Febrile Infection-related Epilepsy Syndrome Research Articles

Steroid-Responsive Involuntary Movements as a Remote Symptom of Febrile Infection-Related Epilepsy Syndrome

Steroid-Responsive Involuntary Movements as a Remote Symptom of Febrile Infection-Related Epilepsy Syndrome

NORSE seasonality may vary geographically in adults.

The mechanisms causing new onset refractory status epilepticus (NORSE) are often unknown. Recently, a seasonal variation with NORSE peaking during the summer was described in a mixed cohort of adults and children why we here studied the seasonal variation in a Danish status epilepticus (SE) cohort. This retrospective cohort study comprised SE patients aged ≥18 diagnosed and treated 2008-2017 at the Odense University Hospital. Clinical characteristics and seasonality of patients fulfilling the diagnostic criteria for NORSE were compared with patients with refractory SE (RSE) due to other reasons and with the seasonal variation of autoantibodies associated with autoimmune encephalitis in the Danish autoimmune encephalitis register. In this cohort, 26 patients met NORSE criteria. As compared to RSE patients not fulfilling NORSE criteria (n = 152), NORSE patients were more likely to have symptoms of systemic inflammation (C-reactive protein concentrations ≥10 mg/L or fever ≥38°C) at admission; nine fulfilled the criteria for febrile infection related epilepsy syndrome (FIRES). In contrast to the even seasonal distribution of patients with RSE not fulfilling the NORSE criteria, admissions due to NORSE peaked during the winter (46.1%, p = 0.04 as compared to non-NORSE RSE); six out of nine FIRES episodes occurred in the winter season. The seasonal variation was not explained by a seasonal variation of the detection rates of autoantibodies associated with autoimmune encephalitis (incl. NMDAR, LGI1, CASPR2, GABAR, GFAP) in a Danish nationwide register (n = 259). In conclusion, we confirm the seasonality of NORSE in a Danish cohort, however, with a peak during winter suggesting a geographical variation not solely explained by autoimmune encephalitis associated with known autoantibodies. PLAIN LANGUAGE SUMMARY: The study investigated the seasonal patterns of new-onset refractory status epilepticus (NORSE), i.e. severe seizures that occur without an obvious cause and require very intensive treatment. In contrast to the previously observed peak frequency in summer, this Danish study found that NORSE cases peak in winter. Furthermore, the seasonal variation in NORSE cases was not found to be associated with autoimmune encephalitis caused by known autoantibodies. Together with the high rate of patients showing symptoms of systemic inflammation compared to other status epilepticus patients, the data suggest a link between misdirected immune system responses and NORSE. The study can therefore help in the further search for the currently unknown causes of NORSE.

Comparative analysis of patients with new onset refractory status epilepticus preceded by fever (febrile infection-related epilepsy syndrome) versus without prior fever: An interim analysis.

Febrile infection-related epilepsy syndrome (FIRES) is a subset of new onset refractory status epilepticus (NORSE) that involves a febrile infection prior to the onset of the refractory status epilepticus. It is unclear whether FIRES and non-FIRES NORSE are distinct conditions. Here, we compare 34 patients with FIRES to 30 patients with non-FIRES NORSE for demographics, clinical features, neuroimaging, and outcomes. Because patients with FIRES were younger than patients with non-FIRES NORSE (median = 28 vs. 48 years old, p = .048) and more likely cryptogenic (odds ratio = 6.89), we next ran a regression analysis using age or etiology as a covariate. Respiratory and gastrointestinal prodromes occurred more frequently in FIRES patients, but no difference was found for non-infection-related prodromes. Status epilepticus subtype, cerebrospinal fluid (CSF) and magnetic resonance imaging findings, and outcomes were similar. However, FIRES cases were more frequently cryptogenic; had higher CSF interleukin 6, CSF macrophage inflammatory protein-1 alpha (MIP-1a), and serum chemokine ligand 2 (CCL2) levels; and received more antiseizure medications and immunotherapy. After controlling for age or etiology, no differences were observed in presenting symptoms and signs or inflammatory biomarkers, suggesting that FIRES and non-FIRES NORSE are very similar conditions.

