Association Between CSF Tau, Brain Swelling, and Neurologic Outcomes in Children With Cerebral Malaria in Malawi

Background and Objectives Higher CSF tau concentration is a marker of neuronal injury in cerebral malaria (CM) and has been associated with long-term neurologic deficits. However, its relationship with CM-associated brain swelling is unknown. Methods We conducted a nested retrospective cohort study of Malawian children with CM who underwent brain MRI and lumbar puncture at admission. Total tau concentrations were measured from stored CSF samples, and MRI-defined brain swelling data were collected. Survivors completed standardized neurocognitive assessments at 6 months after admission, including the Malawi Developmental Assessment Tool (MDAT, ≤60 months), the Kaufman Assessment Battery for Children (KABC, >60 months), and Liverpool Outcome Score (LOS). Associations were evaluated using nonparametric correlation and group comparison tests, and ordinal logistic regression. Results We assessed the association of CSF tau concentrations with clinical outcomes and neuroimaging findings in 119 children with CM (median age, 4 years; 50% female). CSF tau concentrations did not differ significantly between survivors (n = 80) and nonsurvivors (n = 39) (median 146.6 vs 114.9 pg/mL) and were not associated with severity of MRI-defined brain swelling. Among survivors, CSF tau levels were positively correlated with total coma duration ( r = 0.32, p = 0.006), with higher concentrations observed in children with coma lasting ≥72 hours than in those with shorter coma duration (698.2 vs 33.2 pg/mL, p < 0.001). CSF tau concentrations were also higher in children with neurologic sequelae at discharge than in those without sequelae (698.2 vs 101.7 pg/mL, p = 0.008) and were inversely correlated with LOS at 6 months after admission ( r = −0.46, p = 0.001). In adjusted ordinal logistic regression, higher log-transformed CSF tau levels independently predicted worse six-month neurologic outcomes (OR 1.67, 95% CI 1.23–2.28, p = 0.001), whereas coma duration was not independently associated with outcome. Higher admission CSF tau was also associated with severe neurocognitive impairment on the KABC ( p = 0.014). Discussion CSF tau is a biomarker of neuronal injury in CM and an independent predictor of long-term neurocognitive outcomes in Malawian children. The absence of association between brain swelling and CSF tau levels suggests that mechanisms underlying neurocognitive injury may be distinct from those driving severe brain swelling, supporting separate pathways for CM-related mortality and long-term morbidity.