»» Good afternoon and welcome. I'm so glad to see a full room. I hope that everyone will be awake after you've had a good lunch. The carb coma cannot set in until at least the end of our session at 3. So thank you again for being here. I have the privilege today of introducing two colleagues that are both really, I think, a valuable representation of the potential benefit of collaborative care. And it really does allow for us to create a platform of innovative care delivery models. So I'm pleased to be able to introduce two of these team members to you today. Our first speaker will be Dr. Richard Jin. Richard is currently a PGY-3 psychiatry resident, though at this time in the academic year we'll say he's a rising fourth. He is at UCSF. He completed his MD-PhD thesis work in immunology. And his primary research interests are in neuroimmune interactions that may influence neurodevelopment and psychiatric disorders. Specifically, he's interested in neuropsychiatric manifestations of inflammatory disorders. Richard also is working to develop a pathway for clinical care that may allow for patients to have more collaboration between the adult neuroimmunology group and the psychiatry group at UCSF. Richard is going to lead us today first in a conversation about a clinical case. Obviously our topic is centered around autoimmune encephalitis and other autoimmune brain disorders. After Richard gives us the case presentation, then I will present to you on the concept of immunopsychiatry, really bringing in the worry, the watching, and the waiting types of questions. My name is Gina Mooneyham, and I'm a pediatrician, an adult psychiatrist, and a child and adolescent psychiatrist. I work at the National Institute of Mental Health. Previously I was on faculty at Duke, where I was the consult and liaison service director for child psychiatry, and I was the co-director for the autoimmune brain diseases clinic there. In 2020, I was recruited to go to the NIMH and then developed their multidisciplinary translational care program that's looking at the clinical research component of autoimmune encephalitis. After my talk, then Dr. Geflin will be speaking, and Jeff is going to be presenting how to think like a neuroimmunologist. So in this room, in this space, we really need to be well-equipped at talking to one another across specialties. And so Jeff is going to give you a very transparent and candid overview of how a neuroimmunologist might perceive the information, and that may allow for you to be more effective in conversations across disciplines. Dr. Geflin is an associate professor of neurology at UCSF. He specializes in caring for patients with a wide range of neuroinflammatory disorders. Dr. Geflin conducts clinical research focused on advancing new treatments for neuroimmunological diseases and restoring neurological function. Dr. Geflin is also an award-winning medical educator. He directs the Multiple Sclerosis Neuroimmunology Clinical Fellowship Program at UCSF and is the clinical director of the UCSF Center for Encephalitis and Meningitis. He serves as chair of the autoimmune neurology section of the American Academy of Neurology. He received an A.B. in history from Princeton University, an M.D. from Harvard. He completed his internship in internal medicine, a residency in neurology, and subspecialty fellowship training in MS and neuroimmunology all at UCSF. I asked him today. He's developed a good loyalty and feels that he's very committed to staying on the West Coast, even though he's done East and West Coast training. Dr. Geflin went on to earn a master's in advanced study in clinical research at UCSF, and he is board certified in neurology. So without further ado, I'll welcome you again to our session. Please do be mindful of the need to turn cell phones and pagers onto quiet. And if you do have questions, we'll invite you to hold them to the end so that we can reserve time to be able to talk about questions and answers. If we run out of time, we'll stay back for a few minutes to follow up. Thank you again for joining us. Dr. Jin, I'll come and introduce you first. Thank you. Thank you all for coming today. And it's a pleasure to be up here to present a clinical case for you guys and also talk about some diagnostic criteria for autoimmune encephalitis. So like Dr. Moonham had mentioned, I'm a resident, so I really have no disclosures to give. But I'm hoping that after this presentation, we'll have an increased ability to recognize illness models in which the immune system may influence psychiatric symptom burden and vice versa, as well as have an increased ability to identify the core symptoms necessary to diagnose autoimmune encephalitis using a particular consensus criteria, the 2016 Grouse criteria. So just going ahead and jumping into our first, into our case. I've been taking care of a patient. We'll call her patient A. She's 34 years old. She had described to me growing up in a tight-knit family, but ultimately a turbulent childhood punctuated by some bullying and unfortunately a sexual assault early in her adolescence. She graduated high school and ultimately moved away from the state, worked multiple administrative jobs, found her way back to California, was involved in a mountain biking accident, but fortuitously actually had met her husband, who was working as the park ranger at that time, and they've been married for the past seven years. And so in this context, she has actually been engaged in psychiatric care for quite some time, since her early 20s, for the management and treatment of PTSD and depression. She'll tell you that she has been on every SSRI throughout time. She's also been tried on SNRIs, mood stabilizers, and leading up to this current series of events, her regimen was mirtazapine and then olanzapine for augmentation. And she's had three inpatient hospitalizations in the setting of self-injury, a suicide attempt by pill overdose, and also suicidal ideation with a plan. And so that brings us up to our current set of events, which happens in the winter, in mid-December. And so in mid-December, she had presented to the medical emergency room. She had noted that she had worsened depression and anxiety. For the past couple of months, is what she mentioned, she was ascribing this to perhaps some medication changes that happened a couple of months ago. But she also had more acutely worsening migraines, acute and chronic, and also largely an inability to sleep for the past four to five days. And she was ultimately admitted into our inpatient psychiatry unit for a recurrent major depressive episode, endorsing suicidal ideation with intent, but no stated plan. Over the course of her 11-day admission into the inpatient unit, she consented to and started ECT, which she then completed the course of ECT as an outpatient leading into January. In about mid-January is when things began to pick up. She presented to an outside hospital with acute confusion and dysarthria. And at that time, she was found to be COVID positive. And so she was ultimately discharged with the altered mentation being ascribed to a side effect of the ECT, then compounded by her COVID status. The following day, she was continuing to be concerned, and her husband was also concerned for this worsening confusion. They represented, she was found to be mildly hyponatremic. She was given fluids and then discharged with supportive care. Two days later, again, not improving at all, now with fever, she presented to a different outside hospital. At this point in time, neurology was actually consulted given this consolation of symptoms, and an LP was performed showing marked pleocytosis on her CSF, elevated protein. And her CSF was positive for herpes simpex virus by PCR. And so a diagnosis of HSV encephalitis was made. And she was treated inpatient with a course of acyclovir and then ultimately discharged. About three days after discharge, she actually began to experience generalized tonic-clonic seizures. She had two of them and was readmitted into the hospital. During these seizures, she had mentioned she was hearing the persistent sounds of cats and dogs. A repeat lumbar puncture again showed a pleocytosis on her CSF, so elevated whites, elevated protein and glucose, and it was a lymphocyte predominance. Her CSF PCR was PCR positive for E. coli. They ended up starting her on Keppra for seizure treatment and then ceftriaxone and, again, another round of acyclovir for presumed infectious causes. A couple of weeks later, she continued to decline, continued to have worsening confusion. She presented to the emergency room multiple times over a series of days. Her husband noted that she would wake up with the mental capacity of a toddler, which is a wild deviation from her norm. But now she had new behavioral symptoms. She was more impulsive. She also—I didn't advance my slides. She was more impulsive and she also had some new neurologic symptoms. So she had some poor balance and then also right-sided weakness. So out of concern, the husband and our patient decided they wanted to come to UCSF. They lived multiple hours outside of our catchment area, but en route they stopped by an outside hospital to rule out stroke. Their stroke workup was negative, but the MRI was notable for a flare hyperintensity in the left temporal lobe and bilateral insular cortices. They ended up, because the stroke workup was negative, drove to UCSF for further care. The GP MRI was consistent with the outside hospital scan and she was admitted for a video EEG. And so at this time, the ongoing differential, given her constellation of symptoms, both psychiatric and neurologic, was ongoing focal seizure activity, potential recrudescence of injury that she might have sustained during her infectious encephalitis, also probably less likely partially treated HSV encephalitis, given the fact that she's had two rounds of acyclovir at this point in time, and then also, more pertinently, new encephalitis, in particular of autoimmune origin. And so I wanted to take a brief step away from the clinical case to talk about autoimmune encephalitis and antibody-mediated encephalitis, largely because not only is it the topic of our session, but also it's pertinent to this particular case, because we do think that infection, in particular viral infection and HSV encephalitis, can be the trigger for the development of autoimmune encephalitis. And so the way that we think that this might work is that you have a neurotrophic virus that might infect a neuron, and in its infection, cause stress and damage to this neuron, and then through the lytic and non-lytic properties of the virus can then damage this neuron, releasing antigens and peptides that might otherwise not be typically seen by the immune system. These antigens then get sopped up by dendritic cells or antigen-presenting cells in traffic to regional lymph nodes. And then in the regional lymph nodes, these dendritic cells will then present these