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

SUDANESE JOURNAL OF PAEDIATRICS AND CHILD HEALTH Vol 10: 2010Review ArticleCerebral Malaria in Children: A Review of Pathophysiology, ClinicalManifestations and ManagementHaydar EI Hadi Babikir, MD**Associate Professor of Paediatrics and Child Health, Head department of Medical postgraduate Studies, Faculty of Medicine,Gezira University- Sudan,Correspondence: Faculty of Medicine, University of Gezira.E. mail:haydarbabikir@yahoo.comABSTRACTInfection with malaria parasites may result in a widevariety of symptoms, ranging from absent or verymild symptoms to severe disease and even death.In general, malaria is a curable disease if diagnosedand treated promptly and correctly. Severe malariaoccurs most often in persons who have no immunityto malaria or whose immunity has decreased.Cerebral malaria (CM) collectively involves theclinical manifestations of Plasmodium falciparummalaria that induce changes in mental status andcoma. It is an acute, widespread disease of the brainwhich is accompanied by fever. The mortality ratiois between 25 - 50%. If a person is not treated, CMis fatal in 24 - 72% hours. This article is meant toreview the problem of cerebral malaria in childrenwith respect to clinical features, pathophysiology andmanagement.Key words: cerebral malaria, children,pathogenesis, PfEMP-1 IFN-y, TNF-aMalaria is the most important human parasiticdisease. It is caused by an obligate Intracellularprotozoa Plasmodium falciparum, P. vivax, P. ovaleand P. malariae. It is transmitted by female Anophelesmosquitoes, or .may also transmitted via parenteralinjection or congenitally. In malaria endemic areas,severe faciprum malaria usually develops after 6months of age.1Malaria is a public health problem in morethan 90 countries. It affects about 5% of the world'spopulation at any time and it is responsible for thedeath of more people than any other communicabledisease except tuberculosis.2 It causes somewherebetween 0.5 and 2.5 million deaths each year.3 Morethan 90% of all malaria cases are in sub-SaharanAfrica. Young African children mainly succumbto death, especially in remote rural areas with pooraccess to health servicesAMalaria neurological complication, 'cerebralmalaria (CM), is arguably one of the most commonnon-traumatic encephalopathies in the world andremains a major cause of morbidity. It accounts forone in five of all childhood deaths in Africa. Althoughmalaria occurs in millions of people, only 20 - 50%of the cases develop cerebral malaria. In-spite of thebest possible care and intensive therapy with ancillarysupport, the mortality from cerebral malaria remainsunacceptably high. In some reports CM accounts forup to 10% of all cases of P. falciparum malaria inhospitalized persons and for 80% of fatal cases. If aperson is not treated, CM is fatal in 24 - 72% hours.14

SUDANESE JOURNAL OF PAEDIATRICS AND CHILD HEALTH VallO: 2010Like most countries in sub-Saharan Africa, Sudancarries a heavy malaria disease burden. It ranks highas the one of the most endemic country of the world.It accounts for 50% of malaria cases in the EasternMediterranean Region. It is estimated that more than8 million cases and about 35,000 deaths occur peryear. The disease accounts for 20% of all hospitaldeaths and the malaria case fatality rate for paediatrichospitals ranges between «515- per cent».5The epidemiological pattern of severe malariavaries considerably from that of hyperdynamic regionsin sub-Saharan Africa and there is considerablevariation between the individual complications ofsevere malaria.6Severe MalariaSevere malaria occurs when P. falciparuminfections are complicated by serious organ failuresor abnormalities. It is usually manifests in Africanchildren growing up in malarious endemic areas.7Many factors thought to contribute to P. falciparumvirulence these include:-a- The Redundancy and multiplicative Capacityof P. falciparumP. falciparum is able to infect the entirepolymorphic human population; this is due to variantsurface antigens such as Plasmodium falciparumerythrocyte membrane protein-I (PfEMP I) whichspecifically binds to adhesion molecule CD36 andthrombospondin which assists the parasite adherenceto various receptors and removal from the circulationavoiding the snlenic clearance.8b- Parasitized RBCs Membrane Modification:These includefor mation of knob-like structurescomposed of proteins (PfEMP-l), protruding fromtheir surfaces increasing cell wall rigidity and alteringthe metabolites transport. 9c- Cyto-adherence and sequestration of parasitizederythrocytes. This is a specific interaction betweenRBCs and the vascular endothelium leading tosequestration of parasitized RBCs in deep organspredominantly in the brain, heart, lungs and submucosaof the small intestine.10d- Rosetting and Agglutination;e- RBC Deformability: In severe malaria bothparasitized (PRBCs) and non-parasitized RBCs(NPRBCs) become rigid due to oxidative damage tothe RBCs comprising their flow through capillaries.This has strong predictive value for fatal outcome.I IThe polymorphism of genes coding four humanadhesion molecules; intercellular adhesion molecule-l(ICAM-I), endothelial selectin (E-selection), CD36are important variable in the susceptibility to severemalaria.12The manifestations of severe malaria includeamong others; cerebral malaria with abnormalbehaviour, impairment of consciousness, seizures,coma or other neurologic abnormalities and metabolicacidosis presenting as respiratory distress or severeanaemia. Compared with adults, children have ahigher incidence of seizures.12The incidence andpattern of neurological complications are differentand the patients often die with features of braindeath. African children rarely develop renal failure orpulmonary oedema.13Cerebral malaria (CM)There is a clear need for a strict definition ofcerebral malaria in order to properly diagnose andassess the condition. The term «cerebral malaria»often been loosely used in the medical literature todescribe any disturbance of the CNS in a malariainfection. CM collectively involves the clinicalmanifestations of P. falciparum malaria that induceschanges in mental status and coma.13, CM hence,is an acute widespread disease of the brain which isaccompanied by fever.In older children CM can be defined as in adults.15

