To characterize the etiologies, clinical features, and short-term outcomes of pediatric encephalitis, and to compare infectious and immune-mediated causes.

Despite extensive diagnostic testing, prior studies identified a confirmed etiology in fewer than half of pediatric cases. With increasing recognition of immune-mediated encephalitis, the etiologic spectrum may have shifted, highlighting the need to reevaluate the current etiologic profile and associated clinical features.

We retrospectively reviewed patients diagnosed with encephalitis over 10 years (2015 – 2025) in a tertiary pediatric center in the United States. Demographic data, clinical presentation, examination findings, and diagnostic study results were extracted from the electronic medical records and analyzed. 

Among 179 suspected cases, 100 met criteria for encephalitis, including 34 (34%) confirmed, 58 (58%) probable, and 8 (8%) possible cases. Of these, 39 (39%) were classified as infectious encephalitis, most commonly due to herpes simplex virus (11/39, 28.2%), human parechovirus (8/39, 20.5%), and mycoplasma pneumoniae (5/39, 12.8%). 25 cases (25%) were immune-mediated, most commonly myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD; 10/25, 40%), anti–N-methyl-D-aspartate (NMDA) receptor encephalitis (7/25, 28%), and acute disseminated encephalomyelitis (ADEM; 4/25, 16%). The median age was overall 6.5 years (interquartile range [IQR], 0-12). Patients with infectious encephalitis were younger (median 3 years [IQR, 0–11]), whereas those with autoimmune encephalitis, including anti–NMDA receptor encephalitis and glial fibrillary acidic protein astrocytopathy in our cohort, were older (median 14 years [IQR, 10–16]). 48 (48%) required intubation, 3 (3%) died, and 14 (14%) required intensive inpatient rehabilitation due to moderate-to-severe neurological sequelae.

Pediatric encephalitis demonstrates a diverse and evolving etiologic spectrum, with infectious causes predominating in younger children. Significant differences in age, clinical features, and outcomes across etiologies may provide clinically useful clues for early diagnostic differentiation. Despite advances in recognition, encephalitis remains associated with substantial morbidity and mortality, with high rates of critical care utilization.