NEUROLOGICAL ASPECTS OF TROPICAL DISEASE

Cerebral malaria

Charles R J C Newton, Tran Tinh Hien, Nicholas White

AbstractCerebral malaria may be the most com-mon non-traumatic encephalopathy in theworld. The pathogenesis is heterogenousand the neurological complications areoften part of a multisystem dysfunction.The clinical presentation and pathophysi-ology diVers between adults and children.Recent studies have elucidated the mo-lecular mechanisms of pathogenesis andraised possible interventions. Antimalar-ial drugs, however, remain the only inter-vention that unequivocally aVectsoutcome, although increasing resistanceto the established antimalarial drugs is ofgrave concern. Artemisinin derivativeshave made an impact on treatment, butother drugs may be required. With appro-priate antimalarial drugs, the prognosis ofcerebral malaria often depends on themanagement of other complications—forexample, renal failure and acidosis.Neurological sequelae are increasinglyrecognised, but further research on thepathogenesis of coma and neurologicaldamage is required to develop other ancil-lary treatments.(J Neurol Neurosurg Psychiatry 2000;69:433–441)

Keywords: malaria; antimalarial drugs; coma; parasiticdisease

Malaria is the most important of the parasiticdiseases of humans, and its neurologicalcomplication, cerebral malaria is arguably oneof the most common non-traumatic encepha-lopathies in the world. Malaria aVects about5% of the world’s population at any time andcauses somewhere between 0.5 and 2.5 milliondeaths each year. There are four species ofhuman malaria, but Plasmodium falciparumcauses nearly all the deaths and neurologicalcomplications. Severe malaria occurs predomi-nantly in patients with little or no backgroundimmunity—that is, children growing up inendemic areas, or travellers or migrants whocome from areas without malaria, but areexposed to malaria later in life. The manifesta-tions of severe malaria diVer depending on theage of the patient and previous exposure.1 Inthe first 2 years of life severe anaemia is a com-mon presenting feature of severe malaria. Inolder children seizures and cerebral malaria

predominate; whereas in adults acute renalfailure, acute pulmonary oedema, liver dys-function, and cerebral malaria may all occur.Metabolic acidosis, mainly a lactic acidosis, iscommon at all ages. Severe malaria is a multi-system disease, and the outcome often dependson the degree of vital organ dysfunction.

P falciparum is transmitted by female Anoph-eles mosquitoes. In humans, although theparasite undergoes development in the liver, itis the erythrocytic cycle that is responsible fordisease. The merozoites released by the liverinvade the erythrocyte, and during a period of48 hours, pass through morphologically dis-tinct stages, before the meronts (schizonts)rupture the erythrocyte. Ring stages are seen inthe peripheral blood, but trophozoites andmeronts are usually absent, as they are seques-tered within the deep vascular beds.

Pathological features of cerebral malariaThe histopathological hallmark of cerebralmalaria is engorgement of cerebral capillariesand venules with parasitised red blood cells(PRBCs) and non-paratised RBCs(NPRBCs).2 The brain is usually swollen atpostmortem, although evidence of frank her-niation is unusual in adults. The cut brain isslate grey, with petechial haemorrhages. Theendothelium does not demonstrate micro-scopical damage,2 but immunohistochemicalstaining suggests endothelial activation3 anddisruption of the blood-brain barrier.4 Inflam-matory cells and immune complex depositionare not consistent features in necropsy series todate2 3 although some authors think thatcerebral malaria has features of a diVuseencephalomyelitis.5

SequestrationThe sequestration of red cells containingmature forms of the parasite (trophozoites andmeronts) in the microvasculature is thought tocause the major complications of falciparummalaria, particularly cerebral malaria.6 Thisprocess varies considerably between organs(the brain is particularly aVected) and at amicrovascular level varies between vessels. Thesequestration of PRBCs in the relativelyhypoxic venous beds allows optimal parasitegrowth and prevents the PRBCs from beingdestroyed by the spleen.7 It is the sequesteredparasites that cause pathology in severe ma-laria, and prognosis is related to sequestered

J Neurol Neurosurg Psychiatry 2000;69:433–441 433

Neurosciences Unit,Institute of ChildHealth, London,United KingdomC R J C Newton

Centre for TropicalDiseases, Cho QuanHospital, Ho Chi MinhCity, VietnamT T HienN White

Faculty of TropicalMedicine, MahidolUniversity, Bangkok,ThialandN White

Correspondence to:Dr C R J C Newton,Wellcome Trust/ KEMRICentre, PO Box 230, Kilifi,Kenyacnewton@kilifi.mimcom.net

Received 8 May 2000Accepted 6 June 2000

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biomass.8 9 The peripheral blood parasite countis a relatively poor predictor of the size of thisbiomass. In a recent postmortem study of fatalfalciparum malaria in adults, the median ratioof cerebral to peripheral blood parasitaemiawas 40 (range 1.8–1500).10 In this study,although most sequestered parasites were themature stages not seen in the peripheral blood,there were considerably more ring stages thanexpected from a free mixing model. Patientswho have died from non-neurological compli-cations of falciparum malaria also showcerebral sequestration at necropsy, althoughthe intensity is less in patients who die withoutpreceding coma.2 Many authors have com-mented on the lack of correlation between thenecropsy findings and clinical features ofcerebral malaria; although one study showed acorrelation between the degree of PRBCsequestration and depth of coma onadmission.11 Some authors have suggested thatcerebral malaria may occur in the absence ofcerebral sequestration. These discrepanciescan be explained by the variable intervalbetween starting antimalarial treatment anddeath; fatal cases without cerebral sequestra-tion have invariably received many days ofantimalarial treatment before dying.

CytoadherenceSequestration is thought to be a specific inter-action between PRBCs and the vascularendothelium (cytoadherence). This phenom-enon seems to be mediated by plasmodiumderived proteins on the surface of PRBCs andmodified erythrocyte cell wall proteins and lig-ands on endothelial cells.The adhesion of thePRBCs reduces the microvascular blood flow,12

which may explain organ and tissue dysfunc-tion such as coma. The metabolically activesequestered parasites may compete with hosttissues for substrates—for instance, glucose—and also produce toxins that interfere with hosttissue metabolism. Unfortunately, there is nosatisfactory animal model of human cerebralmalaria. In vitro models show that cytoadher-ence begins when the parasites produce visiblemalaria pigment (usually becoming visibleunder light microscopy around 16 hours),which is maximal at the late stages.7 Cytoad-herence occurs predominately in capillariesand venules, as it is overcome by large shearstresses encountered on the arterial side.13

Freshly isolated PRBCs capable of cytoadher-ence have electron dense “knobs” protrudingfrom their surfaces, composed of proteinsderived from the parasite, notably the adhesinP falciparum erythrocyte membrane protein-1(PfEMP-1).14 This family of large proteins(200–350 kDa) which are expressed on theexterior of PRBCs vary antigenically with timein cloned parasites. This programmed variationallows the parasites to evade host immuneresponses. These proteins have adhesive prop-erties and are primarily responsible for cytoad-herence. A family of more than 150 highlyvariable (“var”) genes encode PfEMP-1, whichcan bind to several candidate endothelialreceptors.15 Some of these vascular receptors,such as the main candidate CD36, seem to be

expressed at all times in a wide range of vascu-lar beds and are regarded as constitutive; theirexpression is not related qualitatively or quan-titatively to severity of disease.16 Other recep-tors such as intracellular adhesion molecule-1(ICAM-1) and endothelial selectin (E-selectin)are inducible,17 with increased expression in thecerebral vessels of patients with cerebralmalaria, which co-localises with sequestration,suggesting that they may be responsible forcytoadherence.3 4 Monoclonal antibodiesagainst ICAM-1 improve microcirculatory flowin ex vivo models of malaria sequestration,12

but have not been evaluated in humans. Theprocess of PRBC cytoadherence has severalparallels to that of leucocyte adherence to thevascular endothelium. Firstly, rolling occursalong the endothelial surface, followed by staticadherence, which reduces flow in packedpartially obstructed vessels.

