Jul 2026· International Journal of Epilepsy· 0 citations· 34 references
Abstract
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.
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
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.
Autoimmune-associated epilepsy (AAE) is the epilepsy phenotype most likely to be missed in neurology clinics. Neural autoantibodies are identified in a substantial fraction of adults with epilepsy of unknown aetiology, mostly undiagnosed before testing, and in a sizeable proportion of new-onset refractory status epilepticus (NORSE) and febrile infection-related epilepsy syndrome (FIRES). The barrier to recognition is not the absence of effective therapy, but the absence of systematic testing: autoimmune epilepsy is not rare; it is rarely tested. This review argues for a shift from antibody-driven testing ("test when encephalitis is suspected") to syndrome-driven testing ("epilepsy-plus" phenotypes triggering a reflex panel). We synthesise the 2016-2026 literature across three axes. First, an antibody-by-antibody guide (Table 1) contrasts surface-antigen syndromes (LGI1, NMDAR, CASPR2, GABA-B, GABA-A, AMPA) with the intracellular-antigen GAD65 syndrome. Second, a twelve-domain Red Flag Checklist (Table 2) operationalises the "epilepsy-plus" concept, with a ≥2-flag trigger rule mandating reflex testing of paired serum and cerebrospinal fluid. Third, a 2026 immunotherapy algorithm (Table 3) stratifies first-line, second-line, and refractory therapy on the principle that timing is the active ingredient. We address three ongoing debates - GAD65 low- versus high-titre pathogenicity, seronegative AAE, and immunotherapy duration - proposing a risk-stratified, treat-to-remission framework. The cost of delay is measurable in hippocampi, cognitive function, and lives; the barrier is not cost but habit.
Szymon Skrzypek, Oliwia Żmuda, Natalia Skórka et al.· International Journal of Inn...· 0 citations
Autoimmune encephalitis (AE) comprises clinically and immunopathologically heterogeneous central nervous system disorders whose early recognition should be syndrome-based and should not depend on antibody results alone. Cerebellar and brainstem manifestations occur in selected AE and related central nervous system neuroimmune disorders, but their frequency, anatomical specificity, and mechanisms remain incompletely defined. In this narrative Review, we use the cerebellum–brainstem network as an anatomical and clinical organizing framework rather than proposing a discrete anatomical axis or a new disease entity. In selected neuronal-surface-antibody disorders, antibodies can directly alter receptor trafficking, receptor availability, protein interactions, or synaptic transmission, whereas intracellular-antigen-associated and paraneoplastic syndromes are more often linked to cytotoxic T-cell-dominant neuronal injury. To stabilize disease scope, central AE and directly relevant central nervous system autoimmune syndromes form the core evidence base; immune-mediated cerebellar ataxias, paraneoplastic syndromes, acute disseminated encephalomyelitis, and myelin oligodendrocyte glycoprotein antibody-associated disease are included only when they provide direct infratentorial evidence; and Miller Fisher syndrome and Guillain–Barré syndrome are retained solely as peripheral anatomical comparators, whereas Bickerstaff brainstem encephalitis represents a central brainstem syndrome. We present a hypothesis-generating circuit framework linking immune target engagement to cerebellar output and connected brainstem manifestations, while explicitly marking extrapolations from non-AE models as hypotheses [H]. We also distinguish a predominantly functional pattern from an established structural-injury pattern as non-sequential research constructs rather than stages, biomarker-defined transitions, treatment windows, or clinical algorithms. Current imaging studies demonstrate that infratentorial metabolic and structural abnormalities can occur, but no reproducible cerebellum–brainstem diagnostic, prognostic, or treatment-selection signature has been prospectively validated.
Yan Li, Yuyuan Hu, Yuhang Yang et al.· Frontiers in Immunology· 0 citations
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.
Z. Phong, Si-Lei Fong, Kheng-Seang Lim et al.· Frontiers in Immunology· 0 citations
Autoimmune encephalitis associated with neuronal autoantibodies is increasingly recognized in veterinary medicine. In cats, previously reported antibodies have primarily targeted components of the voltage-gated potassium channel complex, such as leucine-rich glioma-inactivated 1 (LGI1) and contactin-associated protein-like 2 (CASPR2). Anti-metabotropic glutamate receptor 1 (mGluR1) antibodies are well described in human medicine but have not previously been reported in cats. A 5.5-month-old female domestic shorthair cat was presented for recurrent epileptic seizures and episodic behavioral abnormalities, including pica. Neurological examination revealed mild pelvic limb ataxia. Based on the history of epileptic seizures and behavioral abnormalities, the neuroanatomical localization was consistent with the forebrain. Magnetic Resonance Imaging (MRI) of the brain and cerebrospinal fluid (CSF) analysis were unremarkable. Infectious disease testing from CSF, including polymerase chain reaction (PCR) assays for Feline Coronavirus, Toxoplasma gondii, Feline Herpesvirus, and Rustrela virus, was negative. Neural antibody testing using tissue-based and cell-based assays identified an elevated serum mGluR1 antibody titer (1:80; reference <1:20), whereas cerebrospinal fluid and tissue-based assays were negative. Testing for other neuronal autoantibodies, including LGI1 and CASPR2, was negative. Following optimization of antiseizure therapy, the cat showed clinical improvement, accompanied by a decrease in the serum mGluR1 antibody titer. This report describes the first detection of mGluR1 antibodies in a cat with neurological disease and suggests a potential association between mGluR1 autoimmunity and epileptic seizures and episodic behavioral abnormalities in a cat.
Magdalena Putzer, A. Hörmann, Viktoria Stegfellner et al.· Frontiers in Veterinary Scie...· 0 citations