Efficacy and safety of ketamine for pediatric and adolescent super-refractory status epilepticus and the effect of cerebral inflammatory conditions

ObjectiveTo investigate the short-term benefits and adverse effects of ketamine in the treatment of pediatric and adolescent super-refractory status epilepticus (SRSE), with a focus on the inflammatory etiology. MethodsThis retrospective observational cohort study included a consecutive series of 18 pediatric to adolescent patients with SRSE admitted between 2008 and 2023 and treated with ketamine. Seizure frequency per hour before and after ketamine administration and response rate were calculated. Neurological decline, catecholamine administration, and adverse effects were also assessed. The patients were divided into inflammatory and non-inflammatory etiology groups. ResultsThe median age at SRSE onset was 1 year 5 months (range: 11 days-24 years), and 78% of the patients were male individuals. The median duration of treatment was 7.5 days (interquartile range: 2.8–15.5 days). Fifteen (83%) patients achieved >50% seizure reduction. The median seizure frequency before and after ketamine treatment was 5.9 and 0.9, respectively, showing a significant reduction in seizure frequency (p < 0.0001). Ten patients had inflammatory etiologies including bacterial meningitis (n = 2), viral encephalitis (n = 3), and febrile infection related epilepsy syndrome (n = 5). The inflammatory etiology group required a longer treatment duration (p = 0.0453) and showed lower seizure reduction (p = 0.0264), lower response rate (p = 0.0044), and higher neurological decline (p = 0.0003) than the non-inflammatory etiology group. Three (17%) patients experienced transient adverse events requiring intervention within 24 h of initiating ketamine administration. ConclusionsKetamine administration was associated with fewer serious adverse events and a reduced seizure frequency. Additionally, inflammatory conditions may weaken the efficacy of ketamine in patients with SRSE.

Second-line immunotherapy in new onset refractory status epilepticus.

Several pieces of evidence suggest immune dysregulation could trigger the onset and modulate sequelae of new onset refractory status epilepticus (NORSE), including its subtype with prior fever known as febrile infection-related epilepsy syndrome (FIRES). Consensus-driven recommendations have been established to guide the initiation of first- and second-line immunotherapies in these patients. Here, we review the literature to date on second-line immunotherapy for NORSE/FIRES, presenting results from 28 case reports and series describing the use of anakinra, tocilizumab, or intrathecal dexamethasone in 75 patients with NORSE. Among them, 52 patients were managed with anakinra, 21 with tocilizumab, and eight with intrathecal dexamethasone. Most had elevated serum or cerebrospinal fluid cytokine levels at treatment initiation. Treatments were predominantly initiated during the acute phase of the disease (92%) and resulted, within the first 2 weeks, in seizure control for up to 73% of patients with anakinra, 70% with tocilizumab, and 50% with intrathecal dexamethasone. Cytokine levels decreased after treatment for most patients. Anakinra and intrathecal dexamethasone were mainly initiated in children with FIRES, whereas tocilizumab was more frequently prescribed for adults, with or without a prior febrile infection. There was no clear correlation between the response to treatment and the time to initiate the treatment. Most patients experienced long-term disability and drug-resistant post-NORSE epilepsy. Initiation of second-line immunotherapies during status epilepticus (SE) had no clear effect on the emergence of post-NORSE epilepsy or long-term functional outcomes. In a small number of cases, the initiation of anakinra or tocilizumab several years after SE onset resulted in a reduction of seizure frequency for 67% of patients. These data highlight the potential utility of anakinra, tocilizumab, and intrathecal dexamethasone in patients with NORSE. There continues to be interest in the utilization of early cytokine measurements to guide treatment selection and response. Prospective studies are necessary to understand the role of early immunomodulation and its associations with epilepsy and functional outcomes.

