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Georges Emile Raymond Grau*1,2 & Alister Gordon Craig3 Vascular Immunology Unit, Department of Pathology, Sydney Medical School, The University of Sydney, Camperdown NSW 2042, Australia La Jolla Infectious Disease Institute, San Diego, CA 92109, USA 3 Malawi Liverpool School of Tropical Medicine, Liverpool, UK *Author for correspondence: [email protected] 1

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What is cerebral malaria?

adhesive interactions between IE and host cells, including endothelium, but have also ranged from host genetic studies to clinical measurements of a wide range of systemic and local effectors. So, while we do not fully understand the pathology of CM and suspect that it may have multiple etiologies, we do know that it has some differences to, and some overlaps with, other brain inflammatory diseases and we have information about some of the potential contributions from the parasite and the host that could lead to CM.

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Cerebral malaria (CM) forms part of the spectrum of severe malaria, with a case fatality rate ranging from 15% in adults in southeast Asia [1] to 8.5% in children in Africa [2] . Clinical signs of acidosis carry a higher risk of death but nevertheless CM accounts for a significant proportion of malaria mortality, as well as the potential for neurological deficits in survivors. The standard clinical definition of CM centers on a state of unarousable coma partnered with the presence of malaria infected red blood cells in the peripheral circulation and a lack of other potential causes of coma such as other infections or hypoglycemia (for a full definition see [3–5]). More recently ophthalmic observations of retinopathy have been added to this definition in both adults and children to increase the specificity of the clinical diagnosis [6,7] . Most observations of the pathophysiology of disease come from postmortem observations of Plasmodium falciparum (Pf) infections, which are thought to account for the vast majority of CM cases, and show a common feature of vascular sequestration of infected erythrocytes (IE) in the brain [8] . There are also some differences, particularly between CM in adults and children, broadly separable into a ‘pure’ sequestration pattern and IE sequestration with variable (and moderate) vascular pathology. The latter varies from the accumulation of proinflammatory cells such as leukocytes and platelets to localized vascular damage (e.g., vessels partially denuded of endothelium) [9] . With the hallmark of IE sequestration for CM (albeit based on postmortem studies), investigations into the pathology of disease have looked at the

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Cerebral malaria is one of a number of clinical syndromes associated with infection by human malaria parasites of the genus Plasmodium. The etiology of cerebral malaria derives from sequestration of parasitized red cells in brain microvasculature and is thought to be enhanced by the proinflammatory status of the host and virulence characteristics of the infecting parasite variant. In this article we examine the range of factors thought to influence the development of Plasmodium falciparum cerebral malaria in humans and review the evidence to support their role.

Review

Future Microbiology

Cerebral malaria pathogenesis: revisiting parasite and host contributions

10.2217/FMB.11.155 © 2012 Future Medicine Ltd

Parasite contributions PfEMP1 & cytoadherence

When Pf merozoites invade red blood cells they remodel the host cell extensively through changes to the cytoskeleton and insertion of parasite-derived proteins into and onto the erythrocyte membrane (for review see [10]). One such protein, thought to be a major virulence factor in Pf, is the major variant surface antigen PfEMP1. Owing to its expression on the surface of the IE, this protein must undergo antigenic variation to escape host defense mechanisms and a complex mechanism exists to support this [11] . This variable presentation of PfEMP1 proteins to the host results in differences between parasite antigenic variants in the immune response that they provoke and in the repertoire of host receptors that erythrocytes infected with different variants can bind to (as well as the affinity of this binding) [12] . PfEMP1 is encoded by a family of var genes that can be characterized by sequence motifs at the 5´ promoter region and within the first Future Microbiol. (2012) 7(2), 1–xxx

