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The Neurotransmitters: Clinical Neurology Education
Neuroimmunology with Dr. Denis Balaban
Dr. Denis Balaban joins us today to talk about a very challenging topic within neurology, neuroimmunology.
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Hello and welcome back to the Neurotransmitters. I am your host, dr Michael Kentris, and today we are going to be talking about neuroimmunology a scary topic for many of us in neurology, but I am very happy to have an expert with me today, dr Dennis Balaban from the Division of Neuroimmunology and Neuroinfectious Diseases from Massachusetts General Hospital and Harvard Medical School. Is it all right if I call you Dennis today? Yes, absolutely. Thank you so much for coming on the show and talking with us about such a fascinating and confusing topic.
Dr. Denis Balaban:Thank you for having me. I always love talking about neuroimmunology, so I relish any opportunity to do so.
Dr. Michael Kentris:Now, as we were talking before we hit record, let's start with the 50,000 foot view. What do we mean when we say neuroimmunology?
Dr. Denis Balaban:Yeah, absolutely so. What we mean is any sort of neurological disorder in which it is caused by a dysfunction of the immune system leading to the neurological disorder, a dysfunction of the immune system leading to the neurological disorder. So you have, you know, an antibody-mediated disease attacking your peripheral nerves or brain. You have, you know, t or B cells causing that. If you have a cytokine storm, as you can see in neurotoxicity in the setting of CAR T cells, all of those are under the broad umbrella of neuroimmunology.
Dr. Michael Kentris:Yes, I know one of our favorite things to do in neurology is just tack neuro onto the front of a pre-existing discipline.
Dr. Denis Balaban:Indeed exactly.
Dr. Michael Kentris:So what does the pathway to becoming a neuroimmunologist or a neuroimmunology specialist look like for people who might be kind of looking to explore that, whether they're in neurology residency or medical students or in some other primary residency discipline?
Dr. Denis Balaban:people can take. The way I got into neuroimmunology was I had no idea I would be doing this in medical school. My big question was I want to do neurology right, and internal medicine, you know, gave me some questioning thoughts because I love that detective work, but nothing was ever going to be as fascinating as the brain. So when I went into residency I thought I was going to do like cognitive behavioral and then I realized that that was not my cup of tea personally and I really found that I love being on the inpatient general neurology service where a lot of our like folks with new diagnoses of MS, autoimmune encephalitis or we don't know what this is yet, but we shall try some steroids and look, they got better. So I really loved treating those patients because I felt like I had to be at my best in order to be able to diagnose them. So that means like I had to really. It encouraged me to read up even more than I was. It encouraged me to ask that very specific question that maybe no one else asked to really try to get to the diagnosis, try different examination maneuvers that maybe others have not done. I really thought it was, you know, neurology on steroids, figuratively and literally.
Dr. Denis Balaban:And so once I knew that I wanted to be in neuroimmunology, there's a plethora of different fellowships that are available for those interested, and sort of the usual question that residents face is do I want to be mostly MS, do I want to be like MS plus a few other neuroimmunological diseases that I know about, or just like neuroimmunology? The broad gamut include infectious disease in there. What sort of neuroimmunology do I want to practice? Because historically it's been MS and the other demyelinating disorders, but now people have a bit more options. So that is how, and I decided to go as broad as possible and I went to the Advanced General Autoimmune Neurology Fellowship at MGH. But there are people who get into neuroimmunology first from a research standpoint. They'll have done a phd, they'll have, uh, you know, you know, done their research and published quite a bit, and then they realize, no, I actually want to be treating these patients too. And so then they can find their way, uh, into a clinical practice, uh, through that avenue so many roads, I would say no, that's, that's.
Dr. Michael Kentris:That's great to know, because it is one of those things where we see, you know, as the testing and the identification of these different syndromes has evolved, so too has the training pathways. Indeed, indeed. So what does the practice? You know, I know there's a mixture of inpatient and outpatient. So what is the general vibe in the practice? You know, I know there's a mixture of inpatient and outpatient.
Dr. Denis Balaban:So what is the general vibe in the clinic? Yeah, absolutely so. In clinic I have a practice that is, again broad. I will see patients with all sorts of different things People in my general neurology practice whom I've diagnosed with MS and then I bring to my neuroimmunopractice people with autoimmune encephalitis, neurosarcoidosis, vasculitis, stiff person syndrome, you name it. So it runs the gamut. And I also have patients who I'm following where I'm not exactly sure what might be going on quite yet. But they are complicated. And could there be something neuromunological going on? Sure, have I been able to prove that yet? Not really, but I'm keeping an eye on them and I'm going to be keeping them in my practice in neuroimmuno as a just to get more time, uh, with them in my follow-ups. Uh, because I have a longer follow-up for, uh, minor immunology patients depending on their diagnosis or complexity. Um, on the inpatient side, I mean, you know so many different things that can happen Meningitis, encephalitis, uh, you know new strokes from a vasculitis, you name it. Myelitis, my gosh, I could any. Any itis I could name.
