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Pediatr Res. Author manuscript; available in PMC 2011 April 01.
Published in final edited form as:
Pediatr Res. 2010 October ; 68(4): 267–274. doi:10.1203/PDR.0b013e3181eee738.

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Cerebral Malaria; Mechanisms Of Brain Injury And Strategies For
Improved Neuro-Cognitive Outcome
Richard Idro, Kevin Marsh, Chandy C John, and Charles RJ Newton
Department of Paediatrics and Child Health [R.I.], Mulago Hospital, Makerere University,
Kampala, Uganda; Kenya Medical Research Institute and the Wellcome Trust Centre for
Geographic Medicine Research – Coast [R.I., K.M., C.R.J.N.], Kilifi, Kenya; Centre for Clinical
Vaccinology and Tropical Medicine [K.M.], University of Oxford, Oxford OX3 7LJ, UK; Department
of Pediatrics [C.C.J], University of Minnesota, Minneapolis, MN 55455; Clinical Research Unit
[C.R.J.N], London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK;
Neurosciences Unit [C.R.J.N], UCL-Institute of Child Health, London WClN 1EH, UK

Abstract

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Cerebral malaria is the most severe neurological complication of infection with Plasmodium
falciparum. With over 575,000 cases annually, children in sub-Saharan Africa are the most
affected. Surviving patients have an increased risk of neurological and cognitive deficits,
behavioral difficulties and epilepsy making cerebral malaria a leading cause of childhood neurodisability in the region. The pathogenesis of neuro-cognitive sequelae is poorly understood: coma
develops through multiple mechanisms and there may be several mechanisms of brain injury. It is
unclear how an intravascular parasite causes such brain injury. Understanding these mechanisms is
important to develop appropriate neuro-protective interventions. This paper examines possible
mechanisms of brain injury in cerebral malaria, relating this to the pathogenesis of the disease and
explores prospects for improved neuro-cognitive outcome.

INTRODUCTION
Cerebral malaria is the most severe neurological complication of infection with Plasmodium
falciparum malaria. It is a clinical syndrome characterized by coma and asexual forms of the
parasite on peripheral blood smears. Mortality is high and some surviving patients sustain
brain injury which manifest as long-term neuro-cognitive impairments. In this paper, we
review studies that have provided current understanding of the pathogenesis of brain injury
and explore prospects for neuro-protection and improved outcome.
Epidemiology
Falciparum malaria is a leading cause of ill health, neuro-disability and death in tropical
countries. Although 40% of the world’s population is at risk, most transmission occurs in
sub-Saharan Africa where children under the age of 5 years are most affected and the
incidence of disease declines in older children with increasing immunity. In South-East
Asia, malaria occurs more commonly in adults but the clinical features are different(1).
Copyright © 2010 International Pediatric Research Foundation, Inc. All rights reserved.
Corresponding author: Richard Idro, Ph.D., Department of Paediatrics and Child Health, Mulago Hospital, Makerere University
School of Medicine, P.O Box 7072, Kampala, Uganda, ridro1@gmail.com.
