Neurological Complications of Malaria

Abstract

Purpose of review: To discuss the neurological complications and pathophysiology of organ damage following malaria infection.

Recent findings: The principal advancement made in malaria research has been a better understanding of the pathogenesis of cerebral malaria (CM), the most dreaded neurological complication generally caused by Plasmodium falciparum infection. However, no definitive treatment has yet been evolved other than the use of antimalarial drugs and supportive care. The development of severe cerebral edema in CM results from two distinct pathophysiologic mechanisms. First, the development of "sticky" red blood cells (RBCs) leads to cytoadherence, where red blood cells (RBCs) get stuck to the endothelial walls and between themselves, resulting in clogging of the brain microvasculature with resultant hypoxemia and cerebral edema. In addition, the P. falciparum-infected erythrocyte membrane protein 1 (PfEMP1) molecules protrude from the raised knob structures on the RBCs walls and are in themselves made of a combination of human and parasite proteins in a tight complex. Antibodies to surfins, rifins, and stevors from the parasite are also located in the RBC membrane. On the human microvascular side, a range of molecules involved in host-parasite interactions, including CD36 and intracellular adhesion molecule 1, is activated during interaction with other molecules such as endothelial protein C receptor and thrombospondin. As a result, an inflammatory response occurs with the dysregulated release of cytokines (TNF, interleukins 1 and 10) which damage the blood-brain barrier (BBB), causing plasma leakage and brain edema. This second mechanism of CNS injury often involves multiple organs in adult patients in endemic areas but remains localized only to the central nervous system (CNS) among African children. Neurological sequelae may follow both P. falciparum and P. vivax infections. The major brain pathology of CM is brain edema with diffuse brain swelling resulting from the combined effects of reduced perfusion and hypoxemia of cerebral neurons due to blockage of the microvasculature by parasitized RBCs as well as the neurotoxic effect of released cytokines from a hyper-acute immune host reaction. A plethora of additional neurological manifestations have been associated with malaria, including posterior reversible encephalopathy syndrome (PRES), reversible cerebral vasoconstriction syndrome (RCVS), malarial retinopathy, post-malarial neurological syndrome (PMNS), acute disseminated encephalomyelitis (ADEM), Guillain-Barré syndrome (GBS), and cerebellar ataxia. Lastly, the impact of the COVID-19 pandemic on worldwide malaria control programs and the possible threat from co-infections is briefly discussed.

Keywords: Acute disseminated encephalomyelitis; COVID-19 pandemic; Capillary leak; Cerebral edema; Cerebral malaria; Cytoadherence; Delayed cerebellar ataxia; Falciparum malaria; Guillain-Barré syndrome; Malaria; Neurological complications of malaria; Post-malaria neurological syndrome; Severe malaria; Vivax malaria.