Dr. Denis Balaban:So I think the trickiest part when it comes to figuring out is really making the diagnosis and really raising the suspicion of should I be thinking about a neuroimmunological diagnosis in my patients? Because you know, most people are going to first see either their primary care doctor or their general neurologist as sort of that first step. And I'll say that with better knowledge of things like autoimmune encephalitis being more in the zeitgeist, it's less of a problem these days of the diagnostic delay and in fact sometimes there is an over-diagnosis of such things as a paper not too long ago was published describing misdiagnoses. But really the goal, I think, is for the general neurologist, when hearing certain things on the history or seeing certain things on the examination, to raise a flag to say, hey, maybe I should be thinking about a neuroimmunological diagnosis. And the thing with neuroimmunology is it can touch any part of the nervous system and it can present either acutely, subacutely, chronically, it all depends. So then people wonder well, how do I put my arms around this? How do I know that this could be neuroimmunological? Talk today, I think, of what are ways in which that in my general neurology practice I can start to have that intuition and suspicion for something neuroimmunological afoot. So much like in making any diagnosis in neurology.
Dr. Denis Balaban:Onset and pace are of incredible importance. Onset and pace are of incredible importance and really diving down to understand how the symptoms unfolded. And this might seem obvious to any neurologist listening, but it can be more fine-tuned than one might think. So, for example, I had seen a patient who presented with a two-year history of cognitive decline and they were, you know, in, they were older than the age of 50. And the family seemed fairly used to things by then. And you know, it was, I think, anybody in a very busy setting with distractions coming in, phone calls, et cetera. Oh, two year history, cognitive decline, probably neurodegenerative, we're done. Probably neurodegenerative, we're done.
Dr. Denis Balaban:What was helpful is that someone had gotten a brain MRI that had shown that there were these T2 hyperintensities in their temporal lobes. And, oh my gosh, this is actually a limbic encephalitis. And if you just went by this one-liner of two-year history history, you might miss the fact that actually what happened was two years ago. Within about three months, there was this rapid decline and then they plateaued for the rest of the time. And then you, we find out, okay, they have hyponatremia. Okay, they have these brief dizziness spells and lo and and behold, it's LGI1.
Dr. Denis Balaban:So I think, really trying to when you ask well, how long has this been going on X years. Okay, and how did that really evolve? I think that is a key point in some of these and if there were changes, that happened, when did those changes occur? Really trying to hone in on exactly when those changes occurred, because that gives you a much more accurate picture. Because there are some neuroimmunological diseases that are characterized not by a gradual decline but by punctuated declines, so something like a mononuritis multiplex or multiple mononuropathies, for example, where it's like, yeah, I had this carpal tunnel and you know it was painful but I'm a little weak, but you know it's okay and oh well, and now I have a foot drop and oh, now I have this. And so really understanding, like, is this happening in quick succession? Or if the are these like years apart, then okay, maybe not and you should look for something else. But these are that's why I mentioned, like pace onset as like one of the number one things to focus on first, because that will get you the diagnosis.
Dr. Michael Kentris:That's the first step in making a neurological diagnosis, along with localization, of course, course that's a great point is that a lot of times we in the specialty clinics or, you know, even just general neurology, being in some places right three, six months to get in, um, you wind up where you are seeing them at the tail after the action has happened, so to speak, and it is like you're you're asking these people to to go back to these probably much. It is like you're you're asking these people to go back to these probably much more stressful times in their memory and you know, as you said, like someone's made peace with it, as it were, they don't want to go back and think about when things weren't as bad necessarily. It's hard to handle those memories sometimes.
Dr. Denis Balaban:Yeah. So, um, yeah, being able to recognize these things and, uh, you know, offer a diagnosis and treatment like that can be powerful, because those, uh, those patients with encephalitis, depending on the type, um, they, they can be reversible and treatable and they can get back a lot of their quality of life, um, depending, of course.
Dr. Michael Kentris:And I think you also bring up a really good point. One thing I think there's been a big trend towards over probably a few decades now is this in medical training, especially at the medical student level, we see a lot of emphasis on open ended questions, and I find that the more and more that I learn uh, you really need to know how to ask a closed-ended question, and what those closed-ended questions need to be is just as important absolutely, I, I love that you brought that up and uh, because I think on a first meeting, open-ended questions are great, because that's sort of like, if you're if information were fish, you know that's the widest net you can catch and like that's what you're going to bring in, but then, um, you know, if you're really looking for that specific thing, uh, the net approach might miss it.
Dr. Denis Balaban:You might need to spear fish for those questions, and I fully agree. Um, so, for some of those and those knowing when and what those key questions ask really depends on how the patient is presenting. So, for example, if someone is telling me like, oh my gosh, like I have all this terrible stiffness and I have these episodes of spasms that are just killing me stiffness, and I have these episodes of spasms that are just killing me, you know, one question that I ask in those contexts is well, tell me, are you more easily surprised than you used to be when this started? And people will often like why do you ask that? Like they'll have this quizzical look on their face. Really, you know, yeah, I do, I am a bit more easily startled. Their face, really. You know, yeah, I do, I, I am a bit more easily startled. Why did you and and then okay, and um and that can be a very helpful uh question to ask.
