AUTOIMMUNE EPILEPSY: THE UNDERESTIMATED DIAGNOSIS - FROM RED FLAGS TO IMMUNOTHERAPY

Autoimmune Epilepsy: Insights into Pathophysiology, Diagnostic Strategies and Treatment

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.

Frequency of anti‐neural antibodies and autoimmune epilepsy in focal epilepsy of unknown etiology: An observational study in a Singaporean cohort

Abstract Objective Autoimmune epilepsy (AES) is increasingly recognized as a condition in patients with epilepsy of unknown etiology. Early immunotherapy improves outcomes; however, data on its prevalence and the frequency of anti‐neural/neuronal antibodies in Asian populations remain scarce. Herein, we aim to (1) evaluate the frequency of serum anti‐neuronal/neural antibodies, (2) compare the clinical characteristics between seropositive and seronegative patients, and (3) explore the clinical utility of the ACES (Antibodies Contributing to Focal Epilepsy Signs and Symptoms) score in diagnosing AES in a cohort of Singaporean patients with focal epilepsy of unknown etiology. Methods This was a cross‐sectional, observational, single‐center study performed at the National Neuroscience Institute (NNI), Singapore. Patients with focal epilepsy of unknown etiology were prospectively recruited. Serum samples were tested using both cell‐based (CBA) and immunohistochemistry (IHC)‐based tissue assays. Patients were classified into definite, probable, and possible AES based on antibody positivity. Clinical characteristics, MRI and EEG findings, and ACES scores were analyzed. Results One‐hundred‐and‐twenty patients were included. Nine patients (7.50%) were seropositive on IHC, while 2 patients (1.67%) were positive on CBA (1 with concomitant IHC positivity, 1 without). In total, 10 patients (8.33%) were seropositive on IHC and/or CBA. Seropositivity was associated with female sex, autoimmune and psychiatric comorbidities, behavioral changes, speech problems, abnormal MRI brain, medial temporal T2/FLAIR hyperintensities, and ACES ≥2. AUC of ACES for seropositivity was 0.878; sensitivity and specificity were 60.0% and 96.4% respectively at a cutoff of ≥2. Significance The frequency of specific, well‐characterized anti‐neural/neuronal antibodies in focal epilepsy of unknown etiology is low in Singapore. Distinct clinico‐radiological features, in particular those that comprise the ACES score, were useful in identifying AES. Their presence should prompt antibody testing to confirm the diagnosis of AES for earlier immunotherapy. Plain Language Summary This study performed in Singapore investigated autoimmune epilepsy in people who have focal epilepsy with no clear cause. Researchers tested blood samples for antibodies linked to autoimmune epilepsy and compared clinical features between patients with and without these antibodies. Out of 120 patients, 10 had positive antibody tests—they were more often female, more likely to have autoimmune or psychiatric conditions, behavior or speech problems, and abnormal brain MRI findings. An ACES score of 2 or more was useful for identifying patients with antibodies. Using these clinical features can help clinicians decide who should be tested and treated earlier.

Pediatric autoimmune encephalitis: diagnostic delay and long-term neurocognitive outcomes - a narrative review

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.

Neuroimmunology of Epilepsy: Mechanisms, Treatments, and Clinical Insights

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.

Sensitivity of the UT-Hopkins Score in 350 patients with antibody-mediated autoimmune encephalitis

Copine-5-IgG-related autoimmune encephalitis: a novel paraneoplastic neurological syndrome with a strong melanoma association

Although significant progress has been made in identifying antigen targets in autoimmune encephalitis (AIE), in a substantial proportion of patients with presumed AIE no known autoantibodies can be detected. Herein, we describe a novel autoantibody reactivity, directed against copine-5 (CPNE5), in patients with AIE and melanoma. Patients were identified through routine clinical testing for anti-neural autoantibodies by indirect immunofluorescence on neuronal tissue sections. The antigen was identified by immunoprecipitation and mass spectrometry and confirmed by recombinant protein assays. Serum and cerebrospinal fluid (CSF) immunoglobulin G (IgG) from four patients was found to exhibit distinct binding to cerebellar and hippocampal neurons. Copine-5 was identified as the target antigen. Clinical manifestations included cognitive decline, confusion/disorientation, psychosis, seizures and signs and symptoms compatible with basal ganglia involvement (movement disorders, including secondary parkinsonism, and/or abulia/akinetic mutism), alongside pain (including painful tonic spasms and focal allodynia), dysarthria, dysphagia, and abducens nerve palsy. Brain magnetic resonance imaging disclosed hyperintense lesions in the basal ganglia and the temporal lobe. CSF analysis revealed mild pleocytosis, intrathecal IgG synthesis, and blood/CSF barrier dysfunction. Of particular note, all four patients had melanoma, with an occult primary in three. In one patient, melanoma diagnosis and immunotherapy with the anti-PD-1 immune checkpoint inhibitor nivolumab preceded the onset of AIE by 9 months. Glucocorticoid treatment and/or intravenous immunoglobulins led to transient improvement in at least three patients; however, all relapsed and three progressed to hypoactive delirium or mutism. Plasma exchange and cyclophosphamide treatment were followed by clinical improvement and stabilization in one patient, but potentially contributed to fatal infectious complications. Copine-5-IgG belonged to the strongly complement-activating IgG1 subclass and was produced intrathecally. Serum titers ranged between 1:1000 and 1:100,000. Copine-5 is a novel autoantibody target in AIE. Testing for anti-copine-5 autoantibodies should be included in the diagnostic workup of patients with AIE, especially, but not exclusively, if associated with melanoma or positive melanoma-associated tumor markers. Further studies investigating the immunopathogenesis of copine-5-related autoimmunity and the potential significance of anti-copine-5 as a novel paraneoplastic serological marker and of copine-5 as a histopathological tumor marker in patients with suspected melanoma are highly warranted.