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effect of these IE on the host. This is further complicated by findings that the rigidity of IE itself, caused most likely through the parasitederived modifications to the erythrocyte, is also associated with severe disease [25,26] . How might IE sequestration lead to pathology? Earlier considerations of this issue divided into two main hypotheses: mechanical obstruction of vessels and inflammation. More recently the boundaries between these categories have become blurred and it seems most likely that combinations of both of these processes are responsible for disease, and support for mechanical blockage being a significant factor has come recently from elegant observations of the mucosal microvasculature performed by Dondorp et al. [27] . What has become clear is that the binding interaction between IE and host endothelium is not a passive process and the engagement and adjacency for these cell types results in the activation of a range of activities ascribed to the binding interaction itself, biomechanical stimuli and the localized release of soluble or membrane-bound mediators [28–31] . Two major categories of endothelial ‘damage’ have been reported, namely a breakdown of the barrier function of the specialized blood–brain barrier (BBB) and apoptosis of ECs. BBB integrity has been shown in postmortem studies to be subtly disturbed during severe malaria resulting in some leakage from cerebral vessels [32] and further studies in vitro have supported the role of IE as well as host effector cells in this process [33–35] . Much of the latter work has used measurement of transendothelial electrical resistance in EC/IE coculture models, identifying transcriptional changes caused through this interaction [33] and, in some cases, alterations to the junctional proteins (e.g., ZO‑1 and occludin) at the EC–EC interface [36,37] . In terms of apoptosis, patient isolates have been shown to have variable apoptosis-inducing abilities, with a weak relationship between an increased induction of EC apoptosis by isolates taken from children with neurological manifestations [38] . In vitro work also supports the hypothesis that vascular damage may be caused by apoptotic destruction of the ECs, particularly in combination with platelets or microparticles [39–41] . It is possible that a balance exists between the triggering of apoptosis by the engagement of host receptors during cytoadherence and IE–EC apposition, and the ability of the IE to modulate this response [30] , with some of the highly localized vascular damage seen on postmortem of people dying of CM as micro-hemorrhages

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adhesive (DBL) domain. Analysis of these sequence tags has identified associations of specific subsets of var genes with severe disease [13–17] , supporting the idea that PfEMP1 is a virulence factor. For example, Warimwe et al. showed a positive correlation between Group A-like/cys2 (or Ups-A) var gene expression and impaired consciousness, reinforcing a number of studies that had suggested associations between Ups-A var gene expression in the invading isolate and severe malaria. This sequence variant type is also selected from parasite populations using sera from semi-immune children [18,19] , the same category that shows greater susceptibility to CM. The relationship is not exact and many Ups-A/cys2 type infections do not lead to CM or even other aspects of severe malaria, which probably reflects the requirement of particular host–pathogen combinations to drive specific disease patterns. However, in considering potential parasite pathogenic processes, the ability of IE to undergo a range of adhesive interactions with host cells has been a major area of study. Binding interactions between IE and host cells can be divided into three main categories: Cytoadherence (interaction with endothelial cells [ECs] or, in placental malaria, with the syncytiotrophoblast cells of the placenta);

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Rosetting (interaction with uninfected erythrocytes);

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Clumping (interaction with other IE via platelet bridges).

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The molecular basis for these interactions have largely been described (for review see [12]) although there is clearly scope for the identification of further host receptors. The picture emerging is a complex one with over 12 host receptors available to the parasite through its repertoire of PfEMP1 protein variants, used in different permutations and with varying affinities. Several studies have attempted to correlate specific binding activity with clinical outcomes through testing binding phenotypes of patient isolates. Rosetting and clumping have both been variably associated with severe malaria [20–23] but results for cytoadherence to endothelium have been variable with only one recent study showing a statistically significant association between higher binding to ICAM‑1 under flow assay conditions and CM [24] . Nor do these binding experiments explain how the sequestration of IE in the brain leads to CM and an explanation of this awaits further work on the processes leading to differential cerebral IE sequestration and the

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future science group

Cerebral malaria pathogenesis: revisiting parasite & host contributions

potentially being caused through a failure to control EC apoptosis by the parasite.

pathways such as apoptosis, BBB integrity and increased receptor expression.

