Handel, Adam E.

Abstract Background N‐methyl‐D‐aspartate receptor antibody encephalitis (NMDAR‐Ab‐E) is an autoantibody‐mediated disorder, characterized by acute development of neuropsychiatric symptoms, seizures, movement disorders, and autonomic instability. Objectives To describe acute seizure semiology and electroencephalogram (EEG) findings in patients with a first episode of NMDAR‐Ab‐E. Methods Medical records and EEG results were retrospectively evaluated from 14 adult patients with definite NMDAR‐Ab‐E, recruited between April 2009 and September 2017, and followed up until October 2024. Results A total of 92.8% (13/14) were women with a mean age of 29.6 years. 85.7% (12/14) patients experienced seizures. Focal and/or generalized seizures were described at presentation or in the first days of the illness in 57% (8/14). EEGs showed diffuse slowing in 13/14 and this coexisted with epileptiform activity in 10/13; fast frequencies in 7/13 (potentially owing to a benzodiazepine effect); and asymmetric focal slowing in 6/13. Six patients had periods of rhythmic slow activity (focal or diffuse), without evolution to electrographic seizures. An extreme delta brush (EDB) pattern was recorded in 2/13 patients, and this was associated with non‐convulsive status epilepticus in one of these individuals. Significance Most patients in this case series of NMDAR‐Ab‐E were young adult females with early focal and/or generalized seizures. Diffuse slowing in theta/delta range was the most common EEG finding, with or without epileptiform discharges, focal slowing, superimposed fast activities, and focal or diffuse rhythmic slowing. An EDB pattern was rare. Even with non‐specific findings, EEG seems to be a sensitive tool to aid diagnosis and decision‐making in NMDAR‐Ab‐E.

The 2 main subgroups of autoimmune myasthenia gravis, a neuromuscular junction disorder associated with muscle weakness, are early- and late-onset forms, defined by onset before or after 50 years of age. Both carry acetylcholine-receptor autoantibodies but differ in sex ratios, genetics, and occurrence of disease-specific thymus inflammation. To distinguish the 2 forms by cellular immune phenotyping, we applied multimodal techniques, including deep spectral cytometric phenotyping and single-cell sequencing. Analysis of 2 independent cohorts identified immunological differences driven by 3 main lymphocyte populations. Lower frequencies of mucosa-associated invariant T cells and naive CD8 + T cells were observed in late-onset myasthenia, suggesting enhanced immune senescence. A highly differentiated, canonical NK cell population was reduced in early-onset myasthenia and negatively correlated with the degree of thymic hyperplasia. Using only the frequency of these 3 populations, correct myasthenia subgroup assignment could be predicted with 90% accuracy. These distinct immunocellular endophenotypes for early- and late-onset disease suggest differences in immunopathogenic processes. Along with demographic factors and other disease subgroup–specific features, the frequency of the identified cell subpopulations may improve clinical classification.

Autoantibody-mediated diseases targeting one autoantigen provide a unique opportunity to comprehensively understand the development of disease-causing B cells and autoantibodies. Convention suggests that such autoreactivities are generated during germinal center reactions. Here, we explore earlier immune checkpoints, focusing on patients with contactin-associated protein-like 2 (CASPR2)–autoantibody encephalitis. In both disease and health, high (~0.5%) frequencies of unmutated CASPR2-reactive naïve B cells were identified. By contrast, CASPR2-reactive memory B cells were exclusive to patients, and their B cell receptors demonstrated affinity-enhancing somatic mutations with pathogenic effects in neuronal cultures and mice. The unmutated, precursor memory B cell receptors showed a distinctive balance between strong CASPR2 reactivity and very limited binding across the remaining human proteome. Our results identify permissive central tolerance, defective peripheral tolerance, and autoantigen-specific tolerance thresholds in humans as sequential steps that license CASPR2-directed pathology. By leveraging the basic immunobiology, we rationally direct tolerance-restoring approaches, with an experimental paradigm applicable across autoimmunity.

Background N-methyl-D-aspartate receptor antibody encephalitis (NMDAR-Ab-E) can have an onset during, after or prior to a pregnancy. In animal models, transplacental NMDAR immunoglobulin G transfer can affect neurodevelopment. In contrast, clinical reports of mothers affected by NMDAR-Ab-E typically are reassuring. We systematically reviewed maternal, infant and childhood clinical data pertaining to NMDAR-Ab-E with an onset before, during or after pregnancy and compared this to our single autoimmune neurology centre experience. Methods After pre-registration on PROSPERO (CRD42023408447), we searched PubMed and Scopus for NMDAR-Ab-E case reports/series with an onset before, during or after pregnancy (last search 19/10/2023). We extracted maternal, neonatal and childhood outcomes using an idealised checklist to derive summary statistics. Results After quality control, we identified 66 pregnancies in 61 women from 48 reports or series. 72% of women recovered with minimal or no neurological deficits, comparable to non-pregnancy-associated NMDAR-Ab-E. Likewise, 80% of pregnancies resulted in live births with a single neonatal death reported. Data on neonatal outcome measures were frequently unreported, and childhood follow-up was provided in only 60%. Our centre’s experience is consistent: 3/4 mothers recovered with no functional deficits and 7/8 children without evidence of compromise at a median follow-up of 2 years. Conclusions Current evidence does not overall suggest unfavourable maternal, fetal or childhood outcomes after NMDAR-Ab-E. However, the available sample is small, predominantly single case reports with modest follow-up, lacks standardisation, and data are often incomplete. Future approaches should address these caveats: developing multi-centre collaboration towards an international registry.