Febrile infection-related epilepsy syndrome with claustrum lesion: an underdiagnosed inflammatory encephalopathy

Febrile infection-related epilepsy syndrome with claustrum lesion: an underdiagnosed inflammatory encephalopathy

Management strategies for refractory status epilepticus

Refractory status epilepticus (RSE) is defined as the persistence of either clinical or electrographic seizures despite the administration of appropriate doses of an initial benzodiazepine and suitable second-line antiepileptic drugs (AEDs). The Neurocritical Care Society and the American Epilepsy Society have proposed a treatment paradigm for the management of convulsive status epilepticus (CSE). The third-line therapy in refractory CSE may involve general anesthesia using intravenous midazolam, propofol, or other agents, while recent evidence supports the use of ketamine to manage RSE in both adults and children. However, although these treatment strategies are frequently employed in nonconvulsive status epilepticus (NCSE), the efficacy of AEDs and anesthetics in NCSE has not been thoroughly investigated. Recent evidence has demonstrated the safety and efficacy of newer AEDs, including levetiracetam and lacosamide, in the treatment of status epilepticus (SE) and RSE, which also encompasses NCSE. Use of multiple combinations of various intravenous AEDs can also be considered in NCSE before the administration of general anesthesia. In addition, AEDs alone exhibit limited effectiveness in managing SE for new-onset RSE (NORSE) and its subset, febrile infection-related epilepsy syndrome. Therefore, in cases of refractory status, it is imperative to explore treatment options beyond AEDs, including immunotherapy and the incorporation of a ketogenic diet. The present review suggests treatment approaches for RSE based on subgroups, including CSE, NCSE, and NORSE. A discussion of recent clinical studies on AEDs and anesthetics in the management of RSE, as well as proposed treatment methods for NORSE, is also provided.

Neuroinflammation and status epilepticus: a narrative review unraveling a complex interplay

Status epilepticus (SE) is a medical emergency resulting from the failure of the mechanisms involved in seizure termination or from the initiation of pathways involved in abnormally prolonged seizures, potentially leading to long-term consequences, including neuronal death and impaired neuronal networks. It can eventually evolve to refractory status epilepticus (RSE), in which the administration of a benzodiazepine and another anti-seizure medications (ASMs) had been ineffective, and super-refractory status epilepticus (SRSE), which persists for more than 24 h after the administration of general anesthesia. Objective of the present review is to highlight the link between inflammation and SE. Several preclinical and clinical studies have shown that neuroinflammation can contribute to seizure onset and recurrence by increasing neuronal excitability. Notably, microglia and astrocytes can promote neuroinflammation and seizure susceptibility. In fact, inflammatory mediators released by glial cells might enhance neuronal excitation and cause drug resistance and seizure recurrence. Understanding the molecular mechanisms of neuroinflammation could be crucial for improving SE treatment, wich is currently mainly addressed with benzodiazepines and eventually phenytoin, valproic acid, or levetiracetam. IL-1β signal blockade with Anakinra has shown promising results in avoiding seizure recurrence and generalization in inflammatory refractory epilepsy. Inhibiting the IL-1β converting enzyme (ICE)/caspase-1 is also being investigated as a possible target for managing drug-resistant epilepsies. Targeting the ATP-P2X7R signal, which activates the NLRP3 inflammasome and triggers inflammatory molecule release, is another avenue of research. Interestingly, astaxanthin has shown promise in attenuating neuroinflammation in SE by inhibiting the ATP-P2X7R signal. Furthermore, IL-6 blockade using tocilizumab has been effective in RSE and in reducing seizures in patients with febrile infection-related epilepsy syndrome (FIRES). Other potential approaches include the ketogenic diet, which may modulate pro-inflammatory cytokine production, and the use of cannabidiol (CBD), which has demonstrated antiepileptic, neuroprotective, and anti-inflammatory properties, and targeting HMGB1-TLR4 axis. Clinical experience with anti-cytokine agents such as Anakinra and Tocilizumab in SE is currently limited, although promising. Nonetheless, Etanercept and Rituximab have shown efficacy only in specific etiologies of SE, such as autoimmune encephalitis. Overall, targeting inflammatory pathways and cytokines shows potential as an innovative therapeutic option for drug-resistant epilepsies and SE, providing the chance of directly addressing its underlying mechanisms, rather than solely focusing on symptom control.

