Timing, Composition, and Clinical Correlates of Immunotherapy Response in GAD65 Antibody-Associated Epilepsy: A Literature-Derived Patient-Level Analysis of 375 Published Cases

Objective: Glutamic acid decarboxylase 65 (GAD65) antibody-associated epilepsy often presents as chronic focal epilepsy, usually with temporal lobe predominance, marked drug resistance, and inconsistent response to first-line immunotherapy. We assembled a large, harmonized, and literature-derived patient-level cohort to examine whether immunotherapy timing and regimen composition were associated with seizure outcome and to identify clinically meaningful prognostic signals. Methods: We performed a literature-derived patient-level analysis of 375 unique published cases linked to 132 contributory source publications from an audited full-text register of 166 reviewed studies. Descriptive analyses used the whole cohort. Treatment-response analyses assessed seizure outcome at the first evaluable post-immunotherapy assessment and at the last follow-up. Good seizure outcome was defined as seizure freedom and/or ≥50% seizure reduction. The primary timing comparison contrasted early treatment, defined as immunotherapy within 6 months of symptom onset, with late treatment, defined as immunotherapy after more than 12 months; four cases treated in the intermediate >6 to ≤12 month window were retained for descriptive timing summaries but excluded from the primary comparison. Statistical testing used the Fisher exact, Chi-square, Mann–Whitney U, and prespecified clustered logistic sensitivity analyses where appropriate. Results: The pooled phenotype was predominantly female, usually temporal-lobe-based, and frequently drug-resistant, with common autoimmune comorbidity and heterogeneous MRI abnormalities. Among timing-evaluable treated cases, earlier immunotherapy showed a class-specific, exploratory signal rather than a uniform regimen-independent effect. In rituximab/CD20-directed regimens, early treatment was associated with a higher rate of good seizure outcome than late treatment at both the first post-immunotherapy assessment and last follow-up (93.8% vs. 50.0%; risk difference [RD]: 43.8 percentage points; 95% CI: 7.7 to 72.7). A similar pattern was observed in the broader escalation group (94.4% vs. 55.6%; RD: 38.9 percentage points; 95% CI: 6.3 to 68.1). By contrast, steroid-containing regimens showed no clear early-versus-late advantage (84.6% vs. 88.2%; RD: −3.6 percentage points; 95% CI: −18.4 to 20.1). Shorter epilepsy duration before immunotherapy and absence of established drug resistance were the most clinically meaningful favorable baseline features. Significance: In GAD65 antibody-associated epilepsy, the therapeutic window may be most relevant for escalation strategies rather than for steroid-containing first-line regimens. However, these class-specific findings are exploratory and hypothesis-generating. They derive from non-randomized, literature-derived data and may reflect treatment intensity, center practice, publication era, and confounding by indication rather than isolated regimen superiority. Prospective collaborative registries with standardized longitudinal seizure outcome measures are needed to validate these observations.