Neurological involvement in malaria

CM is 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 malarial parasites on peripheral blood smears, and exclusion of other causes of encepha-lopathy [137].

Energy depletion and cerebral oedema

A relatively consistent feature of acute CM in children is raised intracranial pressure (ICP). Studies in African children have demonstrated a raised cerebrospinal fluid (CSF) opening pressure during lumbar puncture in 80% of CM children [138], raised ICP during intracranial pressure monitoring

(23/23 ICP > 10 mmHg) [139]and papilloedema (a late sign of raised ICP) in 44% of CM patients who died [140]. Where computer tomography has been performed, there was evidence of diffuse brain swelling in 40% of patients [139]. The cause of the raised ICP is likely to be multi-factorial and has been postulated to involve both vasogenic and cytotoxic patterns of cerebral oedema.

Vasogenic oedema is characterised by accumulation of interstitial fluid within the brain secondary to increased permeability of the blood-brain barrier (BBB). It has been demonstrated in bacterial cerebral infections, but evidence of significant disruption of the BBB is not conclusive in CM [141]. Others have proposed that ICAM-1 binding by infected erythrocytes may generate a cascade of intracellular signalling events that disrupt the cyto-skeletal-cell junction structure and cause focal disruption to the BBB [142]. Adult post-mortem analysis has shown cerebrovascular endothelial cell activation (increased ICAM-1 endothelial staining, reduction in cell junction staining, and disruption of junction proteins), particularly in vessels containing infected erythrocytes [143]. However, disruption of intercellular junctions is not associated with significant leakage of plasma proteins (fibrinogen, IgG, or C5b-9) into perivascular areas or CSF [143]. In Thai adults, transfer of radioactively labelled albumin into CSF was not raised during unconsciousness compared with convalescence [144]. Similarly, the albumin index (ratio of concentrations of albumin in CSF to those in blood) was not altered significantly in Vietnamese adults [145] or significantly different between Malawian children with CM who died and those who survived [143].

Cytotoxic oedema is increasingly being recognised as an important mechanism of cerebral oedema in traumatic brain injury [146]. As previously discussed, this type of cell swelling involves disturbance of the "pump-leak equilibrium" maintained, under physiological conditions via active elimination of osmotically active solutes through the energy-dependent Na+/K+-ATPase. Thus, cytotoxic oedema can occur secondary to an imbalance in supply and demand of energy within the cells. Several mechanisms, such as sustained increase in neuronal activation, impaired substrate delivery (structural and functional) and impaired mitochondrial utilisation of available substrates, including oxygen, may coexist to generate this imbalance. All these mechanisms could contribute to ATP depletion and Na+/K+ ATPase failure, leading to cytotoxic oedema in CM.

CM is clearly associated with increased neuronal activity. A recent review identified that 80% of African children with CM have a history of seizures, with prolonged and recurrent seizures associated with a poor outcome [147].

Impaired vascular flow during acute CM may limit substrate delivery within the brain and contribute to energy imbalance. In the past, a common premise was that parasite sequestration precipitated cerebral vaso-occlu-sive/ischaemic (i.e. stroke-like) events that manifested clinically as CM. However, CM demonstrates several features that are atypical for stroke. In children, focal neurological signs do not tend to accompany coma, although a sub-set of patients do exhibit hemiparesis or focal brainstem deficits during the agonal period [148]. The incidence of residual neurological deficits following recovery from coma is relatively low (11% [147]) when compared to childhood stroke (93% had residual neurological deficit [149]). Where computer tomography has been performed in children, diffuse brain swelling was observed [150] rather than focal lesions more typical of stroke. Although retinal haemorrhages have been observed in 46% of Malawian children with CM (and in 63% of patients who died), these lesions were also seen in 30% of children with SMA in the same study [140]. Consequently, although associated with CM, retinal haemorrhages do not confirm that focal cerebral vaso-occlusive/ischaemic events underlie CM. Similarly, his-tological examination of 32 fatal CM cases of African children at autopsy demonstrated that one third had little or no evidence of local vascular change in the brain, as indicated by sequestered parasites, monocyte clusters, micro-haemorrhages, local vascular iNOS [151] or haemoxygenase -1 (HO-1) [152] staining. Accepting that CM may occur without ischaemia does not exclude temporary or less severe reductions in vessel flow occurring during acute CM (associated or independent of parasite sequestration) that may contribute to impaired substrate delivery and lead to energy imbalance.

As previously discussed, energy imbalance may also be impaired due to the uncoupling action of inflammatory cytokines on mitochondrial ATP production. In Gambian and Ghanaian children, concentrations of TNF and its receptor were higher in those with CM than in those with mild or uncomplicated malaria [153, 154]. Polymorphisms in the TNF promoter region have also been associated with increased risk of CM and death [155] or neurological sequelae [156]. Cytokines may also up-regulate iNOS in brain endothelial cells, increasing production of NO, which could then diffuse into brain tissue and disrupt neuronal (and/or mitochondrial) function [157, 158].

