Investigate metabolomic biomarkers for precise diagnosis and prognosis of Epstein-Barr Virus (EBV) associated encephalitis (EBVAE).

EBV may trigger multiple neurological disorders including encephalitis, multiple sclerosis, lymphoma, etc. These clinical manifestations and results of auxiliary examinations might be similar to other herpes virus encephalitis or paraneoplastic diseases. However, various pathogens may alter different metabolic pathways, shedding lights on disclosing potential biomarkers for specific antigen to assist diagnosis. 

We collected cerebrospinal fluid (CSF) from 15 patients with EBVAE (9 has Herpes Simplex Encephalitis (HSE), 6 has acute disseminated encephalomyelitis (ADEM)) verified with Next Generation Sequencing and 6 healthy controls. Untargeted metabolomic analysis of the CSF was performed by UPLC- TOF/MS (Agilent 1290 Infinity UHPLC coupled with 6550 iFunnel Q-TOF, Agilent Technologies, CA, USA).  Top metabolites were sorted with a Benjamini-Hochberg (BH)-adjusted false discover rate (FDR) <0.05 and fold change > 1.5.  Finally, Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis was utilized to annotate related metabolic pathways.

We identified 88 and 76 metabolites that were elevated, and 91 and 24 metabolites that were downregulated in positive and negative modes among all patients with EBV infection, respectively. Importantly, gamma-aminobutyric acid (GABA) (BH-adjusted FDR=0.003) and 5-hydroxytryptamine (5-HT) (BH-adjusted FDR=2.03e-06) were upregulated in both positive and negative modes. GABA was also found to be negatively correlated with Glasgow Coma Scale (GCS) scores in patients with ADEM (ρ = −0.390, p = 0.054), compared with HSE patients (ρ = −0.190, p = 0.65). Lastly, 39 and 60 metabolomic pathways were selected via KEGG enrichment analysis in positive and negative modes.