Lancet - Cerebral Malaria

[sharon sanders]

<TABLE width="100%" xmlns="http://www.w3.org/1999/xhtml"><TBODY><TR><TD>Lancet Neurology 2005; 4:827-840
DOI:10.1016/S1474-4422(05)70247-7
Pathogenesis, clinical features, and neurological outcome of cerebral malaria

Dr Richard IdroMMED a b c , Neil E JenkinsMRCP a d and Charles RJC NewtonMD a e

Summary
Introduction
Epidemiology and immunity
Clinical features of cerebral malaria
Diagnosis
Pathogenesis
Outcome of cerebral malaria
Management of cerebral malaria
Areas for research
Search strategy and selection criteria
References

Summary

Cerebral malaria is the most severe neurological complication of Plasmodium falciparum malaria. Even though this type of malaria is most common in children living in sub-Saharan Africa, it should be considered in anybody with impaired consciousness that has recently travelled in a malaria-endemic area. Cerebral malaria has few specific features, but there are differences in clinical presentation between African children and non-immune adults. Subsequent neurological impairments are also most common and severe in children. Sequestration of infected erythrocytes within cerebral blood vessels seems to be an essential component of the pathogenesis. However, other factors such as convulsions, acidosis, or hypoglycaemia can impair consciousness. In this review, we describe the clinical features and epidemiology of cerebral malaria. We highlight recent insights provided by ex-vivo work on sequestration and examination of pathological specimens. We also summarise recent studies of persisting neurocognitive impairments in children who survive cerebral malaria and suggest areas for further research.
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Introduction

Cerebral malaria is the most severe neurological complication of infection with Plasmodium falciparum and is a major cause of acute non-traumatic encephalopathy in tropical countries (panel 1). Mortality is high and over the past two decades the extent of persistent neurocognitive deficits after recovery has become apparent. In this paper, we review work that has provided further understanding of the pathogenesis and describe the long-term neurocognitive outcomes of cerebral malaria.
Panel 1: Cerebral malaria in clinical practice Diagnosis
Suspect cerebral malaria in any patient with impaired consciousness in a malaria-endemic region or recent travel to such areas.
Examine thick and thin peripheral blood smears for P falciparum malaria parasites.
Exclude other causes for encephalopathy (determine blood sugar concentrations to exclude hypoglycaemia, examine cerebrospinal fluid to exclude acute bacterial meningitis).
Mangement
Control seizures, correct hypoglycaemia, hypoxia, shock, and anaemia.
Give recommended antimalaria drugs in that region.
Assess for evidence of neurological damage (visual, speech, hearing, and motor deficits) before discharge.



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Epidemiology and immunity

In 2002, there were 515 million cases of malaria in the world; 25% in southeast Asia and 70% in Africa, mostly sub-Saharan Africa.1 In most developed countries, malaria is seen in immigrants or people returning from travels in malaria-endemic areas. In the UK there were 1722 cases of malaria in 2003.2
In sub-Saharan Africa, children are most commonly affected, such that malaria may account for 40% of paediatric admissions to some hospitals, 10% of which may be due to cerebral malaria.3 The incidence of cerebral malaria in malaria-endemic areas of sub-Saharan Africa is 1?12 cases per/1000 children per year,4 with a mortality of 18?6%.5P falciparum malaria can cause other complications, such as severe anaemia, acidosis or hypoglycaemia, and several complications can occur in a single patient.
Severe malaria in young children in malaria-endemic areas is dependent on age and level of transmission (ie, number of infected mosquito bites per person per year). In areas of intense transmission, infection and clinical disease are rare in children up to age 6 months, symptoms are mild as a result of passive immunity from maternal antibodies. In these areas, the main burden of disease is in infants in the first 2 years of their lives, and by age 4 years clinical disease is rare and typically mild.6 In areas with less intense transmission, the peak incidence of severe disease falls at a later age; severe anaemia is most common in infants younger than age 2 years and the peak incidence of cerebral malaria is later; the cause of this age-related difference is unclear. Repeated infections over several years provide protection against disease. Partial immunity develops but declines in the absence of continuous exposure; although partial protective immunity was reported in Africans who had been resident in France for at least 4 years.7
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Clinical features of cerebral malaria

WHO proposed a definition of cerebral malaria as a clinical syndrome characterised by coma (inability to localise a painful stimulus) at least 1 h after termination of a seizure or correction of hypoglycaemia, detection of asexual forms of P falciparum malaria parasites on peripheral blood smears, and exclusion of other causes of encephalopathy.8 This definition is particularly useful for comparisons of different areas and studies; it is used in children and adults, although, there are notable clinical differences (table 1)9?33 and it is not entirely clear if these differences are associated with immunity or age.

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Table 1. Clinical features and outcomes of cerebral malaria in African children and southeast Asian adults



Clinical features of cerebral malaria in African children

Children who are admitted with cerebral malaria present with a 1?3 day history of fever, anorexia, vomiting, and sometimes coughing. The main neurological features are coma, seizures, and brainstem signs.9,23,30
Coma

Cerebral malaria is a diffuse encephalopathy characterised by coma and bilateral slowing on electroencephalography30,34 (figure 1). This type of malaria has many features similar to metabolic encephalopathy, such as presenting with abnormal pupillary signs and coma being potentially reversible. The cause of impaired consciousness is unclear but is likely to result from several interacting mechanisms. The depth of coma is an important prognostic factor.8,30


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Figure 1. Electroencephalography recordings in cerebral malaria Top: Electroencephalography recording in a Kenyan child with cerebral malaria showing diffuse high amplitude slow-wave activity more marked over the left hemisphere. Bottom: Electroencephalography recording in a Kenyan child with cerebral malaria showing electrical seizure activity (arrows) most prominent over the left temporal region (electroencephalography recordings taken by R Idro).