SUDANESE JOURNAL OF PAEDIATRICS AND CHILD HEALTH Vol 10: 2010The Blantyre Coma Scale, a related diagnostic tool,has been used for young children 10 years of age orless.14,l5 It was devised to assess young childrenresponses (Table 1). However, there is considerabledisagreement between observers in assessing thescale and the scale does not address the inability ofTable: 1 Blantyre and Glasgow Coma Scales.Blantyre coma Scale(Molynux et al.1989)Galsgow Coma scale(Teasdale & Jennett, 1974)Verbal2. Appropriate cry1. Inappropriate cry or moano. No cryvocalization.5. Able to give name and age4. Recognizable and relevant words3. Incomprehensible, but complex2. Cry or grunt1. No responseMotor2. Localizes pain.1. Withdrawal from painO. Non-specific or no response to pain6. Obeys commands5. Localizes pain.4. Withdrawal from pain.3. Flexes to pain2. Extends to pain.1. No response.Eye1. Directed eye movementsO. Not directed4. Spontaneous eye opening3. Opens eyes to voice2. Opens eyes to pain1. No eye openingwith severe malaria and a summated score of 2 isused to define cerebral malaria in many studies.15The Blantyre coma scale has similar componentsto the Glasgow coma scale but it measures differentyoung infants to localize a painful stimulus.16A Glasgow coma scale less than 8 has beenproposed as part of the definition of CM .16A practicaldefinition based on the Glasgow Coma Score exists.17Its key elements are;16

