Characterization Epstein-Barr Virus-Associated Encephalitis via Identification of Metabolomic Biomarkers

Objective: Fulminant Epstein-Barr Virus (EBV) infection may lead to fatal outcomes in patients with EBV-associated encephalitis (EBVAE). To investigate potential biomarkers in EBVAE, we utilized an untargeted metabolomic methodology to identify disease-associated biomarkers in patients with EBVAE. 
Methods: Cerebrospinal fluid (CSF) from 15 patients with EBVAE and 6 control subjects with functional neurological disorders were collected and analyzed utilizing untargeted metabolomics. Metabolites were annotated, clustered, and subjected to statistical analysis.
Results: Significant metabolomic alterations were observed between EBVAE patients and controls: 164 CSF metabolites were identified to be upregulated and 115 downregulated in patients with EBVAE. Among those, serotonin and tryptophan were markedly elevated in patients with EBVAE. Interestingly, 6 patients tested positive for glial fibrillary acidic protein (GFAP) antibodies in CSF met the criteria for GFAP-astrocytopathy (GFAP-A). Astrocytic monoamine derivative methylphenyl ethylene glycol was significantly elevated in GFAP-A subgroup compared with GFAP Ab-negative group. 6 out of 15 patients with EBVAE progressed to acute disseminated encephalomyelitis (ADEM). Gamma-aminobutyric acid (GABA) was found to be negatively correlated with Glasgow Coma Scale (GCS) scores (r = -0.858, p < 0.001) in the ADEM subgroup.
Conclusion: Our study first characterizes the metabolomic profile of patients with EBVAE, including those with EBV positive GFAP-A or ADEM.