Advances in Treatment for Epilepsy-Use of Immunotherapy in the Management of Refractory Status Epilepticus

Video Transcription

I'm Steven Van Herens, as Adriana, and thank you for having me. And thank you all for staying here on a Friday night. Still a pretty full room here.  So we're going to be talking about the use of immunotherapy and the management of refractory status epilepticus. I do have some disclosures.  Only really the extinguished trial is of any relevance. But I think the biggest kind of disclosure is that there actually is no FDA approved  treatments for autoimmune encephalitis or autoimmune associated epilepsy. So we're going to be going through it.  So we might as well just get into it because we're running low on time. But as we've been alluding to with all the speakers today, you know, status epilepticus  is often though etiologically usually fairly easier to figure out. Like either the patient stopped taking their meds or they have a large subdural.  But in 20% of cases, this initial workup, you know, might be unrevealing and then you're left with difficulty in pinpointing one of the many uncommon causes of status epilepticus.  So we're going to focus on autoimmune etiologies. And so despite the proposed kind of, you know, treatment algorithms, as our prior speakers  have brought up, up to 40% of status epilepticus remain refractory. And so finding an etiology of status epilepticus can have therapeutic and prognostic implications.  And then delayed recognition may contribute to a poor outcome. So an immune etiology to epilepsy, acute seizures, or status is also becoming increasingly recognized.  And a Mayo study found that 20% of adult patients with epilepsy or status epilepticus of unknown  etiology were seropositive for a neuronal antibody associated with autoimmune epilepsy or encephalopathy.  And so recognition of the possibility that seizures can be the result of autoimmunity or inflammation can have profound effects on treatment or outcome.  But like everything in neurology, there's always a lot of caveats. So patients with longstanding epilepsy can have these kind of low, especially serum titers  of, you know, undifferentiated voltage-gated potassium or GAD-65. And then you have these nonspecific serum antibodies too, like ANA, TPO antibodies with  the former, you know, Hashimoto's encephalopathy. And so at our study, in a little study, we did look and found that these actually are  more prevalent in autoimmune encephalitis and autoimmune epilepsy, but definitely not specific.  And so I'm a clinician and not a basic scientist, but we have to kind of go through a broad  overview of the immune system, really, especially for those who haven't thought about this in a while, because when we really talk about immunotherapy, we're thinking really kind  of broadly of two arms of the immune system, which interact in a very complex way. So I'm going to try to make this as simple as possible.  But when you think of why would someone even develop autoimmune epilepsy or autoimmune  encephalitis, you know, there's really kind of, I like to put them into three broad categories.  You have your perineoplastic, which have an underlying tumor, maybe with molecular mimicry with then auto-reactivity, or you might have a virus like herpes simplex virus, which has  a known association with NMDA receptor encephalitis, or it might just be idiopathic and we have no idea.  And so then we'll go to two, we'll divide the immune system into two broad categories. You have the B cell mediated autoimmunity, which are, you know, our good friends, B cells  going to plasma cells, which then make antibodies that are presumed to be auto-reactive for the case of this talk. And these are going to be antibodies that are directly pathogenic.  And just for some name recognition, these are like your voltage gated potassium, subtypes NMDA, GABA, AMPA, and they're directly pathogenic.  And that makes sense that these types of conditions would then respond better to like plasmapheresis, where you're removing that pathogenic antibody.  And then you have your T cell line, which are much harder to treat, which we'll get to, where you have an intracellular, where the antibody is actually directed to an intracellular  target. So therefore, it shouldn't really reach that target. And so these are more biomarkers of injury rather than directly toxic antibodies.  And so just kind of, I won't go through these long lists because we're going to be clumpers higher yield today in 20 minutes instead of splitters, but there's multiple different  cell service antibodies like NMDA, voltage gated potassium, AMPA. And then you have your intracellular like anti-HU, which these are almost always associated with cancer.  And so you should really be doing a very thorough perineoplastic oncology screen except for GAD65, which has its own difficulties in treatment for any of you with those patients.  So now let's also take the caveat before we start taking a deeper dive into actual treatments in that what is autoimmune epilepsy?  Because we all know like epilepsy is an enduring kind of predisposition to have seizures. So while some of these patients, if you treat them and you get ahold of these seizures with  immunotherapy early, they might not even have long-term epilepsy. So seizures, like we had talked about, have been well-recognized in a prominent manifestation  of autoimmune encephalitic syndromes. And so when we refer to autoimmune epilepsy or like when you say autoimmune dementia,  you know, really you're kind of referring to the most prominent symptom for the sake of this talk will be epilepsy and seizures.  