Herpes Simplex Virus Type 1 Encephalitis: A Prospective Population-Based Cohort Study

BACKGROUND: This study was performed to investigate the clinical characteristics and outcome of patients with herpes simplex (HSV) type 1 encephalitis. METHODS: Nationwide, prospective, population-based cohort study using the Danish Study Group for Infections of the Brain database to identify all adults hospitalized with microbiologically confirmed HSV-1 encephalitis from 2015 to 2023 in Denmark. Modified Poisson regression was used to estimate the relative risk (RR) with 95% confidence intervals (CI) for 6-month mortality, adjusted for age, sex, immunocompromise, altered mental status, imaging abnormalities, time to acyclovir (>6 hours from admission), and pathogen. Analysis of acyclovir delay >6 hours was repeated post-hoc using time after lumbar puncture as reference. RESULTS: A total of 154 patients with confirmed HSV-1 encephalitis were included, yielding a mean annual incidence of 0.36/100.000. Frequent symptoms at admission included a history of fever (in 101/128 [79%]) and confusion (in 99/154 [78%]). The median times from admission to lumbar puncture and acyclovir treatment were 21 (interquartile range, 6-70) and 24 (7-74) hours, respectively. The adjusted RR for 6-month mortality was 1.15 (95% CI, 0.39-3.41) for acyclovir initiation >6 hours after admission and 1.06 (95% CI, 1.004-1.13) for each day of delay after admission. The adjusted RR of 6-month mortality was 1.85 (95% CI, 1.01-3.45) for delayed acyclovir treatment of >6 hours since lumbar puncture. Anti N-Methyl-D-aspartate receptor encephalitis was diagnosed in 9/154 (6%) of patients after HSV-1 encephalitis. CONCLUSIONS: Early recognition of HSV-1 encephalitis remains challenging, and the condition is associated with high mortality. Delayed acyclovir treatment, especially following lumbar puncture, was associated with increased risks of fatal outcome.