Cerebral malaria: what is known and what is on research.

Malaria is still the world's major important parasitic disease and is responsible for the death of more people than any other communicable disease except tuberculosis. A major change in recent years has been the recognition that severe malaria, predominantly caused by Plasmodium falciparum, is a complex multi-system disorder presenting with a range of clinical features. Some surviving patients have an increased risk of neurological and cognitive deficits, behavioural difficulties and epilepsy, making cerebral malaria a leading cause of childhood neurodisability in the malaria transmission area. It is unclear how an intravascular parasite causes such brain injury. Understanding of these mechanisms is important to develop appropriate neuroprotective interventions. However, due to the high specificity of P. falciparum to the human host and to the fact that clinical studies in human are not always feasible, our knowledge about this syndrome mainly comes from autopsy studies which can only give us a limited view of this deadly syndrome. Efforts developed by the scientific community have shown that development of severe malaria probably results from a combination of parasite-specific factors such as adhesion and sequestration to the vascular endothelium, the release of bioactive molecules, together with host inflammatory responses and metabolic acidosis. Recent studies have shown that endothelial cells could play a central role in the onset of the severe malaria. Indeed, adhesion of parasitized erythrocytes to these cells could drive their activation, which could participate in the trigger of an immune response and haemostatic derangements. Moreover, death of endothelial cells could be at the origin of the blood-lung/brain barrier breakdown. Despite the efforts to find new mechanisms, which explain the physiopathology of severe malaria, research progress is slowed down by the lack of experimental models, which reproduce this complex multi-system disorder. In absence of a vaccine so far, the rapid diagnosis of the disease, an efficient treatment, a correct management and nursing care are the only weapons to control mortality due to P. falciparum. It is important to note that in the future, the treatment of severe malaria may involve adjuvant treatments in addition to a potent antimalarial drug. In the present review, we summarize both what is known and practically useful for a physician, and the most promising and current topics of research.