Background Herpes viruses are a major cause of meningitis/encephalitis in adults. However, their individual clinical phenotypes and outcomes remain incompletely delineated. Metagenomic next-generation sequencing (mNGS) of cerebrospinal fluid (CSF) offers a powerful tool for precise pathogen identification, facilitating the comparison of distinct herpes virus infections. Methods This retrospective cohort study analyzed 66 patients with CSF-mNGS confirmed herpes virus meningitis/encephalitis at a single center between October 2019 and August 2025. The cohort was stratified into five etiological groups: herpes simplex virus type 1 (HSV-1, n = 10), herpes simplex virus type 2 (HSV-2, n = 5), varicella-zoster virus (VZV, n = 27), Epstein–Barr virus (EBV, n = 15), and human herpesvirus 7 (HHV-7, n = 9). Demographic, clinical, laboratory, and neuroimaging data were collected. Outcomes were assessed using the Glasgow Outcome Scale (GOS) at 3 months post-discharge. Results Distinct clinical phenotypes were observed. HSV-1 encephalitis typically presented with psychiatric symptoms, seizures, and temporal lobe involvement on MRI. HSV-2 infection manifested primarily as a febrile headache syndrome with minimal brain parenchymal involvement. VZV infection was associated with the most intense CSF inflammatory response (highest WBC and protein), a higher incidence of hypoglycorrhachia (25.9%) and hypochloridia (40.7%), and unique complications like cranial neuritis and vasculopathy. EBV infections occurred in older patients and showed features overlapping with HSV-1. HHV-7 infected a significantly younger population and was strikingly associated with elevated intracranial pressure (ICP ≥ 330 mmH 2 O in 33.3%). Multivariate analysis identified a longer interval from symptom onset to hospitalization (OR: 1.118, p = 0.025) and an abnormal EEG (OR: 0.066, p 0.001) as independent predictors of an unfavorable outcome (GOS 5). Antiviral or steroid therapy was not significantly associated with prognosis in this cohort. Conclusion CSF-mNGS reveals distinct and clinically significant phenotypic differences among various herpesvirus meningitis/encephalitis. VZV is characterized by a vigorous CSF inflammatory response and vascular complications, while HHV-7 predominantly affects younger adults and is significantly associated with intracranial hypertension. These findings underscore the value of mNGS in enabling pathogen-directed diagnosis and management, moving beyond syndromic approaches.
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