From Bench to Bedside: Unraveling Cerebral Malaria and Malarial Retinopathy by Combining Clinical and Pre-Clinical Perspectives

Infection with Plasmodium falciparum carries a significant risk of cerebral malaria (CM). Children are particularly susceptible to human CM (HCM) which manifests as an acute neurovascular encephalopathy leading to high levels of mortality. Occurring in parallel with CM, malarial retinopathy (MR) is readily detected on ophthalmoscopy as one or more of: white-centered retinal hemorrhage, retinal whitening, and vessel discoloration. It leads to several distinct types of blood retinal barrier (BRB) breakdown. The precise molecular mechanisms underpinning CM and MR remain ill-defined, but parasitemia is known to drive progressive neurovascular obstruction and inflammation leading to cerebral and retinal edema and ischemia. Extensive clinical studies in patients with CM have shown that retinal examination is a useful approach for understanding pathology and an indicator for risk of mortality and morbidity. Fully understanding the cellular and molecular mechanisms that underpin CM and MR is important for developing new therapeutic approaches and in this regard the murine model of experimental CM (ECM) has proved to offer considerable value. Much is known about brain pathology in this model although much less is understood about the retina. In this review, we seek to evaluate MR in clinical scenarios and make comparisons with the retina from mice with ECM. Through detailed in vivo and post-mortem studies in the mouse and human retina, this review highlights the links between CM and MR and how this will aid our understanding of the disease progression and pathogenesis.