The clinical correlates of these in vitro mod-els are poor. Parasitised red blood cells fromGambian children with cerebral malaria didnot bind more avidly to C32 melanoma cellsthan isolates from children with less severedisease.7 18 Although binding to CD3619 hasbeen shown to be directly proportional toparasitaemia, the degree of binding to CD36cells correlated with biochemical indicators ofdisease severity in adult Thai with malaria,19

rather than coma.20 In adults with cerebralmalaria there was an increase in vesselsexpressing ICAM-1 and E-selectin, but notother ligands3; whereas in Kenyan children,there was a relation between cerebral malariaand binding to CD36, ICAM-121 and amutation in the ICAM-1,22 although this wasnot confirmed in other sites in Africa.23 24 Stud-ies on peripheral blood parasites reflect theentire repertoire of adhesins, and may not berepresentative of cytoadherence in a particularorgan.

Rosetting and agglutinationThe adherence of NPRBCs to PRBCs (roset-ting) and PRBCs to PRBCs (agglutination),have also been implicated in the pathogenesisof cerebral malaria, although most clinicalstudies have failed to show an association. Inrosetting, the var genes seem to be responsiblefor the ligands25 and this intererythrocyticinteraction is pH and heparin sensitive.26 It canbe disrupted by antibodies to P falciparum,18

glycosaminoglycans, sulfated glycoconjugatesin a strain and isolate specific manner.27

Rosettes are disrupted at high flow rates,although they reform at lower shear stresses,aggravating the venular obstruction in a rodentex vivo model of sequestration.28 Increasedrosette formation was found in Gambianchildren with cerebral malaria, with a corre-sponding lack of antirosetting antibodies,18

whereas studies from other parts of the worlddid not show such an association.24 29 The con-tribution of agglutination to the pathophysiol-ogy of severe malaria is unclear.

Red cell deformabilityAs the parasite grows within the RBCs, theerythrocyte becomes less deformable,30 which

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may contribute to the RBC destruction andimpair the microcirculatory flow. The reduc-tion in red cell deformability not only occurs inPRBCs, but also the NPRBCs. The NPRBCshave to undergo considerable deformation asthey squeeze through the sequestered microcir-culation. Microvascular perfusion in severe fal-ciparum malaria is therefore limited by me-chanical obstruction, adherence of otherRBCs, and the stiVness of the non-adherentRBCs. Red cell deformity measured at lowshear rates encountered in capillaries andvenules, proved the most powerful prognosticindicator of severe malaria in a study of Thaiadults,31 although not associated with thesyndrome of cerebral malaria itself. Similarstudies in Kenyan children also showed astrong association with severe disease and apredictable increase in red cell deformity withblood transfusions.32

CYTOKINES

Blood concentrations of proinflammatory cy-tokines are raised in cerebral malaria,33 34 as inmany severe infections. Tumour necrosisfactor-á (TNF-á) upregulates endothelial cy-toadherence receptors and can cause hypogly-caemia and dyserythropoiesis, which are fea-tures of severe disease.

In African children, high concentrations ofTNF-á are associated with coma, hypoglycae-mia, hyperparasitaemia, and death.33 34 Earlystudies suggested that increases in proinflam-matory cytokine concentrations were associ-ated with cerebral malaria, generating thehypotheses that cytokines produced coma.Thus Clarke et al suggest that TNF-á inducesthe release of nitric oxide (NO), whichinterferes with synaptic transmission, causingcoma.35 More recent studies in adults indicatethat the increases in cytokine concentrationrelate more to overall severity. Plasma concen-trations of TNF-á, interleukin (IL)-6, andIL-10 were higher in Vietnamese adults whodied with severe malaria than survivors; butthese increases were not associated withcerebral malaria.36 Indeed, concentrations ofproinflammatory cytokines were significantlylower in patients with pure cerebral malariathan in those with multiple organ dysfunction.Fatal malaria is associated with a relative defi-ciency of IL-10 production, an anti-inflammatory cytokine that controls the pro-duction of the proinflammatory cytokines.Persuasive evidence for a role of proinflamma-tory cytokines in lethal malaria comes from thefinding that Gambian children homozygous forthe 308 TNF promoter polymorphism alleleare at a significantly increased risk of dying ofcerebral malaria.37 38

However, there are inconsistencies. In pa-tients with severe malaria, the blood concentra-tions of TNF-á receptors are markedly in-creased and bioactive TNF-á is seldomdetectable.39 There is considerable overlapbetween the distribution of cytokine concen-trations in the diVerent clinical patterns ofmalaria.34 Concentrations of TNF-á measuredin paroxysms of uncomplicated P vivax infec-tions are as high as those measured in patients

with cerebral malaria,40 but this infection rarelycauses neurological disturbances. The admin-istration of monoclonal anti-TNF, reducedtemperature, indicating bioactivity against py-rogenic cytokines,41 but did not eVectoutcome.42 Plasma concentrations of nitrateand nitrite (so called reactive nitrogen interme-diates (RNI)), surrogate measures for NO,have been shown to be raised in some series butlow in others.43 44 The RNIs are crude measuresof NO production, as they are also influencedmarkedly by diet, and their elimination is viathe kidney. In Papua New Guinea, thesemetabolites were highest in children withcerebral malaria, particularly those who died.45

In African children, NO production was lowestin those aged 1–5 years, the age at which chil-dren are most susceptible to cerebral malaria.46

The metabolites are lower in plasma ofchildren admitted with cerebral malaria,47 buthigher in the CSF of children who died in onestudy,48 but not in another.49 In Vietnamese andThai adults the increase in plasma concentra-tion of RNI in severe malaria (particularly fatalcases) was accounted for entirely by renalimpairment, and thus reduced RNI clearancerather than cerebral involvement.50 Therefore,if cytokines and NO have an important patho-genic role, it is likely to be at the local tissuelevel, rather than systemically.

