---
title: "Adaptive Immune Dysregulation in New‑Onset Refractory Status Epilepticus (NORSE)"
id: "frontiers-in-immunology-1-adaptive-immune-dysregulation-drives-new-onset-refractory-status-epilepticus"
canonical_url: "https://medichelpline.com/clinical-feed/frontiers-in-immunology-1-adaptive-immune-dysregulation-drives-new-onset-refractory-status-epilepticus"
content_type: "clinical_feed_article"
specialty: "Infectious Disease"
source_name: "Frontiers in Immunology"
source_url: "https://www.frontiersin.org/articles/10.3389/fimmu.2026.1874730"
published_at: "2026-07-30T00:00:00.000Z"
evidence_level: "Journal Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Adaptive Immune Dysregulation in New‑Onset Refractory Status Epilepticus (NORSE)
## Provenance & Clinical Metadata
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- **Specialty:** [Infectious Disease](https://medichelpline.com/clinical-feed/infectious-disease.md)
- **Primary Source:** Frontiers in Immunology
- **Source URL:** [Original Journal Publication](https://www.frontiersin.org/articles/10.3389/fimmu.2026.1874730)
- **Published At:** 2026-07-30T00:00:00.000Z
- **Evidence Rating:** Journal Feed
## Executive GIST (TL;DR)
- New‑onset refractory status epilepticus (**NORSE**) is an abrupt, life‑threatening presentation of refractory seizures in people without prior epilepsy, often requiring ICU care and prolonged anaesthetic therapy. It carries high mortality and frequent long‑term neurological deficits. - Autoimmune encephalitis (**AIE**) is a leading identified cause of NORSE; up to half of NORSE cases remain cryptogenic (c‑NORSE). AIE mechanisms include **B cell**‑driven autoantibodies against neuronal surface antigens and **T cell**‑mediated responses to intracellular antigens. - Literature to 2026 suggests a central role for immune dysregulation in NORSE, but prior work emphasized innate immunity; this review focuses on adaptive immune contributions, particularly **B cells**, **T cells**, and their interaction with cytokine networks. - Pro‑inflammatory cytokines reported elevated in NORSE include **IL‑6**, IL‑12p70, TNF‑α, CXCL8 (IL‑8), CCL2 and CCL3; higher cytokine levels correlate with worse outcomes. Persistent adaptive immune signatures (IL‑12p70, IL‑17A, TNF‑α) have been observed in c‑NORSE during the chronic phase. - Innate immune activation with monocyte–microglial responses is implicated in blood–brain barrier (BBB) disruption, facilitating peripheral lymphocyte entry and antigen exposure that may prime adaptive responses within the CNS. - B cell responses contribute via autoantibodies (eg, anti‑NMDAR, anti‑GABA receptors) that perturb receptor function and synaptic signalling; sustained IL‑6 can support plasmablast differentiation and intrathecal antibody synthesis. - T‑cell infiltration, especially CD8+ cytotoxic T cells, is documented in NORSE CNS tissue and CSF lymphocytosis; single‑cell transcriptomics show elevated T‑cell signatures beyond baseline surveillance. - CD8+ T cells recognize intracellular neuronal antigens (eg, GAD65, ANNA‑1/Hu, Ma2) presented on MHC I and can induce neuronal death via perforin and granzyme pathways; animal model data support a role for cytotoxic lymphocytes in seizure propagation. - The temporal ordering and causal hierarchy between innate cytokine storms and subsequent adaptive immune activation in AIE‑associated NORSE remain unproven; mechanistic links are hypothesised but not definitively established. - Therapeutic implications include targeting adaptive immunity (monoclonal antibodies, immunomodulators) and emerging strategies inspired by CAR‑T technology; existing agents that modulate T cells or cytokines are mentioned but detailed efficacy data are not reported in the source.