Seizures

Seizures are commonly reported in children with cerebral malaria and occur in over 60% after admission11,23,34,35 (table 1). Many patients with seizures are hypoxic and hypercarbic from hypoventilation and are at risk of aspiration.11,35?37 In a study with 65 Kenyan children, 40 (62%) had seizures after admission and ten (15%) had subtle seizures, manifesting as nystagmoid eye movements, irregular breathing, excessive salivation, and conjugate eye deviation.11 Seizures are often repetitive and prolonged, and 18 children (28%) had an episode of status epilepticus. Multiple and prolonged seizures are associated with increased mortality33,38,39 and neurocognitive deficits.35,40
The causes of seizures are unclear; most are not associated with fever at the time of the seizure.35 In children, seizures do not seem to result from electrolyte disorders41 or antimalarial drugs.34 Electroencephalography shows that many seizures originate over the temporoparietal regions (a watershed area; figure 1), suggesting that ischaemia and hypoxia may play a part.34 Seizures might be caused by sequestration of infected erythrocytes or parasite-derived toxins. Furthermore, immune mechanisms may be important, because children with severe malaria and seizures have high titres of antibodies to voltage gated calcium channels.42

Brainstem signs

Brainstem signs are common and are associated with other features of high intracranial pressure and brain swelling (figure 2), but may occur after seizures.15,16 These brainstem signs do not seem to be associated with hypoglycaemia or electrolyte disorders.15,16 Common signs include changes in pupillary size and reaction and disorders of conjugate gaze and eye movements. Absence of corneal and oculocephalic reflexes are associated with increased mortality.9 Other signs include abnormal respiratory patterns (such as hyperventilatory, ataxic, and periodic breathing),36 posture (decerebrate, decorticate, or opisthotonic posturing), and motor abnormalities of tone and reflexes.9,23 Abnormal motor posturing seems to be associated with raised intracranial pressure rather than seizures.43


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Figure 2. Radiological features of the brain in cerebral malaria Scan of the brain in a Kenyan child with cerebral malaria showing (A) swelling of the brain with compressed ventricles (arrow) and loss of sulci and (B) resolution of the brain swelling. A CT scan showing (C) brain swelling with diffuse hypodensity sparing the basal ganglia (arrows) and (D) convalescent scan in a child showing cerebral atrophy with infarction (arrows) of the right frontal and parietal regions. Reproduced with permission from the BMJ Publishing Group.31




Malarial retinopathy

Retinal abnormalities are common in children with cerebral malaria and may be related to pathological changes.17,44,45 Characteristic features include whitening of the macula (that spares the central fovea), peripheral retina, retinal vessels, papilloedema, and multiple retinal haemorrhages (often with pale centres; figure 3). These signs are best seen by indirect ophthalmoscopy and affect over 60% of children with cerebral malria;45 the specificity might help in the diagnosis of cerebral malaria. In Malawian children, the presence of retinopathy?particularly papilloedema?was associated with prolonged coma and death.17 In patients who recover, these features resolve over 1?4 weeks.


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Figure 3. Retinopathy of malaria White-centred retinal haemorrhage (A) and orange vessels in a Malawian child with cerebral malaria. Macula retinal whitening (B) around the foveola (central dark disc) in a child with cerebral malaria. Cotton wool spots are also visible superiotemporal to the optic disc. Vessel changes (C) in a Malawian child with cerebral malaria?from red to pale orange. Vessel changes (D) in a Malawian child with cerebral malaria?from red to white. Photographs courtesy of Dr Nicholas Beare, Malawi-Liverpool-Wellcome Trust Clinical Research Programme College of Medicine, Malawi.




Concomitant complications

Metabolic perturbations are common in children with cerebral malaria. Hypoglycaemia is present in up to a third of patients on admission and commonly recurs even after initial correction. Causes include depletion of glycogen stores, inadequate intake, impaired hepatic gluconeogenesis and quinine-induced hyperinsulinaemia.9,20,46 Metabolic acidosis presents as deep breathing and is commonly associated with hyperlactaemia; this may be caused by hypovolaemia and inadequate tissue perfusion, anaemia, lactate production by parasites, and cytokine-induced failure of oxygen utilisation.3,36,37,47 Resuscitation with fluids or blood transfusion can improve outcome.48 Many children with dehydration have transient impairment of renal function but, unlike in adults, overt renal failure is rare. Over 50% of patients have hyponatraemia,21 but the cause is unclear.21,49 Concomitant bacterial infections occur in 5?8% of children with cerebral malaria50,51 and leucocyte counts above 15000/μL are associated with poor prognosis.9 Other features include hepatomegaly, splenomegaly, and in some cases jaundice.
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Clinical features of cerebral malaria in adults

Cerebral malaria in adults is part of a multiorgan disease.30 After a few days of illness patients typically present with fever, malaise, headache, joint and body aches, anorexia, and delirium, and they then develop coma. Seizures are less common in southeast Asian adults compared with African children and the incidence seems to be declining generally.30
Encephalopathy in adults is characterised by symmetrical upper-neuron lesion signs. Patients can have dysconjugate eye deviation, extrapyramidal rigidity, trismus, and decorticate and decerebrate rigidity.10 Papilloedema and retinal exudates are rare, but 15% of patients have retinal haemorrhages which are associated with increased mortality.52 Recovery from coma is slower in adults than in children.31 Thiamine deficiency might contribute to some of these neurological symptoms.53 In a few patients, abnormalities such as cortical infarcts, cerebral venous thrombosis, or dural sinus thrombosis (figure 4)54,55 can happen as a consequence of the hypercoagulable state.