autoantigens or autopeptides to helper T-cells or naive B-cells, which may have a particular affinity for these autoantigens or peptides, whether it's because they've somehow escaped or subverted central tolerance. But in either case, in the right context, they can activate and then lead to the differentiation of these naive B-cells into bona fide plasma cells, which create buckets of ITGs and other antibodies, and these autoreactive antibodies can wreak havoc in the body through a number of mechanisms, which I think we'll talk about later in this session. So since autoimmune encephalitis has now entered our differential, I wanted to take some time to talk about the diagnostic criteria for autoimmune encephalitis. So prior to 2016, much of the diagnosis of autoimmune encephalitis was reliant on the known presence of an antineuronal antibody and or a response to immunotherapy. But in 2016, a consortium of experts got together to really revisit these diagnostic criteria, largely motivated by the fact that there's a lack of universal access to antibody testing, that even if you had antibody testing, it can take up to several weeks for those to result, really delaying treatment and diagnosis. You know, the absence of an autoantibody doesn't necessarily exclude the possibility of autoimmune encephalitis. And some patients may not respond in the first round of immunotherapy or the second round of immunotherapy. And so a new framework, a more clinical diagnostic framework, was kind of the result of this consortium of experts. And so in the consensus criteria, we call them the GROUSE criteria, the first step in this workup is diagnostic criteria for possible autoimmune encephalitis. And so this occurs in three parts. The first part is a subacute onset. So that's defined by the progression of symptoms in less than three months, specifically of short-term memory deficits, altered mentation, or psychiatric symptoms. The second component being at least one of the following, a new focal CNS findings, a new seizure not explained by an existing seizure disorder, a CSF pleocytosis of greater than five whites, or MRI features of encephalitis or alternatively FFDG PET. And then the third component is reasonable exclusion of alternatives. And so this includes infections, tumor, epilepsy, and things like this. And so thinking back to our case, we certainly meet the first criteria, progression in less than three months of altered mentation and these behavioral symptoms. And we also meet the second criteria, new seizures and MRI features of encephalitis. And so really the task for this hospitalization is also to exclude reasonable exclusion of alternatives. This consensus group also went on to describe further levels of evidence. So now moving from possible autoimmune encephalitis to probable autoimmune encephalitis. But when they moved from possible to probable, they start to define particular syndromes or syndromic presentations of autoimmune encephalitis. And one such, and maybe the best prototype of which, is anti-NMDA receptor encephalitis. And this is pertinent to our particular case. And again, structured in this kind of three-part model. The first is rapid onset, less than three months of at least four of the six of the following major symptoms. And so in our particular patient, we did see abnormal behavior and cognitive dysfunction, some speech dysfunction, seizures, and then a decreased level of consciousness. The movement disorder piece and the autonomic dysfunction were a little less clear. And she was being admitted for the following. And so the second part is at least one of the following, an abnormal EEG or a CSF with pleocytosis or oligoclonal bands. She was being admitted for the video EEG and a repeat LP was pending. And then the final part was reasonable exclusion of alternative causes. I also wanted to just briefly touch on this point. Just based on this more diagnostic, clinical diagnostic framework for arriving at a diagnosis of autoimmune encephalitis, a clinical score was also developed to predict the likelihood of neural antibody positivity in patients with encephalopathy and or seizures. And this was developed at the Mayo Clinic by Dr. Dubé. And again, the thought is to help expedite the diagnosis and workup of autoimmune encephalitis. But this may act as a nice supplement clinically to what we now know about the diagnostic criteria. So returning back to our case, our patient was admitted for the video EEG, showed mild to moderate diffuse slowing, also some superimposed left hemispheric slowing. So certainly some changes in the EEG. Her repeat LP showed a pleocytosis with a lymphocyte predominance, elevated protein, IgG index of 2.7, and then 11 oligoclonal bands. But also her infectious workup was negative. So now we've really, thinking about those diagnostic criteria, hit the second and third points. And this was later confirmed about a week later when our NMDA receptor antibody titer finally came back. And it did come back positive at 1 to 80. And this was confirmed when the Mayo Autoantibody Panel also came back about three weeks later. So again, kind of speaking to this delay in detection of definitive antibodies. But certainly she met definitive criteria for NMDA receptor encephalitis. And so she was started on IVIG. And then she was also started on IV solumedrol with a course of a prednisone taper following. She also got a number of imaging modalities to rule out tumor or mass. And the thought behind this was that NMDA receptor encephalitis can also arise as a paraneoplastic phenomenon. However, despite immunotherapies, her condition continued to worsen. Cognition worsened. She was less interactive. She became mute, had a right-sided dystonia. Repeat imaging EEG and infectious workup were negative. And the MRI was read as consistent with edema, consistent with ongoing encephalitis by the neuroradiologists. About a week later, she started rituximab, so anti-CD20 monoclonal antibody to knock out the antibody-generating plasma cells. But in the ensuing days, she continued to worsen, have—she was mute. She had waxing and waning mentation. She now had more purposeless movements, stroking her hair, had waxy flexibility. And so this was all concerning for catatonia, which is not necessarily uncommon in autoimmune encephalitis. And so she was treated with a 2-milligram IV Ativan challenge and had somewhat of a Lazarus effect, rapid response to this IV Ativan. And so she was continued on the Ativan and ultimately discharged to a SNF. And so over the course of the next year, in outpatient follow-up, she was tapered off of her Ativan and also tapered off of a lansipine. She also developed some new symptoms, some whole body shaking with retained awareness and some retching fits and some episodic mutism. She was seen in an epilepsy monitoring unit, found to have non-epileptic seizures on top of her genuine seizures. In addition to that, during the course of the Ativan taper, her mood worsened and she did have some return of impulsivity. She had jumped out of a car twice, a moving car. And so she was hospitalized and ultimately the Ativan taper was paused for a period of time and then slowly weaned off again. And then she was started on dazepramine with significant improvement in mood and remission of some of those symptoms. To this day, she continues on rituximab once every six months or so. And overall, she will tell you that she is recovering well, especially considering how acute and how ill she had become during the course of her HSV encephalitis that then later turned into NMDA receptor encephalitis and complicated by catatonia. And so with that, I will turn it over to Dr. Mooningham. All right. So now we're going to jump from the case that Richard has given us. It, I hope, highlights the idea that you can have an autoimmune encephalitis as a byproduct of a post-infectious condition. In the story that he was sharing clinically, that young woman had HSV encephalitis after antigen presentation and cellular destruction that led to a second hit with the autoimmune encephalitis. So keep that framework in your listening ears as we move forward for some of the next parts. I am an employee of the National Institute of Mental Health. The views presented in this lecture do not necessarily represent the views of the Department of Health and Human Services, the NIH, or the U.S. government. I have no financial disclosures to share. My talk will be really divided into three parts. In the first one, I hope to give you a bit of a refresher course about immunopsychiatry, the innate immune system, and the adaptive immune system. In the second part, we're going to highlight some of the clinical pitfalls when considering a diagnosis of autoimmune encephalitis. And then in the third and final component, we'll look at next generation features, technologies, and diagnostic applications that may actually shape the standard of care in years to come. So immunopsychiatry is a phrase that was coined back in 1985, and this is the study of the interaction between the brain and the immune system. So it could be antibody-mediated, cell-mediated, and the concept here is that you're looking at underpinnings or potential pathogenesis of mental illness. A similar but opposite concept would be psychoneuroimmunology, looking at the way that psychological or neurological phenomenon can then influence the immune system. Think about those times when you were in college and you got all of your final exams done, you went on your break, and then you got hit with some terrible version of whatever it was, the flu or something else. So you have this stress adaptation response that can really influence heavily the immune cascade, and now we're talking about this two-direction highway here, the ways in which our psychological state can influence the immune phenomenon, and vice versa, the way that the immune phenomenon can create, manifest, or amplify psychiatric symptom burden. If you felt sick and you had a fever, whether it's COVID, whether it's flu, pick your poison here, you really will often see changes in one's behavior. This goes across the developmental lifespan. You may have mood lability, irritability, you may have cognitive dulling or brain fog, fatigue, low energy. And the next two slides are meant to depict how we have started to really understand more about the cellular underpinnings of a variety of different models of illness, depression being one. The first left-hand side of the slide shows the 2002 game-changing infographic that was put forward by Dennis Charney, looking really at an organ-based perspective of potential influences on depression and the development of depression. In 2009, a more evolved model is showing up in which we're looking at the influence of cytokine cascade and cellular targets for depression, and now 20 years from the original until this publication in 2022, you're seeing cellular mechanisms of illness that have to do with the micro