Herpes simplex encephalitis is known to lead to an autoimmune encephalitis, leading to further neurological damage. The authors were interested in the frequency, symptoms, risk factors and outcomes of this complication. They performed a prospective observational study and a retrospective analysis. In the prospective study, the authors included patients with herpes simplex encephalitis diagnosed by neurologists, paediatricians or infectious disease specialists in 19 secondary and tertiary Spanish centres (Cohort A). Outpatient follow-up was at 2, 6 and 12 months following onset of encephalitis. A further group of patients were studied retrospectively when they developed autoimmune encephalitis after herpes simplex encephalitis (Cohort B). 54 patients with herpes simplex encephalitis were recruited to Cohort A and 51 were included in the analysis (median age 50 years). At the onset of herpes simplex encephalitis, none of the patients had antibodies to neuronal antigens but during follow-up, 27% of patients developed autoimmune encephalitis and all of these had detectable neuronal antibodies (64% NMDA receptor [NMDAR] antibodies and 36% other antibodies) at or prior to the onset of symptoms. The other 37 patients did not develop autoimmune encephalitis, 30% did still develop antibodies (3 to NMDAR, 8 to unknown antigens). They found that antibody detection within 3 weeks of herpes simplex encephalitis was a risk factor for autoimmune encephalitis (odds ratio [OR] 11·5, 95%CI 2·7-48·8). The authors also identified 48 patients for Cohort B with new-onset or worsening neurological symptoms not caused by herpes simplex virus reactivation (median age 8·8 years). 92% of these patients had antibody-confirmed autoimmune encephalitis (34 NMDAR antibodies and ten with other antibodies). In both cohorts (total of 58 patients with antibody-confirmed autoimmune encephalitis), patients older than 4 years frequently presented with psychosis (58% of 31 patients, with younger children not being assessable). Patients aged ≤4 years (n=27) were significantly more likely than patients over 4 years (n=31) to have: shorter intervals between the onset of herpes simplex encephalitis and the onset of autoimmune encephalitis (median 26 days vs. 43 days), choreoathetosis (100% vs. 0%), decreased levels of consciousness (96% vs. 23%), NMDAR antibodies (89% vs. 61%), and worse outcome at 1 year (median modified Rankin Scale 4 vs. 2, and seizures 63% vs. 13%). Therefore it appears that autoimmune encephalitis occurs in 27% of patients with herpes simplex encephalitis, and was associated with the development of neuronal antibodies, with presentation usually within 2 months. However, the symptoms were age-dependent and the neurological outcome was worse in young children.
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