Dr. Denis Balaban:In something like a stiff person spectrum disorder, uh, where their startle is increased, the spasms can be triggered by startle as well. I had a patient where, um, they actually had a stiff limb syndrome and if I brought my hand to the affected limb, not even touching them, it would trigger the startle. So not even a tactile stimulus, just like the possibility of a tactile stimulus, and they were fully aware they were watching me do it as I was moving towards it. Not even that much of a startle. So asking a pointed question like that can be helpful In somebody who has a subacute cognitive decline, for example. In those cases I think it's a very easy question to ask about fascia brachial tonic seizures. Easy question to ask about facial brachial tonic seizures. And so the way I ask that is like have you ever had episodes where your arm or the and the corner of your mouth sort of come together almost and I acted out for them, because you know, if the picture is worth a thousand words, then actually acting it out is worth even more. And I often ask patiently if there's a funny movement that occurs, like can you act that out? Tell me like what that? Show me what that looks like, and then they can perfectly act out what I might've been picturing in my head and like, okay, yeah, that's it. Okay, asking, and that's a great question for LGI1 specifically.
Dr. Denis Balaban:Another thing for LGI1 are asking about brief dizziness spells which can occur, which are thought to be seizures, but we're still not exactly sure. But essentially it's these like five to 10 second episodes of people have described them as like a chill or a vertigo or a dizziness. And you know they can happen with low frequency to begin with, but then as time moves forward, they can start to happen weekly, then daily, then multiple times a day, and that is also a nice clue for the possibility of an LGI-1. You know, if you're wondering about MS, you know something you could ask about is are your symptoms worse in a hot shower or if you've been exercising a lot? And that's asking about, you know, the UTOF phenomenon. So these are like, so, knowing the specific questions, that if you have certain, if you have a list of diagnoses already in mind that might fit the clinical syndrome, ask about those specific things. That can be quite helpful.
Dr. Michael Kentris:Right, and that's as you said. The challenging part with neuroimmunology is that it radically could affect any part of the neural system, from the brain to the muscles, and so you kind of have to have your algorithm for each potential complaint locked and loaded before you can go and get it.
Dr. Denis Balaban:Yeah, exactly Like you having an idea of the syndrome that you're dealing with and then trying to ask those questions. That's and like having that, having that knowledge already in store, because there there are some things that are very easily up-to-date-able or Google-able, but knowing a disease and exactly how it presents in the story of that disease, that's not something that a quick search generally accomplishes and I'll speak.
Dr. Michael Kentris:you know not to throw any shade at the writers for up-to-date, but I do find the neurology up-to-date articles for a lot of topics are not up-to-date. To speak to that right, like neuroimmunology is one of the biggest culprits. Oh yeah, the rate of new knowledge is just such a breakneck pace. Oh my gosh yeah, it's almost impossible to keep a compendium like that current.
Dr. Denis Balaban:Exactly, yeah, it's one of the fastest moving fields and makes it really exciting, but also takes work to stay up to date.
Dr. Michael Kentris:Now in the outpatient setting, is there anything that you know, any chief complaint that perhaps represents the lion's share of referrals, or is it a pretty varied spectrum?
Dr. Denis Balaban:as far as what you've anecdotally observed, oh my gosh, it's such a varied spectrum Because people get referred to neuroimmunology for a wide variety of reasons. Some are due to like an initial workup that revealed something inflammatory appearing. So one example is a meningitis seen on MRI, where you have either a leptomeningeal or pacumenengeal enhancement and so then say, oh my God, they have a pacumenengeitis, send them to neuroimmuno and many times those are actually just chronic CSF leaks. But you know, depending on the story or lack thereof, for a chronic CSF leak we'll do the investigations and find that everything is bland.
Dr. Denis Balaban:There's no history that's suggestive uh, by like prior autoimmune history or family history or anything of that nature. And then, oh, they have a history of men, years, okay, and uh, csf leaks in men years can go hand in hand. Um, so then it says, okay, so CSF leak and we can try and treat that. Um, then there's other people who come in because of funny spots in their brain, uh, on mri, which may or may not be, uh, related to their symptoms, uh, whole, whole variety of things. Or, and the numbness and tingling in the setting of a recent cancer diagnosis, for example, could this be pyreneoplastic or could this be some sort of inflammatory, something related to a myeloma and the high M spike, for example.
Dr. Michael Kentris:So all sorts of reasons people can be referred no-transcript, you know, frustrating, let's say to the general neurologist to approach and that is the, the so-called unidentified or, you know, poorly defined, the UBO, the object on MRI, someone's right T2 flare lesion that maybe it's demyelinating there's one spot it's not enhancing, there's no clinical. They got that for like a headache workup or something like that. And they're like how far down the rabbit trail do I need to run for investigating for something like multiple sclerosis or things like that? Yep, so in your practice, let's start with someone with that vagueness of a complaint. Sure, how did you deal with that kind of setting?
