause spinal cord dysfunction. To make matters even more confusing, the clinical presentations for these disorders may overlap.

In this episode, Teshamae Monteith, MD, FAAN, speaks with Kathryn Holroyd, MD, an author of the article "Metabolic and Toxic Myelopathies," in the Continuum February 2024 Spinal Cord Disorders issue.

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

Dr. Holroyd is an instructor in the Department of Neurology at Yale School of Medicine in New Haven, Connecticut.

Additional Resources

Read the article: Metabolic and Toxic Myelopathies

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Host: @headacheMD

Transcript

Full transcript available on Libsyn

Dr Jones: This is Dr Lyell Jones, Editor-in-Chief of Continuum, the premier topic-based neurology clinical review and CME journal from the American Academy of Neurology. Thank you for joining us on Continuum Audio, a companion podcast to the journal. Continuum Audio features conversations with the guest editors and authors of Continuum, who are the leading experts in their fields. Subscribers to the Continuum journal can read the full article or listen to verbatim recordings of the article by visiting the link in the show notes. Subscribers also have access to exclusive audio content not featured on the podcast. As an ad-free journal entirely supported by subscriptions, if you're not already a subscriber, we encourage you to become one. For more information on subscribing, please visit the link in the show notes. AAN members, stay tuned after the episode to hear how you can get CME for listening.

Dr Monteith: This is Dr Teshamae Monteith, Associate Editor of Continuum Audio. Today, I'm interviewing Dr Kathryn Holroyd on toxic metabolic myelopathies, which is part of the February Continuum issue on spinal cord disorders. Dr. Holroyd is an instructor in the Department of Neurology at Yale School of Medicine in New Haven, Connecticut. Katie, thank you so much for being with us on the podcast, and thank you so much for your excellent article. It was filled with a lot of really great tips.

Dr Holroyd: Thank you - happy to be here.

Dr. Monteith: I want to start off with knowing, how did you gain expertise in spinal cord diseases?

Dr Holroyd: Yeah, I have a fairly diverse clinical background. My primary work now is as a neurohospitalist. But after residency training, I did two one-year fellowships: one in neuroimmunology and one in neuroinfectious diseases. I think, with those things together – you know, a lot of these, especially acute-onset myelopathies, tend to present inpatient for diagnosis – so, we see a lot of those in my hospital practice. Then, I think, specifically for toxic metabolic myelopathies - to identify these, you often have to know what it's not. So, my experience with some of the other autoimmune and infectious disorders really comes into play. Then finally, I kind of focused on global health work, which is why I primarily do neurohospitalist work - to allow for travel. I spent the past year working at a neuro HIV research site in Thailand, and I've done some work (mainly with education) in Zambia. But I've seen that, kind of, all how people's environments and local areas can really affect what disorders are more common, and I think it's really important to take that into account with especially this topic, as well.

Dr Monteith: Well, your work in global health could be a whole other area, a whole other podcast that I would really want to record with you. But let's start with, what did you seek to accomplish when writing your article?

Dr Holroyd: I think, when I was writing the article along with Dr. Berkowitz, the co-author, we really wanted to focus on things that would be clinically relevant, not just for neurologists, but for clinicians all over who may not have access to a subspecialist neurologist. We tried to focus less on metabolic pathways or disturbances and focus more on clinical pearls. I tried to think, "When I see these patients, what are the questions that I have that are not easily answerable from Google or UpToDate or a textbook? And how can we really use primary evidence to answer some of those questions? For example, what percent of patients with B12 deficiency actually have an abnormal MRI? Those are the things we were asking ourselves and, hopefully, that we were able to answer through the article. We focused on three main categories of toxic metabolic myelopathies, as you can see from the work.

Dr Monteith: So, specifically, you've been writing about nutritional deficiencies, environmental and dietary toxins, drug abuse, medical illnesses, and oncological treatments. When you wrote your article and, comparing it to even, like, five or ten years ago, what has changed?

Dr Holroyd: It's a great question because, I think, even when I started writing the article, it's easy to feel like not much has changed in these particular disorders. But if you go deeper, I think that's not the case. The main ways in which things have changed, I think, on the nutritional front, is there's been an increase in weight loss and weight-loss surgery, which is one of the main contributors to all nutritional deficiencies. The second main category is - in some of these toxic myelopathies - is the increasing rates of drug use, particularly heroin, which we talk about in detail in the article. Additionally, along those lines, with climate change - we often don't think about the way that climate change can really affect disorders that are related to nutrition or the way that certain foods are prepared, especially with increasing rates of drought, and that really relates to konzo. Finally, there's been great advances in the treatment of all sorts of cancers, particularly with immunologic therapy. The one immunologic complication we talk about is with immune checkpoint inhibitors, and I think there's been a huge increase in clinicians seeing these as complications of checkpoint inhibition. So, those are the three main ways that I think these have evolved in the past decade.

Dr Monteith: Great. You spoke about your interest in clinical pearls - can you describe some essential points that you wanted readers to take away with when diagnosing and managing patients that are presenting with myelopathies thought to be due to toxic or metabolic etiologies?

Dr Holroyd: Yeah, and a lot of these are so different it's hard to find overarching themes, but I think there are a few that come through in the article. The first is that a lot - not all, but a lot - of these are reversible. Diagnosing them early is important and can really make a difference in patient outcomes. The second is a real clinical principle of all neurology that I learned from Dr Berkowitz, my co-author - is that neurology really is time course and localization. Amongst these, I think it's important to look at the time course, whether it's acute or subacute, and the location in the cord, whether it's a subacute combined degeneration or a more dorsal-column-only-predominant myelopathy - that can help you narrow the differential. A couple other small things is that, overall, these toxic myelopathies tend to be more thoracic cord-predominant and affect the legs more than the arms. In the majority of cases, the MRI will actually be normal, which is a big difference from a lot of the other autoimmune or infectious myelopathies. I think those are some main takeaways. And finally, you really have to be careful when you're interpreting the lab tests and make sure that the clinical picture fits with the lab tests that you're measuring - for example, the vitamin or other cause - and make sure that you really are correlating the diagnosis with that test. Then, I think the cause of the deficiency will affect your treatment choice; whether you're dosing supplements orally or IV, and what dose you choose - those are the major things to take into account.

Dr Monteith: I really like what you say because, I think, as neurologists, we are always thinking about localization, localization, localization, but that time course also matters for a number of diseases.

Dr Holroyd: And to that point, I think the clinical diagnosis is particularly important in resource-limited settings, where advanced diagnostics, such as MRI or lumbar puncture, may not be available. For example, konzo - the WHO has very clear clinical criteria of how to define this disorder, given that in most of the regions where cassava root is primarily eaten, there are not these diagnostics. I think we can apply that globally or even in our own practice in areas of the US or other places - to really rely on your clinical judgment and the time course and the localization of the biolopathy[IG1] .

Dr Monteith: Yeah. What was that like when you were practicing in Zambia?

Dr Holroyd: I worked primarily with Dr Deanna Saylor, who is there funding and working with neurology residents, and we would see a wide variety of clinical cases but have very little real-time information. So, I really admire the residents who train and work in Zambia and have to make clinical decisions with very little information. In those settings, the history – so, asking people about recent ingestions, any drugs, diet at home, any exposures that might cause increased risk of these conditions - is very important. And sometimes you have to rely on empiric treatments, such as vitamin B12, in cases where you may not be able to send for those tests - especially more specific tests, such as methylmalonic acid or homocysteine.

Dr Monteith: With your hospitalist experience, can you think of some cases, or like, one case that stands out that made you lose sleep at night, that you cracked the puzzle? Just so that we have this on our radar.

Dr Holroyd: Yeah, I think that there's some more unusual causes of toxic myelopathies. We saw a young woman who came in with a very acute, very severe myelopathy after studying for a test. She had a dorsal column-predominant hyperintensity, but all of her other diagnostics - lumbar puncture, everything else - was completely normal. We weren't really thinking of nutritional deficiencies because it was such an acute onset in such a young woman; we are really thinking this must be autoimmune or something else. And it actually came out that she had been ingesting whippets – so, inhaled nitric oxide, which came out a bit later in the history. And we checked for a B12, which was very low, and it turned out to be a nitric oxide-induced vitamin B12 myelopathy, which can be seen but is relatively rare and really stuck out in my mind. Thankfully, she made a full recovery with the supplementation of vitamin B12 and cessation of drug use.

Dr Monteith: Wow, that is an impressive story. I'm glad that was on your mind and you figured it out.

