Pathophysiology, Clinical Presentation and Treatment of Cerebral Malaria
Total Page：16
File Type：pdf, Size：1020Kb
Neurology Asia 2005; 10 : 67 – 77 REVIEW ARTICLES Pathophysiology, clinical presentation and treatment of cerebral malaria Arjen M DONDORP MD PhD Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand and Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, John Radcliffe Hospital, University of Oxford, UK Abstract Infection with Plasmodium falciparum can cause severe disease in the non-immune individual. Cerebral malaria is in most cases just one of the organs affected by the disease. The direct cause of coma in cerebral malaria remains obscure. A compromised microcirculation, with sequestration of parasitized erythrocytes, is central in the pathogenesis. Intravenous artesunate is superior to quinine in the treatment of severe malaria, possibly because of its broader stage specificity, preventing young ring forms to mature and sequester. Intravenous artesunate should become the treatment of choice in adults, and possibly also in children. Since multi organ involvement is very common, supportive treatment is essential to improve survival in this disease, which is responsible for more than one million deaths per year. INTRODUCTION 105 till 106 merozoites are released into the bloodstream. In malaria caused by P. vivax and Severe malaria is a potentially fatal disease. Rapid P. ovale, but not P. falciparum, some parasites diagnosis and treatment is essential. It is a multi stay behind in the liver; these hypnozoites can system disease, but cerebral malaria, characterized cause a relapse of the disease long after treatment by unrousable coma, is one of the most common of the blood stage infection. The merozoites features. The direct cause of coma, which has a quickly invade circulating erythrocytes, where remarkable complete recovery in most of the the erythrocytic cycle of the parasite begins. The surviving cases, is not known. This paper will parasite matures from a small ring form to the review the pathophysiological and pathological pigment containing trophozoite, and is named changes associated with cerebral malaria, and the schizont after division of the nucleus. After 48 clinical presentation, diagnosis and treatment of hours the erythrocyte ruptures and 6 to 36 this condition. meroizoites are released, which will invade passing erythrocytes. This gives an exponential PATHOGENESIS expansion of the infection in the human host, with a multiplication factor of around 10, but The parasite sometimes up to 20, per new generation, as Human malaria can be caused by Plasmodium observed in early studies with P. falciparum as a falciparum, P. ovale, P. vivax and P. malariae, treatment for syphilis.2 Thirteen days after although clusters of malaria caused by P. knowlesi inoculation the parasite number has increased jumping species from long-tailed macaque from about 10 till 1010 parasites, and the patient monkeys to men have been described in Southeast starts to have fever. In the non-immune patient Asia.1 The female Anopheles mosquito is the the disease can quickly progress into severe vector, injecting the sporozoite form of the parasite disease if the infection is not treated, with an when probing for a blood meal. After inoculation increase in the total number of parasites in the the parasite hides and replicates in the liver for an body up to 1012 till 1013.3 average of 5.5 days in P. falciparum, after which Address correspondence to: Dr AM Dondorp, Faculty of Tropical Medicine, Mahidol University, 420/6 Rajvithi Road, Bangkok 10400, Thailand. E-mail: [email protected] 67 Neurology Asia December 2005 Cytoadherence. ‘knobs’ has revealed that knobs are positivily charged (+20 mV), whereas the endothelial plasma Although sporadically P. vivax is able to cause membranes and receptors have a negative surface severe disease in humans, including pulmonary charge.14 This could contribute to the promiscuity edema4 , haemoglobinuria and very rarely coma5 , of PfEMP1 for a great variety of receptors. the vast majority of severe disease is caused by P. Recently it has been suggested that platelets, falciparum. Yet this is also the only species that which express CD36, might serve as a sticky induces cytoadherence to vascular endothelium bridge between infected erythrocytes and the of erythrocytes containing the mature forms of endothelium, which could be particularly the parasite. As the parasite matures, parasite important in the brain microvasculature lacking proteins are transported and inserted into the CD36.15 Cytoadherence causes sequestration of erythrocyte membrane. The high molecular parasitized erythrocytes in the microcirculation, transmembrane protein P. falciparum erythrocyte mainly capillaries and post-capillary venules. membrane protein 1 