In this episode of the Better Edge podcast, Northwestern Medicine’s Stephen A. VanHaerents, MD, associate professor of Neurology in the Divisions of Epilepsy and Clinical Neurophysiology, and Neuroinfectious Disease and Global Neurology, and Margaret Y. Yu, MD, assistant professor of Neurology in the Divisions of Comprehensive Neurology and Hospital Neurology, discuss this recent FIRES (febrile infection-related epilepsy syndrome) case.
Selected Podcast
Case Report: FIRES in 20-Year-Old College Athlete
A 20-year-old female college volleyball player developed headaches and high fevers, which led to multiple seizures per day. The patient presented to Northwestern Medicine Neurology when she stopped following commands and conversing intelligibly between seizures.
In this episode of the Better Edge podcast, Northwestern Medicine’s Stephen A. VanHaerents, MD, associate professor of Neurology in the Divisions of Epilepsy and Clinical Neurophysiology, and Neuroinfectious Disease and Global Neurology, and Margaret Y. Yu, MD, assistant professor of Neurology in the Divisions of Comprehensive Neurology and Hospital Neurology, discuss this recent FIRES (febrile infection-related epilepsy syndrome) case.
In this episode of the Better Edge podcast, Northwestern Medicine’s Stephen A. VanHaerents, MD, associate professor of Neurology in the Divisions of Epilepsy and Clinical Neurophysiology, and Neuroinfectious Disease and Global Neurology, and Margaret Y. Yu, MD, assistant professor of Neurology in the Divisions of Comprehensive Neurology and Hospital Neurology, discuss this recent FIRES (febrile infection-related epilepsy syndrome) case.
Featured Speakers:
Learn more about Dr. Yu
Dr. VanHaerents's practice focuses on the medical and surgical treatment of epilepsy. His clinical research interests include neurostimulation, identification and treatment of Autoimmune Epilepsy/Encephalitis, and New-Onset Refractory Status Epilepticus (NORSE). Additionally, Dr. VanHaerents is deeply invested in medical education and currently serves as the Neurology Clerkship Director, Co-module Leader of the M2 Neuroscience course, and Chair-Elect of the Consortium of Neurology Clerkship Directors at the American Academy of Neurology.
Learn more about Dr. VanHaerents
Margaret Yu, MD | Stephen VanHaerents, MD
Dr. Yu is interested in the acute care and management of hospitalized patients with neurological conditions. She is passionate about medical education in the training of other neurohospitalists as well as quality improvement in the inpatient care of patients. She is the associate program director for the Neurohospitalist Fellowship at Northwestern. Other areas of research include clinical trials and publication of case reports amongst other clinical teaching.Learn more about Dr. Yu
Dr. VanHaerents's practice focuses on the medical and surgical treatment of epilepsy. His clinical research interests include neurostimulation, identification and treatment of Autoimmune Epilepsy/Encephalitis, and New-Onset Refractory Status Epilepticus (NORSE). Additionally, Dr. VanHaerents is deeply invested in medical education and currently serves as the Neurology Clerkship Director, Co-module Leader of the M2 Neuroscience course, and Chair-Elect of the Consortium of Neurology Clerkship Directors at the American Academy of Neurology.
Learn more about Dr. VanHaerents
Transcription:
Case Report: FIRES in 20-Year-Old College Athlete
Dr. Andrew Wilner: A 20-year-old female college volleyball player developed headaches and high fevers, which led to multiple seizures per day. The patient presented to Northwestern Medicine Neurology when she stopped following commands and conversing intelligibly between seizures.
This is Better Edge, a Northwestern Medicine podcast for physicians. I'm your host, Dr. Andrew Wilner, Associate Professor of Neurology at the University of Tennessee Health Science Center and Division Director of Neurology at Regional One Health in Memphis, Tennessee.
Today, we are discussing a recent case of FIRES, febrile infection-related epilepsy syndrome. Joining us today are two physicians from Northwestern Medicine who were involved in this patient's treatment and care, Dr. Stephen VanHaerents and Dr. Margaret Yu. Dr. VanHaerents is an Associate Professor of Neurology in the Divisions of Epilepsy and Clinical Neurophysiology and Noninfectious Disease and Global Neurology. Dr. Yu is an Assistant Professor of Neurology in the Divisions of Comprehensive Neurology and Hospital Neurology. Welcome, Drs. VanHaerents and Yu.