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

SUDANESE JOURNAL OF PAEDIATRICS AND CHILD HEALTH VallO: 2010metastasis, transplant rejection, stroke, brain hypoxiaand related conditions. Indeed, platelets have beendetected during rejection episodes41InvolvementTumor necrosisof Cell Adhesion Moleculesfactor can induce or upregulatevarious cell adhesion molecules(CAM)on endothelialcells; the expression of these molecules was analyzedby immunohistochemistry.with CM showed a marked upregulationBrain vessels from miceof ICAM-1and vascular cell adhesion molecule 1(VCAM-1).42An attempt to prevent CM by intravenousinjection of anti-TNF monoclonalantibodies(MAbs)directed against LFA-1, Mac-I, ICAM-I, VCAM-I,VLA-4 and P-selectin;MAb proved to be efficient.showed that only anti-LFA-1The important role ofICAM -1 was confirmed using a SCID mouse modelin which P. falciparum-infectedto brain ICAM-Ideficient mice.43human RBC adhereand more recently using ICAM-1-An adhesion molecule CD36 also known asplatelet glycoprotein IV or IIIb, is an 88 kDamembrane protein expressed on the surface asmulti-ligandreceptor of a wide variety of cell typessuch as platelets, endothelial cells, monocytes andmacrophages. It is involved in host defense against P.falciparum. CD36 is commonly deficient, particularlyin certain ethnic groups including Africans. Its role inCM is debatable.44Obstruction to the cerebral microcirculationresultsin hypoxia and increased lactate production due toanaerobic glycolysis. The parasitic glycolysis mayalso contribute to lactate production. In patients withCM, C.S.F. lactate levels are high and significantlyhigher in fatal cases than in survivors. The adherenterythrocytes may also interfere with gas and substrateexchange throughout the brain. However, completeobstruction to blood flow is unlikely, since thesurvivors rarely have any permanent neurologicaldeficit.The mechanismof coma is not clearly known.Increased cerebral anaerobic glycolysis, interferencewith neurotransmission by sequestered andhighly metabolically active parasites has beenblamed. Cytokines induce a potent inhibitor ofneurotransmission, nitric oxide (NO), synthesisin leukocytes, smooth muscle cells, microglia andendothelium.Clinical ManifestationsCerebral malaria is an acute widespread disease ofthe brain which is accompanied by fever. In severe P.falciparum malaria the neurological dysfunction canmanifest suddenly following a generalized seizureor gradually over a period of hours.46The clinicalmanifestations however, are numerous but there arethree primary symptoms generally common to bothadults and children:(1) Impaired consciousness with non-specific fever,(2) Generalized convulsions and neurologicalsequelae and,(3) Coma that persists for24 -72% hours, initiallyarousable and then unarousable.Neurological Signs in Cerebral Malaria:Mild neck stiffness may be seen, however,neck rigidity and photophobia and signs ofraised intracranial pressure are absent. Retinalhaemorrhages occur in about 15% of cases, exudatesare rare. Pupils are normal. Papilloedema is rareand should suggest other possibilities. A variety oftransient abnormalities of eye movements, especiallydysconjugate gaze are observed. Fixed jaw closureand tooth grinding (bruxism) are common. Pouting orshowing displeasure may occur or may be elicitable,but other primitive reflexes are usually absent. Thecorneal reflexes are preserved except in a case of deepcoma. Motor abnormalities like decerebrate rigidity,decorticate rigidity and opisthotonus can occur. Deepjerks and plantar reflexes are variable. Abdominaland cremasteric reflexes can not be elicited. Thesesigns help in distinguishing CM from behaviouralproblems due to fever of other causes. Rarely, cases19

SUDANESE JOURNAL OF PAEDIATRICS AND CHILD HEALTH Vol 10: 2010of falciparum malaria may present with cerebellarataxia with unimpaired consciousness. It may evenoccur 34- weeks after an attack of falciparum malaria.It completely recovers over 12- weeks.6Management of Cerebral Malaria in ChildrenSevere malaria is a medical emergency andmay rapidly progress to death without promptand appropriate treatment. The main objective ofthe treatment of severe malaria is to prevent thepatient from dying; prevention of recrudescence,transmission or emergence of resistance andprevention of disabilities are secondary objectives.Light microscopy of well stained thick and thinfilms by a skilled microscopist has remained the«gold standard» for malaria diagnosis. However,microscopy cannot detect parasite sequestereddeep in the vascular compartment and in case ofmixed infection often one species suppresses theother, thereby making detection of the suppressedone difficult.ao Blood gases and acid base deficit,renal function profile and blood glucose are usefulpredictors of the outcomeCerebrospinal fluid analysis may have to bedone in all doubtful cases and to rule out associatedmeningitis. In malaria, C.S.F. pressure is normallyelevated, fluid is clear and WBCs are fewer than 10/Jtl; protein and lactic acid levels are elevated.d?Electroencephalogram may show non-specificabnormalities and C.T. scan of the brain is usuallynorma1.48 In addition to brain swelling, corticalinfarcts and white matter lesions can be seen on MRexaminations obtained during the course of cerebralmalaria. White matter lesions can regress witheffective treatment. The MR pattern is compatiblewith toxicity leading to intravascular engorgementand oedema and in some cases, to irreversible myelindamage.49Meticulous nursing is the most important aspectof management in patients with CM and coma.A clear airway must be maintained. In cases ofprolonged deep coma, endotracheal intubation maybe indicated. Naso-gastric aspiration is importantto prevent aspiration pneumonia. Urethral catheterhas to be inserted for monitoring urine output in anycomatose patient. All children with cerebral malariashould be admitted to an ICU if possible and childrenwith impending respiratory failure should be placedon ventilatory support.It is quite helpful to maintain strict intake/outputrecords and to monitor the vital signs every 46-hours.50 Observe for high coloured or black urine.Changes in levels of sensorium, occurrence ofconvulsions should also be observed.It is crucial to control or prevent seizures as theycan cause neuronal damage and are associated with afatal outcome. Witnessed seizures are managed withslow diazepam (0.2 mg/kg IV maximum of 10 mgor 004 mg/kg per rectum) or paraldehyde (0.1 mL/kg 1M). Because diazepam can worsen respiratorydepression, the patient's respiratory status should bemonitored carefully after diazepam administration.Patients with recurrent seizures should be treatedwith Phenobarbital or Phenytoin, as one wouldtreat a patient with status epilepticus. Phenobarbitalprophylaxis for seizures is not recommended inchildren with cerebral malaria. Large studies inAfrican children demonstrated a higher mortality ratein children who received Phenobarbital prophylaxiscompared to controls.51Hypoglycemia is common in children below 3years of age especially with hyperparasitemia orwith convulsion. It also occurs in patients treatedwith quinine. Manifestations are similar to those ofcerebral malaria so it can be easily overlooked. Bloodsugar should be Monitored every 4 to 6 hours.Exchange transfusion generally only beenjustified when peripheral parasitaemia exceeds 10%of circulating erythrocytes. The role of these blood20

