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Pathophysiology, clinical presentation, and treatment of coma and acute kidney injury complicating falciparum malaria

Plewes, Katherine a,b ; Turner, Gareth D.H. c,d ; Dondorp, Arjen M. a,d

a Faculty of Tropical Medicine, Mahidol Oxford Tropical Medicine Research Unit, Mahidol University, Bangkok, Thailand

b Division of Infectious Diseases, Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada

c Department of Cellular Pathology, John Radcliffe Hospital

d Nuffield Department of Clinical Medicine, Center for Tropical Medicine and Global Health, University of Oxford, Oxford, UK

Correspondence to Katherine Plewes, Clinical Investigator, Mahidol-Oxford Tropical Medicine Research Unit (MORU), Clinical Assistant Professor, UBC Division of Infectious Diseases, Heather Pavilion East 452D, Vancouver General Hospital, 2733 Heather Street, Vancouver, British Columbia, V5Z 3J5, Canada. Tel: +1 604 875 4588; fax: +1 604 875 4013; e-mail: [email protected]

This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0

Purpose of review 

Cerebral impairment and acute kidney injury (AKI) are independent predictors of mortality in both adults and children with severe falciparum malaria. In this review, we present recent advances in understanding the pathophysiology, clinical features, and management of these complications of severe malaria, and discuss future areas of research.

Recent findings 

Cerebral malaria and AKI are serious and well recognized complications of severe malaria. Common pathophysiological pathways include impaired microcirculation, due to sequestration of parasitized erythrocytes, systemic inflammatory responses, and endothelial activation. Recent MRI studies show significant brain swelling in both adults and children with evidence of posterior reversible encephalopathy syndrome-like syndrome although targeted interventions including mannitol and dexamethasone are not beneficial. Recent work shows association of cell-free hemoglobin oxidation stress involved in the pathophysiology of AKI in both adults and children. Paracetamol protected renal function likely by inhibiting cell-free-mediated oxidative stress. It is unclear if heme-mediated endothelial activation or oxidative stress is involved in cerebral malaria.

Summary 

The direct causes of cerebral and kidney dysfunction remain incompletely understood. Optimal treatment involves prompt diagnosis and effective antimalarial treatment with artesunate. Renal replacement therapy reduces mortality in AKI but delayed diagnosis is an issue.

INTRODUCTION

Severe malaria incidence is approximately two million cases with nearly 430,000 deaths annually [1] . It is a medical emergency characterized by multisystem disease with different clinical manifestations between adults and children. However, recent studies show that cerebral involvement, kidney dysfunction, and acidosis are independent predictors of mortality in both adults and children ( Fig. 1 ) [2,3] . This is supported by a meta-analysis of children with severe malaria that found prognostic indicators with the strongest association with death to be acute kidney injury (AKI) (odds ratio 5.96, 95% confidence interval, CI: 2.9–12.11) and coma (4.83, 95% CI: 3.11–7.5) [4▪▪] .

Cerebral malaria is a clinical syndrome of impaired consciousness associated with malaria in the absence of hypoglycemia, convulsions, drugs, and nonmalarial causes characterized by unrousable coma defined by a Glasgow Coma Score less than11 (adults) [5] or Blantyre Coma Score less than 3 (children) [6–8] . Two large intervention trials in Asian adults and African children with severe malaria found that 54% of adult and 34% of pediatric patients had cerebral malaria [9,10] . AKI in severe falciparum malaria is caused by acute tubular necrosis and defined as a creatinine more than 265 μmol/l or urea more than 20 mmol/l [6] . In adults with severe malaria, AKI develops in up to 40% of patients, whereas in children, the incidence is historically reported at approximately 10% [9,10] . As the WHO definition does not define AKI adequately for pediatric malaria, the reported incidence of AKI in children is likely underestimated. The recent Kidney Disease: Improving Global Outcomes (KDIGO) classification standardizes AKI for clinical practice and research [11] . In adult severe malaria, 58% had AKI as defined by KDIGO, of whom 40% died, accounting for 71% of overall mortality [12▪] . Among children with severe malaria 46% had AKI as defined by KDIGO, of whom 12–24% died with increasingly severe AKI [13▪] . In two large multicenter studies, approximately 25% of children with severe malaria had increased blood urea nitrogen, accounting for roughly 50% of total deaths [10,14] . These studies imply that AKI complicating pediatric severe malaria has been previously underdiagnosed [13▪] .

Notably, the majority of patients surviving these complications have complete recovery after appropriate treatment. The direct cause of coma and AKI complicating severe malaria are incompletely understood but likely share common pathophysiological mechanisms. This review will highlight recent developments in our understanding of the pathophysiologic and pathologic processes associated with cerebral malaria and malaria-associated AKI in addition to the clinical presentation, diagnosis and treatments of these complications.  

PATHOGENESIS

Severe malaria is predominantly caused by Plasmodium falciparum because of its ability to induce infected red blood cell (RBC) cytoadherence to the vascular endothelium and consequent end-organ dysfunction. Other plasmodium species can cause severe disease and AKI [15] , although their ability to cause coma is debated [6] .

Microvascular obstruction

Parasites developing within the infected RBC transport P. falciparum erythrocyte membrane protein 1 ( Pf EMP1) to the RBC membrane functioning as a key ligand for cytoadherence [16] . Pf EMP1 is expressed on RBC protrusions, or ‘knobs’, that confer points of attachment to the endothelium. Pf EMP1 is strain specific, encoded by a highly variable var gene family, which provides antigenic variation for immune evasion and differential endothelial receptor binding. CD36 is an endothelial receptor constitutively expressed on most vascular beds [17] . The key endothelial receptor in the brain is intercellular adhesion molecule-1 [18] . Recent studies have identified endothelial protein C receptor as an important receptor in the brain that binds to a specific Pf EMP1 domain (CIDRα1) [19▪,20–22] . Cytoadhesion results in sequestration of parasitized RBCs in the capillaries and postcapillary venules causing heterogeneous blockage of the microcirculation and tissue hypoxia [23] . In addition to flow obstruction by sequestered parasitized RBCs, microcirculatory flow is thought to be further compromised by increased rigidity of both infected and uninfected RBCs and clumping of infected RBCs (platelet-mediated autoagglutination) and uninfected RBCs adhering to infected RBCs (rosette formation) [24] .

Direct visualization of microvascular obstruction is observed in the retina of adults and children with cerebral malaria, termed ‘malaria retinopathy’ [25,26] . Cerebral blood flow is not decreased in adults [27,28] . Intracranial pressure is often increased in children, but less so in adult patients [29,30] . Indirect assessment of sequestration via estimated total parasite biomass, measured by P. falciparum histidine rich protein 2, was shown to contribute to AKI in adults with severe malaria [31] . Autopsy studies of adults and retinopathy-positive children dying from cerebral malaria show prominent sequestration in the brain microvasculature compared to adults with fatal noncerebral malaria and retinopathy-negative children [32,33] . Postmortem studies report sequestration of parasitized RBCs in renal glomerular and peritubular capillaries in adults and children [32,34] .

Endothelial activation

Microvascular obstruction-induced tissue hypoxia is compounded by microvascular dysfunction [35,36] and increased oxygen demand [36,37] . In adults with cerebral malaria, there is endothelial and astroglial activation in the brain [18] , with variable inflammatory responses [38] and mild functional change to the blood–brain barrier [39,40] . In children with strictly defined retinopathy-positive cerebral malaria, breakdown of the endothelial barrier is observed particularly in areas of sequestration [32] . Patterns of histopathological change within the brain in cerebral malaria vary between adults and children, with less inflammatory cellular infiltrates and edema in adult cases [41,42] . A recent pediatric autopsy study found that HIV coinfection influences histopathology, increasing the degree of platelet and monocyte infiltration around damaged microvasculature [43] .

In a recent MRI study of similarly defined children, 35% had evidence of brain swelling most commonly in fatal cases implicating brainstem herniation as the cause of death [44] . Another recent serial MRI study in India including adults and children found that 50% of patients had evidence of brain swelling with posterior vasogenic edema and vascular congestion in the basal nuclei [45▪] . All patients had rapid clinical improvement and radiological reversibility with hallmarks suggestive of posterior reversible encephalopathy syndrome. The exact cause of the brain swelling is yet unclear.

Studies of patients with severe malaria having AKI show reduced renal cortical blood flow [46] , increased kidney size [47] , and endothelial changes in both glomerular and peritubular capillaries on histopathology [34] . Cell-free hemoglobin and lipid peroxidation markers are strongly associated with AKI and renal replacement therapy (RRT) requirement in adults with severe malaria [12▪] . In children with severe malaria, an elevated heme-to-hemopexin ratio was associated with hemoglobinuria, stage 3 AKI, and 6-month mortality [48▪] .

There is an imbalance of proinflammatory and anti-inflammatory responses in severe malaria [49] . The role of cytokines and chemokines in cerebral malaria has been recently reviewed [50] . However, many of these studies are in the murine experimental cerebral malaria model, the relevance of which has been questioned [51] . Conflicting evidence has emerged from human studies as to the association between cerebral malaria and levels of numerous cytokines such as tumor necrosis factor α (TNFα) [49,52–56] . Although cytokines and/or chemokines are clearly involved in the pathogenesis of malarial fever and may be associated with disease severity and/or cerebral malaria, it is not established that they are a cause of coma.

The role of cytokines and chemokines in the pathophysiology of AKI in severe malaria was recently highlighted. Plasma-soluble urokinase-type plasminogen activator receptor, a marker of immune activation, was independently associated with AKI and RRT requirement [31] . Previously, it was shown that TNFα, but not inteleukin (IL)6 or IL6:IL10 ratio, was associated with AKI suggesting that TNFα may induce localized renal tubular cell injury [57] .

CLINICAL FEATURES

The clinical presentation of cerebral malaria is diffuse symmetrical encephalopathy with fever and absent or few focal neurological signs. In children, coma can rapidly develop after fever onset (mean, 2 days) [7] . In adults, coma is typically gradual with increasing drowsiness, confusion, obtundation, and high fevers (mean duration, 5 days). Convulsions are present in approximately 15% of adults and 80% of children with severe malaria [9,10] and frequently herald development of coma. Patients may recover full consciousness after a convulsion, thus transient postictal coma must be excluded [6] . Multiple convulsions are common and up to 50% of comatose children have subclinical seizures or status epilepticus. Ocular funduscopic findings include vessel color change, macular and extramacular whitening, and white-centered retinal hemorrhages [58] ( Fig. 2 ).

Among survivors, the median time to coma recovery is roughly 24 h in children and 48 h in adults [9,10] . Retinal abnormalities resolve with no residual visual deficit. Neurologic sequelae occur in less than 1% of adults but up to 12% of children in the quinine-therapy era, including hemiplegia, cortical blindness, aphasia, and cerebellar ataxia [59] . Studies suggest that neurologic deficits may reflect slow neurological recovery [10,60] . Postmalaria neurological syndrome is self-limiting [61] ; however, longer term neurological sequelae, including cognitive deficits and epilepsy, are reported among children [62,63▪] .

• (1) Few severity criteria with prerenal AKI that resolves with fluids.
• (2) Several severity criteria including AKI that resolves without RRT.
• (3) Progressive AKI that resolves with antimalarial treatment and RRT.
• (4) Multiorgan dysfunction, often with anuric AKI and cerebral malaria, who die prior to or during RRT with hemodynamic shock and/or respiratory failure.

Any comatose patient with a history of fever and/or travel to malaria-endemic regions must be considered to have cerebral malaria until proven otherwise. In children, febrile convulsions should be distinguished from cerebral malaria, wherein coma will persist beyond 1 h after anticonvulsive treatment is administered. Absence of fever does not rule out malaria. Antimalarial treatment should not be delayed in severely ill patients if diagnostics are unavailable or delayed.

Parasitological diagnosis is by microscopy of stained thin and thick blood smears. A rapid diagnostic test for parasite antigens can be performed if microscopy is unavailable. Patients may have a low circulating parasitemia because of sequestration, thus a low parasitemia is not reassuring [67] . In high-transmission settings, children with partial immunity tolerate higher parasitemia without severe symptoms and may be asymptomatic at low parasitemia. A parasitemia of more than 1 000 000/μl in African children with cerebral malaria is associated with fatal outcomes [7] .

Funduscopy for malaria retinopathy improves specificity for diagnosis of cerebral malaria and is prognostic in patients with severe malaria [26,68,69] ( Fig. 2 ). Alternative causes of coma must be ruled out including hypoglycemia, and bacterial, fungal, or viral meningoencephalitis. Lumbar puncture does not increase mortality in stable, comatose children with suspected cerebral malaria even when MRI brain swelling or papilledema is present [70▪] .

There is no robust prognostic risk model or biomarker that can predict AKI or RRT requirement [71,72▪] . All patients with malaria should be considered at risk of developing AKI. To improve outcomes, early diagnosis and management is critical. AKI diagnosis requires quantification of creatinine (or urea) or observing low urine volume (<0.5 ml/kg/h) for 6 h ( Fig. 3 ) [6,11] . Urine output is difficult to accurately assess in malaria endemic countries and may delay diagnosis. As the WHO creatinine threshold is not applicable to children, the diagnosis of AKI must be considered using all available patient data. The KDIGO AKI definition of a creatinine rise at least 1.5 times baseline is the current standard, and baseline creatinine can be back-calculated using the Modified Diet in Renal Disease (>19 years) or Swartz equation (≤18 years) [11,73] .

The two key pillars of severe malaria treatment are prompt antimalarial treatment and supportive management. Adjunctive therapies targeted at the underlying pathophysiology are unproven.

Antimalarial treatment

Two landmark trials in patients with severe malaria definitively showed that intravenous artesunate reduced mortality by 35 and 23% in adults and children, respectively, compared to quinine [9,10] . Intravenous artesunate is now the first-line treatment for severe malaria as recommended by the WHO. Artemether and quinine are the second-line therapies [74] . The mechanism of improved survival over quinine is the rapid cidal activity of artesunate on young ring forms, preventing parasite maturation and sequestration [75] . Once the patient is able to take oral medication, and after a minimum of 24 h of artesunate, an oral artemisinin-based combination therapy can be initiated to complete the treatment.

Supportive treatment

Despite the best available artemisinin therapy for malaria, mortality remains unacceptably high and supportive management is key to reducing this. Comatose patients require endotracheal intubation with mechanical ventilation for airway protection. Rapid sequence intubation should be performed to prevent transient hypercapnia and increased intracranial pressure. Routine care should be implemented including regular turning, lateral positioning (‘recovery position’), and catheterization. Nasogastric tube insertion and suctioning may protect against aspiration, however, enteral feeding in nonintubated patients should be delayed (>60 h) because of increased risk of aspiration pneumonia [76] .