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ocular movements or abnormal respiratory patterns) are commonly observed.000/ year in the endemic areas of Africa. but even with this treatment. 15-20% Pediatr Res. lactic acidosis. but other authors attribute the impaired consciousness to metabolic factors and inflammatory mediators(10). children in this region bear the brunt. particularly in those with shock. Author manuscript. seizures papilledema and retinal changes are less common and coma resolution is slower. pupil size and reaction.Idro et al. Thus. Patients in whom coma is caused by other encephalopathies (e. coma develops suddenly with seizure onset often. asexual forms of Plasmodium falciparum parasites on peripheral blood smears and no other cause to explain the coma(7). retinal changes (hemorrhages. in a postmortem study of Malawian children dying with a clinical diagnosis of cerebral malaria. Outcome Without treatment. following 1-3 days of fever. electrolyte imbalance and hyperpyrexia or hypoglycemia and shock are commonly present. repeated seizures. abnormal bleeding. The prognosis is grave in deeply comatose patients with severe metabolic acidosis. Anemia. Compared to African children. hypoglycemia. One percent of symptomatic infections may become complicated and develop into severe malaria. This lack of specificity is problematic for clinical and pathogenesis studies. available in PMC 2011 April 01. Bacterial co-infection may be observed. 4). Some develop cortical infarcts and cerebral venous or dural sinus thrombosis as part of a disordered coagulation. headache. viral encephalitis. pulmonary edema and adult respiratory distress syndrome may develop. poisoning and metabolic disease) or previously unrecognized neurological abnormalities but have incidental parasitemia (a common phenomenon in malaria endemic areas) may be included. Europe PMC Funders Author Manuscripts The clinical hallmark of cerebral malaria is impaired consciousness. 6). 6).000 children in Africa develop cerebral malaria annually(2). Clinical features The clinical features of cerebral malaria have been reviewed extensively(5.g. In practice. with coma the most severe manifestation. 575.120/100. body ache and progressively. jaundice. Brain swelling. The increased specificity accorded by recent descriptions of retinal changes in cerebral malaria is should address this issue(9). there are over 500 million clinical cases. Page 2 Europe PMC Funders Author Manuscripts Every year. Cerebral malaria is the most severe neurological manifestation of severe malaria. coma or multiple organ failure and is estimated to cause over one million deaths annually(1). delirium and coma. Peak incidence is in pre-school children and at a minimum. shock. In adults. A few children develop coma following progressive weakness and prostration. cerebral malaria is part of a multi-organ disease. intracranial hypertension. 24% had other causes of death(8). and accounts for the majority of late deaths(5. Other systemic complications such as anemia. cerebral malaria is invariably fatal. In children. . This is thought to be causes by parasitized red blood cells (pRBCs) sequestered in cerebral micro-circulation. With an incidence of 1. renal failure. we highlight some of the main features. parenteral antimalarials (cinchonoids or artemisinin derivatives) are indicated. Recent reports however suggest that the incidence of severe malaria is on the decline(3. shock. hypoglycemia and repeated seizures. metabolic acidosis. The World Health Organization defines cerebral malaria as a clinical syndrome characterized by coma at least 1 hour after termination of a seizure or correction of hypoglycemia. vessel discoloration and or papilledema) and brainstem signs (abnormalities in posture. Patients develop fever. hemoglobinuria. this definition is non-specific. In this paper. In African children. peripheral and macular whitening. Severe malaria may manifest as anemia. metabolic acidosis.

Author manuscript. Since invasive testing of brain tissue is not safe. Thus. available in PMC 2011 April 01. MECHANISMS OF BRAIN INJURY IN CEREBRAL MALARIA The mechanisms of neural injury in cerebral malaria are poorly understood. an insight into it can provide leads to the mechanisms of brain injury. motor function or behavior impairments and. particularly murine models involving C57BL/6 or CBA mice infected with P. epilepsy develops in 10% (15-18). intracranial hypertension. Although some gross deficits. and hypoglycemia. why do some children have a poor neurological outcome while others improve with hardly any deficits? Europe PMC Funders Author Manuscripts A fundamental problem in assessment of cerebral malaria pathogenesis is the relative paucity of central nervous system pathologic or physiologic data in humans. there are other factors since sequestration is also observed in patients dying of other complications of falciparum malaria(20). ataxia and central hypotonia improve with time(15). . berghei ANKA. which may explain why an intravascular parasite may cause neural dysfunction and why some patients may have a poor outcome. Sequestration impairs perfusion and may aggravate coma through hypoxia. These studies are however limited in sample size and cannot address potential differences in survivors compared to patients who die. important differences in what is known of pathogenesis in humans as compared to mice suggest that direct extrapolation of findings to human cerebral malaria may not be appropriate(19). cerebral malaria is now considered a leading cause of neuro-disability in African children. descriptions of the prognostic factors for neuro-cognitive sequelae and post-mortem studies have provided some understanding. Furthermore. Clearly. particularly blindness. other than causing thousands of deaths. 