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Figure 4. Cerebral infarcts in adults with cerebral malaria Left: infarcts in a 36 year old man with cerebral malaria. Hyperintense cortical areas (infarcts) seen on a fast spin-echo T2 weighted MR image (arrow). Reproduced with permission from the American Society of Neuroradiology.54 Right: contrast enhanced brain CT scan of a 48 year old man who presented with left focal becoming generalised seizures and left hemiparesis. A large area of hemorrhagic infarction is seen in the right frontoparietal cortex with surrounding oedema. Absence of contrast is seen as a hypodense area in the posterior aspect of the superior sagittal sinus. Reproduced with permission from the British Infection Society.55



In some patients, cerebral malaria is complicated by pulmonary oedema or adult respiratory distress syndrome.13,56 Kussmaul's breathing occurs with acute renal failure and severe lactic acidosis.10,19 Other complications of P falciparum malaria such as anaemia, haemoglobinuria, jaundice, shock, and coagulation disorders have been reported.57?60 A high incidence of multiorgan failure is seen among those admitted to intensive care units, this is because mostly very ill patients who have not responded to treatment are admitted to these units.26 Bacterial co-infection is common, particularly in those with shock, and accounts for most late (after 7 days) deaths. Respiratory failure has the worst prognosis and develops late in the course of the illness.26 Chronic hepatitis B infection may be a risk factor for severe malaria, including cerebral malaria in adults.61
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Diagnosis

Cerebral malaria should be considered in the differential diagnosis of any patient who has a febrile illness with impaired consciousness who lives in or has recently travelled to malaria endemic areas. At least three negative blood smears (on microscopy) 8?12 h apart are required before the diagnosis can be excluded. Rapid tests, such as the immunochromatographic test for the histidine-rich protein 2 (from P falciparum) and lactate dehydrogenase can be helpful in the absence of positive blood smear, although, they do not give information about the parasite load and their sensitivity and specificity decreases at low parasitaemia.62 PCR tests are more sensitive than microscopy but expensive and do not give estimates of parasite load.63
In malaria-endemic areas, cerebral malaria is a diagnosis of exclusion. The high prevalence of asymptomatic parasitaemia in these areas makes accurate diagnosis less certain?almost any viral encephalopathy with incidental parasitaemia fulfils the diagnostic criteria for cerebral malaria. In a study by Taylor and colleagues,64 24% of Malawian children who fulfilled the criteria for cerebral malaria before death had evidence at post mortem of an alternative cause for coma, including Reye's syndrome, hepatic necrosis, and ruptured arteriovenous malformation. The presence of malarial retinopathy was the only clinical feature to distinguish patients with typical histopathological features of cerebral malaria from those with other illnesses. Lumbar puncture must be done to exclude other causes for encephalopathy, although there are differences of opinion about the timing of this procedure.16,65 There may be mild pleocytosis and high protein concentrations.66 High plasma and cerebrospinal fluid concentrations of lactate are associated with increased mortality.9,46 Over 40% of children with cerebral malaria have swollen brains18 (figure 2), but this finding is less common in adults.67
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Pathogenesis

In P falciparum infections, consciousness can be impaired by various mechanisms interacting with each other30 (panel 2).68?88 The relative contributions of these mechanisms may differ in children and adults. Thus, unlike in adults, seizures seem to be an important cause of impairment of consciousness in children.
Panel 2: Postulated mechanisms for coma in cerebral malaria Obstruction of cerebral microvascular flow
Parasite-induced sequestration of infected and unifected arythrocytes mediated through cytoadherence,68 rosette formation,69 autoagglutination69,70 and reduced red cell deformability.71
Seizures
Overt seizures11,35,37
Subtle and electrographic seizures11,37
Postictal state37
Impaired delivery of substrate
Hypoglycaemia9,23
Anaemia72
Hypoxia73
Impaired perfusion
Hypovolaemia47,74
Shock75
Acidosis75
Raised intracranial pressure and brain swelling
Disruption of the blood?brain barrier76,77
Raised intracranial pressure15,16,18
Cerebral oedema78?80
Cytotoxic oedema18,78
Toxins
Nitric oxide81
Reactive oxygen species82,83
Excitotoxins30,84?86
Malaria toxin87
Clotting
Intravascular coagulation as a minor mechanism88



Research strategies

The main strategies to study pathogenesis have been clinical case series and case-control studies, post-mortem surveys, in vitro studies, or animal models. However, there are no reliable animal models of cerebral malaria. Many primates naturally have plasmodium infections but rarely develop clinical features similar to human cerebral malaria. P falciparum does infect new-world monkeys, but severe symptoms are common only in splenectomised animals. Some species do develop cerebral dysfunction associated with adherence of infected erythrocytes to cerebral endothelial cells.89,90 Although coma is not a typical consequence of plasmodium infection in these primates, adherence of infected erythrocytes to cerebral endothelial cells has contributed to the understanding of parasite-induced sequestration.
Important research on cerebral malaria has been done with mice. The characteristics of the infection are dependent on the strains of mice and plasmodium. The most popular model is CBA mice infected with the ANKA strain of Plasmodium berghei.91 Coma, seizures, and death were reported, but unlike human cerebral malaria these could not be reversed or prevented with treatment. The pathology is different in mice, infected erythrocytes do not commonly sequester; instead, monocytes occur in cerebral vessels, and inflammatory cytokines are essential for the pathogenesis. However, monocytes are also seen in the cerebral vessels of some African children,64 but the importance of this finding is still unclear. The use of murine models, particularly gene knock-out strains, has provided much information on the immune and inflammatory responses to plasmodium infections.

Sequestration

A consistent histological finding in cerebral malaria in both children and adults is the presence of infected and non-infected erythrocytes packed within cerebral vessels (figure 5). Sequestration might happen as a consequence of cytoadherence of infected erythrocytes to endothelial cells via P falciparum derived proteins on the infected erythrocyte surface attaching to ligands upregulated in the venules. Sequestration can be increased when adherent infected erythrocytes bind other infected erythrocytes (autoagglutination) or non-infected erythrocytes (rosetting) or use platelets to bind other infected erythrocytes (platelet-mediated clumping). Not all parasites display these adhesive properties, but these phenotypes are most commonly present in infected erythrocytes taken from children and adults with severe malaria.