The majority of children with cerebral malaria experience convulsions. Glucose replacement to ensure euglycemia and fever control with paracetamol are important. Prophylactic anticonvulsant therapy is not recommended. A randomized controlled trial (RCT) of phenobarbital in pediatric cerebral malaria showed increased mortality, likely caused by respiratory depression [77] .

Fluid management and nephrotoxic drug avoidance are cornerstones for management of malaria-associated AKI. Cautious fluid management is important, as patients with AKI are not necessarily hypovolemic and are at high risk of developing pulmonary edema [78–81] . Rapid infusions may exacerbate intracranial hypertension and precipitate cerebral herniation. The large multicenter Fluid Expansion as Supportive Therapy study of African children with severe febrile illness showed a relative risk for death of 1.59 (95% CI: 1.10–2.31) with fluid bolus therapy among those with malaria [14] . The WHO recommends individualized restrictive fluid management, keeping the patient slightly dry, using slow infusion of isotonic crystalloids [74] . Patients with BWF require creatinine and hemoglobin monitoring as resulting severe anemia requires whole blood transfusion.

Treatment of malaria-associated AKI with RRT reduces mortality from 75 to 26% [64] . In general, RRT is urgently indicated when biochemical disturbances and volume overload refractory to conventional therapy are present. The additional thresholds included in the WHO malaria guidelines are based on findings that anuria and elevated or rapidly rising creatinine are sensitive indicators for RRT [6,64] . As AKI in malaria rapidly progresses and is often compounded by multiorgan dysfunction, early RRT is recommended. Although intermittent hemodialysis and continuous venovenous hemofiltration have been shown to be superior to peritoneal dialysis in adults with severe malaria [82] , in the absence of hemodialysis, life-saving peritoneal dialysis should be initiated if this is the only modality available [83] . RRT has also been shown to be effective in the management of malaria-associated AKI in pediatric patients [84] .

Many adjunctive therapies have been suggested, mainly driven by studies in murine experimental cerebral malaria. However, none has proven benefit in humans. Evidence for exchange transfusion and the more recently employed RBC exchange transfusion remains limited [85▪,86,87] . Mannitol [88,89] , steroids [90,91] , and monoclonal antibodies to TNF [54,56] are not recommended as treatments in cerebral malaria as studies show no benefits and potential harm. Furosemide and mannitol are ineffective in preventing and treating AKI and BWF, respectively, and may be harmful [92,93] . On the basis of the ability of paracetamol to inhibit hemoprotein-mediated AKI [94] , a recent RCT of paracetamol in Bangladeshi adults with severe malaria found that acetaminophen improved kidney function and reduced the development of AKI, particularly in patients with high cell-free hemoglobin levels at enrollment [95▪,96] . Larger studies of paracetamol in adults and children with malaria are currently ongoing to further assess this renoprotective effect.

Cerebral malaria and AKI complicating severe malaria are prognostic for mortality in both adults and children. Microvascular obstruction and endothelial dysfunction are common mechanisms for both of these complications. Future study of adjunctive therapies should target reducing sequestration, improving endovascular function, and reducing hemoglobin-mediated oxidative stress.

Acknowledgements

Financial support and sponsorship.

This work was supported by the Wellcome Trust of Great Britain.

Conflicts of interest

There are no conflicts of interest.

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• Charles R J C Newton a ,
• Tran Tinh Hien b ,
• Nicholas White b , c
• a Neurosciences Unit, Institute of Child Health, London, United Kingdom, b Centre for Tropical Diseases, Cho Quan Hospital, Ho Chi Minh City, Vietnam, c Faculty of Tropical Medicine, Mahidol University, Bangkok, Thialand
• Dr C R J C Newton, Wellcome Trust/ KEMRI Centre, PO Box 230, Kilifi, Kenya cnewton{at}kilifi.mimcom.net

Cerebral malaria may be the most common non-traumatic encephalopathy in the world. The pathogenesis is heterogenous and the neurological complications are often part of a multisystem dysfunction. The clinical presentation and pathophysiology differs between adults and children. Recent studies have elucidated the molecular mechanisms of pathogenesis and raised possible interventions. Antimalarial drugs, however, remain the only intervention that unequivocally affects outcome, although increasing resistance to the established antimalarial drugs is of grave concern. Artemisinin derivatives have made an impact on treatment, but other drugs may be required. With appropriate antimalarial drugs, the prognosis of cerebral malaria often depends on the management of other complications—for example, renal failure and acidosis. Neurological sequelae are increasingly recognised, but further research on the pathogenesis of coma and neurological damage is required to develop other ancillary treatments.

• antimalarial drugs
• parasitic disease

https://doi.org/10.1136/jnnp.69.4.433

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• Review Article
• Published: 19 October 2023

Pathogenetic mechanisms and treatment targets in cerebral malaria

• Alexandros Hadjilaou   ORCID: orcid.org/0000-0002-2443-9611 1 , 2 ,
• Johannes Brandi 1 ,
• Mathias Riehn   ORCID: orcid.org/0000-0001-8737-5566 1 ,
• Manuel A. Friese   ORCID: orcid.org/0000-0001-6380-2420 2   na1 &
• Thomas Jacobs 1   na1  

Nature Reviews Neurology volume  19 ,  pages 688–709 ( 2023 ) Cite this article

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An Author Correction to this article was published on 06 November 2023

This article has been updated

Malaria, the most prevalent mosquito-borne infectious disease worldwide, has accompanied humanity for millennia and remains an important public health issue despite advances in its prevention and treatment. Most infections are asymptomatic, but a small percentage of individuals with a heavy parasite burden develop severe malaria, a group of clinical syndromes attributable to organ dysfunction. Cerebral malaria is an infrequent but life-threatening complication of severe malaria that presents as an acute cerebrovascular encephalopathy characterized by unarousable coma. Despite effective antiparasite drug treatment, 20% of patients with cerebral malaria die from this disease, and many survivors of cerebral malaria have neurocognitive impairment. Thus, an important unmet clinical need is to rapidly identify people with malaria who are at risk of developing cerebral malaria and to develop preventive, adjunctive and neuroprotective treatments for cerebral malaria. This Review describes important advances in the understanding of cerebral malaria over the past two decades and discusses how these mechanistic insights could be translated into new therapies.

Cerebral malaria is an acute, life-threatening cerebrovascular complication characterized by unarousable coma; children <5 years are most at risk, although cerebral malaria can develop at any age.

Effective treatments for blood-stage malaria include antiparasite drugs such as artesunates and therapies that increase pitting, opsonization and phagocytic clearance of infected erythrocytes.

Host–parasite interactions result in sequestration of infected erythrocytes and immune cells on brain endothelial cells, which can lead to vascular disintegration, disruption of the blood–brain barrier and potentially neuropathology.

CD8 + T cell-mediated immune responses during cerebral malaria contribute to endothelial injury and blood–brain barrier disintegration, highlighting potential roles for therapies that target T cell recruitment, activation and cytotoxicity.

Host–parasite interactions result in the activation of microglia and astrocytes; thus, manipulation of these brain-resident cells might beneficially influence the neuropathology of cerebral malaria.

Cerebral malaria can be alleviated by combinations of therapies that clear infected cells and parasites, ideally complemented in the future by therapies that increase the resilience of the brain to tissue damage.

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Acknowledgements

A.H. was supported by an MD/PhD stipend (TI 07.001_Hadjilaou) and is currently supported by a Clinical Leave stipend of the Bundesministerium für Bildung und Forschung/Deutsches Zentrum für Infektionsforschung (TI 07.002_Hadjilaou).

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These authors contributed equally: Manuel A. Friese, Thomas Jacobs.

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Protozoen Immunologie, Bernhard-Nocht-Institut für Tropenmedizin (BNITM), Hamburg, Germany

Alexandros Hadjilaou, Johannes Brandi, Mathias Riehn & Thomas Jacobs

Institut für Neuroimmunologie und Multiple Sklerose, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany

Alexandros Hadjilaou & Manuel A. Friese

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Potent, low-molecular-weight molecules produced during immune responses that stimulate inflammation, attract white blood cells and modulate immune responses to infection or disease.

The clearance of damaged cells by phagocytosis.

A paravascular system thought to be responsible for waste clearance in the central nervous system, similar to the lymphatic system in other organs.

Small, round, basophilic, nuclear remnants of DNA within mature erythrocytes, which are typically removed in the spleen through a process called ‘pitting’.

Proteasomes in the cytoplasm of immune cells, especially antigen-presenting ones, formation of which is induced by pro-inflammatory cytokines or oxidative stress.

A collection of changes in the retina that can occur during Plasmodium infection.

Cellular metabolic changes that address increased bioenergetic and biosynthetic demands, such as those needed in the transition from a quiescent to an activated phenotype.

The process by which circulating, soluble proteins (opsonins) bind to a cell membrane, thereby marking those cells for phagocytosis.

A chemical modification that enables anchoring of a protein to the cell membrane.

Immature erythrocytes characterized by a reticular network of ribosomal RNA.

The increased cytoadhesion of erythrocytes infected with mature, asexual Plasmodium falciparum causes these cells to stick to uninfected erythrocytes, forming flower-like cell clusters.

The cytoadherence of Plasmodium -infected erythrocytes to the vascular endothelium, a feature predominantly seen in Plasmodium falciparum infections.

A post-translational peptide modification in which a nitrosyl group is added to the sulfur atom of a cysteine residue.

3-Hydroxy-3-methylglutaryl-CoA reductase inhibitors approved for the treatment of hypercholesterolaemia.

A measure of the frequency of malaria spread in a specific area, which is dictated by mosquito population density, local climate conditions and the level of human immunity (which shapes individual exposure to malaria antigens and the development of protective immunity).

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Hadjilaou, A., Brandi, J., Riehn, M. et al. Pathogenetic mechanisms and treatment targets in cerebral malaria. Nat Rev Neurol 19 , 688–709 (2023). https://doi.org/10.1038/s41582-023-00881-4

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Cerebral malaria – clinical manifestations and pathogenesis

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• Published: 08 January 2016
• Volume 31 , pages 225–237, ( 2016 )

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• Rachna Hora 1 ,
• Payal Kapoor 1 ,
• Kirandeep Kaur Thind 1 &
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One of the most common central nervous system diseases in tropical countries is cerebral malaria (CM). Malaria is a common protozoan infection that is responsible for enormous worldwide mortality and economic burden on the society. Episodes of Plasmodium falciparum (Pf) caused CM may be lethal, while survivors are likely to suffer from persistent debilitating neurological deficits, especially common in children. In this review article, we have summarized the various symptoms and manifestations of CM in children and adults, and entailed the molecular basis of the disease. We have also emphasized how pathogenesis of the disease is effected by the parasite and host responses including blood brain barrier (BBB) disruption, endothelial cell activation and apoptosis, nitric oxide bioavailability, platelet activation and apoptosis, and neuroinflammation. Based on a few recent studies carried out in experimental mouse malaria models, we propose a basis for the neurological deficits and sequelae observed in human cerebral malaria, and summarize how existing drugs may improve prognosis in affected individuals.

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Cerebral Malaria: Players in the Pathogenic Mechanism and Treatment Strategies

Pathogenetic mechanisms and treatment targets in cerebral malaria

Pathophysiology and neurologic sequelae of cerebral malaria

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Laboratories of Rachna Hora and Prakash Chandra Mishra are funded by Department of Biotechnology (DBT), Govt. of India, University Grants Commission (UGC, Govt. of India) and Department of Science and technology (DST, Govt. of India). Payal Kapoor is a DST INSPIRE (Department of Science and Technology - Innovation in Science Pursuit for Inspired Research) senior research fellow. Kirandeep Kaur Thind was initially funded by DBT and later supported by junior research fellowship from CSIR (Council of Scientific and Industrial Research), Govt. of India.

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Rachna Hora, Payal Kapoor & Kirandeep Kaur Thind

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Hora, R., Kapoor, P., Thind, K.K. et al. Cerebral malaria – clinical manifestations and pathogenesis. Metab Brain Dis 31 , 225–237 (2016). https://doi.org/10.1007/s11011-015-9787-5

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Received : 09 July 2015

Accepted : 22 December 2015

Published : 08 January 2016

Issue Date : April 2016

DOI : https://doi.org/10.1007/s11011-015-9787-5

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Cerebral Malaria

• Cerebral malaria is a life-threatening complication of P. falciparum infestation that occurs in approximately 2% of patients.
• Pathogenesis may be explained by 2 mechanisms: vascular sequestration of parasitized erythrocytes and the potential cerebral toxicity by cytokines.
• Progressive clinical changes occur, along with high fever and chills.
• Neurologic manifestations are nonspecific because of diffuse involvement of the brain.
• Patients can become drowsy and disorientated, with associated seizures and progressive deterioration in consciousness before they become comatose.
• Appearances may be normal on CT.
• Restricted diffusion representing infarcts
• No restricted diffusion, as with this patient, thought to be secondary to an inflammatory/demyelinating etiology 
• Acute infarcts, which are frequently hemorrhagic, tend to involve the thalami/basal ganglia due to involvement of perforator arteries or cortical/subcortical involvement, represented by T2-FLAIR hyperintensity, diffusion restriction, and susceptibility effects.
• Presence of enhancement may reflect the evolution of acute infarcts or be related to active inflammation/demyelination.
• Demyelination including ADEM
• Neuropsychiatric SLE
• Antimalarial therapy such as artemisinin derivatives
• Supportive management based on clinical and biochemical abnormalities

A 41-year-old woman on HAART with fever and seizures before entering a coma after recent travel to Uganda. MRI performed 2 weeks into admission. 

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Clinical Features of Malaria

At a glance.

• Malaria infection is caused by Plasmodium parasite species.
• Malaria disease can be categorized as uncomplicated or severe (complicated).
• Severity of symptoms and duration of disease can depend on the species of the malaria parasite and level of immunity.
• Generally, malaria is curable if diagnosed and treated promptly and correctly.

Clinical presentation

Infection with malaria parasites may result in a wide variety of symptoms, ranging from absent or very mild symptoms to severe disease and even death. Malaria disease can be categorized as uncomplicated or severe (complicated). In general, malaria is a curable disease if diagnosed and treated promptly and correctly.

