Frequency, symptoms, risk factors, and outcomes of autoimmune encephalitis after herpes simplex encephalitis: a prospective observational study and retrospective analysis

Abstract

Background: Herpes simplex encephalitis (HSE) can trigger autoimmune encephalitis (AE) that leads to neurological worsening. We aimed to assess the frequency, syndromes, risk factors, and outcome of this complication. Methods: Prospective observational study of patients with HSE diagnosed between January 1st 2014 and October 31st 2017 by neurologists, pediatricians, and infectious disease specialists in 19 secondary/tertiary Spanish centers (Cohort-A). Outpatient follow-up was obtained at 2, 6 and 12 months; patients who died within the first 3 weeks or with delay in recruitment >10 days were excluded. Another group of patients was retrospectively studied after they developed AE post-HSE (Cohort-B). Multivariable binary logistic regression models were used to assess risk factors for AE. Findings: Cohort-A included 51 patients (median age 50 years, IQR 6–68; 29 male); 14 (27%) developed AE and all (100%) had neuronal antibodies (9 NMDAR, 5 other); the other 37 did not present AE and 11 (30%) developed antibodies (3 NMDAR, 8 other) (p<0.001). Antibody-detection within 3 weeks post-HSE often heralded AE (OR 11.5; 95% CI2.7–48.8, p=0.001). Within 2 months post-HSE, antibody sensitivity, specificity, positive and negative predictive values for AE were 100%, 76%, 61% and 100% (if only NMDAR considered: 64%, 95%, 82%, 88%; in youngest children: all 100%). Cohort-B included 48 patients (median age 8.8 years, IQR1.1–44.2; 27 male), 44 with AE (34 NMDAR, 10 other). In both Cohorts (n=58 AE), patients ≥4 years old frequently presented with psychosis (18/31, 58%; younger children not assessable). Patients ≤4 years (27) were more likely to have shorter HSE-AE intervals (median 26 vs 43 days, p=0.0073), choreoathetosis (27, 100% vs 0, p<0.001), impaired consciousness (26, 96% vs 7, 23%, p<0.001), NMDAR antibodies (24, 89% vs 19, 61%, p=0.033), and worse outcome at 1 year (median modified Rankin Scale, 4 vs 2, p<0.001; seizures, 12/19 [63%] vs 3/23 [13%], p=0.001). Interpretation: AE occurs in 27% of patients with HSE. It follows the development of neuronal antibodies and usually presents within 3 months post-HSE; the symptoms are age-dependent, and the outcome is worse in young children. Prompt diagnosis is important because patients, mainly those older than 4 years, respond to immunotherapy.