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Figure 5. Sequestration of infected erythrocytes in cerebral vessels Left: P falciparum infected erythrocytes sequestered in a cerebral vessel of a Vietnamese adult with fatal cerebral malaria (haematoxylin and eosin staining ?400. Courtesy of Dr Gareth Turner, Nuffield Department of Histopathology, John Radcliffe Hospital, Oxford. Middle: electron microscopy showing the ultrastructural details of a P falciparum IE adhering to an endothelial cell in vitro. P=parasite, En=endothelial cell and arrows point out the adhesion points at the electron dense knob proteins. Courtesy of Professor David Ferguson, Department of Clinical Laboratory Sciences, Oxford University. Right: freeze fracture electron micrograph of the infected erythrocyte surface revealing the symmetrical distribution of knob proteins on the surface. Courtesy of Professor David Ferguson, Department of Clinical Laboratory Sciences, Oxford University.



Parasite binding is mediated by a group of variant surface antigens expressed at the red-cell surface during development. The best described is P falciparum erythrocyte membrane protein-1 (PfEMP1) which is encoded by a family of about 60 variant genes associated with different binding phenotypes. Each parasite expresses the transcript of only one variant gene but can switch to express a different variant gene (about 2% per generation in vitro),92 and therefore display both a change in binding phenotype and antigen. Although the trigger for variant gene switching is unknown the rapid switching in non-immune volunteers does not support the role of immune pressure.93 Some variant surface antigens seem to be most common in young children with severe disease, and thus might be more capable of causing cerebral malaria than others,94 but whether this is the result of adhesion phenotype or host response is unclear.
PfEMP1 is able to bind to many host receptors on endothelial cells, chief among which are CD36 and the intercellular adhesion molecule 1 (ICAM1).95,96 The binding of infected erythrocytes to ICAM1 has been implicated in the pathogenesis of cerebral malaria.97 Post-mortem studies have revealed upregulation of ICAM1 expression on the cerebral vascular endothelium in cerebral malaria,79,98 which, in adults, was localised to areas of parasite-induced sequestration.99 A common ICAM1 polymorphism (ICAM1Kilifi) that changes protein binding to infected erythrocytes100 was associated with susceptibility to cerebral malaria in Kenyan children,101 but not in The Gambia.102 In a study describing the binding affinities of parasites taken from Kenyan children with malaria, ICAM1 binding was highest in those with cerebral malaria. However, we do not know how representative circulating parasites are of those sequestered within cerebral vessels and although ICAM1 seems important, many host receptors are likely involved in concert in the process resulting in cerebral malaria.

Reduction in microvascular flow

Sequestration of infected and non-infected erythrocytes within the cerebral vessels reduces the microvascular flow. In addition, the presence of parasites inside erythrocytes decreases the ability to deform (low red-cell deformability) so that erythrocytes have more difficulty in passing through the microvasculature. Studies of Thai adults103 and Kenyan children104 have found strong associations between low red-cell deformability and severe disease in adults with outcome. The rapid reversibility of clinical symptoms suggests that tissue necrosis is unlikely to occur. However, there may be a critical reduction in the supply of metabolic substrate to the brain. This will be exacerbated by increased demand during seizures and fever, and may be worse in patients with severe anaemia or hypoglycaemia.23,72 Cerebral blood flow may also be reduced by high intracranial pressure. Inflammatory cytokines can result in inefficient use of substrates.

Inflammatory response

P falciparum infection results in increases in both proinflammatory and anti-inflammatory cytokines. The balance of inflammatory mediators seems critical to parasite control, but their role in the pathogenesis of severe malaria is unclear. In Malian children, concentrations of both interleukin 6 (proinflammatory) and interleukin 10 (anti-inflammatory) were higher in patients with cerebral malaria than in those with non-cerebral malaria?but there was no increase in interleukin 1, interleukin 8, interleukin 12, or tumour necrosis factor.105 In Gambian and Ghanaian children, concentrations of tumour necrosis factor and its receptor were higher in those with cerebral malaria than in those with mild or uncomplicated malaria.106,107 Several polymorphisms in the tumour necrosis factor promoter region have also been associated with increased risk of cerebral malaria and death,108 or neurological sequelae.109 In Vietnamese adults, concentrations of interleukin 6, interleukin 10, and tumour necrosis factor were high in patients with severe multiorgan disease but were low in patients with cerebral malaria alone, suggesting their involvement in the process leading to severe malaria but not coma.110 Post-mortem analysis of Malawian children with cerebral malaria suggest increased local production of tumour necrosis factor and interleukin 1.111 However, there was no association between production or staining for these cytokines and sites of parasite sequestration.
Nitric oxide might be a key effector for tumour necrosis factor in the pathogenesis of malaria. Nitric oxide is involved in host defence by killing intracellular organisms, in maintenance of vascular status, and in neurotransmission. Cytokines may upregulate inducible nitric oxide synthase (iNOS) in brain endothelial cells, increasing production of nitric oxide, which diffuses into brain tissue and disrupts neuronal function.81 Nitric oxide may rapidly and reversibly reduce the level of consciousness81 because it is short-lived and can easily diffuse across the blood?brain barrier to interfere with neuronal function.
The associations found between disease and nitric oxide activity, iNOS, or genetic polymorphisms in the iNOS promoter gene have not been consistent. Results have varied with age, endemicity, and geographical location. Post-mortem staining of brain specimens in African children and southeast Asian adults have revealed increased iNOS in vessel walls associated with sequestered parasites in cerebral malaria,112 whereas in other studies, nitric oxide is associated with protection.113,114 Upregulation of iNOS by tumour necrosis factor may set off a negative feedback mechanism through nitric oxide to control the stimulatory action on iNOS. However, in some individuals, production of nitric oxide happens too slowly to downregulate the primary wave of tumour necrosis factor induction, so that a slow build up of iNOS-induced nitric oxide allows iNOS and nitric oxide to reach the harmful concentrations seen in cerebral malaria.115