Cytoadherence-related signaling pathways

Systemic & localized inflammation

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As well as interactions with endothelium, IE are also able to release mediators directly causing host effector cells (and ECs) to release a range of pro- and anti-inflammatory cytokines. Pf glycosylphosphatidylinositol is released during schizont rupture and is able to stimulate macrophages to release TNF and IL‑1 [50] , contributing to the systemic proinflammatory response seen during malaria infection. Pf glycosylphosphatidylinositol has been shown to increase expression of ICAM‑1, potentially increasing the recruitment of IE to the cerebral vasculature [51] , as well as inducing nitric oxide (NO) production [52] , although the link between NO and CM pathology is less clear. It is also able to induce limited apoptosis in some tissues [53,54] , although these have not included brain. The other major parasite component capable of directly stimulating the host immune system is the malaria pigment known as hemozoin (or hematin). Hemozoin is produced during the digestion of hemoglobin in the parasite digestive vacuole in order to detoxify the heme moiety and mediates a broad range of inflammatory and immunomodulatory activities (for review see [55]). The characteristic brown crystals of hemozoin are seen in a number of different phagocytic cells and appear to be able to persist despite the degradation pathways available within these cells. Hemozoin-containing monocytes and neutrophils have been found in greater numbers in adults dying of severe malaria compared with survivors [56] as well as children with CM [9,57] . Research on the role of hemozoin in inflammation has been complicated by the heterogeneity of experimental conditions, not the least being the source of hemozoin, either synthesized or natural. However it seems clear that it is able to induce the production of proinflammatory cytokines from a range of host cells contributing to the immunopathology of malaria, including CM. Hemozoin is also thought to be able to influence the adaptive immunity [58,59] , altering the ability of the host to make an effective response to infection. It is also involved in the inhibition of erythropoiesis and thereby to malarial anemia [60] . It has recently been suggested that the host fibrinogen bound to hemozoin is principally responsible for at least some of the proinflammatory stimulation seen [61] . A direct link with CM is harder to discern. The systemic proinflammatory response seen with

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Further evidence that the IE/EC interaction is not a passive one comes from various reports demonstrating the activation of signaling pathways. Receptor clustering during adhesive events is a common pathway for activation of signaling cascades and cytoadherence is able to mimic these events. IE binding via CD36 activates a Src-family kinase dependent MAP kinase pathway and this Src-family kinase activity is required for efficient cytoadherence such that treatment of EC with specific inhibitors was able to reduce IE binding [42] . The same group also showed that ectophosphorylation of CD36 itself, through a Src-family kinase/ alkaline phosphatase pathway, also controlled adhesion to this receptor [43] . This information has subsequently been used to support clinical intervention trials with the alkaline phosphatase inhibitor levamisole, which are currently underway [44] . Cerebral endothelium has low levels of CD36 that would not normally support IE adhesion so its relevance to CM has been questioned. In addition, higher levels of binding to CD36 have not been associated with CM, either being linked to non-CM severe malaria in one study [45] and to uncomplicated malaria in another [24] (exref #22). However, studies have shown that platelets and microparticles are able to act as a bridge to support adhesion to cerebral EC [46,47] and even to transfer CD36 to these cells [34] . Thus it is possible that CD36 may sometimes be available for adhesion in the brain, or alternatively supports efficient exponential parasite multiplication during the asexual growth phase indirectly contributing to subsequent pathology. ICAM‑1 is available for IE cytoadherence in the brain in the context of the widespread endothelial activation seen in CM and significant colocalization of this receptor (as well as CD36 and E‑selectin) has been seen with IE sequestration in adults [48] . IE are also able to activate host signaling by binding to ICAM‑1, via the MAP kinases ERK1/2, JNK and p38 [49] . The nuclear transcription factor NF‑kB is also implicated in cerebral cytoadherence, as demonstrated by transcriptional analysis of IE/brain EC coculture showing the differential expression of pathways controlled by NF-kB [31] . The full impact of these signaling changes on CM is not known but experiments have implicated a number of pathogenic

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Tie2 signaling system [83] . Ang1:Ang2 ratios have recently been identified as one of the best biomarkers for CM in African children [84] . In eCM, using the Plasmodium berghei ANKA (PbA) mouse model [85] , TNF [86] and IFN‑g [87] have been identified as important mediators of disease, and LTas being possibly the principal mediator responsible for the triggering of neuropathology [88] . Using an intervention approach, a recent confirmation of the role of cytokines in this model has been provided by the demonstration that CM can be induced in CM-resistant mice by inducing the endogenous secretion of proinflammatory cytokines. This was achieved by injections of CpG [89] . IFN‑g has clearly been shown to be central in eCM pathogenesis [87] , and several pathways can be triggered by this cytokine, notably IP‑10/CXCL10 [90] .A complication with many of these studies (in human and mouse systems) is the balance between protection and pathology elicited by the cytokine response. For example, experiments using the mouse model of eCM have determined that early production of this cytokine in the infection can be protective rather than deleterious [91] . Other host mediators of importance in eCM pathogenesis include histamine [92] , via its H(3) receptor [93] , complement, particularly C5a [94] , endothelin [95] and HO‑1 (reviewed in [96]). Aside from cytokines and noncytokine mediators, coagulation factors also participate in the triggering of pathology of eCM, as reviewed in [97] .

