The Neuropathology of Fatal Cerebral Malaria in Malawian Children

Abstract

We examined the brains of 50 Malawian children who satisfied the clinical definition of cerebral malaria (CM) during life; 37 children had sequestration of infected red blood cells (iRBCs) and no other cause of death, and 13 had a nonmalarial cause of death with no cerebral sequestration. For comparison, 18 patients with coma and no parasitemia were included. We subdivided the 37 CM cases into two groups based on the cerebral microvasculature pathology: iRBC sequestration only (CM1) or sequestration with intravascular and perivascular pathology (CM2). We characterized and quantified the axonal and myelin damage, blood-brain barrier (BBB) disruption, and cellular immune responses and correlated these changes with iRBC sequestration and microvascular pathology. Axonal and myelin damage was associated with ring hemorrhages and vascular thrombosis in the cerebral and cerebellar white matter and brainstem of the CM2 cases. Diffuse axonal and myelin damage were present in CM1 and CM2 cases in areas of prominent iRBC sequestration. Disruption of the BBB was associated with ring hemorrhages and vascular thrombosis in CM2 cases and with sequestration in both CM1 and CM2 groups. Monocytes with phagocytosed hemozoin accumulated within microvessels containing iRBCs in CM2 cases but were not present in the adjacent neuropil. These findings are consistent with a link between iRBC sequestration and intravascular and perivascular pathology in fatal pediatric CM, resulting in myelin damage, axonal injury, and breakdown of the BBB.

Cytoadherence of Plasmodium berghei-Infected Red Blood Cells to Murine Brain and Lung Microvascular Endothelial CellsIn Vitro

“…Brain sections from mice infected with the nonsequestering line P. berghei K173 display little to no sequestered parasites (69), similar to what is observed in severe human malaria without coma (3,4,6,14,36,70,71). On lung MVEC we also observed binding of PbA- Prestimulation with TNF significantly increased the number of mature PbA-iRBC bound compared to that for resting monolayers.…”

“…The majority of sequestered parasites are found in the brain, lung, spleen, liver, kidney, small intestine, heart, and adipose tissue, as well as in the placenta in pregnancy-associated malaria (3,13,14). The microaerophilic venous environment of the deep microvessels nourishes the maturation of the parasites, facilitating their survival (15).…”

Effect of malaria components on blood mononuclear cells involved in immune response

“…Accumulated evidence also demonstrates that levels of endogenous pyrogens such as IL-6, IL-1β, and IL-8 are elevated in Plasmodium vivax (P. vivax) and P. falciparum malaria [23,29,30] . In Malawian children with severe malaria, mortality was observed to increase with increasing serum TNF-α [31] , and in plasma of African children, TNF-α levels were found to be higher among those with cerebral malaria (CM) than in those with uncomplicated P. falciparum malaria [23] . A recent experiment involving P. falciparum infection in malaria-naive individuals has shown a coordinated increase in the level of pro-inflammatory cytokines, including IFN-γ, IL-12, and IL-8, in serum at the time when parasite emergence from the liver and the first appearance of parasitized erythrocytes [32] .…”

Pediatric Cerebral Malaria: A Scourge of Africa

“…In autopsy-derived samples from children with CM, there are conflicting results with one group showing loss of tight junction proteins and a lack of transendothelial leakage of fibrinogen, whereas a more recent report shows significant leakage of fibrinogen into the brain parenchyma [26,27]. Assessment of the integrity of the BBB can be determined in vivo with the use of retinal fluorescein angiography.…”

“…Brain swelling, whether as a result of a disruption of the BBB and vasogenic edema, or cytotoxic edema brought on by inflammation or hypoxia, has been well documented in CM. Autopsy studies show universally increased brain weight in children dying of CM [27], and CT and MRI studies show a large percentage of children with increased brain volume [30,31].…”