Dr. Denis Balaban:Great question, so okay, so just to make sure I got it so somebody with these T2 hyperintensities on brain MRI discovered due to some maybe potentially or initially sounding vague symptoms. So then what I do in evaluating this patient is I, first off, who is the patient? Are they an 80-year-old male with history of high blood pressure, diabetes and hyperlipidemia? Are they a young woman with no significant past medical history? And maybe they don't even get headaches at all, even get headaches at all? So I sort of just go down like, okay, well, what could these be in neuroimmunology? Could these be indicative of MS? So then I ask like, okay, have you had episodes that could be significant for MS, like a patch of numbness or tingling that lasted several days to a week? Have you had optic neuritis? Or you know? I ask about the optic neuritis symptoms of, like painful eye movements with vision loss. I ask about new onset constipation or urinary frequency and urgency. And one thing I want to say is that I feel like in seeing people ask about urinary symptoms are you peeing a lot? No, I'm not peeing a lot and then you get to it it's like, oh, you're peeing every two hours. Yeah, it's better than peeing every hour. Um, so, like the, the way I ask about it is okay. Um, when you feel like you need to pee, are you able to hold your urine, uh, urine, for like 30 minutes to an hour, or are you racing to the bathroom or do you? Are you very like, cognizant of, like, your urinary habits? And that has gotten me a lot farther than a more broad question, because then I'll have people say, oh my gosh, yeah, if I don't, if I don't get to a bathroom within five minutes, I worry I could pee my pants. Or, yeah, I really have to pee every three hours, otherwise bad things will happen. So that has gotten me a lot. And then, for bowel movements, for example, I had a patient who had new onset constipation for no apparent reason. Um, they were a uh, healthy person and they were even hospitalized, uh, for this new constipation that came out of nowhere, and I know. And it turned out that, um, after everything was said and done, that it was due to a demanding lesion in the spinal cord that had yet to be discovered. Um, so, no, not at all. But, um, so, but that's just part of the assessment. So then, uh, after like, new numbness, tingling, weakness, uh, like, uh, stiffness in the legs.
Dr. Denis Balaban:Um, the exercise have, as your workout routines, gotten harder for any reason, are Are you lifting less weights? Are you not able to squat as much? If they're active, that's so helpful, because that sort of high level of activity will be a much more sensitive marker than for someone who is sedentary and like, yeah, I walk up a flight of stairs every now and then. You might not notice the decrements happening until they are quite severe. Um, so then I also take into account, like key past medical history questions. Um, that again, epic is uh, or the medical record can be a minefield of chartomas or, uh, a dearth of information. That's a new one for me. I'm going to keep that one. Oh yeah, I can't claim ownership of that.
Dr. Michael Kentris:That's a new one for me. I'm going to keep that one oh yeah, I can't claim ownership of that.
Dr. Denis Balaban:I had heard that somewhere years ago. But you can ask about history of MS, for example infectious mono, big one. I have significantly raised my own suspicion for MS in someone who is otherwise asymptomatic at the moment due to their history of infectious mono and an asymmetric reflex or two. And lo and behold, it was MS, because it's one of its. The highest risk factor, acquired risk factor, I'll say for MS. The highest risk factor, acquired risk factor, I'll say for MS. But if you're not thinking about MS in particular and you're wondering about, you know, neuroimmunology, rheumatology not otherwise specified, then you can ask a whole host of questions that wouldn't come up in a usual general neurology visit for migraine, let's say. So you could ask about, you know, things such as do you have any new rashes, do you have any new joint pains, and they might say no. They might say like, yeah, I have this like weird lacy rash that's been on my thighs that just won't go away and it's new. And you know they're wearing pants and jeans and so you're not going to be able to see that right away. But you know, a levado or levidoid rash can sometimes be a symptom of something like a vasculitis can be seen in, excuse me, intravascular lymphoma, all sorts, not exactly neuroimmunology but you, but on the rare zebra spectrum of things. So asking about those things, asking about history of uveitis, because many rheumatologic disorders can present with either an anterior or a posterior or pan uveitis, even MS, for intermediate uveitis that can be seen in MS. Sometimes Oral or genital ulcers can be seen in things like Batchett's or lupus, at least for the oral versions. Constitutional symptoms, fevers, chills, night sweats that drench the clothing or the bed, unexplained weight loss drenched the clothing or the bed, unexplained weight loss. I've had a patient with a presumed inflammatory myopathy who had lost almost 100 pounds over the past several years and cancer workup was completely negative and it was presumed due to an underlying undifferentiated connective tissue disorder and seems to be doing better with some immunotherapy and then other things that can cause the immune system to act a little haywire History of HIV to act. A little haywire History of HIV. I've seen there's some thought that the HIV can lead to disimmune problems. For example, we've seen a patient who had in their past the age of 65, new onset of tumifactive demyelination, relapsing, remitting. A biopsy was even done to make sure it wasn't something strange like PML or something otherwise and just demyelinating, looked just like what you'd see in MS. But they had well-controlled HIV for decades and we presume that this was a you know, a disimmune problem related to the HIV, leading to demyelinating lesions.
Dr. Denis Balaban:And then for autoimmune encephalitis of many stripes, a history of herpetic infections, neurologic or systemic. So HSE encephalitis if you see a recurrent encephalitis, be thinking NMDA, not a recurrence of their HSV encephalitis, assuming it was properly treated. But even systemic infections of like HHV-6, for example, have been associated with rarely with autoimmune encephalitis For things like GBS or other neuropathies, dbs or other neuropathies, history of infection in the last two to six weeks. That can be indicative or raise a suspicion. And then, of course, like current cancer or a tumor that looks a lot like cancer, or history of smoking paired with constitutional symptoms, these all can be concerning, for maybe there's a perineoplastic problem going on. Oh, and one other thing frequent infections. Yeah. So common variable immunodeficiency or other immunodeficiencies can create this seeming paradox of someone who has an immune system that doesn't seem to work and they get lots of infections but then at the same time can bounce right back to them and cause autoimmune problems.