Dr Holroyd: Thanks. Yeah - team effort.

Dr Monteith: What should we take away about nutritional deficiencies?

Dr Holroyd: Nutritional myelopathies – I think there are kind of the four main ones that we speak about in the article - vitamin B12, folate, vitamin E and copper - and I think these really have more similarities than differences. They all present clinically very similarly, with the subacute combined degeneration of the cord (the dorsal columns and the corticospinal tracts) - that's going to give you, basically, spasticity and upper motor neuron signs, as well as sensory symptoms (loss of vibration and proprioception). Weakness can be a part of it, but that's usually a bit later in the course. Secondly, they all have similar diagnostics. As I mentioned, the MRI is going to be normal in over 50% of cases of all of these, but when it's abnormal, generally they'll be a T2/FLAIR hyperintensity in the dorsal column, and that will be the most common finding. Often, we don't have a lot of lumbar puncture data from these conditions, but generally, when lumbar puncture is performed, it will be relatively normal or noninflammatory. So, those are some of the similarities. Some of the differences are the risk factors. Vitamin B12 - the risks are going to be mainly bariatric surgery, a vegan diet, or autoimmune pernicious anemia. Folate deficiency from nutritional causes is very rare, so that's usually going to come from someone with an increased folate requirement (sickle cell anemia or certain hematologic malignancies). Vitamin E often comes from malabsorption, as seen in cystic fibrosis, or abetalipoproteinemia, or hepatobiliary disorders. And then finally, copper generally comes from gastric surgeries or from excessive zinc intake, the classic example of being denture cream. I think one way to differentiate these is by looking at the person's risk factors. Finally, I think I tried to categorize them in my head in a few different ways with clues that might give you a specific clue. So, if someone comes in with a subacute myelopathy and they also have a macrocytic anemia, that would push you more towards vitamin B12 or folate. However, if they're presenting with a myeloneuropathy (so, that's upper motor neuron signs) but also a peripheral neuropathy on exam, you might think more vitamin B12 or copper. Then finally, if someone comes in with a myelopathy as well as ataxia, you might think more likely vitamin E deficiency. Those are some ways to categorize these that may otherwise appear very similar. But I think, at the end of the day, and someone with a subacute myelopathy and a nutritional risk factor, you'll end up sending all four of these blood tests to evaluate for appropriate treatment.

Dr Monteith: Well, let's move on to climate change. It's not often that we see climate change in a neurology article, but yet it's a thing that affects patients. Can you talk about konzo? I wasn't familiar with the term before reading your article, so thank you.

Dr Holroyd: Yeah, it's one of these that we debated - should we include this in the article (because it is relatively rare). But I think it is important to keep a global perspective. Konzo and lathyrism are the two nutritional toxic myelopathies that we talk about, but I'll just focus on konzo for brevity. This occurs in populations that rely on the cassava root for nutrition and generally occurs in times of drought, and that's because drought increases the cyanide content in the cassava root. After higher rates of ingestion, especially in people with protein malnutrition (so, a lot of children and young women), you can actually get a toxic myelopathy from cyanide. And the mechanism is not totally understood, but it tends to be quite acute onset, primarily with spasticity, impaired gait, and weakness. It will self-stabilize, but there really is no way to improve symptoms after it's occurred. It is relatively permanent. There really isn't a lot of data on MRI findings or CSF findings, but the few case reports that have been published, they tend to be normal. I think what's important is that there are very easy public health interventions to prevent these toxicities – so, by simply increasing the wetting time of the cassava root (so, soaking it for longer), you can reduce the cyanide content and really effectively prevent this condition. So, I think the big picture takeaway that can be connected to a lot of other neurologic disorders globally is that we need to be aware of how climate change will affect our environment - and dietary changes, environmental exposures - and focus on early public health interventions to prevent these. So, how can we help prevent these rather than treat them once they happen.

Dr Monteith: Are we seeing more of it, or is it just better diagnosed?

Dr Holroyd: There's not great public health data on the rates throughout areas. It (so far) has only been reported in the African continent. There have been increases and decreases in numbers based on, I think, both the climate (so, times of drought or worse, malnutrition), but also, I think the reporting - I think it fluctuates not only with the weather but also with the amount of ability to publish on cases. So, I don't think we have a good grasp on whether, globally, their rates of konzo or lathyrism are increasing or not.

Dr Monteith: Then, heroin - we have to talk about heroin, right? It's just simply remarkable that close to a million individuals in the US over the age of twelve use heroin in 2020. So, now you just have to talk to us about heroin myelopathy because it's something that we could see.

Dr Holroyd: Absolutely. It's not something that I think most clinicians are familiar with as the complication of heroin use. But I'm sure that heroin touches all of our lives as clinicians in any field. There are two types of myelopathy related to heroin. There can be a slower, subacute myelopathy with chronic use. But what's more common, actually, is in people who have a long history of heroin use and then abstain for days to weeks and then use heroin again. This causes a very acute-onset longitudinal myelopathy that often has MRI abnormalities as well and can affect both the cervical and the thoracic cord and be quite severe, affecting all modalities (sensation as well as weakness). The mechanism really is not well understood for this and, therefore, the treatments really aren't well understood, either. Some case reports have trialed IV corticosteroids, but really, there's an unclear benefit for this. Most people will regain some recovery of function, but often it's not full recovery, and some may have no recovery. I think the follow-up question to this is, as we see the composition of drugs change – so, now there's a predominance of fentanyl, actually, whereas most of these case reports were from more traditional heroin. I was actually looking into it - this isn't covered in the article - but there has been one case report in 2019 about fentanyl use in someone who primarily used heroin, was abstinent for eight days but continued to use fentanyl patch, and developed an acute-onset, severe cervical myelopathy quite similar to this traditional heroin myelopathy. So, it seems like fentanyl will probably still have the same risks, but it's slightly less well understood at this point.

Dr Monteith: And important also for chronic pain – just, like, poorly managed chronic pain that we might see, as you do during a hospital consultation.

Dr Holroyd: Absolutely, yes - especially because this was from a fentanyl patch itself.

Dr Monteith: Great. So, why don't you wrap up the most important clinical takeaways from your article?

Dr Holroyd: I think one takeaway that we haven't really focused on is that, actually, most of the primary literature on a lot of these topics, especially the nutritional topics, are twenty to thirty years old, and I think updated case series would really inform clinical practice. When it came down to it, actually - folate deficiency - we really only found four to five case reports in all the literature, which I really think is disproportionate to how much we learned about it in medical school and residency. I think, really, a better understanding of (in this era) what the prevalence of these disorders are, how they're presenting, and effective treatments, is really needed. I think that a lot of the exciting work will also occur in the field of oncology, with new treatments, with immune checkpoint inhibitors, and better understanding of how we can mitigate the risks of neurologic complications while still allowing patients the benefit of their cancer treatment. So, I think diagnosing toxic metabolic myelopathies early is very important. And in someone with a subacute, or even acute myelopathy without a clear cause, you should really delve into nutritional, drug use, demographics (kind of, where they're from) - all of these things that we often don't take time to do on history but might be more important in these cases because a lot of them are treatable - it's really important to get to those risk factors early on. I think that's what I would like clinicians to take away from our article.

Dr Monteith: Well, I think the article is fully packed with a lot of clinical tips - important tips - but a lot of public health relevance in a really special way that it was written. Any exciting breakthroughs that you're excited about or use of technologies to advance this area?

Dr Holroyd: Right now, there really aren't a lot of novel technologies in these areas, or diagnostics. I think, in the future, with some of the more cancer-related radiotherapies or intrathecal chemotherapies, the neuro-oncologists and oncologists will really be at the forefront of minimizing these toxicities. Again, I really think that's where a lot of the more advanced diagnostics will come into play. For the others, I think it's really about early diagnosis and public health awareness, especially as it relates to heroin myelopathy in the US.

Dr Monteith: Well, excellent, and thank you for being a part of that public health awareness. Thank you for being on the podcast.

Dr Holroyd: Thank you. Thank you so much for having me.

Dr Monteith: Thank you, Dr Holroyd for joining me on Continuum Audio. Again, today we've been interviewing Dr Kathryn Holroyd, whose article on toxic metabolic myelopathies appears in the most recent issue of Continuum, on spinal cord disorders. Be sure to check out Continuum Audio podcasts from this and other issues, and thank you to our listeners for joining today.