## Clinical Analysis & Structured Key Points
Frontiers | Adaptive immune dysregulation drives new-onset refractory status epilepticus REVIEW article Front. Immunol. , 30 July 2026 Sec. Autoimmune and Autoinflammatory Disorders : Autoimmune Disorders Volume 17 - 2026 | https://doi.org/10.3389/fimmu.2026.1874730 Published in Frontiers in Immunology Autoimmune and Autoinflammatory Disorders : Autoimmune Disorders 7 impact factor 11.3 citescore Editor & Reviewers Edited by V O Valentyn Oksenych Reviewed by F A Fahad Albassam D M Deepinder Maini S S Saboor Saeed Outline Figures and Tables Figure 1 View in article Figure 2 View in article Table 1 Autoimmune encephalitis targets, mechanisms, and association with NORSE. View in article Table 2 Comparative proposed immune mechanisms in animal model, AIE-associated NORSE and c-NORSE cases. View in article REVIEW article Front. Immunol. , 30 July 2026 Sec. Autoimmune and Autoinflammatory Disorders : Autoimmune Disorders Volume 17 - 2026 | https://doi.org/10.3389/fimmu.2026.1874730 Adaptive immune dysregulation drives new-onset refractory status epilepticus Z P Zhi-Ying Phong 1 S F Si-Lei Fong 2 K L Kheng-Seang Lim 2 S A Suhailah Abdullah 2 H L Hong-Gee Lee 3 C K Ching-Soong Khoo 4 C Y Chung Yeng Looi 5,6 W F Won Fen Wong 1 * 1. Department of Medical Microbiology, Faculty of Medicine, Universiti Malaya, Kuala Lumpur, Malaysia 2. Division of Neurology, Department of Medicine, Faculty of Medicine, Universiti Malaya, Kuala Lumpur, Malaysia 3. Department of Clinical Pharmacy and Pharmacy Practice, Faculty of Pharmacy, Universiti Malaya, Kuala Lumpur, Malaysia 4. Neurology Unit, Department of Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia 5. School of Biosciences, Faculty of Health & Medical Sciences, Taylor’s University, Subang Jaya, Malaysia 6. Department of Biotechnology, Faculty of Applied Sciences, UCSI Universitiy, Cheras, Malaysia See more Article metrics View details Abstract 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. 1 Introduction Epilepsy is the second most prevalent neurological disorder worldwide, affecting approximately 50 million people. It is a chronic, noncommunicable condition characterised by recurrent seizures arising from an imbalance between excitatory and inhibitory neuronal activity in the brain, resulting in hypersynchronous and excessive electrical discharges that disrupt normal neuronal function ( 1 ). Status epilepticus (SE) is a life-threatening neurological emergency defined by prolonged seizure activity, including generalised tonic-clonic seizures lasting beyond 5 min or focal seizures exceeding 10 min ( 2 ). Management of SE requires a rapid, stepwise escalation. First-line treatment involves immediate administration of a benzodiazepine to achieve early seizure termination. If seizures persist, second-line therapy consists of an intravenous anti-seizure medication, such as levetiracetam. When seizures continue or recur despite these first- and second-line interventions, the condition is termed refractory status epilepticus (RSE) and necessitates third-line therapy with continuous intravenous anaesthetic agents. Persistent or recurrent seizure activity despite anaesthetic treatment is classified as super-refractory status epilepticus (SRSE). New-onset refractory status epilepticus (NORSE) is neither a distinct diagnosis nor a clinical entity; rather, it is a terminology used to describe the clinical presentation. NORSE refers to a presentation in individuals without a prior history of epilepsy or other pre-existing relevant neurological disorder who develop new-onset RSE in the absence of a clear acute or active structural, toxic, or metabolic cause ( 3 ). A population-based study in Eastern Finland estimated the incidence rate of NORSE to be around 0.65 per 100,000 person-years ( 4 ). Febrile infection-related epilepsy syndrome (FIRES) is a subgroup of NORSE that is typically preceded by a prior febrile illness two weeks to 24h before the onset of seizure, with or without fever at the onset of SE ( 3 ). Mortality in NORSE and FIRES remains substantial, estimated at approximately 10% in children and up to 30% in adults ( 5 – 8 ). Among survivors, the outcomes are frequently devastating. A large proportion develop chronic, drug-resistant epilepsy, requiring long-term multidrug therapy with limited seizure control. In addition, many patients experience permanent neurocognitive impairment, including deficits in memory, attention, and executive function, often accompanied by behavioural and psychiatric disturbances. Functional