Pathophysiology and neurologic sequelae of cerebral malaria

Abstract

Cerebral malaria (CM), results from Plasmodium falciparum infection, and has a high mortality rate. CM survivors can retain life-long post CM sequelae, including seizures and neurocognitive deficits profoundly affecting their quality of life. As the Plasmodium parasite does not enter the brain, but resides inside erythrocytes and are confined to the lumen of the brain's vasculature, the neuropathogenesis leading to these neurologic sequelae is unclear and under-investigated. Interestingly, postmortem CM pathology differs in brain regions, such as the appearance of haemorragic punctae in white versus gray matter. Various host and parasite factors contribute to the risk of CM, including exposure at a young age, parasite- and host-related genetics, parasite sequestration and the extent of host inflammatory responses. Thus far, several proposed adjunctive treatments have not been successful in the treatment of CM but are highly needed. The region-specific CM neuro-pathogenesis leading to neurologic sequelae is intriguing, but not sufficiently addressed in research. More attention to this may lead to the development of effective adjunctive treatments to address CM neurologic sequelae.

Keywords: Blood brain barrier; Cerebral malaria; Heterogeneity; Inflammation; Neurologic sequelae.

Fig. 1

Graphical abstract of cerebral malaria pathogenesis. Cerebral malaria pathology manifests itself differently in white matter and gray matter of the brain. Whereas haemorragic punctae are abundant in white matter, they are not obvious in gray matter. The cerebral vasculature in these brain areas is different, which may lead to differential attachment of PRBC—as guided by var gene expression—of PfEMP1 and resulting activation of alternate signalling pathways in the brain endothelial vasculature in these regions. The release of chemokines and cytokines from the inflamed BBB endothelium towards the brain, in conjunction with the opening of the blood brain barrier that allows ingress of both neurotoxic plasma substances and soluble Plasmodium factors into the brain, leads to astroglial activation. This, together with an influx of immune cells, causes neurological damage that is responsible for the post CM neurologic sequelae