RARE DISEASE
New-onset refractory status epilepticus
New-onset refractory status epilepticus
New-onset refractory status epilepticus
Synonyms: NORSE
Synonyms: NORSE
Synonyms: NORSE
Drug discovery
11
drugs
With orphan designations
Overview
New-onset refractory status epilepticus (NORSE) is a severe clinical syndrome characterized by de novo refractory status epilepticus without identifiable structural, toxic, or metabolic causes. It predominantly affects previously healthy individuals, with autoimmune encephalitis as the most common identified etiology (19–27% of cases), while up to 52% remain cryptogenic [1][2][6]. Management requires prolonged ICU care, multimodal therapies, and often leads to chronic epilepsy, cognitive deficits, or functional disability despite aggressive treatment [1][4][15].
Therapies
Antiseizure medications + anesthesia: Midazolam, propofol, or ketamine for refractory seizures [3][8].
Immunotherapy: Early steroids/IVIG (<72 hours) ± anakinra/tocilizumab for cryptogenic cases; rituximab if antibody-mediated [6][8][11].
Adjunctive therapies: Ketogenic diet (initiated ≤7 days) and neurostimulation (VNS/ECT) [6][7].
Categories: rare neurological diseases
Research Papers
256 drug discovery papers about New-onset refractory status epilepticus, with 1 first-in-class and 2 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
256 drug discovery papers about New-onset refractory status epilepticus, with 1 first-in-class and 2 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
antibodies
2026-06-02 | Systematic Reviews and Meta-Analyses of the Use of Tocilizumab in Treating Central Nervous Diseases.
To perform systematic reviews and meta-analyses on the use of the tocilizumab in the central nervous system (CNS) diseases. A systematic search was carried out in the PubMed, Embase and Cochrane databases for all years until August 2025. The review revealed 618 CNS diseases patients treated with tocilizumab. The proportion of neuromyelitis optica spectrum disorder (NMOSD) relapse-free patients after tocilizumab was 79.00% (95% confidence interval (CI): 0.67, 0.89). There was a significant correlation between remission and positive anti-AQP4 antibody status (p = 0.001). Tocilizumab significantly reduced the standardized mean Annualized Relapse Ratio (-1.3 (95% CI: -1.94, -0.66; p = 0.00191), Extended Disability Status Scale score (-0.48; 95% CI: -0.92, -0.04; p = 0.0329), and fatigue score (-1.08; 95% CI: -1.53, -0.63; p < 0.0001). The proportion of new-onset refractory status epilepticus (NORSE), febrile infection-related epilepsy syndrome (FIRES), and refractory status epilepticus patients who improved after tocilizumab was 95.00% (95% CI: 0.78, 1.00). The proportion of the anti-NMDAR encephalitis patients with a favorable outcome after tocilizumab was 73.00% (95% CI: 0.64, 0.81). Although other CNS diseases showed improvement following tocilizumab, they did not meet the criteria for meta-analyses. Tocilizumab altered several pro- and anti-inflammatory markers in humans, animals, and cell models. The pooled proportion of tocilizumab adverse effects was 45.00% (95% CI: 0.26, 0.65). This study may guide clinicians in managing patients with CNS diseases and in conducting prospective studies and clinical trials. Some of the CNS diseases may be treated with tocilizumab.
2026-03-12 | [Febrile infection-related epilepsy syndrome (FIRES) with the claustrum sign in a 55-year-old woman: a case report].
A 55-year-old woman presented to our clinic with refractory status epilepticus, which developed after her symptoms of influenza had initially improved. Despite various tests, the definite cause could not be identified; however, her clinical presentation preceded by a febrile infection was consistent with that of febrile infection-related epilepsy syndrome (FIRES), a subtype of new-onset refractory status epilepticus (NORSE). Because the brain MRI on day seven revealed a claustrum sign, we administered aggressive immunotherapy. Thereafter, the patient recovered from status epilepticus, and the claustrum sign disappeared on brain MRI. Although the retrograde amnesia and chronic epilepsy persisted, the patient recovered and was able to live at home upon discharge. In patients with refractory status epilepticus that develops after a preceding infection, FIRES should be considered in the differential diagnosis regardless of age at onset, and early aggressive immunotherapy should be considered, especially in patients with a claustrum sign.
2026-03-11 | FATAL SUPER-REFRACTORY STATUS EPILEPTICUS IN ADULT-ONSET FEBRILE INFECTION-RELATED EPILEPSY SYNDROME (FIRES): A CASE REPORT OF PHARMACOKINETIC CHALLENGES AND EARLY IMMUNOMODULATION
Febrile Infection-Related Epilepsy Syndrome (FIRES), a subcategory of New-Onset Refractory Status Epilepticus (NORSE), is a catastrophic epileptic encephalopathy that is rarely described in adults. This report describes a fatal case of a 25-year-old woman who developed explosive-onset generalized seizures following a mild febrile prodrome. She rapidly progressed to refractory status epilepticus and met criteria for adult-onset FIRES after exclusion of infectious, structural, toxic, and antibody-mediated autoimmune etiologies. Despite aggressive escalation to super-refractory status epilepticus (SRSE) management with quadruple continuous intravenous anesthetics (propofol, midazolam, ketamine, thiopentone) and multiple antiseizure medications, seizure control remained unstable. The clinical course was critically destabilized by a preventable pharmacokinetic interaction: the initiation of meropenem for multidrug-resistant sepsis in a patient receiving valproic acid resulted in a rapid decline in serum valproate exposure and breakthrough seizures. Advanced immunomodulatory strategies including plasmapheresis, rituximab, and interleukin-6 (IL-6) receptor blockade with tocilizumab were instituted. Tocilizumab achieved transient seizure cessation (48 hours) and permitted partial anesthetic weaning but was followed by profound neutropenia and worsening septic shock. The patient ultimately succumbed to multidrug-resistant sepsis and multiple organ dysfunction syndrome (MODS) on day 39. This case highlights the high mortality of adult FIRES, the absolute contraindication of concurrent carbapenem–valproate therapy, and the potential value of earlier cytokine-targeted immunotherapy.
2026-02-17 | The Clinical Characteristics and Prognosis of Children Presenting with New Onset Refractory Status Epilepticus in COVID-19-related Multisystem Inflammatory Syndrome
Introduction: MIS-C is a hyperinflammatory process leading to multiorgan failure and shock, occurring during the acute or post-infectious stage of SARS-CoV-2, and has 2 subtypes: para-infectious and post-infectious varieties. The new onset of refractory status epilepticus has rarely been described as the presenting feature of MIS-C. Methods: This retrospective study, conducted at Dr. B. C. Roy Post Graduate Institute of Pediatric Sciences, included children hospitalised between August 1, 2020 and July 31, 2021, with NORSE and subsequently diagnosed to have MIS-C. Their clinico-demographic variables, treatment courses during hospital stays, laboratory reports, radiological and electrophysiological findings, and outcomes at discharge and follow-up over 1 year were recorded. At their 12-month visits, their motor disabilities (primary) and continuation of anti-epileptic drugs, and persistence of MRI brain abnormalities (secondary) were the outcome measures. The characteristics of the patients in the para-infectious and post-infectious groups were compared using the Mann-Whitney U test for continuous variables and the Chi-square test for categorical variables. Results: There were 8 and 10 patients in groups A and B, respectively. Patients in group B had significantly higher age, more prolonged RSE, use of anaesthetics and ventilation, and longer PICU stay, while other clinical and laboratory parameters and short and long-term outcomes were not significantly different between the two groups. 8 patients developed hemiparesis, while 2 had quadriparesis in the acute stage, but 15 (83%) patients had complete recovery from their motor deficits by 1 year. At 1-year follow-up, 33% and 39% of patients, had abnormal MRI and EEG finding, respectively. Conclusion: The post-infectious group had significantly higher age, longer duration of RSE, ventilation, use of general anaesthetics, and PICU stay. Acute disseminated encephalitis and acute leucoencephalopathy were the most commonly observed MRI abnormalities in the acute phase, with prolonged persistence of cerebritis in patients in the post-infectious group, warranting long-term immunomodulation. Combined immunotherapy with IVIG and steroids was effective in the acute phase. However, long-term anti-epileptic therapy was needed in both groups.
