Clinical phenotype and outcomes in autoimmune encephalitis after herpes simplex virus encephalitis: A systematic review and meta-analysis

Background: Autoimmune encephalitis after herpes simplex virus encephalitis (HSVE-AE) represents the intersection of central nervous system infection and autoimmunity. Defining the phenotype and the safety and effectiveness of immunotherapy in HSVE-AE would help identify immunotherapy candidates, optimise therapeutic strategies, and improve patient outcomes. Methods: We systematically searched Embase, Medline, PubMed, and Web of Science (2007-2024) for cases meeting consensus criteria for AE after confirmed HSVE. Demographics, phenotype, treatment and outcome data were extracted. Dimensionality reduction, network analysis, and multivariate logistic regression was used to explore age- and diagnosis-specific patterns and outcome predictors. Results: From 2259 articles screened, 78 studies (225 patients) were included (median age 7.25 years; 52.9% female). Children (0-12 years) experienced more seizures during HSVE (p=0.003) and movement disorders during AE (p<0.001). Older patients (>12 years) had more headaches during HSVE (p=0.003), and speech dysfunction (p=0.02) and neuropsychiatric symptoms (p=0.02) during AE. HSVE-AE (89.3% N-methyl-D-aspartate receptor-antibody encephalitis [NMDAR-AbE]) differed significantly from a canonical NMDAR-AbE cohort (n=1550) in clinical, paraclinical and outcome domains. Poor outcomes were linked to infant and older adult age, neuropsychiatric symptoms, and AE-phase mRS >4. Rituximab independently predicted better outcomes. Disability improved over time (p<0.001), with adverse event rates comparable to NMDAR-AbE. Conclusions and relevance: This meta-analysis defines novel age-specific HSVE-AE features, outcome predictors, and confirms the safety and improved outcomes of HSVE-AE after immunotherapy.