14). The prevalence (<5%) and pattern of neurological deficits are different in adults. Although they have provided a wealth of information. the ability of pRBCs to deform and pass Pediatr Res. 11% are discharged with gross neurological deficits(13. the majority of pathogenesis studies have been conducted in animal models. A group of parasite antigens including Plasmodium falciparum erythrocyte membrane protein-1 (PfEMP-1) mediate binding to host receptors of which. table 1. Although the pathogenesis of cerebral malaria is also incompletely understood. The sequestered parasite mass is further increased when adherent erythrocytes agglutinate with other pRBCs. Page 3 die. In adults however. available data are largely from autopsy studies. Three observations however raise questions. Sequestration results from adherence of pRBCs to the endothelial lining (cytoadherence) using parasite derived proteins exposed on erythrocyte surface(21). intercellular adhesion molecule-1 (ICAM-1) is the most important and whose expression is upregulated in areas adjacent to sequestered parasites. form rosettes with non-parasitized erythrocytes or use platelet-mediated clumping to bind to each other. The main risk factors include repeated seizures. why is coma so rapidly reversible with treatment and with very little demonstrable tissue necrosis? 3) Despite similar presentation. In addition. it became clear that many children sustain significant brain injury. deep and prolonged coma. This treatment is currently being evaluated in African children. mortality was lower if patients were treated with intravenous artesunate(11). Given this limitation. Parasite sequestration in the brain Parasite sequestration in cerebral microvasculature is thought to be a central factor in pathogenesis and the resulting pathophysiological changes in tissue around the sequestered parasites.Idro et al. Europe PMC Funders Author Manuscripts Earlier studies suggested that surviving patients fully recover(12) but over the past 20 years. 25% have long-term impairments especially cognition. 1) how does a largely intravascular parasite cause so much neuronal dysfunction? 2) despite the large number of parasites in the brain of most patients.

IL-6 and IL-10(29) but low levels of the chemokine RANTES is independently associated with mortality(30). Other inflammatory products such as the metabolites of the kynurenine pathway . Nitric oxide can cross the blood brain barrier (BBB). diffuse into brain tissue and interfere with neurotransmission and may therefore partly be responsible for the reversible coma(33). cell-to-cell signalling and signal transduction. It causes seizures in animal models of brain disease while kynurenic acid is an antagonist and is generally thought of as neuro-protective. 27) and monoclonal antibodies to TNF(28). Page 4 Europe PMC Funders Author Manuscripts through the microvasculature is decreased(22). Despite the prominence of TNF in pathogenesis. There is widespread endothelial activation in vessels containing pRBCs and compared to other complications of falciparum malaria. significant neural tissue necrosis is unlikely since with specific antimalaria treatment. Author manuscript. Quinolinic acid is a NMDA receptor agonist and an excitotoxin. The association between NO activity and inducible nitric oxide synthase with pathogenesis have been inconsistent(31. significant Pediatr Res.Idro et al. the most extensively studied cytokine in cerebral malaria. cytokine mediated synaptic changes may contribute to the syndrome of cerebral malaria. Tumor necrosis factor (TNF). TNF may be protective but prolonged high levels contribute to complications(25). Near areas of sequestration. chemokines and excitotoxicity Cytokines and chemokines play a complex role in pathogenesis and have both protective and harmful effects. in the majority of children. blood-brain barrier (BBB) dysfunction and intracranial hypertension Cytoadherence of pRBCs to the endothelium initiates a cascade of events beginning with the transcription of genes involved in inflammation. Although a critical reduction in metabolite supply (oxygen and glucose) may occur. there is increased local synthesis. apoptosis. NO is involved in host defense. their role in pathogenesis of the neuronal damage is unclear. TNF is also involved in regulating synaptic transmission (strength. Endothelial injury. the risk of neural injury is higher and may be worse if the patient is hypoglycemic(23) or if blood flow is further compromised by intracranial hypertension(24). Thus. coma is rapidly reversible. . Therefore. The role of nitric oxide (NO) is controversial. failed decrease mortality. The timing of this is important since early in disease. interleukin (IL)-1b. release of endothelial micro-particles (EMPs) and apoptosis of host cells(36). It is suggested that inflammatory cytokines upregulate inducible NO synthase in brain endothelial cells leading to increased NO production. maintaining vascular status and in neurotransmission and is thought to be an effector for TNF.and anti-inflammatory cytokines. upregulates ICAM-1 expression on the cerebral vascular endothelium increasing the cytoadhesion of pRBCs. Cytokines. In children. which result in endothelial activation.quinolinic and kynurenic acid . increased levels were associated with impaired renal function(35). However. Europe PMC Funders Author Manuscripts Several other cytokines and chemokines are important and in particular. scaling and long-term potentiation)(10). in the presence of increased metabolic demand such as during seizures and fever. available in PMC 2011 April 01. Parasite antigens released at schizogony trigger the release of both pro. Excitation by quinolinic acid may contribute to convulsions in cerebral malaria. there are graded increases in cerebrospinal fluid concentration across outcome groups of increasing severity(34) although in adults. hypoxia and inadequate tissue perfusion may be major pathophysiological events. pentoxifylline which decreases macrophage TNF production(26. Although the balance between these mediators is critical for parasite control. high levels of quinolinic acid may have long-term deleterious effects on cognitive function. 32). Because of the role of NMDA receptors in modulating neurotransmission and as agonists.may also be important in pathogenesis.