All the clinical symptoms associated with malaria are caused by the asexual erythrocytic or blood stage parasites . When the parasite develops in the erythrocyte, numerous known and unknown waste substances such as hemozoin pigment and other toxic factors accumulate in the infected red blood cell. These are dumped into the bloodstream when the infected cells lyse and release invasive merozoites. The hemozoin and other toxic factors such as glucose phosphate isomerase (GPI) stimulate macrophages and other cells to produce cytokines and other soluble factors which act to produce fever and rigors and probably influence other severe pathophysiology associated with malaria.

Plasmodium falciparum- infected erythrocytes, particularly those with mature trophozoites, adhere to the vascular endothelium of venular blood vessel walls and do not freely circulate in the blood. When this sequestration of infected erythrocytes occurs in the vessels of the brain it is believed to be a factor in causing the severe disease syndrome known as cerebral malaria, which is associated with high mortality.

Incubation Period

Following the infective bite by the female Anopheles mosquito , a period of time (the "incubation period") goes by before the first symptoms appear in a patient. The incubation period in most cases varies from 7 to 30 days. The shorter periods most frequently observed with P. falciparum and the longer ones with P. malariae .

Antimalarial drugs taken for prophylaxis by travelers are highly effective if taken as prescribed. However, antimalarial prophylaxis occasionally can delay the appearance of malaria symptoms by weeks or months, long after the traveler has left the malaria-endemic area. (This can happen particularly with P. vivax and P. ovale , both of which can produce dormant liver stage parasites; the liver stages may reactivate and cause disease months after the infective mosquito bite.)

Such long delays between exposure and development of symptoms can result in misdiagnosis or delayed diagnosis because of reduced clinical suspicion by the health-care provider. Returned travelers should always remind their healthcare providers of any travel during the past 12 months in areas where malaria occurs.

Uncomplicated Malaria

Commonly, the patient initially presents with a combination of the following symptoms (which may be mild):

• Nausea and vomiting
• General malaise

In countries where cases of malaria are infrequent, these symptoms may be attributed to influenza, a cold, or other common infections, especially if malaria is not suspected. Conversely, in countries where malaria is frequent, residents often recognize the symptoms as malaria and treat themselves without seeking diagnostic confirmation ("presumptive treatment"). Physical findings may include the following:

• Elevated temperatures
• Perspiration
• Enlarged spleen
• Mild jaundice
• Enlargement of the liver
• Increased respiratory rate

Diagnosis of malaria depends on the demonstration of parasites in the blood, usually by microscopy. Additional laboratory findings may include mild anemia, mild decrease in blood platelets (thrombocytopenia), elevation of bilirubin, and elevation of aminotransferases.

Severe Malaria

Progression to severe malaria occurs when infections are complicated by serious organ failures or abnormalities in the patient's blood or metabolism, usually following delays in diagnosis and treatment. Criteria for severe malaria may differ slightly depending on the country where you are practicing, see WHO Guidelines for Malaria .

For healthcare providers practicing in the U.S., the criteria for severe malaria include any one or more of the following:

• High percent parasitemia (≥5%)
• Impaired consciousness
• Circulatory collapse/shock
• Pulmonary edema or acute respiratory distress syndrome (ARDS)
• Acute kidney injury
• Abnormal bleeding or disseminated intravascular coagulation (DIC)
• Jaundice (must be accompanied by at least one other sign)
• Severe anemia (Hb <7 g/dL)

Malaria Relapse

In P. vivax and P. ovale infections, patients having recovered from the first episode of illness may suffer several additional attacks ("relapses") after months or even years without symptoms. Relapses occur because P. vivax and P. ovale have dormant liver stage parasites ( "hypnozoites" ) that may reactivate, infect peripheral erythrocytes, and begin a new symptomatic episode of malaria. Treatment to reduce the chance of such relapses is available and should follow treatment of the first attack.

Other manifestations of malaria

• Neurologic defects may occasionally persist (sometimes life-long) following cerebral malaria, especially in children. Such defects include trouble with movements (ataxia), palsies, speech difficulties, deafness, neurocognitive deficits, and blindness.
• Recurrent infections with P. falciparum may result in severe anemia. This occurs especially in young children in tropical Africa with frequent infections that are inadequately treated.
• Malaria during pregnancy (especially P. falciparum ) may cause severe disease in the mother and may lead to premature delivery or delivery of a low-birth-weight baby.
• On rare occasions, P. vivax malaria can cause rupture of the spleen.
• Nephrotic syndrome (a chronic, severe kidney disease) can result from chronic or repeated infections with P. malariae .
• Hyperreactive malarial splenomegaly (also called "tropical splenomegaly syndrome") occurs infrequently and is attributed to an abnormal immune response to repeated malarial infections. The disease is marked by a very enlarged spleen and liver, abnormal immunologic findings, anemia, and a susceptibility to other infections (such as skin or respiratory infections).

Malaria is a serious disease caused by a parasite that infects the Anopheles mosquito. You get malaria when bitten by an infective mosquito.

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Pattern of Clinical and Laboratory Presentation of Cerebral Malaria among Children in Nigeria

Affiliations.

• 1 Department of Paediatrics, Federal Medical Centre, Owo, Ondo, Nigeria.
• 2 Department of Paediatrics and Child Health, Obafemi Awolowo University, Ile-Ife, Osun, Nigeria.
• 3 Department of Paediatrics, University of Medical Sciences Teaching Hospital, Akure, Ondo, Nigeria.
• 4 Department of Psychiatry, Federal Neuropsychiatry Hospital, Benin, Edo, Nigeria.
• PMID: 38680759
• PMCID: PMC11045150
• DOI: 10.4103/jgid.jgid_100_23

Introduction: Cerebral malaria (CM) is the most lethal form of severe malaria with high case fatality rates. Overtime, there is an inherent risk in changing pattern of presentation of CM which, if the diagnosis is missed due to these changing factors, may portend a poor outcome. Variations in the pattern of clinic-laboratory presentations also make generalization difficult. This study was, therefore, set out to report the pattern of clinical and laboratory presentation of CM.

Methods: This was a cross-sectional study among children aged 6 months to 14 years admitted with a diagnosis of CM as defined by the World Health Organization criteria. A pretested pro forma was filled, and detailed neurological examination and laboratory (biochemical, microbiology, and hematology) investigations were done. P <5% was considered statistically significant.

Results: Sixty-four children were recruited with a mean age of 34.9 ± 24.9 months and a male-to-female ratio of 1.9:1. There were 87.5% of under-five children. Fever (96.9%) was the major presenting feature closely followed by convulsions (92.2%). Convulsions were mainly generalized (94.9%) and multiple (76.5%). Profound coma (Blantyre coma score of 0) was present in 12.5% of cases, and the leading features on examination were fever (84.4%) and pallor (75.0%). Retinal vessel whitening (48.4%) was the most common funduscopic abnormality. Metabolic acidosis (47.9%), severe anemia (14.1%), hyperglycemia (17.2%), and hypoglycemia (7.8%) were seen among the children. Few (1.6%) had hyperparasitemia and bacteremia (3.2%).

Conclusion: Early recognition of the clinical presentation and prompt management may improve the outcome of cerebral malaria.

Keywords: Cerebral malaria; Nigeria; clinical features; coma; hyperparasitemia.

Copyright: © 2024 Journal of Global Infectious Diseases.

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Conflict of interest statement

There are no conflicts of interest.

Types and patterns of convulsions…

Types and patterns of convulsions recorded among the children

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What is Cerebral Malaria?

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Cerebral malaria is a serious neurological complication of severe malaria that affects about 1% of children under the age of 5 who have been infected with Plasmodium falciparum.

Malaria. Image Credit: Christoph Burgstedt/Shutterstock.com

An overview of malaria

The Plasmodium genus of unicellular protozoan parasites are responsible for causing the disease malaria in humans, the most deadly of which includes Plasmodium falciparum. Each year, malaria affects about 219 million people, with about 500,000 people dying each year from this disease. It is estimated that about 93% of the people who die from malaria reside in sub-Saharan Africa, many of whom are under the age of 5.

Humans typically acquire malaria after being bitten by an infected female mosquito of the Anopheles genus. In addition, blood-borne transmission through the transfusion of blood products, transplantation, or needle-sharing, as well as congenital transmission of malaria can also occur. Once infected, malaria can either evolve into simple or severe forms, the latter of which is a less frequent presentation of this disease.

Severity of malaria

The severity of malaria is often dependent upon the immune status of the host, as well as the area in which malaria has been acquired. For example, areas that have a stable endemic of P. falciparum will often find that severe malaria commonly occurs in children up to 5 years of age, whereas older children and adults will experience less severe forms of the infection due to partial immunity. Comparatively, areas with lower endemic rates will have a less defined age distribution of severe malaria.

Initially, malaria will cause nonspecific flu-like symptoms including malaise, anorexia, lassitude, dizziness, headache, body aches, nausea, vomiting, and chills. The progression of malaria into more severe symptoms will often depend upon the infecting parasite. For example, infection by P. vivax and P. ovale will typically cause a classical malaria paroxysm that includes three symptom stages, beginning with a cold stage, followed by a hot stage, and ending with a sweating stage.  

Most of the severe complications of malaria will occur in individuals who have been infected with P. falciparum. Severe malaria is often defined as the presence of Plasmodium in peripheral blood. Some of the complications of severe malaria can involve the central nervous system, which is otherwise referred to as cerebral malaria, the pulmonary system, renal system, and/or the hematopoietic system. The progression to these complications is often rapid and can lead to death in many cases.

What is cerebral malaria?

According to the World Health Organization (WHO), cerebral malaria is defined as a severe form of P. falciparum malaria that causes cerebral manifestations. Typically, patients with cerebral malaria will experience a coma that persists for more than 30 minutes after a seizure occurs. While this may be true, patients with any degree of altered consciousness and other signs of cerebral dysfunction should be treated for severe malaria.

It is estimated that about 1% of children who have been infected with P. falciparum will develop cerebral malaria, with the incidence in adults being highly rare. However, low transmission areas will often find that cerebral malaria occurs more commonly in older children and adults. Studies have shown that younger children may be partly protected from cerebral malaria as a result of a process known as premunition, during which maternal immunity is transferred to the child in utero.

Symptoms of cerebral malaria      

As previously mentioned, coma is a hallmark symptom of cerebral malaria; however, the onset of this neurological complication can vary from occurring suddenly or gradually. When coma develops gradually, patients will often initially present with drowsiness, which should always be considered a worrying symptom, confusion, disorientation, delirium, or agitation. Addition observations that might be seen with cerebral malaria include:

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• Open-eyed but non-seeing
• Disconjugate gaze
• Sustained ocular deviation, usually upward or lateral
• Decerebrate rigidity
• Decorticate rigidity
• Opisthotonos
• Neck rigidity
• Electroencephalographic abnormalities

Some other symptoms that are often common manifestations of cerebral malaria include fixed jaw closure and tooth grinding. Cerebral malaria is also often accompanied by non-neurological symptoms including enlargement of the liver and spleen, jaundice, pulmonary edema, renal dysfunction, pallor, hypoglycemia, bleeding, hypotension, and severe anemia.

Another notable complication of cerebral malaria that can be used to differentiate this condition from other encephalopathies that often occur in malaria-endemic areas includes malignant retinopathy. Malignant retinopathy in malaria arises due to the cerebral sequestration of parasites in the brain and can be diagnosed based on the presence of four major symptoms, which include:

• Retinal whitening
• Vessel changes
• Retinal hemorrhages
• papilledema

Treatment for cerebral malaria

Antimalarial treatment can be in the form of two classes of drugs, which include derivatives of artemisinin and those generated from cinconcha alkaloids. Whereas derivatives of artemisinin include artesunate and artemether, those that originate from cinconcha alkaloids include quinine and quinidine.

The ability of severe malaria to affect multiple organ systems, therefore, warrants additional medical interventions to treat these complications. For example, patients who experience a coma should, when necessary, be intubated and supported through mechanical ventilation. Since seizures are also a common complication of cerebral malaria, their medical management through the use of anticonvulsants is also crucial.

If left untreated, cerebral malaria is almost always fatal; therefore, aggressive treatment immediately should be initiated immediately after a diagnosis of cerebral malaria is made. Even after treatment is initiated, cerebral malaria still has a mortality rate of 20% and 15% in adults and children, respectively.

Fortunately, many of the patients who do survive cerebral malaria will typically experience a rapid recovery and a complete reversal of their neurological symptoms. However, some neurological symptoms may persist after recovery from cerebral malaria for several days or several weeks after their onset. These manifestations might include psychosis, cranial nerve lesions, extrapyramidal tremor, ataxia, polyneuropathy, and seizures.

References:

• Luzolo, A. L., & Ngoyi, D. M. (2019). Cerebral malaria. Brain Research Bulletin 145 ; 53-58. doi:10.1016/j.brainresbull.2019.01.010.
• Bruneel, F. (2019). Human cerebral malaria: 2019 mini-review. Revue Neurologique 175 (7-8); 445-450. doi:10.1016/j.neurol.2019.07.008.
• BArtoloni, A., & Zammarchi, L. (2012). Clinical Aspects of Uncomplicated and Severe Malaria. Mediterranean Journal of Hematology and Infectious Diseases 4 (1). doi:10.4084/MJHID.2012.026.

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When to see a doctor, risk factors, complications.

Malaria is a disease caused by a parasite. The parasite is spread to humans through the bites of infected mosquitoes. People who have malaria usually feel very sick with a high fever and shaking chills.

While the disease is uncommon in temperate climates, malaria is still common in tropical and subtropical countries. Each year nearly 290 million people are infected with malaria, and more than 400,000 people die of the disease.

To reduce malaria infections, world health programs distribute preventive drugs and insecticide-treated bed nets to protect people from mosquito bites. The World Health Organization has recommended a malaria vaccine for use in children who live in countries with high numbers of malaria cases.

Protective clothing, bed nets and insecticides can protect you while traveling. You also can take preventive medicine before, during and after a trip to a high-risk area. Many malaria parasites have developed resistance to common drugs used to treat the disease.

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Signs and symptoms of malaria may include:

• General feeling of discomfort
• Nausea and vomiting
• Abdominal pain
• Muscle or joint pain
• Rapid breathing
• Rapid heart rate

Some people who have malaria experience cycles of malaria "attacks." An attack usually starts with shivering and chills, followed by a high fever, followed by sweating and a return to normal temperature.

Malaria signs and symptoms typically begin within a few weeks after being bitten by an infected mosquito. However, some types of malaria parasites can lie dormant in your body for up to a year.

Talk to your doctor if you experience a fever while living in or after traveling to a high-risk malaria region. If you have severe symptoms, seek emergency medical attention.

