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

Systemic tumour necrosis factor‐α (TNF‐α) 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‐α in CM. We assessed plasma (n=249) and cerebrospinal fluid (CSF) (n=167) TNF‐α levels in Ugandan children with CM, plasma TNF‐α in Ugandan community control children (n=198) and CSF TNF‐α in North American control children who had recovered from leukaemia (n=13). Plasma and CSF TNF‐α were measured by magnetic bead assay. We compared plasma and CSF TNF‐α levels in children with CM to mortality, acute and chronic neurologic deficits and long‐term neurocognitive impairment. Plasma and CSF TNF‐α levels were higher in CM than control children (P<.0001 for both). CSF TNF‐α 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‐α was associated with longer coma duration (Spearman's rho .18, P=.02) and deficits in overall cognition in children 5 years and older (β coefficient ?.74, 95% CI ?1.35 to ?0.13, P=.02). The study findings suggest that CNS TNF‐α may be involved in the development of acute and chronic neurologic and cognitive sequelae in children with CM.