. since cerebral symptoms are not seen in perforin-deficient models but only in wild forms that show high increases in perforin mRNA (43). These areas have impaired capillary perfusion on fluorescein angiography(51). angiopoietin-1 and angiopoietin-2 are altered(40). In the eye. single axons. The increased susceptibility to injury may explain the higher prevalence of sequelae in children. Despite this. significant leakage of plasma proteins into perivascular spaces has not been seen(47). Repair of the injured endothelium is also impaired as there is failure to mobilize sufficient circulating endothelial progenitor cells(39) and plasma levels of endothelial regulators. up to 40% of children with deep coma have brain swelling on computerized tomography scans(48). Apoptosis may be induced through a perforin-dependent process. Author manuscript. Many children with severe hypertension are discharged with spastic quadriplegia and subsequently. available in PMC 2011 April 01. multiple discrete areas (100-1000μm) of retinal whitening are observed in most children with cerebral malaria. similar obstruction may be present in the brain and coma in cerebral malaria may partly be a result of under-perfusion in multiple but small areas of the brain. Axons in children appear to be more susceptible to injury since the median CSF microtubule-associated protein tau level is 3-fold greater than in adults(45). Although disruptions at sites of sequestration can expose neurons to plasma proteins. nutrient and oxygen delivery and can lead to global ischemic injury. Page 5 increases in circulating EMPs are seen in patients in coma(37). diffuse or more focal parenchymal patches and neuronal cell bodies(44) and axonal injury correlated with plasma lactate and depth of coma. exposure to hypoxia still leaves many children with subtle (e. Ischemic injury is seen on acute computerized tomography and pattern of injury is consistent with a critical reduction in perfusion pressure(48). Because the patches of brain affected are small. the sequestered mass may be higher. reduced local perfusion is associated with an abnormal electroretinograph(52). intracranial hypertension is common in African children. Perivascular macrophages around vessels with parasites express receptors such as sialoadhesin normally present only if there has been contact with plasma proteins(46). Pediatr Res. Recent studies of the retina have however provided evidence for decreased local perfusion(51. interactions between pRBCs and platelets (which produce platelet microparticles) cause further injury to endothelial cells through a direct cytotoxic effect(38). Physiologically. The convalescent scans in these patients show cerebral atrophy. In those who die or develop severe brain injury.g. apoptosis is first observed in endothelial cells and then in neurons and glia(41). the stimulus being contact of pRBCs with the endothelium(42) (figure 1). If the retina mirrors events in the brain. However. This increase is probably an adaptive response to high a metabolic demand to match oxygen and nutrient delivery to requirements since jugular bulb venous oxygen saturation remains within normal(50). BBB dysfunction may contribute to the hypertension although increased cerebral volume could be caused by sequestration and increased cerebral blood flow from seizures. brainstem compression and death(24. There is accumulation of activated/effector CD8 lymphocytes. figure 2. hyperthermia or anemia. Europe PMC Funders Author Manuscripts In murine models. severe learning disability(24). there is minimal tissue necrosis and early restoration of perfusion may explain the near complete recovery of gross neurological function in the majority of patients. Cerebral blood flow and perfusion Patients with cerebral malaria have an increased cerebral blood flow. In addition. herniation. cognitive) deficits. 52). Europe PMC Funders Author Manuscripts Intracranial hypertension reduces cerebral perfusion pressure. with early treatment and rapid relief of obstruction.Idro et al. blood flow obstruction not readily reversed and hypoxic and ischemic injury more widespread(53). Four patterns of axonal injury have been described. 49).

