Comparing molecular quantification of herpes simplex virus (HSV) in cerebrospinal fluid (CSF) with quantitative structural and functional disease severity in patients with HSV encephalitis (HSVE): Implications for improved therapeutic approaches

•Initial cerebrospinal fluid (CSF) HSV load does not correlate with MRI lesion volumes.•Higher CSF HSV loads do not predict hospital morbidity or long-term clinical outcomes.•Host inflammatory factors may contribute to disease severity in HSV encephalitis. Herpes 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. To correlate molecularly quantified HSV in cerebrospinal fluid (CSF) and disease severity. HSV 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. Initial 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]. Initial 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.