Dr. Stephen VanHaerents: Thank you. Thank you for having us.
Dr. Andrew Wilner: Well, thanks for joining us. Let's get started. Dr. VanHaerents, tell us a little bit about FIRES. Is this a new disease? What's the prevalence?
Dr. Stephen VanHaerents: Sure. So as I said, thank you for having us. And as you said, FIRES actually stands for febrile infection-related epilepsy syndrome, and it's actually a subtype of another syndrome we refer to as NORSE or new-onset refractory status epilepticus. And it's a rare and devastating condition that was more recently defined. And it's characterized by, essentially as the title says, this new onset of refractory status epilepticus without any identifiable cause, such as like a structural, toxic or metabolic etiology. And I should point out that it's also a clinical presentation rather than a specific diagnosis, as a number of different causes can lead to this syndrome.
And so, FIRES is really just a subcategory of that and requires a prior febrile illness, starting between two weeks and 24 hours before that onset of refractory status epilepticus, with or without fever at that onset. And it applies to all age groups. Historically, a lot of people think it's more of a pediatric condition, but it really applies to all age groups. And regarding your question on the prevalence you know, we know it's rare. But given it is so rare, it's hard to know exactly how rare. But the best data we have is from Germany and it seems to be about one in a million per year.
Dr. Andrew Wilner: One in a million?
Dr. Stephen VanHaerents: Yeah.
Dr. Andrew Wilner: All right. So, not something you see every day. So, expand for us how this patient presented to Northwestern Medicine. What were her symptoms?
Dr. Stephen VanHaerents: Yeah. So as you stated out, she's a 20-year-old volleyball player at a college in town. And she started having just fevers up to like about 101 and headaches. And what she really remembers now is really just the headaches and just feeling really unwell. This is COVID season, so she was tested for COVID and had negative respiratory panels. All of that came out negative and she just continued to feel unwell and wasn't eating. And then when they did basic blood work on her, they found that her white count was a little low. And no one really set off any clear alarms until she had her first seizure, which was about four days into the illness, And the seizure, as an epileptologist, I feel the need to explain, it looked like she started with these either a left head version or a right head version, with the gaze deviation, and then would go into a generalized tonic-clonic seizure. And so, these became quite refractory and it was at that point she was transferred to Northwestern for further management.
Dr. Andrew Wilner: Okay. So Dr. Yu, tell us a little bit about what you do and the types of patients you see in the emergency department.
Dr. Margaret Yu: Absolutely. I am a neurohospitalist and I split my time between Northwestern downtown at NMH and at Lake Forest Hospital in the northern suburbs. Given the wide range of reasons that patients present to the emergency department, I see a large range of different neurological conditions. This can include new-onset neurological symptoms concerning for acute ischemic stroke or patients who have known previously well controlled epilepsy who has a breakthrough seizure, and patients like our college athlete who we are discussing today, who have really no known history of any neurological symptoms and are presenting with new rapid progression of acute neurologic change.
Dr. Margaret Yu: I really love my job because I get to see such a wide diversity of patients. And when patients are acutely ill with this rapid deterioration, it can be very frightening initially, but it's also really rewarding to be able to come to a diagnosis and initiate treatment. So, I came to treat this specific patient when I took over the Northwestern Downtown Ward Service. She was initially in our neurosciences ICU after she was transferred from the outside hospital. She was originally on two anti-seizure medications. And then once she got to our ICU, she was having more seizures, so more anti-seizure medications was started. When she was on four anti-seizure medications, she actually had no seizure activity on EEG for 48 hours. So then, she was transferred from the ICU tower neuro step-down unit. And that was actually the day I took over service. However, her seizure frequency started increasing again after that initial period of stability.
Dr. Andrew Wilner: Let's go back for a minute when she presented to the emergency room. Based on the story, she's got some fevers and headache and seizure, my first thought would be meningitis, maybe a viral, meningitis. You know, FIRES probably wouldn't be the first thing that came into my mind. So, what did they do in the ER and when did the concept of FIRES show up?
