This review synthesises current evidence linking adaptive immune responses in NORSE pathogenesis, with particular emphasis on B and T lymphocytes in shaping neuroinflammation, and discusses emerging immunomodulatory therapies targeting adaptive immune components.
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.
This review synthesizes advances in neuroimmunology, clinical phenotyping, diagnostics, immunomodulatory and antiseizure therapies, neuromodulation, and patient and family centered outcomes, and outlines future directions focused on biomarker-driven precision medicine, disease-modifying strategies, and interdisciplinary care models.
Alica M. Goldman, Nora Wong, A. Vezzani et al.· Epilepsy Currents· 0 citations
Abstract Autoimmune epilepsy, once regarded as a rare and poorly understood subset of seizure disorders, has now emerged as a clinically significant and potentially reversible cause of epilepsy. Advances in neuroimmunology have substantially broadened the spectrum of neural autoantibodies implicated in epileptogenesis—particularly those directed against neuronal cell surface and synaptic proteins, such as the N-methyl-D-aspartate receptor (NMDAR), leucine-rich glioma-inactivated protein 1 (LGI1), contactin-associated protein-like 2 (CASPR2), and glutamic acid decarboxylase 65 (GAD65). Distinct autoantibody profiles are now recognized to correlate with characteristic clinical syndromes, facilitating earlier and more targeted diagnosis. For instance, faciobrachial dystonic seizures are highly suggestive of LGI1 antibody-mediated encephalitis, while neuropsychiatric manifestations and movement disorders are typical of NMDAR antibody encephalitis, and chronic temporal lobe epilepsy frequently accompanies GAD65 autoimmunity. Early identification of these immune-mediated forms is critical, as antibody-mediated epilepsies involving cell surface antigens often respond favorably to immunotherapy, leading to substantial recovery. In contrast, epilepsies associated with intracellular antigen targets or cytotoxic T-cell–driven mechanisms, such as Rasmussen encephalitis, typically show poor therapeutic response due to irreversible neuronal injury. Some autoimmune encephalitides also occur as paraneoplastic syndromes, underscoring the importance of comprehensive oncological evaluation in affected patients. Moreover, immune dysregulation has been implicated in catastrophic epileptic conditions such as new-onset refractory status epilepticus and febrile infection-related epilepsy syndrome, further broadening the clinical spectrum of autoimmune-mediated seizures. Although seizures may arise from diverse etiologies, immune mechanisms have gained increasing recognition as an important and potentially modifiable contributor to epileptogenesis. This recognition has been formally endorsed by the International League Against Epilepsy, which classifies autoimmune epilepsy as a distinct diagnostic entity. Nevertheless, true autoimmune epilepsy, in which seizure susceptibility persists after resolution of encephalitic activity, remains relatively uncommon. In most cases, seizures associated with autoimmune encephalitis are acute and reversible with timely immunotherapy. Thus, precise terminology—differentiating acute symptomatic seizures from chronic autoimmune-associated epilepsy—is essential for appropriate management, prognostication, and research standardization.
Monika Singla, Abhishek Dixit, M. Mehndiratta· International Journal of Epi...· 0 citations
Rasmussen's encephalitis (RE) is a rare and devastating immune-mediated epileptic encephalopathy characterized by drug-resistant seizures, progressive hemispheric atrophy, and irreversible neurological decline. Although T-cell-driven neuroinflammation and microglial activation are recognized pathological hallmarks, current models remain insufficient to explain the relentless chronic progression and the limited long-term efficacy of immunotherapies. Here, we propose an integrative neuroinflammation-network remodeling feedback framework to conceptualize RE as a self-sustaining immune-network disorder rather than a purely inflammatory disease. In this model, immune-mediated cytotoxicity, persistent activation of tissue-resident memory T cells, and glial dysregulation converge to disrupt synaptic homeostasis and large-scale network organization. Recurrent epileptic discharges and focal neuroinflammation synergistically compromise blood-brain barrier integrity, facilitating sustained immune infiltration and amplifying glial-driven inflammatory cascades. These processes, in turn, promote excitatory-inhibitory imbalance, pathological network synchronization, and progressive neuronal loss, reinforcing a vicious cycle of network instability and immune activation. This framework integrates immune mechanisms, glial-synaptic interactions, and network-level dysfunction into a unified pathogenic continuum. It thereby explains why interventions targeting only a single aspect, such as immunotherapy or surgical seizure control alone, consistently fail to halt disease progression. Importantly, it highlights the rationale for stage-specific, multi-target therapeutic strategies aimed at simultaneously modulating immune responses and restoring network stability. Beyond RE, this conceptual model provides a broader paradigm for understanding chronic epileptic and neuroimmune disorders driven by maladaptive immune-network coupling.