Dr. Monteith: This is Dr Teshamae Monteith, Associate Editor of Continuum Audio. If you've enjoyed this episode, please consider subscribing to the journal. There's a link in the episode notes. We'd also appreciate you following the podcast and rating or reviewing it. AAN members: go to the link in the episode notes and complete the evaluation to get CME for this episode. Thank you for listening to Continuum Audio.

The explosion in diagnostic tools to identify immune-mediated myelopathies has led to much more precise diagnosis and treatment of these patients, but also created gaps in knowledge.

In this episode, Kait Nevel, MD speaks with Michael Levy, MD, PhD, FAAN author of the article "Immune-Mediated Myelopathies," in the Continuum February 2024 Spinal Cord Disorders issue.

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

Dr. Levy is an associate professor at Massachusetts General Hospital and Harvard Medical School in Boston, Massachusetts.

Additional Resources

Read the article: Immune-Mediated Myelopathies

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Host: @IUneurodocmom

Guest: @mlevy18

Transcript

Full transcript available on Libsyn

Dr Jones: This is Dr Lyell Jones, Editor-in-Chief of Continuum, the premier topic-based neurology clinical review and CME journal from the American Academy of Neurology. Thank you for joining us on Continuum Audio, a companion podcast to the journal. Continuum Audio features conversations with the guest editors and authors of Continuum, who are the leading experts in their fields. Subscribers to the Continuum journal can read the full article or listen to verbatim recordings of the article by visiting the link in the show notes. Subscribers also have access to exclusive audio content not featured on the podcast. As an ad-free journal entirely supported by subscriptions, if you're not already a subscriber, we encourage you to become one. For more information on subscribing, please visit the link in the episode notes. AAN members, stay tuned after the episode to hear how you can get CME for listening.

Dr Nevel: This is Dr Kait Nevel. Today, I'm interviewing Dr Michael Levy on immune-mediated myelopathies, which is part of the February 2024 Continuum issue on spinal cord disorders. Dr Levy is an Associate Professor at Massachusetts General Hospital in Harvard Medical School in Boston, Massachusetts. Welcome to the podcast. Thank you so much for being here today and chatting with me about your article. I really enjoyed reading your article. I read through it, and it felt like, you know, just really enjoyable. I had no concept of time when I was reading it. I encourage all of the listeners to read the article, too. I'll start with just a really broad question, with - what is the most important, clinically relevant thing from your article that you'd like the neurologist listening today to know?

Dr Levy: I would say that the group of conditions in which the immune system can attack the spinal cord are growing. We're getting better at identifying the specific antigens, like in the case of NMO neuromyelitis optica and in MOG antibody disease. We're getting better at identifying targets for treatment, like with neurosarcoidosis - identifying those biologics that seem to help. And then, we're even beginning to characterize some of the idiopathic forms, some of which follow covid, or vaccines, or other conditions. I think the message is that we're getting a lot better out there, and if you have a case of inflammation in the spinal cord, then this is something that has a good workup now (and people should be paying attention to articles like this that give them an idea for how to work this up), and then the most appropriate treatment.

Dr Nevel: Right. And not to get too much "in the weeds," but in your article, you really outlined very nicely an algorithm or stepwise approach in evaluating patients with suspected immune-mediated myelopathies. Could you just briefly go through the general principles of that evaluation and stepwise approach, and what you would consider really necessary tests to order for these patients?

Dr Levy: Sure. I would say that the first thing that you want to do is to make sure that it's inflammatory. And to do that, we have – the blood tests are few and far in between. If you're dealing with inflammation in the spinal cord, the few ways that we have to convince ourselves that there's truly inflammation - there are MRI and spinal fluid - and those objective tests need to be considered in the appropriate clinical context. The order of events is: patient comes in, reports certain neurological functions that localize to the spinal cord - that's step one, Step two, neurological exam that confirms that there's a neurological problem that localizes to the spinal cord. And then, numbers three, four, five are objective workups, including MRI of the spinal cord and other parts of the neuraxis, CSF testing, and blood testing, all of which then support your differential diagnosis. For each diagnosis, that order is the same, and it should always result in an answer for you, which ultimately may all be negative (and then we have a plan for that, too). If all your workup is negative, you don't know what caused it - at least a plan to deal with that as well.

Dr Nevel: Building off of that - in your article, you mentioned that there are shared features between the different immune-mediated myelopathies. We have some tests that can help us differentiate, but what are some of the limitations or strengths of our currently available diagnostic evaluations - our clinical clues to help us differentiate between the different types?

Dr Levy: The biggest limitation, of course, is that it's hard to access the spinal cord. We're not going to biopsy almost any patient unless we really have to rule out cancer. Otherwise, we don't want to take a punch out of a very small spinal cord that's carrying a bunch of fibers going in and out of the brain. So, that is our biggest limitation. We can't physically see it under the microscope, so we have to infer what's going on with MRIs and spinal fluid. And of course, spinal fluid isn't necessarily directly in touch with the inflammation - it could just be around it and bathing it. But we're hoping that there are clues from the spinal cord that shed into the spinal fluid that we can detect by lumbar puncture. I do think that we're getting better and also we're identifying things in the bloodstream that could also impact the spinal cord. And of course, blood tests are much easier to do, and some of these blood tests look for antibodies, which we know last for months and months. So, even if a person is having trouble getting their workup done on time, these antibody tests are still useful, even months after onset.

Dr Nevel: Yeah. In your opinion, what have been some of the bigger breakthroughs? And I know there's been a lot in immune-mediated myelopathies over, let's say, the past five to ten years. That's a long timeframe, and I know a lot of things have happened during that timeframe – but what do you think has made the biggest impact in either evaluation and/or treatment for these patients?

Dr Levy: When I was training, everything in the spinal cord was always MS. It was just - everything was multiple sclerosis in this big bucket of MS that we thought was heterogeneous. Now we're identifying the biomarkers that actually are distinguishing these patients from MS. We know what the immune system is targeting now in many of these conditions. Then, based on that immunological pathway, there are drug targets that have been developed. So, for even a very small disease, with 20,000 people in the US (one in 100,000) who have neuromyelitis optica, we now have three FDA-approved drugs because the science is so well worked out. And now there are two trials in MOG antibody disease, for example. As we identify new biomarkers based on the antigen specificity of the disease, I think we're going to have more and more specific therapies for each of these conditions, even if they're rare diseases.

Dr Nevel: Yeah, that's great. Thanks for mentioning those, and I urge the listeners to check out the article to read a little bit more about some of those treatments for NMO spectrum disorder and MOG antibody disease that are in trials. What's the most common mistake that clinicians can make when evaluating or treating patients with immune-mediated myelopathies. What should we watch out for or to try to avoid doing?

Dr Levy: I would say, at the beginning, there might be an urge to overtreat because we know that "time is spinal cord" - we don't want to waste time; we don't want to lose time. Some clinicians might just be inclined to give high doses of steroids, even in cases that they're not sure are inflammatory. The big overlap here is especially in older people who might have vascular myelopathy, where steroids might make things worse and it might delay their care. So that's the first problem – is, when physicians rush to judgment. Then the other big problem is when they take their time, and they say, "Well, this is just multiple sclerosis, probably. And we know that, in the end, MS patients do the same whether they're treated or not treated, and so we can take our time with this." Whereas if we know that this is actually NMOSD, time is spinal cord and destruction is ongoing and potentially irreversible. I would say that there's problems on both sides of the time window. My approach is to be aggressive very early on and try to identify whether or not it's inflammatory. And then if it's not, then you can take a step back and go to the other chapters in this continuum - try to figure out what this is – and if it is inflammatory, then you definitely want to get on top of the treatment.

Dr Nevel: Yeah, finding that sweet spot; making sure that you're not waiting too long but that you're not treating inappropriately or the wrong thing. So, what do you think - let's say you have a patient with an immune-mediated myelopathy; you've diagnosed them, they're undergoing treatment. What's the most challenging part of ongoing management of a person who has an immune-mediated myelopathy?

Dr Levy: I would say that one of the most satisfying parts of my career lately has been that we're good at preventing the next attack once we know what the disease is. So, for NMO and for MOG and MS, we're good at that. We can suppress the immune system or modulate it in a way that we're preventing the next attack from occurring, and patients are excited about that. But when they come into clinic and I say, "Great job, no new attacks," then they look at me and they go, "But how do I get out of my wheelchair now?" Because the damage done from prior attacks is not touched by any of these meds. So, there's a huge unmet need in that area of regeneration and recovery of function because, while it's all great that we can prevent the next attack and with all these great drugs that are approved, patients are still suffering. They have mobility problems, bowel/bladder problems, and pain, especially neuropathic pain, that really causes a lot of disability, and that's from damage that's already done. It's the same as spinal cord injury from trauma or from tumors or whatever - the spinal cord injury is the same and there's still a huge unmet need in that area.