In the brain, mitochondrial function may also be influenced by neuronal excitotoxins. Within the simplified model of dissociated neuronal culture, mitochondria appear to play a critical role in neuronal homeostasis during excitotoxin exposure. Mitochondria are not only involved with maintaining ATP production but also calcium homeostasis, and generation and detoxification of reactive oxygen species [107]. Excitotoxin production may also be influenced by cytokine release. TNF administration has been shown to alter brain metabolism of tryptophan to produce more kynurinine [159, 160]. Thus, as part of a general inflammatory reaction, increased excitotoxin generation during acute malaria may contribute to cellular energy imbalance. Elevated levels of neuronal excitotoxins (quinolinic and picolinic acid) in the CSF have been associated with a fatal outcome in Malawian children with CM [161]. Similarly, a graded increment of quinolinic acid concentration in CSF was observed across patient outcome groups of increasing severity in African children [162].

Encephalopathy with systemic inflammation but without sequestration

Although a subset of the Malawaian autopsy patients [163] demonstrated negligible histological change in their brains, they did demonstrate inflammation, as indicated by iNOS, MIF [151] and HO-1 [152], staining in other tissues. These systemic changes were shared with the comatose sepsis cases in the study, and therefore are consistent with the premise that coma may in part be secondary to a host inflammatory response to systemic infection. Below are further examples of systemic responses to infection that present with diffuse cerebral syndromes, including coma.

Cerebral malaria manifesting with P. vivax infection

In the past, the term CM has been restricted to falciparum malaria, and patients with P. vivax infection exhibiting symptoms of severe malaria, including coma, have been dismissed as undiagnosed falciparum co-infections. However, the use of more sensitive diagnostic techniques makes such dismissal less tenable. Two such studies report adults exhibiting severe malaria with P. vivax (but not P. falciparum) infection detectable on PCR and serological and testing [142, 143]. The patients exhibited multiple organ failure including cerebral symptoms, renal failure, circulatory collapse, severe anaemia, haemoglobinuria, abnormal bleeding, acute respiratory distress syndrome, and jaundice. Vivax malaria has been associated with a strong systemic inflammatory response [164], but this was not investigated in the above studies.

Sepsis-associated encephalopathy

Sepsis-associated encephalopathy (SAE) syndrome has multiple features that resemble CM. It is characterised by a diffuse disturbance of cerebral function (typically impairment of consciousness) that occurs in the context of systemic response to infection without direct neuroinvasion (i.e. meningitis, macroscopic cerebritis and brain abscesses are excluded). SAE is associated with generalised slow waves on the electroencephalogram (EEG), with the depth of coma linked with mortality. Mild SAE cases often recover completely, while survivors of severe SAE may have persistent neurological deficit [165]). In line with adult CM, the severity of encephalopathy parallels the severity of systemic organ failure [141]. Inflammatory cytokines have been demonstrated to be higher in the serum than in the CSF, suggesting that sepsis encephalopathy is a consequence of the systemic inflammatory response to infection [141]. An animal model in which prior administration of a neutralising antibody to TNF prevented the sepsis encephalopathy of pancreatitis [166] is consistent with this. Further postulated reversible

Table 3.

Influenza encephalopathy Cerebral malaria

Table 3.

Influenza encephalopathy Cerebral malaria

Seizures/coma after high grade fever

+

+

Metabolic acidosis

+

+

Hyperlactataemia

+

+

Serum TNF, IL-6, sTNFRI up

+

+

Serum nitrite/nitrate up

+

+

CSF TNF, IL-6, sTNFRI up

+

+

Multiple organ failure

+

+

Residual neurological deficit

+

+

Thrombocytopaenia

+

+

Damage to vascular endothelial cells

+

+

Brain oedema/damage to BBB

+

+

Apoptosis in neurons/glial cells

+

+

Evidence of active caspase-3 (brains)

+

+

Caspase-cleaved PARP (brains

+

+

mechanisms of pathogenesis include changes in regional cerebral blood flow, neurotransmitter imbalance, mitochondrial dysfunction, BBB impairment and oxidative stress [167].

Influenza encephalopathy

Severe influenza infection can present with encephalopathy, yet as in malaria, the pathogen is not neuroinvasive [168]. Seizures and coma occur after high fever [169], commonly accompanied by thrombocytopaenia [169], with metabolic acidosis and hyperlactataemia in severe cases (T. Ichiyama, personal communication). Similar to adult malaria, neurological sequelae occur concurrently with multiple organ failure [170]. TNF, IL-6, sTNFRI, and soluble E-selectin are increased in serum and CSF [171, 172], and serum nitrite/nitrate levels are increased [173]. Detailed examination of brain has revealed apoptosis of neurons and glial cell, histological evidence of active caspase-3 and caspase-cleaved PARP, cerebral oedema, and BBB impairment [174]. These parallel changes are set out in Table 3. It is clear, therefore, that the presence of sequestering parasitised red cells is not necessary to generate these changes, which are also demonstrable in the falciparum malaria encephalopathy. Notably, high levels of inflammatory cytokine are present in each disease.

Seizures and malaria

Seizures are a very common component of acute malaria illness in children. A recent review documented that 80% of African children had a history of seizures, with 60% exhibiting seizures during hospital admission [175]. The molecular basis of the seizures is unclear. Multiple mechanisms have been postulated, including fever, hypoxia and/or cytokine stimulation leading to an imbalance of neurotransmitters and excitotoxins or neuronal damage [11, 148]. Recently, Lang and co-workers [176] demonstrated that falci-parum parasitaemia is associated with the generation of specific antibodies for voltage-gated calcium channels directed against neurones. Higher antibody concentrations were detectable in sera from patients exhibiting CM or malaria with seizures than uncomplicated malaria, suggesting that these antibodies may influence seizure propensity.

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