Cerebral malaria: mechanisms of brain injury and strategies for improved neurocognitive outcome

Abstract

Cerebral malaria is the most severe neurological complication of infection with Plasmodium falciparum. With >575,000 cases annually, children in sub-Saharan Africa are the most affected. Surviving patients have an increased risk of neurological and cognitive deficits, behavioral difficulties, and epilepsy making cerebral malaria a leading cause of childhood neurodisability in the region. The pathogenesis of neurocognitive sequelae is poorly understood: coma develops through multiple mechanisms and there may be several mechanisms of brain injury. It is unclear how an intravascular parasite causes such brain injury. Understanding these mechanisms is important to develop appropriate neuroprotective interventions. This article examines possible mechanisms of brain injury in cerebral malaria, relating this to the pathogenesis of the disease, and explores prospects for improved neurocognitive outcome.

Figure 1. Changes in and around a cerebral microvessel with sequestered Plasmodium falciparum parasites

A schematic diagram showing changes in and around a cerebral vessel with sequestration of pRBCs. Cytoadherence of parasitized erythrocytes to the endothelial cell lining and sequestration of parasitized and non-parasitized cells in the cerebral capillary or post capillary venule initiates an inflammatory process, endothelial activation, release of endothelial microparticles and apoptosis in the exposed area. At the site of cytoadherence, the blood brain barrier is possibly disrupted and there is an increased inflammatory response in the perivascular area with an increased release of pro-inflammatory cytokines.

Figure 2. Retinal changes and fluorescein angiography in a child with cerebral malaria

Day 1 (admission is day 0): A. Color fundus photograph of a child with cerebral malaria; multiple retinal hemorrhages are visible. No major change from admission. B. Fluorescein angiography shows multiple areas of retinal non-perfusion. These are more clearly delineated than on day 0 (admission). C. At higher magnification and later in the angiography run, there is some mild leakage round the border of the perfused and non-perfused zones. The leakage may suggest dysfunction of the blood-retina barrier. Day 3 of coma: D. There is little change in appearance compared to day 1. E. But there is substantial recovery in areas of non-perfusion. F. At higher magnification and later in the angiography run, leakage of fluorescein from re-perfused capillaries and capillaries previously on the border of non-perfusion is still observed. Photographs courtesy of Dr Nicholas Beare - Royal Liverpool University Hospital and the Wellcome Trust - Liverpool School of Hygiene and Tropical Medicine Program in Malawi.