Successful Use of Tocilizumab in a 2‐Year‐Old Girl With Probable C‐ NORSE / FIRES : A Case Report

New-Onset Refractory Status Epilepticus (NORSE) refers to a clinical presentation in a patient without active epilepsy or other existing relevant neurological disorder, with new onset of refractory status epilepticus in the absence of a clear acute or active structural, metabolic, or toxic cause. Febrile Infection-Related Epilepsy Syndrome (FIRES) is a subset of NORSE that requires a febrile infection between 24 hours and 2 weeks prior to the onset of refractory status epilepticus, with or without fever at the onset of status epilepticus, and with no restriction to the age of the patient. The literature on FIRES is scarce. This article reviews the pathophysiology, clinical features, and various treatment modalities in the treatment of FIRES. A Medline/Pubmed search was conducted using Clinical Queries with the key terms "Febrile Infection-Related Epilepsy Syndrome", "FIRES", "New-Onset Refractory Status Epilepticus" and "NORSE". The search strategy included meta-analyses, randomized controlled trials, clinical trials, reviews and pertinent references. Patents were searched using the key term "FIRES", "NORSE" and "Febrile Epilepsy Syndrome" from www.google.com/patents, www.uspto.gov, and www.freepatentsonline.com. FIRES almost invariably begins with a mild nonspecific febrile illness in an otherwise healthy individual. Twenty-four hours to two weeks later, seizures begin and quickly become very frequent and worsen, becoming status epilepticus. Seizures can be simple motor, complex partial or secondary generalized. The exact etiology is not known. It is possible that the syndrome is caused by an inflammatory or autoimmune mechanism. Seizures in FIRES are notoriously very difficult to treat. Treatment modalities include, among others, various antiepileptic drugs, ketogenic diet, intravenous corticosteroids, intravenous immunoglobulin, and burst-suppression coma. The outcome is poor; most children are left with significant cognitive disability and refractory epilepsy. Recent patents for the management of FIRES are discussed. FIRES is a rare epilepsy syndrome of unclear etiology in which children, usually of school age, suddenly develop very frequent seizures after a mild febrile illness. Seizures in FIRES are typically difficult to treat. The prognosis is poor.

We convened an international group of experts to standardize definitions of New-Onset Refractory Status Epilepticus (NORSE), Febrile Infection-Related Epilepsy Syndrome (FIRES), and related conditions. This was done to enable improved communication for investigators, physicians, families, patients, and other caregivers. Consensus definitions were achieved via email messages, phone calls, an in-person consensus conference, and collaborative manuscript preparation. Panel members were from 8 countries and included adult and pediatric experts in epilepsy, electroencephalography (EEG), and neurocritical care. The proposed consensus definitions are as follows: 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. FIRES is a subcategory of NORSE, applicable for all ages, that requires a prior febrile infection starting between 2 weeks and 24 hours prior to onset of refractory status epilepticus, with or without fever at onset of status epilepticus. Proposed consensus definitions are also provided for Infantile Hemiconvulsion-Hemiplegia and Epilepsy syndrome (IHHE) and for prolonged, refractory and super-refractory status epilepticus. This document has been endorsed by the Critical Care EEG Monitoring Research Consortium. We hope these consensus definitions will promote improved communication, permit multicenter research, and ultimately improve understanding and treatment of these conditions.

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.

ObjectiveWe aimed to characterize the clinical profile and outcomes of new onset refractory status epilepticus (NORSE) in children, and investigated the relationship between fever onset and status epilepticus (SE).MethodsPatients with refractory SE (RSE) between June 1, 2011 and October 1, 2016 were prospectively enrolled in the pSERG (Pediatric Status Epilepticus Research Group) cohort. Cases meeting the definition of NORSE were classified as "NORSE of known etiology" or "NORSE of unknown etiology." Subgroup analysis of NORSE of unknown etiology was completed based on the presence and time of fever occurrence relative to RSE onset: fever at onset (≤24 h), previous fever (2 weeks–24 h), and without fever.ResultsOf 279 patients with RSE, 46 patients met the criteria for NORSE. The median age was 2.4 years, and 25 (54%) were female. Forty (87%) patients had NORSE of unknown etiology. Nineteen (48%) presented with fever at SE onset, 16 (40%) had a previous fever, and five (12%) had no fever. The patients with preceding fever had more prolonged SE and worse outcomes, and 25% recovered baseline neurological function. The patients with fever at onset were younger and had shorter SE episodes, and 89% recovered baseline function.SignificanceAmong pediatric patients with RSE, 16% met diagnostic criteria for NORSE, including the subcategory of febrile infection‐related epilepsy syndrome (FIRES). Pediatric NORSE cases may also overlap with refractory febrile SE (FSE). FIRES occurs more frequently in older children, the course is usually prolonged, and outcomes are worse, as compared to refractory FSE. Fever occurring more than 24 h before the onset of seizures differentiates a subgroup of NORSE patients with distinctive clinical characteristics and worse outcomes.

