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:
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.
2026-07-09 | 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.
2026-08-14 | 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.
2026-07-09 | 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.
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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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