SUDANESE JOURNAL OF PAEDIATRICS AND CHILD HEALTH VallO: 2010transfusions remains highly controversial, as they areboth expensive and potentially dangerous in manymalaria-endemic areas.Pentoxifylline helps microcirculatory flowby reducing the red cell deformability and bloodviscosity, decreases systemic vascular resistanceand impairs platelet aggregation thus improvingmicrocirculatory flow.Desferrioxamine this is an iron-chelating adjuvantagent with antimalarial properties is suggested as itreduces the formation of reactive oxygen species byreducing amount of free iron.52The following drugs should not be administered:Anti-Inflammatories such as corticosteroids.However, there have been few controlled studiesdemonstrating benefit. other antiinflammatory drugs;low molecular weight dextran; adrenaline; heparin;hyperbaric oxygen; cyclosporin should be avoided.Dehydration and hypovolemia in children withcerebral malaria should be corrected with intravenousfluids or colloid. Lactic acidosis can be correctedby aggressive management of malarial infection,volume replacement if the patient is dehydrated andtransfusion of blood as appropriate.The mortality of untreated severe malaria can be100%, but with antimalarial treatment, the overallmortality falls to 15-20%. As death from severemalaria can occur within hours of admission tohospital or clinic, it is essential that therapeuticconcentrations of antimalarial are achieved as soonas possible with intravenous antimalarials. Further,gastrointestinal intolerance and erratic intestinalabsorption make the oral route of administrationunreliable in these patients. As resistance toantimalarial drugs can complicate matters further,proper choice of antimalarials to start the treatmentis of utmost importance; changing the drugs oradding of drugs half-way through the treatment onlycomplicates the issue and adds to the adverse effectsof treatment. Children with cerebral malaria shouldbe treated with intravenous or intramuscular Quinine,or intramuscular Artemisinin derivatives.53Consequences and Prognosis of Cerebral MalariaCerebral malaria carries a mortality of around 20%in adults and 15% in children. Factors associated witha fatal outcome included deep breathing or acidosis(base excess below -8), hypotension (systolic bloodpressure < 80mmHg), raised plasma creatnine (>80]tmolll), low oxygen saturation «90%), dehydrationand hypoglycaemia «2.5 mmolll). Approximately7% of children who survive CM are left withpermanent neurological problems. These includeweakness, spasticity, blindness, speech problemsand epilepsy. Recent evidence suggests that somechildren who appear to have made a completeneurological recovery from cerebral malaria maydevelop significant cognitive problems (attentiondeficits, difficulty with planning and initiating tasks,speech and language problems), which can adverselyaffect school performance and persist for years afterthe attack.54 The limited availability of specializedcare for such children indicates that opportunitiesfor subsequent learning and for attainment ofindependence, are compromised even further.References1- Newton. CR.1nteraction between Plasmodium falciprum andhuman immunodeficiency virus type 1on the central nervoussystem of African children.».I Neurovirol 2005; 11 suppl 3:4551-.2--Luhan, M. Malaria. WHO Press Office fact sheet 94. P. 1-3.World Health Organization, Geneva, Switzerland. 1996.3- WHO. Current epidemiological situation.TDR Roll BackMalaria. Report: 2002.4- Chin, 1. (Ed.) (2000). Control of communicable diseasesmanual (17th ed.). Washington, DC: American Public HealthAssociation.21

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