they did not reduce the risk of subsequent epilepsy(61). Although the seizures are different from simple febrile seizures. The likely scenario is that brain injury is caused by the seizure initiating noxious agent. irreversible neuron damage is described following prolonged seizure activity. Seizures are a common feature of childhood cerebral malaria. Thus. Death and neurological sequelae may arise from different mechanisms. Those with convert status epilepticus on the other hand present following prolonged seizures. duration and cause of coma Europe PMC Funders Author Manuscripts It has been suggested that cerebral malaria is not a single homogenous syndrome rather. In Gambian children. . Similarly. Depth. Author manuscript. In other models. neurological sequelae were associated with repeated seizures and with deep and prolonged coma while death was associated with hypoglycemia and acidosis suggesting that most early deaths in cerebral malaria may result from an overwhelming metabolic derangement(65). available in PMC 2011 April 01. Impaired consciousness is a secondary phenomenon to an unfavourable environment.Idro et al. a linear relationship between cerebral perfusion pressure and blood flow velocity was observed suggesting that auto-regulation was impaired. high dose prophylactic Phenobarbital in children with cerebral malaria significantly reduced seizure recurrences(62) but did not improve cognitive outcome(63). this is replaced by local atrophy and gliosis(58). sonographic features suggesting progressive intracranial hypertension were seen in some who later died. In a transcranial Doppler study. Patients with prolonged post-ictal state have coma secondary to seizures. In addition. In this study however. Page 6 Europe PMC Funders Author Manuscripts Regional blood flow may also be altered. while in patients with severe intracranial hypertension. four distinct groups: a prolonged post-ictal state. Seizures Plasmodium falciparum is epileptogenic and the risk of seizures increases with parasitemia(55). Again prolonged periods of either hypoglycemia or acidosis may cause neuronal dysfunction or death and among survivors. although prophylactic anticonvulsants in traumatic brain injury (TBI) prevented immediate seizure recurrence. over 80% are admitted with seizures and seizures recur in 60% during admission(56). Prolonged seizures may worsen this injury and setup a vicious circle of neural injury and more seizures. The neuro-cognitive outcome may depend on how long the seizures have lasted. sonographic abnormalities were associated with lateralizing deficits in six out of eleven children who developed severe functional deficits on recovery(54). Failure to detect the state can be disastrous since these patients are hypoxic and hypercarbic from hypoventilation and at risk of aspiration. The physical signs of seizure activity are often so minimal that they may not be recognized. Early correction of these derangements may buy time for definitive Pediatr Res. 60). the same risk factors may be at play. A fifth group maybe patients with false cerebral malaria in whom coma has other causes and parasitemia is incidental(8). edema is recognized on magnetic resonance imaging (MRI)(57) but overtime. There is however no consensus as to whether seizures cause the brain injury or are a manifestation of an injured brain(59. Patients with severe metabolic derangement may regain consciousness a few hours after resuscitation. prophylactic Phenobarbital was associated with increased mortality (from respiratory depression) and the cognitive outcome study included only half of the original cohort. outcome may depend on duration of exposure. covert status epilepticus. within days. regain consciousness within 6 hours and have a good neurological recovery. severe metabolic derangement and a primary neurological syndrome(64).