Dr Nevel: On that note, who else do you usually consider part of the team, if you will - who else should be involved in the management of these patients?

Dr Levy: A lot of people. We have urologists involved for bladder, we have physical therapists involved for mobility, and occupational therapy for things related to hand and hand function. We have psychiatrists related to mental illness and also just dealing with these issues, because even if you don't have clinical depression, you still have an adjustment from the disease process and from all the treatments. Social workers, because this is a huge financial burden for a lot of people. An often rheumatologists, because NMO, for example, has about 25 percent overlap with other diseases. We don't want to double treat - we'll often choose a treatment that's applicable to both the rheumatologic disease and the neurological disease. So, I'd say that we don't work alone in almost any case; it's usually quite a big team involved.

Dr Nevel: One of the questions that I always like to ask is, what do you think the next big breakthrough is going to be in immune-mediated myelopathies? What's most exciting to you - what do you think is on the horizon here?

Dr Levy: I think probably the most exciting area is in multiple sclerosis, where we're starting to understand the role of the Epstein-Barr virus in triggering the disease, and potentially, even in driving the disease. Up to now, we've been suppressing immune systems in people with MS. But maybe we should be looking more at how can we prevent MS from occurring in the first place. And in cases where MS has already started, how does the virus play a role, and can we potentially modulate the outcome of disease with something like antivirals against EBV? So, I think that's the huge, exciting area. It's dominating a lot of the conversations at neuroimmunology conferences. But I think it's well worth the investigation because if MS turns out to be just an Epstein-Barr virus infection, I think a lot of what we've been doing up to now might not be as relevant. So, this is something that's very important.

Dr Nevel: Yeah - to have a way to prevent disease rather than treating it after, too, would be a super powerful thing.

Dr. Levy: And there are lots of Epstein-Barr virus vaccines that are being developed. But then the question comes up, "Well, are we going to prevent one in a thousand people from getting MS by vaccinating all thousand kids?" Is that really worth it? Can we pick out the ones who are more high risk for developing MS and just vaccinate those kids? A lot of ethical questions involved in that, too. Then what happens if we don't let our population get infected with EBV? We've evolved with that virus for hundreds of thousands of years. What if we abolish it all of a sudden - what does that do? Does it have any implications? I don't know.

Dr Nevel: Yeah, lots of really complicated things to think through, with exciting potential but a lot of unknowns.

Dr Levy: A lot of unknowns.

Dr. Nevel: Talking about patients with seronegative relapsing transverse myelitis - what's your general approach to those patients? When you feel like you've exhausted the extent of your workup but they have a relapsing transverse myelitis, how do we approach those patients and take care of them?

Dr Levy: "Seronegative" refers to patients who test negative for aquaporin-4, which is NMO, and test negative for MOG antibody disease (so they are double seronegative), but they have a recurring disease that looks an awful lot like one of the two. We generally stratify these patients into the "aquaporin-4-like," "MOG-like" or "MS- like." So, we try to put them into a category even if they're seronegative because we think that the treatments would be the same. So, for the MOG-like, for example: these are patients who have recurring attacks; they're not necessarily all long, but they do tend to remyelinate, and they can be severe at first but then they do get better over time. That's "MOG-ish," so we treat those people with MOG treatments. Whereas people who have this sort of aquaporin-4 type, they have severe attacks and they really don't get better, and they have a lot of necrosis if you look at it under the microscope. And those people we tend to treat with aquaporin-4 NMO drugs. And then we have the MS type that kind of lingers or is more focal white matter lesions. Even if they don't have a lot of brain lesions, they might be oligoclonal band-positive; we put them in the category of MS. But we have a very active research effort to identify new antibodies in case any of these diseases that are seronegative and don't fit into any category - it's certainly possible that there's an antigen of their own that they're attacking, so we'd like to try to identify that in these novel assays that we're doing in the lab.

Dr Nevel: How do you counsel patients on what to expect in the future, who you're seeing in the hospital with their first episode of transverse myelitis, for whatever the cause? Because one of the biggest questions I suspect most patients ask is, "Am I going to get better? Is this going to happen to me again?" How do you navigate those tough discussions, and what do you tell patients?

Dr Levy: In the hospital, it's tough, because a lot of our testing takes time - it takes ten, fourteen days. So, in the hospital, I say, "Look, we're going to focus on here and now - we're going to suppress the inflation; we're going to try to get you better from this event." It could have been a severe optic neuritis or transverse myelitis, or brain stem injury, or whatever - we're going to try to focus on that. And then I say, "When you come back to my clinic, we'll have the results from all of your testing and we're able to talk about the future and how to prevent the next one, if we have to." It does take time, unfortunately, to get all that data back, and it is a little bit suspenseful for patients, but that's what we have at the moment.

Dr Nevel: Yeah, the most honest answer that you can give them is always the best one. And that's the scenario when you're in the hospital - that there just isn't full answers.

Dr Levy: Yeah. One of the reassuring things I can say is, "We have a lot of medications that target different parts of the immune system, so no matter what you have, we can probably treat it."

Dr Nevel: Right. Obviously, really important to give people a sense of hope and reassurance that you're there and you're going to help find a treatment that's going to help them in the future. Well, thank you so much for chatting with me today. I really enjoyed our conversation and reading your article and learning more about immune-mediated myelopathies.

Dr Levy: It's been a pleasure. Thank you.

Dr Nevel: Thank you, Dr Levy, for joining me on Continuum Audio. Again, today we've been interviewing Dr Michael Levy, whose article on immune-mediated myelopathies appears in the most recent issue of Continuum, on spinal cord disorders. Be sure to check out Continuum Audio podcasts from this and other issues, and thank you to our listeners for joining us today.

Dr. Monteith: This is Dr Teshamae Monteith, Associate Editor of Continuum Audio. If you've enjoyed this episode, please consider subscribing to the journal. There's a link in the episode notes. We'd also appreciate you following the podcast and rating or reviewing it. AAN members: go to the link in the episode notes and complete the evaluation to get CME for this episode. Thank you for listening to Continuum Audio.

While collectively uncommon, the clinical presentation of genetically-mediated spinal cord disorders frequently overlaps with other neurologic conditions. Our understanding of these disorders has grown considerably.

In this episode, Kait Nevel, MD, speaks with Kara Stavros, MD, FAAN, author of the article "Genetic Myelopathies," in the Continuum February 2024 Spinal Cord Disorders issue.

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

Dr. Stavros is an associate professor of neurology and clinician educator at Warren Alpert Medical School of Brown University in Providence, Rhode Island.

Additional Resources

Read the article: Genetic Myelopathies

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Social Media

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Host: @IUneurodocmom

Guest: @StavrosKara

Transcript

Full transcript available on Libsyn

Dr Jones: This is Dr. Lyell Jones, Editor-in-Chief of Continuum, the premier topic-based neurology clinical review and CME journal, from the American Academy of Neurology. Thank you for joining us on Continuum Audio, a companion podcast of the journal. Continuum Audio features conversations with the guest editors and authors of Continuum, who are the leading experts in their fields. Subscribers to the Continuum journal can read the full article or listen to verbatim recordings of the article by clicking on the link in the show notes. Subscribers also have access to exclusive audio content not featured on the podcast. As an ad-free journal entirely supported by subscriptions, if you're not already a subscriber, we encourage you to become one. For more information on subscribing, please visit the link in the episode notes. AAN members, stay tuned after the episode to hear how you can get CME for listening.

Dr Nevel: This is Dr Kait Nevel. Today, I'm interviewing Dr Kara Stavros on genetic myelopathies, which is part of the February 2024 Continuum issue on spinal cord disorders. Dr Stavros is an Associate Professor of Neurology and Clinician Educator at Warren Alpert Medical School at Brown University in Providence, Rhode Island. Welcome to the podcast. What is the biggest takeaway from your article that you'd like the neurologists listening to this to know?

