Lumbar puncture opening pressure, brain network hub integrity, and delirium in herpes simplex virus encephalitis: a prospective cohort study

Background Herpes simplex virus (HSV) encephalitis is the most common sporadic viral encephalitis, frequently complicated by delirium. Intracranial pressure (ICP) elevation is a common feature, but its role in delirium via brain functional network disruption remains unclear. This study investigated whether surrogate marker of ICP burden (LP opening pressure) mediates delirium in HSV encephalitis by reducing degree centrality (DC), a measure of functional network hub integrity, in key brain regions. Methods In a prospective two-center cohort study (December 2023–November 2025), 55 HSV encephalitis patients and 30 healthy controls underwent clinical assessments, ICP monitoring, and resting-state functional MRI (rs-fMRI). Delirium was evaluated using the Delirium Rating Scale (DRS; ≥12 indicating presence). DC was calculated from rs-fMRI data in regions of interest. Associations were analyzed via logistic regression, ANOVA, linear regression, and mediation models with bootstrapping. Results Of 55 patients, 22 (40%) developed delirium. The delirium group had higher LP opening pressure (23.5 ± 4.8 vs. 15.5 ± 3.2 cmH₂O; p < 0.001), lower Glasgow Coma Scale scores, and worse outcomes. Elevated LP opening pressure (≥20 cmH₂O) increased delirium odds (OR 1.86; 95% CI 1.58–2.11; p < 0.001), amplified in subgroups with severe inflammation. DC was reduced in the delirium group in the right amygdala, right hippocampus, left insula, and left precuneus (all p < 0.05 vs. non-delirium and controls). LP opening pressure inversely correlated with DC in these regions (except left insula), and DC inversely correlated with DRS scores. Mediation analyses confirmed partial mediation by DC in the right amygdala ( β = 0.129; 95% CI 0.079–0.158; p = 0.031), right hippocampus ( β = 0.312; 95% CI 0.277–0.458; p = 0.002), and left precuneus ( β = 0.275; 95% CI 0.187–0.398; p = 0.011). Conclusion Our exploratory findings suggest that LP opening pressure may be partially associated with delirium in HSV encephalitis through reduced degree centrality in limbic and default mode network hubs. As a preliminary investigation, these hypothesis-generating results highlight ICP management and DC as potential imaging biomarkers that warrant further validation in larger, longitudinal studies for delirium risk stratification and prevention.