Dr. Margaret Yu: Yeah. So you know, common things being common for someone who is presenting with this constellation of symptoms, definitely meningitis would be top of the differential. When she initially presented to the outside hospital emergency department, there was first a head CT that was done just to make sure that there wasn't any masses, any evidence of any intracranial hemorrhages. And then subsequently, once that was shown to not be present, a lumbar puncture was pursued. And with her lumbar puncture, she had a mild elevation in her white blood cell count, and it was about 14 or 15, and it was lymphocytic predominance. She also had a slightly elevated protein count. In addition to serum testing for viral bacterial serologic testing, they also sent off the infectious testing in the cerebrospinal fluid, looking for the meningitis panel, which is a whole host of different viruses, bacteria that could possibly cause meningitis, and then specifically for HSV-1 and 2 PCR in the spinal fluid. She was started empirically on meningitic coverage because, as you said, it's kind of the first thing that we think of and you wouldn't want to just not treat a meningitis. So, that was initiated. But the rapid progression of the seizures was a little bit more concerning and out of the ordinary for what we would see out of an infectious meningitis, which is why the thinking was transitioned a little bit, and that was why she was transferred to us for escalation of care.
Dr. Andrew Wilner: So the tipoff, because everything you told me, a few white cells elevated protein, nothing grew in the cultures, that's all consistent with a viral meningitis. But the tipoff seems to be that she had these seizures on a daily basis that did not respond to anti-seizure drugs. Is that right?
Dr. Margaret Yu: Correct. And the rapid progression of her seizures and the fact that when she needed multiple agents, and even with multiple agents, she was still having recurrent seizures. That was a tip off that there was something a little bit more insidious and uncommon that was happening.
Dr. Andrew Wilner: All right. So, you're making rounds in the ICU and a medical student says, "Hey, maybe this could be FIRES, right?" Then, how do you figure out if it is or isn't?
Dr. Margaret Yu: Yeah. So first of all, I would tell that medical student, that it's great to think about on your differential, and they've definitely done some reading. She's having new-onset refractory status epilepticus. And there's four big buckets that we want to consider when someone is coming in with that.
First, you want to consider this kind of paraneoplastic inflammatory autoimmune component, infectious component, genetic disorders and toxic disorders. So, you want to do a very thorough workup. And for the laboratory work, that includes urine toxicology, your basic lab works, an autoimmune workup in terms of ANA, autoimmune disease panel. And you also want to look for these more insidious things, and FIRES is definitely one of them. But there's other things too that you want to consider and not just anchor on one diagnosis. So, you also want to consider if this could be some kind of paraneoplastic autoimmune phenomenon and you would like to send in the blood the Mayo autoimmune paraneoplastic panel in addition to sending it in the cerebral spinal fluid because there are some autoantibodies that are more sensitive in the cerebrospinal fluid and some that are more sensitive in the serum. So, you want to send off both.
So for her, we did repeat the lumbar puncture because there were some tests that were sent at the outside hospital, but we wanted to be definitive that it didn't seem like more infectious component, which is why we also got our infectious disease colleagues involved making sure that we were sending off all the right testing, not just for the common things that we see, but some that are maybe a little less common, but are endemic to our region and as well as to the season that she presented. So, we definitely wanted to consider arboviruses and also wanted to consider could this potentially be a more insidious fungal phenomenon? So, you wanted to send off all those things. Because if it were infectious, then you definitely want to treat the underlying infection. And there are times when it's a more uncommon infection causing the symptoms, which if you miss that component and you kind of go down a rabbit hole of this inflammatory, paraneoplastic component, then you're not adequately treating the patient, which is why we repeated the lumbar puncture, making sure to check those labs and also sending off the Mayo autoimmune paraneoplastic panel.
Also, we sent off cytokines because maybe Dr. VanHaerents can talk about this a little bit later, but the cytokines really help us see if there is something that's a little bit more rare or more inflammatory that is happening in this particular patient. She was put on EEG just to see what the pattern of her EEG was, and also to make sure that we tried to control her seizures as best as we could. And the way that her EEG looked, it wasn't just one seizure pattern, which also made us more concerned that there was something that was happening that was more of an inflammatory autoimmune condition. And if you think that someone has an inflammatory autoimmune paraneoplastic condition, you want to look to see if they have a systemic situation that's happening. So, we did a CT chest, abdomen, and pelvis looking for occult malignancies, sent off a CSF for cytology and flow. Also, she had a bone marrow biopsy as well at the outside hospital. And we got a repeat pelvic ultrasound as we know that when patients can have ovarian teratomas that can be associated with auto-antibody generation. And all of that was really unrevealing in terms of that imaging, looking for an acute malignancy or some kind of systemic autoimmune condition.