environment within the central nervous system. So we're going to talk about these in bits and pieces today. As a psychiatrist, you're either sitting here thinking, why do I need to know immunology again? Or you're loving it, and I don't know which side of that spectrum that you're on, but my point is in your inbox or in your lit reviews, you're going to see a paper every day, every week, every month that looks at some potential connection of the immune system and psychiatry. So I think it behooves us all to do a little bit of a refresher course. Hang in here with me on this. All right, we've got the innate side and we have the adaptive side. On the innate immunity side, this is quick, non-specific. It's really about solving the problem, but it's doing so in a broad sweeping strokes that acts fast. So you'll have phagocytosis of the bad guy invaders. You will have complement poking holes in cells and leading to cells bursting and cell lysis. That all happens within hours to days. Then you go on to the longer pathway, which is adaptive immunity, looking at the ways in which we have conferred immunological memory. This takes time. In order to develop B cells, to grow up plasma cells so that you have these antibody making factories, it does require exposure as well as time. The other side of this though is T cell mediated disease, and this is important. All right, I'm not asking you to be an immunologist, but think with me about the importance. When I go hunting for antibodies, that is a B cell associated byproduct and phenomenon. But if it's a T cell mediated disease, there are no antibodies. We're looking at T cell receptors, so it's a bit of a different problem. Really the same concept, but what's on the T cell side versus the B cell side means that you may not get antibody positivity on antibody panels if it's a T cell mediated phenomenon. Complement. I'm giving this to you in words or in pictures. Take your preference here. Here's the picture version. But complement is a series of cascading things that happen. You may have PTSD if you remember C3, big B, little B, C4, big B, little B, and all that stuff. But basically you have these proteins that are present in an inactive state waiting until the moment in time in which it sees an invader. Then it becomes activated and it has this tick over effect where all three paths, regardless of how it gets activated, all three paths end up with a little thing at the bottom that's the membrane attack complex, the MAC. The MAC pokes holes in the cell wall and then the cells will lyse and be destroyed. Now the second part of what we're going to talk about today is a particular disease model, autoimmune encephalitis, but it is one example of a whole host of different autoimmune brain diseases. You may have lupus cerebritis, neurobushets, CNS vasculitis, even narcolepsy. That's an antibody mediated attack or a T cell activation that seems to target the orexin producing cells of the hypothalamus. That's kind of cool. That is not how a lot of people think about narcolepsy. While you don't wish to have the disease model, I think the acknowledgement of how this happens is something that is a bit shocking or surprising that this is an immune mediated phenomenon. Autoimmune encephalitis is a fantastic disease model to study from a research perspective because it's tractable, it's inducible, it's reversible, I can test for it because it's B cell antibody mediated, and then I also have the potential high impact factor with early recognition, early treatment, and mobilization of care drastically influencing your symptom burden and progression, whether or not you will have sequelae of disease. The use of NMDA, as we're having our conversation today, is meant to be one example. Please do not leave this talk thinking that NMDA, autoimmune encephalitis, is the only one that exists. It is the first, perhaps most well-known one, established in 2007 when Joseph Dalmau first published on these findings of women that had peroneoplastic phenomenon from ovarian teratomas. If you've seen the book or rather if you've seen the movie or read the read the book Brain on Fire by Susanna Cahalan, it's a great one to be able to bring into medical education, residency training, or on your own knowledge base and just understanding more about the lived experience, but it is one disease model. We are in a very active era of discovery, and watch closely here for the time stamp. Take a look at the second one, 1894 Devik syndrome. That's where the clinical phenomenon was identified, but we did not know until way later down the page in the green, 2004, that that disease model was because of the aquaporin 4 AQP4 antibody. So my point is we probably see a lot of things that we won't know yet exactly what the cause and the effect relationship is. There are, while many positive reasons to study autoimmune encephalitis, there are some barriers to care. One of which is that there is a stigma against mental health conditions. There are also symptoms that may be assigned to a pre-morbid diagnosis. Sometimes you encounter provider counter-transference, and that could influence how much or how little workup is done for a particular patient. We also live in health care systems where you may see silos of care. You've got a behavioral health carve-out, the insurance authorization to get those two extra days on your inpatient unit. Those individuals on the telephone are not going to be the people you talk to if you ultimately need to get a prior auth for an MRI, or a prior auth for rituximab, or IVIG, or anything else. And so this split, the silos of care, decreases the speed in which we can often diagnose and mobilize treatment. That's why I believe that multidisciplinary and collaborative care is a must in disease models like this. Just as a frame of reference, this is the same grouse criteria that Richard has already shared with you. We have a huge bucket of symptoms, psychiatric symptoms, and that's what we're trying to decode through clinical phenotyping. So a subacute onset, paired with memory deficits, change in mental status. The addition of psychiatric symptoms certainly is a big one that you will be a part of the consult question for. And it's also connected to other paraclinical findings, like something new on the neuro exam, seizures that cannot be explained by a previously known seizure disorder. MRI features, particularly those residents in the room, if you're thinking about pride exam or board exams, it's going to be T2 hyperintensities every time. That's the question, T2 hyperintensities. This is a paper with a sample size of 577. Though it's now 10 years by date, it's still a really great one to go back and reference the degree of heterogeneity in symptom burden. You'll see the darkest shaded bars are your pediatric patients, less than 12 years. And then you have your adolescent patients, 12 to 18, in the middle shaded bars. And on the right hand, the lighter shading, that's your adult cohort. The point is, you could see changes in speech, changes in gait, changes in cognition, changes in behavior. It's a really mixed bag. And so it's important to acknowledge that not all of the antibody-mediated autoimmune encephalitides are the same. Each antibody gets its own storyboard. The one we're going to talk about today is the NMDA receptor antibody. And that one leads to cross-linking. If you remember the Y-shaped structure of the antibody, you get this cross-linking phenomenon with the receptor. The receptor gets pulled intracellularly. It invaginates into the cell. Now you have a reduction of receptors available, so decreased density of receptors, and you have aberrant function. That's why we see the symptoms that we do. But it's one antibody subtype, and there are several others. Dr. Galfin is going to teach you a little bit more about some of the second and third ones that are on this slide. You will see patients really presenting to you, often with first episode psychosis, without a prior history, or with a pattern of abrupt onset and acute decline. Another really important sub-cohort of patients are those that have catatonia features. The concept of a medical model of psychosis is not new. You look back at the Meninger papers after the Spanish influenza pandemic in 1918, he had a whole cohort of patients that he followed. They looked like dementia praecox, or having dementia before their time. Really the first way in which he was thinking of schizophrenia. But he has this great tagline in there where he says that this fascinating component is that these patients resolved and did not, quote-unquote, dement. After the acute infection, following them over time led to a different trajectory in their care. We have other examples here on the slide, but my point is that autoimmune encephalitis leads to the necessity for mobilizing a medical workup. But the same thing could have been said for historical times or disease models in which they too were causing features of psychosis. The potential workup could be huge. This is overwhelming and intimidating sometimes. If you're in an outpatient clinic, or you're in a freestanding psychiatric care facility where you may not have quick access to things like MRI, PET, lumbar punctures, this can feel like a huge stumbling block. But I do want you to just pause and take a look and acknowledge that there are some components of this that you can do and take responsibility for immediately. That would be a first pass thumbs up or thumbs down. Is there or is there not a problem on an immune perspective? Is there or is there not a problem on markers of inflammation? You can do those things very quickly and take ownership and responsibility for the decision-making there. The next big question that I get asked routinely is, do you do a lumbar puncture for every patient with psychosis? My answer at present is no, but I have grave concerns about the lack of parity in care. If I have a patient that rolls through the doorway on the general pediatric side, their care experience and care delivery may be very different than if they show up on the psychiatry triage board side first, or if they make it to Jeff's office on the neurology or neuroimmunology side. It's not the same. Insurance barriers to care, the health system that you're working in, provider familiarity, these things all influence who does or does not get a lumbar puncture. And so from a clinical research question, I have a huge level of interest in this, but I don't do an LP for everyone under clinical purposes. I try to use a stair-step approach to ask, did they have a prior history of psychosis symptoms? And I don't just take the word for it, I ask for collateral. Did they have special education testing done years past? Did they have high-performance academically gifted testing done in years past? What was their job review like? Anybody that you can get to talk with you about the prior illness, I think that's so helpful, and whether or not they