independence is commonly compromised, which significantly impacts the quality of life. NORSE may arise from diverse aetiologies, including viral infections, rare genetic factors, and autoimmune encephalitis (AIE) ( 6 ). Notably, up to 50% of NORSE cases remain cryptogenic (c-NORSE) with no identifiable underlying cause, and these cases are often associated with poorer clinical outcomes ( 9 ). Among cases with an identified aetiology, AIE represents a leading cause ( 9 ). Mechanistically, AIE can be broadly classified into two major categories ( 10 ). The first comprises antibody-mediated disease, in which autoreactive B cells produce pathogenic autoantibodies targeting neuronal surface antigens such as antibodies against N-methyl-D-aspartate (NMDA) receptor and γ-aminobutyric acid (GABA A /GABA B ) receptors, leading to receptor dysfunction and synaptic disruption. The second category involves T cell–mediated disease, in which intracellular neuronal antigens are presented on major histocompatibility complex (MHC) class I molecules and recognised by cytotoxic CD8 + T cells, resulting in direct neuronal injury through cell-mediated cytotoxicity. The growing recognition of AIE as a leading identifiable cause of NORSE, underscores the central role of immune dysregulation in disease pathogenesis. NORSE is a clinical presentation rather than a specific diagnosis. Critically ill NORSE/FIRES patients are often intubated and mechanically ventilated, requiring prolonged intensive care unit (ICU) stays. These patients are at exceptionally high risk of malnutrition due to catabolic stress from ongoing seizures, parenteral/enteral feeding, and altered gastrointestinal function. In addition, sepsis, intercurrent infections, and the development of multiorgan dysfunction can further alter the systemic and central nervous system cytokine responses. Similarly, aggressive therapies, including administration of sedatives, anaesthetic agents, and antiseizure medications, may also influence the immune signatures. Collectively, these factors can independently contribute to elevations in both pro- and anti-inflammatory cytokines. These overlapping pathophysiology mechanisms complicate the interpretation of cytokine profiles in NORSE/FIRES, as these confounding factors may significantly exaggerate or obscure the true inflammatory state in these disorders ( 8 , 11 ). While both antibody-mediated and T cell–mediated mechanisms contribute to neuronal dysfunction, increasing evidence highlights a complex interplay between autoreactive B cells, pathogenic autoantibodies, T cell–driven responses, and cytokine-mediated inflammatory networks that sustain seizure activity. These observations emphasise the need to move beyond aetiological classification towards a unified mechanistic framework integrating adaptive immune responses with cytokine signalling. Accordingly, this review focuses on the roles of B cells and autoantibodies, T cell–mediated immunity, and their interactions with pro-inflammatory cytokine networks. In particular, understanding how these immune components influence blood–brain barrier (BBB) integrity, immune cell trafficking, and neuroinflammation will be critical for elucidating disease progression and guiding therapeutic strategies in NORSE. 2 Methods This narrative review was conducted using a non-systematic literature search of PubMed, Scopus, and Web of Science to identify relevant studies published up to 2026. The search focused on literature related to NORSE, B cell, or T cell–mediated immune mechanisms, and cytokine profiling ( Supplementary Table 1 ). Original research articles, including cohort studies, case series, and case reports, were considered, with higher priority given to studies providing stronger clinical or mechanistic evidence, such as cohort studies and larger case series. Additional relevant references were identified through manual screening of the reference lists of eligible articles. The included literature was critically evaluated based on study design, sample size, methodological rigour, consistency of findings, and relevance to the review objectives. Given the rarity of NORSE and the limited availability of high-level evidence, findings from well-documented case reports were also incorporated where they provided important mechanistic or clinical insights. 