Dr. Michael Kentris:Fascinating. Yeah, it is like again. Like you were mentioning that disimmune sort of thing where it's not necessarily just a. We call things deficiencies but it's not quite accurate 100% of the way.
Dr. Denis Balaban:Yeah, like a Goode syndrome, for example, is another good example of this, where there is both an immunodeficiency as well as a problem of autoimmunity in some cases.
Dr. Michael Kentris:Now something that kind of came to mind while you were talking about like these historical questions. You know, like the classic systemic rheumatologic disease symptoms dry eyes, dry mouth, oh yeah.
Dr. Michael Kentris:All that, all the rashes, all that kind of stuff, and that always to me brings up a bit of a conundrum. Right, because we're talking about neuroimmunologic syndromes, but it may not be in isolation. So when you see perhaps a more systemic autoimmune condition, like, let's say, lupus or rheumatoid arthritis or any of the other hundred other things that are out there, raise your antenna for a concurrent neurologic manifestation of that same syndrome or a separate autoimmune condition that is just comorbid with the other previous diagnosis.
Dr. Denis Balaban:So just to make sure I understand, if you have a patient who has a known systemic autoimmune disease and then you have a new neurologic symptom, is that related to the systemic autoimmune disease or is it just a another one that they have also affecting their brain?
Dr. Michael Kentris:like uh, an example I think I saw a case reporter series recently. It was like uh, people who have like a diagnosis of systemic lupus and then they get diagnosed with neuromyelitis, optica spectrum disorder, with like the positive aquaporin four. Yeah, that lupus still, or is it lupus and nmo?
Dr. Denis Balaban:um, if they have a positive nmo antibody, then that's nmo. Um, it's just a uh. And I and people, some people think that all the the many cases of like lupus myelitis diagnosed in the past, maybe those were just NMO before we had the antibody. So I think that's more of an example of autoimmune diseases grouping together rather than it all being under one autoimmune disease.
Dr. Denis Balaban:And the other thing is that, uh, sometimes, uh, you know, patient will come in for a symptom and it might be as simple as like really, really bad migraines and in the course of just my like review of systems, all like, yep, I got dry eyes and yep, I got ulcers in my mouth and and like, oh, and then I ask more because my interest is peaked now and they'll have have like something like Sjogren's or Bechets or something like that, and they're like oh my God, are my headaches because of this? I'm like, well, or like a meningitis, for example, you have a systemic autoimmune disease and that might be playing a role in your terrible migraines. But at the end of the day, they're just terrible migraines and we will treat them as such. And maybe, if your rheumatologist is treating your systemic autoimmune disease, maybe that could help potentially. But yeah, so we see neurologic problems in the patient with a systemic autoimmune issue and they have nothing. They have uh, it's not a neuroimmunological issue per se. I'll say that.
Dr. Michael Kentris:I'm going to ask you a loaded question, okay.
Dr. Michael Kentris:Uh now this is anecdotal, you know, just to the places I've practiced myself. But it seems that a lot of times I'll have a neuroimmunologist or not, a dime, a dozen across the country. So a lot of times I'll be trying to work in conjunction with a rheumatologist and it seems like, if it's not a systemic rheumatologic disorder, that they don't necessarily have a huge amount of interest in becoming involved in the management of these patients. And I was just curious is that because it is neurology and no one except neurologists like neurology?
Dr. Denis Balaban:Or is it something else that I'm missing?
Dr. Denis Balaban:I think that I can't speak to what the rheumatologists that you've encountered are thinking, but I have noticed this as well, where if it's not a systemic rheumatologic disorder, then it's like, well, I'm not sure what to do with this.
Dr. Denis Balaban:Like, for example, trying to treat somebody with autoimmune encephalitis and partnering with a rheumatologist. I don't think that the rheumatologist would feel comfortable doing that, even though we use the steroids and you know things that they would probably be very the treatments they would be very comfortable with, but in terms of what it is, I don't think that they have. I don't think they received the training in that specific thing and thus they would logically not feel comfortable with that. I think that if it is a neuro-rheumatologic issue, where they have a systemic rheum issue and they have a neurological issue, so Sjogren's ganglionopathy, for example, or lupus cerebritis or something of that nature, then I think they would feel much more comfortable treating that. But if it doesn't fit sort of the main things that they are used to seeing or have the training for, I think there would be logically less of an appetite. That would be my guess.
Dr. Michael Kentris:That's fair. I remember I had a case with a good friend of mine who's a rheumatologist. She had an extensive transverse myelitis. It was probably like seven or eight segments long and everything came back negative. Even the LP just had elevated protein kind of mild lymphocytic thiositosis, Nothing knocking your socks off and the only thing that came back positive was a double-stranded DNA. But she didn't have any systemic symptoms. Yep, Is this something? And he was like I don't think it's something. And I was like I'm going to give her steroids anyway, steroids anyway.
Dr. Denis Balaban:And he's like okay, and what did you say?
Dr. Michael Kentris:the symptom was that she came in. She had a really bad lower extremity weakness and numbness.