had features of psychosis premorbid. Next, after I do my own risk stratification labs on serum, then I would decide, yes or no, do I need to move forward with an EEG or an MRI? If the patient is acutely decompensating, if I'm starting to see features of malignant catatonia, that might be the time when I'm looking towards completion of the CSF testing if we have not already done so. I've included this here and I apologize because I realize it's too small for you to be able to see, but just take a peek at this paper as a follow-up to our conversation today. It was published last year in 2022. GOSP is the main author on the publication, and what they did was they looked over one year in time, comparing a cohort of patients, about 20-something for each arm, 27 for each arm. I think one group had 28. The blue represents patients with identified NMDA receptor autoimmune encephalitis on these radar plots. Then you also have your healthy controls in green, and you have patients that have a maroon bar shading, which are those with a known diagnosis of schizophrenia. Time point one on the left-hand upper corner there is zero, and they looked at full-scale IQ, attention, memory, focus, concentration. They repeated it at the six-month mark, leaving out full-scale IQ because of the learning bias there. Then at the one year, they repeated the full battery again. The summary of this is that patients with schizophrenia had relative stability over time on those metrics. Patients with autoimmune encephalitis, though, showed a hugely dynamic course in which they would see a lot of deficits early on that could then be overcome with improvements in their full-scale IQ and recovery over time. This is specific to the NMDA model, which is not neurally destructive, and if you remember that mental image of the invagination intracellularly of the NMDA receptors, you can push them extracellularly again too. That's one of the hypothesized mechanisms for ECT in this patient group. Common pitfalls. So you might be a little bit careful if you see a high ESR and CRP. Do not assume that is autoimmunity. Be sure you have not missed an infection. You may also get stuck with a lack of hypothesis flexibility, and so I really want to empower you to know how to ask for the workup, but also not to get stuck in that as an anchored bias. If everything is coming back truly negative and you're seeing a patient that is responding or partially responding to usual care algorithms, you are going to need to have that hypothesis flexibility, and it is okay to test and come to the answer of no in the workup. That is okay. I think some of the divide or missed opportunities in conversation with the neuroimmunology side are when we are really worried about the patient, and we're trying to tell and share about that worry, but we're not able to point to something for bioclinical markers or anything that would be a concrete piece of the puzzle, and so I would just invite you to hold that hypothesis flexibility. This was an infographic from a 2020 publication by one of my colleagues, Heather Van Matter, and others that were on the publication, really trying to move away from being fixed in the seronegative autoimmune encephalitis group if you have honestly all negatives on your paraclinical markers, and simply to acknowledge that you're risking missing the right diagnosis if you stay a little too stuck sometimes in the seronegative. I still see and treat patients actively with seronegative autoimmune encephalitis, so this is not to discredit that category. It's simply to say, have we crossed our T's? Have we dotted our I's, and have we made sure that we did not miss something else? Because you can have metabolic causes, infectious causes, a whole host of other clinical symptoms that may lead you to think about something else in your differential. One other word of warning is those patients that come to you with a prior history of a neurodevelopmental disorder. You may be the sole person that is able to decode what's different from the baseline, and the assumption, the false assumption, that the patient has always been this way, or has always had these symptoms, that can decrease a lot of teams' willingness to go after the workup, or to facilitate moving forward in the workup. But if you can show those old videos, so find the old videos of the graduation, watch the piano recital, or the ballet recital, or the band concert, and understand what is different. Look for cues about social reciprocity, or the ability to demonstrate joint attention when you have a known premorbid history of autism spectrum disorder, you expect that. But if you have a patient that did not actually have an autism spectrum disorder diagnosis, and these symptoms are now being clustered as assumed to be because of autism spectrum disorder or intellectual disability, I think that's a missed advocacy opportunity to share with your colleagues what is different from the baseline. So this is a powerful advocacy piece that we can do. For the sake of time, I'm going to leave the conversation about decoding laboratory results more squarely with Dr. Gelfand for today, but I'm happy to follow up with you if you have questions about this, because I believe it's incredibly important that you know how to read the labs. The oligoclonal banding will often be listed as OCB, oligoclonal banding, and if you have bands that are present within the CSF only, that should make you worried that you've got intrathecal antibody production behind what should have been your protected blood-brain barrier. If you have matched bands between the serum and the CSF, that could be concerning for a more permissive blood-brain barrier, but it doesn't have to be an intrathecal antibody synthesis. Out of the whole slide, this is probably the more important one here. And then the second easy one is just to confirm when you hear a case presentation. Was it CSF antibody-positive? Was it serum antibody-positive? Or was it both? If you get a GAD65 titer that's positive on your serum and it's a low titer, that does not mean the same thing as a high titer true GAD65 antibody that's within the CSF. So please be watchful about where is that antibody positivity coming from, and make sure that your note is not propagating chart lore where you're just passing it on because so-and-so said it and that's what you heard. Go back and look at the labs yourself. Make sure you know the information. It will allow for you to be far more effective when you're at the conversation table with neurology and neuroimmunology too. The different microenvironment pieces of the puzzle as it relates to the cytokine cascade are also incredibly important. I talked at the beginning about the experience of having a fever or feeling sick. You've got TNF alpha elevations. You feel crummy. You might act differently. You also can see a targeted approach sometimes if we're able to identify on cytokine panels that there's an IL-6 elevation that's really striking. That can influence the medicine that we choose. I might opt to go for tocilizumab or something like that if I have a really distinct IL-6 elevation as opposed to broader markers of inflammation or autoimmunity. This is one paper as an example. It is by Russell Dale and his team in Australia. They did a fabulous job looking at ways in which you may find utility in applying cytokine profiling to different disease subtypes, whether it's demyelinating, whether it's viral, post-viral, or whether it's truly self-propagating autoantibodies such as an NMDA receptor encephalitis. For next-generation diagnostic sequencing, there is a whole world of exciting stuff that's happening that will be coming in the years. Parts of it you can get now on the research side. The one I'd like to make sure you've heard about is single-cell RNA sequencing. You may hear people talk about the catchphrase RNA-seq or single cell, but this really is treating different cells within the cerebral spinal fluid much like they are caviar. These very, very high-value individual targets. If you can look visually here on the top left-hand corner, what single-cell RNA sequencing will do and is doing on the research platform is allows for us to tell with greater detail what cell types are present. Top left-hand corner, all of the cells are blue. True, but they're different shades of blue. You're able to identify different cell groups or clusters even within a larger name or category of cells. On the right-hand upper corner, you're looking at the comparison of the microenvironment across tissues. While it may be that it's a phagocyte, it is acting differently, named differently, and perhaps even functioning a little bit differently based on the tissue that it finds itself in. Middle row, left-hand side, this is really representing the influence of time and fate trajectories. You might start as one cellular fate and then different influences over time push that cell, whatever type it may be, to its ultimate destination or fate. This is a really valuable technology that's not a part of current clinical practice. It is definitely a huge, huge, huge component on the research side, and I suspect that you will be hearing more about this over the next three to five years. This is a flashcard just to bank in your mind for later. Another point to add here is that when we look at whole genome sequencing we're really asking and answering the question about the DNA building blocks, whereas when we look at the RNA that's transcriptomics. When we look at the proteome that's the protein expression. So having a genetic finding is really the first series of what is the downstream phenomenon of the different proteins that are assembled or expressed. As we close out, the times that you will need to watch are when someone is partially responsive to your usual care algorithm. You've started a med, you're targeting a symptom, whether that's mood liability, psychosis, or catatonia. If you're seeing a response and the patient is continuing to move forward, just keep watching. Have patience, keep watching. If you have made a big move as a multidisciplinary team, you just started an immunomodulatory med, go and look at the time of impact. This is a really important thing and can be a beautiful med student-led project. Pick every medicine on that patient's list, know the mechanism of action, and know how long it takes to work. If you give rituximab, you should not expect it to work tomorrow. It takes three to four months to get to full B cell depletion, and it still doesn't wipe out all the B cells that are floating around in the periphery. It only reduces the production of new cells. So you're going to have to hang on tight for that rocky road between when you start these immunomodulatory meds and when you see symptom resolution or improvement. So know the time and know the mechanism of action for each med. After a med wean, if I'm making a bold move on an Ativan wean, I need to be on the phone with Jeff to