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Malaria is caused by a single-celled parasite of the genus plasmodium. The parasite is transmitted to humans most commonly through mosquito bites.

Mosquito transmission cycle

• Malaria transmission cycle

Malaria spreads when a mosquito becomes infected with the disease after biting an infected person, and the infected mosquito then bites a noninfected person. The malaria parasites enter that person's bloodstream and travel to the liver. When the parasites mature, they leave the liver and infect red blood cells.

• Uninfected mosquito. A mosquito becomes infected by feeding on a person who has malaria.
• Transmission of parasite. If this mosquito bites you in the future, it can transmit malaria parasites to you.
• In the liver. Once the parasites enter your body, they travel to your liver — where some types can lie dormant for as long as a year.
• Into the bloodstream. When the parasites mature, they leave the liver and infect your red blood cells. This is when people typically develop malaria symptoms.
• On to the next person. If an uninfected mosquito bites you at this point in the cycle, it will become infected with your malaria parasites and can spread them to the other people it bites.

Other modes of transmission

Because the parasites that cause malaria affect red blood cells, people can also catch malaria from exposure to infected blood, including:

• From mother to unborn child
• Through blood transfusions
• By sharing needles used to inject drugs

The greatest risk factor for developing malaria is to live in or to visit areas where the disease is common. These include the tropical and subtropical regions of:

• Sub-Saharan Africa
• South and Southeast Asia
• Pacific Islands
• Central America and northern South America

The degree of risk depends on local malaria control, seasonal changes in malaria rates and the precautions you take to prevent mosquito bites.

Risks of more-severe disease

People at increased risk of serious disease include:

• Young children and infants
• Older adults
• Travelers coming from areas with no malaria
• Pregnant women and their unborn children

In many countries with high malaria rates, the problem is worsened by lack of access to preventive measures, medical care and information.

Immunity can wane

Residents of a malaria region may be exposed to the disease enough to acquire a partial immunity, which can lessen the severity of malaria symptoms. However, this partial immunity can disappear if you move to a place where you're no longer frequently exposed to the parasite.

Malaria can be fatal, particularly when caused by the plasmodium species common in Africa. The World Health Organization estimates that about 94% of all malaria deaths occur in Africa — most commonly in children under the age of 5.

Malaria deaths are usually related to one or more serious complications, including:

• Cerebral malaria. If parasite-filled blood cells block small blood vessels to your brain (cerebral malaria), swelling of your brain or brain damage may occur. Cerebral malaria may cause seizures and coma.
• Breathing problems. Accumulated fluid in your lungs (pulmonary edema) can make it difficult to breathe.
• Organ failure. Malaria can damage the kidneys or liver or cause the spleen to rupture. Any of these conditions can be life-threatening.
• Anemia. Malaria may result in not having enough red blood cells for an adequate supply of oxygen to your body's tissues (anemia).
• Low blood sugar. Severe forms of malaria can cause low blood sugar (hypoglycemia), as can quinine — a common medication used to combat malaria. Very low blood sugar can result in coma or death.

Malaria may recur

Some varieties of the malaria parasite, which typically cause milder forms of the disease, can persist for years and cause relapses.

If you live in or are traveling to an area where malaria is common, take steps to avoid mosquito bites. Mosquitoes are most active between dusk and dawn. To protect yourself from mosquito bites, you should:

• Cover your skin. Wear pants and long-sleeved shirts. Tuck in your shirt, and tuck pant legs into socks.
• Apply insect repellent to skin. Use an insect repellent registered with the Environmental Protection Agency on any exposed skin. These include repellents that contain DEET, picaridin, IR3535, oil of lemon eucalyptus (OLE), para-menthane-3,8-diol (PMD) or 2-undecanone. Do not use a spray directly on your face. Do not use products with oil of lemon eucalyptus (OLE) or p-Menthane-3,8-diol (PMD) on children under age 3.
• Apply repellent to clothing. Sprays containing permethrin are safe to apply to clothing.
• Sleep under a net. Bed nets, particularly those treated with insecticides, such as permethrin, help prevent mosquito bites while you are sleeping.

Preventive medicine

If you'll be traveling to a location where malaria is common, talk to your doctor a few months ahead of time about whether you should take drugs before, during and after your trip to help protect you from malaria parasites.

In general, the drugs taken to prevent malaria are the same drugs used to treat the disease. What drug you take depends on where and how long you are traveling and your own health.

The World Health Organization has recommended a malaria vaccine for use in children who live in countries with high numbers of malaria cases.

Researchers are continuing to develop and study malaria vaccines to prevent infection.

Feb 09, 2023

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• Jameson JL, et al., eds. Malaria. In: Harrison's Principles of Internal Medicine. 20th ed. New York, N.Y.: The McGraw-Hill Companies; 2018. https://accessmedicine.mhmedical.com. Accessed Oct. 9, 2018.
• Tintinalli JE, et al., eds. Malaria. In: Tintinalli's Emergency Medicine: A Comprehensive Study Guide. 8th ed. New York, N.Y.: McGraw-Hill Education; 2016. http://www.accessmedicine.mhmedical.com. Accessed Oct. 9, 2018.
• Malaria. Merck Manual Professional Version. http://www.merckmanuals.com/professional/infectious-diseases/extraintestinal-protozoa/malaria. Accessed Oct. 9, 2018.
• Malaria. Centers for Disease Control and Prevention. http://wwwnc.cdc.gov/travel/diseases/malaria. Accessed Nov. 6, 2015.
• Breman JG. Clinical manifestations of malaria in nonpregnant adults and children. https://www.uptodate.com/contents/search. Accessed Oct. 9, 2018.
• Daily J. Treatment of uncomplicated falciparum malaria in nonpregnant adults and children. https://www.uptodate.com/contents/search. Accessed Oct. 9, 2018.
• Key points: World malaria report 2017. World Health Organization. https://www.who.int/malaria/media/world-malaria-report-2017/en/. Accessed Oct. 9, 2018.
• Malaria. World Health Organization. https://www.who.int/malaria/en/. Accessed Oct. 9, 2018.
• Mutebi JP, et al. Protection against mosquitoes, ticks, & other arthropods. In: CDC Yellow Book 2018: Health Information for International Travelers. https://wwwnc.cdc.gov/travel/yellowbook/2018/the-pre-travel-consultation/protection-against-mosquitoes-ticks-other-arthropods. Accessed Oct. 27, 2018.
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Cerebral malaria induced by plasmodium falciparum : clinical features, pathogenesis, diagnosis, and treatment

Xiaonan song.

1 School of Basic Medical Sciences, Hubei University of Medicine, Shiyan, China

2 Beijing School of Chemistry and Bioengineering, University of Science and Technology Beijing, Beijing, China

Weijia Cheng

3 Key Laboratory of National Health Commission on Technology for Parasitic Diseases Prevention and Control, Jiangsu Provincial Key Laboratory on Parasites and Vector Control Technology, Jiangsu Institute of Parasitic Diseases, Wuxi, China

Haifeng Dong

4 Guangdong Key Laboratory for Genome Stability and Human Disease Prevention, Department of Biochemistry and Molecular Biology, School of Medicine, Shenzhen University, Shenzhen, China

Cerebral malaria (CM) caused by Plasmodium falciparum is a fatal neurological complication of malaria, resulting in coma and death, and even survivors may suffer long-term neurological sequelae. In sub-Saharan Africa, CM occurs mainly in children under five years of age. Although intravenous artesunate is considered the preferred treatment for CM, the clinical efficacy is still far from satisfactory. The neurological damage induced by CM is irreversible and lethal, and it is therefore of great significance to unravel the exact etiology of CM, which may be beneficial for the effective management of this severe disease. Here, we review the clinical characteristics, pathogenesis, diagnosis, and clinical therapy of CM, with the aim of providing insights into the development of novel tools for improved CM treatments.

Introduction

Malaria, a mosquito-transmitted infectious disease caused by Plasmodium species, remains a significant public health concern globally ( XP D, L S, 2021 ). In 2020, 241 million malaria cases were estimated, and 627,000 deaths occurred, with 77% found among children under five years of age ( Jiang et al., 2021 ). Currently, five Plasmodium spp. are reported to infect humans, including P. falciparum , P. ovale , P. vivax , P. malariae , and P. knowlesi . As we know, P. falciparum is considered the most severe species and the primary cause of mortality, notably in young children ( Su and Wu, 2021 ). Cerebral malaria (CM) is a fatal neurological complication of P. falciparum malaria ( Luzolo and Ngoyi, 2019 ), and children aged under 3 years and pregnant women are most susceptible ( World Health Organization, 2021 ). The mortality of CM is estimated to be 20% in children and 30% in adults ( Solomon et al., 2014 ). Furthermore, 15-20% of survivors suffer long-term neurological sequelae, such as hemiplegia, ataxia, speech disorders, and epilepsy, resulting in lifelong neurological deficits and even death ( Birbeck et al., 2010 ). Hereby, we review the clinical manifestations, pathogenesis, diagnosis, and treatment of CM so as to provide insights into the management of CM.

Clinical manifestations of CM

CM is clinically characterized as a diffuse encephalopathy with a history of fever for 2 to 3 days, subsequent seizures, and loss of consciousness (coma). Previous studies have demonstrated substantial differences in the clinical manifestations of CM between children and adults ( Table 1 ). Although this may be attributed to immune status and age, there are still many questions that remain to be answered ( Olliaro, 2008 ; Sahu et al., 2021 ). Pediatric CM usually manifests with coma, seizures, and severe anemia, while renal failure and respiratory distress rarely occur in African children ( Waller et al., 1995 ; Newton et al., 2000 ). Nevertheless, adult CM is frequently associated with multiple organ complications, including central nervous system (CNS) and liver dysfunction, respiratory failure, and acute kidney failure ( Mishra et al., 2007 ; Wassmer et al., 2015 ).

Table 1

Clinical manifestations of pediatric and adult cerebral malaria.

Neurological system

Compared with adults, children have a higher incidence rate of seizures ( Postels and Birbeck, 2013 ). In children, focal motor and generalized tonic–clonic convulsions are the most common clinically detected seizures; however, subtle or subclinical seizures detected with electroencephalography (EEG) are also common ( Newton et al., 2000 ; Postels and Birbeck, 2013 ). Subtle seizures manifest as nystagmoid eye movements, irregular breathing, excessive salivation, and conjugate eye deviation ( Crawley et al., 1996 ). Most seizures in adult CM patients are generalized seizures; however, focal motor seizures may also occur. Occasionally, the sign of seizure activity is subtle, such as repetitive eye or hand movements, and may be easily overlooked. Subtle seizure activity seems to be more common in children than in adults ( Newton et al., 2000 ). The level of consciousness after a seizure is usually lower than that preceding it. Status epilepticus is unusual in adults, although more than one seizure is frequent ( Vespa et al., 1999 ). Previous studies reported an association between status epilepticus and neurological sequelae among CM patients, which occur in 5-15% of survivors ( Brewster et al., 1990 ), and it has been shown that prolonged seizure activity may damage the brain, causing deficits in both motor and cognitive functions ( Stafstrom et al., 1993 ).

Coma usually develops rapidly after seizures among children living in malaria-endemic areas, and consciousness recovers to normal rapidly (within 24-48 h) ( Genton et al., 1997 ). Different disease processes may affect awareness in children with malaria, including convulsions, hypoglycemia, hyperpyrexia, acidosis, severe anemia, and sedative drugs. Although the cause of impaired consciousness or coma remains unclear, it is likely to result from several interacting mechanisms ( Newton et al., 2000 ). Adhesion of malaria parasite-infected red blood cells (iRBCs) reduces microvascular blood flow ( Kaul et al., 1998 ), which may be the cause of organ tissue dysfunction, such as coma. High concentrations of tumor necrosis factor-α (TNF-α) are associated with coma ( Kwiatkowski et al., 1990 ; Kaul et al., 1998 ). Compared to children, coma gradually develops in adults following drowsiness, disorientation, delirium, and agitation within 2 to 3 days ( Kochar et al., 2002 ). Convulsion leads to the development of a coma and occurs in approximately 15% of adults and 80% of children ( Plewes et al., 2018 ).

Neurologic features

Abnormal corneal and oculocephalic reflexes (doll’s eye) are likely to occur in children with deep coma. Abnormal plantar reflexes are also detected, and abdominal reflexes are almost invariably absent. In adults with profound coma, corneal and eyelash reflexes are usually intact unless in a state of deep coma, and the pupils are normal. Forcible jaw closure and teeth grinding (bruxism) are commonly seen in CM. Pout reflex usually indicates a “frontal release”; however, the grasp reflex is frequently absent. In addition, increased muscle tone and tendon reflexes are found. CM may elicit ankle and patellar clonus, and extensor plantar responses. Nevertheless, abdominal and cremasteric reflexes are invariably absent ().

Neurological impairments

CM affects the CNS, and although most survivors have a full recovery, 3-31% of patients still develop neurological deficits and cognitive sequelae ( Oluwayemi et al., 2013 ). The prevalence of neurological deficits is higher in children than in adults, ranging from 6% to 29% at the time of discharge ( Idro et al., 2004 ; Hawkes et al., 2013 ). Children with CM frequently present long-term neurologic deficits, and episodes of CM imply the development of long-term sequelae in children. In children, the most common sequelae include ataxia, paralysis, paresis, cortical blindness, epilepsy, deafness, behavioral disorders, language disorders, and cognitive impairment ( Brewster et al., 1990 ). Sequelae are less common in adults. During the acute phase of CM, neurologic abnormalities include psychosis, ataxia, transitory cranial nerve palsies or tremor ( Peixoto and Kalei, 2013 ).

Retinopathy

The characteristic features of retinopathy due to CM include retinal whitening (macula whitening sparing central fovea and peripheral whitening of the fundus), retinal vessel discoloration to pink–orange or white, retinal hemorrhages, and papilledema ( Hora et al., 2016 ). The first two abnormalities are considered specific symptoms of CM. Commonalities between pediatric and adult patients include retinal hemorrhage, a common manifestation but a less distinctive feature. Retinal hemorrhage correlates with disease severity and cerebral hemorrhage in the microvascular dissection of the brain ( White et al., 2001 ). Papilledema is rare in children and adults. Although it is a nonspecific symptom of CM, it reflects increased intracranial pressure and portends a poor prognosis in children ( Beare et al., 2004 ). A prominent difference between children and adults is vessel discoloration. Orange or white discoloration of the retinal vessels has been attributed to the hemoglobinization of stationary erythrocytes infected with mature parasites ( Beare et al., 2011 ). The degree of retinal microvascular damage is comparable to cerebral damage ( Beare et al., 2004 ; Lewallen et al., 2008 ).