Dr. Andrew Wilner: Okay. So mega workup, took weeks. At least in my institution, those are all sendouts. You don't get them back the next day. So Dr. Yu, after you ordered all these panels and these tests, how did you make the definitive diagnosis of FIRES?
Dr. Margaret Yu: Yes. The first thing to do is to rule out the things that it wasn't, the infectious component, the more structural component, MRI was negative; vessel imaging, unrevealing; no evidence of a sinus thrombosis. And then with the cerebrospinal fluid, we did these send out tests, which often take many days to come back. But one of the tests that we sent out under the guidance of Dr. VanHaerents were the CSF cytokines with the hypothesis being that when there's this strong dysregulated immune hyperactivation, your cytokines elevate when that is present and that can be seen in FIRES. It's not saying that everybody who comes in with a cytokine elevation in their spinal fluid has FIRES, but it is strongly suggestive that there is this kind of inflammatory immune hyperactivation that is present in the right clinical picture.
Dr. Andrew Wilner: Okay. So, I guess the cytokines were elevated, right?
Dr. Margaret Yu: Correct.
Dr. Andrew Wilner: So, is there an anti-cytokine potion? What do you do now?
Dr. Margaret Yu: Yeah. So before we got the cytokines that were even elevated, we had been in close contact with our epilepsy team, and the idea was that it just smelled like this was some kind of inflammatory immune-mediated process. So, we already started with immunomodulating treatments with IV steroids as well as IViG. However, before the cytokines came back, we didn't say we were going to start something for FIRES. But when they came back elevated and she really fit into that clinical picture, then we started the drug called anakinra, which is an inhibitor of IL-1 and has been shown to be helpful in these kinds of situations, mostly in the pediatric population more so, as it is more commonly seen in the pediatric population.
Dr. Andrew Wilner: Wow. So, real state-of-the-art therapy. So, how did she do?
Dr. Margaret Yu: She did really well on the inpatient side. Initially, it was so scary with all these seizures, but we had a great team working to stabilize her and make sure that she was doing well, and we had our great nurses and our techs who monitored her so closely. And most of all, we have a world-renowned expert in autoimmune epilepsy, Dr. VanHaerents, who's really been involved in her case since the beginning. And since he was involved, he knew her case very well. And when she transitioned to the outpatient setting, it was a very smooth transition.
Dr. Andrew Wilner: Dr. VanHaerents, give us an update. How is she doing?
Dr. Stephen VanHaerents: So, she's been doing remarkably well. You know, as most patients with FIRES, she had a road of recovery afterwards. But she's been returning back to school, she's been taking full-time classes, she's back to playing Division I volleyball. She has had a couple breakthrough seizures, but obviously not back in status or in the ICU. And we've been titrating medications for her tolerance and have also been lowering the anakinra as well.
Dr. Andrew Wilner: Well, that's fantastic. And she's, I guess, just on one or two anti-seizure drugs now instead of four?
Dr. Stephen VanHaerents: Well, she was on five. And now, she's on three and a half, I guess I would say. So, we are making progress. But as you know, it is a slow process. It's not one that can be done quickly. And like many patients post-NORSE and/or FIRES, they're not cured per se in that many of them will go on to have lifelong epilepsy as a result.
Dr. Andrew Wilner: All right. Let me ask both of you to address this question as you wish. What can neurologists learn about this case? What are the key takeaways?
Dr. Stephen VanHaerents: I would say despite proposed algorithms, up to 40% of status epilepticus patients will remain refractory. And delayed etiology and recognition, particularly autoimmune causes can contribute to poor outcome. So, I would say to keep autoimmune and autoinflammatory causes in your differential when seeing a status epilepticus patient and recognize that about half of these, if you do see, you know, an adult NORSE patient, that their etiologies can remain unknown. But we have now published recommendations and guidelines, which are based a lot on case reports, but you know, a lot of expert opinion on how to guide these therapies moving forward. And hopefully, more research down the line will better solidify these treatment options.
Dr. Andrew Wilner: One practical point, I'm curious, the next time I do an LP in a status patient, should I send it for cytokines? Is that something that's readily available?