DEFINITION OF CEREBRAL MALARIA

The term “cerebral malaria” has often beenused loosely in the medical literature todescribe any disturbance of the CNS in amalaria infection. In the case reports of thecerebral involvement caused by P vivax, othercauses of an encephalopathy or mixed infec-tions with P falciparum have not been ad-equately excluded. In falciparum malaria,disturbances of consciousness can be caused bysystemic complications—for example, fever,hypoglycaemia, hyponatraemia, and uraemia.To allow comparison between patient popula-tions in diVerent countries, a strict definition ofcerebral malaria was suggested51 52: defined as adeep level of unconsciousness (inability tolocalise a painful stimulus) in the presence of aP falciparum asexual parasitaemia, after thecorrection of hypoglycaemia and exclusion ofother encephalopathies, especially bacterialmeningitis and locally prevalent viral encepha-litides. In adults, coma was required for morethan 6 hours after a generalised convulsion toexclude a transient postictal state (which rarelylasts more than 1 hour), although in childrenthis was reduced to 1 hour.53 In fatal cases, thediagnosis of cerebral malaria is supported byfinding cerebral capillaries and venules packedwith PRBCs. These features may be absent ifthe patient dies after several days of treatment,and are not specific for cerebral malaria. Inclinical practice, any impairment of conscious-ness or other sign of cerebral dysfunction is anindication for parenteral treatment and inten-sive care management.

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Cerebral malaria in adultsCLINICAL FEATURES

Cerebral malaria is a diVuse encephalopathy inwhich focal neurological signs are relativelyunusual. The patient is febrile and unconsciouswith divergent gaze and variable tone.54 Theremay be passive resistance to neck flexion, but ofa lesser degree to the “meningism” associatedwith meningitis. There is no rash, and no lym-phadenopathy. As cerebral malaria is oftenaccompanied by multisystem dysfunction, anassessment of the degree of anaemia, jaundiceand, most importantly, the presence of acidotic(Kussmaul’s) breathing is important. Theprognosis of cerebral malaria worsens consid-erably with coexistent renal failure, severejaundice, or metabolic acidosis. The metabolicacidosis is caused by either an acute renal fail-ure, or a lactic acidosis, or a combination ofboth. Acute pulmonary oedema may occur.Rarely, patients with severe malaria havedisseminated intravascular coagulation52 andevidence of bleeding, usually from the uppergastrointestinal tract but sometimes in the skin.The pulse is usually rapid and full, with a lowor normal blood pressure. The peripheries arewell perfused, although shock may occur and isoften terminal. Hypoglycaemia (plasma glu-cose<2.2 mmol/l) is common in severe malaria,occurring in about 8% of adults55 and about20% of children with cerebral malaria.1 56 It isusually not accompanied by noticeable sweat-ing or gooseflesh or other physical signs ofhypoglycaemia. All patients with severe malariashould have frequent checks of blood glucose.Restoration of normoglycaemia, however, isoften not associated with a change in the levelof consciousness.

On direct ophthalmoscopy retinal haemor-rhages are found in about 15% of patients.57

These are boat or flame shaped and sometimesresemble Roth spots with a pale centre. Theyusually spare the maculae. Indirect ophthal-moscopy discloses haemorrhages in a muchhigher proportion of patients.58 These haemor-rhages seldom involve the macula. Areas ofunusual retinal “whitening” may also be seenand occasional cotton wool spots.58 Papil-loedema is very unusual in adults. Thepupillary reactions are usually normal and therange of eye movements full, although gaze isdysconjugate. Sixth nerve palsies may occurrarely.54 The corneal reflexes are usuallypresent although in very deep coma they maybe lost. The remainder of the cranial nerveexamination is usually normal. A pout reflexmay sometimes be elicited and bruxism iscommon but other “frontal release” signs areunusual.54 Stereotyped movements, commonlyseen in encephalitides, are not seen in cerebralmalaria. Tone and reflexes are variable. Theabdominal reflexes are almost always absent,the plantars often upgoing, and ankle andpatellar clonus can sometimes be elicited inhypertonic patients.54

SEIZURES

The incidence of convulsions in adults withcerebral malaria varies. In the early 1980sstudies conducted in Thailand and Vietnam,

50% of adults with cerebral malaria had gener-alised seizures,59 whereas in these countries inthe 1990s the incidence was less than 10%.The reason for this diVerence is not clear. Pos-sible explanations include diVerences in para-site virulence characteristics, or possibly thedecrease in the use of chloroquine pretreat-ment. Partial motor seizures may also occurand in occasional cases the evidence for seizureactivity is subtle, such as repetitive eye or handmovements, and may be easily overlooked.Subtle evidence for seizure activity seems to bemore common in children than in adults. Thelevel of consciousness after a seizure is usuallylower than that preceding it. Status epilepticusis unusual in adults, although more than oneseizure is common.59

OUTCOME

The overall mortality of adult cerebral malariais about 20%.52 Mortality depends on the asso-ciated vital organ dysfunction. In patients with“pure” cerebral malaria and no other evidenceof vital organ dysfunction the mortality is 8%,whereas it rises towards 50% with associatedacute renal failure and metabolic acidosis.Mortality is also dependent on the availabilityof intensive care facilities. If the patient can beventilated if needed and renal replacementtherapy (preferably haemofiltration) provided,and there is careful nursing of the unconsciouspatient, then mortality is reduced.The patientmay die from a sudden acute respiratory arrest,often after a period of respiratory irregularity,but with a normal blood pressure. Otherpatients may die from shock and others fromhypoxia and hypotension secondary to acutepulmonary oedema or sometimes aspirationpneumonia. Most deaths occur within 48hours of admission. Full recovery of conscious-ness takes a median of 2 days in patients with asummated Glasgow coma score <11 but occa-sional adult patients may take more than 1week to recover consciousness.

Cerebral malaria in African childrenIn African children growing up in malariousendemic areas, severe falciparum malaria usu-ally manifests as seizures, impaired conscious-ness, or metabolic acidosis presenting as respi-ratory distress or severe anaemia.60 Comparedwith adults, children have a higher incidence ofseizures61; the incidence and pattern of neuro-logical sequelae are diVerent and they often diewith features of brain death.1 African childrenrarely develop renal failure or pulmonaryoedema.

In older children, cerebral malaria can bedefined as in adults. The Blantyre coma scale(table 1), was devised to assess young childrenwith severe malaria53 and a summated score<2is used to define cerebral malaria in manystudies.34 62 The Blantyre coma scale hassimilar components to the Glasgow coma scale,but measures diVerent responses. However,there is considerable disagreement betweenobservers in assessing the scale,63 and the scaledoes not address the inability of young infantsto localise a painful stimulus.63

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African children with cerebral malaria areolder (40–45 months of age), than childrenwith other complications of the disease,60 butcerebral malaria is rarely encountered after theage of 10 years in people exposed to Pfalciparum since birth. Cerebral malariapresents usually with a 1–4 day history of feverand convulsions, the second often precipitatescoma.53 62 Focal motor and generalised tonic-clonic convulsions are the most common clini-cally detected seizures,64 65 but subtle orsubclinical seizures detected with EEG are alsocommon.66 Furthermore in some children, thelevel of consciousness improves with theadministration of anticonvulsant drugs, sug-gesting that seizures contribute to the coma.Seizures are associated with a pooroutcome,53 67 particularly prolonged seizures.64

Between seizures the EEG shows bilateral dif-fuse slowing of the brain waves, often asymmet-ric (not inevitably associated with clinicalsigns).65

Most African children with cerebral malariasurvive with appropriate treatment, regainingconsciousness within 48–72 hours of startingtreatment.53 62 68 69 The median time for recov-ery of consciousness is 32.3 hours (95% CI23.4–41.1). In children, a median of 10.9%(95% CI 8.3–13.5) have neurological sequelae,a median 18.69% (95% CI 16.3–21.0) die.1

Most deaths occur within 24 hours of startingtreatment,53 60 68 70 usually with brainstem signs,respiratory arrest, or overwhelming acidosis.

