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Malaria Journal
Published in: Malaria Journal 1/2020

01-12-2020 | Malaria | Review

Pathophysiology and neurologic sequelae of cerebral malaria

Authors: Nicoline Schiess, Andres Villabona-Rueda, Karissa E. Cottier, Katherine Huether, James Chipeta, Monique F. Stins

Published in: Malaria Journal | Issue 1/2020

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Abstract

Cerebral malaria (CM), results from Plasmodium falciparum infection, and has a high mortality rate. CM survivors can retain life-long post CM sequelae, including seizures and neurocognitive deficits profoundly affecting their quality of life. As the Plasmodium parasite does not enter the brain, but resides inside erythrocytes and are confined to the lumen of the brain’s vasculature, the neuropathogenesis leading to these neurologic sequelae is unclear and under-investigated. Interestingly, postmortem CM pathology differs in brain regions, such as the appearance of haemorragic punctae in white versus gray matter. Various host and parasite factors contribute to the risk of CM, including exposure at a young age, parasite- and host-related genetics, parasite sequestration and the extent of host inflammatory responses. Thus far, several proposed adjunctive treatments have not been successful in the treatment of CM but are highly needed. The region-specific CM neuro-pathogenesis leading to neurologic sequelae is intriguing, but not sufficiently addressed in research. More attention to this may lead to the development of effective adjunctive treatments to address CM neurologic sequelae.
Literature
1.
2.
Kochar DK, Das A, Kochar SK, Saxena V, Sirohi P, Garg S, et al. Severe Plasmodium vivax malaria: a report on serial cases from Bikaner in northwestern India. Am J Trop Med Hyg. 2009;80:194–8.PubMed
3.
Battle KE, Lucas TCD, Nguyen M, Howes RE, Nandi AK, Twohig KA, et al. Mapping the global endemicity and clinical burden of Plasmodium vivax, 2000-17: a spatial and temporal modelling study. Lancet. 2019;394:332–43.PubMedPubMedCentral
4.
Gething PW, Casey DC, Weiss DJ, Bisanzio D, Bhatt S, Cameron E, et al. Mapping Plasmodium falciparum mortality in Africa between 1990 and 2015. N Engl J Med. 2016;375:2435–45.PubMedPubMedCentral
5.
Weiss DJ, Lucas TCD, Nguyen M, Nandi AK, Bisanzio D, Battle KE, et al. Mapping the global prevalence, incidence, and mortality of Plasmodium falciparum, 2000–17: a spatial and temporal modelling study. Lancet. 2019;394:322–31.PubMedPubMedCentral
6.
Severe malaria. Trop Med Int Health. 2014;19 Suppl 1:7-131.
7.
Boivin MJ, Bangirana P, Byarugaba J, Opoka RO, Idro R, Jurek AM, et al. Cognitive impairment after cerebral malaria in children: a prospective study. Pediatrics. 2007;119:e360–6.PubMed
8.
Birbeck GL, Beare N, Lewallen S, Glover SJ, Molyneux ME, Kaplan PW, et al. Identification of malaria retinopathy improves the specificity of the clinical diagnosis of cerebral malaria: findings from a prospective cohort study. Am J Trop Med Hyg. 2010;82:231–4.PubMedPubMedCentral
9.
Phillips MA, Burrows JN, Manyando C, van Huijsduijnen RH, Van Voorhis WC, Wells TNC. Malaria. Nat Rev Dis Primers. 2017;3:17050.PubMed
10.
Feintuch CM, Tare A, Cusumano LR, Benayoun J, Ryu S, Sixpence A, et al. Type I interferon receptor variants in gene regulatory regions are associated with susceptibility to cerebral malaria in Malawi. Am J Trop Med Hyg. 2018;98:1692–8.PubMedPubMedCentral
11.
Marquet S, Conte I, Poudiougou B, Argiro L, Dessein H, Couturier C, et al. A functional IL22 polymorphism (rs2227473) is associated with predisposition to childhood cerebral malaria. Sci Rep. 2017;7:41636.PubMedPubMedCentral
12.
Hunt NH, Ball HJ, Hansen AM, Khaw LT, Guo J, Bakmiwewa S, et al. Cerebral malaria: gamma-interferon redux. Front Cell Infect Microbiol. 2014;4:113.PubMedPubMedCentral
13.
Jenkins NE, Mwangi TW, Kortok M, Marsh K, Craig AG, Williams TN. A polymorphism of intercellular adhesion molecule-1 is associated with a reduced incidence of nonmalarial febrile illness in Kenyan children. Clin Infect Dis. 2005;41:1817–9.PubMed
14.