Dr. Stephen VanHaerents: So, I wouldn't say it's readily available. And not every institution can send them off. You know, we're lucky that we can, although there is a delay in getting them back. So, I don't think that that should preclude you from treatment. When I advise people on what to do in these cases, first once you've stabilized a seizures with either using, anesthetic drugs, if once you kind of have gone through that diagnostic algorithm looking for if this was, as Dr. Yu pointed out, like paraneoplastic and you've done the cancer screens, you've looked for like is there any inborn errors in metabolism? Is this an immunocompromised patient? Is this infectious? Does this seem like it's a mitochondrial disorder? Once you've kind of gone through that diagnostic algorithm and these maintain being cryptogenic or an unknown etiology that you really want to start initiating these immune therapies. And as Dr. Yu said, in this case, we start typically with either steroids or intravenous immunoglobulins. But you know, if you get an incomplete response, that's when you wanna start things like ketogenic diet. And if there's no antibody confirmed or you don't have it back yet, to start these pro-convulsant cytokine inhibitors like anakinra, which is an IL-1 receptor antagonist or tocilizumab, which is an IL-6 antagonist. So, I would say yes, but you also have to know what you're sending as well and how these patients can also develop ICU infections and other things that can also change these kind of cytokines so they do have a limited use if not tested very early.
Dr. Andrew Wilner: Okay. Well, Dr. VanHaerents, I want to thank you very much for those recommendations. Thanks again to both of you, Dr. VanHaerents and Dr. Yu, for joining me today on Better Edge.
Dr. Margaret Yu: Thank you so much.
Dr. Andrew Wilner: To refer your patient or for more information, head on over to our website at BreakthroughsforPhysicians.NM.Org/Neuro to get connected with one of our providers. And that wraps up this episode of Better Edge, a Northwestern Medicine Podcast for physicians. I'm your host, Dr. Andrew Wilner. Thank you for listening.
Case Report: FIRES in 20-Year-Old College Athlete
Dr. Andrew Wilner: A 20-year-old female college volleyball player developed headaches and high fevers, which led to multiple seizures per day. The patient presented to Northwestern Medicine Neurology when she stopped following commands and conversing intelligibly between seizures.
This is Better Edge, a Northwestern Medicine podcast for physicians. I'm your host, Dr. Andrew Wilner, Associate Professor of Neurology at the University of Tennessee Health Science Center and Division Director of Neurology at Regional One Health in Memphis, Tennessee.
Today, we are discussing a recent case of FIRES, febrile infection-related epilepsy syndrome. Joining us today are two physicians from Northwestern Medicine who were involved in this patient's treatment and care, Dr. Stephen VanHaerents and Dr. Margaret Yu. Dr. VanHaerents is an Associate Professor of Neurology in the Divisions of Epilepsy and Clinical Neurophysiology and Noninfectious Disease and Global Neurology. Dr. Yu is an Assistant Professor of Neurology in the Divisions of Comprehensive Neurology and Hospital Neurology. Welcome, Drs. VanHaerents and Yu.
Dr. Stephen VanHaerents: Thank you. Thank you for having us.
Dr. Andrew Wilner: Well, thanks for joining us. Let's get started. Dr. VanHaerents, tell us a little bit about FIRES. Is this a new disease? What's the prevalence?
Dr. Stephen VanHaerents: Sure. So as I said, thank you for having us. And as you said, FIRES actually stands for febrile infection-related epilepsy syndrome, and it's actually a subtype of another syndrome we refer to as NORSE or new-onset refractory status epilepticus. And it's a rare and devastating condition that was more recently defined. And it's characterized by, essentially as the title says, this new onset of refractory status epilepticus without any identifiable cause, such as like a structural, toxic or metabolic etiology. And I should point out that it's also a clinical presentation rather than a specific diagnosis, as a number of different causes can lead to this syndrome.
And so, FIRES is really just a subcategory of that and requires a prior febrile illness, starting between two weeks and 24 hours before that onset of refractory status epilepticus, with or without fever at that onset. And it applies to all age groups. Historically, a lot of people think it's more of a pediatric condition, but it really applies to all age groups. And regarding your question on the prevalence you know, we know it's rare. But given it is so rare, it's hard to know exactly how rare. But the best data we have is from Germany and it seems to be about one in a million per year.
Dr. Andrew Wilner: One in a million?
Dr. Stephen VanHaerents: Yeah.
Dr. Andrew Wilner: All right. So, not something you see every day. So, expand for us how this patient presented to Northwestern Medicine. What were her symptoms?
