Fatal cerebral malaria: a venous efflux problem

Abstract

Most Plasmodium falciparum-infected children with cerebral malaria (CM) die from respiratory arrest, but the underlying pathology is unclear. Here we present a model in which the ultimate cause of death from CM is severe intracranial hypertension. Dynamic imaging of mice infected with P. berghei ANKA, an accepted model for experimental CM, revealed that leukocyte adhesion impairs the venous blood flow by reducing the functional lumen of postcapillary venules (PCV). The resulting increase in intracranial pressure (ICP) exacerbates cerebral edema formation, a hallmark of both murine and pediatric CM. We propose that two entirely different pathogenetic mechanisms—cytoadherence of P. falciparum-infected erythrocytes in pediatric CM and leukocyte arrest in murine CM—result in the same pathological outcome: a severe increase in ICP leading to brainstem herniation and death from respiratory arrest. The intracranial hypertension (IH) model unifies previous hypotheses, applies to human and experimental CM alike, eliminates the need to explain any selective recognition mechanism Plasmodium might use to target multiple sensitive sites in the brain, and explains how an intravascular parasite can cause so much neuronal dysfunction.

CD8+ T cells target cerebrovasculature in children with cerebral malaria

“…Interestingly, HIV coinfection shifted the distribution of activated IBA1 + CD68 + monocytes/macrophages away from the luminal surface in CM + Seq hi patients ( Figure 6, E-H) -a pattern also observed with CD3 + CD8 + T cells ( Figure 5). Collectively, these data demonstrate that high iRBC sequestration is associated with a strong innate cerebrovascular immune response due to iRBC and immune cell sequestration within venous vasculature in which flow velocities are already significantly decreased compared with arterial vasculature (39). We therefore examined whether there were differences in CD3 + CD8 + T cell accumulation in arteries versus veins.…”

Reduction of TNFR2 Expression in Brain Endothelial Cells in Cerebral Malaria Mice Models after Hyperbaric Oxygen Exposure

“…Cerebral malaria was a malaria complication characterized by decreased awareness or the appearance of neurological disorders (ataxia, seizures, paraplegic, etc.). The emergence of various neurological disorders and decreased awareness of cerebral malaria is associated with the occurrence of excessive inflammatory processes in response to a high degree of parasitemia [4].…”

Sonographic Measurement of Optic Nerve Sheath Diameter: A Prognostic Tool for Childhood Cerebral Malaria?

“…The pathophysiology of CM is still poorly clarified. However, several studies demonstrated the presence and the role of raised intracranial pressure (ICP) in the occurrence of deaths and neurological sequelae [3] [4] [5] [6] [7]. The reference method for the diagnosis (gold standard) of raised ICP is continuous measurement of ICP with intraventricular catheter or intraparenchymal sensor.…”