Evidence of Brain Alterations in Noncerebral Falciparum Malaria.

BACKGROUND: Cerebral malaria in adults is associated with brain hypoxic changes on magnetic resonance (MR) images and has a high fatality rate. Findings of neuroimaging studies suggest that brain involvement also occurs in patients with uncomplicated malaria (UM) or severe noncerebral malaria (SNCM) without coma, but such features were never rigorously characterized. METHODS: Twenty patients with UM and 21 with SNCM underwent MR imaging on admission and 44-72 hours later, as well as plasma analysis. Apparent diffusion coefficient (ADC) maps were generated, with values from 5 healthy individuals serving as controls. RESULTS: Patients with SNCM had a wide spectrum of cerebral ADC values, including both decreased and increased values compared with controls. Patients with low ADC values, indicating cytotoxic edema, showed hypoxic patterns similar to cerebral malaria despite the absence of deep coma. Conversely, high ADC values, indicative of mild vasogenic edema, were observed in both patients with SNCM and patients with UM. Brain involvement was confirmed by elevated circulating levels of S100B. Creatinine was negatively correlated with ADC in SNCM, suggesting an association between acute kidney injury and cytotoxic brain changes. CONCLUSIONS: Brain involvement is common in adults with SNCM and a subgroup of hospitalized patients with UM, which warrants closer neurological follow-up. Increased creatinine in SNCM may render the brain more susceptible to cytotoxic edema.

Determinants of brain swelling in pediatric and adult cerebral malaria.

Cerebral malaria (CM) affects children and adults, but brain swelling is more severe in children. To investigate features associated with brain swelling in malaria, we performed blood profiling and brain MRI in a cohort of pediatric and adult patients with CM in Rourkela, India, and compared them with an African pediatric CM cohort in Malawi. We determined that higher plasma Plasmodium falciparum histidine rich protein 2 (PfHRP2) levels and elevated var transcripts that encode for binding to endothelial protein C receptor (EPCR) were linked to CM at both sites. Machine learning models trained on the African pediatric cohort could classify brain swelling in Indian children CM cases but had weaker performance for adult classification, due to overall lower parasite var transcript levels in this age group and more severe thrombocytopenia in Rourkela adults. Subgrouping of patients with CM revealed higher parasite biomass linked to severe thrombocytopenia and higher Group A-EPCR var transcripts in mild thrombocytopenia. Overall, these findings provide evidence that higher parasite biomass and a subset of Group A-EPCR binding variants are common features in children and adult CM cases, despite age differences in brain swelling.

Brain Magnetic Resonance Imaging Reveals Different Courses of Disease in Pediatric and Adult Cerebral Malaria.

BACKGROUND: Cerebral malaria is a common presentation of severe Plasmodium falciparum infection and remains an important cause of death in the tropics. Key aspects of its pathogenesis are still incompletely understood, but severe brain swelling identified by magnetic resonance imaging (MRI) was associated with a fatal outcome in African children. In contrast, neuroimaging investigations failed to identify cerebral features associated with fatality in Asian adults. METHODS: Quantitative MRI with brain volume assessment and apparent diffusion coefficient (ADC) histogram analyses were performed for the first time in 65 patients with cerebral malaria to compare disease signatures between children and adults from the same cohort, as well as between fatal and nonfatal cases. RESULTS: We found an age-dependent decrease in brain swelling during acute cerebral malaria, and brain volumes did not differ between fatal and nonfatal cases across both age groups. In nonfatal disease, reversible, hypoxia-induced cytotoxic edema occurred predominantly in the white matter in children, and in the basal ganglia in adults. In fatal cases, quantitative ADC histogram analyses also demonstrated different end-stage patterns between adults and children: Severe hypoxia, evidenced by global ADC decrease and elevated plasma levels of lipocalin-2 and microRNA-150, was associated with a fatal outcome in adults. In fatal pediatric disease, our results corroborate an increase in brain volume, leading to augmented cerebral pressure, brainstem herniation, and death. CONCLUSIONS: Our findings suggest distinct pathogenic patterns in pediatric and adult cerebral malaria with a stronger cytotoxic component in adults, supporting the development of age-specific adjunct therapies.