2026-02-13 | Pediatric new-onset super refractory status epilepticus: Potential of timely immunotherapy in a resource-limited PICU.
To describe the clinical profile, management, and outcomes of children with new-onset super-refractory status epilepticus (NOSRSE), and to identify predictors of survival. This was a retrospective observational study conducted in the Pediatric Intensive Care Unit at PGIMER, Chandigarh, India, from January 2019 to August 2024. Thirty-six children diagnosed with NORSE who progressed to super-refractory status epilepticus were included. Clinical characteristics, neurodiagnostic findings, treatment details, and outcomes were analyzed. Univariate logistic regression was used to identify predictors of survival. Median age was 8 years; 63.9 % were male. No etiology was identified in 28 (77.7 %) children, autoimmune encephalitis in 5 (13.9 %) and viral encephalitis in 3 (8.3 %) children. MRI abnormalities were seen in 72.7 %, and non-convulsive seizures on EEG in 55.6 %. Seizure control was achieved in 80.6 %, and 72.2 % survived to hospital discharge. Median PCPC score improved from 5 at discharge to 3 at 6-month follow-up. Early immunotherapy (OR 0.83; 95 % CI (0.69, 0.99); p 0.04) was associated with better survival. Despite the severity of illness, favorable outcomes were achievable. Early immunotherapy was associated with improved survival. These findings underscore the need for time-sensitive, protocolized care in pediatric NOSRSE, especially in resource-limited settings.
cell therapies
2026-08-14 | Adaptive immune dysregulation drives new-onset refractory status epilepticus.
New-onset refractory status epilepticus (NORSE) is a life-threatening neurological condition that emerges abruptly in individuals without a prior history of epilepsy and is characterised by seizures that are refractory to standard antiseizure medications. NORSE is associated with high mortality and long-term neurological deficits, and autoimmune encephalitis (AIE) represents a major identifiable cause of NORSE. Growing evidence implicates immune-mediated mechanisms as central drivers of NORSE; however, existing studies have focused predominantly on innate immune dysregulation, including cytokine-driven neuroinflammation and microglial activation, whilst the role of adaptive immune mechanisms in AIE-mediated NORSE remains relatively underexplored. This review synthesises current evidence linking adaptive immune responses in NORSE pathogenesis, with particular emphasis on B and T lymphocytes in shaping neuroinflammation. B cell-mediated response is implicated in NORSE cases associated with AIE where autoantibodies such as anti-N-methyl-D-aspartate receptor (NMDAR) disrupt neuronal signalling and contribute to seizure generation. Beyond humoral immunity, T-cell subsets, for instance, cytotoxic T cells, contribute to neuronal damage through recognition of neuronal intracellular antigens. Emerging immunomodulatory therapies targeting adaptive immune components are also discussed, including monoclonal antibody therapies and innovative approaches inspired by conventional chimeric antigen receptor (CAR) T-cell technology. A deeper understanding of the complex interplay between innate and adaptive immune responses is essential to elucidate disease mechanisms and guide future development of more precise mechanism-based therapeutic strategies for NORSE.
2026-03-25 | Vagus nerve stimulation as an adjunctive therapy for super-refractory status epilepticus including NORSE: a retrospective cohort study.
Resistance to anti-seizure medications (ASMs) remains a major challenge in managing super refractory status epilepticus (SRSE), including new-onset refractory status epilepticus (NORSE). Vagus Nerve Stimulation (VNS) has emerged as a potential adjunctive therapy, but clinical evidence in SRSE is limited. We retrospectively identified patients who underwent VNS implantation for SRSE during hospitalization within a large tertiary hospital system in New York City (July 2018 - June 2024). Electronic medical records were reviewed for demographic, clinical features, neuroimaging, EEG findings, medications, VNS parameters, and short- and long-term functional outcomes. Fifteen patients (14 female; age 16-77 years) underwent VNS implantation for SRSE, including 8 with NORSE (6 cryptogenic; 2 with a later-identified etiology) and 7 non-NORSE patients. Compared to non-NORSE patients, NORSE patients received more ASMs (median 5 vs. 4) and anesthetic infusions (3 vs 2) for longer duration (14.5 vs. 11 days) before implantation. All but one patient was successfully weaned off anesthetics without SE recurrence; VNS output at weaning was higher in NORSE patients (0.88 vs. 0.50 mA). No complications were observed related to VNS implantation or titration. Despite longer hospitalization (86.5 vs 47 days) and similar ASM burden (4) and functional status at discharge (GOS-E 3), NORSE patients showed a trend toward better long-term functional outcomes (GOS-E 7 vs 1, p = 0.31), despite developing post-NORSE epilepsy. In exploratory analyses, earlier implantation showed non-significant trends toward shorter hospitalization (47 vs. 116 days, p = 0.09) and higher discharge GOS-E (4 vs. 2.5, p = 0.06). Our findings suggest that VNS is likely a safe addition to the established treatment for SRSE. However, given the retrospective and uncontrolled design, efficacy of VNS cannot be determined. Prospective controlled studies are needed to assess clinical benefit and to define optimal implantation timing, titration strategies, and short-and long-term outcomes, including post-NORSE epilepsy.
2025-01-13 | NORSE secondary to anti-GAD65 antibody-positive encephalitis treated with novel adjunctive rapid titration VNS protocol.
New Onset Refractory Status Epilepticus (NORSE) is a rare and severe condition characterized by refractory seizures in individuals without a prior history of epilepsy. This case report describes a 37-year-old woman diagnosed with anti-glutamic acid decarboxylase 65 (anti-GAD65) antibody-positive encephalitis-related NORSE. Her seizures were refractory to multiple interventions, including anti-seizure medications, anesthetics, immunotherapies, a ketogenic diet, and electroconvulsive therapy. Seizures recurred twice during the tapering of anesthetic medications. However, after 32 days of treatment, the seizures were successfully controlled. To maintain seizure control and facilitate the weaning of anesthetics, a Vagus Nerve Stimulator (VNS) was implanted using a novel rapid titration protocol. This allowed for the successful tapering of anesthetics by day 50, with no recurrence of seizures. At her 9-month follow-up, the patient remained seizure-free and had an improved quality of life. This case highlights that early initiation of immunosuppressive treatment may lead to a favorable prognosis. The novel application of VNS therapy assisted seizure control in NORSE, thus encouraging further research investigating the potential role of VNS in this condition. PLAIN LANGUAGE SUMMARY: New Onset Refractory Status Epilepticus (NORSE) is a rare and severe condition characterized by relentless seizures in individuals without a prior epilepsy history. This report shares the case of a 37-year-old woman with NORSE, associated with a high anti-glutamic acid decarboxylase 65 antibody titer. Her seizures were super-refractory, requiring multiple anti-seizure medications, anesthetics, immunotherapies, a ketogenic diet, and electroconvulsive therapy. Seizures recurred twice during the tapering of anesthetic medications. However, by hospital day 32, the seizures were successfully controlled with these interventions. To further stabilize seizure control and enable the successful discontinuation of anesthetics, a Vagus Nerve Stimulator (VNS) was implanted. The patient had no further seizures and gradually recovered back to her pre-disease baseline. This case suggests that a novel rapid VNS titration protocol could be a promising treatment option for NORSE, warranting further investigation.