or PfEMP1 is the most Autopsy studies show that sequestration is not important ligand for cytoadherence.6 Under febrile distributed equally throughout the body and is conditions, which enhance expression, PfEMP1 greatest in the brain, but also prominent in the mediated cytoadhesion begins at approximately heart, eyes, liver, kidneys, intestines, and adipose 12 h of parasite development, 50% of the tissue.16 It is also inhomogeneous in a specific maximum effect is obtained at 14–16 h, and vascular bed, with patent capillaries adjacent to adherence is highly effective in the second half of vessels packed with sequestered parasitized the parasite life cycle.7 As a result late stages of erythrocytes. Both light microscopic and electron the parasite are only sparsely detected in a microscopic studies have found that patients dying peripheral blood slide, and when they do appear from cerebral malaria have more prominent in significant numbers (>20% of the total sequestration in the brain microvasculature parasites) this is a poor prognostic sign compared to severe but non-comatose fatal representing a large sequestered parasite load.8 cases.17 ,18 Sequestration is prominent in cerebrum, PfEMP1 is encoded by the highly variable VAR cerebellum as well as the medulla oblongata. gene family, comprising around 60 genes. The Autopsy studies in children dying from cerebral high switch rate between these genes gives rise to malaria in Malawi describe, in addition to a new variant PfEMP1 in 2% of the parasites erythrocyte sequestration, intravascular every new cycle, and this clonal antigenic variation accumulation of platelets, which could play a helps the parasite escaping the immune system.9 role in cytoadherence.19 ,20 PfEMP1 is expressed on the surface of ‘knobs’, which can be identified electron-microscopically Red cell deformability, rosetting and auto- as protrusions from the erythrocyte membrane agglutination acting as points of attachment to the vascular endothelium. Other surface proteins that might Sequestration of parasitized erythrocytes will play a role in cytoadherence are rifin10 and compromise the microcirculation in vital organs. sequestrin.11 On the vascular endothelium In addition the deformability of both parasitized numerous receptors that can bind Pf EMP1 have and uninfected erythrocytes is markedly reduced been identified, with different distributions in in severe malaria, and this is strongly associated various organs and different contributions to with a fatal outcome of the disease.21 Acting rolling, tethering and finally stable binding of the synergistically with the reduction in lumen caused parasitized erythrocyte. Of these only CD36, by sequestration, rigid erythocytes presumably which is constitutionally expressed on most further reduce blood flow in the microcirculation vascular beds but remarkably absent in brain of vital organs, causing dysoxya with lactic vessels, and chondroitin sulphate A (CSA), the acidosis, organ dysfunction and death. It should main receptor in the placenta, are able to support be noted that lactic acidosis is a strong and firm adhesion under flow conditions.12 The reproducible predictor for disease outcome in intercellular adhesion molecule 1 (ICAM-1) is falciparum malaria, both in children and adults.22 the most important receptor on brain In addition formation of erythrocyte clumps endothelium13 , and its expression is upregulated through rosetting and auto-agglutination could by the pro-inflammatory cytokine TNF-α. further compromise flow. Rosette formation is Electrostatic forces are probably important in the in vitro phenomenon in which uninfected red addition to steric factors in the binding of PfEMP1 blood cells adhere to erythrocytes containing the to its receptors. Surface potential spectroscopy of mature forms of the parasite. However, whereas 68 all erythrocytes containing the mature parasite primary cause for coma it is more likely a feature cytoadhere, not all rosette.23 ,24 In epidemiological developing in the later stages of the disease. studies rosette forming strains have been associated with severe disease25 ,26 ,27 , whereas Cytokines other studies have not found this association.28 The extent to which rosettes have a In severe malaria, as in other severe infections, pathophysiologic role is not clearly established blood concentrations of proinflammatory α and will depend on their resistance to shear stresses cytokines like TNF- , Il-1, Il-6 and Il-18 are encountered in the human circulation. Rosettes raised, as well as anti-inflammatory Th2 cytokines are quite resistant against pulling forces29 , but (Il-4, Il-10), but there is an imbalance in patients 45 less against more physiologic shearing forces.30 with a fatal course of the disease. A potent A more recently described adherence property