Non-CNS abnormalities in CM

Systemic complications include anemia (20% to 50% incidence), hypoglycemia (30% incidence), hyponatremia (>50% incidence), jaundice (8% incidence), metabolic acidosis characterized by respiratory distress, and hepatosplenomegaly in children living with CM ( White et al., 1987 ; English et al., 1996 ; Idro et al., 2005 ; Maitland and Newton, 2005 ). Renal failure and pulmonary edema are unusual in children ( Newton et al., 1991 ). CM predominantly manifests as CNS dysfunction in children; however, it is mainly present in multisystem and organ (circulatory, hepatic, coagulation, renal, and pulmonary) dysfunctions in adults ( Day et al., 2000 ; Krishnan and Karnad, 2003 ).

In adults, anemia is an inevitable consequence of CM and develops exceptionally rapidly. CM has been reported in patients together with pulmonary edema, adult respiratory distress syndrome and hemoglobinuria, and Kussmaul’s breathing occurs with acute renal failure and severe lactic acidosis ( Newton and Warrell, 1998 ). Hypoglycemia occurs in 8% of patients aged 26 to 28 years ( White et al., 1983 ). Other complications included jaundice, shock, abnormal bleeding, and coagulopathy.

Pathogenesis of CM

Although the pathophysiology of CM has been extensively investigated, the exact pathogenesis remains unclear. Currently, CM is widely accepted as a multifactorial process related to the adhesion and sequestration of iRBCs, immunological responses, endothelial cell (EC) activation, and loss of BBB integrity ( Idro et al., 2005 ). Nevertheless, any of these mechanisms alone fail to explain the pathogenesis of human CM, and they jointly participate in this potentially fatal infection. A mouse model of experimental cerebral malaria (ECM) has been used to simulate and explain the pathogenesis of human CM ( Figure 1 ).

Schematic of experimental cerebral malaria (ECM) pathogenesis. The ECM is initiated by dendritic cells (DCs) processing and presenting infected red blood cell (iRBC) antigens to CD4 + and CD8 + T cells in the spleen (1). NK cells and macrophages are activated by iRBCs to secrete inflammatory cytokines (2). The iRBCs adhere to endothelial cells (ECs) of the brain microvasculature through the interaction between P. falciparum erythrocyte membrane protein-1 (PfEMP-1) of iRBCs and cell adhesion molecules of ECs (3). The adhesion of iRBCs to the cerebral microvascular endothelium is also further accompanied by agglutination to other iRBCs, platelets, white blood cells (WBCs), and the rosetting effect formed by the adhesion of iRBCs and RBCs. ECs are activated by interactions with iRBCs and responses to inflammatory cytokines. Activated ECs promote the upregulation of cell adhesion molecules (CAMs) on brain ECs and release cytokines and chemokines simultaneously (4). Activated CD8 + T cells express CXCR3 and CCR5 chemokine receptors, which bind to chemokines such as CXCL9, CXCL10, and CXCL4, inducing T-cell migration to the brain (5). Meanwhile, LFA-1 on CD8 + T cells promotes their adhesion to endothelial ICAM-1 (6). Parasitic antigens can be transferred from the vascular lumen to brain ECs. Brain ECs can cross-present parasitic antigens on MHC-1 molecular antigens and bind with antigen receptors (TCRs) on CD8 + T cells (7). The interaction induces apoptosis of ECs, leading to the destruction of the BBB (8). Meanwhile, the iRBCs directly activate platelets and stimulate the release of CXCL4. CXCL4 induces the production of TNF by T cells and macrophages, which causes more platelets to adhere to ECs (9). As leukocytes and platelets are recruited and activated, a local proinflammatory cycle ensues, with a positive feedback loop of EC activation, leukocyte/platelet sequestration, and parasite accumulation (10).

Adhesion and sequestration

Cerebral iRBCs adherence is an indicative marker of CM in adults and children, and it is considered a starting point during the development of CM. Sequestration is thought to be a specific interaction between iRBCs and vascular ECs, which is not limited to brain tissues but also occurs on ECs in different organs, including the lung, kidney, liver, and intestine.

The adhesion of iRBCs to the vascular endothelium is mediated by P. falciparum erythrocyte membrane protein 1 (PfEMP1) ( Jensen et al., 2020 ), a specific cell-surface ligand expressed by iRBCs. PfEMP1 belongs to the antigen-variant protein family, and the var genes encoding the protein are a large multigene family ( Kim, 2012 ). To date, 60 different var genes have been characterized, and var gene-encoded proteins have shown dual functions in regulating antigen variation and cell adhesion ( Tembo et al., 2014 ). PfEMP1 contains a host molecule binding domain and binds to several cell adhesion molecules (CAMs) on ECs, such as CD36 ( Berendt et al., 1989 ; Ockenhouse et al., 1989 ), intercellular adhesion molecule 1 (ICAM-1) ( Berendt et al., 1989 ), vascular adhesion molecule 1 (VCAM-1) ( Ockenhouse et al., 1989 ; Ockenhouse et al., 1992 ), endothelial protein C receptor (EPCR) ( Mohan Rao et al., 2014 ), thrombospondin, E-selectin ( Turner et al., 1994 ) and chondroitin sulphate A ( Rogerson et al., 1995 ; Fried and Duffy, 1996 ). Adhesion of iRBCs to the cerebral microvascular endothelium is further accompanied by agglutination to other iRBCs, platelets, white blood cells (WBCs), and rosetting produced by adhesion of iRBCs and uninfected erythrocytes ( Fried and Duffy, 1996 ). Sequestration of iRBCs in microvessels may protect iRBCs from clearance by the spleen. In addition, it weakens the capability of iRBCs and RBCs to denature, leading to blood vessel blockage. Previous studies reported a significant correlation between sequestration of iRBCs in cerebral vessels and coma in CM patients ( Silamut et al., 1999 ; Ponsford et al., 2012 ; Storm et al., 2019 ). Taken together, sequestration of iRBCs leads to increased vasoconstriction and vascular obstruction, as well as decreased cerebral blood flow and hypoxia.

Inflammatory responses

Excessive immune responses and the release of a large number of inflammatory factors play important roles in the pathogenesis of CM ( Shikani et al., 2012 ). The humoral response to malaria parasites includes immune activation of macrophages and lymphocytes (CD8 + , CD4 + , natural killer (NK) cells) and activation of monocytes, resulting in accumulation of immune cells in the microvasculature and a systemic inflammatory response secreted by proinflammatory cytokines, including tumor necrosis factor (TNF)-α, interferon (IFN)-γ, and interleukin-1β (IL-1β), which are elevated in an episode of acute CM.

At the early stage of malaria infection, CD4 + and CD8 + T cells are activated by antigen-presenting cells (APCs) to initiate antimalarial protective cellular immune responses. The chemotaxis of T cells to peripheral cerebral vessels is one of the prominent features of CM. Recruitment of CD8 + T cells is the most predominant characteristic ( Riggle et al., 2020 ), and priming of CD4 + and CD8 + T cells initiates CM in the spleen by dendritic cells (DCs) presenting iRBCs antigens. NK cells and macrophages are activated by iRBCs to release inflammatory cytokines, such as TNF-α, IFN-γ, IL-1β, IL-12 and chemokines ( Dunst et al., 2017 ). Adhesion of iRBCs and the release of inflammatory cytokines can activate brain ECs, triggering ECs to produce chemokines and inflammatory cytokines and upregulate CAM expression. Activation of CD8 + T cells results in the expression of chemokine receptors, including CXCR3 and CCR5. Subsequently, chemokine receptors bind to chemokine ligands expressed by ECs to induce CD8 + T-cell migration and infiltration into brain ECs. CD11a (LFA-1) on CD8 + T cells promotes adhesion to endothelial ICAM-1 ( Howland et al., 2015 ; Dunst et al., 2017 ), and upregulated expression of CAMs induces increased recruitment of iRBCs, WBCs, and platelets in brain capillaries, which enhances cerebral microvascular sequestration ( McEver, 2001 ; Shikani et al., 2012 ). The rupture of iRBCs releases merozoites, which are endocytosed by ECs and then cross-presented on major histocompatibility complex class 1 (MHC-1) molecules. MHC-1 binds to antigen receptors (TCRs) on effector CD8 + T cells to activate CD8 + T cells ( Howland et al., 2013 ). Activated CD8 + T cells release perforin, granzyme-B, and chemokines, triggering NK cells and macrophages to migrate toward the brain. Immune cell accumulation and perforin release induce apoptotic signaling in ECs and alter the tight junctions of ECs, resulting in EC dysfunction and increased cerebral vascular permeability ( Yañez et al., 1996 ; Belnoue et al., 2002 ; Haque et al., 2011 ). Disruption of BBB integrity frequently results in perivascular space enlargement, edema formation, and increased intracranial pressure, eventually resulting in death.

Activation of vascular ECs

Activation of microvascular ECs is a central component of brain microvascular pathology, resulting from the sequestration of iRBCs on the surface of vascular ECs and systematic release of inflammatory cytokines ( Siddiqui et al., 2020 ). Activated ECs are well characterized by aggravation of brain microvascular sequestration, breakdown of tight junctions, and initiation of coagulation cascading reactions.

EPCR, a host receptor involved in anticoagulation and endothelial protection, has been identified as a receptor of PfEMP1 ( Turner et al., 2013 ). It is speculated that EPCR mediates iRBCs sequestration and participates in thrombin-induced disruption of the BBB. EPCR plays a crucial role in stabilizing ECs by activating activated protein C, an inhibitor of thrombin production that prevents EC activation ( Mohan Rao et al., 2014 ). In CM, some variants of the Plasmodium adhesins PfEMP-1 (called DC8 and DC13) preferentially bind to EPCR. Upon binding to EPCR, iRBCs reduce the level of available EPCR binding sites and block the activation of activated protein C by EPCR ( Shabani et al., 2017 ). Induction of the coagulation pathway by reducing the synthesis of EPCR and activated protein C leads to increased thrombin production and EC activation, as well as decreased protective effects of ECs.

Platelets are considered effector cells of the hemostasis system and contribute to CM. It is actively involved in sequestration, inflammation, and coagulation dysfunction and is identified as their joint point ( Cox and McConkey, 2010 ). Platelets bind to iRBCs (agglutination) and ECs via adhesion receptors (CD36, ICAM-1, P-selectin). In addition, platelets promote immune activation by binding Toll-like receptors to parasite-derived molecules, expressing chemokine receptors, and releasing cytokines, chemokines, and other immunomodulatory molecules. All these activated cells (ECs, platelets, monocytes) release microparticles (TNF-α, IFN-γ) ( Combes et al., 2004 ). Taken together, microparticles alter EC functions and are regarded as proinflammatory factors and cellular activation markers.

BBB disruption

The BBB is a semipermeable membrane that separates the peripheral blood from the cerebral parenchyma and maintains balance by protecting the brain from potentially harmful blood pathogens and chemicals. The BBB consists of the microvascular endothelium, pericytes, microglia, astrocyte end-feet, neurons, and basement membrane. Microvascular ECs have tight junctions that impede the passive paracellular diffusion of small and large molecules ( Abbott et al., 2010 ; Moura et al., 2017 ).

Binding of PfEMP1 to receptors on ECs, including ICAM-1, VCAM-1, and EPCR, may trigger multiple signaling pathways in ECs, leading to reorganization of the tight junction complex and ultimately resulting in BBB leakage. ICAM-1 induces endothelial cytoskeletal remodeling via Rho-dependent phosphorylation of cytoskeleton-associated proteins, including FAK, paxillin, p130Cas, and cortactin, thereby promoting BBB opening ( Wittchen, 2009 ). In addition, VCAM-1 cross-linking results in the activation of Rac1 signaling, which induces the attenuation of tight junctions through Rho-dependent induction of stress fibers. Binding of PfEMP1 to EPCR fosters activation of tissue factors Va and VIIIa, thereby disrupting the anticoagulant pathway. Activation of these tissue factors results in thrombin generation, leading to fibrin deposition. In addition, PfEMP1 binding to EPCR activates the Rho A and NF-κB pathways through thrombin-mediated cleavage of PAR1, which induces a proinflammatory response, leading to BBB disruption ( Bernabeu and Smith, 2017 ; Kessler et al., 2017 ). Microglia also disrupt the BBB by producing TNF and IL-1β. Adhesion of iRBCs, leukocytes, and platelets to ECs also causes EC damage and irreversible changes ( Nishanth and Schlüter, 2019 ). iRBCs stimulate leukocytes (monocytes, NK cells) to release inflammatory cytokines (TNF-α, IL-1α, IL-1β) by releasing parasitic toxins ( Medana and Turner, 2006 ; Nishanth and Schlüter, 2019 ). TNF-α upregulates miR-155 expression in ECs, leading to dysfunction of BBB integrity by altering tight junctions ( Barker et al., 2017 ). IL-1α and IL-1β activate ECs to release the chemokines CCL2, CCL4, CXCL8, and CXCL10, which promote leukocyte accumulation ( Dunst et al., 2017 ), and infiltrated leukocytes induce EC apoptosis through granzyme-B and perforin-mediated cytotoxicity ( Rénia et al., 2012 ). CD8 + T cells directly induce neuronal cell death through their cytotoxic function and activation of neurons. Due to increased BBB permeability, cytokines, chemokines, immune cells, and plasma factors enter the brain parenchyma and activate neurons and astrocytes, resulting in nerve injury and neurological sequelae ( Schiess et al., 2020 ). Kynurenic acid produced by macrophages and ECs during tryptophan metabolism is further converted into cytotoxic quinoline ( Bosco et al., 2003 ; Medana et al., 2003 ; Guillemin, 2012 ). All othese molecules induce disruption of the BBB ( Figure 2 ).