be sure he hasn't just changed the cells up two weeks ago or something like that, because we could end up tripping over one another in our clinical decision-making. If you make a med wean, name it and claim it in the chart. Communicate that out to your other team members on the multidisciplinary care, and vice versa. Ask them, have you made any bold moves that mean that we need to be in a waiting zone a little bit right now? Significant psychosocial transitions are also a very big deal. Never underestimate the influence of transitional-age youth going off to college. I have seen kids with a true and true autoimmune encephalitis that have also totally fallen apart and then have been able to pick themselves back up, recover, and thrive solely because of those psychosocial transitions. So this is another partnership opportunity where I believe that we as psychiatrists bring quite a lot to the table in connection with our other care team members. But that might also be a time where you're holding on to your provider-based anxiety of, should we be asking them to do something else on the neuroimmunology side or immunomodulatory meds? And I would encourage you just to really talk this out about the psychosocial stressors. When to worry. If you're in rounds, people are not talking, there's grumbling, there's disagreement, people are writing snappy notes back and forth, they're signing off cases, you know how this goes. So if you cannot fix it, at least talk about it. We are amazing at this. That is what we do. We can process anything, right? Get your team around a table, have a multidisciplinary care conference, because I worry the most when there is a failure to communicate. It influences the patient, the family, the care team, the group dynamic, and it's hard to come back from if you don't invest early on. So if you start to see this almost malignant dynamic that's developing, that's hard to really dial it back in. But if you ask for an opportunity to communicate and you talk openly about the questions that you have, teach me why you think this, right? Ask questions. This really facilitates awesome communication lines back and forth between neurology and neuroimmunology. Assumptions being made about premorbid functioning. I do worry about this, so please make sure to take the time to ask about prior function. And another big-time worry moment is if you start to see features concerning for malignant catatonia. That is a potentially life-threatening state. Go with things that you know from training. Go after your Ativan. Start asking, can I get access to ECT? But communicate out to your ICU colleagues why your level of worry is so high or shifting and changing over time. So if you see rigidity, everybody worrying about a septic workup but it's negative and nobody can figure out what's going on and they're febrile and tremulous and hyperreflexive, white count starts to trend up, that CK starts to go up, that's you guys. This is you stepping in to say I see this, I recognize it, this is malignant catatonia, these are the things that we need to do, this is how we act. The words that we use are also notably different. So I may say psychomotor slowness, Jeff may say bradykinesia, right? So when you're thinking about neurology and psychiatry, you also have to know that common crosstalk and be able to speak with shared language. You may be acknowledging similar phenomenon but you just get stuck between the disciplines. And last, when to do the workup. If you have acute onset, abrupt decline, a trajectory of ongoing decline, those are times when you're asking for the workup. If you see psychosis plus, psychosis plus speech changes, cognition changes, gait changes, that should make you worry and that's reasonable to ask for the workup. If you see treatment refractory symptoms, I've tried three or four, pick your category of meds, mood stabilizers, antipsychotics, I've tried usual algorithms for catatonia and I've maxed out on Ativan and we're really seeing this treatment refractory picture, those are times when you might be asking for help mobilizing the workup. In terms of future directions, I sincerely hope that we will have greater clarity over time about this group of patients with seronegative autoimmune encephalitis. Some of them may have other immune mediated phenomenon that are not B-cell dependent and so I think we have to work on increasing our awareness on the T-cell side. We also would hope to see a greater level of parity in care with less difference between the groups and between the health systems. So these are all targets that we're trying to work on and also I believe that next generation sequencing and the opportunities for immunophenotype immunophenotyping may allow for us to provide the kind of care that is more approaching a precision medicine style where we're asking what are the differences from an immune profile and how can I target that. The need to be able to be a part of the team and offer your expertise is very real as it relates to mood changes, psychosis, catatonia, OCD features, cognitive change and decline. You can be a really valuable team member so I do hope that you will take this talk as the starting point or if it's a topic that you already love and it's near and dear to your heart, reach out. I'd love to collaborate. We can ask and answer more questions over time. I have many people to thank, two of which are Dr. Marilyn Powell, our clinical director at the National Institute of Mental Health on the intramural research side and Dr. Avi Nath. Avi is one of the most kind team members I have ever had the pleasure of working with. He's a neuroimmunologist, a neuroinfectious disease expert that has partnered with us on the NIMH side so that we have this opportunity for collaborative care as well as a really synergistic clinical research portfolio. Many, many of our team members on the One Southwest inpatient unit, those of you that are into med psych care spaces, give me a call or an email because we trained our nurses up with about a 16-week curriculum to be able to go from a general inpatient psychiatry unit into a unit that has the competencies on the nursing side to really become med psych capable for being able to give IVIG, IV methylpred, retox, things like that. My email is here and I am so pleased to be able to shift over to our last talk which will be by Dr. Jeff Gelfand. Thank you. Well good afternoon, good afternoon everyone. I think that's working perfect. So my name is Jeff Gelfand. I'm a neurologist at UCSF and I'm going to be speaking about how neuro neurologists and neuro immunologists think especially as we work together to care for patients with neuroinflammatory disorders and autoimmune causes of neuropsychiatric symptoms. Thank you to Dr. Mooneyham for the kind introduction and putting this session together. These are my disclosures which relate to research funding and consulting. As a neurologist one way we think about encephalitis is that there are many causes of encephalopathy of altered mental status with a very broad differential and we defined encephalitis as inflammation. The itis is inflammation and there needs to be some direct evidence whether it's clinical or pathological evidence of itis of active inflammation causing the brain dysfunction. When we have an autoimmune cause of a syndrome for example a rapidly progressive dementia that's antibody mediated in this case that's autoimmune encephalitis it sometimes goes by the name autoimmune dementia and increasingly when there are autoimmune causes of psychosis many of which are antibody mediated there's a separate heading of autoimmune psychosis but functionally we're all saying versions of this larger umbrella of this autoimmune brain-based inflammation and we have other versions of this with autoimmune ataxia for cerebellar dysfunction. And then just a reminder that when there's inflammation of the coverings of the lining of the brain the meninges we call that meningitis and sometimes people have both and we call that meningoencephalitis or meningomyelitis when the spinal cord's involved. When I evaluate patients and when neurologists think through a patient evaluation several things will be really really important. History history history and I don't say this lightly like in neurology and especially for the autoimmune encephalitis diagnosis most of the answer is in the history and it's really that story part of that subacute rapidly progressive symptomatology specifically sorting out what those symptoms are localizing it neuro anatomically within the nervous system and then evaluating for the range of causes and then doing diagnostics to support that. The questions would be are there focal neurologic findings or symptoms and then any physical exam or historical findings to suggest a systemic syndrome. The examples of some of these archetypical antibody mediated syndromes like anti-NMDA receptor autoimmune encephalitis is an exquisitely and compartmentalized brain based disorder whereas for example systemic lupus erythematosus lupus is a multi-system inflammatory disorder that can also affect the nervous system that can affect the brain and when someone has a systemic vasculitis for example there may be other clues you know rashes synovitis swollen joints other kinds of features that we look for to link the diagnosis and then what's the evidence of inflammation in the central nervous system in other words is this an encephalitis or is this the broader view of encephalopathy. We use neuroimaging brain MRI on the left is sort of the classic example of what a limbic encephalitis looks like this is a t2 hyper intensity on the left side of the screen the right temporal lobe MRI it's inverted right left and you can compare that the right side is a little brighter than the left both are bright here this is a temporal lobe hyper intensity brightness on t2 and flare that in this case is from an autoimmune encephalitis specifically LGI1 encephalitis but if I gave you a different clinical history this could be herpes a simplex 1 encephalitis so there's a broad radiologic differential but the radiologists will say this looks like encephalitis and then help figure out what the cause is. You can also have gadolinium enhancement and so if you have a choice of giving with or without contrast we prefer with contrast with gadolinium because leakage of the gadolinium through the blood-brain barrier is a sign of acute at this moment of time when you do the scan active inflammation as opposed to old news you know when you have for example in multiple sclerosis there can be lesions form and then they enhance for a couple months and then they stop enhancing and there can be scar the gliosis or the sclerosis as part of that and that will be there on MRI for the long run and so the definition of active inflammation will be gadolinium enhancement and with encephalitis as an example you can have active inflammation I show the t2 flare on the left image in the