Sequestration and microvascular congestion are associated with coma in human cerebral malaria

Abstract

The pathogenesis of coma in severe Plasmodium falciparum malaria remains poorly understood. Obstruction of the brain microvasculature because of sequestration of parasitized red blood cells (pRBCs) represents one mechanism that could contribute to coma in cerebral malaria. Quantitative postmortem microscopy of brain sections from Vietnamese adults dying of malaria confirmed that sequestration in the cerebral microvasculature was significantly higher in patients with cerebral malaria (CM; n = 21) than in patients with non-CM (n = 23). Sequestration of pRBCs and CM was also significantly associated with increased microvascular congestion by infected and uninfected erythrocytes. Clinicopathological correlation showed that sequestration and congestion were significantly associated with deeper levels of premortem coma and shorter time to death. Microvascular congestion and sequestration were highly correlated as microscopic findings but were independent predictors of a clinical diagnosis of CM. Increased microvascular congestion accompanies coma in CM, associated with parasite sequestration in the cerebral microvasculature.

Figure 1.

A–C, Images of cortical brain sections from patients with malaria that were stained for glycophorin A. A, Low-power image showing noncongested vessels. Examples of vessels without erythrocytes indicated with arrows (magnification ×250; scale bar, 100 μm; counterstained with hematoxylin). B, Low-power image showing vessels congested with parasitized and nonparasitized erythrocytes (arrows; magnification ×250; scale bar 100 μm; counterstained with hematoxylin). C, High-power image of a congested vessel showing both infected and uninfected red blood cells in a congested vessel (scale bar, 100 μm). D, Box plots showing a comparison of the number of congested vessels per square millimeter in non–cerebral malaria, cerebral malaria, and control cases. Boxes show median values with interquartile ranges and limiting values.

Figure 2.

A, Box plot showing the difference between sequestration in cerebral malaria and non–cerebral malaria cases. This measured the percentage of vessels in cortical brain sections showing sequestration of parasitized red blood cells. Boxes show median values with interquartile ranges and limiting values. B, Dot plot showing the correlation between sequestration and microvascular congestion in individual cases.