Molecular mechanisms of blood–brain barrier dysfunction. The binding of P. falciparum erythrocyte membrane protein-1 (PfEMP-1) to the receptors on the ECs, including ICAM-1, VCAM-1, and EPCR, may trigger multiple signaling pathways in ECs, leading to the change to cytoskeleton-associated proteins, ultimately resulting in the disruption of the BBB. Meanwhile, signaling pathways triggered by PfEMP1 lead to activation and injury of astrocytes, microglia, neurons, and perivascular macrophages and initiate the process of neuropathological injury. The binding of PfEMP1 to EPCR fosters the activation of tissue factors Va and VIIIa, thereby disrupting the anticoagulant pathway. Activation of these tissue factors results in thrombin generation, leading to fibrin deposition. Microglia also disrupt the BBB by producing TNF and IL-1β. Astrocytes retract their end feet from ECs, resulting in reduced vascular wrapping. Angiopoietin-2 produced by ECs also leads to reduced vascular wrapping by inducing pericyte dysfunction. The iRBCs stimulate leukocytes to release inflammatory cytokines (TNF-α, IL-1α, IL-1β) by releasing parasitic toxins. These cytokines disrupt BBB integrity by altering tight junctions and activating ECs to release chemokines (CCL2, CCL4, CXCL4, CXCL8, and CXCL10), which promote leukocyte accumulation, including CD4 + T cells and CD8 + T cells. Infiltrated leukocytes induce EC apoptosis through granzyme B and perforin-mediated cytotoxicity. Granzyme B and perforin directly induce neuronal cell death. Adhesion of iRBCs, leukocytes, and platelets to ECs also causes EC damage and irreversible changes. Due to the increased permeability of the BBB, cytokines, chemokines, immune cells, and plasma factors flood into the brain parenchyma and activate neurons and astrocytes, resulting in nerve injury and neurological sequelae. Kynurenic acid produced by macrophages and ECs during tryptophan metabolism is further converted into cytotoxic quinoline, which plays a vital role in stromal cells and microglia. These molecules induce the disruption of the BBB.

Recently, multiomics platforms, including genomics, transcriptomics, proteomics and metabolomics, have been widely used to unravel the underlying pathogenesis of cancer and design therapeutic strategies ( Nam et al., 2021 ). To date, there has been no combined use of multiomics approaches for CM studies, which has inspired the joint analysis of individual omics data. Analysis of DNA markers, RNA transcripts, proteins, and metabolites generated during the progression of CM contributes to understanding CM pathogenesis, which facilitates the precise diagnosis of CM and the discovery of novel therapeutic targets.

Diagnosis of CM

Diagnosis is central to malaria control, and early diagnosis is one of the crucial factors affecting the prognosis of CM. Unfortunately, there is no gold standard for the diagnosis of CM because of its complex and nonspecific clinical manifestations. Currently, the primary clinical symptoms that are available for CM diagnosis include (1) nonarousal coma (no local responses to pain) that persists for more than six hours after experiencing a generalized convulsion; (2) presence of asexual forms of P. falciparum on both thick and thin blood smears; and (3) exclusion of other causes of encephalopathy. To improve the accuracy of CM diagnosis, state-of-the-art cerebral imaging tools are available to assist the diagnosis of CM ( Table 2 ).

Table 2

Advantages and disadvantages of different approaches for the diagnosis of cerebral malaria.

Malarial retinopathy

The presence of malarial retinopathy facilitates the improvement in the specificity for the clinical diagnosis of CM and offers strong evidence for CM diagnosis in both adults and children ( MacCormick et al., 2014 ). In pediatric patients, the degree of retinal microcirculation is comparable to that of the brain, making it an easily observable surrogate marker to assess the severity of cerebral pathology during CM ( Bearden, 2012 ). It has been shown that malarial retinopathy presents 100% specificity and 95% sensitivity for the detection of CM, with autopsy as the diagnostic gold standard ( Beare et al., 2006 ).

Fundoscopy is a relatively low-cost and simple technique for the detection of retinopathy, which allows accurate differentiation between malarial and nonmalarial comas. The diagnosis of malarial retinopathy depends on the presence of peripheral retinal whitening, orange and white discoloration of retinal vessels, white-centered hemorrhages, and mild papilledema. The unique retinopathy of patchy retinal whitening and focal changes in vascular color are highly specific for CM diagnosis ( Beare et al., 2006 ; MacCormick et al., 2014 ). In addition, retinal hemorrhage is a common but less distinctive feature, while papilledema is not specific to CM and is unavailable for CM diagnosis alone.

Optical coherence tomography

OCT is an in vivo imaging tool that detects retinal changes and is feasible for qualitatively and quantitatively evaluating high-resolution cross-sectional retinal images, papilla of the optic nerve, and even retinal nerve fiber layer thickness ( Spaide et al., 2018 ). OCT is a noninvasive, high-resolution measure; however, this technique fails to diagnose malarial retinopathy.

Teleophthalmology

The introduction of fundoscopy improves the accuracy of CM diagnosis; however, it requires well-trained ophthalmologists and expensive equipment, which restrains its applications in resource-limited settings ( Abu Sayeed et al., 2011 ). To overcome these problems, an innovative approach, teleophthalmology, has emerged for retinal assessment ( Salongcay and Silva, 2018 ). This technique uses a simple and inexpensive portable fundus camera to capture images by well-trained professionals, and then, the images are transferred to ophthalmologists for rapid diagnosis. Teleophthalmology requires little additional training, minimizes healthcare-seeking inconvenience and is feasible in various settings ( Maude et al., 2011 ).

Fluorescein fundus angiography

With improvements in optical technology and high-resolution digital imaging, FFA has been extensively used by ophthalmologists across the world. FFA measures the integrity of retinal blood perfusion and the blood–retinal barrier by observing a map of the intraretinal fluorescein. CM patients have nonperfusion in the central retina and extensive nonperfusion in the peripheral retina ( Glover et al., 2010 ). Nevertheless, FFA requires a bulky tabletop retinal camera, whose weight and stillness make it difficult to capture clear images from conscious CM patients.

EEG and micro-EEG

EEG pulses are recorded by measuring voltage fluctuations caused by ionic currents within the neural tissues. This noninvasive technique has made it possible to detect delayed CM sequelae ( Sahu et al., 2015 ), including neurological disorders such as status epilepticus. CM patients’ EEG abnormalities manifest as diffuse slowing, atypical sleep elements (fusiform and parietal waves), and epileptiform activity ( Postels et al., 2018 ).

Although EEG is a noninvasive and relatively inexpensive diagnostic method, a significant limitation is continuous follow-up assessment of brain activity after discharge from the hospital. To address this concern, micro-EEG, a miniature, wireless, and battery-powered portable headset, was developed, and this device achieved a comparable accuracy for the diagnosis of status epilepticus with standard EEG systems ( Grant et al., 2014 ). This new tool facilitates the recording of brain activity after discharge from the hospital and may provide an option for CM diagnosis.

In addition, other imaging tools, including magnetic resonance imaging (MRI) ( Grant et al., 2014 ; Sahu et al., 2021 ), computed tomography (CT) ( Mohanty et al., 2011 ; Sahu et al., 2021 ), intravital microscopy (IVM) ( Volz, 2013 ), and in vivo bioluminescent imaging ( Franke-Fayard et al., 2006 ), may serve as additional diagnostic approaches for CM.

In addition to imaging tools, biomarkers have been extensively used for the rapid diagnosis of CM. Soluble ICAM-1, which is strongly associated with CM, was reported to be upregulated in the brain microvasculature ( Ramos et al., 2013 ). The soluble EPCR (sEPCR) level at admission is positively correlated with CM and malaria-related mortality, and admission sEPCR was identified as an early biomarker of prognosis among CM patients ( Ramos et al., 2013 ). Angiopoietin-1 (Ang-1) and Ang-2 have been characterized as mediators of endothelial activation and integrity, and Ang-1 maintains vascular quiescence, while Ang-2 displaces Ang-1 upon endothelial activation and sensitizes cells to become responsive to subthreshold concentrations of TNF. Reduced Ang-1 and Ang-2 and increased Ang-2/Ang-1 are detected in patients with CM ( Conroy et al., 2012 ; Eisenhut, 2012 ), which is consistent with the pathophysiological changes of activation and dysfunction of ECs among CM patients. In addition, elevation of specific plasma smooth muscle proteins, including carbonic anhydrase III (CA3), creatine kinase (CK), creatine kinase muscle (CKM), and myoglobin (MB), indicates muscular damage and microvasculature lesions during CM ( Bachmann et al., 2014 ). These proteins may serve as novel biomarkers for predicting CM severity and therapeutic targets for CM.

Previous reports have demonstrated that the expression of circulating microRNAs (miRNAs) is highly sensitive to physiological and pathological stimuli ( Paul et al., 2018 ). As a consequence, their changes in response to P. falciparum infection raise the possibility of new diagnostic and potentially prognostic tools for CM. Hsa-miR-3158-3p was found to be effective for the diagnosis of severe/cerebral malaria across all age groups, and hsa-miR-3158-3p represents a promising biomarker candidate for predicting CM prognosis in all age groups ( Gupta et al., 2021 ). In addition, previous studies have shown associations of the relative expression of miR-19a-3p, miR-19b-3p, miR-146a, miR-193b, miR-467a, miR-27a, and miR-146a with CM ( Martin-Alonso et al., 2018 ; Wah et al., 2019 ; Assis et al., 2020 ).

Spatial metabolomics is an emerging omics tool that provides precise determination of species, contents, and differential spatial distributions of metabolites in animal/plant tissues ( Martin-Alonso et al., 2018 ; Geier et al., 2020 ). In the ECM, both kidney and spleen metabolism are differentially perturbed in CM compared with noncerebral malaria, and lipid metabolism and the TCA cycle are altered in the kidney and spleen ( Ghosh et al., 2012 ). Spatial metabolomics is beneficial for the diagnosis, biomarker discovery, and prognosis prediction of CM.

Antimalarial therapy

Early standard antimalarial treatment is crucial for CM. In 2011, parenteral artesunate was recommended as the first-line treatment for CM by the World Health Organization (WHO). Although artesunate is effective in clearing malaria parasites, administration with potent artemisinin derivatives alone is insufficient to protect against cell death, nerve damage, and cognitive impairment ( Brejt and Golightly, 2019 ), and the long-term and widespread use of artemisinins alone may lead to the emergence of drug-resistant strains. Artemisinin-based combination therapies (ACTs) are therefore introduced to improve clinical outcomes, reduce mortality, prevent long-term neurocognitive deficits and delay the emergence of artemisinin resistance.

Potential adjuvant therapy

Targeting a single signaling pathway may be insufficient to reduce mortality or improve neurological conditions among CM patients, since CM is a multiprocess disorder. Therefore, adjuvant therapy targeting multiple physiological processes of CM is needed to improve clinical outcomes, prolong survival, and reduce neurological damage in survivors ( John et al., 2010 ). Adjuvant therapy aims to decrease cytoadherence and sequestration, modulate immune responses and improve endothelial functions, with neuroprotection given as a priority, and previous studies have shown the effectiveness of adjuvant therapy in reducing mortality due to CM in ECM models ( Wei et al., 2022 ). However, the results from clinical trials are disappointing.

Targeting parasite adhesion to vascular endothelium

Clinical episodes of CM are associated with the expression of var genes encoding the specific PfEMP1 protein, while Var genes are independently observed to bind to the brain endothelium in vitro ( Avril et al., 2012 ; Claessens et al., 2012 ). Once the crucial var ligand and its endothelial receptors are identified, high-throughput screening may be used to identify small molecules that block the binding or activation of microvascular endothelium by iRBCs. Levamisole was found to interrupt CD36-dependent binding by inhibiting CD36 dephosphorylation, which is required for high-affinity binding ( Miller et al., 2013 ). It is therefore suggested that blockade of malaria parasite adhesion to the vascular endothelium may be a promising strategy for CM treatment.

Regulating immune responses

Preventive measures prior to malaria may alter the immune system status and delay CM development; therefore, adjuvant therapy targeting immune regulation is difficult. Previous animal studies have identified modulators of host targets as potential adjuvant therapies, opening up new avenues for developing highly selective adjuvant therapies for CM. Targeting mammalian targets of rapamycin (mTOR) with rapamycin has been proven to be effective in suppressing immune responses ( Mejia et al., 2015 ), thus supporting the potential of rapamycin as an adjuvant treatment for CM. 6-Diazo-5-oxo-L-norleucine (DON), a glutamine analog, was found to block the glutaminase-mediated conversion of glutamine to glutamate, thereby inhibiting T-cell activation ( Crunkhorn, 2015 ), and administration of DON resulted in survival from CM and brain recovery in ECM ( Gordon et al., 2015 ). These data demonstrate that regulation of immune balance may be effective for CM treatment.

Improving endothelial functions and maintaining endothelial barrier integrity

Several therapeutics have been found to target endothelial dysfunction, including a platelet-activating factor receptor antagonist ( Lacerda-Queiroz et al., 2012 ), statins such as atorvastatin ( Souraud et al., 2012 ) and lovastatin ( Reis et al., 2012 ), activated protein C ( Mohan Rao et al., 2014 ), and erythropoietin ( Kaiser et al., 2006 ). In addition, Ang protein was reported to regulate endothelial barrier integrity and is associated with CM-induced retinopathy and death ( Conroy et al., 2012 ). In response to TNF stimulation, Ang-2 causes destruction of endothelial barrier integrity and triggers endothelial adhesion molecule expression. Secretion of Ang-2 in endothelial Weibel-Palade bodies may lead to vascular leakage, inflammation, and encephaledema associated with CM. Endothelium-targeted therapy that inhibits Weibel-Palade extracellular secretion may block the pathogenic autocrine activity of Ang-2 ( Yeo et al., 2008 ).

Neuroprotection

CM is a severe neurological syndrome that may cause epilepsy, coma and death, and survivors may present with neurological and cognitive deficits. Protection of nerve cells is therefore highly essential. Among the potential neuroprotective agents, erythropoietin (EPO) is one of the most promising. In addition to stimulating erythropoiesis, EPO has neuroprotective functions and increases the stability of endothelial barriers ( Ghezzi and Brines, 2004 ; Maiese et al., 2005 ). Artesunate plus recombinant human erythropoietin (rhEPO) has been found to reduce endothelial activation and improve BBB integrity in murine ECM models, resulting in faster recovery, increased survival rates, and high neuroprotective effects ( Du et al., 2017 ). Administration of peroxisome proliferator-activated receptor-gamma (PPARγ) has been proven to improve long-term cognitive ability and prolong survival ( Serghides et al., 2014 ). In addition, PPARγ has shown neuroprotective effects via various pathways and promotes neuronal repair, making it an attractive adjuvant therapy. Dysregulation of the limk-1/cofilin-1 pathway might lead to alterations in neuronal morphology and is considered the cause of cognitive defects in patients surviving CM ( Simhadri et al., 2017 ); therefore, the LIMK-1/cofilin-1 pathway is considered a potential therapeutic target for CM. In addition, granzyme-B produced by CD8 + T cells directly kills neurons through cytotoxic function and activation of caspase-3 and calpain1 ( Kaminski et al., 2019 ). Therefore, targeting granzyme-B may be an option to prevent neuronal cell death.