BRAIN SWELLING

Opening CSF pressures are raised in mostAfrican children with cerebral malaria70 71 andthere is evidence of brain swelling on CT72 andat postmortem.68 Kenyan children dying withcerebral malaria had clinical signs compatiblewith transtentorial herniation,70 and half of thechildren had sonographic features of progres-sive intracranial hypertension during the ago-nal phases.73 In a postmortem study of sevenNigerian children dying of cerebral malaria,transtentorial herniation was seen in one, andthree others had evidence of brain oedema.68

Monitoring intracranial pressure (ICP) con-firmed that children deeply unconscious fromcerebral malaria had raised ICP74 and thosechildren who developed severe intracranialhypertension either died or survived withsevere neurological sequelae.

The most likely cause of raised ICP incerebral malaria is an increase in cerebral bloodvolume,70 particularly during the initial stagesand in those children with moderate degrees ofintracranial hypertension. Cerebral blood vol-ume could be increased by the sequestration ofPRBCs in the vascular compartment, eitheracting as a diVuse space occupying lesion or

obstructing venous outflow.70 An increasedcerebral blood flow72 75 could be caused byother features of cerebral malaria, such asseizures, hyperthermia, and anaemia. Kenyanchildren with severe neurological sequelae havetomographic evidence of cytotoxic oedemaduring recovery that may contribute to thesevere intracranial hypertension.72

Whether intracranial hypertension is a pri-mary pathophysiological process remains to beestablished. Mannitol was eVective in loweringthe ICP and may have prevented children withmild degrees of intracranial hypertension fromdying or developing neurological sequelae, butit did not prevent the development of intracta-ble intracranial hypertension in those childrenwith a poor outcome.74

NEUROLOGICAL SEQUELAE

Neurological sequelae are associated with pro-tracted seizures,64 67 prolonged and deepcoma,64 67 hypoglycaemia,64 67 and severe anae-mia in some studies,67 but not in others.64 Someneurological deficits are transient (for example,ataxia), whereas others (for example, hemi-paresis and cortical blindness), often improveover months, although they may not com-pletely resolve. African children with severeneurological sequelae (spastic tetraparesis,vegetative states) usually die within a fewmonths of discharge. More subtle deficits—forexample, cognitive diYculties, and languageand behavioural problems—are increasinglyrecognised. A study of 87 children withimpaired consciousness found impairment ofexecutive functions in children without obviousneurological deficits.76 The incidence of epi-lepsy after cerebral malaria is not determined,although often reported.1 Furthermore, as theseizures that occur during the acute illness areoften focal, repetitive, or prolonged, damage tothe hippocampus may occur, producingmemory impairment and complex partialseizures, which may be underreported.

The causes of the sequelae are largelyunknown and are likely to be multifactorial.Severe neurological sequelae are associatedwith severe intracranial hypertension.74 Half ofthe children with hemiparesis have stenosis orocclusion of the basal cerebral arteries demon-strated by angiography77 78 or transcranialDoppler.73 The cause of large vessel disease isunknown but may be related to vasospasm orunderlying conditions such as haemoglobin-opathies. Some children with hemiparesis havethe CT appearances of hemiconvulsion-hemiparesis syndrome. Blindness is usuallycortical,1 often follows seizures, and is usuallyassociated by evidence of more diVuse damage,although it can occur in isolation. Braindamage could be caused by a mismatchbetween the delivery of oxygen (anaemia,decreased microcirculatory flow) and glucose(hypoglycaemia), in the presence of increaseddemand (seizures, fever). The generation ofexcitotoxins (seizures, hypoglycaemia),49 reac-tive oxygen species (during reperfusion of themicrocirculatory bed) or toxins produced bythe parasite may also contribute.1

Table 1 Blantyre coma scale53

Verbal 0: No cry1: Inappropriate cry or moan2: Appropriate cry

Motor 0: Non-specific or no response1: Withdrawal from pain2: Localises pain

Eye 0: Not directed1: Directed eye movements

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Seizures and malariaSeizures are the other common neurologicalmanifestation of falciparum malaria, often pre-cipitating admission to hospital. P falciparumseems to be particularly epileptogenic becauseit was the most common cause of seizures inchildren admitted to a Kenyan hospital61 andmore often associated with seizures comparedwith P vivax infections in Thai children.79

Although fever may precipitate some seizures,most seizures occur when the rectal tempera-tures are less than 38.0oC.61 By comparisonwith simple febrile seizures, the seizures inmalaria are often recurrent, and 84% of theseizures are complex, most often with a focalnature.61 The seizures may be caused by intrac-ranial sequestration of metabolically activeparasites or “toxins” produced by the parasites,but seem not to be associated with hypoglycae-mia and hyponatraemia.53 61 Some antimalarialdrugs—for example, chloroquinine—may pre-cipitate seizures.80

Management of patients with suspectedcerebral malariaCerebral malaria is a medical emergencydemanding urgent clinical assessment andtreatment. Impairment of consciousness, con-vulsions, and other neurological featuresshould raise the possibility of cerebral malariain any person who might possibly have beenexposed to this infection during the previousyear. Most cases occur within 3 months ofexposure. Such cases deserve transfer to thehighest available level of care; where an appro-priate antimalarial drug should be adminis-tered as soon as possible, ideally by theparenteral route. Complications of cerebralmalaria, such as convulsions, hypoglycaemia,and hyperpyrexia, should be prevented ordetected and treated early. Fluid, electrolyte,and acid-base balance may need correction.Skilled nursing care of the unconscious patientis crucial. Ancillary treatments should beavoided unless they have proved safe and eVec-tive.

The management of cerebral malaria is simi-lar to that of any seriously ill unconsciouspatient. Intensive care with rehydration andthereafter careful fluid balance managementare necessary to navigate the narrow dividebetween underhydration and worsening renalimpairment and lactic acidosis, and overhydra-tion and pulmonary oedema. Children are lesslikely to develop pulmonary oedema and morelikely than adults to be hypovolaemic andunderperfused. Many require rapid restorationof an adequate circulating blood volume.81

Adults with severe malaria are particularlylikely to develop the adult respiratory distresssyndrome, more so than patients with bacterialsepticaemia, so management is aided consider-ably by monitoring of central venous pressure,and if necessary, pulmonary artery occlusionpressure. Blood transfusion is indicated whenthe packed cell volume falls below 20%, andmay be beneficial above this threshold. Theblood glucose must be checked often andhypoglycaemia must be corrected. The stom-ach should be drained via a nasogastric tube. Ifventilation is required, an experienced operatorshould perform intubation. Hypoxia and hy-pocapnoea may cause a fatal rise in ICP.82 Alumbar puncture should be performed toexclude meningitis. In patients with acute renalfailure or severe acidosis, haemofiltrationshould be started early if available.

