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The neuropathology of pediatric cerebral malaria Schmidt, Kristopher Lee


Cerebral Malaria (CM) results from a Plasmodium falciparum infection and is characterized by severe neurologic dysfunction, coma and death; it is responsible for the deaths of 1-2 million people annually and affects primarily sub-Saharan African children. Several theories have been proposed regarding the pathogenesis of pediatric CM, but a lack of basic information regarding the neuropathological features of this disease in children, and how these features relate to clinical findings and parasitological data, make it difficult to establish the relative role that any pathological mechanisms might play in CM. The purpose of this study was to determine the nature and extent of the axonal, myelin and endothelial damage and gliosis in pediatric CM by staining brain sections obtained post-mortem using immunohistochemistry (anti-P-Amyloid Precursor Protein, anti-Fibrinogen, anti-Glial Fibrillary Acidic Protein) and neurohistological stains (Hematoxylin and Eosin, Luxol Fast Blue). We also sought to determine if significant associations could be established between neuropathological changes and either retinal pathology or ocular fundus findings observed during life, potential indicators of disease severity and outcome in CM. A series of correlations between neuropathological findings and several clinical parameters were also carried out. A common finding in the brains of CM patients (n=25) was the presence of parasite sequestration; anoxic neurons and Durck's granulomas were observed rarely or not at all in this group. CM patients differed significantly from malaria patients without neurologic dysfunction (severe malarial anemia, SMA, n=5) and patients dying with comas unrelated to malaria (comas of other causes, COC, n=19) with respect to both the presence and degree of perivascular ring hemorrhages (RH, 18/25 patients) and axonal damage (AD, 24/25 patients) (p<0.05). The distribution of these features varied across the CNS of CM patients, but both were greatest in the sub-cortical white matter. No correlation was observed between these features and general parasite sequestration, but positive correlations were observed between these features and the presence and degree of extra-erythrocytic pigment observed histologically (RH, R=0.402, p<0.05 and AD, R=0.766, p<0.05), suggesting a role for a parasite-stage specific involvement in the production of neuropathological changes. The number of RH and extent of AD in the retinas of CM patients correlated with the number and severity of corresponding pathologies in CM brains (R=0.415, p<0.05 and R=0.490, p<0.05, respectively), and the patterns of hemorrhage and axonal damage in the brains of CM patients were reflected in their retinas. Together, these findings suggest that retinal pathology reflects brain pathology in CM. Other neuropathological features observed in this study, namely, blood-brain-barrier (BBB) dysfunction (as measured by fibrinogen leakage), and gliosis were common in CM, though both of these features were also common in SMA patients without neurologic dysfunction, suggesting that BBB dysfunction and gliosis may be involved in malaria pathogenesis more generally. As with AD and RH, BBB dysfunction and gliosis were observed in the retinas of CM patients, further suggesting that retinal pathology reflects brain pathology in this disease.

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