Unfortunately, the clinical efficacy and safety of these adjuvant treatments have not been tested until now. Inclusion of specific PfEMP-1 receptors on the surface of iRBCs may allow its connection with T cells to yield the ability to kill iRBCs, thus inhibiting the downstream pathological reactions initiated by iRBC adhesion. Chimeric antigen receptor T (CAR-T) immune cell therapy is a breakthrough for cancer therapy ( Herzig et al., 2019 ; Bertoletti and Tan, 2020 ). Since iRBC adhesion is the initial step during the development of CM, the efficacy and safety of CAR-T immune cell therapy for CM deserve further investigation.

Conclusions and perspectives

CM is a multifactorial and multiprocess disorder. Administration of antimalarials alone is effective in clearing malaria parasites; however, such a treatment fails to protect against nerve cell death, neurological damage and cognitive impairment. This urges the development of novel treatment for improved outcomes of CM. In addition, the rapid developments of -omics offer an opportunity for understanding the etiology of CM and provide insights into the clinical diagnosis and therapy of this potentially fatal disorder.

Author contributions

JL, HD, and WWe conceived and designed the study. XS, WW, WC, HZ, WWa, HD, and JL wrote the paper. All the authors read and approved the final manuscript.

This study was supported by the National Natural Science Foundation of China (Grant Number 81802046), the Principle Investigator Program of Hubei University of Medicine (Grant Number HBMUPI202101) and the Advantages Discipline Group (Public health) Project in Higher Education of Hubei Province (2022PHXKQ1).

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher’s note

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• Open access
• Published: 23 August 2024

Longitudinal associations of plasma amino acid levels with recovery from malarial coma

• Donald L. Granger 1 , 2 ,
• Daniel Ansong 3 ,
• Tsiri Agbenyega 3 ,
• Melinda S. Liddle 4 ,
• Benjamin A. Brinton 5 ,
• Devon C. Hale 1 ,
• Bert K. Lopansri 4 ,
• Richard Reithinger 6 &
• Donal Bisanzio 6  

Malaria Journal volume  23 , Article number:  253 ( 2024 ) Cite this article

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Disordered amino acid metabolism is observed in cerebral malaria (CM). This study sought to determine whether abnormal amino acid concentrations were associated with level of consciousness in children recovering from coma. Twenty-one amino acids and coma scores were quantified longitudinally and the data were analysed for associations.

In a prospective observational study, 42 children with CM were enrolled. Amino acid levels were measured at entry and at frequent intervals thereafter and consciousness was assessed by Blantyre Coma Scores (BCS). Thirty-six healthy children served as controls for in-country normal amino acid ranges. Logistic regression was employed using a generalized linear mixed-effects model to assess associations between out-of-range amino acid levels and BCS.

At entry 16/21 amino acid levels were out-of-range. Longitudinal analysis revealed 10/21 out-of-range amino acids were significantly associated with BCS. Elevated phenylalanine levels showed the highest association with low BCS. This finding held when out-of-normal-range data were analysed at each sampling time.

Longitudinal data is provided for associations between abnormal amino acid levels and recovery from CM. Of 10 amino acids significantly associated with BCS, elevated phenylalanine may be a surrogate for impaired clearance of ether lipid mediators of inflammation and may contribute to CM pathogenesis.

Of the complications associated with Plasmodium falciparum infection, unarousable coma, the hallmark of cerebral malaria (CM), may lead to long-term disability and death [ 1 , 2 ]. Recent research aided by autopsy and imaging indicates that coma may be the result of generalized brain swelling due to accumulation of sequestered infected erythrocytes in the microvasculature [ 3 , 4 , 5 , 6 ]. Sequestration is the physical adherence of infected cells to activated endothelial cells within brain capillaries and venules. Microscopic, sequestered foci with patchy distribution restrict blood flow with downstream consequences including anoxia and acidosis. Leakage of intravascular fluid and, in some cases, erythrocytes into adjacent brain parenchyma through endothelial junctions adds to pathogenic events [ 7 , 8 ].

In addition to the anatomical pathology in the brain, there are systemic abnormalities involving carbohydrate [ 9 , 10 ] lipid [ 11 ] and amino acid [ 12 , 13 ] metabolism. None are specific for CM—indeed, they are also seen in septic syndrome and other severe inflammatory diseases [ 14 , 15 , 16 ]. Metabolic causes of coma in CM have been sought, but no convincing pathogenic mechanism has been found. Nevertheless, these changes may contribute to coma in ways not yet recognized.

Research on the role of nitric oxide in malaria pathogenesis noted abnormalities in the plasma levels of several amino acids in children presenting with CM [ 17 , 18 ]. All abnormal amino acid levels were below the normal ranges, except for one, phenylalanine, which was consistently above 80 micromolar . Healthy controls (HC) rarely exceeded this cutoff concentration. With resolution of coma in treated survivors, phenylalanine levels normalized. This study questioned whether longitudinal measurements of abnormal amino acid levels might be associated with the level of consciousness as children recovered. Such analysis may uncover an amino acid or group of amino acids involved in P. falciparum pathogenesis.

To address this question, a prospective observational study was conducted in Ghana, in which children entering hospital in coma due to malaria were observed frequently (every 12–24 h) for 60 h and their level of consciousness was quantified by Blantyre coma score(s) (BCS) [ 19 ]. At the same time intervals, blood samples were obtained and processed for 21 plasma amino acid levels. The a priori hypothesis was that the levels of one or more amino acid(s) would be most closely associated with the BCS as participants regained consciousness. A healthy control group was enrolled to determine whether amino acid levels in Ghanaian children matched reference laboratory normal ranges for healthy children in the US. The control group also provided disease versus normal comparisons at the time of presentation to hospital.

Study design and site

The study was a prospective, observational, longitudinal investigation at Komfo Anokye Teaching Hospital in Kumasi, Ashanti Region, Ghana (6.697479° N 1.631690° W) from 2004 to 2006. Enrolled were children who presented to the hospital with CM, as well as healthy control children who were asymptomatic hospital visitors or attendees at well-clinic check-ups. Children with uncomplicated malaria were not included, as the study was designed to address amino acid levels associated with recovery from coma. Study participants largely resided in Kumasi and its surrounding districts. The study was conducted by senior Ghanaian physicians in the Department of Pediatrics assisted by infectious diseases faculty, fellows, and medical students from the University of Utah. Plasma samples for amino acid analysis were obtained at enrollment (i.e., at admission) and at least every 24 h during hospitalization.

Enrollment criteria

Children were 6 months to 6 years of age (median age, 2.8). WHO case definition for CM was used as inclusion criteria [ 20 ]: (1) any level of P. falciparum parasitaemia on peripheral blood film; (2) unarousable coma as assessed by BCS ≤ 2 not attributable to hypoglycaemia (i.e., blood glucose level < 40 mg/dl); (3) coma persisting more than 60 min after any convulsion; and (4) no other identifiable cause of coma. Exclusion criteria were any of the following: (1) microscopic or culture evidence of bacterial or viral co-infection; (2) oral or intravenous quinine or oral artemisinin-based combination therapy initiated > 18 h prior to enrollment; (3) haemoglobin < 5 mg/dl when blood transfusion was unavailable at the study site.

Similar aged healthy children were prospectively enrolled as HC. Weight was not included as criterion for enrollment and therefore there is significant missing data for this variable (Table  1 ). Eligible HC had no symptoms or signs of active illness, no febrile illness within the past 2 weeks, no history or evidence of an active inflammatory condition, and negative blood film for malaria parasites. Availability of HCs for enrollment at the study site was limited and resulted in fewer than anticipated children in this group.

Clinical evaluation and management

Demographic information, clinical history, and physical examination were documented using standardized case report forms. History of last food or liquid intake for CM participants was recorded to assess potential confounding influence of protein intake on plasma amino acid concentrations. The severity of CM resulting in anorexia ruled out this possible confounder for the majority of participants. Capillary blood samples were obtained for malaria thick and thin blood films and were prepared by Giemsa staining. Venous samples for routine laboratory analysis included complete blood count, electrolytes, creatinine, and lactate. Because laboratory service was not always available, there are significant missing data (Table  2 ) for these analytes. Urine was obtained for dipstick analysis and culture. Blood and urine laboratory results were immediately available to clinicians. Blood cultures were obtained on all participants with CM. Lumbar puncture was done to investigate possible bacterial meningitis unless it was clear to the presiding clinicians that this diagnosis was unlikely. Thirty-four CM cases received lumbar puncture. Cerebrospinal fluid analysis included: (a) determination of glucose and protein concentrations; (b) cell count with differential performed by personnel trained in microscopy; (c) Gram stain and bacterial and fungal cultures.

Children with CM received anti-malarial therapy and supportive care as per standard Ghanaian Ministry of Health protocols for the years during which the study was conducted (intravenous quinine or intravenous artesunate as recommended by WHO protocols). Treatment was initiated as soon as the diagnosis of malaria was suspected.

BCS was assessed at presentation and at least every 24 h until hospital discharge or death. For some participants (year 1 of the study) BCS was measured at admission and at 12-h intervals for up to 60 h. For years 2 and 3, midnight blood draws became impractical due to transportation and safety concerns, and samples were taken every 24 h. For each child at each interval, three clinicians independently assessed BCS. The assessments were done by a Ghanaian faculty physician, a US infectious diseases faculty or fellow, and a Ghanaian or US medical student. After assessment, the three clinicians met to obtain a consensus for BCS. For some patients this required returning to the bedside to review the findings. In all cases, consensus was reached by the three examiners and one BCS was recorded. At the time of BCS assessments the clinician examiners were unaware of any data pertaining to plasma amino acid concentrations.

Plasma amino acid analysis

Blood samples were collected into heparin tubes, mixed, and immediately centrifuged to sediment blood cells. Supernatant plasma was placed into polypropylene freezer tubes and stored at − 80 °C until shipment. Samples were transported in a liquid nitrogen dry shipper to the US for amino acid analysis. All amino acid analyses for the 3-year study were performed within 1 month after collection for each year. Amino acid analyses were performed at the Biochemical Genetics Section, ARUP Laboratories, University of Utah School of Medicine in collaboration with Dr. Marzia Pasquali. The amino acid analyzer employed ion exchange chromatography for separation and quantification. With two exceptions, all plasma amino acids were quantified. Exceptions were tryptophan, which emerged from the column lastly at a long retention time unsuitable for analysis, and hydroxyproline, which gave frequent values of zero or below the level of sensitivity of the assay. Computer output results from the amino acid analyzer were electronically transferred to Excel spread sheets for subsequent data analysis.

Statistical methods

Data was compared for CM cases and healthy controls at entry (Tables 1 , 2 , 3 ). Data was analysed using GraphPad Prism version 10.1.1. Data sets for each variable were tested for normality. Parametric data (Tables 1 , 2 ) for both CM and healthy control groups were compared for significant difference using two-tailed Student’s t-test. For non-parametric data (Table  3 ) the two-tailed Mann–Whitney test was used. A significant difference was defined as P ≤ 0.05.

Association between BCS values and amino acid levels was investigated using statistical modeling. The aim was to assess if an out-of-range level of each amino acid was linked to a low BCS. Since BCS is based on an ordinal discrete scale from 0 to 5, an ordinal logistic regression, which is the most appropriate modeling technique for ordinal variables, was employed [ 21 , 22 ]. The model was formulated using a generalized linear mixed-effects model (GLM-EM) [ 23 ]. It incorporated children as a random effect to account for variations in the sampling period. The ordinal logistic regression model describes the association between the dependent variable and independent variables by estimating odds ratios (OR). Odds ratio was used to identify the association between out-of-range amino acid levels and BCS. An OR significantly below 1.0 indicated that having an amino acid level outside the normal range was associated with low BCS. An OR above 1.0 indicated that having an amino acid level within the normal range was associated with a high BCS. The model equation was the following:

where BCS was children’s BCS expressed as an ordinal variable from 0 to 5, Year was the sampling year, and Child ID random was children’s ID included as a random effect.

A logistic regression GLM-EM was also built to investigate the effect of time on the levels of amino acids [ 24 ]. This model aimed to identify the time threshold after which the levels of amino acids returned to the normal range. An OR significantly above 1.0 indicated a high probability that the amino acid level was normal at a given time, while an OR significantly below 1.0 indicated a high probability that the amino acid level was abnormal at a given time. The equation for the GLM-EM was the following:

where Amino acid level (0,1) was a dichotomous variable reporting if the amino acid level was normal (value = 1) or out of normal range (value = 0), Sampling time was the time intervals of sampling, Year was the sampling year, and Child ID random was children’s ID included as a random effect.

All statistical modelling was performed using BayesX software through R language interface [ 25 , 26 ]. All P values were adjusted using the Bonferroni correction [ 27 ]. A significant association was defined as P ≤ 0.05.

The study was approved by the ethics committee at Komfo Anokye Teaching Hospital and the Institutional Review Board at the University of Utah, USA. Written informed consent was obtained from either parent or guardian of all participants. Consent forms were presented in Twi or in English, depending on the consenting parent or guardian preference. US Department of Health and Human Services guidelines for human subjects research, the University of Utah guidelines, and the guidelines for the Komfo Anokye Teaching Hospital were followed.

Clinical and laboratory findings

Forty-two children were enrolled with CM due to P. falciparum; of CM cases, 6 were enrolled in 2004, 19 in 2005, and 17 in 2006; note: fewer children were enrolled in year 1 due to lack of dedicated study personnel and difficulties for setting up the Study Protocol requirements. Thirty-six healthy controls were enrolled during these same years. The enrollment periods for each year were the same, i.e., during the long rainy season. Two CM participants were excluded from the analyses due to missing data; six children with CM died (14.3%) during hospitalization, all within the first 48 h of admission.

Clinical characteristics for the two groups are listed in Table  1 . The groups were closely matched for age, gender, and weight. Physical findings revealed the degree of illness in the CM group, including significant differences in pulse, respiratory rate, and temperature. Of those CM cases for whom clinical data was available, 68% experienced a witnessed seizure and 59% received diagnostic lumbar puncture. Historical data on most recent food intake indicated that plasma amino acid levels in CM participants were unlikely to be confounded by recent protein ingestion. The length of pre-admission symptoms (mean, 4 days) was consistent with the acute course of CM leading to coma prompting presentation at hospital.

Laboratory findings in CM cases were consistent with CM, including anemia, thrombocytopenia, and metabolic acidosis (Table  2 ). Elevated creatinine was likely due to acute kidney injury [ 28 ]. Hypoglycaemia in CM participants was obscured by immediate intravenous glucose-containing fluid begun on all children presenting in coma.