2024-03-21 | Refractory status epilepticus arrested by vagus nerve stimulation.
A 54-year-old man developed altered mental state and generalised tonic-clonic seizures after 1 week of upper respiratory tract symptoms and diarrhoea, having been previously well. His MR scan of brain showed multifocal progressive T2 cortical signal changes. He was diagnosed with new-onset refractory status epilepticus (NORSE), initially treated as being secondary to autoimmune/paraneoplastic limbic encephalitis, although subsequent investigations were negative. His seizures and electrographic epileptiform activity continued despite escalating doses of antiseizure medications, immunosuppression with corticosteroids, immunoglobulins, plasma exchange and rituximab, and thereafter anaesthetic agents. A vagus nerve stimulator (VNS) was implanted 6 weeks after admission and its voltage rapidly increased over 4 days; his seizure activity resolved in the third week after VNS implantation. This case highlights the role of VNS in the early management of NORSE.
2023-11-14 | Role of Vagus Nerve Stimulation in Refractory and Super Refractory Status Epilepticus: A Pediatric Case Series
Background: Status epilepticus is a life-threatening condition that is defined as refractory (RSE) when the seizure activity continues despite treatment with benzodiazepine and a second appropriate treatment. Super refractory status epilepticus (SRSE) is an RSE that persists or recurs for ≥24 h. Few papers have reported the outcomes of pediatric patients affected by RSE and SRSE and treated with neuromodulation therapies. Vagus nerve stimulation (VNS) is an approved treatment for drug-resistant epilepsy. We present our findings of pediatric patients treated with VNS for RSE/SRSE. Methods: We present a case series of seven consecutive pediatric patients treated with VNS for SRSE since 2012 by a single surgeon in Monza and Padua. A rapid titration was started soon after implantation. We considered electroclinical data before and after VNS implantation and at the last follow-up. Results: We achieved the resolution of SRSE in five out of seven patients in a mean time of two weeks. At the last follow-up, these patients had a significant reduction of seizure burden without any relapse of SE. Discussion and Conclusions: Based on our limited findings, we discuss the potential role of VNS therapy in similar but distinct clinical contexts. For patients with drug-resistant epilepsy and RSE/SRSE, prompt VNS consideration is suggested, offering rapid responses and potentially reducing pharmacological load. Meanwhile, in NORSE/FIRES, we suggest early neuromodulation during the acute phase if standard treatments prove ineffective or not tolerated. This approach may leverage VNS’s potential anti-inflammatory effects and neuromodulation, enhancing patient-specific treatments. Expanding case studies and prolonged follow-ups are recommended to strengthen these clinical insights.
small molecules
2026-07-09 | Refractory epilepsy from lead poisoning.
Lead exposure remains a significant yet under-recognised public health concern in the UK, particularly among vulnerable paediatric populations. Its non-specific, multisystemic involvement and rare neurological presentations make recognition and timely treatment of lead poisoning especially challenging. We report a case of a 6-year-old boy with autism spectrum disorder and pica presenting with new-onset refractory status epilepticus, unresponsive to standard antiepileptic therapy. Diagnostic evaluation demonstrated microcytic anaemia with basophilic stippling on blood film, diffuse cortical changes on MRI and markedly elevated blood lead levels, establishing the diagnosis of acute-on-chronic lead poisoning. Treatment with intravenous sodium calcium edetate and polyethylene glycol bowel irrigation led to progressive clinical improvement and seizure resolution. Serial measurements confirmed a declining lead burden, and the patient was discharged on oral chelation therapy. This case highlights the importance of considering lead toxicity in unexplained encephalopathy or refractory seizures in children, with early recognition to prevent irreversible neurological sequelae.
2026-07-05 | Cenobamate use in super-refractory status epilepticus: A report of three cases.
Super-refractory status epilepticus (SRSE) is a neurological emergency with high morbidity and mortality. Cenobamate, a novel antiseizure medication, may be helpful in managing SRSE, but evidence is limited. This retrospective case series reports the use of cenobamate as add-on therapy in the management of three cases of SRSE. Median age at status epilepticus (SE) onset was 28 years (range 27-75). The etiologies of SRSE included one case of febrile infection-related epilepsy syndrome (FIRES), one patient with a probable genetic etiology (SCN7A variant of uncertain significance), and one case of unknown etiology. Cenobamate was introduced at a median of 27 days (range 13-103) after SE onset. Resolution of SRSE was observed after a median of 7 days (range 3-30) once cenobamate was started. Median dose of cenobamate at SRSE cessation was 25 mg/day (range 12.5-50 mg/day), and the median maintenance dose at the time of discharge was 200 mg/day (range 100-400 mg/day). Two patients died and one patient achieved functional independence. No severe medication side effects, specifically drug reaction with eosinophilia and systemic symptoms (DRESS), were observed. Cenobamate may have a role in the management of SRSE. Further studies are needed to define the optimal timing of initiation, titration strategy, and target dose of cenobamate in the context of SE.
2026-06-23 | Graph-based analysis of inflammatory profiles in New Onset Refractory Status Epilepticus (NORSE)
Background and Objectives: Cryptogenic new-onset refractory status epilepticus (cNORSE) represents one of the most severe forms of status epilepticus, occurring in patients without prior neurological disease, and remaining of unknown aetiology despite extensive diagnostic evaluation. Emerging evidence supports a role for immune dysregulation in cNORSE; however, marked heterogeneity in inflammatory signatures has been reported, complicating the selection of targeted immunotherapies. Therefore, a critical need for tools facilitating the interpretation of cytokine panels exists. Methods: Building on the identification of distinct inflammatory groups of cNORSE patients using a graph clustering approach applied to a cohort of 62 patients with serum profiling of 96 cytokines, we tailored new models to quantify attribution probability to biologically validated clusters. Statistical assessment of the most informative model involved Monte-Carlo simulations and custom-developed parametric tests. Ultimately, we applied our framework to the implementation of a clinician-friendly interface for inflammatory profiling. Results: Our approach enables quick processing of several cytokine profiles, providing the most likely inflammatory cluster, associated attribution probability, and statistical confidence. For longitudinal assessments, the proposed method may also allow tracking the evolution of inflammatory trajectories over time. Conclusion: Systematic statistical characterization of the inflammatory heterogeneity in cNORSE requires the development of clinically actionable support tools. Our study offers a framework that may support personalized immunomodulatory strategies in cNORSE patients through clustering-based cytokine profiling.