memory or attention(69). Coma may be a primary consequence of intracranial sequestration of malaria parasites. Clinical seizures may develop when these discharges coalesce and involve more of the surrounding normal brain(73). Most deficits are observed in a sub-group of children some of whom have concurrent impairments in nonverbal functioning. The paucity of literature on risk factors for cognitive impairment highlights the need for additional studies in this area. mostly generalized tonic-clonic and secondarily generalized seizures are observed(71). Europe PMC Funders Author Manuscripts iii) Epilepsy—Epilepsy develops in about 10% of exposed children months to years after exposure(16) and the cumulative incidence increases with time(70).8% of surviving children have deficits especially in vocabulary. 67. depth and duration of coma and hyporeflexia(18. Europe PMC Funders Author Manuscripts Patients with a primary neurological syndrome present with seizures often without severe metabolic disturbances and have the worst neuro-cognitive outcome. This concept has been studied in animal models and in patients with intractable temporal lobe epilepsy in who there is extensive neural cell loss.Idro et al. available in PMC 2011 April 01. 72) or global ischemic injury(48. instead. Surviving neurons and glia express genes encoding ion channels and receptors . 11. iv) Behavior and neuro-psychiatric disorders—In children. They are not severely anemic and coma persists for 24-48 hours well beyond the resolution of seizures. 67). axonal sprouting and formation of new synapses in the hippocampus. The pathogenesis is poorly understood. Author manuscript. .changes thought to be responsible for the altered physiologic features of the injured region(74). serum levels of multiple cytokines and chemokines did not correlate with impairment 6 months after discharge. Intracranial hypertension is common. 23. in cerebral malaria. seizures. Recent phase II trials of albumin as a resuscitative fluid have supported this assertion(66) and has led to the on going Fluid Expansion as Supportive Therapy trial for very sick children in several African hospitals. If the concept is true. Page 7 treatment. 68). impulsiveness and hyperactivity. Only one study has investigated the immuno-pathogenesis of cognitive impairment(29). behavior problems include inattention. long-term cognitive impairment was described in 25% of children(18). Recent concepts of epileptogenesis hypothesize that in patients exposed to brain injury. gliosis. hypoxic/ischemic neural injury in areas of non-perfusion may be the casual mechanism. Although seizures in cerebral malaria occur in the context of a febrile illness and many have complex features. The pathogenesis of epilepsy is poorly understood although it may be a consequence of focal hypoxic/ischemic injury in borderzone areas of cerebral circulation(56. temporal lobe epilepsy is uncommon. Studies with functional imaging may be useful in delineating pathogenesis. Risk factors for cognitive impairment included hypoglycemia. 72). conduct disorders and impaired social Pediatr Res. it is unclear if the language deficits are part of a global injury or severe malaria causes injury to specific language centers. Retrospective studies had documented rates of 14-24%(17. In this study. but CSF levels of TNF correlated with working memory and attention suggesting that elevated levels of central nervous system TNF adversely affects long-term cognitive outcome. ii) Speech and language impairment—Cerebral malaria is a leading cause of acquired language disorder in the tropics. multiple areas of hyperexcitable networks each with different seizure probability and independent discharges may develop in the brain. Pathogenesis of some specific impairment i) Cognitive sequelae—In a prospective study. word finding and phonology. receptive and expressive speech.

anti TNF agents. personal observations). These included interventions targeting elements of pathogenesis and risk factors for brain injury.Idro et al. The noxious insults and epileptogenic parasites cause seizures which in turn may setup a vicious circle of brain injury and more seizures. anti-inflammatory. examine pathogenesis and initiate therapeutic studies. causing NO mediated coronary vasodilatation. To improve outcome. properties of compounds used (e. Sequestration impairs local perfusion and may cause hypoxic injury. high dose erythropoietin reduced brain-infarct size and improved functional outcome(82). which has anti-apoptotic. Studies in cerebral malaria have also been disappointing. This has raised the possibility that early intervention may limit injury. Obsessive. immunoglobulin. In adults. infectious and hypoxic ischemic encephalopathy(80) and offered protection against endothelial injury in the heart. inflammation. was associated with a lower risk of cerebral malaria in treated animals(78). there is an ongoing trial evaluating a less respiratory depressant prophylactic anticonvulsant. Thus. A poor understanding of pathophysiological mechanisms. high dose erythropoietin Pediatr Res. In another study. cytoadherence and sequestration of pRBCs in cerebral microvasculature initiates local endothelial injury and apoptosis. degree of microvascular obstruction and inflammatory response. Attenuation of these processes left an intact BBB integrity(77). self injurious and destructive behaviors are also observed (17. The extent of brain injury may depend on causation of coma. More recent studies have examined the possibility of preventing endothelial injury or reversing rossetting