Brain Swelling and Death in Children with Cerebral Malaria

Abstract

BACKGROUND Case fatality rates among African children with cerebral malaria remain in the range of 15 to 25%. The key pathogenetic processes and causes of death are unknown, but a combination of clinical observations and pathological findings suggests that increased brain volume leading to raised intracranial pressure may play a role. Magnetic resonance imaging (MRI) became available in Malawi in 2009, and we used it to investigate the role of brain swelling in the pathogenesis of fatal cerebral malaria in African children. METHODS We enrolled children who met a stringent definition of cerebral malaria (one that included the presence of retinopathy), characterized them in detail clinically, and obtained MRI scans on admission and daily thereafter while coma persisted. RESULTS Of 348 children admitted with cerebral malaria (as defined by the World Health Organization), 168 met the inclusion criteria, underwent all investigations, and were included in the analysis. A total of 25 children (15%) died, 21 of whom (84%) had evidence of severe brain swelling on MRI at admission. In contrast, evidence of severe brain swelling was seen on MRI in 39 of 143 survivors (27%). Serial MRI scans showed evidence of decreasing brain volume in the survivors who had had brain swelling initially. CONCLUSIONS Increased brain volume was seen in children who died from cerebral malaria but was uncommon in those who did not die from the disease, a finding that suggests that raised intracranial pressure may contribute to a fatal outcome. The natural history indicates that increased intracranial pressure is transient in survivors. (Funded by the National Institutes of Health and Wellcome Trust U.K.)

miR-155 Modifies Inflammation, Endothelial Activation and Blood-Brain Barrier Dysfunction in Cerebral Malaria

“…Endothelial and BBB dysfunction is a central feature of CM in humans and ECM in murine models (9,35,36). In this study, we used a combination of in vivo preclinical models of ECM to provide direct evidence for a role for miR-155 as a negative regulator of endothelial and BBB integrity during severe malaria.…”

Dynamic interactions ofPlasmodiumspp. with vascular endothelium

“…Both pediatric and adult BBB function has been studied clinically using fluorescein angiography of the retina, 13 cerebrospinal fluid (CSF) protein analysis, [17][18][19] and more recently magnetic resonance imaging (MRI) studies of the brain. 20,21 In children with cerebral malaria, there is clinical evidence of increased intracranial pressure leading to brainstem herniation. 22,23 In a recent antemortem MRI study of 168 children with CM in Malawi, brain swelling emerges as the most reliable predictor of severity.…”

“…22,23 In a recent antemortem MRI study of 168 children with CM in Malawi, brain swelling emerges as the most reliable predictor of severity. 20 The cause of brain swelling is postulated to be due to cytotoxic edema from impaired perfusion, metabolic injury and cell death. Endothelial cell activation leading to barrier disruption may also occur.…”

Severe adult malaria is associated with specific PfEMP1 adhesion types and high parasite biomass

“…The important role of the EPCR-activated protein C (APC) pathway in regulating coagulation, inflammation, and endothelial barrier properties (24) has led to the hypothesis that EPCR-binding parasites may drive pathogenic mechanisms by inhibiting the APC-EPCR interaction (23,(25)(26)(27)(28), thus increasing vascular dysfunction and permeability. Indeed, cerebral swelling is a major risk factor for pediatric death (29) and there is loss of EPCR and fibrin depositions at sites of cerebral sequestration in pediatric autopsies (30). However, the extent to which severe malaria isolates disrupt EPCR function is poorly understood.…”