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Cerebral Malaria J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.69.4.433 on 1 October 2000. Downloaded from J Neurol Neurosurg Psychiatry 2000;69:433–441 433 NEUROLOGICAL ASPECTS OF TROPICAL DISEASE Cerebral malaria CharlesRJCNewton, Tran Tinh Hien, Nicholas White Abstract predominate; whereas in adults acute renal Cerebral malaria may be the most com- failure, acute pulmonary oedema, liver dys- mon non-traumatic encephalopathy in the function, and cerebral malaria may all occur. world. The pathogenesis is heterogenous Metabolic acidosis, mainly a lactic acidosis, is and the neurological complications are common at all ages. Severe malaria is a multi- often part of a multisystem dysfunction. system disease, and the outcome often depends The clinical presentation and pathophysi- on the degree of vital organ dysfunction. ology diVers between adults and children. P falciparum is transmitted by female Anoph- Recent studies have elucidated the mo- eles mosquitoes. In humans, although the lecular mechanisms of pathogenesis and parasite undergoes development in the liver, it raised possible interventions. Antimalar- is the erythrocytic cycle that is responsible for ial drugs, however, remain the only inter- disease. The merozoites released by the liver vention that unequivocally aVects invade the erythrocyte, and during a period of outcome, although increasing resistance 48 hours, pass through morphologically dis- to the established antimalarial drugs is of tinct stages, before the meronts (schizonts) grave concern. Artemisinin derivatives rupture the erythrocyte. Ring stages are seen in have made an impact on treatment, but the peripheral blood, but trophozoites and other drugs may be required. With appro- meronts are usually absent, as they are seques- priate antimalarial drugs, the prognosis of tered within the deep vascular beds. cerebral malaria often depends on the management of other complications—for Pathological features of cerebral malaria example, renal failure and acidosis. The histopathological hallmark of cerebral Neurological sequelae are increasingly malaria is engorgement of cerebral capillaries recognised, but further research on the and venules with parasitised red blood cells pathogenesis of coma and neurological (PRBCs) and non-paratised RBCs (NPRBCs).2 The brain is usually swollen at damage is required to develop other ancil- http://jnnp.bmj.com/ lary treatments. postmortem, although evidence of frank her- (J Neurol Neurosurg Psychiatry 2000;69:433–441) niation is unusual in adults. The cut brain is slate grey, with petechial haemorrhages. The Keywords: malaria; antimalarial drugs; coma; parasitic endothelium does not demonstrate micro- disease scopical damage,2 but immunohistochemical Neurosciences Unit, staining suggests endothelial activation3 and Institute of Child disruption of the blood-brain barrier.4 Inflam- Health, London, Malaria is the most important of the parasitic United Kingdom matory cells and immune complex deposition on September 30, 2021 by guest. Protected copyright. CRJCNewton diseases of humans, and its neurological are not consistent features in necropsy series to complication, cerebral malaria is arguably one date23 although some authors think that Centre for Tropical of the most common non-traumatic encepha- cerebral malaria has features of a diVuse Diseases, Cho Quan lopathies in the world. Malaria aVects about encephalomyelitis.5 Hospital, Ho Chi Minh 5% of the world’s population at any time and City, Vietnam T T Hien causes somewhere between 0.5 and 2.5 million Sequestration N White deaths each year. There are four species of The sequestration of red cells containing human malaria, but Plasmodium falciparum mature forms of the parasite (trophozoites and Faculty of Tropical causes nearly all the deaths and neurological meronts) in the microvasculature is thought to Medicine, Mahidol complications. Severe malaria occurs predomi- cause the major complications of falciparum University, Bangkok, nantly in patients with little or no background malaria, particularly cerebral malaria.6 This Thialand N White immunity—that is, children growing up in process varies considerably between organs endemic areas, or travellers or migrants who (the brain is particularly aVected) and at a Correspondence to: come from areas without malaria, but are microvascular level varies between vessels. The Dr C R J C Newton, exposed to malaria later in life. The manifesta- sequestration of PRBCs in the relatively Wellcome Trust/ KEMRI Centre, PO Box 230, Kilifi, tions of severe malaria diVer depending on the hypoxic venous beds allows optimal parasite Kenya age of the patient and previous exposure.1 In growth and prevents the PRBCs from being cnewton@kilifi.mimcom.net the first 2 years of life severe