Reply to the article entitled “International consensus recommendations for management of new onset refractory status epilepticus (NORSE) including febrile infection-related epilepsy syndrome (FIRES): Summary and clinical tools”. Doi: 10.1111/epi.17391

Reply to the article entitled “International consensus recommendations for management of new onset refractory status epilepticus (NORSE) including febrile infection-related epilepsy syndrome (FIRES): Summary and clinical tools”. Doi: 10.1111/epi.17391

Spectrum, Evolution, and Clinical Relationship of Magnetic Resonance Imaging in 31 Children with Febrile Infection-Related Epilepsy Syndrome.

Describing spectrum, evolution, and clinical relationship of brain magnetic resonance imaging (MRI) findings in a large case series of children with febrile infection-related epilepsy syndrome (FIRES). This retrospective study included 31 children with FIRES. Clinical data and MRI findings of the brain were evaluated. Poor clinical outcome was defined as severe disability, persistent vegetative state or stupor, very low intelligence quotient (<80), or death (modified Rankin scale 4-6 and Glasgow Outcome Score 1-3). Seventeen (54.8%) children with FIRES showed no abnormalities in the initial MRI, whereas 28 (90.3%) children showed MRI abnormalities at follow-up. The most frequent abnormalities were brain atrophy (74.2%) and T2/fluid-attenuated inversion recovery changes (64.5%), mostly hippocampal (45.2%). Generalized brain atrophy was the most frequent type of atrophy (58%). The earliest atrophy was recorded 9 days after the onset of disease. It progressed even beyond the acute phase in most children (51.6%). The exploratory data analysis revealed nominal significance between all MRI abnormalities considered together and poor outcome (p = 0.049) and between generalized brain atrophy and anesthesia (p = 0.024). After adjustment for multiple testing, the p-values were not significant. The outcome in four (12.9%) children was not poor despite generalized brain atrophy. In contrast to the uniform clinical course, MRI demonstrated a broad spectrum of findings. Initially, these were mostly normal and therefore indicative of FIRES but then changed rapidly and were mostly progressive despite the stable chronic course. The cause may be ongoing disease, treatment intensity, or both. Future studies should focus on what process underlies the onset and the progression of brain atrophy. However, brain atrophy was not always related to poor outcomes in children despite FIRES.

Severe and rare neurological manifestations following COVID-19 infection in children: A Malaysian tertiary centre experience

IntroductionSince the emergence of COVID-19, we have experienced potent variants and sub-variants of the virus with non-specific neurological manifestations. We observed a surge of the Omicron variant of COVID-19 patients with neurological manifestations where less cases of multisystem inflammatory syndrome in children (MIS-C) were reported. This article describes our experience of children with severe and rare neurological manifestations following COVID-19 infection. MethodsThis is a retrospective observational case series of patients under 18 years old who fulfilled the WHO COVID-19 case definition and were referred to our paediatric neurology unit at Hospital Tunku Azizah Kuala Lumpur. Their demographic data, neurological symptoms, laboratory and supporting investigations, neuroimaging, treatment and outcomes were collected and analysed. ResultsThere were eleven patients with neurological manifestations who fulfilled the WHO COVID-19 case definition. Nine patients presented with seizures and/or encephalopathy, one patient with eye opsoclonus and another patient with persistent limbs myokymia. Based on the history, clinical, electrophysiological and radiological findings, two of them had febrile infection-related epilepsy syndrome, two had acute disseminated encephalomyelitis, two had acute necrotising encephalopathy of childhood, one each had hemiconvulsion-hemiplegia-epilepsy syndrome, acute encephalopathy with bilateral striatal necrosis, hemi-acute encephalopathy with biphasic seizures and reduced diffusion, infection-associated opsoclonus and myokymia. ConclusionsThis case series highlighted a wide spectrum of neurological manifestations of COVID-19 infection. Early recognition and prompt investigations are important to provide appropriate interventions. It is essential that these investigations should take place in a timely fashion and COVID-19 quarantine period should not hinder the confirmation of various presenting clinical syndromes.

