BackgroundHerpes Simplex Virus encephalitis (HSVE) is a devastating disease of all ages. Rigorous studies correlating viral load with neuroradiological and clinical severity have not been performed, particularly in neonates. Understanding these relationships may improve therapies. ObjectivesTo correlate molecularly quantified HSV in cerebrospinal fluid (CSF) and disease severity. Study DesignHSV loads (VL) were evaluated by real-time PCR from the CSF of 33 patients (20 neonates, 5 children, 8 adults) with HSVE. We studied relationships between CSF VL and structural and volumetric brain abnormalities (MRI); hospital morbidity; and discharge and long-term (>3 month) clinical outcomes. ResultsInitial CSF VL did not differ in neonates vs non-neonates (median 4.6 vs 5.1 log10 copies/mL, p = 0.75). Initial CSF VL was higher in neonates with HSV-2 vs HSV-1 (median 4.8 vs 3.2 log10 copies/mL, respectively, p = 0.02). Persistently detectable DNA in CSF despite acyclovir trended towards higher odds of unfavorable outcome at discharge for neonates [0.87 (CI 0.75–1), p = 0.07]. Initial VL correlated with higher CSF protein concentrations for the cohort and for neonates (p = 0.03 and 0.01, respectively), but not with lesion volume or subarachnoid exposure of involved brain (p all >0.05), hospital morbidity (p all >0.05), nor with higher odds of unfavorable discharge or long-term outcomes for the cohort [OR = 0.9(CI 0.5–1.6), p = 0.72; OR = 1.0(CI 0.5–1.8), p = 0.9] or for neonates [OR = 1.3(CI 0.5–3.3), p = 0.57; OR = 2.3(CI 0.7–8), p = 0.2]. ConclusionsInitial HSV VL did not predict neuroradiological or clinical outcomes in patients with HSVE, suggesting host inflammatory factors contribute to disease in treated patients with good viral clearance.