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

Objective: This post hoc analysis of the CHAMPION-NMOSD trial evaluated the safety and efficacy of ravulizumab in patients with aquaporin-4 antibody-positive (AQP4-Ab+) neuromyelitis optica spectrum disorder (NMOSD) previously exposed or naïve to rituximab (RTX). Methods: Patients received weight-based intravenous ravulizumab with a loading dose followed by maintenance dosing every 8 weeks. Patients were stratified by prior RTX exposure: no RTX exposure (RTX-naïve) vs RTX exposure > 3 months before initiating ravulizumab (RTX-exposed). Key outcomes included treatment-emergent adverse events (TEAEs), serious TEAEs (TESAEs), relapse rates, and vaccination timing from the last RTX dose. Results: Of the 58 patients enrolled, 89.7% were female, with a mean age of 47.4 years, and 21/58 (36.2%) were RTX-exposed. Relapses occurred in 12/21 (57.1%) RTX-exposed patients between their first RTX dose and study entry. The safety profile of ravulizumab was generally similar between RTX-exposed and RTX-naïve groups. Common TEAEs included COVID-19, headache, urinary tract infection, and upper respiratory tract infection. UTIs were more frequent in RTX-exposed individuals. One patient in each group experienced a meningococcal infection. No adjudicated on-trial relapses were reported while on ravulizumab. Conclusions: Following initiation of ravulizumab, RTX-exposed and RTX-naïve patients with AQP4-Ab+ NMOSD achieved sustained disease control and demonstrated a manageable safety profile. Clinical Trial Information: The CHAMPION-NMOSD Trial; ClinicalTrials.gov identifier: NCT04201262 (registered October 06, 2020).

ABSTRACT Patients with neuromyelitis optica spectrum disorder (NMOSD) may experience increased signs and symptoms of their underlying disease when vaccinated against meningococcal disease before receiving complement component 5 inhibitor therapies. This retrospective analysis indicated an overall low relapse incidence (mean [range], 3.3% [0.7%–10.6%]) of physician‐reported relapses occurring within 4 weeks of meningococcal vaccination in those screened in CHAMPION‐NMOSD (NCT04201262), randomized to eculizumab or placebo in PREVENT (NCT01892345), and from the Japanese postmarketing surveillance of eculizumab in patients with anti‐aquaporin‐4 antibody‐positive NMOSD. Further studies are needed to determine if postvaccination relapses are attributable to vaccination or inherent relapse risk among these patients.

ABSTRACT Objectives To evaluate the impact of semaglutide on body mass index (BMI) and cardiometabolic markers in adolescents with obesity and genetic variants associated with monogenic or syndromic obesity. Methods A retrospective chart review was conducted in adolescents with severe obesity who underwent multigene panel testing and were treated with semaglutide. Results Twenty‐seven adolescents (mean age 15 ± 1.9 years); BMI % of the 95th percentile 158 ± 29; (70% White) were treated with semaglutide for a mean of 10 ± 4.7 months. Participants were classified into three groups: (1) Dominant or Known Risk Variants ( n = 7); (2) Carriers of Rare Variants in Recessive Genes ( n = 10); and (3) Negative or Unmatched Genetic Findings ( n = 10). All groups showed reductions in BMI, which was not different between the groups. Adolescents with dominant or known risk variants experienced a significant decrease in BMI % of the 95th percentile (−17, (IQR −26 to −10) p = 0.022) and in BMI by −9.4% ± 7% ( p = 0.035). Significant improvements in median non‐HDL cholesterol (−16 mg/dL), total cholesterol (−15 mg/dL), and HbA1c (−0.3%) were noted in children with dominant or known risk variants ( p = 0.036). Conclusions Semaglutide was associated with significant reductions in BMI and cardiometabolic markers in adolescents (majority White) with dominant or known risk variants for monogenic obesity.

Abstract Description Background Glutamic acid decarboxylase 65 (GAD65) antibodies are found in patients with stiff-person syndrome (SPS), cerebellar ataxia (CA), epilepsy and type-I diabetes (T1D). Given the intracellular localization of the antigenic target, a direct pathogenic role for GAD65 antibody (GAD65Ab) is unlikely. Methods PBMC-derived dendritic cells (DCs) from GAD65Ab+ patients with SPS (n = 6), epilepsy (n = 4), CA (n = 5), or T1D (n = 4) were pulsed with full-length GAD65 proteins or with 15-mer peptides from GAD65. T cell activation, exhaustion, and cytotoxicity were measured via cytometric bead array, FluoroSpot, flow cytometry, and live cell imaging. Results CD8+ T cells from patients with GAD65Ab-associated neurological disorders (AD) were activated by exposure to DCs pulsed with full-length GAD65 (p < 0.01 vs unstimulated, Mann-Whitney test; n = 16). We found 3 peptides of interest that caused a 10-30% increase in activated CD8+ T cells in GAD65AbAD patients, as assessed by surface CD69+ labeling. Using NetMHCpan4.2, we identified 8 different 9-mer peptides with high predicted affinity for HLA-C*03:03/04 and HLA-C*07:01/02. Two of these peptides showed high binding to HLA-C and subsequently demonstrated tetramer labeling of CD8+ T cells in GAD65AbAD patients. Conclusions We demonstrated that both full-length GAD65 protein and specific GAD peptides activated CD8+ T cells derived from patients with GAD65AbAD, indicating a potential pathogenic role for these effectors in these disorders. Funding Sources Support from Aditxt Immune Health Project (EU CT number: 2023-504798-19-00) and the Center for MS and Autoimmune Neurology in Mayo Clinic. Topic Categories Neuroimmunology (NEUR)

Abstract Context Pharmacological options for the treatment of early severe childhood obesity are limited. Objective This retrospective case series evaluates the effect of topiramate on weight and cardiometabolic parameters in young children with severe obesity, including those with hypothalamic etiologies. Methods This is a retrospective case series including 14 children with severe obesity, who were treated with topiramate prior to age 12 years. Anthropometric and metabolic data were analyzed. Results The median age at initiation of topiramate treatment was 10.1 years (range, 7.9-11.2 years) and 64% were boys. At baseline, the median body mass index (BMI) was 149% of the 95th percentile (range, 136%-200%). The median treatment duration was 14 months (interquartile range, 9.5-24 months), with a maximum tolerated dose of 75 mg (range, 50-150 mg). There was a median decrease in BMI% of the 95th percentile of 8% (95% CI, −15 to −1.02; P = .042), and a reduction in BMI z score by 0.37 (95% CI, −0.66 to −0.05; P = .028). The most notable response was in a child with hypothalamic obesity who experienced a 35-point reduction in BMI% of the 95th percentile over 24 months. While 11 of 14 children showed reduction in BMI, 3 had no change or increase in their BMI. No significant changes were observed in cardiometabolic markers or linear growth. Conclusion Topiramate monotherapy resulted in significant BMI reductions in young children with severe obesity, including those with hypothalamic obesity. Further prospective randomized controlled trials are warranted to assess its long-term efficacy for obesity management in young children.

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.