For the past nine years, we have been working on the first controlled autopsy-based study of fatal cerebral malaria in African children. We have learned that the traditional clinical case definition is often incorrect. Autopsies revealed that 25% of the children who were assumed to have cerebral malaria actually died for other reasons. Despite obvious neuropathology in the brains of children dying of cerebral malaria, we cannot yet conclude that the deaths are actually due to central nervous system damage. The overall goals of this project are to understand what kills children who die of cerebral malaria and to determine if the relevant pathogenic mechanisms can be identified in life. With this knowledge, new interventions, capable of reducing the mortality rate of cerebral malaria (1-2 million African children each year) can be developed. We now recognize that we have reached the limit of autopsy-based studies: the data are generated from a single point in time (the time of death) and thus cannot reveal processes, and tissues are only available from those who die, precluding comparisons with survivors. We propose to overcome these shortcomings by incorporating two new approaches that have not been applied systematically to cerebral malaria: magnetic resonance imaging and neurophysiologic assessments of the brain. With this combination of in vivo and post mortem data, we will move beyond descriptive pathology to an improved understanding of relevant pathogenic mechanisms. Our inquiry will be structured around the following two Specific Aims: 1. Establish the 0.35T magnetic resonance imaging correlates of: a. specific pathological features of autopsy-confirmed cerebral malaria b. specific clinical features (including ocular fundus findings), laboratory investigations and neurophysiologic functional assessments in children with clinically defined cerebral malaria (""""""""true CM"""""""" and """"""""faux CM"""""""") 2. Compare """"""""true CM"""""""" patients with coma (the survivors) and """"""""true CM"""""""" patients with fatal malaria (the deaths), using serial magnetic resonance imaging and neurophysiologic functional assessments to a. differentiate between mechanisms of coma and mechanisms of death b. identify pathophysiological processes unfolding over time.
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