Results from our studies in Ugandan children with severe malaria suggest children with severe malaria other than cerebral malaria may have cognitive sequelae and that the functional areas, degree, and pathogenesis of cognitive impairment may differ by type of severe malaria. African countries plan to switch from quinine to artesunate for treatment of severe malaria because lower mortality has been documented with artesunate treatment. However, the effects of artesunate on neurodevelopment in children with severe malaria are unknown, as quinine has been used in all studies of neurodevelopment in severe malaria to date. Artesunate has effects that may be neuroprotective (e.g., more rapid parasite clearance, fewer seizures, less hypoglycemia than quinine), but high-dose artesunate has been associated with neurotoxicity in some animal studies. We propose to study the pathogenesis of developmental sequelae in the five most common types of severe malaria, in children treated with artesunate. The study's central hypothesis is that different types of severe malaria affect distinct pathogenic pathways leading to specific functional areas and levels of impairment. Our study has two primary aims.
Aim 1 is to establish the areas and level of neurodevelopmental function affected by the five major types of severe malaria in children treated with artesunate. To accomplish this aim, we will compare areas and age-adjusted level of neurologic, developmental, and behavioral impairment in children with severe malaria (cerebral malaria [CM], severe malarial anemia [SMA], repeated seizures, respiratory distress, prostration) treated with artesunate versus healthy children, 12 months after enrollment. Level of impairment in children with CM or SMA will be compared between children in the present (artesunate) and in past (quinine) studies.
Aim 2 is to identify immunologic, metabolic, and nutritional risk factors associated with neurodevelopmental impairment in children with severe malaria who are treated with artesunate. To accomplish this aim, we will compare the presence/level of risk factors in children with severe malaria to the level of neurologic, developmental, and behavioral deficits 12 months after enrollment. We will assess markers of endovascular and central nervous system inflammation, metabolic changes, and micronutrients that are affected by inflammation and associated with developmental impairment. We predict neurodevelopmental impairment will be present in all forms of severe malaria that level of impairment after artesunate treatment will be lower than after quinine treatment, and that specific immunologic, metabolic, and nutritional factors will be associated with risk of impairment. We expect this study will constitute a significant advance in the understanding of malaria-associated developmental impairment, and will provide a basis for interventions to prevent neurodevelopmental impairment in the millions of children who develop severe malaria every year.

Public Health Relevance

Identification of key factors associated with neurodevelopmental or behavioral impairment in severe malaria could lead to interventions that prevent brain injury and the loss of developmental potential in hundreds of thousands of children in sub-Saharan Africa.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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Special Emphasis Panel (ZRG1-BDCN-N (55))
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Hirtz, Deborah G
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University of Minnesota Twin Cities
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