Serendipitous Pathways in Autoimmune Neurology

Many autoimmune neuromuscular disorders are reversible with prompt diagnosis and early treatment. Understanding the potential utility and limitations of antibody testing in each clinical setting is critical for practicing neurologists.

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

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

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

Additional Resources

Read the article: Autoimmune Neuromuscular Disorders Associated With Neural Antibodies

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Host: @headacheMD

Guest: @Div_Dubey

Transcript

Full episode transcript available here

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Dr Monteith: So, very personalized targeted therapies?

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

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

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

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

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