This MRI study in sub-Saharan African children with cerebral malaria will seek to validate initial evidence about how the disease damages the brain and produces severe cognitive and motor disabilities.
Nine million children in sub-Saharan Africa develop malaria infection and about one-third of them subsequently develop “cerebral” malaria because their infection spreads to the brain. Cerebral malaria produces long-term severe problems including epilepsy, behavioral disabilities, and language, sensory and motor deficits. Infection arises from bites by mosquitoes that carry the parasite. But scientists do not yet know how the infection sometimes reaches the brain. And, because information about cerebral malaria traditionally has depended on autopsy studies, scientists do not know how malaria damages the brain throughout the course of illness, especially in its earliest stages, when therapeutic interventions might be most effective. This situation is changing with the availability of MRI. Clinical investigators in Malawi who compose the Blantyre Malaria Project have 25 years of cerebral malaria clinical and epidemiological data in addition to autopsy results, and they recently obtained an early model, weakly-powered MRI. Michigan State collaborators who analyzed the MRI data uncovered surprising findings, which they will seek to validate using a stronger MRI in neighboring Zambia.
Investigators will undertake MRI scans in Zambia in 25 children newly diagnosed with cerebral malaria. They will seek to confirm the following: 1) There is an absence of small hemorrhages in the brain in early-stage cerebral malaria. This would upend the current thinking that hemorrhages are the primary disease process, and confirm instead that hemorrhage is a late-occurring event. 2) There is focal cerebral ischemia (lack of blood) in white and gray matter areas. Ischemia is reversible during the acute episode; validation would highlight the importance of acute intervention. 3) There is an intact blood brain barrier, with no increased permeability. Validation would confirm that steroid treatment will not be beneficial. 4) Severity of cerebral edema correlates with subsequent mortality. Validation would highlight the critical importance of reducing edema. Finally, they will see whether imaging maps can identify a potential biomarker that indicates how much parasite is in the brain. Scientists then could determine whether parasite burden directly relates to clinical severity. In aggregate, validation of these findings would change clinical care. It also would give confidence in results of clinical trials of new prevention and treatment approaches, as measured by Malawi MRI.
Significance: If confirmed, these MRI findings will change clinical care of cerebral malaria and lead to significant new approaches to prevent cerebral malaria or minimize its destructive effects in the brain.