middle there and then on the right is the corresponding enhancement in this case from an encephalitis and on the bottom there is a example of the flare showing some sort of hyper intensities that are sort of vaguish but suggest an inflammation and then you can see in the bottom left corner the right parietal lobe there and posterior frontal that there's enhancement and this is a case of an anti-mog antibody acute disseminated encephalitis but it's the idea that active enhancement is a sign of active inflammation there's a radiologic differential and there can be other things that cause it but that's a really important marker the spinal cord can also show inflammation this way now FDG PET is often done as a whole body scan looking for glucose hyper metabolism and tumors are hyper metabolic and so in the oncology world this is a common test to look for evidence of active disease or metastases but it can also be a sign of other kinds of inflammation generally when you take the same technology to the brain you can look at hyper or hypo too much or too little glucose metabolism and there is an emerging literature suggesting that people with autoimmune encephalitis largely have abnormal FDG PET the problem clinically is that it's sort of a mix some is hypo some is hyper it's different regions of the brain and so it's just one piece of the supportive evidence and there's still a lot of variability in this clinically and we have to interpret this usually with MRI and spinal fluid and the rest of the evaluation to actually make a clinical diagnosis when you do a spinal fluid examination what you're doing is measuring the spinal fluid looking under the microscope and seeing is there active inflammation and the base studies are to look at the cell count and differential glucose and protein and that's sort of like the standard ER everyone sends that test and normally there should be five cells or less as part of just normal immune surveillance so if someone has six cells or 60 cells or 600 cells or 6,000 cells that's different degrees of inflammation and then we look at the differential which actual immune cells are there are there neutrophils polymorphic nuclear cells suggesting certain kinds of inflammation are there eosinophils which would be a unique subset or it might suggest a fungal infection or a mycobacterial infection low glucose can be seen in certain bacterial or fungal infections for example we use that pattern recognition but for the case of where you're doing a spinal fluid exam to explain a neuropsychiatric symptom I would highly encourage that you ask your colleagues please please please send the oligoclonal bands and the IgG index this requires a blood test at the same time now the same time doesn't have to be that minute right it can be an hour or two but it can't be two weeks later or it can't be something where someone says oh can you add that on ten days later we're gonna have to redo the spinal tap if it wasn't sent because what you're doing is you're comparing the spinal fluid immunology with the blood immunology at that moment in time and then seeing is there a unique antibody production in the spinal fluid and then literally it's like a button push and when you order oligoclonal bands or IgG index usually most EMRs now will say here's your blood test too but the idea is you have to ask for this this cannot be added on later and you can have honest-to-goodness autoimmune encephalitis where you have a normal cell count but you have oligoclonal bands or an elevated IgG index and that's actually one of these markers of and like you're directly measuring intrathecal inflammation and I think it's sometimes a mistake to just use cell count as your only cutoff if your clinical suspicion is high now if your clinical suspicion isn't high then you know you don't do this and it can lead to gray zone findings but but if your suspicion is high go for that what is an oligoclonal band by definition it's oligoclonal it's not monoclonal if we have a monoclonal antibody you're just going to see one and it's going to be high and we need to understand with flow cytometry for example is this lymphoma or what is going on but an oligoclonal band or what you do is you take the CSF and you do what's called isoelectric focusing sort of imagine it's sort of like Western blot but it's using electricity and you're sorting out these different clones of the antibody they may all be for example to herpes simplex one a particular protein or they may all be to your nr1 receptor of the NMDA receptor that causing the autoimmune encephalitis but each one has a different specificity and they're different clones and we call that oligoclonal and by definition we think that there are plasma cells the antibody producing maturist of B cells circulating in the central nervous system that are making these cells and we can also measure an IgG index which is a measure of antibody production in the nervous system compared to the periphery and so if that's elevated there's this compartmentalized immune response now itis inflammation can also be infectious right it's not always autoimmune and this is one of these things that keeps me as a neurologist up at night is not wanting to miss you know any infectious cause because the treatment is a very fork in the road right do we lower the immune system to target overactive or misdirected inflammation or do we use antimicrobial or anti you know infectious disease type agents so you can also send culture and then there's a very new test called metagenomic next-generation sequencing which which is a big deal in our world right now we can do what meningitis and encephalitis panels certain PCRs that can sort of help you just try to list the major ones but this is an unbiased approach where you sequence the RNA and DNA of everything in the spinal fluid get rid of everything non-human you use the same machines we use for whole exome sequencing when we do genetic testing but in this case you're trying to find is there anything non-human in the spinal fluid and then use bioinformatics to say what's shouldn't be there and if you for example get a very high hit of some novel virus that hasn't been seen in California in 30 years why would we have even sent that PCR right like that like you'd have no idea but with this unbiased PC approach metagenomic next-generation genetic approach it tells you if there's anything that shouldn't be there and then you have to use clinical correlation to sort out what is sort of a low-grade false positive or not and these are clinical tests not just research and you can send that through many clinical laboratories I'm going to talk in detail about antibody testing but we send the neuronal or glial autoantibodies as part of this and then there's a whole bunch of other things you can do looking for research-based antibody discovery and nerve breakdown protein so spinal fluid is more than just cell count there's all this stuff if you're going to go down this road so if you're going to do it make it count would be the idea when you send perineoplastic or autoimmune encephalitis antibodies what are you doing you send it to a reference lab and all the major reference labs do this testing now this is regular clinical care this is not exotic anymore when I started my training this was really hard to get often we had to do research-based testing all of the major tests are now clinical Clio lab this should be part of routine clinical care when there's the right question on the left is the traditional perineoplastic antibody so in this case these are intracellular antigens think of this as the anti-hue the re the yo these were sort of the classical cancer associated antibodies described in the 1970s these are intracellular and really intranuclear antigens and it's not actually clear when you think about it how would an antibody have access to something inside the cell and it has to be expressed some way to cause a harmful immune response and so increasingly the data suggests that a lot of this is probably a byproduct of a harmful anti-tumor response that gets misdirected against neurons and a lot of this is t-cell driven and in some cases the antibody may be just the marker of abnormal inflammation rather than the cause the big breakthrough is on the right and when we were going through the history earlier in this course of autoimmune psych or of immunopsychiatry and what I'll call autoimmune neurology you know we're same organ and we're having converging mechanisms here this is all 21st century discovery a lot of these antibodies were discovered in the early 2000s and then the 2010s why is it a 21st century thing the big conceptual breakthrough was that you have to express cell surface antigens in their proper 3d confirmation to be able to do testing when you do the testing on the left and just denature things you lose your 3d confirmation and Western blot just doesn't give you that so if you tried to do NMDA antibody testing using the technique on the left there's nothing there to see because you lose the 3d confirmation so what changed the technical approach was expressing it on tissue in this case either using rodent brain slices or if you actually know what the antigen in its case a the nr1 receptor of NMDA you transfect it and express it in a cell like a heck 293 cell and then use standard immunofluorescence to see that or you have cultured hippocampal neurons and then use immunofluorescence and in the clinical labs they use rodent brain slice staining and a human who's expert at this looks at this and says this staining pattern looks like an antibody against a cell surface receptor this is NMDA this is LGI one and then does a separate test using the cell based assay and we call that an orthogonal confirmation you'd use two different techniques and if you're seeing the same things using different ways that's increasing your confidence that this is the real thing at least laboratory wise and then you have to use clinical correlation to decide if that makes sense and so that's what's happening behind the scenes, and this is why I fully support what Dr. Mooneyham was suggesting too, which is it's not just positive or negative, it's from what, you know, is it blood, is it CSF, on which, was it just brain slice, was it also seen on cell-based assay, that's what the transfected cells look like there, and how confident are we that this is the real thing? On the research side, you use the brain slices as the screen, but then can also use chip-based approaches where everything in the proteome is expressed using something called FIP-seq and using phage displays, it's really cool technology, and essentially run the spinal fluid down and see what hits as a hypothesis generator for novel antibodies, and then use more traditional techniques to validate this, and through this approach, we're discovering, and through colleagues in the basic science labs who run this, novel antibodies to explain syndromes and trying to