Ndila CM, Uyoga S, Macharia AW, Nyutu G, Peshu N, Ojal J, et al. Human candidate gene polymorphisms and risk of severe malaria in children in Kilifi, Kenya: a case-control association study. Lancet Haematol. 2018;5:e333–45.PubMedPubMedCentral
15.
Mohanty S, Singh US, Mohanty S, Mohanty AK, Pande V, Das A. Evolutionary interplay of single nucleotide polymorphisms at the promoter region of TNF-alpha gene in different clinical outcomes of malaria in India. Infect Genet Evol. 2019;69:107–16.PubMed
16.
Schrum JE, Crabtree JN, Dobbs KR, Kiritsy MC, Reed GW, Gazzinelli RT, et al. Cutting edge: plasmodium falciparum induces trained innate immunity. J Immunol. 2018;200:1243–8.PubMed
17.
Qidwai T, Jamal F, Singh S. Exploring putative molecular mechanisms of human pyruvate kinase enzyme deficiency and its role in resistance against Plasmodium falciparum malaria. Interdiscip Sci. 2014;6:158–66.PubMed
18.
Quin JE, Bujila I, Cherif M, Sanou GS, Qu Y, Vafa Homann M, et al. Major transcriptional changes observed in the fulani, an ethnic group less susceptible to malaria. Elife. 2017;6:e29156.PubMedPubMedCentral
19.
Gupta H, Chaudhari S, Rai A, Bhat S, Sahu PK, Hande MH, et al. Genetic and epigenetic changes in host ABCB1 influences malaria susceptibility to Plasmodium falciparum. PLoS ONE. 2017;12:e0175702.PubMedPubMedCentral
20.
Arts RJ, Novakovic B, Ter Horst R, Carvalho A, Bekkering S, Lachmandas E, et al. Glutaminolysis and fumarate accumulation integrate immunometabolic and epigenetic programs in trained immunity. Cell Metab. 2016;24:807–19.PubMedPubMedCentral
21.
Franklin BS, Parroche P, Ataide MA, Lauw F, Ropert C, de Oliveira RB, et al. Malaria primes the innate immune response due to interferon-gamma induced enhancement of toll-like receptor expression and function. Proc Natl Acad Sci USA. 2009;106:5789–94.PubMedPubMedCentral
22.
Hochman SE, Madaline TF, Wassmer SC, Mbale E, Choi N, Seydel KB, et al. Fatal pediatric cerebral malaria is associated with intravascular monocytes and platelets that are increased with HIV coinfection. MBio. 2015;6:e01390.PubMedPubMedCentral
23.
Swanson PA, Hart GT, Russo MV, Nayak D, Yazew T, Pena M, et al. CD8+T cells induce fatal brainstem pathology during cerebral malaria via luminal antigen-specific engagement of brain vasculature. PLoS Pathog. 2016;12:e1006022.PubMedPubMedCentral
24.
Riggle BA, Manglani M, Maric D, Johnson KR, Lee MH, Neto OLA, et al. CD8+T cells target cerebrovasculature in children with cerebral malaria. J Clin Invest. 2020;130:1128–38.PubMedPubMedCentral
25.
Barrera V, Haley MJ, Strangward P, Attree E, Kamiza S, Seydel KB, et al. Comparison of CD8(+) T cell accumulation in the brain during human and murine cerebral malaria. Front Immunol. 2019;10:1747.PubMedPubMedCentral
26.
Idro R, Marsh K, John CC, Newton CR. Cerebral malaria: mechanisms of brain injury and strategies for improved neurocognitive outcome. Pediatr Res. 2010;68:267–74.PubMedPubMedCentral
27.
Karunaweera ND, Grau GE, Gamage P, Carter R, Mendis KN. Dynamics of fever and serum levels of tumor necrosis factor are closely associated during clinical paroxysms in Plasmodium vivax malaria. Proc Natl Acad Sci USA. 1992;89:3200–3.PubMedPubMedCentral
28.
Birbeck GL, Molyneux ME, Kaplan PW, Seydel KB, Chimalizeni YF, Kawaza K, et al. Blantyre malaria project epilepsy study (BMPES) of neurological outcomes in retinopathy-positive paediatric cerebral malaria survivors: a prospective cohort study. Lancet Neurol. 2010;9:1173–81.PubMedPubMedCentral
29.
Postels DG, Taylor TE, Molyneux M, Mannor K, Kaplan PW, Seydel KB, et al. Neurologic outcomes in retinopathy-negative cerebral malaria survivors. Neurology. 2012;79:1268–72.PubMedPubMedCentral
30.
