Citations

Objective To estimate the prevalence, incidence, and disease burden of autoimmune seizures and epilepsies in Olmsted County. Methods We conducted a retrospective, population‐based study using the Rochester Epidemiology Project (1996–2019). Age‐ and sex‐standardized rates (2019 United States standard population) per 100,000 were calculated with 95% confidence intervals (95% CIs). Temporal trends in incidence were assessed over 3 consecutive 8‐year intervals (1996–2003, 2004–2011, and 2012–2019) using Poisson regression to estimate rate ratios per period and trend. Disability‐adjusted life years (DALYs), years of life lost (YLL), and years lived with disability (YLD) and 95% uncertainty intervals (95% UIs) were estimated for 2019. Results Twenty‐three patients were identified between 1996 and 2019. In 2019, the standardized prevalence of all autoimmune seizures and epilepsies was 9.81 (95% CI, 5.59–15.21) per 100,000, including autoimmune‐associated epilepsy (AAE) 7.27 (3.74–11.95) and acute symptomatic seizures secondary to autoimmune encephalitis (ASSAE) 2.55 (0.69–5.60). From 1996 to 2019, the standardized incidence was 0.50 (0.29–0.77) per 100,000 person‐years overall, with AAE 0.36 (0.19–0.59) and ASSAE 0.15 (0.05–0.30). By period, the standardized incidence of all autoimmune seizures and epilepsies suggested a rising trend from 0.28 (95% CI, 0.06–0.68) in 1996 to 2003 to 0.60 (95% CI, 0.24–1.12) in 2004–2011, then plateaued at 0.53 (95% CI, 0.21–1.00) in 2012 to 2019 (rate ratio per 8‐year interval 1.30, 95% CI, 0.71–2.38), largely driven by the seropositive subgroup. The standardized DALY rate was 26.27 (95% Uncertainly intervals [UI], 5.30–67.09) per 100,000 (YLL 20.07 [0.00–60.21] and YLD 6.20 [5.06–7.39]). Interpretation Although autoimmune seizures and epilepsies remain rare, they result in a disproportionately high disease burden. ANN NEUROL 2026;100:74–83

ABSTRACT Objective We sought to characterize the sixth most common finding in our neuroimmunological laboratory practice (tissue assay‐observed unclassified neural antibodies [UNAs]), combining protein microarray and phage immunoprecipitation sequencing (PhIP‐Seq). Methods Patient specimens (258; 133 serums; 125 CSF) meeting UNA criteria were profiled; October 2022–September 2023. Top‐ranking candidate antigens were validated in silico, by dual‐staining confocal microscopy, and ≥ 1 protein‐specific assay. Clinical data were reviewed. Results Among 21 patients, 11 autoantibodies were characterized (serum, 19; CSF, all 9 available). Autoantigens were CACNA1I, 1; CAMK2B, 2; CLIP2, 1; FMN2, 2; MAP1A, 2; MAP2, 5; NECAB1, 1; SNAP91, 3; SRCIN1, 1; SYNJ1, 1; SYT3, 2. Analytical validation was by confocal TIIFA (all), western blot (10/10 available), and cell‐based assay (5/5 performed). Clinical accompaniments were: encephalitis, 6; brainstem encephalitis, 2; encephalomyelitis, 2; cerebellar ataxia, 2; longitudinally extensive transverse myelitis (LETM), 2; sensory neuronopathy, 1; peripheral neuropathy, 4, and movement disorders, 2. Inflammatory MRI abnormalities were identified in 5/16 patients (31%) with CNS disorders: T2 signal change (2), LETM (2), leptomeningeal enhancement (1). Seven of 8 (88%) had inflammatory CSF (pleocytosis, 5 [median 25.5 cells, range 7–294]; elevated IgG index/synthesis rate, 4; CSF‐exclusive oligoclonal bands, 4). Six had paraneoplastic causation (lung cancer, 2; other, 4); 3 were postinfectious (1 each of COVID‐19, HSV‐1, and post‐Group A streptococcal infection). Of 9 immunotherapy‐treated patients, 5 improved. Interpretation UNAs are partly accounted for by a repertoire of diverse mostly intracellular synaptic antigens. Their characterization is expedited by protein arrays and PhIPSeq. Further individual studies are needed to assess them as disease biomarkers.

Abstract Objectives γ‐Aminobutyric acid B receptor (GABA B R)‐IgG (immunoglobulin G) is an intermediate‐risk paraneoplastic autoantibody often associated with seizures. We aimed to assess the clinical and oncological features of GABA B R‐IgG autoimmune encephalitis (AE) and evaluate the performance of antibody testing. Methods Patients testing positive for GABA B R‐IgG in serum/cerebrospinal fluid (CSF) at Mayo Clinic Neuroimmunology Laboratory were identified. Archived sera were retested by cell‐based assay (CBA) at 1:100 and 1:200 dilutions. A live‐cell flow cytometry–based assay (LCFBA) was developed and validated using archived sera and CSF. True positivity included patients with classic presentations of GABA B R‐IgG AE or oncological explanations for antibody presence. Results Eighty‐six patients (median age 63 years; 43 female) presented with classic presentations of GABA B R‐IgG AE: encephalopathy with prominent seizures ( n = 55), status epilepticus ( n = 23), and rapidly progressive dementia ( n = 8). In addition, 44 patients (33%) had a false‐positive result for GABA B R‐IgG characterized by non‐specific symptoms/alternate diagnoses. Malignancy was identified in 78% of true‐positive patients, predominantly small cell lung carcinoma (SCLC). Testing serum at 1:100 dilution on CBA and using tissue immunofluorescence assay (IFA) in serum and CSF improved the identification of true‐positive patients ( p < 0.001). CBA at 1:100 dilution performed better than conventional CBA (at 1:10 dilution, p < 0.001) and tissue IFA ( p = 0.031). An in‐house LCFBA showed 100% sensitivity and specificity in CSF, performing similarly to conventional CBA ( p = 0.125) in CSF, but better than tissue IFA ( p = 0.031). Furthermore, serum LCFBA performed better than conventional CBA ( p = 0.022) and tissue IFA ( p = 0.006). LCFBA had the highest diagnostic accuracy and was closely followed by CBA at 1:100 dilution. Significance GABA B R‐IgG AE often presents as encephalopathy with seizures or status epilepticus in the context of an underlying SCLC. Multimodal evaluation using tissue IFA and fixed CBA at higher dilutions improves detection of true cases. LCFBA performs very well as a diagnostic test with very high sensitivity and specificity.

ABSTRACTCavin‐4 was identified as a potential autoantigen for immune‐mediated rippling muscle disease (iRMD). To validate this, we developed and tested various immunoassays, including a cell‐based assay (CBA), cavin‐4 recombinant protein ELISA, and multi‐peptide ELISA. Among 19 iRMD patients, all exhibited muscle rippling, and 13 had percussion‐induced mounding. All immunoassays demonstrated clinical and analytical specificities greater than 95%. The protein ELISA had the highest sensitivity (94.7%) and specificity (99.9%), outperforming CBA (sensitivity 89.5%, specificity 99.6%) and the multi‐peptide ELISA (sensitivity 79.0%, specificity 97.2%). Our results suggest that the cavin‐4 protein ELISA is a promising tool for high‐throughput clinical testing in iRMD.