Dr. Stephen VanHaerents: Yeah. So as you stated out, she's a 20-year-old volleyball player at a college in town. And she started having just fevers up to like about 101 and headaches. And what she really remembers now is really just the headaches and just feeling really unwell. This is COVID season, so she was tested for COVID and had negative respiratory panels. All of that came out negative and she just continued to feel unwell and wasn't eating. And then when they did basic blood work on her, they found that her white count was a little low. And no one really set off any clear alarms until she had her first seizure, which was about four days into the illness, And the seizure, as an epileptologist, I feel the need to explain, it looked like she started with these either a left head version or a right head version, with the gaze deviation, and then would go into a generalized tonic-clonic seizure. And so, these became quite refractory and it was at that point she was transferred to Northwestern for further management.
Dr. Andrew Wilner: Okay. So Dr. Yu, tell us a little bit about what you do and the types of patients you see in the emergency department.
Dr. Margaret Yu: Absolutely. I am a neurohospitalist and I split my time between Northwestern downtown at NMH and at Lake Forest Hospital in the northern suburbs. Given the wide range of reasons that patients present to the emergency department, I see a large range of different neurological conditions. This can include new-onset neurological symptoms concerning for acute ischemic stroke or patients who have known previously well controlled epilepsy who has a breakthrough seizure, and patients like our college athlete who we are discussing today, who have really no known history of any neurological symptoms and are presenting with new rapid progression of acute neurologic change.
Dr. Margaret Yu: I really love my job because I get to see such a wide diversity of patients. And when patients are acutely ill with this rapid deterioration, it can be very frightening initially, but it's also really rewarding to be able to come to a diagnosis and initiate treatment. So, I came to treat this specific patient when I took over the Northwestern Downtown Ward Service. She was initially in our neurosciences ICU after she was transferred from the outside hospital. She was originally on two anti-seizure medications. And then once she got to our ICU, she was having more seizures, so more anti-seizure medications was started. When she was on four anti-seizure medications, she actually had no seizure activity on EEG for 48 hours. So then, she was transferred from the ICU tower neuro step-down unit. And that was actually the day I took over service. However, her seizure frequency started increasing again after that initial period of stability.
Dr. Andrew Wilner: Let's go back for a minute when she presented to the emergency room. Based on the story, she's got some fevers and headache and seizure, my first thought would be meningitis, maybe a viral, meningitis. You know, FIRES probably wouldn't be the first thing that came into my mind. So, what did they do in the ER and when did the concept of FIRES show up?
Dr. Margaret Yu: Yeah. So you know, common things being common for someone who is presenting with this constellation of symptoms, definitely meningitis would be top of the differential. When she initially presented to the outside hospital emergency department, there was first a head CT that was done just to make sure that there wasn't any masses, any evidence of any intracranial hemorrhages. And then subsequently, once that was shown to not be present, a lumbar puncture was pursued. And with her lumbar puncture, she had a mild elevation in her white blood cell count, and it was about 14 or 15, and it was lymphocytic predominance. She also had a slightly elevated protein count. In addition to serum testing for viral bacterial serologic testing, they also sent off the infectious testing in the cerebrospinal fluid, looking for the meningitis panel, which is a whole host of different viruses, bacteria that could possibly cause meningitis, and then specifically for HSV-1 and 2 PCR in the spinal fluid. She was started empirically on meningitic coverage because, as you said, it's kind of the first thing that we think of and you wouldn't want to just not treat a meningitis. So, that was initiated. But the rapid progression of the seizures was a little bit more concerning and out of the ordinary for what we would see out of an infectious meningitis, which is why the thinking was transitioned a little bit, and that was why she was transferred to us for escalation of care.
Dr. Andrew Wilner: So the tipoff, because everything you told me, a few white cells elevated protein, nothing grew in the cultures, that's all consistent with a viral meningitis. But the tipoff seems to be that she had these seizures on a daily basis that did not respond to anti-seizure drugs. Is that right?
Dr. Margaret Yu: Correct. And the rapid progression of her seizures and the fact that when she needed multiple agents, and even with multiple agents, she was still having recurrent seizures. That was a tip off that there was something a little bit more insidious and uncommon that was happening.
Dr. Andrew Wilner: All right. So, you're making rounds in the ICU and a medical student says, "Hey, maybe this could be FIRES, right?" Then, how do you figure out if it is or isn't?