Specific parenteral antimalarial treatment isthe only intervention that unequivocally aVectsthe outcome of cerebral malaria. Resistancehas meant that chloroquine can no longer berelied on in most tropical countries. TheCinchona alkaloid quinine (or in the UnitedStates its diastereomer quinidine) remains themainstay of antimalarial treatment of severemalaria (table 2). There has been controversyover many years over the optimum dosage andmethods of administering quinine in severemalaria. Quinine must be given with anadequate loading dose (20 mg/kg of thedihydrochloride salt infused over 4 hours) toensure that parasiticidal concentrations arereached in blood as soon as possible in the dis-

Table 2 Antimalarial treatment of cerebral malaria

Loading* Maintenance

Cinchona alkaloid:Quinine dihydrochloride

Intravenous 7 mg salt/kg over 30 min (infusion pump)followed immediately by 10 mg/kg over 4 h101

10 mg/kg over 4h repeated every 8–12 h‡§ 101,102

20 mg salt/kg over 4 h102 Same as aboveIntramuscular 20 mg salt/kg (dilute iv formulation to 60

mg/ml given by deep im injection dividedbetween both anterior thighs)101102

10 mg salt/kg repeated every 8–12 h‡¶ 101102

Quinidine gluconateIntravenous 10 mg salt/kg¶ infused over 1–2 h95 or 20 mg

salt/kg infused over 4 h1030.02 mg salt/kg/min continuously for up to 72 h†‡§ 95

10 mg salt/kg infused over 4 h every 8–12 h†§ 103

Artemisinin derivatives:**Artesunate††

Intravenous 3.2 mg/kg 1.6 mg/kg repeated 12–24 hourly‡‡Artemether

Intramuscular 3.2 mg/kg104 1.6 mg/kg repeated 12–24 hourly‡‡

*Avoid loading dose if quinine, quinidine, or mefloquine taken in previous 24 h.†Adjust rate of quinidine infusion to maintain blood concentration at 3–7 mg/l and prevent prolongation of ECG QRS>50%, QTc>25% of pretreatment values.‡Change to oral quinine as soon as possible and complete 7 days of treatment.§Add 1 g/day tetracycline in four divided doses for 7 days in non-pregnant adults in some areas.¶This dose may be too low.**Not marketed/licensed in many countries.††Artesunate is reconstituted with bicarbonate solution immediately before use.‡‡Change to oral mefloquine (single dose 15–25 mg/kg; max 1500 mg) as soon as possible.

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ease. In Zambian children a loading dose wasassociated with a shorter duration of coma andfaster parasite clearance and resolution offever.83 Thereafter 30 mg/kg/day is given for 7days, usually in 2–4 hour infusions of 10 mg/kgevery 8 hours. Infusion rates must be moni-tored and these drugs must not be given bymanual intravenous injection. The dose of qui-nine is reduced by 30–50% after 48 hours ifthere is no evidence of clinical improvement.84

Oral treatment should be substituted when thepatient can swallow reliably. Quinine is a pow-erful stimulant of pancreatic insulin secretionand may cause iatrogenic hypoglycaemia,55

particularly in pregnant women.Artemisinin (qinghaosu) derivatives of the

plant Artemisia annua have been used exten-sively in the treatment of cerebral and otherforms of severe falciparum malaria.85 86 Inuncomplicated malaria, these compounds clearparasitaemia and fever faster than the cinchonaalkaloids, but although in recent large ran-domised controlled trials of intramuscularartemether and quinine in African children,87

and Vietnamese adults,88 there was no improve-ment in the mortality. These trials had onlylimited power to detect mortality reductions;none were powered to detect a reduction of<30%. A meta-analysis of these and other ran-domised trials indicates that in adults arte-mether did reduce mortality (by about onefifth), but there was no convincing diVerence inchildren.89 Nevertheless, because of their safetyand simplicity in administration, and decliningsensitivity to quinine in some areas, they maywell supercede quinine as the treatment ofchoice for severe malaria. Suppository formu-lations of artemisinin and artesunate haveproved eVective in cerebral and severe falci-parum malaria.90 Although concerns aboutneurotoxicity have arisen from animal studies,no significant side eVects have been docu-mented in humans and there is not anincreased incidence of neurological sequelae.89

In many parts of the world, complete curerequires the addition of a course of oralsulfadoxine/pyrimethamine or tetracycline/doxycycline for 7 days (clindamycin in preg-nant women and children), which is started assoon as the patient is able to swallow tablets.

Hypovolaemia must be excluded in acidoticpatients. Renal replacement, preferably usinghaemofiltration, should be started early inpatients with acute hypercatabolic renal failure.Patients developing pulmonary oedema shouldbe ventilated and overhydration excluded.Patients who deteriorate suddenly should betreated with glucose (if hypoglycaemia cannotbe excluded rapidly) and broad spectrum anti-biotics as concomitant septicaemia is notuncommon.

ANCILLARY TREATMENTS

Phenobarbital (3.5 mg intramuscularly) re-duced the frequency of convulsions in adults,59

but higher doses are needed to prevent convul-sions in children.91 In a recent double blindcontrolled trial in Kenyan children, phenobar-bital (20 mg/kg) reduced seizures by 50%, butdoubled the mortality.92 There seemed to be an

interaction with diazepam in these unventilatedchildren. There was not a reduction in longterm neurological sequelae.92 Brain swellingshould be excluded by imaging in patients whoshow a deteriorating level of consciousness andappearance of neurological abnormalities inthe absence of hypoglycaemia. If there isevidence of cerebral swelling, 20% mannitolsolution should be infused.74 In adults, cortico-steroids did not benefit patients with CM51 93;consciousness was prolonged, and there was anincreased incidence of infection and gastro-intestinal bleeding in the corticosteroid treatedgroup.51

The use of exchange transfusion has beenreported in more than 100 published cases ofsevere falciparum malaria, but no adequaterandomised control data are available.86 94 95 Onempirical grounds, this intervention is prob-ably justified when peripheral parasitaemiaexceeds 10% of circulating erythrocytes in apresumed non-immune patient who has dete-riorated on optimal conventional treatment.

Management of cerebral malaria in childrenis similar to adults. Dehydration and hypogly-caemia are more common in children andshould be treated aggressively. Hypoglycaemiais often recurrent. The timing of the lumbarpuncture to exclude other CNS infections iscontroversial.74 96 The disposition of antimalar-ial drugs may be diVerent in children.97 Bloodtransfusions may be needed to correct severeanaemia and acidosis, and exchange transfu-sions for hyperparasitaemia have been used inAmerican children.98 The role of ancillarytherapies is controversial. Desferrioxamine hasnot been shown to be of any benefit in adults orAfrican children; indeed mortality was in-creased in desferrioxamine recipients in a morerecent trial.99 Pentoxifylline seems to shortenthe duration of coma in African children,100 butthe trial was too small to detect diVerences inmortality.

