To study the pathogenesis of fatal cerebral malaria, we conducted autopsies in 31 children with this clinical diagnosis. We found that 23% of the children had actually died from other causes. The remaining patients had parasites sequestered in cerebral capillaries, and 75% of those had additional intra- and perivascular pathology. Retinopathy was the only clinical sign distinguishing malarial from nonmalarial coma. These data have implications for treating malaria patients, designing clinical trials and assessing malaria-specific disease associations.

We identified 33 Malawians who had undergone total splenectomy for traumatic injury. We reviewed these and 33 controls by clinical and parasitological examination monthly for 1 year. Splenectomized patients (S) were 2.5 times as likely as controls (C) to complain about febrile symptoms during the month preceding a visit (P < 0.0001). They were nearly twice as likely as controls to have Plasmodium falciparum parasitaemia (S: 176/283 person visits; C: 86/262; P < 0.0001). Parasitaemia was more likely to be associated with febrile symptoms in splenectomized individuals (S: 104/176, 59%; C: 24/86, 28%; P < 0.0001). There were three deaths (two non-malarial, one unexplained) among splenectomized subjects and none in the control group. Parasite densities reached significantly higher levels, and mature parasite stages were more often seen in the peripheral blood, in asplenic individuals. In a partially immune population, asplenic individuals are at increased risk of malarial infections and illness. In a larger group without the benefit of regular review and prompt therapy, there may be an increased risk of life-threatening malaria. Splenectomy should be avoided when possible in an area with endemic transmission of P. falciparum.

BackgroundThe sequestration of Plasmodium falciparum-infected erythrocytes in brain microvasculature through cytoadherence to endothelium, is the hallmark of the definitive diagnosis of cerebral malaria and plays a critical role in malaria pathogenesis. The complex pathophysiology, which leads each patient to the final outcome of cerebral malaria, is multifaceted and thus, metrics to delineate specific patterns within cerebral malaria are needed to further parse patients.MethodsA method was developed for quantification utilizing counts of capillary contents (early-stage parasites, late-stage parasites and fibrin) from histological preparations of brain tissue after death, and compared it to the standard approach, in which the percentage of parasitized vessels in cross-section is determined.ResultsWithin the initial cohort of 50 patients, two different observers agreed closely on the percentage of vessels parasitized, pigmented parasites and pigment globules (ICC = 0.795-0.970). Correlations between observers for correct diagnostic classification were high (Kendall’s tau-b = 0.8779, Kappa = 0.8413). When these methods were applied prospectively to a second set of 50 autopsy samples, they revealed a heterogeneous distribution of sequestered parasites in the brain with pigmented parasites and pigment globules present in the cerebellum > cortex > brainstem. There was no difference in the distribution of early stages of parasites or in the percentage of vessels parasitized across the same sites. The second cohort of cases was also used to test a previously published classification and regression tree (CART) analysis; the quantitative data alone were able to accurately classify and distinguish cerebral malaria from non-cerebral malaria. Classification errors occurred within a subclassification of cerebral malaria (CM1 vs CM2). A repeat CART analysis for the second cohort generated slightly different classification rules with more accurate subclassification, although misclassification still occurred.ConclusionsThe traditional measure of parasite sequestration in falciparum malaria, the percentage of vessels parasitized, is the most reliable and consistent for the general diagnosis of cerebral malaria. Methods that involve quantitative measures of different life cycle stages are useful for distinguishing patterns within the cerebral malaria population; these subclassifications may be important for studies of disease pathogenesis and ancillary treatment.