Real-world experience with cannabidiol as add-on treatment in drug-resistant epilepsy

PurposeTo evaluate the efficacy and safety of cannabidiol (CBD) for the treatment of epilepsy in a real-world setting. MethodsIn this retrospective observational study, we included PwE with epilepsy who received a prescription for CBD between 01.03.2019 and 30.11.2022 and had a follow-up period ≥ 3 months. Participants were evaluated at baseline and after 3, 6, and 12 months. "Responders" were defined as individuals experiencing a reduction in seizure frequency > 30% but < 80% compared to baseline, while "super responders" were those with a reduction ≥ 80%. Adverse events were recorded to assess safety. ResultsForty-two PwE were included (mean age 36.1 ± 10.9 years; 14 females). In 24 patients CBD was prescribed on-label (Lennox-Gastaut syndrome, n = 18; Dravet syndrome, n = 5; tuberous sclerosis, n = 1), while 18 patients were treated off-label (ring chromosome 20 syndrome, n = 1; ring chromosome 17 syndrome, n = 1; Lafora disease, n = 3; Unverricht-Lundborg disease, n = 1; polymicrogyria, n = 2; febrile infection-related epilepsy syndrome, n = 1; non-lesional focal epilepsy, n = 2; developmental and/or epileptic encephalopathy of unknown etiology n = 6). The mean number of concomitant antiseizure medications was 3.4 (≥2 for all patients). At 3 months, 10 subjects (23%) were “responders” and 12 (29%) were “super-responders”. Efficacy was sustained at 6 and 12 months of follow-up. Twenty-two patients (52.3%) developed AEs, with drowsiness (36.5%) and diarrhea (9.8%) being the most common. The retention rate was 85.7%, 78.6%, and 71.4% at 3, 6, and 12 months, respectively. ConclusionsIn this monocentric real-world study, CBD was a safe and effective therapeutic option for highly drug-resistant patients, leading to a dramatic reduction in seizure frequency in over one-fourth of them, including off-label indications.

No evidence of neuronal/glial autoantibodies in febrile infection-related epilepsy syndrome (FIRES): a prospective clinic-serologic analysis.

The pediatric febrile infection-related epilepsy syndrome (FIRES) manifests with encephalopathy with super-refractory status epilepticus (SE) a few days after or accompanying a febrile illness. It often results in refractory epilepsy and cognitive dysfunction in previously healthy children and adolescents. The underlying pathomechanism is unknown, which is why causative neuronal and/or synaptic antibodies have been discussed. We report a prospective consecutive cohort of 14 children (10 male, four female) diagnosed with FIRES in the acute phase, whose serum and CSF were comprehensively screened for underlying synaptic/neuronal autoantibodies. The median age at onset was 6 years (range 4-9 years). None of the children had a medical history of epilepsy. Duration of SE varied from less than 1 week to 2.5 months (Median: 1 month, range < 1 week-2.5 months). Clinical response to treatment with antiseizure medications was poor as well as the outcome: one child died in the acute phase of SE, and two died in the long term. All surviving children showed neuropsychological impairments. No underlying synaptic or neuronal autoantibodies were identified in 13 of 14 children's sera or CSF. One child had currently uncharacterized neuronal autoantibodies in CSF, yet clinical presentation was atypical for FIRES. Based on our findings, the child was later diagnosed with autoimmune encephalitis (AE). We conclude that FIRES is not an autoantibody-mediated disease. However, a comprehensive screening for known and yet unknown antineuronal antibodies in serum and CSF is warranted to rule out AE mimicking FIRES.

CSF neopterin and quinolinic acid are biomarkers of neuroinflammation and neurotoxicity in FIRES and other infection-triggered encephalopathy syndromes.