And so the ILEE then, you know, has this immune category. However, like we were just saying that, you know, many patients with self-service antibodies  especially can achieve complete seizure freedom after treatment. So now we've kind of subdivided these into acute symptomatic seizures secondary to autoimmune  encephalitis and autoimmune associated epilepsy. So the symptomatic seizures are going to be more of that, you know, antibody-mediated  cell service where you're actually having antibody-mediated ictogenesis. And these are going to be usually more responsive to immunotherapy, more so than anti-seizure  medications alone. And the outcome, especially if you get them early enough, they might not have long-term epilepsy.  Immune-associated epilepsy on the other hand, these are like your GAD-65 or, you know, anti-HU.  And these are going to be a combination of epileptogenesis due to structural like post, you know, encephalitic pathology so you have that structural piece.  And then you have your ongoing T-cell-mediated brain inflammation piece. And so when you're treating these types of patients, you know, it's very challenging  of the balance of immunotherapy and anti-seizure medications to really get control of their seizures.  And the unfortunate reality is, in this group, is that they are very refractory. And so anti-seizure medications are often ineffective.  Epilepsy surgery usually has an incomplete response. And immunotherapy is also usually with a poor response. They're just very pharmacoresistant focal epilepsies.  So this kind of just further is a pictorial study of what I just kind of went through in that here when you look at the cell surface antibodies that, you know, all of these each  notch here is a year. These actually stop seizing while the intracellular ones looks pretty flat because they kind of continue seizing.  So how do I approach treatment before we get into specific kind of treatment paradigms? So I do use the kind of Mayo Clinic 3Ms that they have that nice branding on.  But it's really true that when you're dealing with a patient in status epilepticus, my first goal is really to get, you know, at least 50% seizure reduction.  And keeping in mind that you may not be able to reverse but only stop any progression.  And then you want to maintain that reversibility with a minimal therapeutic dose of an immunosuppressant.  And before you really get started, especially if you're unsure of the diagnosis, you really want to have, and I can't stress this enough, objective markers for what you're treating.  The worst thing you want to get into is blasting someone with immunotherapy and being like, uh, I think they're a little better.  You know, you really want like very specific, either seizure frequency with their cognition and not just cognition like, oh, they were kind of off before, but like a mocha or some  sort of objective sign to follow. Or you're following like MRIs, a PET, something objective. And so this is kind of the algorithm that we published two years ago now, which is based  off of Jenny Linoila's paper from 2016, just updated a little. And so we'll go through this kind of piece by piece.  And so if you don't have an antibody identified or you're still waiting for it, as soon as I have like essentially like your herpes virus is ruled out, like you get started with  some steroids, IVIG, maybe you even plex them. And if you don't have improvement, especially in an unstable patient who might be in status,  that's usually when you start increasing the therapy with rituximab, especially if you end up getting a cell surface antibody coming back versus like cyclophosphamide.  And if you do get improvement, this is when we go to that kind of acute symptomatic seizures versus enduring autoimmune-associated epilepsy.  And that like LGI-1 or some of the cell surface are monophasic diseases at times. So once you get control, you don't just stop the immunotherapy, but then you start slowly  tapering it over months because you don't want an immediate relapse. And then you kind of then, if they relapse further out, then you kind of know that they  need that enduring continued immunotherapy. And then you have to bridge that therapy, knowing that a lot of these immunotherapies  like azathioprine and things might take like 12 weeks to really kick in. So then you have to redo the steroids and get them bridged back onto immunotherapy.  Now if it's intracellular, then I don't really waste any time. I usually just start cyclophosphamide monthly pulses.  I mean, you really, as we've said many times today, time is brain. And their brains literally start to melt away if you don't get control of this very fast.  And then with all of these, you definitely want to do your tumor screen too and treat the... If there is an underlying tumor, you don't just punt it to oncology.  But recognizing that you can't just remove the tumor, these antibodies are already made and they still need immunotherapy.  Okay. So like I said, once you get the steroids or IVIG, you start gradually extending it. If you're using oral prednisone, which I don't recommend because a lot of these patients  have a lot of psychiatric comorbidity and that can really agitate them. So I do prefer IV pulses if you're able.  But I usually start with 60 and then slowly wean and then remember to overlap. And like I said, there's always caveats to all these types of treatments.  And it's important to note that, like I said, just because you have a neuronal antibody does not guarantee a good response.  And like I said, successful immune treatment may be marked by just stopping clinical progression. And it's also important to recognize that a full recovery may take months.  And seizures may show early improvement, but cognitive improvements can take years at times. So really keep that in mind. Don't just say that they failed.  And so approximately 20 to 50% of patients with autoimmune encephalitis may show inadequate response to second-line therapies.  And so for instance, Bortizumab, I've now used in super, very refractory NMDA patients now with positive success too.  So there are other kind of new novel, Tocrelizumab with IL-6 have emerged as novel second-line immunotherapies for management of refractory cases.  