Blood?brain-barrier function

Because parasites are largely confined to intravascular spaces, one main question regarding the pathogenesis of cerebral malaria is how these parasites cause neuronal dysfunction.116 There is growing evidence that parasite-induced sequestration of infected and uninfected erythrocytes changes blood?brain barrier function. In Thai adults, transfer of radioactively labelled albumin into cerebrospinal fluid was not raised during unconsciousness compared with convalescence.117 No significant changes were reported in the albumin index (ratio of concentrations of albumin in cerebrospinal fluid to those in blood) in Vietnamese adults.77 However, in Malawian children, albumin indices were significantly higher than in UK controls (adults dying from non-neurological or infectious causes),76 although, there were no differences between children who died and those who survived.
Post-mortem analysis has shown widespread cerebrovascular endothelial cell activation (increased ICAM1 endothelial staining, reduction in cell-junction staining, and disruption of junction proteins), particularly in vessels containing infected erythrocytes.118 Perivascular macrophages in these areas expressed scavenger receptor and sialoadhesin?normally expressed only after contact with plasma proteins. However, such disruption of intercellular junctions was not associated with significant leakage of plasma proteins (fibrinogen, IgG, or C5b-9) into perivascular areas or cerebrospinal fluid.76 Adams and colleagues119 suggested that ICAM1 binding by infected erythrocytes results in a cascade of intracellular signalling events that disrupt the cytoskeletal-cell junction structure and cause focal disruption to the blood?brain barrier. Focal disruptions in the barrier at sites of sequestration could result in the exposure of sensitive perivascular neuronal cells to plasma proteins and increased concentrations of cytokines and metabolites caused by abnormalities in microcirculation; this may contribute to reduced consciousness and seizure activity.

Brain swelling

In Kenyan children in deep coma, 40% had evidence of brain swelling on CT (figure 2); however, during recovery some children with severe encephalopathy had evidence of cytotoxic oedema, which can contribute to severe intracranial hypertension.18 Severe intracranial hypertension was associated with death or neurological sequelae.15 In a study of 21 Indian adults, abnormalities on CT scans were related to the Glasgow coma score and mortality.120 Cerebral oedema was seen in eight patients, two of whom died. Other studies of Thai adults have found little evidence of cerebral oedema on CT121 or MRI67 but documented brain swelling. Although no substantial leakage of plasma proteins has been reported,76 the blood?brain-barrier disruption can contribute to the high intracranial pressure reported in African children. However, the most likely cause of raised intracranial pressure is increased cerebral blood volume as a result of sequestration of infected erythrocytes and increased cerebral blood flow from seizures, hyperthermia, or anaemia.5,30

Pathological findings

Post-mortem studies have provided a wealth of detailed information but they reflect, at best, pathology at a single point after death in the most severely ill patients. Recent surveys from Malawi and southeast Asia have found a significant association between the amount of sequestration and ante-mortem diagnosis of cerebral malaria. Sequestration is extensive, occurring in all parts of the brain to a similar extent, but with substantial variability between individuals and between vessels in an individual.122 Brain swelling is common but evidence for frank herniation is rare in adults, although more common in children.80 Cut surfaces show petechial haemorrhages (figure 6).123 Electron microscopy shows knob-like protrusions on the surface of infected erythrocytes and at sites of attachment to vascular endothelium (figure 5).78 Studies in Malawian children show intravascular and perivascular pathological changes (haemorrhages, accumulation of pigmented white blood cells and thrombi) in 75% of cases. These are associated with high concentrations of extraerythrocytic haemozoin (a product of haemoglobin metabolism by malaria parasites) inside cerebral vessels. Thus, rupture of infected erythrocytes can lead to an inflammatory process within and around brain capillaries.64 These findings are not consistent in adults122,124 and may reflect differences between adults and children.


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Figure 6. Gross pathological appearance of the brain in cerebral malaria Macroscopic section of the brain from a fatal case of cerebral malaria showing petechial haemorrhages in white matter, particularly in the subcortical rim and corpus callosum. Reproduced with permission from International Society of Neuropathology.123



Amyloid-β precursor protein staining (a marker of axonal injury) was found on post-mortem brain specimens of adults with cerebral malaria.125 Two patterns were observed; a diffuse increase or a predominance of axonal injury in one brain region?typically the internal capsule or pons. Axonal injury correlated with plasma lactate, cerebrospinal fluid protein, and Glasgow coma score. Increased concentrations of the microtubule-associated protein tau (from degenerated axons)?but not neural cell body or astrocyte proteins in cerebrospinal fluid?suggested that most of the brain parenchymal damage is in axons.126 High concentrations of quinolinic acid were found in cerebrospinal fluid,84 but in Vietnamese adults this was related to impaired renal function.85
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Outcome of cerebral malaria

Most patients with cerebral malaria seem to make a full recovery, but neurocognitive sequelae have been increasingly recognised, particularly in African children in the past 20 years.
Mortality

The mortality rate in adults and children is about 20%, and most deaths happen within 24 h of admission, before antimalarial drugs may have had time to work. The mechanisms of death seem to vary (figure 7).


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Figure 7. Possible mechanisms for death and neuro-cognitive impairment in cerebral malaria and some areas for possible intervention (1) P falciparum infected erythrocytes adhere to the vascular endothelium and possibly sequester in large numbers in the brain. (2) Local and systemic changes produce significant vital organ dysfunction leading to severe metabolic derangement, which may result in death unless urgent correction (eg, correction of blood glucose, dialysis or ventilation) is initiated. (3) Sequestration of infected erythrocytes within the cerebral vessels increases the cerebral volume, which together with the increase in cerebral blood flow caused by seizures, anaemia, and hyperthermia (4), and the altered blood?brain barrier function lead to brain swelling and raised intracranial pressure (ICP; 5). This may cause death (through global cerebral ischaemia, transtentorial herniation or brainstem compression) or result in neuronal damage with consequent neuro-cognitive impairments. Sequestered parasites may also produce local toxins and ischaemia or influence the production of inflammatory products such as cytokines and result in multiple seizures and neuronal damage. Metabolic derangement is more common in adults whereas raised ICP and seizures are commoner in children. Possible areas for intervention are highlighted.