High dose cannabidiol (CBD) in the treatment of new-onset refractory status epilepticus (NORSE)

New-onset refractory status epilepticus(NORSE) is a clinical syndrome, not a specific diagnosis of diseases in patients with new onset of refractive status epilepticus without active epilepsy or other preexisting relevant neurological disorders and is not associated with a clearly acute or active structrue, toxic or metabolic cause.Febrile infection-related epilepsy syndrome(FIRES) is a subcategory of NORSE, applicable for all ages, occurring in a prior febrile infection starting between 24 hours and 2 weeks before onset of refractory status epilepticus(RSE) with fever or not.Proposed consensus definitions are also applicable for infantile hemiconvulsion-hemiplegia and epilepsy syndrome, RSE, super-RSE, prolonged RSE and prolonged super-RSE.These consensus definitions will promote much more effective communication and multicenter research, and ultimately improve recognition and treatment of these conditions. Key words: New-onset refractory status epilepticus; Febrile infection-related epilepsy syndrome; Infantile hemiconvulsion-hemiplegia and epilepsy syndrome; Super-refractory status epilepticus; Consensus definition; Clinical characteristics; Autoimmune encephalitis

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.

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.

Editorial on the Research Topic Advances in diagnosing and treating new-onset refractory status epilepticus (NORSE) New-onset refractory status epilepticus (NORSE) is a rare but devastating condition describing a group of diseases and disorders that are characterized by de novo onset of uncontrollable seizures, so called refractory status epilepticus (RSE), without an identifiable acute or active structural, toxic, or metabolic cause (1). Febrile infection-related epilepsy syndrome (FIRES) is a subcategory of NORSE with the addition of prior febrile infection between 2 weeks and 24 h before the onset of RSE (1, 2). Reliable numbers regarding its incidence are lacking, but occurrence has been estimated to be ∼1-2 per 100,000 person years (3, 4). In case an etiology is found, such as autoimmune encephalitis, treatment can be directed at the underlying pathophysiology. However, therapeutic effects are often not sufficient, and in ∼75% of patients, the underlying etiology remains unknown (5-7). Although plenty of studies have been published on NORSE and FIRES over the last decades, no high-level evidence exists on which to base diagnostic and treatment recommendations. Given the very poor prognosis with a mortality rate of 10-30% and severe sequelae in most surviving patients (8), this lack of evidence is troublesome. Hence, this Research Topic aimed at collecting novel research and findings on the matter in order to ease the effort of systematically assessing the body of evidence in future. A detailed description of the clinical, etiological, electrophysiological neuroimaging and outcomes of new onset status epilepticus (SE) cases and their differences from SE developing in epileptic patients is reported by Benaiteau et al.. As NORSE/FIRES identifies a "clinical presentation, " it could be sustained by many different etiologies, and more than 200 uncommon disorders have been described so far (9). Inflammatory/autoimmune and paraneoplastic causes reach up to 40% of all etiologies representing the most relevant group followed by infective unusual causes that represents up to 10%, while genetic, metabolic, and toxic causes are considered rare (10). However, assessing the genetic landscape of Frontiers in Neurology frontiersin.org

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.

FIRES is defined as a disorder that requires a prior febrile infection starting between 2 weeks and 24 h before the onset of the refractory status epilepticus with or without fever at the onset of status epilepticus. The patients, previously normal, present in the acute phase recurrent seizures and status epilepticus followed by a severe course with usually persistent seizures and residual cognitive impairment. Boundary with “new onset refractory status epilepticus (NORSE) has not clearly established. Pathogenetic hypothesis includes inflammatory or autoimmune mechanism with a possible genetic predisposition for an immune response dysfunction.Various types of treatment have been proposed for the treatment of the acute phase of the disorder to block the rapid seizures evolution to status epilepticus and to treat status epilepticus itself. Prognosis is usually severe both for control of the seizures and for cognitive involvement.FIRES is an uncommon but severe disorder which must be carefully considered in the differential diagnosis with other epileptic encephalopathy.

Autoimmune Encephalitis–Related Seizures and Epilepsy: Diagnostic and Therapeutic Approaches

P-EP010. Extinguishing fires using Tocilizumab: Malaysia’s first

New-onset refractory status epilepticus (NORSE) is a clinical presentation, not a specific diagnosis, in a patient without active epilepsy or other preexisting relevant neurologic disorder, with new onset of refractory status epilepticus (RSE) that does not resolve after 2 or more rescue medications, without a clear acute or active structural, toxic, or metabolic cause. Febrile infection-related epilepsy syndrome is a subset of NORSE in which fever began at least 24 hours prior to the RSE. Both terms apply to all age groups. Until recently, NORSE was a poorly recognized entity without a consistent definition or approach to care. We review the current state of knowledge in NORSE and propose a roadmap for future collaborative research. Research investigating NORSE should prioritize the following 4 domains: (1) clinical features, etiology, and pathophysiology; (2) treatment; (3) adult and pediatric evaluation and management approaches; and (4) public advocacy, professional education, and family support. We consider international collaboration and multicenter research crucial in achieving these goals.

New-onset refractory status epilepticus (NORSE) and febrile infection-related epilepsy syndrome (FIRES) of unknown aetiology: A comparison of the incomparable?