So anti-seizure drugs will stick to immune therapy, but I do want to just kind of briefly  state this one paper, which did show that carbamazepine was more effective than levotiracetam in reducing seizures in anti-LGI1 encephalitis.  So in these patients seizure-med wise, I do try to stick with sodium channel blockers in general.  So let's kind of switch gears from autoimmune encephalitis to more what is thought to be more of an auto-inflammatory kind of disorder with NORS.  So NORS being new onset refractory status epilepticus, rare devastating condition characterized  by de novo onset of refractory status epilepticus without an identifiable active structural toxic or metabolic cause.  And it is a clinical presentation rather than a specific diagnosis. All this definition is written by people in this room actually.  So FIERS, a subcategory of NORS, requires a prior febrile illness starting between two weeks and 24 hours before the onset of refractory status epilepticus with or without the fever  at onset. And it does apply to all age group, and it's not just pediatrics, just keep that in mind.  And cryptogenic, if it's cryptogenic meaning it's unknown etiology with no explanation, and about half of them will have that kind of unknown cryptogenic presentation.  And interestingly, these cases do not differ much from autoimmune cases suggesting this kind of similar etiology and questioning if there is unidentified antibodies.  And the CSF abnormalities are similar in both the cryptogenic cases and autoimmune infectious cases too.  And there has been shown now evidence of these proconvulsant cytokines have been documented in the CSF.  So Ronnie Wickstrom, who's in the audience, as well as 48 experts, at least seven I think  are in this room, created a total of 85 recommendations concerning diagnoses, treatment, and follow-up were developed to aid clinicians and present this care.  So Dr. Wickstrom presented this last year, so I won't go into full detail, but just we'll go kind of use an illustrative case and then come back to this algorithm of how I use it.  So this is a patient I had this summer. She's 20 years old. She was a college student, collegiate athlete at a university in Chicago, and essentially  had presented with what was thought just to be a regular virus. She got a fever to 101.8, headache, she had lymphadenopathy, she had a negative respiratory panel.  They checked like COVID, of course. She did have kind of a low white count, but not like dangerously low, but a little leukopenia.  And she continued to have malaise, headache, but no neck stiffness like meningeal signs. She had poor oral intake, and she was started on meropenem and encyclovere empirically as  she started actually having generalized tonic-clonic seizures, however, not just one. She had one after another, and then followed by multiple with focal onset.  She could have left head version, right head version. And once she was placed on EEG, she just seized and seized. They're coming from both sides.  And so her initial CSF was actually fairly bland, except for some elevated protein. And I'll pretend that we got all these antibodies back immediately, even though we know it takes  weeks, but they were negative. So she also had a negative MRI initially and a negative cancer screen.  And her follow-up lumbar puncture had like a low kind of white blood cell lymphocytic predominant.  And then she started, as we were talking about MRI changes of the status, she started developing some nice T2 changes in her mesial temporal lobes.  So seizures continued despite now five seizure meds. She was placed in birth suppression. I should also say, too, she had next-gen sequencing for any viral, which were all negative.  And we did actually order initially a cytokine panel, which, as you know, didn't come back immediately either. We had already started treatment at that point.  But it did come back elevated with IL-6. So in this patient, she had what I would classify as fires.  So the initial treatment is really stabilization, which we didn't really talk about in this group. But with anti-seizure medications, she was given anesthetics.  And essentially, that is when we started with the concern that this was fires, is when we started immunotherapy. So she got steroids and IVIG.  And we did initiate in the ICU a ketogenic diet and got her into ketosis as well. And we then also elected to use an IL-1 receptor blocker, our antagonist, I should say, Anakinra.  And so she was started on that as well. And I was like a positive story. And so now I made these slides a month ago. So now we're four months out.  And she is back in college. And she's playing Division I volleyball. And so she's doing amazingly well. On her ambulatory EEG, she still has bitemporal sharp waves.  But it hasn't had any subsequent seizures. I have now weaned her off steroids. And she's on a lower dose of Anakinra. But now we're working on kind of lowering seizure meds.  I never like to lower immunotherapy and seizure meds at the same time, because then if they have a breakthrough seizure, you don't know what to do.  So one at a time, if I can give anyone any advice. So take-home points, you know, despite proposed treatment algorithms, up to 40% of status remain refractory.  So don't forget about immunotherapies and immunoideologies. Delayed ideology recognition can contribute to poor outcome.  And you know, I didn't show these slides, but delay in outcome is associated with continued long-term seizures. So time is brain. I don't know how many times we say that today.  But you know, it is important to note that the presence of neural antibody does not guarantee a good response to treatment.  And a successful immune treatment may be marked by just stopping clinical progression and not necessarily reversal. And that it can take months to fully recover.  These are my references. And thank you.