Potchen MJ, Kampondeni SD, Seydel KB, Birbeck GL, Hammond CA, Bradley WG, et al. Acute brain MRI findings in 120 Malawian children with cerebral malaria: new insights into an ancient disease. Am J Neuroradiol. 2012;33:1740–6.PubMedPubMedCentral
31.
Seydel KB, Kampondeni SD, Valim C, Potchen MJ, Milner DA, Muwalo FW, et al. Brain swelling and death in children with cerebral malaria. N Engl J Med. 2015;372:1126–37.PubMedPubMedCentral
32.
Idro R, Carter JA, Fegan G, Neville BG, Newton CR. Risk factors for persisting neurological and cognitive impairments following cerebral malaria. Arch Dis Child. 2006;91:142–8.PubMed
33.
Kariuki SM, Abubakar A, Newton CR, Kihara M. Impairment of executive function in Kenyan children exposed to severe falciparum malaria with neurological involvement. Malar J. 2014;13:365.PubMedPubMedCentral
34.
Dorovini-Zis K, Schmidt K, Huynh H, Fu W, Whitten RO, Milner D, et al. The neuropathology of fatal cerebral malaria in Malawian children. Am J Pathol. 2011;178:2146–58.PubMedPubMedCentral
35.
Taylor TE, Fu WJ, Carr RA, Whitten RO, Mueller JS, Fosiko NG, et al. Differentiating the pathologies of cerebral malaria by postmortem parasite counts. Nat Med. 2004;10:143–5.PubMed
36.
Nagatake T, Hoang VT, Tegoshi T, Rabbege J, Ann TK, Aikawa M. Pathology of falciparum malaria in Vietnam. Am J Trop Med Hyg. 1992;47:259–64.PubMed
37.
Wijdicks EFM, Park JG. Surviving cerebral malaria. Neurology. 2018;91:978–9.PubMed
38.
Villabona-Rueda A, Erice C, Pardo CA, Stins MF. The evolving concept of the blood brain barrier (BBB): from a single static barrier to a heterogeneous and dynamic relay center. Front Cell Neurosci. 2019;13:405.PubMedPubMedCentral
39.
Claessens A, Rowe JA. Selection of plasmodium falciparum parasites for cytoadhesion to human brain endothelial cells. J Vis Exp. 2012;59:e3122.
40.
World Health Organization. Communicable Diseases Cluster Severe falciparum malaria. Trans R Soc Trop Med Hyg. 2000;94(Suppl 1):S1–90.
41.
Barrera V, Hiscott PS, Craig AG, White VA, Milner DA, Beare NA, et al. Severity of retinopathy parallels the degree of parasite sequestration in the eyes and brains of Malawian children with fatal cerebral malaria. J Infect Dis. 2015;211:1977–86.PubMed
42.
Kochar DK, Shubhakaran A, Kumawat BL, Thanvi I, Joshi A, Vyas SP. Ophthalmoscopic abnormalities in adults with falciparum malaria. QJM. 1998;91:845–52.PubMed
43.
Beare NA, Southern C, Chalira C, Taylor TE, Molyneux ME, Harding SP. Prognostic significance and course of retinopathy in children with severe malaria. Arch Ophthalmol. 2004;122:1141–7.PubMed
44.
MacCormick IJ, Beare NA, Taylor TE, Barrera V, White VA, Hiscott P, et al. Cerebral malaria in children: using the retina to study the brain. Brain. 2014;137:2119–42.PubMedPubMedCentral
45.
Potchen MJ, Kampondeni SD, Seydel KB, Haacke EM, Sinyangwe SS, Mwenechanya M, et al. 1.5 tesla magnetic resonance imaging to investigate potential etiologies of brain swelling in pediatric cerebral malaria. Am J Trop Med Hyg. 2018;98:497–504.PubMedPubMedCentral
46.
Medana IM, Idro R, Newton CR. Axonal and astrocyte injury markers in the cerebrospinal fluid of Kenyan children with severe malaria. J Neurol Sci. 2007;258:93–8.PubMed
47.
White NJ, Warrell DA, Looareesuwan S, Chanthavanich P, Phillips RE, Pongpaew P. Pathophysiological and prognostic significance of cerebrospinal-fluid lactate in cerebral malaria. Lancet. 1985;1:776–8.PubMed
48.
Macherson GG, Warrell MJ, White NJ, Looareesuwan S, Warrell DA. Human cerebral malaria A quantitative ultrastructural analysis of parasitized erythrocyte sequestration. Am J Pathol. 1985;119:385–401.
49.