Dr Stavros: I would have to say that there's maybe two big takeaways that I would want to highlight. One would be that, generally speaking, in a nutshell, the genetic myelopathies can present with chronic and progressive symptoms, oftentimes (but not always) a family history of similar symptoms, and involvement of other structures outside of the spinal cord. Exclusion of the more treatable causes of myelopathy is a really key and important step in the diagnostic process. And because there are many different causes of genetic myelopathies, in some cases, the symptoms can overlap. I think this really underscores the utility of doing genetic testing to really confirm the precise underlying neurologic condition. The second takeaway that I would want to highlight is that, while treatment for most of these conditions is typically supportive, there have been a number of recent therapeutic breakthroughs for treatments in ALS, spinal muscular atrophy, adrenal myeloneuropathy, and Friedreich ataxia. While these aren't cures, it's really exciting and gratifying to see new therapeutics emerge via different mechanisms for patients with conditions that we've had very little treatment options for in the past.

Dr Nevel: Yeah, I really enjoyed reading that in your article - about these treatments that have been coming out over the past several years. The one with Friedreich's ataxia, too - that looked like it was really just recently approved this year.

Dr Stavros: Yes.

Dr Nevel: And so, kind of jumping off of that topic - there have been these exciting treatments that have been coming through. What do you think is going to be the next big thing? Or what do you think is the next thing that might come through? Or what's going on in research in genetic myelopathies that might help our patients?

Dr Stavros: That's a really great question. I think that, as far as the future in this area, genetic testing has definitely grown in terms of being able to identify more genes now that are implicated in these disorders than ever before. But this is still an area where our knowledge is continuing to evolve. So, I think the future holds further advancements in our ability to successfully diagnose patients who have these conditions and provide them with the sense of closure that having a definitive diagnosis brings, as well as opening the door to potentially targeted treatment options once a specific diagnosis is made. Another thing I think the future holds is continued development of expanded treatment options for patients with these conditions, both in terms of advancing our supportive care capabilities and then also providing more disease-modifying therapies. Again, as I mentioned, in recent years, new disease-modifying treatments have actually become available for several of these conditions. And I think that's just the beginning. There's going to be more to come, for sure.

Dr. Nevel: Yeah, that would be great. Going back to the genetic testing and how things are - we're finding more and more and more genes. When you decide that genetic testing is indicated, how do you counsel your patients about genetic testing and walk them through that process?

Dr Stavros: Okay - I would say that it usually starts with having a conversation with the patient about whether they want to pursue genetic testing or not for the particular condition or conditions that are suspected. Genetic testing is really helpful to, again, confirm the diagnosis once the initial diagnostic workup perhaps has given you some clues as to what the underlying condition might be. Again, because sometimes the clinical symptoms can overlap in different genetic myelopathies in particular, the genetic diagnosis can be really important as far as getting a definitive, final diagnosis. Usually testing is pretty carefully considered and the risks versus the benefits are explored with the patient. Oftentimes, this is done in conjunction with a genetic counselor or with genetics clinic. So, there's a lot of teamwork there in working with the genetics department, at least in my experience. There's a lot of options that might include testing a panel of genes for the suspected condition, to up to whole-exome sequencing. Again, this is really like an evolving landscape. So, we have a current understanding of the genes that are implicated in some of the genetic myelopathies, but there's still so much that we don't know. So, a lot of times, testing can result inconclusive or may be falsely negative, and it can be tough because a negative test doesn't necessarily exclude a potential genetic etiology. It becomes a very nuanced, I think, conversation and journey with the patient.

Dr Nevel: Yeah, and in your article you mentioned some of the health care disparities that exist around genetic testing and access to genetic testing, specifically. How do we, as clinicians, try to mitigate inequities in regard to access, or in regards to being able to offer our patients genetic testing - is there anything that we can do?

Dr Stavros: I do think there are some resources available, where free or sponsored testing can be utilized from nonprofit organizations or pharmaceutical companies. But you're right that this is a real area for potential health care disparities. And making sure that we have equitable access to genetic testing is really important. Some of the issues that come up are: limited access due to location; due to socioeconomic factors; a lack of awareness on the part of the patient or sometimes the provider about testing that's available; cost, of course, being a big issue, oftentimes; and sometimes, distrust of how the medical information, the genetic information, might be used or protected.

Dr Nevel: What do you think is one of the most challenging things about managing patients with genetic myelopathies?

Dr Stavros: I think one of the more challenging aspects of the care is the diagnostic journey. I think that some of these conditions - most of them are not terribly common – and they may not always be at the top of our differential diagnosis in the course of a workup for myelopathy. The first step, I think, is really continuing to be aware of these conditions and not letting them become a "blind spot" when we're formulating a differential diagnosis for a patient with myelopathic symptoms. I think it can really take some time to reach the ultimate diagnosis for most of these conditions. Another challenging aspect, which I alluded to earlier, is sometimes when genetic testing might come back inconclusive or nonrevealing, and there remains some diagnostic uncertainty despite best efforts and a thorough workup -that can be frustrating as well, sometimes. Again, our knowledge of these genetics and the genetic mutations underlying these disorders is still really evolving. But on the flip side, there's a lot of rewarding aspects as well. I think one of the most rewarding aspects is trying to help patients identify interventions that improve their quality of life, and working with the patients and their families (who oftentimes become very expert in their own rare conditions in their own right), and working amongst the interdisciplinary teams. So many of these conditions are associated with extraneurologic manifestations, and so patients need coordination of care with other specialists. Hereditary spastic paraplegia is a great example, as well as Friedreich ataxia, where you often work closely with the cardiologist and of course, ALS, where there are a lot of multidisciplinary needs.

Dr Nevel: Yeah, I'm so glad that you mentioned that because, in neurology in general (and specifically in this area), I can imagine the benefit to patients when there are multiple specialists involved in their care who are experts in the various aspects that are impacted from their underlying condition. Shifting gears a little bit - but going back to something that you've mentioned a few times, about making sure that we don't have a blind spot to genetic myelopathies, and that we consider this in part of our differential diagnosis when we're evaluating patients - in the patient who doesn't have an extensive family history of the exact same neurological symptoms, when should we consider genetic testing for patients that we're seeing in clinic? Like, at what point should we say, "Okay, we've done the other tests and now is the time to consider genetic testing." Because I think, unless somebody has that really strong family history, it's probably not on the top of your list to do it right away, for a variety of reasons.

Dr Stavros: I think you make a great point. Family history is tricky because, typically, we use that as a really strong clue of an inherited disorder of any type. But it can be tricky because, for a variety of reasons, it might be negative. Sometimes there is a de novo mutation, or there's variable phenotypes within the family, variable penetrance within the same family. Autosomal recessive inheritance can actually be, sometimes, hard to pick out. Or sometimes, patients don't have knowledge of their family members' medical histories. For all of these reasons, there may be information lacking in the family history. But I would say one of the most important things to exclude when you're working up patients initially is, of course, acquired causes of myelopathy, because you wouldn't want to miss a more treatable cause. And so, things like structural causes, nutritional, vascular or demyelinating causes (things that are explored more deeply in some of the other articles in this issue) are important. But if you've excluded acquired causes despite lacking a strong family history, I think, at that point, it's worth broadening your differential diagnosis to consider whether you might have reason to suspect a genetic myelopathy, particularly if you have some extraneurologic manifestations, some systemic symptoms that might be a clue towards a more systemic process. In genetic myelopathy, sometimes imaging can actually be quite helpful. It helps you exclude - MRI of the spine can help you exclude acquired causes, but it also helps you sometimes get clues toward a genetic cause. Typically, the finding might be either normal or show some spinal cord atrophy (but typically without signal change, so that can sometimes be a clue).

Dr Nevel: What's one mistake that is made in managing patients with genetic myelopathies? Maybe "mistake" is too strong a word; maybe "misconception" about treating patients with genetic myelopathies.

Dr Stavros: That's a great question. I think that one of the, maybe, misconceptions might be that these are homogeneous entities, these different diseases. But one of the things that surprised me anew in going back to research this topic and prepare this article was a reminder of just how variable both the genotypes and the phenotypes are within what we consider sometimes just one diagnosis, like hereditary spastic paraplegia, for example, spinocerebellar ataxia. There's so many different presentations and genotypes associated with these. It's really a family of different conditions. You could say the same thing about ALS as well. So, the spectrum of disease, I think, is important to recognize.

Dr Nevel: Yeah, and I can imagine because of that spectrum of disease, just having an open mind in considering genetic testing and not excluding a potential genetic cause because it doesn't fit into what we think is the most typical presentation of that genetic condition.

Dr Stavros: Yes - I'm in total agreement.

