Involvement of the brain occurs in patients who are infected with Plasmodium falciparum and results in cerebral malaria. P. vivax, P. ovale, and P. malariae do not cause cerebral malaria.

Falciparum malaria is found in large parts of Asia, sub-Saharan Africa, the Middle East, and Central and South America. People who live in endemic areas may acquire a degree of immunity that diminishes with time. Those most at risk of developing severe malaria are the traveller who has no immunity and is being exposed for the first time, the emigrant returning home from a long spell abroad whose immunity has lapsed, pregnant women, and those who have immune suppression. It is not always necessary to stay in an endemic country to contract the disease; "runway malaria" occurs when an infected mosquito that has travelled on an aeroplane from an endemic country bites a person.134

Cerebral malaria is an acute diffuse encephalopathy with fever, which can kill within 72 hours if not recognised and treated, and even then carries a mortality of 25-50%.135 Delay in making the diagnosis and initiating treatment is a major factor contributing to this mortality.

Female Anopheles mosquitoes spread falciparum malaria. When they feed on humans they inject sporozoites, which circulate in the blood and are rapidly cleared by the liver, where they enter hepatocytes and reproduce asexually. One to three weeks later they rupture into the bloodstream as motile merozoites, which rapidly invade erythrocytes, where they can be seen microscopically on blood films. There they feed on haemoglobin and further asexual reproduction occurs (schizogeny). The progeny mature through the stage of trophozoite to merozoite, multiplying approximately 10-fold, to rupture out of the red cell and invade other uninfected red cells. This dispersal occurs every 48 hours and induces fever. A proportion of merozoites develop into the sexual gametocyte stage of the parasite and it is these that are ingested by a feeding mosquito to continue the cycle.

The clinical manifestations of cerebral malaria are the end result of a complex and not fully understood series of interactions mediated by humoral, vascular, and haematological factors within the cerebral capillaries. There is evidence of immune mediated inflammatory reactions that release vasoactive products and produce endothelial damage.135 The presence of trophozoites within erythrocytes induces changes, which renders the cells capable of adhering to vascular endothelium. These red cells packed with mature trophozoites are to be found sequestrated in small cerebral vessels, resulting in microvascular congestion and tissue hypoxia.

Other organ systems are vulnerable to similar changes. Acute tubular necrosis and the adult respiratory distress syndrome may need simultaneous treatment. Disseminated intravascular coagulation occurs in severe cases. Whether cerebral oedema contributes significantly to the pathogenesis of cerebral malaria is debatable. It would be surprising if a disease which causes intracranial vasculitis and microthrombosis did not raise intracranial pressure, but it is clear that administration of dexamethasone does not improve the outcome.136

Hypoglycaemia is an important and frequent complication of cerebral malaria and undoubtedly contributes to depression of consciousness and the appearance of neurological signs. It results from a complex series of interactions, which include malabsorption of glucose from the gut, hyperinsulinaemia (which may be induced by treatment using intravenous quinine), the metabolic demands of infection, and increased metabolism of available glucose by a large biomass of parasites. Pregnant women are particularly susceptible.

Definitions of the clinical criteria required to justify a diagnosis of cerebral malaria have been drawn up to standardise parameters for research.135 For the purposes of this discussion, any person from an endemic area with cerebral symptoms or signs should be suspected of suffering from cerebral malaria and demands immediate monitoring, investigation, and treatment. Such a patient will usually have been ill for days and have a high temperature. Exceptions occur: the onset of neurological symptoms may be abrupt and very ill patients may be hypothermic. Commonly there are convulsions, more so in the young, and in 45% of adults coma follows the convulsion. Young children have convulsions associated with many varieties of infection and with those, consciousness is rapidly regained. Coma lasting more than an hour or two in such circumstances should raise the suspicion of cerebral malaria.

Symptoms before the onset of the cerebral state are diverse and non-specific and the most common misdiagnosis is of flu. The level of consciousness is invariably impaired and there is evidence of an organic brain syndrome that manifests as confusion, hallucinations, delirium, and psychosis, complicated in some by motor signs and movement disorders. Meningism and opisthotonus may be found and it is important to remember that bacterial and other forms of meningitis may coexist with malaria. Furthermore, severely ill patients are susceptible to gram negative septicaemia. There may be signs of damage to other organ systems: anaemia is common and may be severe, jaundice complicates severe infection in adults, hepatosplenomegaly of mild to moderate degree is frequent, and haemorrhages may be found in the retina. Prolonged coma and frequent convulsions should trigger a search for hypoglycaemia and pyogenic meningitis.

Confirmation of the diagnosis of a case of suspected malaria must be obtained forthwith but if this cannot be done and suspicion is high, treatment should be given straight away. The best way to confirm the diagnosis is to have thick and thin smears of blood examined by an experienced microscopist after appropriate staining. If no parasites are seen and the diagnosis seems likely, treatment should be given and the blood re-examined every six to eight hours for the next 48 hours. Blood sugar should be estimated and monitored frequently and hypoglycaemia corrected if found. A full blood count, urea, electrolytes, and blood gases must be checked and monitored as treatment progresses. All such patients should be nursed in intensive care.

Because of widespread resistance of P. falciparum to chloroquine, this should not be used; quinoline compounds or artemisinin derivatives are the treatments of choice. Quinine is the most widely used. In severe malaria, when there is intensive care support the World Health Organization recommends it should be given in an initial dose of 7 mg/kg over 30 minutes, followed immediately by 10 mg/kg over four hours.135 Infusions of 10 mg/kg over four hours are repeated eight to twelve hourly. Use of quinine loading doses reduces the fever resolution in severe malaria but has not been clearly shown to reduce the risk of death or convulsions.136 Quinine should not be given by bolus injection. Plasma glucose and ECG should be monitored. After the patient regains consciousness, oral quinine (600 mg) may be given. Quinine therapy should be followed by either pyrimethamine-sulfadoxine (Fansidar, three tablets as a single dose) and/or doxycycline for one week. In situations where quinine is not available, quinidine may be used but there is still discussion about the correct dosage regimens.135 Various artemisinin derivatives are as effective as quinine in preventing death in severe or complicated malaria.137 If the parasite load is very high and the patient very ill, exchange transfusion may be beneficial.135 The utility of the routine use of anticonvulsants in cerebral malaria is still unclear.138 Full intensive care support is required for patients with cerebral malaria,135 but there is no evidence of benefit from corticosteroids.139

Features that adversely affect the outcome are failure to make the diagnosis or delay in starting treatment, not recognising concurrent infection, deep and prolonged coma, and continuing seizures.

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