3 Pro-inflammatory cytokine networks driving neuroinflammation and BBB disruption in NORSE In NORSE, markedly elevated levels of serum pro-inflammatory cytokines have been reported, including interleukin 6 (IL-6), IL-12p70, tumour necrosis factor alpha (TNF-α), and key chemokines such as C-X-C motif chemokine ligand 8 (CXCL8/IL-8), C-C motif chemokine ligand 2 (CCL2) and CCL3. Notably, higher concentrations of these cytokines correlate with poorer clinical outcomes ( 12 ). These pro-inflammatory mediators converge on shared inflammatory pathways that amplify immune activation and contribute to disease progression in NORSE. Interestingly, whilst most serum pro-inflammatory cytokines decline over time following SE resolution, c-NORSE patients exhibit persistent or evolving immune activation during the chronic phase, a period of at least 3 months after SE resolution when post-NORSE epilepsy may develop ( 13 , 14 ). This is characterised by sustained elevated serum levels of adaptive immune disturbances, including IL-12p70, IL-17A, and TNF-α, coinciding with the development of post-NORSE epilepsy ( 13 ). Furthermore, dysregulated innate immunity in NORSE, characterised by monocyte–microglial activation and a pro-inflammatory cytokine milieu, is thought to drive BBB dysfunction, antigen presentation and lymphocyte activation, thereby potentially bridging early innate responses with downstream adaptive autoimmunity in susceptible patients ( 15 ). In general epilepsy, IL-6 is associated with promoting neuroinflammation and disrupting blood–brain barrier (BBB) integrity, whilst TNF-α further amplifies inflammatory signalling cascades. In parallel, CXCL8 drives neutrophil recruitment, whereas CCL2 and CCL3 facilitate monocyte recruitment and microglial activation via C-C chemokine receptor type 2 (CCR2) and CCR5, respectively. These coordinated processes enhance immune cell trafficking into the central nervous system (CNS), exacerbating neuroinflammation and tissue injury. Consistent with this, patients with NORSE exhibit increased BBB permeability, particularly in the thalamus and basal ganglia compared with encephalitis patients without SE, thereby permitting leukocyte extravasation into the CNS ( 16 ). This heightened and predominantly innate immune activation has been linked to astrogliosis, BBB disruption, and long-term neurological sequelae following NORSE ( 17 ). However, direct causal relationships between individual cytokines, BBB disruption, and immune cell infiltration in NORSE have not been definitively established. It is hypothesised that, in AIE-associated NORSE, acute cytokine storms involving IL-6, TNF-α, CXCL8, and related mediators may promote BBB disruption and permit non-specific (polyclonal) trafficking of peripheral immune cells into the CNS. Following entry into the inflamed CNS, B cells may encounter neuronal surface antigens such as NMDAR, supporting a model in which activation and selection of antigen-specific clones may occur. Within the CNS pro-inflammatory microenvironment, sustained IL-6 signalling may enhance the survival of activated B cells, plasmablast differentiation and clonal expansion, which may be associated with intrathecal antibody synthesis targeting NMDAR. Persistent inflammatory signalling may facilitate adaptive immune priming by enhancing antigen presentation, promoting T-cell activation, and supporting clonal expansion and long-term survival of autoreactive lymphocyte populations. Following resolution of the acute phase, innate cytokine levels may decline, followed by a transition towards adaptive immune-dominated activity. In particular, IL-12p70, IL-17A, and TNF-α contribute to the maintenance of pro-inflammatory T-cell effector memory phenotypes by promoting T (T H ) helper cell differentiation, particularly T H 1 and T H 17 lineages. These activated T cells may in turn contribute to sustained activation of autoreactive B-cell clones, including NMDAR-specific B-cell responses through cytokine signalling and cell–cell interactions. Collectively, these processes may sustain long-term neuroimmune activation and potentially contribute to post-NORSE epileptogenesis. Nevertheless, there is no definitive evidence establishing the temporal sequence or causal hierarchy of innate and adaptive immune activation in AIE-mediated NORSE or c-NORSE. The proposed mechanistic linkage between these immune compartments therefore remains hypothetical. 