ConclusionCerebral malaria is common and should beconsidered in any patient with impairment ofconsciousness. Urgent treatment with appro-priate antimalarial drugs is required, but theprognosis often depends on the management ofother complications—for example, renal fail-ure, acidosis. Therapies that interfere withunderlying pathophysiological processes—forexample, reduced red cell deformability andcytoadherence—require further investigation.Further research on the pathogenesis of comaand neurological damage is required to developother ancillary treatments.

We thank all our colleagues with whom we have carried outinvestigations into malaria, in Kenya, Thailand, and Vietnam.CRJCN holds a Wellcome Career Post in Clinical TropicalMedicine (050533).

1 Newton CR, Krishna S. Severe falciparum malaria inchildren: current understanding of pathophysiology andsupportive treatment. Pharmacol Ther 1998;79:1–53.

2 MacPherson GG, Warrell MJ, White NJ, et al. Human cer-ebral malaria. A quantitative ultrastructural analysis ofparasitized erythrocyte sequestration. Am J Pathol 1985;119:385–401.

3 Turner GDH, Morrison H, Jones M, et al. An immunohis-tiochemical study of the pathology of fatal malaria. Am JPathol 1994;145:1057–69.

Cerebral malaria 439

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group.bmj.com on March 28, 2015 - Published by http://jnnp.bmj.com/Downloaded from

4 Brown H, Hien TT, Day N, et al. Evidence of blood-brainbarrier dysfunction in human cerebral malaria. NeuropatholAppl Neurobiol 1999;25:331–40.

5 Toro G, Roman G. Cerebral malaria. A disseminated vascu-lomyelinopathy. Arch Neurol 1978;35:271–5.

6 White NJ, Ho M. The pathophysiology of malaria. AdvParasitol 1992;31:83–173.

7 Marsh K, Marsh VM, Brown J, et al. Plasmodiumfalciparum: the behavior of clinical isolates in an in vitromodel of infected red blood cell sequestration. Exp Parasi-tol 1988;65:202–8.

8 Davis TME, Krishna S, Looareesuwan S, et al. Erythrocytesequestration and anemia in severe falciparum malaria. JClin Invest 1990;86:793–800.

9 Silamut K, White NJ. Relation of the stage of parasite devel-opment in the peripheral blood to prognosis in severe falci-parum malaria. Trans R Soc Trop Med Hyg 1993;87:436–43.

10 Silamut K, Phu NH, Whitty C, et al. A quantitative analysisof the microvascular sequestration of malaria parasites inthe human brain. Am J Pathol 1999;155:395–410.

11 Riganti M, Pongponratn E, Tegoshi T, et al. Human cerebralmalaria in Thailand: a clinico-pathological correlation.Immunol Lett 1990;25:199–205.

12 Kaul DK, Liu XD, Nagel RL, et al. Microvascular hemody-namics and in vivo evidence for the role of intercellularadhesion molecule-1 in the sequestration of infected redblood cells in a mouse model of lethal malaria. Am J TropMed Hyg 1998;58:240–7.

13 Nash GB, Cooke BM, Marsh K, et al. Rheological analysisof the adhesive interactions of red blood cells parasitized byPlasmodium falciparum. Blood 1992;79:798–807.

14 Fujioka H, Aikawa M. The molecular basis of pathogenesisof cerebral malaria. Microb Pathog 1996;20:63–72.

15 Borst P, Bitter W, McCulloch R, et al. Antigenic variation inmalaria: minireview. Cell 1995;82:1–4.

16 Berendt AR, Ferguson DJ, Gardner J, et al. Molecularmechanisms of sequestration in malaria. Parasitology 1994;108(suppl):S19–28.

17 Berendt AR, Simmons DL, Tansey J, et al. Intracellularadhesion molecule-1 is an endothelial cell adhesion recep-tor for Plasmodium falciparum. Nature 1989;341:57–9.

18 Treutiger CJ, Hedlund I, Helmby H, et al. Rosette formationin Plasmodium falciparum isolates and anti-rosette activityof sera from Gambians with cerebral or uncomplicatedmalaria. Am J Trop Med Hyg 1992;46:503–10.

19 Ockenhouse CF, Ho M, Tandon NN, et al. Molecular basisof sequestration in severe and uncomplicated Plasmodiumfalciparum malaria: diVerential adhesion of infected eryth-rocytes to CD36 and ICAM-1. J Infect Dis 1991;164:163–9.

20 Ho M, Singh B, Looareesuwan S, et al. Clinical correlates ofin vitro Plasmodium falciparum cytoadherence. InfectImmun 1991;59:873–8.

21 Newbold C, Warn P, Black G, et al. Receptor-specific adhe-sion and clinical disease in Plasmodium falciparum. Am JTrop Med Hyg 1997;57:389–98.

22 Fernandez RD, Craig AG, Kyes SA, et al. A high frequencyAfrican coding polymorphism in the N-terminal domain ofICAM-1 predisposing to cerebral malaria in Kenya. HumMol Genet 1997;6:1357–60.

23 Bellamy R, Kwiatkowski D, Hill AV. Absence of anassociation between intercellular adhesion molecule 1,complement receptor 1 and interleukin 1 receptor antago-nist gene polymorphisms and severe malaria in a West Afri-can population. Trans R Soc Trop Med Hyg 1998;92:312–16.

24 Rogerson SJ, Tembenu R, Dobano C, et al. Cytoadherencecharacteristics of Plasmodium falciparum-infected erythro-cytes from Malawian children with severe and uncompli-cated malaria. Am J Trop Med Hyg 1999;61:467–72.

25 Rowe A, Newbold CI, Marsh K. Plasmodium falciparumrosetting is associated with malaria severity in Kenya.Nature 1997;63:2323–6.

26 Carlson J, Helmby H, Hill AV, et al. Human cerebralmalaria: association with erythrocyte rosetting and lack ofanti-rosetting antibodies. Lancet 1990;336:1457–60.

27 Barragan A, Spillmann D, Kremsner PG, et al. Plasmodiumfalciparum: molecular background to strain-specific rosettedisruption by glycosaminoglycans and sulfated glycoconju-gates. Exp Parasitol 1999;91:133–43.

28 Kaul DK, Roth EF, Nagel RL, et al. Rosetting ofPlasmodium falciparum-infected red blood cells withuninfected red blood cells enhances microvascular obstruc-tion under flow conditions. Blood 1991;78:812–19.

29 Rowe A, Obeiro J, Newbold CI, et al. Plasmodiumfalciparum rosetting is associated with malaria severity inKenya. Infect Immun 1995;63:2323–6.

30 Cranston HA, Boylan CW, Carroll GL, et al. Plasmodiumfalciparum maturation abolishes physiologic red celldeformability. Science 1984;223:400–3.

31 Dondorp AM, Angus BJ, Hardeman MR, et al. Prognosticsignificance of reduced red blood cell deformability insevere falciparum malaria. Am J Trop Med Hyg 1997;57:507–11.

32 Dondorp AM, Nyanoti M, Mithwani S, et al. Reduced redcell deformability in the pathogenesis of severe falciparummalaria and its restoration by blood transfusion. Am J TropMed Hyg 2000;(in press).