validate those, and so research-based testing can be very helpful. So one approach is when you see a patient with a clinical syndrome of encephalitis wearing my neurology hat, the first question is rule out infection, then decide am I missing some other cause of encephalopathy, but if then I'm saying this is a non-infectious inflammatory cause, is it autoimmune slash perineoplastic? And then we have rigorous criteria and clinical judgment. There's a new paper that came out talking about misdiagnosis in this context, and the big things that came up were being an atypical story, and not applying criteria, and essentially anchoring too much on either a low-titer antibody, or just sort of not following the data enough, and then having an alternate diagnosis on expert review. This is the broader view of this antibody approach, and I think it's important to think of this not just neuron-specific, but glia as well, and so on the left are the classical perineoplastic antibodies, then the big breakthrough was this neuronal cell surface and synaptic antigens, this is the NMDA-LG1, this is the sort of autoimmune encephalitis category, but then astrocytes, so NMO or antibody called GFAP can cause a meningoencephalitis that's steroid responsive, we have MOG, which is a myelin antigen that can cause an acute disseminated encephalitis in children and adults. We're starting to identify antibodies to the broader view of the neurons and the glia. I'm just gonna give a brief neurology approach to how I think about NMDA, we've heard about this through our earlier talks, so I'm gonna essentially say from a neurology standpoint, this is a pediatric disease in addition to an adult disease, a third of cases are in pediatric age patients, and it's probably the most common of the autoimmune encephalitis syndromes, and there's a whole range of progressive neurologic symptoms that happen with this prodrome, a neuropsychiatric rapidly progressive syndrome, sometimes language or memory, seizures, interestingly, usually not leading to longer term epilepsy, these are sort of immunotherapy responsive seizures, and then abnormal movements are particularly common, think about this, 95% of kids with NMDA encephalitis have hyperkinetic movements in 75% of adults, and about two thirds or three quarters of these patients need ICU level care, especially for the autonomic instability, but the amazing thing is that people can recover, and with our ICU colleagues, we need to help them take the long view and explain what the natural history is of this condition, and so the tumor association was high with a tumor called ovarian teratoma, teratoma is a tumor that expresses different tissue types including nerve, so it expresses NMDA receptors, and then gets misdirected, causing a perineoplastic syndrome, we talked about HSV earlier today, one of my colleagues, Dr. Jin did, and this is probably one of the cleanest examples now, at least associationally, because we don't yet have the mechanism of a post-infectious antibody mediated autoimmune encephalitis, and so the challenge is that you can have a new onset psychosis as the phenotype, at least for some time, until we get the broader neurologic syndrome, and this is where screening blood tests can be helpful, but the big teaching point is that you'll miss about 14% of cases of NMDA encephalitis specifically if you don't do a spinal fluid exam, we also have better specificity with the spinal fluid exam, so usually it's reasonable to think of screening with the blood test, but certainly if there's a positive, or if there's a high clinical suspicion, a spinal fluid exam is particularly helpful. Colleagues have also looked at this with the new onset psychosis cohorts, prospectively, and shown that measurable nerve breakdown proteins, something called neurofilament light chain, this is widely studied now for other neurologic diseases, it's not specific to encephalitis, but essentially showing that if you're measuring nerve breakdown proteins in a new onset psychosis patient, that should probably lead to exploring autoimmune causes as opposed to other causes of primary psychiatric disease. And so the teaching here is that you usually do get a pleocytosis, MRI may not show anything, so it's clinical suspicion, and then serology, CSF more sensitive than serum for this disease. We've talked about these diagnostic criteria, refer to them and talk with your friendly neurology colleagues. I'm gonna talk about just very briefly another archetypical syndrome, LGI1 encephalitis, this is one where you get an antibody to a different protein called LGI1, and it causes a rapidly progressive amnesia, memory dysfunction with seizures, and then hyponatremia. And here, this is probably one of the most common ones we'll see in middle-age and older patients, especially in the inpatient and clinic setting. And so what we see here is there's an HLA phenotype, and there's probably some post-infectious component or some other environmental triggers in autoimmune susceptible people for this particular immune finding. And so what we see here is this limbic encephalitis syndrome and we use serology to define this as well, and then patients respond to immunosuppression. Now there are several other antibodies being discovered that are beyond the scope of my talk right now, but just an example, someone who comes with an encephalopathy, abnormal behavior, seizures, here's an example where oligoclonal bands suggest inflammation, MRI shows lesions that suggest inflammation, and in this case, the patient had antibodies to the GABA-A receptor, and so different syndromes that look different, but they're all coming under this heading of autoimmune encephalitis. GABA-B, on the other hand, causes more of an amnesia-type syndrome that's a classic limbic encephalitis. And then this one, just to sort of open your minds to this, is a new syndrome that was described in 2013 where there's a GI prodrome, intense diarrhea, and then hyperexcitability, seizures, encephalopathy, and it's to an antigen called DPPX, and it's just a reminder that the gut has as many neurons as the spinal cord in the myenteric nervous system, and you can have an autoimmune encephalitis that affects gut and brain, really opening our minds to phenotype. From a treatment standpoint, we use acute inflammatory treatments, glucocorticoid steroids and IVIG or plasma exchange. Often we'll then either do cyclophosphamide, sort of old standby cytotoxic therapy, in this case used for the autoimmune context rather than the cancer-focused context, different dosing, and we use it for autoimmune treatment, or monoclonals, including anti-CD20 therapy, and then increasingly other approaches that are more mechanistically targeted. And then just to say, for a disease spectrum that was really starting to be mechanistically defined really a decade plus ago, it's exciting that we finally have active clinical trials, multicenter global trials now, in both LGI1 and NMDA encephalitis. So if you have patients with this diagnosis, ask, you know, think of research as well, because this is how we're gonna really define what the evidence-based treatments are so that we can guide patients forward in the future. So these are the trials going on right now in NMDA. I will stop there, and we wanted to leave time for questions. Thanks so much. Thank you. Thank you all so much for hanging in there with us. We are open to taking questions if you wanna come up to the microphone. I'm gonna go on to the online questions, and we'll give those one or two that came through, but please don't be shy. If you have a question, come up to the microphone. We'll have about, I think, 10 minutes or so. So I'll read the question aloud. Richard, it looks like this one is for you. What was your patient's COVID vaccine status, and how did this fit in temporally with respect to symptoms? Was it considered that COVID after vaccine could have played a role in this case? Why or why not? Yeah, at the time she was COVID-vaccinated, and as you know, you can still get COVID even if you're COVID-vaccinated. Temporally, I suppose it did kind of arise at around the same time as the HSV, though I think just given the arc of the narrative and what we know epidemiologically, it makes more sense that the NMDA receptor encephalitis arose as a result of the HSV as opposed to COVID itself. I think our understanding of autoantibody-mediated encephalitis after post-COVID is much more limited than something that is more horse-like than zebra-like. I agree, and I'll just piggyback on that with another question that came through. How may COVID exposure be associated with triggering autoimmune encephalitis? I'm gonna give my two-cent psychiatry answer, and then Jeff, you can expand on that. And then Jeff, you can expand on this if you'd like. I usually think about a post-infectious encephalopathy more often than I'm going with a true autoimmune encephalitis and that's simply because we have not seen as many hits on antibody testing panels after post-COVID, but we have had lots of patients, many referrals, where you could have COVID being the triggering cause leading into features of acute onset abrupt decline with psychotic features being predominant. So the post-infectious paradigm is really broad and it does not rely so much on landing on a named known antibody. But Jeff, I'd welcome you to comment on that too. Sure. Most of the neurologic literature suggests that fortunately it looks like active viral invasion into the brain is likely rare or not a common feature from active COVID infection. There've been well-described cases of post-infectious, post-COVID autoimmune neuropsychiatric conditions. My colleagues, Sam Pleasure and Michael Wilson, for example, published a case series of some teenagers who had a post-COVID psychosis and what I think is framed as an autoimmune encephalitis with novel antibodies using that FIPSEC antibody discovery platform. They also had other markers of CSF inflammation and they improved with immunotherapy. I think we're particularly good at measuring COVID, but I think this is probably a broader sign of post-infectious and post-viral autoimmunity that I think clinicians have known have been there a long time. And so I don't think this is unique to COVID, but I think it's well-measured with COVID. Perfect. Let's see, who had a question? Oh, go ahead. Is fever ever an indication of autoimmune encephalitis coming with an infectious? The question is, is fever ever an indication of autoimmune encephalitis? I will say that there are a lot of times in which you will have a viral prodrome and so you may see a febrile course prior to the onset of other cognitive changes, gait changes, or decline. Short answer is yes. You can very much have fever as part of NMDA or as part of other autoimmune encephalitis syndromes. It does not distinguish between infectious and autoimmune. And we have to use other clinical diagnostics and symptoms to do that. And it's