What is cerebral malaria? Cerebral malaria (CM) collectively involves the clinical manifestations of Plasmodium falciparum malaria that induce changes in mental status and coma. It is an acute, widespread disease of the brain which is accompanied by fever. The mortality ratio is between 25-50%. If a person is not treated, CM is fatal in 24-72 hours. The histopathological hallmark of this encephalopathy is the sequestration of cerebral capillaries and venules with parasitized red blood cells (PRBCs) and non-PRBCs (NPRBCs). Ring-like lesions in the brain are major characteristics. Disease risk factors include being a child under 10 years of age and living in malaria-endemic area. There is a clear need for a strict definition of cerebral malaria in order to properly diagnose and assess the condition. A pragmatic definition based on the Glasgow Coma Score exists. Its key elements are: (1) unrousable coma no localizing response to pain persisting for more than six hours if the patient has experienced a generalized convulsion; (2) asexual forms of P. falciparum found in blood; and (3) exclusion of other causes of encephalopathy, i.e. viral or bacterial. (Newton and Warrell) The Blantyre Coma Scale, a related diagnostic tool, has been devised for young children. What are the symptoms? Clinical manifestations of cerebral malaria are numerous, but there are three primary symptoms generally common to both adults and children: (1) impaired consciousness with non-specific fever; (2) generalized convulsions and neurological sequelae; and (3) coma that persists for 24-72 hours, initially rousable and then unrousable. What is the cause? Sequestration of parasites and obstruction of brain vessels (RPH) The cause of cerebral malaria is not well understood. Currently, there are two major hypotheses explaining its etiology. They are the mechanical and the humoral hypotheses.

The mechanical hypothesis asserts that a specific interaction between a P. falciparum erythrocyte membrane protein (PfEMP-1) and ligands on endothelial cells, such as ICAM-1 or E-selectin, reduces microvascular blood flow and induces hypoxia. This selective cytoadherence of PRBCs and non-PRBCs, also known as rosetting, can apparently better account for CMs histopathological hallmark and its characteristic coma condition. However, this hypothesis is inadequate in explaining the relative absence of neurological deficit even after days of unconsciousness.

The humoral hypothesis suggests that a malarial toxin may be released that stimulates macrophages to release TNF-a and other cytokines such as IL-1. The cytokines themselves are not harmful, but they may induce additional and uncontrolled production of nitric oxide. Nitric oxide would diffuse through the blood-brain barrier and impose similar changes on synaptic function as do general anesthetics and high concentrations of ethanol, leading to a state of reduced consciousness. The biochemical nature of this interaction would explain the reversibility of coma. What are possible treatment options? As cerebral malaria is the fatal within days of malaria infection if left untreated, immediate treatment is crucial. Because natural immunity to malaria is not fully understood (Immunity) and thus cannot yet be artificially imitated by drugs, control and prevention strategies are significant. Two of these are antimalarial chemotherapy and adjunctive measures. Public health interventions are also critical (Public Health). P. falciparum parasites in brain capillary

Chemotherapy for cerebral malaria now primarily involves the use of quinine, for a patient with severe CM must be assumed to have chloroquine resistance. It is one of the four main alkaloids found in the bark of the Cinchona tree and is the only drug which over a long period of time has remained largely effective for treating the disease. Quinine has similar activity to chloroquine in that it is likely to interfere with the parasites enzymatic digestion.

have been shown in some clinical trials to clear parasitemia and fever faster than quinine or chloroquine, but they had no effect on mortality rates. Artemisinin has been used by the Chinese as a traditional treatment for fever and malaria. It is a sesquiterpene lactone derived from Artemisia annua. The two most widely used are artesunate and artemether. Because it is both cheap and effective, it is beginning to be included in treatment schedules. However, it is not yet licensed for use in Australia, North America or Europe. Its main value is in the treatment of multi-drug resistant falciparum malaria. As the possibility of quinine resistance looms, artemisinin and its derivatives may soon become the drugs of choice for CM treatment (Newton and Warrell).

Adjunctive measures for CM treatment exist, but they are debatable in both use and efficacy:

Anti-pyretics Such as paracetamol to reduce fever. However, it is not clear if a reduction in core temperature benefits cerebral consequences.
Anti-convulsants Such as phenobarbital sodium for seizures. It is crucial to control or prevent seizures, as they can cause neuronal damage and are associated with a fatal outcome.
Reduce intracranial pressure Using agents such as osmotic diuretics.
Hypoglycemia correction Using hypertonic glucose. However, theoretically, correcting hypoclycemia in the presence of tissue hypoxia can worsen tissue acidosis.
Exchange transfusion Generally only been justified when peripheral parasitemia exceeds 10% of circulating erythrocytes. The role of these blood transfusions remains highly controversial, as they are both expensive and potentially dangerous in many malaria-endemic areas.
Anti-Inflammatories Such as corticosteroids. However, there have been few controlled studies demonstrating benefit.
Desferrioxamine An iron-chelating adjuvant agent with antimalarial properties. Reduces formation of reactive oxygen species by reducing amount of free iron.
Microcirculatory Flow Such as pentoxifylline. Reduces red cell deformability and blood viscosity, decreases systemic vascular resistance, and impairs platelet aggregation, thus improving microcirculatory flow.