2026-06-15 | New-Onset Refractory Status Epilepticus (NORSE): A Comprehensive Review of Etiology, Pathophysiology, and Management
New-onset refractory status epilepticus (NORSE) represents one of the most challenging and clinically urgent presentations in modern neurology, defined as refractory status epilepticus occurring in a patient without preexisting epilepsy or an immediately identifiable acute structural, toxic, or metabolic cause. This condition, along with its febrile-associated subset known as febrile infection-related epilepsy syndrome (FIRES), carries disproportionate morbidity and mortality, with in-hospital mortality reaching 16–27% in adults and long-term survivors often left with drug-resistant epilepsy and significant cognitive disability. The etiological landscape of NORSE is characterized by a striking duality: in approximately half of rigorously investigated cases, no cause is identified despite extensive testing, while in the remainder, autoimmune encephalitis—most notably anti-NMDA receptor encephalitis—predominates, followed by paraneoplastic syndromes and uncommon viral or bacterial infections. Pathophysiologically, current evidence points toward an immune-mediated inflammatory cascade within the central nervous system, marked by cerebrospinal fluid cytokine overproduction, T-cell and glial activation, and possibly genetic predispositions involving human leukocyte antigen subtypes and interleukin-1 pathway variants. Clinically, patients typically experience a brief prodromal illness followed by a crescendo of focal motor seizures that rapidly evolve into refractory status epilepticus, requiring intensive care unit admission, continuous electroencephalographic monitoring, and aggressive treatment with intravenous anesthetic agents. Management follows a sequential paradigm: first-line benzodiazepines, second-line standard antiepileptic drugs, and third-line continuous anesthetic infusions for refractory cases. Given the high likelihood of an underlying autoimmune process, early initiation of immunotherapy—high-dose corticosteroids, intravenous immunoglobulin, or plasmapheresis—is recommended empirically while diagnostic testing proceeds. Second-line immunotherapies such as rituximab, cyclophosphamide, or anakinra may be considered in nonresponders. Despite these interventions, outcomes remain guarded, and an interprofessional team approach involving neurology, critical care, pharmacy, nursing, and palliative care is essential to optimize patient and family outcomes. This review synthesizes current evidence on NORSE, emphasizing the need for early recognition, systematic diagnostic evaluation, timely immunotherapy, and collaborative care.
2026-05-26 | Longitudinal changes in brain volume, cognitive function, and seizure outcomes in cryptogenic new-onset refractory status epilepticus.
To evaluate long-term structural, cognitive, functional, and seizure outcomes among survivors of cryptogenic new-onset refractory status epilepticus (C-NORSE) according to the timing of intravenous cyclophosphamide (IVCPA) initiation. We examined seven consecutive patients with C-NORSE treated between 2012 and 2025. Of those, super-refractory status epilepticus (SRSE, n = 5) cases were stratified into SRSE-Early IVCPA (IVCPA initiated within 20 days after seizure onset) and SRSE-Late/No IVCPA (IVCPA initiated >20 days after onset or not administered); the refractory status epilepticus (RSE) group served as a reference. 4 of the 5 SRSE patients received IVCPA (3 cases were classified as early and 1 case as late). We assessed whole-brain volume change quantified on serial MRI, neurocognition by standardized tests, functional outcomes by mRS, and seizure outcomes during the acute phase, at discharge, and in the chronic phase (≥1 year) among groups. The median follow-up was 5 years (range, 2-11 years). Whole-brain volume loss remained <10% in the RSE and SRSE-Early IVCPA groups, whereas marked medial temporal and diffuse brain atrophy developed in the two cases in the SRSE-Late/No IVCPA group, with whole-brain volume losses of 18.2% and 16.0%. Neurocognitive trajectories improved gradually in SRSE-Early IVCPA and showed severe chronic impairment in SRSE-Late/No IVCPA. Functional outcomes were excellent in SRSE-Early IVCPA and RSE but were poorer in SRSE-Late/No IVCPA. All patients developed drug-resistant epilepsy. In this case series, earlier IVCPA initiation in patients with SRSE due to C-NORSE was potentially associated with less chronic brain atrophy and more favorable neurocognitive and functional trajectories. Future studies are warranted to determine whether early seizure control plus immunotherapy reduces the risk of chronic drug-resistant epilepsy and improves long-term cognition.
proteins
2025-11-26 | Case Report: Successful multimodal management of FIRES in a pediatric patient using anakinra, ketogenic diet, and induced hypothermia.
Febrile infection-related epilepsy syndrome is a devastating, refractory epileptic encephalopathy that typically occurs in school-aged, otherwise healthy, children after a brief, non-specific, febrile illness. In this study, we discuss a case of a previously healthy 10-year-old girl with FIRES in whom high dosages of conventional and non-conventional antiepileptic drugs were ineffective in treating refractory status epilepticus, after which a treatment involving intravenous corticosteroids, immunoglobulins, a ketogenic diet, and induced hypothermia was adopted. We conducted a diagnostic workup that included lumbar puncture, blood tests, continuous electroencephalogram monitoring, brain MRI, and autoimmunity and infectious disease panels to shed light on the etiology of the condition. Our patient responded to immunosuppressive therapy and the ketogenic diet, and her condition gradually improved to full recovery with only mild neurocognitive sequelae. Although patients with FIRES have been described in the literature, optimal management has not yet seen the light of day, and therefore, prospective cohort studies are needed. This case highlights the potential benefit of a timely, multimodal therapeutic approach combining immunomodulation, metabolic support, and neuroprotection. Early administration of anakinra and initiation of a ketogenic diet may help control seizures and reduce the duration of ICU stay. Prompt diagnosis and interdisciplinary care are essential to improve outcomes in patients with this life-threatening pediatric condition.
2025-07-05 | Retrospective multicenter study on cryptogenic NORSE/FIRES patients treated with anakinra.
Refractory status epilepticus (RSE) is a neurological emergency characterized by persistent seizures despite two appropriate antiseizure medications. It is defined as new-onset RSE (NORSE) when occurring in previously healthy people. NORSE is defined as cryptogenic (cNORSE) when no cause is found. Febrile-infection related epilepsy syndrome (FIRES) is now defined as the cNORSE variant preceded by fever. In 2016 anakinra was reported effective in an anecdotal case. After this experience, second-line immunotherapy has been increasingly used, being incorporated in cNORSE recommendations in 2022. We conducted a retrospective study in an Italian case series of 14 patients with cNORSE (including FIRES cases) treated with anakinra in Italy before implementation of the international recommendations, that could serve as historical reference for futures studies based on the shared recommendations. In our population higher duration of intensive care stay period was associated with later time of anakinra use, although no evidence of efficacy on the long-term neurological outcome was demonstrated. There is an urgent need for well-designed head-to-head multicenter prospective clinical trials to clarify the benefits of available treatments and the role of biomarkers to guide choices.
2024-05-10 | 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.
2023-12-11 | The Beneficial Outcome of Subsequent Treatment with Anakinra during the Chronic Phase of Febrile Infection-Related Epilepsy Syndrome (FIRES): A Case Report
This case report presents the clinical course of an eight-year-old boy diagnosed with febrile infection-related epilepsy syndrome (FIRES) at the age of four. Following a febrile infection, the patient experienced his initial episode of serial generalized clonic seizures. The severity of his condition led to 11 hospital admissions, totaling 157 days of hospitalization. Anakinra was initially administered during the acute phase in 2019 but was discontinued after 29 days. In 2022, the patient experienced a chronic-phase exacerbation and underwent a second course of anakinra treatment, which demonstrated a positive effect on seizure activity. With a year of anakinra therapy, the patient exhibited significant improvement in both seizure frequency and severity. This report adds to the existing evidence supporting the potential use of anakinra in the treatment of FIRES, highlighting its effectiveness during the chronic phase and suggesting the potential benefits of subsequent administration.