33 Grau GE, Taylor TE, Molyneux ME, et al. Tumor necrosisfactor and disease severity in children with falciparummalaria. N Engl J Med 1989;320:1586–91.

34 Kwiatkowski D, Hill AV, Sambou I, et al. TNF concentra-tion in fatal cerebral, non-fatal cerebral, and uncomplicatedPlasmodium falciparum malaria. Lancet 1990;336:1201–4.

35 Clark IA, Rockett KA, Cowden WB. Possible central role ofnitric oxide in conditions clinically similar to cerebralmalaria. Lancet 1992;340:894–6.

36 Day NP, Hien TT, Schollaardt T, et al. The prognostic andpathophysiologic role of pro- and antiinflammatory cy-tokines in severe malaria. J Infect Dis 1999;180:1288–97.

37 McGuire W, Hill AVS, Allsopp CEM, et al. Variation in theTNF-á promoter region associated with the susceptibilityto cerebral malaria. Nature 1994;371:508–10.

38 McGuire W, Knight JC, Hill AV, et al. Severe malarial ane-mia and cerebral malaria are associated with diVerenttumor necrosis factor promoter alleles. J Infect Dis1999;179:287–90.

39 Kern P, Hemmer CJ, Gallati H, et al. Soluble tumor necro-sis factor receptors correlate with parasitemia and diseaseseverity in human malaria. J Infect Dis 1992;166:930–4.

40 Karunaweera ND, Grau GE, Gamage P, et al. Dynamics offever and serum TNF levels are closely associated duringclinical paroxysms in Plasmodium vivax malaria. Proc NatlAcad Sci USA 1992;89:3200–3.

41 Kwiatkowski D, Molyneux ME, Stephens S, et al. Anti-TNFtherapy inhibits fever in cerebral malaria. Q J Med1993;86:91–8.

42 van Hensbroek MB, Palmer A, Onyiorah E, et al. The eVectof a monoclonal antibody to tumor necrosis factor on sur-vival from childhood cerebral malaria. J Infect Dis1996;174:1091–7.

43 Nussler AK, Eling W, Kremsner PG. Patients with Plasmo-dium falciparum malaria and Plasmodium vivax malariashow increased nitrate and nitrate plasma levels. J Infect Dis1994;169:1418–19.

44 Al Yaman FM, Mokela D, Genton B, et al. Associationbetween serum levels of reactive nitrogen intermediatesand coma in children with cerebral malaria in Papua NewGuinea. Trans R Soc Trop Med Hyg 1996;90:270–3.

45 al-Yaman FM, Genton B, Clark IA. The ratio of reactivenitrogen intermediates to tumour necrosis factor and clini-cal outcome of falciparum malaria disease. Trans R Soc TropMed Hyg 1998;92:417–20.

46 Anstey NM, Weinberg JB, Wang Z, et al. EVects of age andparasitemia on nitric oxide production/leukocyte nitricoxide synthase type 2 expression in asymptomatic, malaria-exposed children. Am J Trop Med Hyg 1999;61:253–8.

47 Agbenyega T, Angus B, Bedu-Addo G, et al. Plasmanitrogen oxides and blood lactate concentration in Ghana-ian children with malaria. Trans R Soc Trop Med Hyg 1997;91:298–302.

48 Weiss G, Thuma PE, Biemba G, et al. Cerebrospinal fluidlevels of biopterin, nitric oxide metabolites, and immuneactivation markers and the clinical course of humancerebral malaria. J Infect Dis 1998;177:1064–8.

49 Dobbie MS, Crawley J, Waruiru C, et al. CSF studies inchildren with cerebral malaria: an excitoxic mechanism?Am J Trop Med Hyg 2000;(in press).

50 Taylor AM, Day NPJ, Sinh DXT, et al. Reactive nitrogenintermediates and outcome in severe adult malaria. Trans RSoc Trop Med Hyg 1998;92:170–5.

51 Warrell DA, Looareesuwan S, Warrell MJ, et al. Dexametha-sone proves deleterious in cerebral malaria. A double-blindtrial in 100 comatose patients. N Engl J Med 1982;306:313–19.

52 Warrell DA, Molyneux ME, Beales PF. Severe and compli-cated malaria. Trans R Soc Trop Med Hyg 1990;84(suppl2):1–65.

53 Molyneux ME, Taylor TE, Wirima JJ, et al. Clinical featuresand prognostic indicators in paediatric cerebral malaria: astudy of 131 comatose Malawian children. Q J Med 1989;71:441–59.

54 White NJ, Looareesuwan S. Cerebral malaria. In: KennedyPGE, Johnson RI, eds. Infections of the nervous system.London: Butterworths, 1987:118–43.

55 White NJ, Warrell DA, Chanthavanich P, et al. Severehypoglycemia and hyperinsulinemia in falciparum malaria.N Engl J Med 1983;309:61–6.

56 Taylor TE, Molyneux ME, Wirima JJ, et al. Blood glucoselevels in Malawian children before and during theadminstration of intravenous quinine for severe falciparummalaria. N Engl J Med 1988;319:1040–7.

57 Looareesuwan S, Warrell DA, White NJ, et al. Retinal hem-orrhage, a common sign of prognostic significance incerebral malaria. Am J Trop Med Hyg 1983;32:911–15.

58 Lewallen S, Harding SP, Ajewole J, et al. A review of thespectrum of clinical ocular fundus findings in P falciparummalaria in African children with a proposed classificationand grading system. Trans R Soc Trop Med Hyg 1999;93:619–22.

59 White NJ, Looareesuwan S, Phillips RE, et al. Single dosephenobarbitone prevents convulsions in cerebral malaria.Lancet 1988;ii:64–6.

60 Marsh K, Forster D, Waruiru C, et al. Indicators oflife-threatening malaria in African children. N Engl J Med1995;332:1399–404.

61 Waruiru cerebral malaria, Newton CR, Forster D, et al. Epi-leptic seizures and malaria in Kenyan children. Trans R SocTrop Med Hyg 1996;90:152–5.

62 Gordeuk V, Thuma P, Brittenham G, et al. EVect of ironchelation therapy on recovery from deep coma in childrenwith cerebral malaria. N Engl J Med 1992;327:1473–7.

63 Newton CRJC, Chokwe T, Schellenberg JA, et al. Comascales for children with severe falciparum malaria. Trans RSoc Trop Med Hyg 1997;91:161–5.

64 Bondi FS. The incidence and outcome of neurologicalabnormalities in childhood cerebral malaria: a long term

440 Newton, Hien, White

www.jnnp.com

group.bmj.com on March 28, 2015 - Published by http://jnnp.bmj.com/Downloaded from

follow up of 62 surviviors. Trans R Soc Trop Med Hyg 1992;86:17–19.

65 Crawley J, Smith S, Kirkham FJ, et al. Seizures and statusepileticus in childhood cerebral malaria. Q J Med 1996;89:591–7.

66 Crawley J, English M, Waruiru C, et al. Abnormalrespiratory patterns in childhood cerebral malaria. Trans RSoc Trop Med Hyg 1998;92:305–8.