Dr. Margaret Yu: Yeah. So first of all, I would tell that medical student, that it's great to think about on your differential, and they've definitely done some reading. She's having new-onset refractory status epilepticus. And there's four big buckets that we want to consider when someone is coming in with that.
First, you want to consider this kind of paraneoplastic inflammatory autoimmune component, infectious component, genetic disorders and toxic disorders. So, you want to do a very thorough workup. And for the laboratory work, that includes urine toxicology, your basic lab works, an autoimmune workup in terms of ANA, autoimmune disease panel. And you also want to look for these more insidious things, and FIRES is definitely one of them. But there's other things too that you want to consider and not just anchor on one diagnosis. So, you also want to consider if this could be some kind of paraneoplastic autoimmune phenomenon and you would like to send in the blood the Mayo autoimmune paraneoplastic panel in addition to sending it in the cerebral spinal fluid because there are some autoantibodies that are more sensitive in the cerebrospinal fluid and some that are more sensitive in the serum. So, you want to send off both.
So for her, we did repeat the lumbar puncture because there were some tests that were sent at the outside hospital, but we wanted to be definitive that it didn't seem like more infectious component, which is why we also got our infectious disease colleagues involved making sure that we were sending off all the right testing, not just for the common things that we see, but some that are maybe a little less common, but are endemic to our region and as well as to the season that she presented. So, we definitely wanted to consider arboviruses and also wanted to consider could this potentially be a more insidious fungal phenomenon? So, you wanted to send off all those things. Because if it were infectious, then you definitely want to treat the underlying infection. And there are times when it's a more uncommon infection causing the symptoms, which if you miss that component and you kind of go down a rabbit hole of this inflammatory, paraneoplastic component, then you're not adequately treating the patient, which is why we repeated the lumbar puncture, making sure to check those labs and also sending off the Mayo autoimmune paraneoplastic panel.
Also, we sent off cytokines because maybe Dr. VanHaerents can talk about this a little bit later, but the cytokines really help us see if there is something that's a little bit more rare or more inflammatory that is happening in this particular patient. She was put on EEG just to see what the pattern of her EEG was, and also to make sure that we tried to control her seizures as best as we could. And the way that her EEG looked, it wasn't just one seizure pattern, which also made us more concerned that there was something that was happening that was more of an inflammatory autoimmune condition. And if you think that someone has an inflammatory autoimmune paraneoplastic condition, you want to look to see if they have a systemic situation that's happening. So, we did a CT chest, abdomen, and pelvis looking for occult malignancies, sent off a CSF for cytology and flow. Also, she had a bone marrow biopsy as well at the outside hospital. And we got a repeat pelvic ultrasound as we know that when patients can have ovarian teratomas that can be associated with auto-antibody generation. And all of that was really unrevealing in terms of that imaging, looking for an acute malignancy or some kind of systemic autoimmune condition.
Dr. Andrew Wilner: Okay. So mega workup, took weeks. At least in my institution, those are all sendouts. You don't get them back the next day. So Dr. Yu, after you ordered all these panels and these tests, how did you make the definitive diagnosis of FIRES?
Dr. Margaret Yu: Yes. The first thing to do is to rule out the things that it wasn't, the infectious component, the more structural component, MRI was negative; vessel imaging, unrevealing; no evidence of a sinus thrombosis. And then with the cerebrospinal fluid, we did these send out tests, which often take many days to come back. But one of the tests that we sent out under the guidance of Dr. VanHaerents were the CSF cytokines with the hypothesis being that when there's this strong dysregulated immune hyperactivation, your cytokines elevate when that is present and that can be seen in FIRES. It's not saying that everybody who comes in with a cytokine elevation in their spinal fluid has FIRES, but it is strongly suggestive that there is this kind of inflammatory immune hyperactivation that is present in the right clinical picture.
Dr. Andrew Wilner: Okay. So, I guess the cytokines were elevated, right?
Dr. Margaret Yu: Correct.
Dr. Andrew Wilner: So, is there an anti-cytokine potion? What do you do now?
Dr. Margaret Yu: Yeah. So before we got the cytokines that were even elevated, we had been in close contact with our epilepsy team, and the idea was that it just smelled like this was some kind of inflammatory immune-mediated process. So, we already started with immunomodulating treatments with IV steroids as well as IViG. However, before the cytokines came back, we didn't say we were going to start something for FIRES. But when they came back elevated and she really fit into that clinical picture, then we started the drug called anakinra, which is an inhibitor of IL-1 and has been shown to be helpful in these kinds of situations, mostly in the pediatric population more so, as it is more commonly seen in the pediatric population.