Hemmer CJ, Kern P, Holst FG, Radtke KP, Egbring R, Bierhaus A, et al. Activation of the host response in human Plasmodium falciparum malaria: relation of parasitemia to tumor necrosis factor/cachectin, thrombin-antithrombin III, and protein C levels. Am J Med. 1991;91:37–44.PubMed
50.
Jimmy EO, Saliu I, Ademowo O. Fibrinopeptide-A and fibrinogen interactions in acute, Plasmodium falciparum malaria. Ann Trop Med Parasitol. 2003;97:879–81.PubMed
51.
Clemens R, Pramoolsinsap C, Lorenz R, Pukrittayakamee S, Bock HL, White NJ. Activation of the coagulation cascade in severe falciparum malaria through the intrinsic pathway. Br J Haematol. 1994;87:100–5.PubMed
52.
Avril M, Bernabeu M, Benjamin M, Brazier AJ, Smith JD. Interaction between endothelial protein C receptor and intercellular adhesion molecule 1 to mediate binding of Plasmodium falciparum-infected erythrocytes to endothelial cells. MBio. 2016;7:e00615–6.PubMedPubMedCentral
53.
Brown A, Turner L, Christoffersen S, Andrews KA, Szestak T, Zhao Y, et al. Molecular architecture of a complex between an adhesion protein from the malaria parasite and intracellular adhesion molecule 1. J Biol Chem. 2013;288:5992–6003.PubMedPubMedCentral
54.
Lau CK, Turner L, Jespersen JS, Lowe ED, Petersen B, Wang CW, et al. Structural conservation despite huge sequence diversity allows EPCR binding by the PfEMP1 family implicated in severe childhood malaria. Cell Host Microbe. 2015;17:118–29.PubMedPubMedCentral
55.
Shabani E, Hanisch B, Opoka RO, Lavstsen T, John CC. Plasmodium falciparum EPCR-binding PfEMP1 expression increases with malaria disease severity and is elevated in retinopathy negative cerebral malaria. BMC Med. 2017;15:183.PubMedPubMedCentral
56.
Wassmer SC, Moxon CA, Taylor T, Grau GE, Molyneux ME, Craig AG. Vascular endothelial cells cultured from patients with cerebral or uncomplicated malaria exhibit differential reactivity to TNF. Cell Microbiol. 2011;13:198–209.PubMedPubMedCentral
57.
Armah H, Dodoo AK, Wiredu EK, Stiles JK, Adjei AA, Gyasi RK, et al. High-level cerebellar expression of cytokines and adhesion molecules in fatal, paediatric, cerebral malaria. Ann Trop Med Parasitol. 2005;99:629–47.PubMed
58.
Tripathi AK, Sullivan DJ, Stins MF. Plasmodium falciparum-infected erythrocytes decrease the integrity of human blood-brain barrier endothelial cell monolayers. J Infect Dis. 2007;195:942–50.PubMed
59.
Tripathi AK, Sullivan DJ, Stins MF. Plasmodium falciparum-infected erythrocytes increase intercellular adhesion molecule 1 expression on brain endothelium through NF-kappaB. Infect Immun. 2006;74:3262–70.PubMedPubMedCentral
60.
Feintuch CM, Saidi A, Seydel K, Chen G, Goldman-Yassen A, Mita-Mendoza NK, et al. Activated neutrophils are associated with pediatric cerebral malaria vasculopathy in malawian children. MBio. 2016;7:e01300–15.PubMedPubMedCentral
61.
Brown H, Rogerson S, Taylor T, Tembo M, Mwenechanya J, Molyneux M, et al. Blood-brain barrier function in cerebral malaria in Malawian children. Am J Trop Med Hyg. 2001;64:207–13.PubMed
62.
63.
Introini V, Carciati A, Tomaiuolo G, Cicuta P, Guido S. Endothelial glycocalyx regulates cytoadherence in Plasmodium falciparum malaria. J R Soc Interface. 2018;15:20180773.PubMedPubMedCentral
64.
Yeo TW, Bush PA, Chen Y, et al. Glycocalyx breakdown is increased in African children with cerebral and uncomplicated falciparum malaria. FASEB J. 2019;33:14185–93.PubMedPubMedCentral
65.
Hempel C, Sporring J, Kurtzhals JAL. Experimental cerebral malaria is associated with profound loss of both glycan and protein components of the endothelial glycocalyx. FASEB J. 2019;33:2058–71.PubMed
66.
Sierro F, Grau GER. The ins and outs of cerebral malaria pathogenesis: immunopathology, extracellular vesicles, immunometabolism, and trained immunity. Front Immunol. 2019;10:830.PubMedPubMedCentral
67.