Dr. Denis Balaban:So it was oh, yeah, the myelin. Yeah, in that case, yeah, I mean, yeah, that would be concerning I, you know. Similarly, I had a patient who, uh, when I was a resident they had come with subacute cognitive decline and at first we were like, oh, it's a UTI, oh wait, we treated the UTI. But now they have C diff. Oh, shoot, okay, well, they're still confused, but this makes sense, it's all toxic, metabolic, right. And then our attending rightly was like, wait, they've been on antibiotics for a week now and they're still not better. Okay, no. And so then we did a lot more work up and all that came back was a sky-high ana and a sky-high dsdna and mri brain, normal csf, normal eeg, you know, non-specific um and really lup, no constitutional anything at all, nothing else that would have met criteria for lupus. And we consulted Rheum and they were interested, but they were like it's hard to call this lupus, but we're going to treat them like lupus and got better with steroids and rituximab. So, yeah, we see stuff like that.
Dr. Michael Kentris:Yeah, that's, that's see, that's why no one likes neuroimmunology oh, that's why I love neuroimmuno.
Dr. Denis Balaban:It's so cool, it's like what is this, what's going on? And they got better uh with, with treating, uh with their immunosuppressive medications. There's just, it's such, it's a field so ripe for discovery. It's a field ripe with excitement and wonder. Yeah, everyone should be a neurobiologist.
Dr. Michael Kentris:It's very funny you say that Because I mean it is exciting, it's like hey, maybe we can do something to fix this and that'd be great for everybody. And I think a lot of it is a little bit of a holdover from, kind of the old guard of neurology. I remember one of my MS attendings in residency saying that neurologists are weenies. End quote what Talking specifically about giving these more robust chemotherapeutic agents. Well, robust remilitive right Like rituximab or cyclophosphamide or things like that right. It's like, you know, because she she was retired military so she would say sometimes you just have to put on your big boy pants and make a decision. You know, I've tried to embody that spirit, even sometimes when I was like, oh, I think this is the right thing to do and you know there's not a lot of good evidence sometimes in some of these situations. But it's like, mechanistically I gotta take a page critical care colleagues.
Dr. Michael Kentris:It's like, well, physiologically, this should make sense. Yes, uh, you know.
Dr. Denis Balaban:Just cross your fingers and pray for the best I mean there there's so much yet to be discovered in neuroimmunology. I think we've come a long way. But there's so many cases where it's like we don't have an antibody for this, we don't have a test for this. The way this is acting, the way this looks at MRI, the way that your symptoms are worsening, like yeah, we should do steroids because we've looked at you know, it's not a metabolic thing, we've checked the labs reasonable to check, we've. You know, we don't think this fits the profile of like something else neurodegenerative or vascular or something like that. And so then we just have to empirically treat.
Dr. Denis Balaban:You know, anyone who's treated someone for seronegative autoimmune encephalitis can know that internal tension of how sure am I, this is an autoimmune encephalitis? How sure am I about my history in getting this like three month subacute decline? What about that? Like three month subacute decline? What about that? You know, well, maybe this started actually a few years ago with this symptom, but or maybe that was just their depression, or like, like, I've played this game with myself, like trying to make sure that I feel as comfortable as possible with the history that I've gotten.
Dr. Denis Balaban:And sometimes you know, you do the MRI, you do the lumbar puncture. You check your amyloid to make sure it wasn't like some sort of neurodegenerative thing, at least commonly and if you're not coming up with things that would reasonably fit otherwise. And if you look at the Grouse 2016 criteria for a possible seronegative, a possible autoimmune encephalitis, and it's lining up not so bad A trial of six weeks of steroids. You know if it gets better, well worth it. And if it doesn't, well, you got IVIG. You can try too, and if it doesn't work, then maybe it's not immunoresponsive. But sometimes the diagnosis is in the treatment, which we don't like. But sometimes that's what we have and sometimes it works.
Dr. Michael Kentris:Very true, I find you know. In the epilepsy world as well, I find myself doing that. It's like doing that. It's like those recurrent spells. Your eegs have been normal, but we haven't caught a spell. So here's some kepra.
Dr. Denis Balaban:Let's see how things go over the next four weeks yep, uh, yeah, definitely you've done that too and uh, that has worked sometimes and it's great.
Dr. Michael Kentris:You know, it's I I remember one of my my fellowship instructors. You know it's. I remember one of my my fellowship instructors and he would say, like it is just so humbling because you are just wrong, so like your initial gut check is wrong, so often you just have to. You know it doesn't fit that, but yeah, anchor on this too hard just yet.
Dr. Denis Balaban:Yeah, and so just to like for another story of empiric treatment, we published a case of somebody who had presented with hallucinations, altered mental status and personality and hemichorea, and it was onset was like a week or so and MRI was normal, labs were normal, csf normal, everything normal. So it wasn't like a stroke or hyperglycemia or any phospholip syndrome or anything like that. It was seronegative something and treated with IVIG Korea melted away and it was one of those rare cases of a seronegative autoimmune movement disorder and it was relapsing. So I think it was when we said three to five months of no immunotherapy, then it would come right back and so mycophenolate then evened things out. But yeah, that was a case where no test was ever going to give you the answer and sometimes you have to treat.
Dr. Denis Balaban:Now, when it comes to treating things with like cyclophosphamide, for example, or rituximab you want to, you try to be much more certain because those carry higher risk than once weekly pulse dose steroids, because those carry higher risk than once-weekly pulse dose steroids.
