Herpes Simplex Encephalitis: A Systematic Review of Clinical Outcomes and Treatment Duration
Gerome Vallejos1, Anlys Olivera1, Luisa Alviz Rodriguez1, Carla Kim1, Christopher Bunting1, Sanaullah Mudassir1, Rachelle Dugue2, John Probasco3, Ava Easton4, Benedict D. Michael5, Tom Solomon6, Jacob Bodilsen7, Rodrigo Hasbun8, Arun Venkatesan3, Kiran T. Thakur1
1Program in Neuroinfectious Diseases, Department of Neurology, Columbia University Irving Medical Center, New York Presbyterian Hospital, New York, NY, USA, 2Department of Neurology & Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA, 3Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD USA, 4Encephalitis International, Malton UK; Department of Clinical Infection, Microbiology and Immunology, Institute of Infection, Veterinary, and Ecological Science, University of Liverpool, UK, 5Department of Clinical Infection, Microbiology and Immunology, Institute of Infection, Veterinary, and Ecological Science, University of Liverpool, UK; National Institute for Health and Care Research Health Protection Research Unit in Emerging and Zoonotic Infections, University of Liverpool, Liverpool, UK; Walton Centre NHS Foundation Trust, Liverpool, UK, 6National Institute for Health and Care Research Health Protection Research Unit in Emerging and Zoonotic Infections, University of Liverpool, Liverpool, UK; Walton Centre NHS Foundation Trust, Liverpool, UK; The Pandemic Institute, Liverpool, UK, 7Department of Infectious Diseases, Aalborg University Hospital, Aalborg, Denmark; Department of Clinical Medicine, Aalborg University Hospital, Aalborg, Denmark; European Society of Clinical Microbiology and Infectious Diseases, Study Group for Infections of the Brain (ESGIB), Basel, Switzerland, 8Division of Infectious Diseases, Department of Internal Medicine, University of Texas-Houston, Houston, TX USA
Objective:
To systematically review the literature on intravenous acyclovir (ACV) treatment for herpes simplex encephalitis (HSE) and summarize clinical outcomes.
Background:
HSE is the leading cause of sporadic fatal encephalitis worldwide and carries high morbidity despite the availability of intravenous ACV. While ACV has dramatically reduced mortality compared to the pre-antiviral era, neurological sequelae remain common, and the optimal duration of therapy is uncertain.
Design/Methods:
We conducted a systematic search in PubMed, ISI Web of Science, and Google Scholar up to August 19, 2025, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, to identify studies reporting outcomes of patients with confirmed HSE treated with intravenous ACV. Eligible designs included randomized controlled trials, cohorts, and case series with reported treatment durations. Outcomes of interest were mortality, functional disability, neurological deficits, seizure and epilepsy. Risk of bias was assessed using design-specific criteria.
Results:
Seven studies (n=351 patients) from 2007–2024 met inclusion criteria, spanning neonatal to adult populations across six countries. HSV-1 encephalitis was confirmed by CSF PCR. Patient demographics varied, with mean ages from 0.02 to 46.9 years and 66% male. Treatment approaches were heterogeneous, with acyclovir dosing ranging from 30–60 mg/kg/day, variable treatment durations, and sporadic corticosteroid use across studies. Clinical outcomes were highly variable: seizures occurred in 0–71% of patients, epilepsy was reported mainly in a pediatric ICU cohort, and focal neurological deficits ranged from 18–100%. Functional recovery was mixed, with favorable outcomes (mRS 0–2) in 52–64% of patients. Mortality was generally low, ranging from 0–16% across cohorts.
Conclusions:
Current evidence does not clearly demonstrate superiority of 14-day versus 21-day IV ACV regimens for HSE, with substantial neurological morbidity persisting across both strategies. Robust prospective multi-center studies and randomized trials using standardized outcome measures are urgently needed to optimize treatment duration and improve long-term outcomes.
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