and improving blood flow. . acetyl salicylic acid. However. patient selection or choice of endpoints have been blamed for the failure(76). there have been trials of steroids. In mice with cerebral malaria. administration of a lowmolecular weight thiol.treatment with z-VAD (a pan-caspase inhibitor) and over-expression of Bcl-2 (a gene which prevents the release of apoptotic mediators from the mitochondria) . an immuno-modulatory agent. Page 8 development. the B5 complex pro-vitamin pantethine. The pathogenesis is also unclear. Europe PMC Funders Author Manuscripts In summary. However. prevented the development of cerebral malaria. In a murine model. Two different anti-apoptotic approaches .g. heparin. Pantethine appeared to offer this protection by down-regulating platelet reactivity and release of micro-particles from the activated endothelium. different mechanisms of injury may require separate interventions. iron chelation. available in PMC 2011 April 01. increasing blood flow. appropriate therapeutic time-window). Erythropoietin provided neuro-protection in animal models of TBI. brain swelling and intracranial hypertension. particularly in TBI. the cytokine erythropoietin. Severe metabolic derangement may worsen the injury. In adults with stroke. BBB dysfunction. duration of exposure. Author manuscript.did not reduce cerebral malaria mortality in mice(79). presence of concurrent complications such as shock and availability and speed of interventions. In both cases. human trials are awaited. STRATEGIES FOR IMPROVED NEURO-COGNTIVE OUTCOME Neuro-protective and adjuvant therapies Europe PMC Funders Author Manuscripts Brain injury following exposure to noxious insult evolves over hours or days. have been disappointing. vaso-dilating and neurotrophic properties and widespread receptors in the brain has shown greater promise. Because prophylactic Phenobarbital was associated with respiratory depression(62). fosphenytoin. the post-malaria neurological syndrome (table 1) develops after parasites have been cleared(75). 55) (Richard Idro. enhancing repair and reducing apoptosis(81). Prospective studies are needed to describe these problems clearly. most neuroprotective interventions in man. micronutrients and prophylactic anticonvulsants. Symptoms develop 1-4 months after exposure and the pathogenesis is unclear. Glatiramer acetate. It crosses the BBB and local synthesis is increased during hypoxia. mannitol.

Earlier studies of heparin and acetyl salicylic acid were not continued because they either failed to demonstrate sufficient evidence of benefit or because of toxicity. In addition. a modified form of heparin with minimal anticoagulant activity and plan to take this to Phase II studies (Anna Vogt. K. Page 9 reduced mortality by 40-90%. More recently however. ABBREVIATIONS BBB Blood brain barrier Pediatr Res. behavior and speech therapy. A Swedish group has recently completed a Phase I trial of DFO2.. Particular areas include physical and occupational therapy. Rehabilitation Europe PMC Funders Author Manuscripts Because of the high mortality associated with cerebral malaria. MR imaging may provide important insights into pathogenesis. coma develops through multiple mechanisms and there are several mechanisms of brain injury. few studies have focused on rehabilitation for children with sequelae. Cerebral blood flow can be measured using arterial spin labeling while functional MRI can be used to describe neural activity in coma. biochemical and functional features of the brain in vivo(87). (reviewed in(83)) and in children.M. . are supported by the Wellcome Trust.J.. in children with cerebral malaria was recently concluded without any major concerns about the safety(85).J is supported by the NIH. Acknowledgments Statement of financial support The research activities of R. a poor understanding of pathogenesis is a major hindrance to progress in cerebral malaria research. compounds with less anticoagulant effects have been developed. With declining child mortality in the region and the growing number of exposed and therefore potentially impaired children.N. develop and implement rehabilitation. CONCLUSION Cerebral malaria causes brain injury in an unacceptable number of children. and C.I. systems are needed to detect impairments. In the meantime. metabolic. 1500u/kg. in different patients. Author manuscript. Interfering with this binding can potentially reduce parasite sequestration.C. MRI offers a way out including a non-invasive study of the structural.R. proton MR spectroscopy can be used to measure levels of substrates and metabolites. C. personal communication).Idro et al. Clearly. A combination of time of flight angiography and diffusion weighted imaging can describe obstruction to flow and the effects of obstruction in distal areas. cognitive rehabilitation and hearing aids. Europe PMC Funders Author Manuscripts Heparan sulfate on endothelial cells mediates binding of pRBCs via DBL1 alpha domain of PfEMP1(86). A phase I study of erythropoietin. plasma levels >200u/L were associated with ~80% less risk of sequelae(84). There are no guidelines to assess impairments or guide rehabilitation(88). It is not a single and discrete syndrome. Combinations of adjuvant therapies targeting specific mechanisms of brain injury may be needed to improve neuro-cognitive outcome. A preliminary study of cognitive rehabilitation using a computerized program has demonstrated improved neuropsychological and behavioral outcomes in exposed children suggesting that similar interventions are possible(89). available in PMC 2011 April 01.