Infection-triggered encephalopathy syndromes (ITES) are potentially devastating neuroinflammatory conditions. Although some ITES syndromes have recognisable MRI neuroimaging phenotypes, there are otherwise few biomarkers of disease. Early detection to enable immune modulatory treatments could improve outcomes. We measured CSF neopterin, quinolinic acid, kynurenine and kynurenine/tryptophan ratio using a liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) system. The CSF of 18 children with ITES were compared with acute encephalitis (n = 20), and three control groups, namely epilepsy (n = 20), status epilepticus (n = 18) and neurogenetic controls (n = 20). The main ITES phenotypes in 18 patients were acute encephalopathy with biphasic seizures and late restricted diffusion (AESD, n = 4), febrile infection-related epilepsy syndrome (FIRES n = 4) and other ITES phenotypes. Influenza A was the most common infectious trigger (n = 5), and 50% of patients had a preceding notable neurodevelopmental or family history. CSF neopterin, quinolinic acid and kynurenine were elevated in ITES group compared to the three control groups (all p < 0.0002). The ROC (area under curve) for CSF neopterin (99.3%, CI 98.1-100) was significantly better than CSF pleocytosis (87.3% CI 76.4-98.2) (p = 0.028). Elevated CSF neopterin could discriminate ITES from other causes of seizures, status epilepticus and febrile status epilepticus (all p < 0.0002). The elevated CSF metabolites normalised during longitudinal testing in two patients with FIRES. CSF neopterin and quinolinic acid are neuroinflammatory and excitotoxic metabolites. This CSF metabolomic inflammatory panel can discriminate ITES from other causes of new onset seizures or status epilepticus, and rapid results (4 h) may facilitate early immune modulatory therapy.

Claustrum sign in febrile infection-related epilepsy syndrome (FIRES).

Claustrum sign in febrile infection-related epilepsy syndrome (FIRES).

Interleukin-1 in Febrile Infection-Related Epilepsy Syndrome

Febrile infection-related epilepsy syndrome (FIRES) characteristically affects previously healthy children, who experience a sudden and explosive onset of super-refractory status epilepticus preceded by febrile infection and accompanied by fulminant neurogenic inflammation. FIRES, however, can affect individuals of all ages and is a subcategory of new-onset refractory status epilepticus. This definition of FIRES excludes febrile status epilepticus in infants. FIRES is a rare type of epileptic encephalopathy with rapidly progressive onset of seizures and a devastating prognosis, as drug-resistant epilepsy often follows without a latency period. Although the exact pathogenesis of FIRES has not been elucidated, a functional deficiency in the endogenous interleukin-1 receptor antagonist has been implicated in a genetic predisposition to FIRES. Dysregulation of the interleukin-1β–interleukin-1 receptor 1 (IL-1β–IL-1R1) signaling pathway appears to be involved in the pathogenesis of FIRES. In this review, the authors summarize the definition of FIRES, IL-1β–IL-1R1 signaling, the nucleotide-binding oligomerization domain the NLRP3 inflammasome, and IL-1 targeted therapy for FIRES.

A practical approach to in-hospital management of new-onset refractory status epilepticus/febrile infection related epilepsy syndrome.

New-onset refractory status epilepticus (NORSE) is "a clinical presentation, not a specific diagnosis, in a patient without active epilepsy or other preexisting relevant neurological disorder, with new onset of refractory status epilepticus without a clear acute or active structural, toxic, or metabolic cause." Febrile infection related epilepsy syndrome (FIRES) is "a subcategory of NORSE that requires a prior febrile infection, with fever starting between 2 weeks and 24 h before the onset of refractory status epilepticus, with or without fever at the onset of status epilepticus." These apply to all ages. Extensive testing of blood and CSF for infectious, rheumatologic, and metabolic conditions, neuroimaging, EEG, autoimmune/paraneoplastic antibody evaluations, malignancy screen, genetic testing, and CSF metagenomics may reveal the etiology in some patients, while a significant proportion of patients' disease remains unexplained, known as NORSE of unknown etiology or cryptogenic NORSE. Seizures are refractory and usually super-refractory (i.e., persist despite 24 h of anesthesia), requiring a prolonged intensive care unit stay, often (but not always) with fair to poor outcomes. Management of seizures in the initial 24-48 h should be like any case of refractory status epilepticus. However, based on the published consensus recommendations, the first-line immunotherapy should begin within 72 h using steroids, intravenous immunoglobulins, or plasmapheresis. If there is no improvement, the ketogenic diet and second-line immunotherapy should start within seven days. Rituximab is recommended as the second-line treatment if there is a strong suggestion or proof of an antibody-mediated disease, while anakinra or tocilizumab are recommended for cryptogenic cases. Intensive motor and cognitive rehab are usually necessary after a prolonged hospital stay. Many patients will have pharmacoresistant epilepsy at discharge, and some may need continued immunologic treatments and an epilepsy surgery evaluation. Extensive research is in progress now via multinational consortia relating to the specific type(s) of inflammation involved, whether age and prior febrile illness affect this, and whether measuring and following serum and/or CSF cytokines can help determine the best treatment.