In African children, most deaths occur with brainstem signs after a respiratory arrest (initially with a good cardiac output), suggestive of transtentorial herniation or cardiorespiratory arrest in association with severe metabolic acidosis. Four of seven children in Nigeria had cerebral oedema or features of herniation at autopsy.80 Mortality is high among children with shock, hypoglycaemia, multiple and prolonged seizures, deep coma, or severe acidosis.9,23,127
Many adults die with renal failure or pulmonary oedema. Mortality is particularly high in pregnant patients or those with vital organ dysfunction.28,128 Patients can die with an acute respiratory arrest, commonly after a period of respiratory irregularity, but with a normal blood pressure. Others die with shock or hypoxia secondary to acute pulmonary oedema.

Neurocognitive deficits

In African children, a high incidence of neurological deficits (10?9%) was reported in a meta-analysis which used studies with a similar definition of cerebral malaria.5 Some deficits are transient (eg, ataxia), whereas others (eg, hemiparesis) improve over months but may not resolve completely. Children living in Africa with severe neurological sequelae (spastic quadriparesis and vegetative states) often die within a few months of discharge.129 Recent studies have reported that epilepsy is associated with cerebral malaria.130
Cognitive impairments have been described in some studies,39 but not in others.131 Impairment has been reported in a wide range of cognitive functions; memory, attention, executive functions and language.39,129,132?134 Neurocognitive impairments can be associated with protracted seizures,11,32,38 deep and prolonged coma,33 hypoglycaemia, and severe anaemia, but are not always.32,38 The consistent association found between prolonged seizures or hypoglycaemia and neurocognitive impairment suggest hippocampal damage, which can manifest as memory impairment and complex partial seizures at a later date. The development of impairments might be associated with pathophysiological processes, such as raised intracranial pressure.15 Most of these factors are also associated with death, and may simply reflect the severity of the underlying insult, rather than a specific neuropathogenic process. 24% of children have evidence of some impairments after cerebral malaria, so this represents a substantial burden in malaria-endemic areas, suggesting that at least 250000 children will develop neurocognitive impairments from malaria in sub-Saharan Africa each year.134
In non-immune adults, the prevalence (<5%) and severity of subsequent neurological impairments is less than in children. Impairments are not confined to cerebral malaria, but may follow non-cerebral malaria.135 They include cranial-nerve lesions, neuropathies, and extrapyramidal disorders.10,136 Some patients develop transient psychosis or delirium during recovery, whereas others develop focal epilepsy sometimes associated with transient tomographic opacities in the brain. In Vietnam, a self-limiting ?post-malaria neurological syndrome? consisting of acute confusional state, acute psychosis, generalised convulsions, or tremor occurred in 0?12% of patients with P falciparum malaria.135
Cognitive deficits after malaria in adults are not well documented. There are case reports of impairment of memory and naming ability. Psychological tests did not detect any residual defects in a small group of American soldiers after cerebral malaria,137 although a recent retrospective study suggests that cerebral malaria results in multiple neuropsychiatric symptoms, including poor dichotic listening, personality change, depression, and in some cases partial-seizure-like symptoms.138 A study of Ghanaian adults suggested that subclinical mixed anxiety?depression syndrome can occur after P falciparum malaria.139
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Management of cerebral malaria

WHO has developed guidelines for management of patients with cerebral malaria8 and new guidelines were recently proposed for the UK.140 Emergency management aims to rapidly correct severely deranged metabolic states, restoring vital physiological functions (panel 3), and the administration of an effective and rapidly active parasiticidal drug.
Panel 3: Emergency management and supportive care

?Maintain airway, give high-flow oxygen if hypoxaemic or respiratory distress

?Treat hypoglycaemia with a bolus infusion 2 mL/kg of 25% dextrose, monitor for recurrence

?Control seizures (benzodiazepines, paraldehyde, phenytoin, phenobarbital)

?Correct shock with normal saline, initial infusion of 20 mL/kg over 30 min

?Offer blood transfusion if haematocrit is <15% in children or <20% in adults

?Give fresh blood transfusion and vitamin K for spontaneous bleeding

?Give first-line antibiotics for pyogenic meningitis and bacterial sepsis until these are excluded

?Ventilate adults with pulmonary oedema and offer dialysis if in renal failure






Resuscitation on admission

Because most patients die within 24 h of admission before therapeutic benefits of antimalaria drugs,5 supportive therapy might improve outcome. Treatment of hypoxaemia, hypoglycaemia, shock, severe metabolic acidosis, and seizures is important. Urgent resuscitation with fluids might be required for those with hypovolaemia,22,47,48,140 although fluids should be given carefully. The administration of albumin reduced mortality in a small trial in children with cerebral malaria,75 but trials to confirm this finding are still needed. Whole-blood or packed-cell transfusions should be given for severe anaemia. Recurrences of hypoglycaemia can be prevented by continuous infusion of fluids containing glucose until consciousness is regained.

Antimalarial therapy

Cinchona alkaloids (quinine, quinidine, and cinchonine) and artemisinin derivatives (artesunate, artemether and arteether) are recommended for cerebral malaria (table 2).5,8,141?145 Cinchona alkaloids take effect during the later stages of parasite development, whereas artemisinins are active at both early and late stages. A loading dose of either drug should be given to rapidly achieve antiparasiticidal concentrations.