AbstractBackgroundLGI1‐antibody encephalitis (LGI1‐Ab‐E) is a common form of autoimmune encephalitis where most patients demonstrate ‘good’ clinician‐rated outcomes. However, more targeted questionnaires reveal numerous debilitating symptoms for many years. To better quantify these persistent features, we designed the LGI1‐Antibody Encephalitis Rating (LANTERN) scale, a quantified, disease‐specific patient‐reported outcome measure (PROM), adhering to FDA guidelines.MethodsA participant‐driven mixed‐methods approach to develop a clinically valid questionnaire over three stages: (1) Item generation through semi‐structured interviews; (2) Repeated cognitive debriefing rounds to advance comprehensibility, relevance and comprehensiveness; (3) Psychometric survey to condense the most sensitive and valid questions. Analyses incorporated sensitivity testing with multiple internal and external validations.ResultsFrom 73 items across six domains (Stage 1; n = 18), a questionnaire assessing the frequency and severity of 43 symptoms (80 questions), plus nine activities of daily living (ADL), was developed through cognitive debriefing (Stage 2; n = 15). This 89‐question survey was completed (Stage 3; n = 66 patients and 32 relatives) and distilled, using exploratory factor analyses, to a three‐factor symptom‐burden questionnaire comprising 41 questions (19 symptoms and 6 ADL), separated into physical, cognitive/behavioural and ADL domains. These factors demonstrated strong internal reliability (Cronbach alpha: 0.85–0.91), correlations with relative‐completed questionnaires (R = 0.73–0.85; p < 0.001), good‐to‐excellent intraclass re‐testing correlations (0.81–0.98; n = 19) and strong associations with numerous predefined external measures.DiscussionLANTERN represents a PROM for LGI1‐Ab‐E, with initial content, structural and construct validity and test–retest reliability. It can be used as a reliable, tailored, efficient and sensitive method to establish symptom burden in people with LGI1‐Ab‐E, both in clinical practice and trials.

The long‐term clinical outcomes and associated prognostic factors in contactin‐associated protein‐like 2 (CASPR2)‐antibody diseases are unknown. A total of 75 participants with CASPR2 antibodies were longitudinally assessed for disability, quality‐of‐life, and chronic pain. Although most symptoms improved within 6 months of treatment, neuropathic pain and fatigue were the most immunotherapy refractory, and persisted for up to 6 years. Furthermore, these two factors—but not CASPR2 antibody levels or subclasses—independently predicted worse disability and quality‐of‐life at 24 months. Quality‐of‐life varied widely for any given modified Rankin Scale score, indicating a divergence between patient and clinician assessed outcomes. Further work should study the relative importance of these measures, and the immunopathogenesis underlying intractable symptoms. ANN NEUROL 2025;97:521–528

Abstract Autoimmunity affects 10% of the population. Within this umbrella, autoantibody-mediated diseases targeting one autoantigen provide a unique opportunity to comprehensively understand the developmental pathway of disease-causing B cells and autoantibodies. While such autoreactivities are believed to be generated during germinal centre reactions, the roles of earlier immune checkpoints in autoantigen-specific B cell tolerance are poorly understood. We address this concept in patients with CASPR2-autoantibody encephalitis and healthy controls. In both groups, comparable and high (∼0.5%) frequencies of unmutated CASPR2-reactive naïve B cells were identified. By contrast, CASPR2-reactive memory B cells were exclusive to patients, and their B cell receptors demonstrated affinity-enhancing somatic mutations with heterogenous binding kinetics. These effector molecules possessed epitope-dependent pathogenic effects in vitro neuronal cultures and in vivo. The unmutated common ancestors of these memory B cells showed a distinctive balance between strong CASPR2 reactivity and very limited binding across the remaining human proteome. Our results are the first to propose mechanisms underlying autoantigen-specific tolerance in humans. We identify permissive central tolerance, defective peripheral tolerance and heterogenous autoantibody binding properties as sequential pathogenic steps which licence CASPR2-directed pathology. By leveraging the basic immunobiology, we rationally direct tolerance-restoring approaches in CASPR2-antibody diseases. This paradigm is applicable across autoimmune conditions.