Elevated cerebrospinal fluid tumour necrosis factor is associated with acute and long-term neurocognitive impairment in cerebral malaria

Systemic tumour necrosis factor-alpha (TNF-alpha) may contribute to the pathogenesis of cerebral malaria (CM) by promoting endothelial activation and parasite sequestration. However, less is known about the role of central nervous system (CNS) TNF-alpha in CM. We assessed plasma (n=249) and cerebrospinal fluid (CSF) (n=167) TNF-alpha levels in Ugandan children with CM, plasma TNF-alpha in Ugandan community control children (n=198) and CSF TNF-alpha in North American control children who had recovered from leukaemia (n=13). Plasma and CSF TNF-alpha were measured by magnetic bead assay. We compared plasma and CSF TNF-alpha levels in children with CM to mortality, acute and chronic neurologic deficits and long-term neurocognitive impairment. Plasma and CSF TNF-alpha levels were higher in CM than control children (P<.0001 for both). CSF TNF-alpha levels were higher in children who had neurologic deficits at discharge or 6-month follow-up (P <=.05 for both). Elevated CSF but not plasma TNF-alpha was associated with longer coma duration (Spearman's rho .18, P=.02) and deficits in overall cognition in children 5 years and older (beta coefficient -.74, 95% CI -1.35 to -0.13, P=.02). The study findings suggest that CNS TNF-alpha may be involved in the development of acute and chronic neurologic and cognitive sequelae in children with CM.