Cerebral Malaria in Children: A Review of ... - Sudanjp.org

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SUDANESE JOURNAL OF PAEDIATRICS AND CHILD HEALTH VallO: 2010(1) Unrousable coma- No localizing response to painpersistinghas experiencedfor more than six hours if the patienta generalized convulsion.(2) Asexual forms of P. falciparum found in bloodand(2) Exclusion of othercauses of encephalopathy, i.e.viral or bacterial.Pathophysiologyof Cerebral MalariaCerebral malaria causes and pathophysiology isnot well identified. To investigatethe pathogenesisof CM, several animal models have been establishedin which animals are infected with parasitized RBCsby various types of Plasmodium. Although theseanimal models do not exactly reproducethe humandisease, they nevertheless exhibit some similarities tohuman CM such as clinical signs of nervous systemdysfunction and cerebral pathology. 18Infected RBCs become structurally andantigenic ally modified as a consequence ofintracellular parasite development. Parasite encodedproteins such as histidine-rich proteins-I give riseto RBC surface antigen.I9These proteins link tocells surface produce knobby protrusions. Theoccurrence and severity of these early changes inthe microcirculation correlated with the subsequentdevelopment of cerebral symptoms.20 ,21The histopathological hallmark of malariaencephalopathy is the sequestration of cerebralcapillaries and venules with parasitized red bloodcells and non-PRBCs.22Monocyte marginationappeared to be the mostsignificant factor associated with the developmentcerebral symptoms. Ring-like lesions in the brain aremajor characteristics.ofThe leukcocyte sequestration inhuman CM at least in paediatric patients is now wellsubstantiated, this agrees with murine CM animalmodels.23Currently, there are two major hypothesesexplainingCM aetiology, these are the mechanicaland the humoral hypotheses.24i- The mechanical hypothesis: The underlyingdefect seems to be blocking of the cerebralmicrocirculations by the parasitized RBCs. Thesecells develop knobs on their surface increasingtheir cytoadherence properties as a result; theytend to adhere to the endothelium of capillaries andvenules.25Thisin the deeper blood vessels.leads to sequestration of the parasitesThe mechanical hypothesis asserts that a specificinteraction between a P. falciparum PtEMP-I andligands on endothelial cells, such as ICAM-l orE-selectin, reduces microvascular blood flow andinduces hypoxia.26 Sequestration of P. falciparuminfected erythrocytes III post-capillary brainendothelium is induced by immune response onvascular receptors such as CD36. The degree ofbinding to CD36 is correlated with biochemicalindicators of disease severity. Other receptors suchas intracellular adhesion molecule-I (l CAM -1),E-selectin and inducible nitric oxide synthase(iNOS) significantly reduce the RBCs cytoadherencewith increased expressionpatients with cerebral malaria.27in the cerebral vessels ofRosetting is associated with severe malaria inAfrican children.28 Rosetting of the parasitizedand non-parasitized red cells and decreaseddeformability of the infected red cells furtherincreases the obstruction of the microcirculation. Ithas been observed that the adhesiveness is greaterwith the mature parasites. Rosetting thus, accountsvery well for CM histopathological hallmark andits characteristic coma condition. However, thishypothesis is inadequate to explain the relativeabsence of neurological deficit even after days ofcoma.28Petechial haemorrhage into the brain indicatesthat, brain vasculaturein patients with P. falciparummalaria is often damaged. Several studies using dyeextrusion into tissue have documentedthat vascularpermeability is markedly increased in the brain.2917
SUDANESE JOURNAL OF PAEDIATRICS AND CHILD HEALTH VallO: 2010However, the exact contribution of vascular leakageto human CM is still not defined and no significantvascular leakage was detected into brains of patientswith severe P. falciparum malaria.30No definite evidence of cerebral oedema has beenfound on imaging studies. 80% children with CMhave raised intracranial pressure due to increasedcerebral blood volume and biomass rather thanincreased permeability.Animal models in susceptible mice infected withP. berghei develop neurological abnormalities 6 daysafter injection with parasite.31 These mice exhibitbrain edema, petechial haemorrhages and monocyteinfiltration. In addition, injection of P. bergheiinfectedmice with folic acid results in convulsions,indicating that folic acid has crossed the normallyimpermeable blood-brain barrier and is mediatingaltered brain signaling.32ii- The humoral hypothesis: This hypothesissuggests that a malarial toxin may be released thatstimulates macrophages to release tumor necrosisfactor TNF-a and other cytokines such as IL-1.33The cytokines themselves are not harmful but theymay induce additional and uncontrolled productionof nitric oxide. Nitric oxide would diffuse throughthe blood-brain barrier and impose similar changeson synaptic function as do general anesthetics andhigh concentrations of ethanol leading to a state ofreduced consciousness. The biochemical nature ofthis interaction would explain the reversibility ofcoma.34Tumor necrosis factor and gamma interferon(IFN- y) were shown to be important mediators in thepathogenesis of CM. Second, helper T lymphocytesplaya significant role in the development of murineCM.23The role of IFN-y and its receptor in eMGamma interferon IFN-y is produced inabundance during clinical episodes of malaria.35The role of IFN -y in the pathology of malariadisease was demonstrated by murine model of CMin which disruption of interferon gamma receptor1 gene (IFNGR 1) was protective against cerebralcomplications of P. berghei.36Pathogenic Role of TNFR2Previous results suggested that TNF is a keyelement in the pathogenesis of experimental CM. Highlevels of this cytokine is noticed in the serum at thetime of CM. More recently, additional confirmation ofthe pathogenic role of TNF in CM has been providedin experiments with transgenic mice expressing highlevels ofTNF receptor 1 (TNFRl).37 The interactionbetween membrane TNF and TNFR2 is crucial tothe development of the neurological syndrome seenin severe malaria.38 More recently, TNFR2 wasshown to be important in endothelial cell apoptosisin the absence of sensitizing agents, i.e., underpathophysiologically relevant condition.39The receptor involved in the parasite-inducedmonocyte and macrophage stimulation has not beencharacterized. Malaria toxins are important moleculesthat are responsible for the direct induction by theparasite ofTNF secretion by host monocytesAOPlatelet-Endothelial Interactions in MicrovascularPathology beyond Cerebral Malaria: The effects ofanti-LFA-l monoclonal antibody (anti-LFA-IMAb)on CM and on platelet accumulation in brain vesselsmay offer insight into the mechanism of action ofthis antibody in vivo. Apart from their beneficial rolein haemostasis, platelets also in vitro experimentswith human cells have indicated a role for LFA-lin platelet-endothelium interactions, substantiatedthe fusion phenomenon and confirmed that plateletscan potentiate the TNF-induced endothelial killing.A pathogenic role for platelets is also suspected indisorders other than CM, such as gram-negativebacterial septic shock, acute respiratory distresssyndrome, vasculitides pulmonary fibrosis, tumor18
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