Plasma amino acid levels at entry

Plasma samples collected from 40 CM enrollees at various time-points during hospitalization were available for amino acid analysis with one exception: a single sample at time zero. Of the 36 healthy control enrollees there were 6 samples unavailable for analysis because of insufficient venipuncture blood for plasma separation or because samples went missing.

For healthy controls, normal distribution was usually the case. However, all amino acid data for the CM group showed non-parametric distributions. For 5 of the 21 amino acids (Asp, Cys, Leu, Tyr, Val), there were no significant differences between CM versus healthy controls at entry (Table  3 ). In all cases but one, the levels of the remaining amino acids (Ala, Arg, Cit, Glu, Gln, Gly, His, Ilu, Lys, Met, Orn, Pro, Ser, Tau, Thr) were significantly lower in the CM group compared to healthy controls. One amino acid (Phe) was significantly elevated in CM participants compared to healthy controls. Also shown in Table  3 are the normal ranges (mean ± 2SD) for each amino acid, which were established at the ARUP diagnostic laboratory based on a large age-dependent database of healthy US children. For Ghanaian healthy control children, amino acid levels were largely within the US normal ranges.

Longitudinal association between BCS and amino acid levels outside the normal range

Results obtained from the ordinal GLM-EM showed that BCS was significantly associated with amino acid levels outside the normal range for 10 of the 21 amino acids (Table  4 ). Nine of the 10 amino acids were associated with significant probability for having a low BCS; the lower the odds ratio the greater the probability of having a low BCS. A phenylalanine level outside the normal range was associated with the highest probability of having a low BCS (lowest odds ratio). Conversely, valine out-of-range levels were significantly associated with a high probability of having a high BCS (highest odds ratio). Odds ratios calculated using statistical modeling (GLM-EM) do not specify whether an amino acid association significance is above or below its normal range. In this regard it is notable that only one of the ten amino acids (phenylalanine) with significant association for a low BCS is above its normal range. All other significant amino acid associations are below their normal ranges.

For completeness box plots showing raw data for out-of-range versus normal range individual samples for each amino acid at a given BCS are shown in Supplementary data (Supplementary Fig. 1, panels A–D).

Logistic regression assessment of time to reach normal range levels for the 10 amino acids significantly associated with BCS

For clarity, the time course was plotted for plasma levels (mean ± SEM) of each of the ten amino acids (Table  4 ) significantly associated with a low BCS (Fig.  1 ). In each panel the right axis reproduces the mean ± SEM BCS. A dashed horizontal line marks the normal range lower limit for nine of the ten amino acids. For these nine all abnormal levels were below the normal range. The one exception is phenylalanine where the dashed line shows the upper limit of normal, commensurate with hyperphenylalaninaemia for this amino acid. Some amino acids (Arg, Cit, Gln) exhibit a time lag before returning to within their normal ranges while BCS rose to a near conscious level (BCS ~ 3–4) by 24 h. Others (Gly, Ilu, Lys, Ser, Thr) showed borderline low levels, but rose to within their normal ranges as time progressed. Exceptionally, high phenylalanine levels promptly fell in concert with rising BCS.

Out-of-range amino acid levels significantly associated with Blantyre Coma Score at sampling time intervals. Plasma levels of each amino acid (circles, mean ± SEM) significantly associated with BCS (Table  4 ) are shown at sampling times. Blantyre Coma Score (triangles, mean ± SEM) at the same sampling times are reproduced for each amino acid panel

A logistic regression model was used to determine the time after which there was a high probability that amino acid levels reached the normal range (Fig.  2 ). Bar graphs for each of the ten amino acids show odds ratios (± 95% CI) at each sampling time. Odds ratios below 1.0 with Asterix denote significant association with levels outside normal ranges. Odds ratios above 1.0 with Asterix denote significant association with levels within normal ranges. Bars without Asterix are without significance. Almost all amino acids normalized by 48–60 h post admission and initiation of treatment. However, the analyses showed marked variability across amino acids: for example, phenylalanine and isoleucine reached their normal range at 36 h, while for other amino acids it took 48 and 60 h to reach the normal range. An outlier was valine, with significant normal range values at zero and 12 h and abnormal range values at 36, 48 and 60 h. The changes were associated with increasing BCS as time elapsed. For reference, Fig.  2 (lower right-most panel) shows BCS data at each sampling time.

Effect of sampling time on having an amino acid level outside of, or within, the normal range. Bar graphs for each amino acid show odds ratios (± 95% CI) at each sampling time. Odds ratios below 1.0 with Asterix denote significant association with levels outside normal ranges. Odds ratios above 1.0 with Asterix denote significant association with levels within normal ranges. Bars without Asterix are without significance. Box plot in the lower right hand panel shows median BCS with variance measures at sampling intervals. Boxes represent interquartile ranges (IQR). Dark lines within boxes are medians. Whiskers indicate minimum and maximum values within 1.5 times the IQR

Plasma amino acid abnormalities in CM at hospital entry

Abnormal amino acid levels based on age-dependent normal ranges were defined for 21 amino acids as established for healthy US children in the reference laboratory. To determine whether these normal ranges applied to healthy Ghanaian children, an age-matched healthy control group was enrolled and their amino acid plasma levels were measured. The healthy control levels were within normal ranges save for slight median decreases of cystine and glutamine (Table  3 ).

Amino acid levels were compared in CM versus healthy control cohorts at hospital entry. Sixteen of the 21 amino acids were significantly different. The results mirror those reported by others for children [ 13 ] and adults [ 12 ] with severe malaria, including CM. Fifteen of the 16 were below the normal range and one (phenylalanine) was elevated. The hypercatabolic state induced by the inflammatory response in severe malaria, in which amino acids are oxidatively degraded to yield chemical energy likely contributes to the low levels observed [ 29 , 30 ] Additionally, gluconeogenesis in liver consumes glucogenic amino acids. Acute kidney injury associated with amino acid reabsorption abnormalities poses yet another source of loss [ 13 ]. Significantly low levels of glutamine, glutamate, proline, ornithine, citrulline and arginine comprise the pathway of de novo arginine synthesis [ 18 ] a finding consistent with low nitric oxide production [ 31 ]. Longitudinal data found low arginine levels associated with nitric oxide-dependent endothelial dysfunction [ 32 ].

Longitudinal associations between out-of-range amino acid levels and BCS

These results extended amino acid abnormalities by longitudinal measurements with analysis for association with BCS. By employing the GLM-EM model the data showed that ten of the sixteen out-of-range amino acids at entry were significantly associated with BCS (P ≤ 0.05, Table  4 ). Six of the ten (arginine, glycine, isoleucine, phenylalanine, threonine, and valine) showed high significance for association with BCS (P ≤ 0.01). Of this set, phenylalanine and valine stood out. Phenylalanine was the only amino acid with levels above the normal range in CM participants compared to healthy controls. Of all significant BCS-associated amino acids, phenylalanine showed the highest association (lowest odds ratio, 0.25). Valine out-of-range values were associated with high BCS.

For the ten amino acids significantly associated with BCS, the out-of-range values at each sampling time were analysed by calculating odds ratios with the GLM-EM model. With time, 9 of 10 amino acids normalized by 60 h post admission and initiation of treatment (odds ratios > 1.0). At 24 to 36 h post admission and initiation of treatment, levels transitioned to normal ranges for isoleucine, lysine, phenylalanine, and threonine. At these same time-points median BCS rose from about 1 to 4–5. Thus, regaining consciousness occurred at the time when these four amino acids normalized. The outlier was valine with significant normal range values at entry and at 12 h with transition to abnormally low levels at 36, 48, and 60 h post admission and initiation of treatment.

Significance of association of abnormal valine levels with high BCS

Of the ten amino acids associated with BCS, a unique association between BCS and valine was found. Out-of-range valine levels bore significant probability to have high, rather than low, BCS. This finding could relate to the complex catabolism of the branched-chain amino acids (Leu, Ilu, Val). In experimental animal models and possibly in humans, high leucine levels antagonize valine degradation at the decarboxylation (keto acid dehydrogenase) step by competitive inhibition [ 33 , 34 ]. This might delay valine catabolic kinetics resulting in out-of-range levels at later times during recovery, when BCS had risen to 4 or 5.

Possible significance of hyperphenylalaninaemia as a surrogate for malarial coma

Like other amino acids, the phenylalanine degradation supplies carbon to the TCA cycle for oxidation [ 35 ]. Why then did investigators find consistently elevated phenylalanine levels in CM? In a previous study, a possible mechanism to explain hyperphenylalaninaemia was found [ 36 ]. The liver enzyme, phenylalanine hydroxylase (PHA), requires the cofactor tetrahydrobiopterin (BH 4 ) for mono-oxygenation of phenylalanine to yield its product, tyrosine [ 37 ]. In health biopterin is poised in the reduced state (BH 4 ) such that with each phenylalanine to tyrosine reaction, the oxidized cofactors, biopterin (B) and dihydrobiopterin (BH 2 ), are reduced back to BH 4 via two pathways (recycling and salvage) [ 37 ]. The reducing equivalents for restoring biopterin to its reduced state are supplied by the nicotinamide adenine dinucleotides NADH and NADPH [ 37 ]. In the systemic compartment (i.e., plasma and liver) about 2/3 of biopterin is poised in the reduced state (BH 4 ) [ 38 ]. This provides sufficient reducing power for tight regulation of plasma phenylalanine below 80 micromolar [ 39 ]. Phenylalanine regulation prevents hyperphenylalaninaemia, which is toxic to the brain (e.g., in the congenital disease, phenylketonuria [ 39 ]). While total biopterins (B + BH2 + BH 4 ) were slightly increased in CM, the percentage of reduced biopterin fell by 75% [ 36 ]. This suggests that hyperphenylalaninaemia in CM results from a diminution of PAH catalysis in the liver due to insufficient BH 4 availability, possibly a result of oxidative stress.

Potential role of BH 4 in CM pathogenesis

BH 4 is a unique cofactor in that there are only 6 enzymes for which it is required [ 37 , 40 ]. These are the enzymes for (a) synthesis of catecholamines and serotonin in the brain, (b) systemic and CNS synthesis of nitric oxide, (c) PAH in liver, and (d) a little studied liver enzyme for catabolism of membrane ether lipids, alkylglycerol mono-oxygenase (AGMO) [ 40 , 41 , 42 ]. Accumulation of membrane-derived ether lipids from impaired AGMO activity resulting from limited BH 4 availability might adversely affect the CNS [ 43 ]. Blood–brain barrier permeability is markedly increased in experimental animals treated with short chain alkyl (ether) glycerols [ 44 , 45 ]. Limiting AGMO activity could enhance circulating ether lipid mediators such as platelet activation factor (PAF). This possibility is yet to be investigated [ 46 , 47 ]. There is evidence from malaria models that PAF could enhance sequestration of infected red cells if regulation control mechanisms fail [ 48 , 49 ]. The possible role for an ether lipid(s) in malaria pathogenesis should be explored .

Limitations

Because a group of children with severe malaria without coma was not included, one cannot infer that amino acid abnormalities described here are specific for the depth of coma itself, but rather could reflect broader associations with severe disease states. The cohort of 40 CM cases is relatively small. BCS are subjective, therefore open to observer bias. The linear mixed effects model can only assign an association between out-of-range amino acid levels and BCS, and thus cannot establish cause and effect. Diagnosis of CM carries a significant false positive fraction [ 50 ]. However, 59% of the CM cohort received lumbar puncture to rule out meningitis, thus diminishing the likelihood of non-malarial causes of coma.

Longitudinal data on normalization of amino acid levels with recovery from malarial coma found a highly significant association for phenylalanine. Unlike other coma-associated amino acids, abnormal phenylalanine levels were above, not below, normal range. Hyperphenylalaninaemia likely results from insufficient reducing power normally provided by tetrahydrobiopterin. A previous study found a marked diminution of tetrahydrobiopterin. Therefore, the single other liver tetrahydrobiopterin-dependent enzyme, responsible for degrading biologically active ether lipids (AGMO), may be impaired. Elevated bioactive ether lipids are known to permeabilize the CNS blood–brain barrier and lead to platelet activation, events shown to be critical in CM pathogenesis. If impaired, restoration of AGMO activity could provide efficacious adjunctive therapy.

Data availability

No datasets were generated or analysed during the current study.

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Acknowledgements

Research reported in this publication was supported by the National Center for Advancing Translational Sciences of the National Institutes of Health under Award Number UL1TR002538. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or their employers. John Hibbs Jr., J. Brice Weinberg, and Guy Zimmerman (deceased) provided useful comments. Tsin Yeo and Nick Anstey reviewed the manuscript and raised important suggestions for statistical analysis. Mary MacFarland aided in the preparation of the manuscript. Thanks to Will J. Fennelly for data entry and to Arthur L. Granger for arranging statistical assistance. Special appreciations go to Justice Sylverken, Clinical Assistant, and the pediatric nursing staff at Komfo Anokye Teaching Hospital for their dedicated patient care and service to the study.

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D.L.G wrote the main manuscript text. B.K.L., R.R., and D.B provided edits to the manuscript. D.L.G. and D.B. assembled the Tables and Figures. D.A., T.A., M.S.L., B.A.B., D.C.H., and B.K.L. carried out the study protocol in Kumasi, Ghana. D.B., R.R., and D.L.G. analyzed the data. D.B. and R.R. provided statistical expertise. All authors reviewed and approved the manuscript.

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12936_2024_5077_moesm1_esm.zip.

Additional file1Supplementary Fig. 1. Box plots show out-of-range versus normal-range amino acid plasma levels at given BCS. Fig. 1 A–1D show results for all 21 amino acids analysed. Coloured circles represent individual amino acid levels for participants with cerebral malaria. An Asterix denotes significant association between amino acid levels within or outside the normal ranges at given Blantyre Coma Scores as determined by the generalized linear mixed-effects model

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Granger, D.L., Ansong, D., Agbenyega, T. et al. Longitudinal associations of plasma amino acid levels with recovery from malarial coma. Malar J 23 , 253 (2024). https://doi.org/10.1186/s12936-024-05077-9

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Received : 14 May 2024

Accepted : 13 August 2024

Published : 23 August 2024

DOI : https://doi.org/10.1186/s12936-024-05077-9

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• Cerebral malaria
• Blantyre coma score
• Amino acids
• Generalized linear mixed-effects model
• Tetrahydrobiopterin
• Glyceryl lipid ethers

Malaria Journal

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