4 T-cell infiltration and activation in NORSE Emerging evidence indicates increased T-cell infiltration in the brain of NORSE patients, consistent with the findings reported in epilepsy ( 15 , 16 , 18 ). This is supported by the presence of CSF pleocytosis, with a median CSF white blood cell count of 18/μl, predominantly comprising lymphocytes ( 15 ). Such lymphocyte predominance is further corroborated by single-cell transcriptomic data demonstrating T-cell presence exceeding baseline immune surveillance levels in the CNS of NORSE patients ( 18 ). Similarly, neuropathological studies in NORSE indicate that 14% of the cases exhibit perivascular leukocyte infiltration within the CNS, predominantly consisting of CD8 + T cells ( 19 ). This infiltration is likely facilitated by BBB disruption and a concurrent pro-inflammatory milieu that promotes immune cell trafficking into the CNS. From a therapeutic perspective, targeting T cell–mediated inflammation may offer clinical benefit. 4.1 CD8 + cytotoxic T cell–mediated neuronal injury in NORSE T cells in the hippocampus of NORSE patients exhibit greater functional activity than those in the cortex, as indicated by gene expression signatures associated with CD8 + cytotoxic activity, apoptosis, and immune infiltration ( 18 ). Apart from human studies, complementary evidence from animal models reinforces this association, as studies using pilocarpine-induced epilepsy in mice and rats demonstrate increased splenic CD3 + and CD8 + T-cell populations, highlighting a contributory role of lymphocytes in seizure development ( 20 ). Furthermore, perforin, a key cytolytic effector released upon CD8 + T-cell activation, has been identified as a critical mediator linking peripheral intravascular inflammation to seizure activity ( 20 ), in part through the induction of vascular permeability and BBB disruption ( 21 ). CD8 + cytotoxic mechanisms are well established in AIE associated with intracellular antigens, such as anti-glutamic acid decarboxylase 65 (GAD65), anti-Hu (anti-neuronal nuclear antibody type 1, ANNA-1), and anti-Ma2 (Paraneoplastic Ma antigen 2, PNMA2) encephalitis ( Figure 1 ) ( 22 ). These intracellular neuronal antigens serve distinct physiological functions within the CNS. GAD65 catalyzes the conversion of GABA, thereby maintaining excitatory–inhibitory balance. The Hu protein is neuronal RNA-binding protein involved in the regulation of mRNA stability, splicing, and a neuronal differentiation, whereas Ma2 is implicated in neuronal signalling and survival, although its precise role remains incompletely defined. Figure 1 Proposed mechanism of B-cell and T-cell involvement in AIE-mediated NORSE. Disruption of the BBB facilitates infiltration of peripheral immune cells into the CNS. CXCL13 released by stromal cells drives B-cell recruitment whereas MCAM promotes T-cell adhesion to brain microvascular endothelial cells and transmigration across the BBB. Infiltrating T H 1 and T H 17 cells release pro-inflammatory cytokines such as IFN-γ, TNF-α, IL-17A, and IL-23a, which promote the pro-inflammatory state of microglia and astrocytes. M1 microglia and A1 astrocytes further amplify oxidative stress and excitotoxicity through pro-inflammatory cytokine production, ultimately leading to neuronal and axonal injury. Meanwhile, excessive pro-inflammatory mediators impair T REG function by disrupting IL-10 signalling, leading to reduced FOXP3 expression. Reduced T REG numbers result in decreased production of anti-inflammatory cytokines such as IL-10 and TGF-β. The neuroprotective effect of T REG via CD47-SIRPα signalling is also diminished. Existing immunotherapies, including tacrolimus and tofacitinib, can inhibit T-cell activation and differentiation, whereas tocilizumab and anakinra reduce pro-inflammatory cytokine signalling. In NORSE secondary to AIE, B cells produce antibodies against neuronal cell-surface antigens such as NMDAR, AMPAR, GABA A R, or GABA B R, causing receptor internalization and synaptic dysfunction. CD8 + cytotoxic T cells recognise intracellular neuronal antigens including GAD65, ANNA-1, or Ma2, and induce neuronal damage via perforin-mediated pore formation and granzyme-dependent apoptosis. Ultimately, these mechanisms lead to neuronal injury, disruption of excitatory–inhibitory synaptic balance, network hyperexcitability, and seizure generation and perpetuation. In these conditions, intracellular neuronal antigens are processed and presented on MHC class I molecules, triggering autoreactive CD8 + cytotoxic T-cell responses. Upon activation, these cells induce neuronal injury through perforin-mediated membrane pore formation and granzyme B–dependent activation of caspase pathways, leading to apoptosis. Notably, this cytotoxic process occurs irrespective of the presence of detectable autoantibodies, indicating that neuronal injury is predom
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