Integrating Cerebrospinal Fluid Metagenomic Next-Generation Sequencing and Immune Profiling in Recurrent HSV-1 Encephalitis: A Case Report and Narrative Review

Background Recurrent herpes simplex virus type 1 (HSV-1) encephalitis in children is rare, and its pathophysiology remains incompletely understood. Both viral reactivation and host immune dysregulation have been implicated. Advances in metagenomic next-generation sequencing (mNGS) and immune profiling provide new opportunities to elucidate disease mechanisms. Case Presentation: We detail a 13-year-old boy of Qiang ethnicity who experienced 3 neurologic episodes, including 2 virologically confirmed HSV-1 encephalitis events over 7 years. The third recurrence involved fever, seizures, and progressive bilateral temporal lobe lesions visible on magnetic resonance imaging. Cerebrospinal fluid (CSF) mNGS confirmed HSV-1 reactivation, and viral genomic sequencing demonstrated a highly conserved viral genome without high-confidence nonsynonymous mutations. Immune profiling showed compartmentalized central nervous system inflammation with elevated CSF cytokines (interleukin [IL]-6, IL-8, IL-10, interferon [IFN]-α, IFN-γ) and altered lymphocyte subsets, despite normal serum results. The patient was treated with acyclovir, intravenous immunoglobulin, and low-dose corticosteroids, which controlled seizures but left persistent neurocognitive deficits. Multidisciplinary follow-up is crucial to mitigate long-term neurocognitive sequelae. Literature Review: We reviewed 10 previously published pediatric cases of recurrent HSV-1 encephalitis, which demonstrated heterogeneous recurrence intervals, contralateral or novel lesion involvement, and frequent cognitive sequelae. Few studies integrated viral genomics or immune profiling. Conclusions The findings suggest that recurrent pediatric HSV-1 encephalitis may be driven by viral reactivation in the context of CNS-restricted immune dysregulation, rather than reinfection or viral evolution.