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hemozoin would directly support cytoadherence-mediated pathology and some evidence exists to support activation of matrix metalloproteinases (e.g., MMP‑9 [62]) that could cause vascular damage and induce morphological changes to endothelium [63] . The modulation of host protective responses could also have an indirect action via parasite multiplication and retention of parasite material in cerebral vessels. Endothelial activation appears to be strongly associated with CM [48,64] and the basis for this is likely to be multifactorial. Von Willebrand factor (vWF) is raised in CM [65,66] at the same time that ADAMTS13 activity, which is responsible for degrading the bioactive ultra-large vWF multimers expressed on the EC surface, is reduced [67–69] . Part of the mechanism responsible for this association may be the cytoadherence of IE to platelets decorating the ultra-large vWF expressed on the EC [47] , including brain tissues. Release of ultra-large vWF requires activation and mobilization of the Weibel-Palade bodies (for review see [70]), which can occur through several mediators including histamine. The malaria parasite Pf produces a protein, PfTCTP, which is a homolog for the mammalian histamine releasing factor and can induce histamine release from basophils [71] .

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Host contributions

For the sake of clarity, we will address findings in human CM (hCM) and those in experimental CM (eCM), separately.

Effector cells

More than half a century after Brian Maegraith’s original suggestions [72,73] that endogenous mediators have a pathogenic role in severe malaria, a body of evidence suggests that cytokines are involved in CM pathogenesis: reviewed in [74–76] . In hCM, high levels of such proinflammatory cytokines have been reported for more than two decades [77–79] , and confirmed by numerous groups [80] even if some reports suggest that there is no association with severity and that endothelial molecules might be more reliable [64] . In the human disease, at least in its in vitro modeling, attention has been drawn on the role of TF [81] and more recently vWF [47] . The latter seems crucial in the early steps of Pf cytoadherence, in a dynamic flow chamber setting [82] . In addition to the release of vWF, the activation of the Weibel-Palade body also influences local EC activation through release of Ang2 via the

In hCM, only a few intravascular leukocytes are seen in brain sections of CM2 patients [9,98] , but the potential role of these cells remains unknown. HIV‑1 positive subjects are at risk of developing severe malaria (reviewed in [99]) but, while it has been proposed that AIDS and CM do not influence each other [100] , the relationship between these two syndromes is exceedingly complex, as discussed in [101,102] . In eCM, the T‑cell dependency of the neurological syndrome is clear, involving both CD4 + [103,104] and CD8 + [105,106] T cells (reviewed in [74,107]). Histopathologically, in eCM the presence of leukocytes is more conspicuous than in hCM, but no CD8 T‑cells are visible locally, yet CD8 depletion prevents eCM [97] . The issue of Tregs in eCM has been addressed by Engwerda’s team [108] , who showed that CD4 + CD25 + regulatory T cells suppress CD4 + T‑cell function

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Leukocytes



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In African patients with hCM, platelets have been found to accumulate in brain vessels, but not in cases of severe malarial anemia or coma of other causes [98] . This intravascular accumulation has been recently confirmed at the level of CM-associated retinopathy [113]. In eCM, platelets are found to accumulate in organs before these show lesions, as revealed by radiolabeled platelet localization experiments [114] , and intervention experiments have demonstrated that they are involved in pathology (reviewed in [115]). Furthermore, intravascular platelets are detectable by the laser-induced breakdown spectroscopy technology even before microvascular dysfunction can be detected by MRI [116] . These in vivo data have been analyzed in further detail in vitro, using mouse EC [117] , as well as human [39] EC, cocultures, notably disclosing the importance of the release of TGF‑b1 by platelets [118] . More recently, using an in vitro model of human CM, it was found that platelets can trigger a number of EC genes [119] involved in inflammation and apoptosis, such as genes involved in chemokine, TREM1, cytokine, IL‑10, TGFb, death-receptor and apoptosis signaling.