The NORSE/FIRES Family Registry: Comparing new-onset refractory status epilepticus (NORSE) without preceding fever to febrile infection-related epilepsy syndrome (FIRES) (P9-1.003)

<h3>Objective:</h3> In this work, we compare differences in clinical presentation, survivorship, and quality of life in people with new-onset refractory status epilepticus (NORSE) without preceding fever to febrile infection-related epilepsy syndrome (FIRES). <h3>Background:</h3> NORSE is a clinical presentation affecting previously healthy adults and children. FIRES is a subcategory of NORSE and applies when a preceding fever occurs within 24h to 2 weeks prior to the onset of NORSE. FIRES is thought to be more common in children and robust data describing FIRES in adults is lacking. <h3>Design/Methods:</h3> Survivors, surrogates, and physicians can enter data into a registry via a link on the NORSE Institute Webpage (https://www.norseinstitute.org/norse-registry-2). The registry collects the following information: past medical history, clinical presentation, disease course, survivorship, clinical sequelae and quality of life, among others. Participants are invited to complete follow-up surveys for up to two years following clinical presentation of seizures. <h3>Results:</h3> To date, there are 69 participants and 46/69 are survivors in the registry. There are 28 adults (18 survivors) and 41 children (28 survivors). 60/69 (87%) patients had a preceding fever, meeting the criteria for FIRES, with significantly more children having a preceding fever (p &lt; 0.001; 19/28 or 68% adults, 40/41 or 98% children). Adults with FIRES more often had fatigue (p &lt; 0.01) compared to adults with NORSE without fever. Adults with FIRES more often had flu-like illness (p &lt; 0.0001) as presenting symptoms compared to children with FIRES. The presence or absence of fever was not associated with the likelihood of survival, number of seizures per month or quality of life in adults. <h3>Conclusions:</h3> These data suggest that FIRES is common in adults and children presenting with NORSE. Further prospective epidemiologic studies will be important to determine the incidence and prevalence of adult FIRES and whether fever is relevant to management or outcomes associated with NORSE. <b>Disclosure:</b> Mr. Kazazian has nothing to disclose. Prof. Gaspard has nothing to disclose. Dr. Hirsch has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Aquestive. Dr. Hirsch has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Ceribell. Dr. Hirsch has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for marinus. Dr. Hirsch has received personal compensation in the range of $0-$499 for serving as a Consultant for Medtronic. Dr. Hirsch has received personal compensation in the range of $500-$4,999 for serving as a Consultant for UCB. Dr. Hirsch has received personal compensation in the range of $0-$499 for serving as a Consultant for Accure. Dr. Hirsch has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Neuropace. Dr. Hirsch has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Neurelis. Dr. Hirsch has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Eisai. Dr. Hirsch has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Rafa Laboratories, Ltd. Dr. Hirsch has received publishing royalties from a publication relating to health care. Dr. Hirsch has received publishing royalties from a publication relating to health care. Dr. Hirsch has received personal compensation in the range of $500-$4,999 for serving as a Speaker with Neuropace. Dr. Hirsch has received personal compensation in the range of $500-$4,999 for serving as a Speaker with Natus. Dr. Hirsch has received personal compensation in the range of $500-$4,999 for serving as a speaker with UCB. Dr. Kellogg has nothing to disclose. The institution of Dr. Hocker has received research support from Yale University. Dr. Hocker has received publishing royalties from a publication relating to health care. Ms. Wong has nothing to disclose. Dr. Farias-Moeller has nothing to disclose. The institution of Dr. Eschbach has received research support from Neurocrine Biosciences. The institution of Dr. Eschbach has received research support from UCB Biopharma. Dr. Eschbach has a non-compensated relationship as a Medical Science Advisory Board Member with NORSE Institute that is relevant to AAN interests or activities. The institution of Dr. Gofton has received research support from Government of Canada. The institution of Dr. Gofton has received research support from Canadian Institutes of Health Research. The institution of Dr. Gofton has received research support from Academic Medical Organisation of Southwestern Ontario. Dr. Gofton has a non-compensated relationship as a Medical Advisory Board Member with NORSE Institute that is relevant to AAN interests or activities.