Video Summary

Steven Van Herens discusses the use of immunotherapy in managing refractory status epilepticus, emphasizing the absence of FDA-approved treatments for autoimmune encephalitis and epilepsy. He highlights the complexity of diagnosing autoimmune causes, which constitute around 20% of status epilepticus cases and may involve seropositive neuronal antibodies. He categorizes autoimmune epilepsies into subtypes, focusing on antibodies and their pathogenic roles. Van Herens outlines treatment strategies, such as using IVIG and steroids, and emphasizes the importance of objective markers for treatment efficacy. He also addresses the challenges in treating conditions like NORSE and FIRES, noting the potential of emerging therapies like Bortizumab and Tocrelizumab. Through a case study, Van Herens illustrates successful treatment approaches, highlighting time sensitivity in managing these conditions. Overall, the presentation stresses the importance of early recognition and tailored immunotherapeutic strategies to optimize patient outcomes.

Asset Subtitle

Presenter:

Stephen Vanhaerents, MD, is an Associate Professor in Neurology and Medical Education at Northwestern University Feinberg School of Medicine. His practice focuses on the medical and surgical treatment of epilepsy with particular emphasis on the treatment of medically intractable seizures. His clinical research interests include neurostimulation, identification and treatment of Autoimmune-Associated Epilepsy, and New-Onset Refractory Status Epilepticus (NORSE). Additionally, Dr. VanHaerents is deeply invested in medical education and currently serves as the Director of Medical Student Education in Neurology. He is also the Chair Elect for the Consortium of Neurology Clerkship Directors with the American Academy of Neurology. He also serves as the Co-Chair for the Neurology and Neurosurgery Health Equity, Diversity and Inclusion Committee at Northwestern University Feinberg School of Medicine and Northwestern Medicine. He was elected a member of Alpha Omega Alpha national honor society at Wayne State University School of Medicine in Detroit, Michigan where he received his medical degree. He completed a neurology residency and neurophysiology fellowship in epilepsy at Harvard Medical School / Beth Israel Deaconess Medical Center in Boston, Massachusetts.

Keywords

immunotherapy

autoimmune encephalitis

status epilepticus

treatment strategies

emerging therapies