Pongponratn E, Riganti M, Punpoowong B, Aikawa M. Microvascular sequestration of parasitized erythrocytes in human falciparum malaria: a pathological study. Am J Trop Med Hyg. 1991;44:168–75.PubMed
68.
Ponsford MJ, Medana IM, Prapansilp P, et al. Sequestration and microvascular congestion are associated with coma in human cerebral malaria. J Infect Dis. 2012;205:663–71.PubMed
69.
Silamut K, Phu NH, Whitty C, Turner GD, Louwrier K, Mai NT, et al. A quantitative analysis of the microvascular sequestration of malaria parasites in the human brain. Am J Pathol. 1999;155:395–410.PubMedPubMedCentral
70.
Mandala WL, Msefula CL, Gondwe EN, Drayson MT, Molyneux ME, MacLennan CA. Cytokine profiles in Malawian children presenting with uncomplicated malaria, severe malarial anemia, and cerebral malaria. Clin Vaccine Immunol. 2017;24:e00533–616.PubMedPubMedCentral
71.
Eeka P, Phanithi PB. Cytotoxic T lymphocyte granzyme-b mediates neuronal cell death during Plasmodium berghei ANKA induced experimental cerebral malaria. Neurosci Lett. 2018;664:58–65.PubMed
72.
Huggins MA, Johnson HL, Jin F, et al. Perforin expression by CD8 T cells is sufficient to cause fatal brain edema during experimental cerebral malaria. Infect Immun. 2017;85:e00985–1016.PubMedPubMedCentral
73.
Medana IM, Mai NT, Day NP, Hien TT, Bethell D, Phu NH, et al. Cellular stress and injury responses in the brains of adult Vietnamese patients with fatal Plasmodium falciparum malaria. Neuropathol Appl Neurobiol. 2001;27:421–33.PubMed
74.
Finney CA, Hawkes CA, Kain DC, Dhabangi A, Musoke C, Cserti-Gazdewich C, et al. S1P is associated with protection in human and experimental cerebral malaria. Mol Med. 2011;17:717–25.PubMedPubMedCentral
75.
Harawa V, Njie M, Kessler A, Choko A, Kumwenda B, Kampondeni S, et al. Brain swelling is independent of peripheral plasma cytokine levels in Malawian children with cerebral malaria. Malar J. 2018;17:435.PubMedPubMedCentral
76.
Gupta S, Seydel K, Miranda-Roman MA, Feintuch CM, Saidi A, Kim RS, et al. Extensive alterations of blood metabolites in pediatric cerebral malaria. PLoS ONE. 2017;12:e0175686.PubMedPubMedCentral
77.
McDonald CR, Conroy AL, Hawkes M, Elphinstone RE, Gamble JL, Hayford K, et al. Brain-derived neurotrophic factor is associated with disease severity and clinical outcome in Ugandan children admitted to hospital with severe malaria. Pediatr Infect Dis J. 2017;36:146–50.PubMed
78.
Molyneux ME, Engelmann H, Taylor TE, Wirima JJ, Aderka D, Wallach D, et al. Circulating plasma receptors for tumour necrosis factor in Malawian children with severe falciparum malaria. Cytokine. 1993;5:604–9.PubMed
79.
Moussa EM, Huang H, Thezenas ML, Fischer R, Ramaprasad A, Sisay-Joof F, et al. Proteomic profiling of the plasma of Gambian children with cerebral malaria. Malar J. 2018;17:337.PubMedPubMedCentral
80.
Punsawad C, Viriyavejakul P. Reduction in serum sphingosine 1-phosphate concentration in malaria. PLoS ONE. 2017;12:e0180631.PubMedPubMedCentral
81.
Esamai F, Ernerudh J, Janols H, Welin S, Ekerfelt C, Mining S, et al. Cerebral malaria in children: serum and cerebrospinal fluid TNF-alpha and TGF-beta levels and their relationship to clinical outcome. J Trop Pediatr. 2003;49:216–23.PubMed
82.
Park GS, Ireland KF, Opoka RO, John CC. Evidence of endothelial activation in asymptomatic Plasmodium falciparum parasitemia and effect of blood group on levels of von Willebrand factor in malaria. J Pediatric Infect Dis Soc. 2012;1:16–25.PubMedPubMedCentral
83.
Phiri HT, Bridges DJ, Glover SJ, van Mourik JA, de Laat B, M’baya B, et al. Elevated plasma von Willebrand factor and propeptide levels in Malawian children with malaria. PLoS ONE. 2011;6:e25626.PubMedPubMedCentral
84.