Dr. Denis Balaban:But I've run into some cases of recurrent stroke where we try to treat with all the things usual to treat stroke at maximal medical therapy and they keep having TIAs, they keep having infarcts and we've done all the work up there we can think of to try and make ourselves more sure about a vasculitis first, and sometimes there are no good biopsy sites.
Dr. Denis Balaban:Sometimes there are no great places to even think about a biopsy, or like there's no nothing on the MRI that is biopsiable. And we had a case where we treated with cyclophosphamide once monthly for six months and no more strokes, no more TIAs. So yeah, and I was nervous about treating with that, but after, I mean, it was what we needed to do and I, you know, made sure everyone was on the same page and it worked. So again, few and far between, but there are. There are those cases where you need to do that, so having the courage to treat, but then there are also the cases where you must have the courage not to treat as well then there are also the cases where you must have the courage not to treat as well.
Dr. Michael Kentris:So from a kind of practical, I know people are going to wonder, I, because I'm wondering myself. So if you are seeing someone who you're thinking has like maybe a subacute, you know, autoimmune encephalitis or something like that, that subacute cognitive decline, what's your, what's your steroid dosing regimen look like for that period of time?
Dr. Denis Balaban:Oh yeah, so let so if they meet criteria for autoimmune encephalitis and you've done your work up with, like, making sure it's nothing metabolic, making sure that you've got an MRI, csf, um, and for CSF I don't just treat, I don't just um, you know, use the basics plus the Mayo autoimmune panel, but I also check for oligoclonal bands, igg index, beta-2 microglobulin, which is a lymphocyte turnover marker, because those can be sort of secondary measures of inflammation. And I've definitely seen those cases where CSF is completely bland but, like the IgG index could be elevated and that's helpful. But for steroid treatment, this is based off of Mayo's structured steroids protocol where they use one gram of solumedrol for three days in a row and then they do once weekly for six to twelve weeks, twelve for, like, the cases that have seizures, six for those that don't and you reassess for treatment response and if there's not been a response then you can go to using IVIG. And if there's no response with that and these are in the seronegative cases, specifically, if you have an antibody that helps guide your treatment. So yeah, especially if it's a, so like that's like for the all comer, like you know, in general like first line treatments for autoimmune encephalitis In the cases of a like high risk antibody for something like high risk for cancer, antibodies.
Dr. Denis Balaban:So these would be like your um, anna, one anti-yo, um you know where. If you see the antibody, even without any neurological symptom, you're still looking for the cancer. Or amphiphysin, yeah, um, if that's causing encephalitis, then like steroids, cyclophosphamide. Still looking for the cancer. Or amphiphysin, yeah, um, if that's causing encephalitis, then like steroids, cyclophosphamide. Get rid of the cancer. Because and the reason for jumping the cyclophosphamide in those cases is because these are generally t-cell mediated diseases and your steroids can, are going to help with that. Your, your IVIG probably not as much, and then your rituximab doesn't really touch your T cells, so cyclophosphamide does so, yeah, and in the ataxia cases too, like if you have an autoimmune cerebellitis, those are often T cell mediated disorders and that's where you're reaching earlier for the cyclophosphamide as well, gotcha.
Dr. Michael Kentris:That makes sense, yeah. So one last clinical conundrum I would like. When you get a referral from a general neurologist, let's say who was like patient with, let's just say, x vague symptom, they get a, you know, mayo perineoplastic panel and you get this weak.
Dr. Denis Balaban:I love it. I love it.
Dr. Michael Kentris:I'm gonna send you to neuro. I'm gonna send you to an expert yeah let's send you to the neuroimmunology guys down the hallway here and uh, what do you guys do with that? Uh, other than I assume lots of counseling uh, well, yes, a lot of Um.
Dr. Denis Balaban:So we do see cases of like I think the the GAD 65 is the neurologist's ANA. Um, yeah, so for low levels of GAD 65 antibody, um, first I like, do you have symptoms like that would be relevant to a GAD-65 antibody? So those things would be like stiff person syndrome and autoimmune encephalitis, seizures, things of that nature. And if they do not, then I counsel that this is not an antibody that is relevant neurologically likely. Some people think that it can be a marker of like tendency to inflammation. So, because GAD-65 autoantibodies are seen in type 1 diabetes and sometimes that can exist before the type 1 diabetes starts, and so if you have the diabetic phenotype and you got the GAD-65 antibodies, that's type 1 diabetes, whatever the level. But if it's for stiff persons, at least a neurological level, like a neurological level um. So depending on if you're using, uh, you know, a radioimmune assay versus a enzyme immunoassay, like your level, cutoffs vary, um, but these, there are published cutoffs there that should raise or lower your suspicion.
Dr. Denis Balaban:Then you start to get more concerned about something like a stick persons and then go from there um, but know, I've also seen like very weak positivity to something like you know, a voltage-gated calcium channel autoantibody for example, and you know, completely normal autonomic function. Their muscle strength is fine, there's no fatigability. And then I say something similar, like you might have a tendency to autoimmunity and if they have another autoimmune disorder but they have zero symptoms of you know, whatever the antibody is generally associated with and it might be just like your immune syndrome, like kicking off something else. I mean, they're definitely like, for example, in lupus, like you can have some positive rheumatoid factor, positive Sjogren's. It's not that they have Sjogren's necessarily, but they might just be tagalongs. We see tagalong antibodies not infrequently like GFAP antibodies, for example the setting of NMO or NMDA. They probably have NMDA and NMO, not a GFAP astrocytopathy.