2023-05-21 | 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.
antibodies
2026-06-02 | Systematic Reviews and Meta-Analyses of the Use of Tocilizumab in Treating Central Nervous Diseases.
To perform systematic reviews and meta-analyses on the use of the tocilizumab in the central nervous system (CNS) diseases. A systematic search was carried out in the PubMed, Embase and Cochrane databases for all years until August 2025. The review revealed 618 CNS diseases patients treated with tocilizumab. The proportion of neuromyelitis optica spectrum disorder (NMOSD) relapse-free patients after tocilizumab was 79.00% (95% confidence interval (CI): 0.67, 0.89). There was a significant correlation between remission and positive anti-AQP4 antibody status (p = 0.001). Tocilizumab significantly reduced the standardized mean Annualized Relapse Ratio (-1.3 (95% CI: -1.94, -0.66; p = 0.00191), Extended Disability Status Scale score (-0.48; 95% CI: -0.92, -0.04; p = 0.0329), and fatigue score (-1.08; 95% CI: -1.53, -0.63; p < 0.0001). The proportion of new-onset refractory status epilepticus (NORSE), febrile infection-related epilepsy syndrome (FIRES), and refractory status epilepticus patients who improved after tocilizumab was 95.00% (95% CI: 0.78, 1.00). The proportion of the anti-NMDAR encephalitis patients with a favorable outcome after tocilizumab was 73.00% (95% CI: 0.64, 0.81). Although other CNS diseases showed improvement following tocilizumab, they did not meet the criteria for meta-analyses. Tocilizumab altered several pro- and anti-inflammatory markers in humans, animals, and cell models. The pooled proportion of tocilizumab adverse effects was 45.00% (95% CI: 0.26, 0.65). This study may guide clinicians in managing patients with CNS diseases and in conducting prospective studies and clinical trials. Some of the CNS diseases may be treated with tocilizumab.
2026-03-12 | [Febrile infection-related epilepsy syndrome (FIRES) with the claustrum sign in a 55-year-old woman: a case report].
A 55-year-old woman presented to our clinic with refractory status epilepticus, which developed after her symptoms of influenza had initially improved. Despite various tests, the definite cause could not be identified; however, her clinical presentation preceded by a febrile infection was consistent with that of febrile infection-related epilepsy syndrome (FIRES), a subtype of new-onset refractory status epilepticus (NORSE). Because the brain MRI on day seven revealed a claustrum sign, we administered aggressive immunotherapy. Thereafter, the patient recovered from status epilepticus, and the claustrum sign disappeared on brain MRI. Although the retrograde amnesia and chronic epilepsy persisted, the patient recovered and was able to live at home upon discharge. In patients with refractory status epilepticus that develops after a preceding infection, FIRES should be considered in the differential diagnosis regardless of age at onset, and early aggressive immunotherapy should be considered, especially in patients with a claustrum sign.
2026-03-11 | FATAL SUPER-REFRACTORY STATUS EPILEPTICUS IN ADULT-ONSET FEBRILE INFECTION-RELATED EPILEPSY SYNDROME (FIRES): A CASE REPORT OF PHARMACOKINETIC CHALLENGES AND EARLY IMMUNOMODULATION
Febrile Infection-Related Epilepsy Syndrome (FIRES), a subcategory of New-Onset Refractory Status Epilepticus (NORSE), is a catastrophic epileptic encephalopathy that is rarely described in adults. This report describes a fatal case of a 25-year-old woman who developed explosive-onset generalized seizures following a mild febrile prodrome. She rapidly progressed to refractory status epilepticus and met criteria for adult-onset FIRES after exclusion of infectious, structural, toxic, and antibody-mediated autoimmune etiologies. Despite aggressive escalation to super-refractory status epilepticus (SRSE) management with quadruple continuous intravenous anesthetics (propofol, midazolam, ketamine, thiopentone) and multiple antiseizure medications, seizure control remained unstable. The clinical course was critically destabilized by a preventable pharmacokinetic interaction: the initiation of meropenem for multidrug-resistant sepsis in a patient receiving valproic acid resulted in a rapid decline in serum valproate exposure and breakthrough seizures. Advanced immunomodulatory strategies including plasmapheresis, rituximab, and interleukin-6 (IL-6) receptor blockade with tocilizumab were instituted. Tocilizumab achieved transient seizure cessation (48 hours) and permitted partial anesthetic weaning but was followed by profound neutropenia and worsening septic shock. The patient ultimately succumbed to multidrug-resistant sepsis and multiple organ dysfunction syndrome (MODS) on day 39. This case highlights the high mortality of adult FIRES, the absolute contraindication of concurrent carbapenem–valproate therapy, and the potential value of earlier cytokine-targeted immunotherapy.
2026-02-17 | The Clinical Characteristics and Prognosis of Children Presenting with New Onset Refractory Status Epilepticus in COVID-19-related Multisystem Inflammatory Syndrome
Introduction: MIS-C is a hyperinflammatory process leading to multiorgan failure and shock, occurring during the acute or post-infectious stage of SARS-CoV-2, and has 2 subtypes: para-infectious and post-infectious varieties. The new onset of refractory status epilepticus has rarely been described as the presenting feature of MIS-C. Methods: This retrospective study, conducted at Dr. B. C. Roy Post Graduate Institute of Pediatric Sciences, included children hospitalised between August 1, 2020 and July 31, 2021, with NORSE and subsequently diagnosed to have MIS-C. Their clinico-demographic variables, treatment courses during hospital stays, laboratory reports, radiological and electrophysiological findings, and outcomes at discharge and follow-up over 1 year were recorded. At their 12-month visits, their motor disabilities (primary) and continuation of anti-epileptic drugs, and persistence of MRI brain abnormalities (secondary) were the outcome measures. The characteristics of the patients in the para-infectious and post-infectious groups were compared using the Mann-Whitney U test for continuous variables and the Chi-square test for categorical variables. Results: There were 8 and 10 patients in groups A and B, respectively. Patients in group B had significantly higher age, more prolonged RSE, use of anaesthetics and ventilation, and longer PICU stay, while other clinical and laboratory parameters and short and long-term outcomes were not significantly different between the two groups. 8 patients developed hemiparesis, while 2 had quadriparesis in the acute stage, but 15 (83%) patients had complete recovery from their motor deficits by 1 year. At 1-year follow-up, 33% and 39% of patients, had abnormal MRI and EEG finding, respectively. Conclusion: The post-infectious group had significantly higher age, longer duration of RSE, ventilation, use of general anaesthetics, and PICU stay. Acute disseminated encephalitis and acute leucoencephalopathy were the most commonly observed MRI abnormalities in the acute phase, with prolonged persistence of cerebritis in patients in the post-infectious group, warranting long-term immunomodulation. Combined immunotherapy with IVIG and steroids was effective in the acute phase. However, long-term anti-epileptic therapy was needed in both groups.
2026-02-13 | Pediatric new-onset super refractory status epilepticus: Potential of timely immunotherapy in a resource-limited PICU.