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release of endothelial microparticles and apoptosis in the exposed area. Page 15 Europe PMC Funders Author Manuscripts Figure 1. Author manuscript. .Idro et al. endothelial activation. Cytoadherence of parasitized erythrocytes to the endothelial cell lining and sequestration of parasitized and non-parasitized cells in the cerebral capillary or post capillary venule initiates an inflammatory process. At the site of cytoadherence. the blood brain barrier is possibly disrupted and there is an increased inflammatory response in the perivascular area with an increased release of pro-inflammatory cytokines. Europe PMC Funders Author Manuscripts Pediatr Res. Changes in and around a cerebral microvessel with sequestered Plasmodium falciparum parasites A schematic diagram showing changes in and around a cerebral vessel with sequestration of pRBCs. available in PMC 2011 April 01.

Fluorescein angiography shows multiple areas of retinal non-perfusion. Europe PMC Funders Author Manuscripts Pediatr Res. Retinal changes and fluorescein angiography in a child with cerebral malaria Day 1 (admission is day 0): A. The leakage may suggest dysfunction of the blood-retina barrier. E. C. available in PMC 2011 April 01. At higher magnification and later in the angiography run. These are more clearly delineated than on day 0 (admission). there is some mild leakage round the border of the perfused and nonperfused zones. multiple retinal hemorrhages are visible. Day 3 of coma: D. Page 16 Europe PMC Funders Author Manuscripts Figure 2. At higher magnification and later in the angiography run.Idro et al. B. There is little change in appearance compared to day 1. . F. No major change from admission. Author manuscript. Color fundus photograph of a child with cerebral malaria. Photographs courtesy of Dr Nicholas Beare Royal Liverpool University Hospital and the Wellcome Trust .Liverpool School of Hygiene and Tropical Medicine Program in Malawi. leakage of fluorescein from re-perfused capillaries and capillaries previously on the border of non-perfusion is still observed. But there is substantial recovery in areas of non-perfusion.

available in PMC 2011 April 01. self injurious and destructive behavior in children and the post malaria neurological syndrome (acute psychosis. and convulsions) in adults Europe PMC Funders Author Manuscripts Pediatr Res. tremors and dystonia Dystonia. hallucinations. word finding. quadriparesis or quadriplegia) and cranial palsies. . impairments in pragmatics (use of language). receptive and expressive language. Visual impairment Blindness and milder degrees of visual impairment Most visual impairment resolves Speech and language impairments Aphasia Aphasia. attention and learning Impairments in attention. Page 17 Table 1 Neuro-cognitive sequel of cerebral malaria Europe PMC Funders Author Manuscripts Type of sequel Sequel on discharge Long term sequel Motor Spasticity (hemiplegia. quadriparesis or quadriplegia). catatonia. non verbal functioning and learning Epilepsy Generalized tonic clonic seizures and secondarily generalized seizures Mostly generalized tonic clonic seizures and secondarily generalized seizures Behavior difficulties and neuropsychiatric sequel Attention difficulties. conduct disorders.Idro et al. Ataxia and tremors resolve. content. inappropriate speech and behavior. vocabulary and phonology Cognitive deficits Impairments in working memory. Author manuscript. Central hypotonia mostly resolves Movement disorders Ataxia. cranial nerve palsies and central hypotonia Spasticity (hemiplegia. executive function and working memory. impulsiveness and hyperactivity.