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has been shown in vitro, using human cells [126] . The effect of these direct interactions is amplified by the cascade of inflammatory reactions discussed in the ‘Mediators: cytokines & coagulation factors’ and ‘Effector cells’ sections. Associated with this, a number of endothelial functions become altered [34] , notably permeability, leading to brain edema, which can be mild in adult CM [127] and more pronounced in pediatric CM [128] . In this respect, eCM reproduces the type of brain edema seen in pediatric rather than adult hCM, as evidenced by MRI [129] , including at the eye level [130] and by quantitative immunohistochemistry [131] . The latter study showed a marked upregulation of aquaporin 4 on astrocytic foot processes in eCM, a finding that has recently been found marginally modified in hCM, in adults where brain edema does not appear to be the cause of death [132] . However, even if brain swelling is found in adult patients with CM, simple therapeutic measures against brain edema, such as mannitol do not protect against the neurological syndrome, and may even be harmful [133] . Therefore, fine mechanisms leading to brain edema need to be investigated in more depth. Angiogenic dysregulation in severe malaria has been substantiated by the demonstration of altered levels of VEGF, soluble VEGFR‑2 [134] , and Ang2 [135] . Howver, studies differ in recording an increase or decrease in VEGF, perhaps owing to differences in the clinical groups being considered. In specific comparisons of hCM from India, VEGF was reduced in plasma from patients with hCM compared with mild malaria cases and healthy controls, and further reduced in patients dying from hCM [136] . Yeo et al. have suggested that the increase in endothelial activation marked by increasing levels of Ang2 could be owing to reduced bioavailability of NO, which in turn may result from a reduction in its precursor, l‑arginine. It is possible that the sequestered IE may cause this reduction through the release of arginases on schizont rupture. They showed that endothelial function, measuring reperfusion by reactive hyperemiaperipheral arterial tonometry [137] , was reduced in severe malaria and subsequently demonstrated that this deficiency could be partially rectified by the infusion of l‑arginine [138] . Most likely is that a subtle balance between positive and negative regulation of endothelial functions contributes to the endothelial pathology of CM, as discussed elsewhere [139] . Interestingly, an association has been found between susceptibility to CM development and

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and inhibit the development of P. berghei-specific Th1 responses involved in eCM pathogenesis [109] . More recently, however, in 2010, Haque et al. demonstrated that in vivo expansion of Treg by using IL‑2/anti-IL‑2 complexes prevents eCM [110] . In African patients, Treg deficiency appears to be protective and Treg cells have been found to be increased in patients with hyperparasitemia, therefore immune (or inflammation-based) pathology is clearly important in human severe malaria, including hCM [111,112] . The involvement of monocytes in eCM has been reviewed [74] .

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ECs: both targets & effectors in CM

Severe malaria is characterized by a pleomorphic endothelial cell (EC) activation. While studying various aspects of EC changes in relation to tissue damage, we showed that IE, together with host cells, leads to profound endothelial alterations [120] . In turn, EC can trigger immunopathological changes, as detailed in [121] . Among others, we identified miRNAs able to regulate ECs that are modulated in murine CM but not in uncomplicated malaria [122] . A central feature of endothelial changes in CM is activation [123–125] , resulting from the direct contact with IE, as discussed in the ‘Parasite contributions’ section, or with leukocytes, as future science group


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endothelial reactivity to cytokines [140] , as had been suggested in the CM model [141] . The endothelial hyper-reactivity notably included the production of membrane microparticles, which are found in dramatically high numbers in patients with hCM [40,41,142] and could be novel players of disease pathogenesis, as reviewed extensively in [120,143–145] . Repercussions on brain parenchyma Glial changes