To describe the clinical profile, management, and outcomes of children with new-onset super-refractory status epilepticus (NOSRSE), and to identify predictors of survival. This was a retrospective observational study conducted in the Pediatric Intensive Care Unit at PGIMER, Chandigarh, India, from January 2019 to August 2024. Thirty-six children diagnosed with NORSE who progressed to super-refractory status epilepticus were included. Clinical characteristics, neurodiagnostic findings, treatment details, and outcomes were analyzed. Univariate logistic regression was used to identify predictors of survival. Median age was 8 years; 63.9 % were male. No etiology was identified in 28 (77.7 %) children, autoimmune encephalitis in 5 (13.9 %) and viral encephalitis in 3 (8.3 %) children. MRI abnormalities were seen in 72.7 %, and non-convulsive seizures on EEG in 55.6 %. Seizure control was achieved in 80.6 %, and 72.2 % survived to hospital discharge. Median PCPC score improved from 5 at discharge to 3 at 6-month follow-up. Early immunotherapy (OR 0.83; 95 % CI (0.69, 0.99); p 0.04) was associated with better survival. Despite the severity of illness, favorable outcomes were achievable. Early immunotherapy was associated with improved survival. These findings underscore the need for time-sensitive, protocolized care in pediatric NOSRSE, especially in resource-limited settings.
cell therapies
2026-08-14 | Adaptive immune dysregulation drives new-onset refractory status epilepticus.
New-onset refractory status epilepticus (NORSE) is a life-threatening neurological condition that emerges abruptly in individuals without a prior history of epilepsy and is characterised by seizures that are refractory to standard antiseizure medications. NORSE is associated with high mortality and long-term neurological deficits, and autoimmune encephalitis (AIE) represents a major identifiable cause of NORSE. Growing evidence implicates immune-mediated mechanisms as central drivers of NORSE; however, existing studies have focused predominantly on innate immune dysregulation, including cytokine-driven neuroinflammation and microglial activation, whilst the role of adaptive immune mechanisms in AIE-mediated NORSE remains relatively underexplored. This review synthesises current evidence linking adaptive immune responses in NORSE pathogenesis, with particular emphasis on B and T lymphocytes in shaping neuroinflammation. B cell-mediated response is implicated in NORSE cases associated with AIE where autoantibodies such as anti-N-methyl-D-aspartate receptor (NMDAR) disrupt neuronal signalling and contribute to seizure generation. Beyond humoral immunity, T-cell subsets, for instance, cytotoxic T cells, contribute to neuronal damage through recognition of neuronal intracellular antigens. Emerging immunomodulatory therapies targeting adaptive immune components are also discussed, including monoclonal antibody therapies and innovative approaches inspired by conventional chimeric antigen receptor (CAR) T-cell technology. A deeper understanding of the complex interplay between innate and adaptive immune responses is essential to elucidate disease mechanisms and guide future development of more precise mechanism-based therapeutic strategies for NORSE.
2026-03-25 | Vagus nerve stimulation as an adjunctive therapy for super-refractory status epilepticus including NORSE: a retrospective cohort study.
Resistance to anti-seizure medications (ASMs) remains a major challenge in managing super refractory status epilepticus (SRSE), including new-onset refractory status epilepticus (NORSE). Vagus Nerve Stimulation (VNS) has emerged as a potential adjunctive therapy, but clinical evidence in SRSE is limited. We retrospectively identified patients who underwent VNS implantation for SRSE during hospitalization within a large tertiary hospital system in New York City (July 2018 - June 2024). Electronic medical records were reviewed for demographic, clinical features, neuroimaging, EEG findings, medications, VNS parameters, and short- and long-term functional outcomes. Fifteen patients (14 female; age 16-77 years) underwent VNS implantation for SRSE, including 8 with NORSE (6 cryptogenic; 2 with a later-identified etiology) and 7 non-NORSE patients. Compared to non-NORSE patients, NORSE patients received more ASMs (median 5 vs. 4) and anesthetic infusions (3 vs 2) for longer duration (14.5 vs. 11 days) before implantation. All but one patient was successfully weaned off anesthetics without SE recurrence; VNS output at weaning was higher in NORSE patients (0.88 vs. 0.50 mA). No complications were observed related to VNS implantation or titration. Despite longer hospitalization (86.5 vs 47 days) and similar ASM burden (4) and functional status at discharge (GOS-E 3), NORSE patients showed a trend toward better long-term functional outcomes (GOS-E 7 vs 1, p = 0.31), despite developing post-NORSE epilepsy. In exploratory analyses, earlier implantation showed non-significant trends toward shorter hospitalization (47 vs. 116 days, p = 0.09) and higher discharge GOS-E (4 vs. 2.5, p = 0.06). Our findings suggest that VNS is likely a safe addition to the established treatment for SRSE. However, given the retrospective and uncontrolled design, efficacy of VNS cannot be determined. Prospective controlled studies are needed to assess clinical benefit and to define optimal implantation timing, titration strategies, and short-and long-term outcomes, including post-NORSE epilepsy.
2025-01-13 | NORSE secondary to anti-GAD65 antibody-positive encephalitis treated with novel adjunctive rapid titration VNS protocol.
New Onset Refractory Status Epilepticus (NORSE) is a rare and severe condition characterized by refractory seizures in individuals without a prior history of epilepsy. This case report describes a 37-year-old woman diagnosed with anti-glutamic acid decarboxylase 65 (anti-GAD65) antibody-positive encephalitis-related NORSE. Her seizures were refractory to multiple interventions, including anti-seizure medications, anesthetics, immunotherapies, a ketogenic diet, and electroconvulsive therapy. Seizures recurred twice during the tapering of anesthetic medications. However, after 32 days of treatment, the seizures were successfully controlled. To maintain seizure control and facilitate the weaning of anesthetics, a Vagus Nerve Stimulator (VNS) was implanted using a novel rapid titration protocol. This allowed for the successful tapering of anesthetics by day 50, with no recurrence of seizures. At her 9-month follow-up, the patient remained seizure-free and had an improved quality of life. This case highlights that early initiation of immunosuppressive treatment may lead to a favorable prognosis. The novel application of VNS therapy assisted seizure control in NORSE, thus encouraging further research investigating the potential role of VNS in this condition. PLAIN LANGUAGE SUMMARY: New Onset Refractory Status Epilepticus (NORSE) is a rare and severe condition characterized by relentless seizures in individuals without a prior epilepsy history. This report shares the case of a 37-year-old woman with NORSE, associated with a high anti-glutamic acid decarboxylase 65 antibody titer. Her seizures were super-refractory, requiring multiple anti-seizure medications, anesthetics, immunotherapies, a ketogenic diet, and electroconvulsive therapy. Seizures recurred twice during the tapering of anesthetic medications. However, by hospital day 32, the seizures were successfully controlled with these interventions. To further stabilize seizure control and enable the successful discontinuation of anesthetics, a Vagus Nerve Stimulator (VNS) was implanted. The patient had no further seizures and gradually recovered back to her pre-disease baseline. This case suggests that a novel rapid VNS titration protocol could be a promising treatment option for NORSE, warranting further investigation.
2024-03-21 | Refractory status epilepticus arrested by vagus nerve stimulation.
A 54-year-old man developed altered mental state and generalised tonic-clonic seizures after 1 week of upper respiratory tract symptoms and diarrhoea, having been previously well. His MR scan of brain showed multifocal progressive T2 cortical signal changes. He was diagnosed with new-onset refractory status epilepticus (NORSE), initially treated as being secondary to autoimmune/paraneoplastic limbic encephalitis, although subsequent investigations were negative. His seizures and electrographic epileptiform activity continued despite escalating doses of antiseizure medications, immunosuppression with corticosteroids, immunoglobulins, plasma exchange and rituximab, and thereafter anaesthetic agents. A vagus nerve stimulator (VNS) was implanted 6 weeks after admission and its voltage rapidly increased over 4 days; his seizure activity resolved in the third week after VNS implantation. This case highlights the role of VNS in the early management of NORSE.