Dr Nevel: I've asked you about what some of the misconceptions are and what some of the challenges are, but what's the most rewarding part about taking care of patients with genetic myelopathies for you?

Dr Stavros: I think one of the most rewarding parts has to be working with the patients and the families. Like I mentioned earlier, sometimes they become so expert in their own conditions - it's amazing. And, working with them, working with the interdisciplinary teams, is a really rewarding process. I think that the more I've encountered patients with some of these rare conditions, the more I've learned from their stories and experiences, and so, that's, I think, been the most rewarding aspect to me.

Dr Nevel: You've mentioned the multidisciplinary team a couple of times that we've talked about this, but who specifically do you usually include or contributes to the care of these patients?

Dr Stavros: It may depend on the condition in question. So, for example, for Friedreich ataxia, there's always going to be a cardiologist involved in the patient's care. For ALS, there's going to be a larger team. For those who are familiar with ALS multidisciplinary clinics, this often includes physical therapy, speech therapy, nursing, pulmonary, and many others. And so, it really depends. I think in most cases though, genetics evaluation and genetic counseling is a really important piece.

Dr Nevel: How do you work with the genetic counselors in counseling families about testing other family members? Because that's something that's really challenging in genetic conditions, especially for people with children that may be underage, and this is a really complicated topic. But how do you approach that?

Dr Stavros: I think that it may depend on your particular institution. Where I'm at, typically, that's something that our genetics department will take the lead on and they will meet with the patient first and then also meet with and bring in any interested family members who are hoping to pursue the possibility of testing themselves. There's a bit of controversy or differing opinions around genetic testing, specifically for presymptomatic individuals for inherited ALS, because - certainly, there's pros and cons for being tested for any condition, but some special considerations come into play when someone is presymptomatic. There's actually been studies done, in particular, on patients who have a family history of ALS who are presymptomatic, and generally, the studies have shown that those patients are usually - the majority - in favor of being tested. But it does certainly bring up some ethical implications. Of course, any discussion is going to be undertaken with the goal of informing the patient and discussing the risks versus the benefits in detail. There's actually recommendations on the principles and the practice of presymptomatic testing for ALS, which is available and referenced in the article.

Dr Nevel: Do you think as - hopefully, in the future, as more treatments become available - that presymptomatic genetic testing could play a role in how we manage patients?

Dr Stavros: I think that's a great thought. I think it may, especially as more treatments become available, I think there may be a greater interest in demand for finding out early whether you might have a likelihood of developing a certain condition so that you can plan accordingly and perhaps even pursue treatments early on.

Dr Nevel: You know, you mentioned this (and this isn't maybe quite exactly the same thing), but in SMA - you mentioned newborn screening for SMA and new treatment for SMA, and that newborn screening is not always a standard, and that there's controversy around that, now that we have treatment for it.

Dr Stavros: Yes. That's another area where some controversy comes up as well, as far as cost and treatment, for sure.

Dr Nevel: Thank you, Dr Stavros, for joining me on Continuum Audio. Again, today we've been interviewing Dr Kara Stavros, whose article on genetic myelopathies appears in the most recent issue of Continuum on spinal cord disorders. Be sure to check out Continuum Audio podcasts from this and other issues. And thank you to our listeners for joining today.

Dr Monteith: This is Dr Teshamae Monteith, Associate Editor of Continuum Audio. If you've enjoyed this episode, please consider subscribing to the journal. There's a link in the episode notes. We'd also appreciate you following the podcast and rating or reviewing it. AAN members, go to the link in the episode notes and complete the evaluation to get CME for this episode. Thank you for listening to Continuum Audio.

Tumors affecting the spine are fortunately uncommon, and may arise within the spine or metastasize from malignancies elsewhere. Effective treatment is determined by tumor type, location, and urgency.

In this episode, Allison Weathers, MD, FAAN, speaks with J. Ricardo McFaline-Figueroa, MD, PhD, author of the article "Spinal Cord Neoplasms," in the Continuum February 2024 Spinal Cord Disorders issue.

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

Dr. McFaline-Figueroa is a physician at Dana-Farber Cancer Institute and instructor in neurology at Brigham and Women's Hospital and Harvard Medical School in Boston, Massachusetts.

Additional Resources

Read the article: Spinal Cord Neoplasms

Subscribe to Continuum: shop.lww.com/Continuum

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

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

More about the American Academy of Neurology: aan.com

Social Media

facebook.com/continuumcme

@ContinuumAAN

Transcript

Full transcript available on Libsyn

Dr Jones: This is Dr Lyell Jones, Editor-in-Chief of Continuum, the premier topic-based neurology clinical review and CME journal from the American Academy of Neurology. Thank you for joining us on Continuum Audio, a companion podcast to the journal. Continuum Audio features conversations with the guest editors and authors of Continuum, who are the leading experts in their fields. Subscribers to the Continuum journal can read the full article or listen to verbatim recordings of the article by visiting the link in the show notes. Subscribers also have access to exclusive audio content not featured on the podcast. As an ad-free journal entirely supported by subscriptions, if you're not already a subscriber, we encourage you to become one. For more information on subscribing, please visit the link in the show notes. AAN members, stay tuned after the episode to hear how you can get CME for listening.

Dr Weathers: This is Dr Allison Weathers. Today I'm interviewing Dr Riccardo McFaline-Figueroa on spinal cord neoplasms, which is part of the February Continuum issue on spinal cord disorders. Dr McFaline-Figueroa is a physician at Dana Farber Cancer Institute in Boston, Massachusetts, an instructor in neurology at Brigham and Women's Hospital and Harvard Medical School in Boston, Massachusetts. Welcome to the podcast. You do a really fantastic job in the article providing a comprehensive overview. But if you had to come up with the most important clinical takeaway from the article that you want our listeners to walk away with, what would that be?

Dr McFaline-Figueroa: I think the most important thing to remember about tumors of the spinal cord is, one, that there is no specific diagnostic feature on imaging that can be used to determine what a neoplasm of the spinal cord is or even if it is a neoplasm - I think, going in broadly, when you're looking at a mass lesion of the spinal cord, is very important. Then the second is just to know that there's just such a wide range of cancer possibilities that can do this, that getting an appropriate diagnosis becomes very important.

Dr Weathers: I think two really salient points right there. I want to explore something that you said a little bit more. You talk about the concept that there's no one diagnostic feature of the MRI, and actually, I was thinking about this as I was reading your article. What struck me, too, is that that holds true, actually, for the patient's presenting signs and symptoms, right? As a neurohospitalist, I'm constantly struggling with always how to balance not missing a diagnosis such as this (a diagnosis of spinal cord tumor), versus putting a patient through what can be an often unnecessary and very costly workup, right? So, this is such a rare diagnosis, but the presenting symptoms and signs, just back radicular pain and weakness, are shared by so many common conditions. What's your approach to distinguishing between them, and what are some of the red flags you look for to know when further workup really is indicated?

Dr McFaline-Figueroa: Certainly. I think there's not one way to decide whether you need to go down the route of exploring a neoplasm of the spinal cord, but there are certainly things that would clue someone into this needing to be the case. I think, one, as opposed to a lot of the monophasic illnesses that we see in neurology, certainly it's something that is progressive; is certainly something that increases the certainty, and it's different from ischemia of the spinal cord or an acute demyelinating event. I think another important feature is also just the context. I think, even though these are rare, when you're dealing with a patient with a known history of cancer, that's when "the rare" becomes common, and that's when you have to really start thinking about it being a neoplasm of the spinal cord. It's still not perfect; it covers some of the side effects of treatment that can look a little bit like a spinal cord neoplasm. But certainly, that should increase the level of suspicion for something going on in that compartment that's neoplastic.

Dr Weathers: I think that's such a great take-home quote for our listeners to think about - when the rare becomes common. You actually hit on the point that I wanted to ask you about next. In neurology, we always talk about how important the history and the exam are - it's kind of our core of what we do. But it feels especially true when talking about neoplasms of the spinal cord. You mentioned, obviously - the big one is that if they have a history of cancer, especially in active history, that's a pretty big clue that something more serious could be going on. But what else is key in the history? Why are the history and the exam so especially important when you're concerned about or dealing with neoplasms of the spinal cord?

