Managing Neurosarcoidosis: Strategies and Treatments

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

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

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

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

Additional Resources

Read the article: Neurologic Manifestations of Rheumatologic Disorders

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Host: @headacheMD

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Transcript

Full episode transcript available here

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

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

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

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

Dr McCombe: Thank you for having me.

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

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

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

Dr McCombe: Yeah.

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

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

Dr Nevel: Yeah.

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

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

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

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

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

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

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

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

Dr McCombe: Million-dollar question always.

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

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

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

Dr McCombe: Mm hmm.

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

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

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

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

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

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

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

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

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

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

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

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

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

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