Dr. Michael Kentris:So I think just putting the antibody into the clinical context is the important thing. I think that is somewhere we're probably lagging behind the rheumatology folks is, uh, like putting our pre-test probabilities into a better perspective as far as like, what does it mean if it comes back? You know, weakly positive, strongly positive? Does it match the clinical phenotype right, because we've definitely seen you?
Dr. Denis Balaban:know I've had patients.
Dr. Michael Kentris:You know they have like an rf factor. You know like two, three, four hundred, whatever yeah, they have no joint pain, they have no, no stiffness, blah, blah, blah. So there's nothing clinically there, and so they're like well, you don't have RA, yeah. And I'm like oh okay, I think we're probably heading in that direction, as we start seeing these panels getting ordered more and more often for more and more vague complaints.
Dr. Denis Balaban:Yep, Absolutely absolutely.
Dr. Michael Kentris:Any final thoughts or clinical pearls that you think the trainee out there should be aware of, whether neurology, internal medicine, what have you that should raise the? I know we've talked about a lot of things already, but the biggest takeaway for you from this discussion should raise the raise. I know we've talked about a lot of things already.
Dr. Denis Balaban:The biggest takeaway for you from this discussion would be what learn one thing from our conversation? Oh my gosh, you're limiting me to just one thing. Okay, one to three. Okay, I think, let me think about that, I think, let me think about that. So I think one point is making sure that if the syndrome and the symptoms could fit with a rheumatologic disease or a neurone immunologic disorder, make sure that you're asking specific questions for those disorders. So, if you're worried about something like a vasculitis, don't just ask about stroke symptoms. Ask about systemic symptoms like coughing, coughing up blood, sinus issues, peeing blood, rashes, things like that. So that's, they're asking those in your HPI and review of systems.
Dr. Denis Balaban:Similarly, getting a really good family history. And not just do you have any family history of autoimmune disease? No one knows what that means, or very few people do, like, do you have a family history of autoimmune disease? No one knows what that means, or very few people do, um, like, do you have a family history of psoriasis, celiac, lupus, rheumatoid arthritis, inflammatory bowel disease? Just list them, um, and you will sometimes be surprised by the answers. You so I think that's. I'm going to lump that as one, two, really dive in to the onset and the pacing of the symptoms and make sure that you have that as down pat as possible. So that's number two, and do I have the third one as a catch all for our discussions? I will just say be curious. And that applies to both interacting with your patients, as well as reading more and familiarizing yourself with the wondrous world of neuroimmunology.
Dr. Michael Kentris:That's a great point. I can't. I probably said it today, I just finished rounding a few hours ago, and probably at least a handful of times I had to say what do you mean by that, in response to something the patient had just told me. Yes, you know it's like. Could you tell me, tell me more about exactly it is? That's that funny thing of language where they know exactly what they mean, but I I don't. So I need you to break it down for me tell me more about.
Dr. Denis Balaban:That is my favorite open-ended question. That that is. That is one of the most useful open-ended questions in my experience it's just like, yeah, I don't know there's, there's already something satisfying.
Dr. Michael Kentris:It's like you finally have heard something in the history is like triggered yes, for you to go down. It's like maybe I can figure out what's going on here it's like a lifeline for me to try and solve this puzzle.
Dr. Denis Balaban:Yes, it's the clearing in the forest, absolutely.
Dr. Michael Kentris:Well, thank you so much for taking the time and talking with us. We'll definitely have to have you back on and talk about more specific neuroimmunologic disorders in the future.
Dr. Denis Balaban:Oh, thank you. Yes, I would love to do that. Thank you so much for having me.
Dr. Michael Kentris:And if people want to find you, find your work, uh, where should they? Or should they track you down online?
Dr. Denis Balaban:So I do have a uh Twitter slash X accounts, um, just at Dennis Balaban MD. I'll say that I do not post as frequently as I once did, um, but I have that account. Um, let's see, I mean I have, I have my MGH websites that uh people can look me up uh as well, but yeah, and then PubMed, I suppose.
Dr. Michael Kentris:A real researcher, not like me.
Dr. Denis Balaban:I'm slowly getting more publications to my name, but there are certainly far more published than I.
Dr. Michael Kentris:So, thank you so much. And, as always, you can always find me also on Twix. I've heard people call it Twix. I kind of like that. It's a little bit better than X, I think. Oh, twix you so much. And, as always, you can always find me also on twix. I've heard people call it twix. I kind of like that. Uh, it's a little bit better than x, I think oh, twix, I I do like that, though.
Dr. Denis Balaban:I think the candy bar company may have words about that.
Dr. Michael Kentris:That's true but I'm at dr kentris d-r-k-e-n-t-r-i-s and you can, of course, find all of our past stuff on the website at the neurotransransmitterscom. Dennis, thank you again so much. Really appreciate you taking the time.
Dr. Denis Balaban:Thank you so much for having me. This was a treat.
Dr. Michael Kentris:Likewise.
