Retinopathy-Positive Cerebral Malaria Is Associated With Greater Inflammation, Blood-Brain Barrier Breakdown, and Neuronal Damage Than Retinopathy-Negative Cerebral Malaria

Abstract

Background: Our prior study findings suggest that Plasmodium falciparum is the cause of disease in both malaria retinopathy-positive (RP) and most retinopathy-negative (RN) cerebral malaria (CM), and that absence of retinopathy and decreased disease severity in RN CM may be due to shorter duration of illness, lower parasite biomass, and decreased var gene expression in RN compared to RP CM. In the present study, we assessed the pathophysiology of RP and RN CM. Methods: We compared markers of systemic and central nervous system inflammation, oxidative stress, neuronal injury, systemic endothelial activation, angiogenesis, and platelet activation in Ugandan children with RP (n = 167) or RN (n = 87) CM. Results: RP children had higher plasma C-reactive protein (P = .013), ferritin and erythropoietin (both P < .001) levels, an elevated cerebrospinal fluid (CSF):plasma albumin ratio (P < .001), and higher CSF tau protein levels (P = .049) than RN children. Levels of plasma and CSF proinflammatory and anti-inflammatory cytokines and oxidative stress markers did not differ between RP and RN children. RN children had higher plasma levels of endothelin 1 (P = .003), platelet-derived growth factor (P = .012), and platelet factor 4 (P = .034). Conclusions: RP and RN CM may represent different phases of CM. RN CM may be driven by early vasospasm and platelet activation, whereas the more advanced RP CM is associated with greater inflammation, increased erythropoietic drive, blood-brain barrier breakdown, and neuronal injury, each of which may contribute to greater disease severity.