interesting because it really is part of that inflammation response. Don't be shy. We have microphones. So if I've got the microphone up here, you go to the microphone right there. So since there are no more questions right now, let me ask you about quickly about a case we saw in the clinic the other day. I'm a geriatric psychiatrist. I work at a neurology dementia clinic. We saw a patient with Parkinson's disease dementia who had been on, so she was already on Sinemet. She was also receiving Requip for RLS. She had a TGA-like episode when she was traveling. She was found on the road with a bag. She had no idea where she was, what she was doing there. So she was taken to the ER and she had the T2 flare hyperintensity in both the hippocampi, but she also had restricted diffusion on her DWI. There were no findings on the SWI sequence and her inflammatory and infectious workups were negative. She got five cycles of plasmapheresis, actually responded. But interestingly, since then, her visual hallucinations have become worse. So she used to have these transparent visual hallucinations and now they're very much opaque and like real people. And that's why she was coming in to see me, but we still don't know what that episode was because we don't usually have restricted diffusion as far as I know in patients with autoimmune encephalitis, even though she was treated as seronegative autoimmune encephalitis. So any thoughts about that? I think that's a challenging one to give an answer in 30 seconds or less. I would acknowledge that the medication list, I would certainly go after questions on, was there any acute med adverse effects that could have been associated with that? And then the second, obviously, you've done a great job trying to rule out infection. You obviously sound like you've gotten a good and thoughtful effort on workup for the autoimmune causes. And then you mobilized an immunomodulatory intervention by using pharesis, you said five rounds. Did you, help me out, did you say she had symptom full resolution or partial resolution post-pharesis? So she had almost complete resolution of symptoms after the pharesis except that the hallucinations have become worse and now she's reacting to them in a very negative way, like they're frightening to her at this point in time, which it did not used to be the case. Fascinating. Yeah, in the differential, when we look at T2 flare changes and especially depending on the specifics of diffusion would also just be seizure, depending on timing. It's in then it's sort of a circular question of what's causing the seizure. Could it be an encephalitis causing that? But one question here would be sort of thinking through that and could there be a role that way? And then with the age group and just sort of thinking of LGA1, sometimes CSF can be normal. So if that wasn't actually sent for as part of a panel but you had T2 flare changes, that would be a serology that can be helpful just because sometimes the MRI and CSF can be normal in up to a third of cases. Here you have an MRI that's abnormal. You just need a reason for it. So just some initial thoughts as to how we might approach that. Thank you for sharing your case. Next. Just kind of a mildly naive question in terms of if you got the Gauss criteria so you suspect something. So we have the Grouse criteria and then Gauss was the author on the one I showed about schizophrenia, healthy controls and NMDA cross-comparison over a year with neuropsych testing. Thank you. Both with a G. No, thank you very much. What's the benefit if you've already starting to treat and there's a response to further investigating to figure out which of these it is? From a psychiatry perspective, if you're starting from the seronegative group, you are absolutely at the cross point of figuring out which direction for interventions and how long. So if you have a named known antibody, it almost gives us a roadmap a little bit of, okay, well, I'm probably gonna be committed in over the next two years with two or three rounds of retox seeing where we go. But if you don't have a named known antibody and the symptoms are not responsive to immunomodulatory meds, that's the time in which you need to go back to the drawing board and be sure that you're not missing something. Because what I worry about is that at times we become so fixated and anchored on that that we actually are missing the opportunity to mobilize treatments for other more diagnostically specific care points. But that's my take. And I would say the attraction of confirming the pathophysiology is that these syndromes have different prognosis. They will hopefully and probably do based on how we read the literature have different approaches to treatment about tumor screening. And so it really does matter what the name is. Seronegative encephalitis is accounts for about half of all cases of autoimmune encephalitis in a lot of our cohorts in terms of well phenotyped cases. But so an example is someone who has a classic MRI finding of CSF pleocytosis and extensive infectious workup and then all the antibody testing is negative. But I think really pushing that is also helpful. One to see if there's a novel antibody and then two is also just to make sure we're not missing infectious causes. So it really does matter. But the goal of the criteria was to also recognize that access to antibody testing is resource specific and not everyone has it in a timely fashion. So it's helpful to offer this empiric treatment but you got to be able to reassess over time too especially over do you give longer term immune suppression versus just the acute one. Perfect. We are at 2.59 but we'll answer these two questions for those at the microphone and then we'll be available here at the front. For those that do have to leave and go to the next session, thank you, thank you for taking time to come in on day one of the conference. Please do complete the feedback evaluation so that we'll know more for years to come. Thank you for amazing presentation. I have a very naive, naive question. Go for it. Lupus, Lyme's disease, fibromyalgia, Epstein-Barr, chronic fatigue, constantly showing up with borderline personality disorder. Is there any discussion, research, interest in why that keeps happening? I would say that's a bit of a loaded question too. So there's a lot of research and interest in Lyme's and EBV and all of the other ones like chronic fatigue and fibromyalgia that you mentioned. I have not to date seen a study that was linking anything in particular to a borderline personality diagnostic construct but I think I understand where you're coming from and I think it's a great question to ask. I have not personally seen that asked in a research perspective yet. But the influence of the immune system, the how are you feeling physiologically and how does that influence your psychological experience is absolutely a phenomenon worthy of conversation and worthy of exploration. If you are in an immune activated state, the potential for you having psychiatric symptom burden increased, amplified or new is quite real. These disease models are different mechanisms of illness so it's hard a little bit to cross compare Lupus versus Lyme's disease but the concept of immune activation that broadly does influence your psychological state of mind. Thank you. You're welcome. And the last gentleman there. I see you two. I promised we would answer the two that were there but please still come to the front and we'll chat so don't leave. Okay. Yeah. One question. For now we know several infections disease cause encephalitis and et cetera. But during the infection we can do something to modulate and to prevent the outcome of autoimmune encephalitis. Maybe, I don't know, immunomodulators, glucocorticoids. I don't know that there's some evidence about. The evidence right now would suggest that early recognition, prompt treatment is associated with better outcomes. So a reduction in morbidity and a reduction in mortality. The concept of using neurally protective interventions is a little bit more new. You sometimes will see conversations about which antipsychotic or which mood stabilizer to use and there is a little bit of evidence about the potential neuroprotective role of Depakote if you are targeting things like almost a traumatic brain injury-esque clinical presentation and picture with cognitive dulling. Totally different mechanism but there is, I would say that's the only one I've seen that has a bit of evidence on the neural protection side. It tends to be a good fit if you had a known seizure disorder paired with mood lability in a patient that has an autoimmune encephalitis. But that's, I would say that's still very early on and we don't have medication moves, at least on the psychotropic side, that would be considered standard of care proactively. It's much more about supportive augmentation strategies for symptom control. Jeff. I think the best example in neurology is probably myasthenia gravis, which is an antibody to the neuromuscular junction that causes weakness. We treat that with immunomodulator steroids but we also treat it with pruritostigmine, a physiology restorer. There's a lot of basic science looking at what happens when an NMDA antibody binds to the NMDA receptor, does this cross-linking and changes that physiology separately with LGI1 or GABA. And it's my hope that with that, there'll also be therapies restoring physiology based on that and that five years, 10 years from now, whatever the timeline is, we'd be able to say here's your immunomodulatory therapy and then here's your neurophysiology specific restorer of NMDA function or of GABA A function or whatever it's gonna be. And I think, and then combined with elegant prescribing from a symptom management standpoint that's evidence-based, I think that's gonna be the model. My hope would be 10 years from now, this talk would have that. Great, and I also would acknowledge that our ancillary care providers on physical therapy, speech therapy, occupational therapy, these are really valuable opportunities to be able to help create a more robust enriched environment as a patient is going through their trajectory of care. So engaging them gives you a bunch of detail concretely about observations made at the bedside that you don't have if you're only relying on clinical care practice on the psychiatry side. So I would engage your colleagues early, PT, OT, and speech. I think there's a lot of value in that from a neural protective perspective. We're gonna close the formal session simply because it is now right on 3.05. But please, if you do have follow-up questions, feel empowered to come up and we'll stay back for a few. Thank you.

collaborative care

autoimmune encephalitis

related disorders

Dr. Richard Jin

Dr. Gina Mooneyham

Dr. Jeff Gelfand

immunopsychiatry

neuropsychiatric disorders

interdisciplinary collaboration

seronegative cases

diagnostic imaging

COVID-19

neuroimmune conditions