2023-11-14 | Role of Vagus Nerve Stimulation in Refractory and Super Refractory Status Epilepticus: A Pediatric Case Series
Background: Status epilepticus is a life-threatening condition that is defined as refractory (RSE) when the seizure activity continues despite treatment with benzodiazepine and a second appropriate treatment. Super refractory status epilepticus (SRSE) is an RSE that persists or recurs for ≥24 h. Few papers have reported the outcomes of pediatric patients affected by RSE and SRSE and treated with neuromodulation therapies. Vagus nerve stimulation (VNS) is an approved treatment for drug-resistant epilepsy. We present our findings of pediatric patients treated with VNS for RSE/SRSE. Methods: We present a case series of seven consecutive pediatric patients treated with VNS for SRSE since 2012 by a single surgeon in Monza and Padua. A rapid titration was started soon after implantation. We considered electroclinical data before and after VNS implantation and at the last follow-up. Results: We achieved the resolution of SRSE in five out of seven patients in a mean time of two weeks. At the last follow-up, these patients had a significant reduction of seizure burden without any relapse of SE. Discussion and Conclusions: Based on our limited findings, we discuss the potential role of VNS therapy in similar but distinct clinical contexts. For patients with drug-resistant epilepsy and RSE/SRSE, prompt VNS consideration is suggested, offering rapid responses and potentially reducing pharmacological load. Meanwhile, in NORSE/FIRES, we suggest early neuromodulation during the acute phase if standard treatments prove ineffective or not tolerated. This approach may leverage VNS’s potential anti-inflammatory effects and neuromodulation, enhancing patient-specific treatments. Expanding case studies and prolonged follow-ups are recommended to strengthen these clinical insights.
small molecules
2026-07-09 | Refractory epilepsy from lead poisoning.
Lead exposure remains a significant yet under-recognised public health concern in the UK, particularly among vulnerable paediatric populations. Its non-specific, multisystemic involvement and rare neurological presentations make recognition and timely treatment of lead poisoning especially challenging. We report a case of a 6-year-old boy with autism spectrum disorder and pica presenting with new-onset refractory status epilepticus, unresponsive to standard antiepileptic therapy. Diagnostic evaluation demonstrated microcytic anaemia with basophilic stippling on blood film, diffuse cortical changes on MRI and markedly elevated blood lead levels, establishing the diagnosis of acute-on-chronic lead poisoning. Treatment with intravenous sodium calcium edetate and polyethylene glycol bowel irrigation led to progressive clinical improvement and seizure resolution. Serial measurements confirmed a declining lead burden, and the patient was discharged on oral chelation therapy. This case highlights the importance of considering lead toxicity in unexplained encephalopathy or refractory seizures in children, with early recognition to prevent irreversible neurological sequelae.
2026-07-05 | Cenobamate use in super-refractory status epilepticus: A report of three cases.
Super-refractory status epilepticus (SRSE) is a neurological emergency with high morbidity and mortality. Cenobamate, a novel antiseizure medication, may be helpful in managing SRSE, but evidence is limited. This retrospective case series reports the use of cenobamate as add-on therapy in the management of three cases of SRSE. Median age at status epilepticus (SE) onset was 28 years (range 27-75). The etiologies of SRSE included one case of febrile infection-related epilepsy syndrome (FIRES), one patient with a probable genetic etiology (SCN7A variant of uncertain significance), and one case of unknown etiology. Cenobamate was introduced at a median of 27 days (range 13-103) after SE onset. Resolution of SRSE was observed after a median of 7 days (range 3-30) once cenobamate was started. Median dose of cenobamate at SRSE cessation was 25 mg/day (range 12.5-50 mg/day), and the median maintenance dose at the time of discharge was 200 mg/day (range 100-400 mg/day). Two patients died and one patient achieved functional independence. No severe medication side effects, specifically drug reaction with eosinophilia and systemic symptoms (DRESS), were observed. Cenobamate may have a role in the management of SRSE. Further studies are needed to define the optimal timing of initiation, titration strategy, and target dose of cenobamate in the context of SE.
2026-06-23 | Graph-based analysis of inflammatory profiles in New Onset Refractory Status Epilepticus (NORSE)
Background and Objectives: Cryptogenic new-onset refractory status epilepticus (cNORSE) represents one of the most severe forms of status epilepticus, occurring in patients without prior neurological disease, and remaining of unknown aetiology despite extensive diagnostic evaluation. Emerging evidence supports a role for immune dysregulation in cNORSE; however, marked heterogeneity in inflammatory signatures has been reported, complicating the selection of targeted immunotherapies. Therefore, a critical need for tools facilitating the interpretation of cytokine panels exists. Methods: Building on the identification of distinct inflammatory groups of cNORSE patients using a graph clustering approach applied to a cohort of 62 patients with serum profiling of 96 cytokines, we tailored new models to quantify attribution probability to biologically validated clusters. Statistical assessment of the most informative model involved Monte-Carlo simulations and custom-developed parametric tests. Ultimately, we applied our framework to the implementation of a clinician-friendly interface for inflammatory profiling. Results: Our approach enables quick processing of several cytokine profiles, providing the most likely inflammatory cluster, associated attribution probability, and statistical confidence. For longitudinal assessments, the proposed method may also allow tracking the evolution of inflammatory trajectories over time. Conclusion: Systematic statistical characterization of the inflammatory heterogeneity in cNORSE requires the development of clinically actionable support tools. Our study offers a framework that may support personalized immunomodulatory strategies in cNORSE patients through clustering-based cytokine profiling.
2026-06-15 | New-Onset Refractory Status Epilepticus (NORSE): A Comprehensive Review of Etiology, Pathophysiology, and Management
New-onset refractory status epilepticus (NORSE) represents one of the most challenging and clinically urgent presentations in modern neurology, defined as refractory status epilepticus occurring in a patient without preexisting epilepsy or an immediately identifiable acute structural, toxic, or metabolic cause. This condition, along with its febrile-associated subset known as febrile infection-related epilepsy syndrome (FIRES), carries disproportionate morbidity and mortality, with in-hospital mortality reaching 16–27% in adults and long-term survivors often left with drug-resistant epilepsy and significant cognitive disability. The etiological landscape of NORSE is characterized by a striking duality: in approximately half of rigorously investigated cases, no cause is identified despite extensive testing, while in the remainder, autoimmune encephalitis—most notably anti-NMDA receptor encephalitis—predominates, followed by paraneoplastic syndromes and uncommon viral or bacterial infections. Pathophysiologically, current evidence points toward an immune-mediated inflammatory cascade within the central nervous system, marked by cerebrospinal fluid cytokine overproduction, T-cell and glial activation, and possibly genetic predispositions involving human leukocyte antigen subtypes and interleukin-1 pathway variants. Clinically, patients typically experience a brief prodromal illness followed by a crescendo of focal motor seizures that rapidly evolve into refractory status epilepticus, requiring intensive care unit admission, continuous electroencephalographic monitoring, and aggressive treatment with intravenous anesthetic agents. Management follows a sequential paradigm: first-line benzodiazepines, second-line standard antiepileptic drugs, and third-line continuous anesthetic infusions for refractory cases. Given the high likelihood of an underlying autoimmune process, early initiation of immunotherapy—high-dose corticosteroids, intravenous immunoglobulin, or plasmapheresis—is recommended empirically while diagnostic testing proceeds. Second-line immunotherapies such as rituximab, cyclophosphamide, or anakinra may be considered in nonresponders. Despite these interventions, outcomes remain guarded, and an interprofessional team approach involving neurology, critical care, pharmacy, nursing, and palliative care is essential to optimize patient and family outcomes. This review synthesizes current evidence on NORSE, emphasizing the need for early recognition, systematic diagnostic evaluation, timely immunotherapy, and collaborative care.