Carter JA, Ross AJ, Neville BG, Obiero E, Katana K, Mung’ala-Odera V, et al. Developmental impairments following severe falciparum malaria in children. Trop Med Int Health. 2005;10:3–10.PubMed
85.
Carter JA, Mung’ala-Odera V, Neville BG, Murira G, Mturi N, Musumba C, et al. Persistent neurocognitive impairments associated with severe falciparum malaria in Kenyan children. J Neurol Neurosurg Psychiatry. 2005;76:476–81.PubMedPubMedCentral
86.
Oluwayemi IO, Brown BJ, Oyedeji OA, Oluwayemi MA. Neurological sequelae in survivors of cerebral malaria. Pan Afr Med J. 2013;15:88.PubMedPubMedCentral
87.
Brim R, Mboma S, Semrud-Clikeman M, Kampondeni S, Magen J, Taylor T, et al. Cognitive outcomes and psychiatric symptoms of retinopathy-positive cerebral malaria: cohort description and baseline results. Am J Trop Med Hyg. 2017;97:225–31.PubMedPubMedCentral
88.
Holding PA, Stevenson J, Peshu N, Marsh K. Cognitive sequelae of severe malaria with impaired consciousness. Trans R Soc Trop Med Hyg. 1999;93:529–34.PubMed
89.
Boivin MJ, Gladstone MJ, Vokhiwa M, Birbeck GL, Magen JG, Page C, et al. Developmental outcomes in Malawian children with retinopathy-positive cerebral malaria. Trop Med Int Health. 2011;16:263–71.PubMed
90.
Idro R, Kakooza-Mwesige A, Asea B, Ssebyala K, Bangirana P, Opoka RO, et al. Cerebral malaria is associated with long-term mental health disorders: a cross sectional survey of a long-term cohort. Malar J. 2016;15:184.PubMedPubMedCentral
91.
Ssenkusu JM, Hodges JS, Opoka RO, Idro R, Shapiro E, John CC, et al. Long-term behavioral problems in children with severe malaria. Pediatrics. 2016;138:e20161965.PubMedPubMedCentral
92.
Idro R, Kakooza-Mwesige A, Balyejjussa S, Mirembe G, Mugasha C, Tugumisirize J, et al. Severe neurological sequelae and behaviour problems after cerebral malaria in Ugandan children. BMC Res Notes. 2010;3:104.PubMedPubMedCentral
93.
Postels DG, Birbeck GL. Children with retinopathy-negative cerebral malaria: a pathophysiologic puzzle. Pediatr Infect Dis J. 2011;30:953–6.PubMedPubMedCentral
94.
Ngoungou EB, Koko J, Druet-Cabanac M, et al. Cerebral malaria and sequelar epilepsy: first matched case-control study in Gabon. Epilepsia. 2006;47:2147–53.PubMed
95.
Christensen SS, Eslick GD. Cerebral malaria as a risk factor for the development of epilepsy and other long-term neurological conditions: a meta-analysis. Trans R Soc Trop Med Hyg. 2015;109:233–8.PubMed
96.
Opoka RO, Bangirana P, Boivin MJ, John CC, Byarugaba J. Seizure activity and neurological sequelae in Ugandan children who have survived an episode of cerebral malaria. Afr Health Sci. 2009;9:75–81.PubMedPubMedCentral
97.
Ibiwoye MO, Howard CV, Sibbons P, Hasan M, van Velzen D. Cerebral malaria in the rhesus monkey (Macaca mulatta): observations on host pathology. J Comp Pathol. 1993;108:303–10.PubMed
98.
Pasini EM, Zeeman AM, van der Wel A, Kocken CHM. Plasmodium knowlesi: a relevant, versatile experimental malaria model. Parasitology. 2018;145:56–70.PubMed
99.
Rest JR. Cerebral malaria in inbred mice I A new model and its pathology. Trans R Soc Trop Med Hyg. 1982;76:410–5.PubMed
100.
Hunt NH, Golenser J, Chan-Ling T, Parekh S, Rae C, Potter S, et al. Immunopathogenesis of cerebral malaria. Int J Parasitol. 2006;36:569–82.PubMed
101.
Desruisseaux MS, Gulinello M, Smith DN, Lee SC, Tsuji M, Weiss LM, et al. Cognitive dysfunction in mice infected with Plasmodium berghei strain ANKA. J Infect Dis. 2008;197:1621–7.PubMed
102.
White NJ, Turner GD, Medana IM, Dondorp AM, Day NP. The murine cerebral malaria phenomenon. Trends Parasitol. 2010;26:11–5.PubMedPubMedCentral
103.
