Adjunctive corticosteroids in herpes simplex virus encephalitis: a meta-analysis of randomized and observational studies.

BACKGROUND: Even when antiviral treatment is initiated promptly, herpes simplex virus encephalitis (HSVE) may cause death and enduring cognitive, seizure-related, and functional morbidity. Corticosteroids could lessen inflammation-mediated brain injury, but their clinical effectiveness and safety have not been established. METHODS: We searched PubMed/MEDLINE, Embase, and CENTRAL from inception through 4 July 2026 and examined trial registries and relevant reference lists. Eligible randomized-controlled trials and comparative observational studies evaluated systemic corticosteroids added to background antiviral therapy versus the same antiviral therapy alone or with placebo in patients with HSVE. Acyclovir was the background antiviral agent in all studies that specified the regimen. Study-defined unfavorable global neurological or functional outcome and all-cause mortality were co-primary outcomes. Secondary endpoints comprised serious adverse events, seizures during follow-up, cognition, persistent HSV DNA in cerebrospinal fluid, relapse, and Barthel Index-based functional independence. Randomized-trial risk ratios and mean differences were combined with Mantel-Haenszel and inverse-variance random-effects methods, respectively. Because non-randomized treatment allocation introduced important clinical heterogeneity and confounding, observational evidence was evaluated separately. RESULTS: The review included four comparative studies (209 patients): two randomized trials and two retrospective studies. Across the randomized trials, the pooled estimates did not show a difference in unfavorable global outcome (RR, 1.00; 95% confidence interval [CI], 0.68-1.47), mortality (RR, 0.92; 95% CI, 0.35-2.40), serious adverse events (RR, 1.14; 95% CI, 0.54-2.44), or seizures during follow-up (RR, 0.73; 95% CI, 0.33-1.62). Barthel Index results were likewise inconclusive at approximately 6 months (MD, 3.05 points; 95% CI, -6.99 to 13.09) and at discharge/day 30 (MD, 0.30 points; 95% CI, -13.84 to 14.45). Cognitive findings were not consistently favorable. The retrospective estimates conflicted and were seriously compromised by confounding. In DexEnceph, HSV DNA remained detectable at approximately day 14 in 4/36 dexamethasone recipients and 9/43 controls. Five relapses were reported with dexamethasone and none with control, although a few events did not allow a causal conclusion. CONCLUSIONS: Available evidence does not support the routine use of adjunctive corticosteroids in unselected patients with HSVE. Clinically meaningful benefit or harm cannot be excluded, because the evidence is limited and imprecise. The evidence is insufficient to determine the benefits or harms of corticosteroids in selected patients with life-threatening cerebral edema, because this indication was not specifically evaluated. Future adequately powered, multicenter randomized trials should use standardized treatment protocols and prespecify severity- and edema-defined subgroups.