Click to view table

Table 2. Antimalarial treatment of cerebral malaria



Quinine is still used extensively and can be given intravenously or intramuscularly. A loading dose is associated with faster clearance of parasitaemia and resolution of fever and coma.145 A 12 hourly dose regimen can be used in younger children.146 Quinidine is more toxic (especially cardiotoxicity) and expensive than quinine and a dose reduction might be necessary if the corrected QT interval is prolonged.147 In some parts of French-speaking Africa, quinimax (a combination of quinine, quinidine, cinchonine, and cinchonidine) is commonly used.148 The main side-effects of cinchona alkaloids are hyperinsulinaemic hypoglycaemia, and cinchonism (giddiness, tinnitus, high-tone deafness, and colour aberrations [in which patients see rings of colour around objects]). Although high doses of quinine can induce uterine contractions, normal therapeutic doses can be used safely in pregnancy.149 Doses of the cinchona alkaloids should be reduced by 30?50% if intravenous therapy is required beyond 3 days to avoid accumulation.
Artemisinin derivatives clear circulating parasites faster than other antimalarial drugs,150 and adults treated with artesunate have a lower mortality than those treated with quinine.151 The artemisinin derivatives should be used in combination with other antimalarial drugs to prevent resistance. Side-effects are not common152 and artemisinin derivatives are easier to give than cinchonoids. Studies with mice show that parenteral artemether and arteether (artemotil) are associated with damage to brainstem nuclei,153 but no evidence of these neurotoxic effects have been detected in human beings.154 Rectal preparations may be useful in rural health facilities.142

Supportive therapy

Ventilation and dialysis can be life saving in adults with pulmonary oedema or renal failure respectively. Children should receive antimicrobials to cover the possibility of bacterial infections until these can confidently be excluded by examination of cerebrospinal fluid, blood, and urine.8 Exchange transfusion has been recommended for non-immune adult patients with parasite densities >30% as it reduces parasitaemia and improves red-cell flow, but there is no conclusive evidence that it reduces mortality.143

Therapies with deleterious or unproven value

Several other adjunct therapies have been tested but as yet remain unproven.8 Steroids are deleterious, whereas acetyl-salicylic acid, sodium bicarbonate, and heparin can be harmful. Desferoxamine and dextran have unclear roles. Hyperimmune serum confers no benefit, whereas, monoclonal antibodies to tumour necrosis factor were associated with a worse neurological outcome. Although pentoxifylline was associated with early resolution of coma and low mortality in Burundian children, no benefit was reported in other studies.155 Mannitol reduces intracranial hypertension but such decreases are neither sustained nor does it prevent the development of severe intracranial hypertension.15 Prophylactic phenobarbital (10 mg/kg) did not control seizures,156 20 mg/kg phenobarbital was associated with increased mortality in unventilated Kenyan children157 but in Thai adults a single intramuscular injection of 3?5 mg/kg prevented convulsions.158 Dichloroacetate, an activator of pyruvate dehydrogenase, reduces blood concentrations of lactic-acid, but clinical trials are needed to assess how it affects outcome.159
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Areas for research

Prevention of malaria is a priority and the widespread use of preventive measures such as insecticide-treated materials can reduce all childhood deaths by 20%.160 Together with prompt treatment of fever with effective antimalarial drugs, these interventions can reverse rising mortality as a result of malaria in Africa. Basic research continues to explore vaccines as an ideal preventive instrument for malaria. There is no vaccine against infection because of the complexity of parasite biology. Insights into the processes leading to cerebral malaria might identify targets for a vaccine that allows infection and the acquisition of immunity, but prevents cerebral malaria.
Further definition of the phenotype of cerebral malaria would help provide insights into the pathogenesis, in particular the associations with genetic polymorphisms. A robust exclusion of other causes of encephalopathies in patients presenting with coma and a peripheral parasitaemia in endemic areas would reduce the contamination effect of these disorders on the pathogenesis and outcome of studies of cerebral malaria. Careful documentation of retinal findings may be particularly important.
There are technical difficulties in the study of subtle cerebral processes in comatose patients. The development of a reliable animal or in-vitro model may provide further insights. The technology exists to refine the murine model by inserting human genes (transgenics) into the mouse genome to allow the replacement of murine proteins with human ones. Infection of these models with P falciparum would recreate the key clinical and pathological processes.
Most deaths happen before antimalarials have had time to kill the parasites. In addition to addressing public-health problems resulting in delayed presentation to hospital and ensuring children receive prompt and appropriate resuscitation, new interventions that address pathophysiological processes causing these early deaths is a priority.
The scale of neurocognitive impairment reflects an enormous socioeconomic burden in resource-poor countries. Research is needed to clearly define the patients at risk and identify risk factors for persistent impairments. MRI, particularly of African children during acute illness and on recovery can provide insights into the pathogenesis of the neurocognitive damage. Interventions to prevent brain damage and rehabilitation programmes for those with neurocognitive impairments are needed. Such interventions might include; development of neuroprotective drugs, improvement in prophylactic anticonvulsant regimens, treatment of raised intracranial pressure in children, or correction of changes in brain (figure 7).
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Search strategy and selection criteria


Data for this review were identified by searches of PubMed and references derived from author lists from January 1965 to September 2005. The search terms used were ?cerebral malaria?, ?pathophysiology?, ?outcome?, and ?therapy?. Abstracts and reports from meetings were not used. We included some articles not published in English that had abstracts in English providing pertinent information unavailable from English-language publications. The final reference list was generated from papers that were relevant to this review.





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Authors' contributions
All authors contributed equally to reviewing the data and writing the paper.
Conflicts of interest
We have no conflicts of interest.