anaemia is a com- destroyed by the spleen.7 It is the sequestered Received 8 May 2000 mon presenting feature of severe malaria. In parasites that cause pathology in severe ma- Accepted 6 June 2000 older children seizures and cerebral malaria laria, and prognosis is related to sequestered www.jnnp.com J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.69.4.433 on 1 October 2000. Downloaded from 434 Newton, Hien, White biomass.89The peripheral blood parasite count expressed at all times in a wide range of vascu- is a relatively poor predictor of the size of this lar beds and are regarded as constitutive; their biomass. In a recent postmortem study of fatal expression is not related qualitatively or quan- falciparum malaria in adults, the median ratio titatively to severity of disease.16 Other recep- of cerebral to peripheral blood parasitaemia tors such as intracellular adhesion molecule-1 was 40 (range 1.8–1500).10 In this study, (ICAM-1) and endothelial selectin (E-selectin) although most sequestered parasites were the are inducible,17 with increased expression in the mature stages not seen in the peripheral blood, cerebral vessels of patients with cerebral there were considerably more ring stages than malaria, which co-localises with sequestration, expected from a free mixing model. Patients suggesting that they may be responsible for who have died from non-neurological compli- cytoadherence.34 Monoclonal antibodies cations of falciparum malaria also show against ICAM-1 improve microcirculatory flow cerebral sequestration at necropsy, although in ex vivo models of malaria sequestration,12 the intensity is less in patients who die without but have not been evaluated in humans. The preceding coma.2 Many authors have com- process of PRBC cytoadherence has several mented on the lack of correlation between the parallels to that of leucocyte adherence to the necropsy findings and clinical features of vascular endothelium. Firstly, rolling occurs cerebral malaria; although one study showed a along the endothelial surface, followed by static correlation between the degree of PRBC adherence, which reduces flow in packed sequestration and depth of coma on partially obstructed vessels. admission.11 Some authors have suggested that The clinical correlates of these in vitro mod- cerebral malaria may occur in the absence of els are poor. Parasitised red blood cells from cerebral sequestration. These discrepancies Gambian children with cerebral malaria did can be explained by the variable interval not bind more avidly to C32 melanoma cells between starting antimalarial treatment and than isolates from children with less severe death; fatal cases without cerebral sequestra- disease.718 Although binding to CD3619 has tion have invariably received many days of been shown to be directly proportional to antimalarial treatment before dying. parasitaemia, the degree of binding to CD36 cells correlated with biochemical indicators of Cytoadherence disease severity in adult Thai with malaria,19 Sequestration is thought to be a specific inter- rather than coma.20 In adults with cerebral action between PRBCs and the vascular malaria there was an increase in vessels endothelium (cytoadherence). This phenom- expressing ICAM-1 and E-selectin, but not enon seems to be mediated by plasmodium other ligands3; whereas in Kenyan children, derived proteins on the surface of PRBCs and there was a relation between cerebral malaria modified erythrocyte cell wall proteins and lig- and binding to CD36, ICAM-121 and a ands on endothelial cells.The adhesion of the mutation in the ICAM-1,22 although this was PRBCs reduces the microvascular blood flow,12 not confirmed in other sites in Africa.23 24 Stud- which may explain organ and tissue dysfunc- ies on peripheral blood parasites reflect the tion such as coma. The metabolically active entire repertoire of adhesins, and may not be sequestered parasites may compete with host representative of cytoadherence in a particular tissues for substrates—for instance, glucose— organ. http://jnnp.bmj.com/ and also produce toxins that interfere with host tissue metabolism. Unfortunately, there is no Rosetting and agglutination satisfactory animal model of human cerebral The adherence of NPRBCs to PRBCs (roset- malaria. In vitro models show that cytoadher- ting) and PRBCs to PRBCs (agglutination), ence begins when the parasites produce visible have also been implicated in the pathogenesis malaria pigment (usually becoming visible of cerebral malaria, although most clinical under light microscopy around 16 hours), studies have failed to show an association. In 7 which is maximal at the late stages. Cytoad- rosetting, the var genes seem to be responsible on September 30, 2021 by guest. Protected copyright. herence occurs
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