Dr McFaline-Figueroa: When we're dealing with the spinal cord, we're dealing with a lot of different compartments. I think, to your question, the one where thinking about history and physical becomes the most important is when you're thinking about the possibility of leptomeningeal involvement, right? The leptomeningeal space is not easily imaged, right? We can't really see much what's going on in the CSF. And so, we rely on - imaging-wise - on there being deposition of cancer cells along the dura or along the direct surface of the cord. But oftentimes, that's not the case. That's when knowing exactly what someone's cancer history is, what their stage in the natural history is, whether they're progressing or not progressing, have some knowledge of what the oncologic medications that they're on are (because brain penetration is different for several of them), and then really hearing for those signs and symptoms that are connected to that compartment - signs of increased intracranial pressure, signs of cranial neuropathy that may or may not be evidence on imaging, radiculopathies. So those are the things that are very important in all investigations of spinal cord tumors. But certainly for leptomeninges, it's often the case that, really, history and physical are all you have to try to get the diagnosis right.

Dr Weathers: You make, actually, a really great point in the article that I think it bears mentioning here. Because I was embarrassed when I read it, because I said, "I have been guilty of that" - that the history of, kind of, these very generic histories of cancer; you know, "Oh, they had lung cancer" - is probably not sufficient, right? That there's value in getting really specific. Why is that?

Dr McFaline-Figueroa: That's certainly why we all specialize in different things, right? For a neuro-oncology standpoint, it sounds very different to me to hear the same history in a patient with melanoma versus the patient with bladder cancer. You think of melanoma from a neuro-oncologic standpoint, you're thinking of a cancer that is incredibly trophic for the brain and spinal cord, probably because it's derived also from ectoderm (so it's kind of the same origin of the cells), and it just makes your level of suspicion go so much higher when you are in that mind space. Thinking of a melanoma patient versus someone with a tumor, that very rarely (if it all) goes to the central nervous system. I think that's something that's really important. And those are two big extremes. But even - like I mentioned - even in lung cancer, certainly, small cell versus non-small cell are very different in terms of when and how they can affect the spinal cord or any part of the central nervous system. So, that one is a little bit more nuanced and, being a neuro-oncologist - but still, it's specific as you can be when you're discussing with your neuro-oncology colleagues or medical oncology colleagues, and the better for trying to figure these things out.

Dr Weathers: An excellent pro tip right there. You were very gracious about it - about that we all have different specialties. I was reflecting on that, too - this is such an important yet definitely pretty specialized topic; how did you become interested and develop your expertise in it?

Dr McFaline-Figueroa: My clinical work is on all sorts of tumors of the central nervous system. Actually, in neuro-oncology, we also do a little bit of peripheral nervous system tumors, depending on how they present. And it's all a continuum. Not to use that - well, we just happen to be on Continuum. But it's all a continuum: brain, spinal cord - it's all one big compartment. And it forces you to be really familiar with all of those. And I think it's an interesting topic - we don't talk about it as much as we do for some of the other – you know, cancers of the brain, for example. In terms of becoming an expert, for me, I mean a lot of it is just, at this point, experience. And I will say, a lot of reading, because you don't see all of these. I cover some topics, like primary glioneuronal tumors of the leptomeninges, which are incredibly rare - I've never seen a patient with one. But it's one of those things where you should know the basics of these, at least for my field, and certainly beyond.

Dr Weathers: What about neuro-oncology in general? How did you decide that you wanted to specialize in that?

Dr McFaline-Figueroa: Well actually, me, personally - I spent a lot of my residency trying to decide between being a neurointensivist and being a neuro-oncologist. I think, for me is that I like taking care of patients who are potentially very sick. I think I just enjoyed the process of the more longitudinal relationship you have as a neuro-oncologist - seeing people in clinic, walking them through all these treatments and difficult disease courses – and that, to me, I just found really fulfilling, while still having lots of internal medicine to think about, lots of interesting neurology, just in a different context.

Dr Weathers: It's such an interesting field. And I was also really thinking about this - that while neurology overall has had so many incredible advancements in terms of diagnostic and therapeutic capabilities in the last several years, neuro-oncology, in some ways, is almost like an entirely different field since I was in residency training, which wasn't all that long ago. How have these changes impacted how you diagnose and manage spinal cord tumors?

Dr McFaline-Figueroa: Certainly, there's been a lot of changes in technology that I think have been helpful. And then, certainly, slowly but surely, we are coming up with better treatments for patients. When I speak of technologies, one thing that, for example, comes to mind is - historically, it's just so difficult to diagnose. I keep coming to the same anatomic compartment, but it's so difficult to diagnose leptomeningeal carcinomatosis or leptomeningeal involvement by a tumor, even more so, I think, in the spinal cord, because it's just difficult to catch on imaging. But over the last few years, so many advances in, like, molecular testing of cerebral spinal fluid to be able to look for cell-free DNA; to be able to enrich for rare cell populations and then identify them, which really, kind of, have changed that "we need to do three LPs" mentality. We have things that are sensitive enough that are rolling out. And in terms of treatment, certainly, the field is changing. There's so many now targeted therapies emerging for tumors as we understand the biology, which is probably the biggest roadblock to better care for the primary spinal cord tumors - it's also a very exciting time to be in neuro-oncology because of that.

Dr Weathers: On perhaps a less positive note - the fields change so quickly; has this led to any controversies in the field?

Dr McFaline-Figueroa: I think the biggest controversies are less so controversies in the traditional sense, in that I don't think anyone's fighting with each other. But it's become really difficult to know, particularly as those therapies that I mentioned come out, what is the right first step. Is the right first step for somebody to have, for example – well, actually, this is less controversial now - but for example, someone with von Hippel-Lindau, who might have multiple hemangioblastomas. We're reaching a point that, with approvals of targeted therapies for that disease, you might not necessarily go for surgery (which could be quite morbid in some instances) or radiation for progressive disease. So, I think one of the issues there is that we're not necessarily at the point where we are sure that, you know, definitely the intervention with the longest survival is targeted therapy first, and then maybe surgery, and then maybe radiation, versus the other. I think the order at which we treat these tumors is just a little bit in flux.

Dr Weathers: Hopefully, with time and more evidence, that will become more definitive and clear. You just mentioned - just in that answer alone - surgery and radiation. The other really fascinating thing about this topic (about neoplasms of the spinal cord) is how truly a multidisciplinary effort the management of patients with spinal cord tumors is. What other specialists do you work with to diagnose and manage this patient population, and what's everyone's role in these cases?

Dr McFaline-Figueroa: Certainly, neurosurgery still plays a huge role, particularly because even when you are relatively sure that it's a tumor of the spine (particularly if you think it's a primary tumor of the spine), there's really no - again, just no diagnostic test; that's just imaging. The only way that we have to establish the diagnosis is through tissue examination. In neurosurgery, in a lot of diseases, still plays a huge role. For example, ependymoma is one where, really, gross total resection is one of the biggest (if not the biggest) prognostic factor in treatment. Radiation oncology - there are still histologies that we have no good systemic therapies for. For example, for diffuse midline gliomas, most of them are not very sensitive to the therapies that we have that are systemic. So, for these tumors, it becomes important to do radiation as the most significant step in management that we have - we just don't have anything efficacious for those tumors, at the moment, although we're learning a lot about the biology. A lot of these have histone mutations that people are trying to target for more effective treatments. So, radiation oncology, again, still plays a huge role in the treatment of our patients. Certainly, when you're dealing with patients with metastatic cancer to the spine, medical oncology is huge. And that's where - me, as a neuro-oncologist, I'm less of an oncologist and more as a person who the medical oncology can bounce ideas from. We talk about - sit down and talk about - their expertise in how to treat these tumor types. And then, me bringing in what might be brain-penetrant, what things may or may not be toxic to the nervous system - stuff like that. It's really a group effort, and that's not even mentioning nurses, nurse practitioners, amazing people who coordinate care, and stuff like that. And like I mentioned early on, one of the most important things is to know exactly what type of tumor or cancer these are before proceeding with any conversation about treatment. And that's where our neuropathologists really drive the direction of what we're doing.

Dr Weathers: Even as I was thinking about this question, in my mind, what I thought your response point may be - that was even more of a complex team than I think I had envisioned, and it really speaks to, again, the true multidisciplinary effort, the "team of teams" that's needed to provide care for these patients. And I think I heard you say this in your - that wonderful answer, but that as things are evolving and as we are better understanding the biology, that we're getting better with our targeted treatments. But that could possibly include, at some point, even targeted therapies for midline gliomas, which would be incredible. I know that's always been one with, not only especially poor prognosis, but given the population it tends to affect (younger patients), it can be quite devastating. That definitely struck me as I heard you say it. So, I think this is a field where we're going to continue to see so many breakthroughs. And that leads me, actually, into my last question. I always like ending these on a hopeful note, and I think that certainly does it. But we've talked about so many changes already, and again, I know even more to come. What do you think the next big breakthrough will be? Did we cover it already? Is there anything else that you're excited about that's coming down the pike?