Acknowledgments
Two of the authors were supported by The Wellcome Trust, UK (CRJCN, grant number 070114 and NEJ, grant number GR066684MF).
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<!--start tail=-->References

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<!--end tail-->Affiliations

a. Centre for Geographic Medicine Research-Coast, Kenya Medical Research Insitute, Kilifi, Kenya
b. Department of Paediatrics and Child Health, Mulago Hospital/Makerere University Medical School, Kampala, Uganda
c. Department of Infectious Diseases, Tropical Medicine and AIDS, Academic Medical Centre, Amsterdam, The Netherlands
d. Liverpool School of Tropical Medicine, Pembroke Place, Liverpool, UK
e. Neurosciences Unit, Institute of Child Health, London, UK

Correspondence to: Dr Richard Idro, Centre for Geographic Medicine Research-Coast, Kenya Medical Research Institute, PO Box 230, Kilifi (80108), Kenya


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[sharon sanders]

Table 1

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Table 1. Clinical features and outcomes of cerebral malaria in African children and southeast Asian adults
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[sharon sanders]

Figure 1


Figure 1. Electroencephalography recordings in cerebral malaria
Top: Electroencephalography recording in a Kenyan child with cerebral malaria showing diffuse high amplitude slow-wave activity more marked over the left hemisphere. Bottom: Electroencephalography recording in a Kenyan child with cerebral malaria showing electrical seizure activity (arrows) most prominent over the left temporal region (electroencephalography recordings taken by R Idro).

[sharon sanders]

Figure 2

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Figure 2. Radiological features of the brain in cerebral malaria
Scan of the brain in a Kenyan child with cerebral malaria showing (A) swelling of the brain with compressed ventricles (arrow) and loss of sulci and (B) resolution of the brain swelling. A CT scan showing (C) brain swelling with diffuse hypodensity sparing the basal ganglia (arrows) and (D) convalescent scan in a child showing cerebral atrophy with infarction (arrows) of the right frontal and parietal regions. Reproduced with permission from the BMJ Publishing Group.<!--start ce:cross-ref=--><!--start ce:sup=-->31
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[sharon sanders]

Figure 3


Figure 3. Retinopathy of malaria
White-centred retinal haemorrhage (A) and orange vessels in a Malawian child with cerebral malaria. Macula retinal whitening (B) around the foveola (central dark disc) in a child with cerebral malaria. Cotton wool spots are also visible superiotemporal to the optic disc. Vessel changes (C) in a Malawian child with cerebral malaria?from red to pale orange. Vessel changes (D) in a Malawian child with cerebral malaria?from red to white. Photographs courtesy of Dr Nicholas Beare, Malawi-Liverpool-Wellcome Trust Clinical Research Programme College of Medicine, Malawi.

[sharon sanders]

Figure 4

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Figure 4. Cerebral infarcts in adults with cerebral malaria
Left: infarcts in a 36 year old man with cerebral malaria. Hyperintense cortical areas (infarcts) seen on a fast spin-echo T2 weighted MR image (arrow). Reproduced with permission from the American Society of Neuroradiology.<!--start ce:cross-ref=--><!--start ce:sup=-->54<!--end ce:sup--><!--end ce:cross-ref--> Right: contrast enhanced brain CT scan of a 48 year old man who presented with left focal becoming generalised seizures and left hemiparesis. A large area of hemorrhagic infarction is seen in the right frontoparietal cortex with surrounding oedema. Absence of contrast is seen as a hypodense area in the posterior aspect of the superior sagittal sinus. Reproduced with permission from the British Infection Society.<!--start ce:cross-ref=--><!--start ce:sup=-->55
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[sharon sanders]

Figure 5


Figure 5. Sequestration of infected erythrocytes in cerebral vessels
Left: <!--start ce:italic=-->P falciparum<!--end ce:italic--> infected erythrocytes sequestered in a cerebral vessel of a Vietnamese adult with fatal cerebral malaria (haematoxylin and eosin staining ?400. Courtesy of Dr Gareth Turner, Nuffield Department of Histopathology, John Radcliffe Hospital, Oxford. Middle: electron microscopy showing the ultrastructural details of a <!--start ce:italic=-->P falciparum<!--end ce:italic--> IE adhering to an endothelial cell in vitro. P=parasite, En=endothelial cell and arrows point out the adhesion points at the electron dense knob proteins. Courtesy of Professor David Ferguson, Department of Clinical Laboratory Sciences, Oxford University. Right: freeze fracture electron micrograph of the infected erythrocyte surface revealing the symmetrical distribution of knob proteins on the surface. Courtesy of Professor David Ferguson, Department of Clinical Laboratory Sciences, Oxford University.

[sharon sanders]

Figure 6


Figure 6. Gross pathological appearance of the brain in cerebral malaria
Macroscopic section of the brain from a fatal case of cerebral malaria showing petechial haemorrhages in white matter, particularly in the subcortical rim and corpus callosum. Reproduced with permission from International Society of Neuropathology.<!--start ce:cross-ref=--><!--start ce:sup=-->123

[sharon sanders]

Figure 7


Figure 7. Possible mechanisms for death and neuro-cognitive impairment in cerebral malaria and some areas for possible intervention
(1) <!--start ce:italic=-->P falciparum<!--end ce:italic--> infected erythrocytes adhere to the vascular endothelium and possibly sequester in large numbers in the brain. (2) Local and systemic changes produce significant vital organ dysfunction leading to severe metabolic derangement, which may result in death unless urgent correction (eg, correction of blood glucose, dialysis or ventilation) is initiated. (3) Sequestration of infected erythrocytes within the cerebral vessels increases the cerebral volume, which together with the increase in cerebral blood flow caused by seizures, anaemia, and hyperthermia (4), and the altered blood?brain barrier function lead to brain swelling and raised intracranial pressure (ICP; 5). This may cause death (through global cerebral ischaemia, transtentorial herniation or brainstem compression) or result in neuronal damage with consequent neuro-cognitive impairments. Sequestered parasites may also produce local toxins and ischaemia or influence the production of inflammatory products such as cytokines and result in multiple seizures and neuronal damage. Metabolic derangement is more common in adults whereas raised ICP and seizures are commoner in children. Possible areas for intervention are highlighted.

[sharon sanders]

Table 2

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Table 2. Antimalarial treatment of cerebral malaria
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