Dr. Andrew Wilner: Wow. So, real state-of-the-art therapy. So, how did she do?
Dr. Margaret Yu: She did really well on the inpatient side. Initially, it was so scary with all these seizures, but we had a great team working to stabilize her and make sure that she was doing well, and we had our great nurses and our techs who monitored her so closely. And most of all, we have a world-renowned expert in autoimmune epilepsy, Dr. VanHaerents, who's really been involved in her case since the beginning. And since he was involved, he knew her case very well. And when she transitioned to the outpatient setting, it was a very smooth transition.
Dr. Andrew Wilner: Dr. VanHaerents, give us an update. How is she doing?
Dr. Stephen VanHaerents: So, she's been doing remarkably well. You know, as most patients with FIRES, she had a road of recovery afterwards. But she's been returning back to school, she's been taking full-time classes, she's back to playing Division I volleyball. She has had a couple breakthrough seizures, but obviously not back in status or in the ICU. And we've been titrating medications for her tolerance and have also been lowering the anakinra as well.
Dr. Andrew Wilner: Well, that's fantastic. And she's, I guess, just on one or two anti-seizure drugs now instead of four?
Dr. Stephen VanHaerents: Well, she was on five. And now, she's on three and a half, I guess I would say. So, we are making progress. But as you know, it is a slow process. It's not one that can be done quickly. And like many patients post-NORSE and/or FIRES, they're not cured per se in that many of them will go on to have lifelong epilepsy as a result.
Dr. Andrew Wilner: All right. Let me ask both of you to address this question as you wish. What can neurologists learn about this case? What are the key takeaways?
Dr. Stephen VanHaerents: I would say despite proposed algorithms, up to 40% of status epilepticus patients will remain refractory. And delayed etiology and recognition, particularly autoimmune causes can contribute to poor outcome. So, I would say to keep autoimmune and autoinflammatory causes in your differential when seeing a status epilepticus patient and recognize that about half of these, if you do see, you know, an adult NORSE patient, that their etiologies can remain unknown. But we have now published recommendations and guidelines, which are based a lot on case reports, but you know, a lot of expert opinion on how to guide these therapies moving forward. And hopefully, more research down the line will better solidify these treatment options.
Dr. Andrew Wilner: One practical point, I'm curious, the next time I do an LP in a status patient, should I send it for cytokines? Is that something that's readily available?
Dr. Stephen VanHaerents: So, I wouldn't say it's readily available. And not every institution can send them off. You know, we're lucky that we can, although there is a delay in getting them back. So, I don't think that that should preclude you from treatment. When I advise people on what to do in these cases, first once you've stabilized a seizures with either using, anesthetic drugs, if once you kind of have gone through that diagnostic algorithm looking for if this was, as Dr. Yu pointed out, like paraneoplastic and you've done the cancer screens, you've looked for like is there any inborn errors in metabolism? Is this an immunocompromised patient? Is this infectious? Does this seem like it's a mitochondrial disorder? Once you've kind of gone through that diagnostic algorithm and these maintain being cryptogenic or an unknown etiology that you really want to start initiating these immune therapies. And as Dr. Yu said, in this case, we start typically with either steroids or intravenous immunoglobulins. But you know, if you get an incomplete response, that's when you wanna start things like ketogenic diet. And if there's no antibody confirmed or you don't have it back yet, to start these pro-convulsant cytokine inhibitors like anakinra, which is an IL-1 receptor antagonist or tocilizumab, which is an IL-6 antagonist. So, I would say yes, but you also have to know what you're sending as well and how these patients can also develop ICU infections and other things that can also change these kind of cytokines so they do have a limited use if not tested very early.
Dr. Andrew Wilner: Okay. Well, Dr. VanHaerents, I want to thank you very much for those recommendations. Thanks again to both of you, Dr. VanHaerents and Dr. Yu, for joining me today on Better Edge.
Dr. Margaret Yu: Thank you so much.
Dr. Andrew Wilner: To refer your patient or for more information, head on over to our website at BreakthroughsforPhysicians.NM.Org/Neuro to get connected with one of our providers. And that wraps up this episode of Better Edge, a Northwestern Medicine Podcast for physicians. I'm your host, Dr. Andrew Wilner. Thank you for listening.