67 Brewster DR, Kwiatkowski D, White NJ. Neurologicalsequelae of cerebral malaria in children. Lancet 1990;336:1039–43.

68 Walker O, Salako LA, Sowunmi A, et al. Prognostic risk fac-tors and post mortem findings in cerebral malaria inchildren. Trans R Soc Trop Med Hyg 1992;86:491–3.

69 Waller D, Krishna S, Crawley J, et al. Clinical features andoutcome of severe malaria in Gambian children. Clin InfectDis 1995;21:577–87.

70 Newton CR, Kirkham FJ, Winstanley PA, et al. Intracranialpressure in African children with cerebral malaria. Lancet1991;337:573–6.

71 Waller D, Crawley J, Nosten F, et al. Intracranial pressure inchildhood cerebral malaria. Trans R Soc Trop Med Hyg1991;85:362–4.

72 Newton CR, Peshu N, Kendall B, et al. Brain swelling andischaemia in Kenyans with cerebral malaria. Arch Dis Child1994;70:281–7.

73 Newton CRJC, Marsh K, Peshu N, et al. Perturbations ofcerebral hemodynamics in Kenyan children with cerebralmalaria. Pediatr Neurol 1996;15:41–9.

74 Newton CR, Crawley J, Sowumni A, et al. Intracranialhypertension in Africans with cerebral malaria. Arch DisChild 1997;76:219–26.

75 Clavier N, Rahimy C, Ayivi B, et al. No evidence for cerebralhypoperfusion during cerebral malaria. Crit Care Med1999;628–32.

76 Holding PA, Stevenson J, Peshu N, et al. Cognitive sequelaeof severe malaria with impaired consciousness. Trans R SocTrop Med Hyg 1999;93:529–34.

77 Collomb H, Rey M, Dumas M, et al. Les hemiplegies aucours du paludisme aigu. Bulletin de la Societe D’AfriqueNoire de longue Francaise 1967;7:791–5.

78 Omanga U, Ntihinyurwa M, Shako D, et al. Les hemiplegiesau cours de l’acces pernicieux a plasmodium falciparum del’enfant. Annals de Pediatrie 1983;30:294–6.

79 Wattanagoon Y, Srivilairit S, Looareesuwan S, et al. Convul-sions in childhood malaria. Trans R Soc Trop Med Hyg1994;88:426–8.

80 Luijckx GJ, De Krom MC, Takx-Kohlen BC. Does chloro-quine cause seizures? Presentation of three new cases and areview of the literature. Seizure 1992;1:183–5.

81 English M, Waruiru C, Marsh K. Transfusion for respira-tory distress in life-threatening childhood malaria. Am JTrop Med Hyg 1996;55:525–30.

82 Looareesuwan S, Wilairatana P, Krishna S, et al. Magneticresonance imaging of the brain in patients with cerebralmalaria. Clin Infect Dis 1995;21:300–9.

83 van der Torn M, Thuma PE, Mabeza GF, et al. Loadingdose of quinine in African children with cerebral malaria.Trans R Soc Trop Med Hyg 1998;92:325–31.

84 White NJ, Looareesuwan S, Warrell DA, et al. Quininepharmacokinetics and toxicity in cerebral and uncompli-cated Falciparum malaria. Am J Med 1982;73:564–72.

85 Hien TT, White NJ. Qinghaosu. Lancet 1993;341:603–8.86 White NJ. The treatment of malaria. N Engl J Med

1996;335:800–6.

87 van Hensbroek MB, Onyiorah E, JaVar S, et al. A trial ofartemether or quinine in children with cerebral malaria. NEngl J Med 1996;335:69–75.

88 Hien TT, Day NP, Nguyen HP, et al. A controlled trial ofartemether or quinine in Vietnamese adults with severe fal-ciparum malaria. N Engl J Med 1996;335:76–83.

89 McIntosh HM, Olliaro P. Treatment of severe malaria withartemisinin derivatives. A systematic review of randomisedcontrolled trials. Med Trop (Mars) 1998;58:61–2.

90 Hien TT, Arnold K, Vinh H, et al. Comparison of artemisi-nin suppositories with intravenous artesunate and intra-venous quinine in the treatment of cerebral malaria. TransR Soc Trop Med Hyg 1992;86:582–3.

91 Winstanley PA, Newton CR, Pasvol G, et al. Prophylacticphenobarbitone in young children with severe falciparummalaria: pharmacokinetics and clinical eVects. Br J ClinPharmacol 1992;33:149–54.

92 Crawley J, Waruiru C, Mithwani S, et al. Phenobarbitonehalves the seizure frquency, but doubles the mortality inchildhood cerebral malaria: results of a double blind,randomised controlled trial. Lancet 2000;26:355:701–6.

93 HoVman SL, Rustama D, Punjabi NH, et al. High-dosedexamethasone in quinine-treated patients with cerebralmalaria: a double-blind, placebo-controlled trial. J InfectDis 1988;158:325–31.

94 Looareesuwan S, Phillips RE, Karbwang J, et al. Plasmo-dium falciparum hyperparasitaemia: use of exchange trans-fusion in seven patients and a review of the literature. Q JMed 1990;227:471–81.

95 Miller KD, Greenberg AE, Campbell CC. Treatment ofsevere malaria in the United States with continousinfusions of quinidine gluconate and exchange transfusion.N Engl J Med 1989;321:65–70.

96 White NJ. Lumbar puncture in cerebral malaria. Lancet1991;338:640–1.

97 Winstanley PA, Mberu EK, Watkins WM, et al. Towardsoptimal regimens of parenteral quinine for young Africanchildren with cerebral malaria: unbound quinine concen-trations following a simple loading dose regimen. Trans RSoc Trop Med Hyg 1994;88:577–80.

98 McCaslin RI, Pikis A, Rodriquez WJ. Pediatric Plasmodiumfalciparum malaria: a ten-year experience from WashingtonDC. Pediatr Infect Dis J 1994;13:709–15.

99 Thuma PE, Mabeza GF, Biemba G, et al. EVect of iron che-lation therapy on mortality in zambian children withcerebral malaria. Trans R Soc Trop Med Hyg 1998;92:214–18.

100 Di Perri G, Di Perri IG, Monteiro GB, et al. Pentoxifyllineas a supportive agent in the treatment of cerebral malaria inchildren. J Infect Dis 1995;171:1317–22.

101 Davis TM, Supanaranond W, Pukrittayakamee S, et al. Asafe and eVective consecutive-infusion regimen for rapidquinine loading in severe falciparum malaria. J Infect Dis1990;161:1305–8.

102 White NJ, Looareesuwan S, Warrell DA, et al. Quinineloading dose in cerebral malaria. Am J Trop Med Hyg 1983;32:1–5.

103 Phillips RE, Warrell DA, White NJ, et al. Intravenous qui-nidine for the treatment of severe falciparum malaria.Clinical and pharmacokinetic studies. N Engl J Med 1985;312:1273–8.

104 Murphy SA, Mberu E, Muhia D, et al. The disposition ofintramuscular artemether in children with cerebral malaria;a preliminary study. Trans R Soc Trop Med Hyg 1997;91:331–4.

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Cerebral malaria

Charles R J C Newton, Tran Tinh Hien and Nicholas White

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