Associations of viral infections and antiviral vaccinations with anti-NMDAR and other forms of autoimmune encephalitis

Abstract

Background Autoimmune encephalitis (AIE) comprises a diverse group of neurological disorders characterized by autoantibodies targeting specific antigens of the central nervous system (CNS). While the pathophysiological effects of these autoantibodies have been extensively studied, the principles and immunological triggers underlying their generation remain less well understood. Viral infections and antiviral vaccinations have been reported as potential immunological triggers. However, a systematic overview of their specific associations and frequencies across AIE subtypes is lacking. Methods Here, we performed a systematic literature review in PubMed to identify published cases of AIE linked to viral infections or antiviral vaccinations, and to test whether herpes simplex virus (HSV)-associated anti-N-methyl-D-aspartate receptor encephalitis (NMDAR-E) represents a disproportionately strong association. We quantified the frequencies of viral infection- or vaccine-related AIE across ten common antibody-defined subtypes, and characterized their epidemiological and clinical features, complemented by data from 23 population-based viral encephalitis cohorts. Results We identified 556 cases, of which 488 were infection-associated and 68 followed vaccination. The most frequent combination was HSV infection in association with NMDAR-E, which outnumbered all other reported virus-AIE associations combined and was almost exclusively attributable to preceding HSV encephalitis (HSE). Other recurrent associations included Japanese encephalitis virus, Epstein-Barr virus (EBV), and SARS-CoV-2 infections, although EBV- and SARS-CoV-2-associated cases were less clearly suggestive of causal post-infectious autoimmunity. Across 23 population-based viral encephalitis cohorts from five continents, HSV was the leading causative pathogen. Despite this high background frequency, HSV was significantly overrepresented among viral CNS infection-associated NMDAR-E cases in our dataset compared with the reference cohorts (< 0.0001), indicating a disproportionate association. Most reported HSE-associated NMDAR-E cases originated from Europe and occurred in young children (median age 6 years), with a balanced sex distribution and a median interval between infection and NMDAR-E onset of 30 days. Conclusion Collectively, these findings provide the most comprehensive overview of viral infection- and antiviral vaccination-associated AIE to date and support a pathogen-specific link between HSE and secondary NMDAR-E as the most dominant virus-AIE association in the published literature. They underscore the need to elucidate the underlying immunological mechanisms and to develop biomarkers predictive of secondary NMDAR-E. abs0010