Riley EM, Couper KN, Helmby H, Hafalla JC, de Souza JB, Langhorne J, et al. Neuropathogenesis of human and murine malaria. Trends Parasitol. 2010;26:277–8.PubMed
104.
Craig AG, Grau GE, Janse C, Kazura JW, Milner D, Barnwell JW, et al. The role of animal models for research on severe malaria. PLoS Pathog. 2012;8:e1002401.PubMedPubMedCentral
105.
de Souza JB, Hafalla JC, Riley EM, Couper KN. Cerebral malaria: why experimental murine models are required to understand the pathogenesis of disease. Parasitology. 2010;137:755–72.PubMed
106.
Langhorne J, Buffet P, Galinski M, Good M, Harty J, Leroy D, et al. The relevance of non-human primate and rodent malaria models for humans. Malar J. 2011;10:23.PubMedPubMedCentral
107.
108.
Renia L, Grau GE, Wassmer SC. CD8+T cells and human cerebral malaria: a shifting episteme. J Clin Invest. 2020;130:1109–11.PubMedPubMedCentral
109.
de Miranda AS, Lacerda-Queiroz N, de Carvalho Vilela M, Rodrigues DH, Rachid MA, Quevedo J, et al. Anxiety-like behavior and proinflammatory cytokine levels in the brain of C57BL/6 mice infected with Plasmodium berghei (strain ANKA). Neurosci Lett. 2011;491:202–6.PubMed
110.
Brant F, Miranda AS, Esper L, Gualdron-Lopez M, Cisalpino D, de Souza DDG, et al. Suppressor of cytokine signaling 2 modulates the immune response profile and development of experimental cerebral malaria. Brain Behav Immun. 2016;54:73–85.PubMed
111.
Campos AC, Brant F, Miranda AS, Machado FS, Teixeira AL. Cannabidiol increases survival and promotes rescue of cognitive function in a murine model of cerebral malaria. Neuroscience. 2015;289:166–80.PubMed
112.
Liu M, Solomon W, Cespedes JC, Wilson NO, Ford B, Stiles JK. Neuregulin-1 attenuates experimental cerebral malaria (ECM) pathogenesis by regulating ErbB4/AKT/STAT3 signaling. J Neuroinflammation. 2018;15:104.PubMedPubMedCentral
113.
D’Orleans-Juste P, Akide Ndunge OB, Desbiens L, Tanowitz HB, Desruisseaux MS. Endothelins in inflammatory neurological diseases. Pharmacol Ther. 2019;194:145–60.PubMed
114.
Dai M, Freeman B, Bruno FP, Shikani HJ, Tanowitz HB, Weiss LM, et al. The novel ETA receptor antagonist HJP-272 prevents cerebral microvascular hemorrhage in cerebral malaria and synergistically improves survival in combination with an artemisinin derivative. Life Sci. 2012;91:687–92.PubMedPubMedCentral
115.
Freeman BD, Martins YC, Akide-Ndunge OB, Bruno FP, Wang H, Tanowitz HB, et al. Endothelin-1 mediates brain microvascular dysfunction leading to long-term cognitive impairment in a model of experimental cerebral malaria. PLoS Pathog. 2016;12:e1005477.PubMedPubMedCentral
116.
Darling TK, Mimche PN, Bray C, Umaru B, Brady LM, Stone C, et al. EphA2 contributes to disruption of the blood-brain barrier in cerebral malaria. PLoS Pathog. 2020;16:e1008261.PubMedPubMedCentral
117.
Varo R, Crowley VM, Sitoe A, Madrid L, Serghides L, Kain KC, et al. Adjunctive therapy for severe malaria: a review and critical appraisal. Malar J. 2018;17:47.PubMedPubMedCentral
118.
Hemmer CJ, Kern P, Holst FG, Nawroth PP, Dietrich M. Neither heparin nor acetylsalicylic acid influence the clinical course in human Plasmodium falciparum malaria: a prospective randomized study. Am J Trop Med Hyg. 1991;45:608–12.PubMed
119.
Charunwatthana P, Abul Faiz M, Ruangveerayut R, Maude RJ, Rahman MR, Roberts LJ, et al. N-acetylcysteine as adjunctive treatment in severe malaria: a randomized, double-blinded placebo-controlled clinical trial. Crit Care Med. 2009;37:516–22.PubMedPubMedCentral
120.
Maude RJ, Silamut K, Plewes K, Charunwatthana P, Ho M, Abul Faiz M, et al. Randomized controlled trial of levamisole hydrochloride as adjunctive therapy in severe falciparum malaria with high parasitemia. J Infect Dis. 2014;209:120–9.PubMed
121.
