Malaria is the most important parasitic disease affecting humankind. Cerebral malaria is clinically diagnosed when a patient with an otherwise unexplained coma has a positive blood test for malaria parasites. Children diagnosed with cerebral malaria may be subdivided as to the presence of absence of a malaria specific retinopathy. It is unclear whether retinopathy negative cerebral malaria is due to an acute malarial illness with host modifying disease expression (e.g. mortality rates, retinopathy status) or due to a non-malarial etiology of coma with an asymptomatic parasitemia. Although autopsy studies support the latter possibility, disease in those who survive may be different than those who succumb.Studies are conflicting as to whether retinopathy negative cerebral malaria is solely due to acute malarial infection or has an acute etiology of illness that is non-malarial. This grant application looks for three treatable etiologies of coma in children with retinopathy negative cerebral malaria: viral central nervous system infection, bacteremia, and non-convulsive seizures. It compares the proportion of these etiologies and pathogen identities to children with acute aparasitemic coma.Using the results of this K23 Research Plan, we anticipate performance of clinical trials of adjunctive antiviral, antibiotic, or anticonvulsant therapies in children with retinopathy negative cerebral malaria. Adaptive trial designs may be useful in these studies, particularly adaptive randomization, combining Phase IIb and Phase III studies, and shifting target populations.
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