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In hCM, alterations of glial cells have been studied in tissues from patients as well as in culture systems. As integral constituents of the BBB, astrocytes can show signs of dysfunction as a result of the IE sequestration. In patients with CM, several aspects of microglial activation have also been reviewed [146] . In vitro, soluble factors from Pf induce apoptosis in human brain vascular endothelial and neuroglia cells. More DNA fragmentation is found in brain EC than in neuroglia, suggesting that extended exposure to high levels of these soluble factors in circulation is critical [147] . In eCM, similar glial changes, involving both astrocytes and microglial cells have been reported. The potential consequences of glial activation, notably glial-derived proteinases, in structural damage of the CNS have been reviewed in detail [148] . Among the inflammatory mediators, selected chemokines are dramatically upregulated in microvessels and adjacent glial cells [149] .

early changes not only in the optic but also the trigeminal nerves. Cranial nerve injury was the earliest anatomic hallmark of the disease, visible even before brain edema became detectable [130] . The overproduction of IFN‑g, whose crucial role in ECM has been shown [87] , can increase expression of the heme enzyme indoleamine 2,3-dioxygenase in microvascular ECs. Raised indoleamine 2,3-dioxygenase levels leads to increased production of a range of biologically active metabolites that may be part of a tissue protective response. Damage to astrocytes may result in reduced production of the neuroprotectant kynurenic acid, leading to a decrease in its ratio relative to the neuroexcitotoxic quinolinic acid. This imbalance may contribute to some of the neurological signs of human and experimental CM, as reviewed in Hunt et al. [154] . Reactive astrocytes also can show expression of a molecule that was thought to be a neuronspecific, hypoxia-responsive and neuroprotective protein: neuroglobin was found to be present, aside from neurons, in reactive astroglia and in scar-forming astrocytes in various neuropathological conditions, including CM [155] . CM is a complex pathology that illustrates the impact and the role of endothelial, glial and neuronal cells in the process. The global role of the neurovascular unit, considered as a whole or as an organ is discussed elsewhere [Grau et al. Manuscript in preparation] .

Neuronal

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In hCM, immunohistochemistry has been used to identify a variety of cellular stress and injury responses in the brains of patients with fatal falciparum malaria. Oxidative stress predominated in the vicinity of vessels and hemorrhages. Some degree of DNA damage was found in the majority of malaria patients, but staining patterns suggest considerable stress response and reversible neuronal injury [150] . Both axonal and astrocytic injury markers, the tau protein and S‑100B, respectively, have been found in elevated concentrations in CSF samples from CM patients [151] . A disruption of axonal transport was further demonstrated by detection of µ- and m‑calpain, the specific inhibitor calpastatin, in postmortem brain tissue from patients who died from severe malaria [152] . The first evidence for a loss of axonal viability in eCM and the first demonstration of optic nerve involvement was provided by Ma et al. [153] . Recently, MRI in this model revealed very

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Behavioral/cognitive changes

The development of neurological sequelae after hCM has long been recognized and have been recently characterized in detail. It was found that Kenyan children have neurocognitive impairments that are evident as long as 9 years later [156,157] . Potential cognitive rehabilitation solutions such as cognitive exercises, environmental enrichment, nutritional supplementation, physical therapy and speech therapy have been proposed [158] . In Ugandan children, a computerized cognitive training program 3 months after severe malaria had an immediate effect on cognitive outcomes but did not affect academic skills or behavior [159] . In addition to previously described neurological and cognitive sequelae, severe behavior problems may follow CM in children, including ADHD. In another study in Ugandan children, observed differences in patterns of sequelae may be owing to different pathogenic mechanisms, brain regions affected or extent of injury [160] . In eCM, inflammatory changes in the CNS are also associated with behavioral impairment future science group


Conclusion

Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.

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It seems likely that the pathologies underlying CM in humans are highly variable and reflect a range of attributes, including parasite virulence, host susceptibility and comorbidities ranging from malnutrition to coinfection.

Understanding the contribution of these components using all the tools at our disposal will be essential to the development of new antidisease interventions aimed at reducing the mortality and postinfection morbidity associated with cerebral malaria.

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in P. berghei (strain ANKA)-infected mice 2010 [161] . As there is evidence that these behavioral changes may be due to – or at least associated with – oxidative stress, as assessed by elevated levels of malondialdehyde and conjugated dienes in the brains of PbA-infected C57BL/6 mice with CM, antioxidant treatment was evaluated as adjunct therapy. PbA-infected C57BL/6 mice with additive antioxidants together with chloroquine at the first signs of CM prevented the development of persistent cognitive damage [162] .

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