Immune-Mediated Myelopathies with Dr. Michael Levy

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

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

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

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

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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.