2026-05-26 | Longitudinal changes in brain volume, cognitive function, and seizure outcomes in cryptogenic new-onset refractory status epilepticus.
To evaluate long-term structural, cognitive, functional, and seizure outcomes among survivors of cryptogenic new-onset refractory status epilepticus (C-NORSE) according to the timing of intravenous cyclophosphamide (IVCPA) initiation. We examined seven consecutive patients with C-NORSE treated between 2012 and 2025. Of those, super-refractory status epilepticus (SRSE, n = 5) cases were stratified into SRSE-Early IVCPA (IVCPA initiated within 20 days after seizure onset) and SRSE-Late/No IVCPA (IVCPA initiated >20 days after onset or not administered); the refractory status epilepticus (RSE) group served as a reference. 4 of the 5 SRSE patients received IVCPA (3 cases were classified as early and 1 case as late). We assessed whole-brain volume change quantified on serial MRI, neurocognition by standardized tests, functional outcomes by mRS, and seizure outcomes during the acute phase, at discharge, and in the chronic phase (≥1 year) among groups. The median follow-up was 5 years (range, 2-11 years). Whole-brain volume loss remained <10% in the RSE and SRSE-Early IVCPA groups, whereas marked medial temporal and diffuse brain atrophy developed in the two cases in the SRSE-Late/No IVCPA group, with whole-brain volume losses of 18.2% and 16.0%. Neurocognitive trajectories improved gradually in SRSE-Early IVCPA and showed severe chronic impairment in SRSE-Late/No IVCPA. Functional outcomes were excellent in SRSE-Early IVCPA and RSE but were poorer in SRSE-Late/No IVCPA. All patients developed drug-resistant epilepsy. In this case series, earlier IVCPA initiation in patients with SRSE due to C-NORSE was potentially associated with less chronic brain atrophy and more favorable neurocognitive and functional trajectories. Future studies are warranted to determine whether early seizure control plus immunotherapy reduces the risk of chronic drug-resistant epilepsy and improves long-term cognition.
proteins
2025-11-26 | Case Report: Successful multimodal management of FIRES in a pediatric patient using anakinra, ketogenic diet, and induced hypothermia.
Febrile infection-related epilepsy syndrome is a devastating, refractory epileptic encephalopathy that typically occurs in school-aged, otherwise healthy, children after a brief, non-specific, febrile illness. In this study, we discuss a case of a previously healthy 10-year-old girl with FIRES in whom high dosages of conventional and non-conventional antiepileptic drugs were ineffective in treating refractory status epilepticus, after which a treatment involving intravenous corticosteroids, immunoglobulins, a ketogenic diet, and induced hypothermia was adopted. We conducted a diagnostic workup that included lumbar puncture, blood tests, continuous electroencephalogram monitoring, brain MRI, and autoimmunity and infectious disease panels to shed light on the etiology of the condition. Our patient responded to immunosuppressive therapy and the ketogenic diet, and her condition gradually improved to full recovery with only mild neurocognitive sequelae. Although patients with FIRES have been described in the literature, optimal management has not yet seen the light of day, and therefore, prospective cohort studies are needed. This case highlights the potential benefit of a timely, multimodal therapeutic approach combining immunomodulation, metabolic support, and neuroprotection. Early administration of anakinra and initiation of a ketogenic diet may help control seizures and reduce the duration of ICU stay. Prompt diagnosis and interdisciplinary care are essential to improve outcomes in patients with this life-threatening pediatric condition.
2025-07-05 | Retrospective multicenter study on cryptogenic NORSE/FIRES patients treated with anakinra.
Refractory status epilepticus (RSE) is a neurological emergency characterized by persistent seizures despite two appropriate antiseizure medications. It is defined as new-onset RSE (NORSE) when occurring in previously healthy people. NORSE is defined as cryptogenic (cNORSE) when no cause is found. Febrile-infection related epilepsy syndrome (FIRES) is now defined as the cNORSE variant preceded by fever. In 2016 anakinra was reported effective in an anecdotal case. After this experience, second-line immunotherapy has been increasingly used, being incorporated in cNORSE recommendations in 2022. We conducted a retrospective study in an Italian case series of 14 patients with cNORSE (including FIRES cases) treated with anakinra in Italy before implementation of the international recommendations, that could serve as historical reference for futures studies based on the shared recommendations. In our population higher duration of intensive care stay period was associated with later time of anakinra use, although no evidence of efficacy on the long-term neurological outcome was demonstrated. There is an urgent need for well-designed head-to-head multicenter prospective clinical trials to clarify the benefits of available treatments and the role of biomarkers to guide choices.
2024-05-10 | 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.
2023-12-11 | The Beneficial Outcome of Subsequent Treatment with Anakinra during the Chronic Phase of Febrile Infection-Related Epilepsy Syndrome (FIRES): A Case Report
This case report presents the clinical course of an eight-year-old boy diagnosed with febrile infection-related epilepsy syndrome (FIRES) at the age of four. Following a febrile infection, the patient experienced his initial episode of serial generalized clonic seizures. The severity of his condition led to 11 hospital admissions, totaling 157 days of hospitalization. Anakinra was initially administered during the acute phase in 2019 but was discontinued after 29 days. In 2022, the patient experienced a chronic-phase exacerbation and underwent a second course of anakinra treatment, which demonstrated a positive effect on seizure activity. With a year of anakinra therapy, the patient exhibited significant improvement in both seizure frequency and severity. This report adds to the existing evidence supporting the potential use of anakinra in the treatment of FIRES, highlighting its effectiveness during the chronic phase and suggesting the potential benefits of subsequent administration.
2023-05-21 | 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.
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Drug Discovery Landscape
11 orphan drug designations for New-onset refractory status epilepticus, including 1 approved therapy.
11 orphan drug designations for New-onset refractory status epilepticus, including 1 approved therapy.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Ketamine Hydrochloride | small molecules | FDA | 2022-01-31 | — | PharmaTher Inc. |
phenobarbital sodium | small molecules | FDA | 2020-02-26 | — | Accord Healthcare Inc. |
midazolam | small molecules | FDA | 2018-01-30 | — | Crossject SA |
1-(2-chlorophenyl)-1-(S)-hydroxy-2-(S)-carbamoyloxy-propane | small molecules | FDA | 2016-07-07 | — | Bio-Pharm Solutions Co., Ltd. |
ganaxolone | small molecules | FDA | 2016-04-14 | — | Immedica Pharma AB |
midazolam | small molecules | FDA | 2016-02-18 | — | Laboratorios Lesvi, S.L. |
midazolam [SEIZALAM] | small molecules | FDA | 2016-02-04 | 2018-09-14 | Meridian Medical Technologies |
allopregnanolone | small molecules | FDA | 2014-04-20 | — | Sage Therapeutics |
alpha-1 proteinase inhibitor (human) | proteins | FDA | 2011-07-28 | — | Kamada, Ltd. |
Pr-320 (molecusol-carbamazepine) | small molecules | FDA | 1990-07-20 | — | Pharmos |
Pr-122 (redox-phenytoin) | small molecules | FDA | 1990-07-05 | — | Pharmos |
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