title: 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.
authors.affiliation: Division of Medical Parasitology, Department of Microbiology, New York University School of Medicine New York, NY, USA.
authors.forename: Ute
authors.initials: U
authors.lastname: Frevert
authors.affiliation: Unité de Biologie des Interactions Hôte-Parasite, Département de Parasitologie et Mycologie, Institut Pasteur Paris, France.
authors.forename: Adéla
authors.initials: A
authors.lastname: Nacer
mesh_terms: D000818:Animals; D002423:Cause of Death; D004195:Disease Models, Animal; D006801:Humans; D019586:Intracranial Hypertension / Q000175:diagnosis / Q000209:etiology* / Q000401:mortality*; D016779:Malaria, Cerebral / Q000150:complications*; D051379:Mice; D010963:Plasmodium falciparum
keywords: CD8+ T cell; Plasmodium; brain edema; cytoadherence; intracranial hypertension; macrophage; postcapillary venule; vascular leakage