Dr McFaline-Figueroa: I think we covered some of it, which is really being able to bring more systemic therapies (more oral therapies or intravenous therapies) that treat these tumors, as opposed to things like aggressive surgery or radiation, which are effective. But the hope here is that we can delay those so that we can have people living longer with these cancers, or cured of these cancers, and trying to spare them as many side effects of treatment as we can - which historically, in the spinal cord, is quite significant because it's a difficult space to do surgery on and it tolerates only a certain amount of radiation before coming into toxicity. So, I think it's a really exciting time to be on the medical side of things as a neuro-oncologist and see all these treatments coming in that really improve people's quality of life.

Dr Weathers: Definitely an exciting time to do what you do. Well, again, thank you for the incredible article, for taking the time to speak with me today. Any last thoughts for our listeners?

Dr McFaline-Figueroa: Just be mindful when working up those spinal cord tumors. There's a lot to think about, but there's also a lot of good can be done by doing good diagnostic workup.

Dr Weathers: Thank you, Dr McFaline-Figueroa for joining me on Continuum Audio. Again, today we've been interviewing Dr. Riccardo McFaline-Figueroa, whose article on spinal cord neoplasms appears in the most recent issue of Continuum, on spinal cord disorders. Be sure to check out Continuum Audio podcasts from this and other issues. And thank you to our listeners for joining today.

Dr. Monteith: This is Teshamae Monteith, Associate Editor of Continuum Audio. If you've enjoyed this episode, please consider subscribing to the journal. There's a link in the episode notes. We'd also appreciate you following the podcast and rating or reviewing it. AAN members: go to the link in the episode notes and complete the evaluation to get CME for this episode. Thank you for listening to Continuum Audio.

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

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

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

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

Additional Resources

Read the article: Structural Myelopathies

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American Academy of Neurology website: aan.com

Social Media

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@ContinuumAAN

Guest: @Ligia_OnofreiMD

Transcript

Full transcript available on Libsyn

Dr Jones: This is Dr. Lyell Jones, editor-in-chief of Continuum, the premier topic-based neurology clinical review and CME journal from the American Academy of Neurology. Thank you for joining us on Continuum Audio, a companion podcast of the journal. Continuum Audio features conversations with the guest editors and authors of Continuum, who are the leading experts in their fields. Subscribers to the Continuum journal can read the full article or listen to verbatim recordings of the article by visiting the link in the show notes. Subscribers also have access to exclusive audio content not featured on the podcast. As an ad-free journal entirely supported by subscriptions, if you're not already a subscriber, we encourage you to become one. For more information on subscribing, please visit the link in the show notes. AAN members, stay tuned after the episode to hear how you can get CME for listening.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Dr. Onofrei: Thank you for having me.

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

Dr Monteith: This is Dr. Teshamae Monteith, Associate Editor of Continuum Audio. If you've enjoyed this episode, please consider subscribing to the journal. There's a link in the episode notes. We'd also appreciate you following the podcast and rating or reviewing it. AAN members, go to the link in the episode notes and complete the evaluation to get CME for this episode. Thank you for listening to Continuum Audio.

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

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

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

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

Additional Resources

Read the article: Traumatic Spinal Cord Injury

Subscribe to Continuum: shop.lww.com/Continuum

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

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

American Academy of Neurology website: aan.com

Social Media

facebook.com/continuumcme

@ContinuumAAN

Host: @AaronLBerkowitz

Guest: @SaefIzzy

Full transcript available here

Dr Jones: This is Dr. Lyell Jones, editor-in-chief of Continuum, the premier topic-based neurology clinical review and CME journal from the American Academy of Neurology. Thank you for joining us on Continuum Audio, a companion podcast of the journal. Continuum Audio features conversations with the guest editors and authors of Continuum, who are the leading experts in their fields. Subscribers to the Continuum journal can read the full article or listen to verbatim recordings of the article by clicking on the link in the show notes. Subscribers also have access to exclusive audio content not featured on the podcast. As an ad-free journal entirely supported by subscriptions, if you're not already a subscriber, we encourage you to become one. For more information on subscribing, please visit the link in the episode notes. AAN members, stay tuned after the episode to hear how you can get CME for listening.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Dr Izzy: Absolutely. My pleasure.

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

Dr Monteith: This is Dr. Teshamae Monteith, Associate Editor of Continuum Audio. If you've enjoyed this episode, please consider subscribing to the journal. There's a link in the episode notes. We'd also appreciate you following the podcast and rating or reviewing it. AAN members, go to the link in the episode notes and complete the evaluation to get CME for this article. Thank you for listening to Continuum Audio.

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

In this episode, Teshamae Monteith, MD, FAAN, speaks with Carlos Pardo, MD, author of the article "Clinical Approach to Myelopathy Diagnosis," in the Continuum February 2024 Spinal Cord Disorders issue.

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

Dr. Pardo is a professor of neurology and pathology at Johns Hopkins University School of Medicine and director of the Johns Hopkins Myelitis and Myelopathy Center in Baltimore, Maryland.

Additional Resources

Read the article: Clinical Approach to Myelopathy Diagnosis

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Transcript

Full Transcript Available Here

Dr Jones: This is Dr. Lyell Jones, Editor-in-Chief of Continuum, the premier topic-based neurology clinical review and CME journal, from the American Academy of Neurology. Thank you for joining us on Continuum Audio, a companion podcast of the journal. Continuum Audio features conversations with the guest editors and authors of Continuum, who are the leading experts in their fields. Subscribers to the Continuum journal can read the full article or listen to verbatim recordings of the article by visiting the link in the show notes. Subscribers also have access to exclusive audio content not featured on the podcast. As an ad-free journal entirely supported by subscriptions, if you're not already a subscriber, we encourage you to become one. For more information on subscribing, please visit the link in the show notes. AAN members, stay tuned after the episode to hear how you can get CME for listening.

Dr Monteith: This is Dr Teshamae Monteith, Associate Editor of Continuum Audio. Today, I'm interviewing Dr Carlos Pardo about his article on an Integrative Clinical Approach to Myelopathy Diagnosis, which is found in the February 2024 Continuum issue on spinal cord disorders. Dr Pardo is a professor of neurology and pathology at Johns Hopkins University School of Medicine in Baltimore, Maryland. Welcome to the podcast. Carlos, thank you so much for this wonderful article. I think it was great!

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

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

Dr Pardo: That's a very nice question.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Dr Monteith: Thank you, Dr Pardo for joining me on Continuum Audio. Again, today we've been interviewing Dr Carlos Pardo, whose article on an integrative clinical approach to myelopathy diagnosis appears in the most recent issue of Continuum on Spinal Cord Disorders. Thank you to our listeners for joining today.

Dr Monteith: This is Dr. Teshamae Monteith, Associate Editor of Continuum Audio. If you've enjoyed this episode, please consider subscribing to the journal. There's a link in the episode notes. We'd also appreciate you following the podcast and rating or reviewing it. AAN members,go to the link the episode notes and complete the evaluation to get CME for this episode. Thank you for listening to Continuum Audio.

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

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

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

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

Additional Resources

Continuum website: ContinuumJournal.com

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Host: @LyellJ

Guest: @shamik_b

Full transcript available here

Transcript

Dr Jones: This is Dr. Lyell Jones, Editor-in-Chief of Continuum, the premier topic-based neurology clinical review and CME journal from the American Academy of Neurology. Thank you for joining us on Continuum Audio, a companion podcast to the journal. Continuum Audio features conversations with the guest editors and authors of Continuum, who are the leading experts in their fields. Subscribers to the Continuum journal can read the full article or listen to verbatim recordings of the article by visiting the link in the show notes. Subscribers also have access to exclusive audio content not featured on the podcast. As an ad-free journal entirely supported by subscriptions, if you're not already a subscriber, we encourage you to become one. For more information on subscribing, please visit the link in the show notes.

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

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

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

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

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

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

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

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

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

Dr Bhattacharyya: Right.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Dr. Monteith: This is Dr. Teshamae Monteith, Associate Editor of Continuum Audio. If you've enjoyed this episode, please consider subscribing to the journal. There's a link in the episode notes. We'd also appreciate you following the podcast and rating or reviewing it. Thank you for listening to Continuum Audio.

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

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