Pathogenesis of brain injury in cerebral malaria: emerging mechanisms and implications for intervention

Purpose of review Cerebral malaria (CM) in children has high mortality and leads to substantial long-term cognitive impairment. We review recent advances in defining the pathogenesis of brain injury in pediatric cerebral malaria. Recent findings The cascade of events leading to brain injury in pediatric CM includes blood−brain barrier (BBB) impairment due to local hypoxemia, ischemia, and endothelial activation after sequestration of infected erythrocytes; and oxidative stress after release of free heme. Tumor necrosis factor alpha (TNF-α), reactive oxygen species, CD8+ T cells and parasite toxins can then cross the impaired BBB and through activation of central nervous system immune responses and direct cytotoxicity lead to neuronal injury. Acute kidney injury and hyperuricemia may worsen BBB impairment and cerebral edema. Cytotoxic or vasogenic edema, abnormal blood flow states, and increased microvascular hemoglobin are present in pediatric CM, but their relationship to brain injury is not yet fully defined. Summary New studies of CM in children, including neuroimaging and electrophysiology studies, along with novel in vitro BBB model studies and ongoing experimental CM studies, show promise in improving our understanding of brain injury in CM and identifying interventions to decrease this injury.