Yujie Bo, Chongyang Tang, Xiongfei Wang et al.· Autoimmunity Reviews· 0 citations
Abstract Introduction Rasmussen’s encephalitis (RE) is a rare immune-mediated neurological disorder characterized by refractory focal epilepsy, progressive neurological deficits, and unilateral cerebral atrophy. Although typically a pediatric disease, adult-onset cases account for fewer than 10% of reported diagnoses and remain poorly characterized. Early recognition and prompt immunotherapy are critical to limit irreversible neurological damage. Case Presentation We report the case of a 46-year-old woman with adult-onset RE presenting with focal non-motor seizures and progressive cognitive impairment. Neuroimaging demonstrated progressive left hemispheric atrophy with hippocampal and mammillary involvement, while continuous electroencephalographic monitoring revealed persistent left frontotemporal epileptogenic activity. Cerebrospinal fluid analysis showed intrathecal antibody synthesis. Immunotherapy with oral tacrolimus was initiated, resulting in stabilization of cognitive decline and reduction of seizure frequency from approximately 30–40 to 15–20 episodes per day. Due to persistent seizures and intolerance to multiple antiseizure medications (ASMs), a classical ketogenic diet was introduced as adjunctive therapy, leading to an additional reduction in seizure frequency of approximately 50% 6 months after initiation, and subjective stabilization of cognitive symptoms despite minimal change in screening scores. Seizure control and clinical state have remained stable up to current follow-up, almost 5 years after combined treatment initiation. Conclusion This case highlights the potential therapeutic benefit of combining immunomodulatory therapy with ketogenic dietary intervention in adult-onset RE. Beyond its established role in refractory epilepsy, ketogenic therapy may exert anti-inflammatory and neurometabolic effects through modulation of microglial activation, cytokine signaling, and cellular metabolism pathways implicated in RE pathogenesis. The combination of tacrolimus and a ketogenic diet was associated with substantial seizure reduction and stabilization of cognitive impairment in this patient with adult-onset RE. These findings suggest that ketogenic dietary therapy may represent a promising adjunctive therapeutic strategy alongside immunomodulatory treatment in this rare and challenging condition. Further studies are needed to clarify its role in disease progression and seizure control.
Sergio Andrés Salgado Rueda, Nicolás Moreno Guerra, Jorge Luis Vargas Rojas· Case Reports in Neurology· 0 citations
Autoimmune encephalitis (AE) is an increasingly recognised cause of subacute encephalopathy, behavioural change, seizures, and movement disorders in children. The recognition of antibody-mediated syndromes—principally anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis—has transformed the field, and refined diagnostic criteria now allow earlier treatment initiation. However, diagnostic delay remains common in paediatric practice and contributes to long-term neurocognitive morbidity. We review the contemporary spectrum of paediatric autoimmune encephalitis, including anti-NMDAR encephalitis, MOG antibody-associated disease overlap syndromes, and seronegative AE phenotypes, with emphasis on early recognition, diagnostic algorithms, immunotherapy, and long-term outcomes. Anti-NMDAR encephalitis is the most frequent paediatric AE worldwide, characterised by behavioural change, language regression, seizures, dyskinesias, and autonomic instability; ovarian teratoma is uncommon in prepubertal children. MOG antibody-associated disease can present with encephalopathy, particularly in younger children, often with concurrent demyelinating features. Seronegative AE poses particular diagnostic challenges. Across cohorts, diagnostic delay is associated with worse outcomes, more relapses, and persistent cognitive, behavioural, and academic difficulties. Earlier recognition through clinician education, paediatric-specific diagnostic algorithms, and rapid antibody testing pathways is essential. Long-term neurocognitive surveillance and individualised rehabilitation are critical, even in children with apparently good motor recovery. Research priorities include validation of paediatric-specific diagnostic criteria, biomarker-guided immunotherapy escalation, and population-based cohorts capturing developmental trajectories.
Current evidence on advances in clinical research and immunotherapy across the major autoimmune CNS disease groups is synthesized, with a particular focus on trial designs, endpoints, and the evolution from observational cohorts to randomized controlled trials.