Clinical features and biomarkers of acute encephalitis with claustrum sign (P5-5.027)

<h3>Objective:</h3> To determine clinical features and biomarkers of acute encephalitis with claustrum sign on brain MRI and to clarify the pathogenetic mechanism. <h3>Background:</h3> The claustrum sign has been described as reversible bilateral claustrum MRI hyperintensity on a T2-weighted MRI image. This finding has been reported in acute encephalitis, including acute necrotizing encephalopathy, febrile infection–related epilepsy syndrome, a subcategory of new-onset refractory status epilepticus. <h3>Design/Methods:</h3> We retrospectively analyzed the clinical features and cerebrospinal fluid (CSF) findings of three patients with acute encephalitis with claustrum sign. <h3>Results:</h3> All patients had prior symptoms suspected of infection, including fever, cough, and general fatigue. Two patients had meningeal signs and refractory status epilepticus. One patient had pyramidal signs and tremor. Claustrum sign was noted at 8, 28, and 52 days after the onset. In CSF, a glial fibrillary acidic protein (GFAP) antibody was detected in one patient with pyramidal signs and tremor. The other two patients had no antineuronal antibodies detected by tissue-based immunofluorescence assay using frozen rat brain sections. Compared with GFAP antibody-negative patients, GFAP antibody-positive patients had increased levels of CSF cell counts (antibody-positive vs antibody-negative; 127/μL vs 13 and 32/μL), protein concentrations (157 mg/dL vs 39 and 58 mg/dL), and tumor necrosis factor α (25.3 pg/mL vs 2.82 and 2.95 pg/mL). Interleukin 6 (IL-6) in CSF with GFAP antibody-negative patients was significantly higher than those with antibody-positive patients (195 and 609 pg/mL vs. 19.2 pg/mL). All patients required ventilator management and received immunotherapies. Two GFAP antibody-negative patients had improved, but a GFAP antibody-positive patient had died due to pneumonia. <h3>Conclusions:</h3> Acute encephalitis with claustrum sign is associated with at least increased levels of IL6 and GFAP antibody (i.e., GFAP astrocytopathy). In addition to CSF cytokine measurements, it is considered that GFAP antibody measurements should be performed in this disorder. <b>Disclosure:</b> Dr. Shimohata has nothing to disclose. Akira Takekoshi has nothing to disclose. Kimihiko Kaneko has nothing to disclose. Juichi Fujimori has nothing to disclose. Dr. Ioku has nothing to disclose. Keisuke Imai has nothing to disclose. Dr. Kimura has nothing to disclose.

Cannabidiol in the acute phase of febrile infection-related epilepsy syndrome (FIRES).

Febrile infection-related epilepsy syndrome (FIRES) is a prolonged refractory status epilepticus (SE) that develops among healthy individuals after a febrile infection. FIRES treatment is challenging due to its poor response to antiseizure medications (ASMs) and anesthetic drugs. The use of cannabidiol (CBD) as an adjunctive treatment has been suggested, albeit data about its role in the acute phase is lacking. This report describes the use of purified CBD in the acute phase of two pediatric cases of FIRES and their long-term outcome. Both children were treated with several ASMs, immunomodulators, anesthetics, and nonpharmacological treatment (ketogenic diet). CBD was administered, as an adjunctive treatment, through nasogastric tube about 30 days after onset. SE resolved within 3 days of reaching the target dose and both were seizure-free for 1 year after. Although it is difficult to define the extent to which each previous therapy contributed to recovery, in both cases CBD therapy was a turning point, reinforcing its potential role as add-on treatment in the acute phase of FIRES.