Watt G, Jongsakul K, Ruangvirayuth R. A pilot study of N-acetylcysteine as adjunctive therapy for severe malaria. QJM. 2002;95:285–90.PubMed
122.
Treeprasertsuk S, Krudsood S, Tosukhowong T, Maek-A-Nantawat W, Vannaphan S, Saengnetswang T, et al. N-acetylcysteine in severe falciparum malaria in Thailand. Southeast Asian J Trop Med Public Health. 2003;34:37–42.PubMedPubMedCentral
123.
Warrell DA, Looareesuwan S, Warrell MJ, Kasemsarn P, Intaraprasert R, Bunnag D, et al. Dexamethasone proves deleterious in cerebral malaria A double-blind trial in 100 comatose patients. N Engl J Med. 1982;306:313–9.PubMed
124.
Namutangula B, Ndeezi G, Byarugaba JS, Tumwine JK. Mannitol as adjunct therapy for childhood cerebral malaria in Uganda: a randomized clinical trial. Malar J. 2007;6:138.PubMedPubMedCentral
125.
van Hensbroek MB, Palmer A, Onyiorah E, Schneider G, Jaffar S, Dolan G, et al. The effect of a monoclonal antibody to tumor necrosis factor on survival from childhood cerebral malaria. J Infect Dis. 1996;174:1091–7.PubMed
126.
Das BK, Mishra S, Padhi PK, Manish R, Tripathy R, Sahoo PK, et al. Pentoxifylline adjunct improves prognosis of human cerebral malaria in adults. Trop Med Int Health. 2003;8:680–4.PubMed
127.
Di Perri G, Di Perri IG, Monteiro GB, Bonora S, Hennig C, Cassatella M, et al. Pentoxifylline as a supportive agent in the treatment of cerebral malaria in children. J Infect Dis. 1995;171:1317–22.PubMed
128.
Hemmer CJ, Hort G, Chiwakata CB, Seitz R, Egbring R, Gaus W, et al. Supportive pentoxifylline in falciparum malaria: no effect on tumor necrosis factor alpha levels or clinical outcome: A prospective, randomized, placebo-controlled study. Am J Trop Med Hyg. 1997;56:397–403.PubMed
129.
Wenisch C, Looareesuwan S, Wilairatana P, Parschalk B, Vannapann S, Wanaratana V, et al. Effect of pentoxifylline on cytokine patterns in the therapy of complicated plasmodium falciparum malaria. Am J Trop Med Hyg. 1998;58:343–7.PubMed
130.
Lell B, Kohler C, Wamola B, Olola CH, Kivaya E, Kokwaro G, et al. Pentoxifylline as an adjunct therapy in children with cerebral malaria. Malar J. 2010;9:368.PubMedPubMedCentral
131.
Iosif RE, Ekdahl CT, Ahlenius H, Pronk CJ, Bonde S, Kokaia Z, et al. Tumor necrosis factor receptor 1 is a negative regulator of progenitor proliferation in adult hippocampal neurogenesis. J Neurosci. 2006;26:9703–12.PubMedPubMedCentral
132.
Clelland CD, Choi M, Romberg C, Clemenson GD Jr, Fragniere A, Tyers P, et al. A functional role for adult hippocampal neurogenesis in spatial pattern separation. Science. 2009;325:210–3.PubMedPubMedCentral
133.
Deng W, Saxe MD, Gallina IS, Gage FH. Adult-born hippocampal dentate granule cells undergoing maturation modulate learning and memory in the brain. J Neurosci. 2009;29:13532–42.PubMedPubMedCentral
134.
Gimenez F, de Lagerie S, Fernandez C, Pino P, Mazier D. Tumor necrosis factor alpha in the pathogenesis of cerebral malaria. Cell Mol Life Sci. 2003;60:1623–35.PubMed
135.
Lou J, Gasche Y, Zheng L, Critico B, Monso-Hinard C, Juillard P, et al. Differential reactivity of brain microvascular endothelial cells to TNF reflects the genetic susceptibility to cerebral malaria. Eur J Immunol. 1998;28:3989–4000.PubMed
136.
Armah HB, Wilson NO, Sarfo BY, Powell MD, Bond VC, Anderson W, et al. Cerebrospinal fluid and serum biomarkers of cerebral malaria mortality in Ghanaian children. Malar J. 2007;6:147.PubMedPubMedCentral
137.
Solomon W, Wilson NO, Anderson L, Pitts S, Patrickson J, Liu M, et al. Neuregulin-1 attenuates mortality associated with experimental cerebral malaria. J Neuroinflammation. 2014;11:9.PubMedPubMedCentral
138.
Patel SN, Berghout J, Lovegrove FE, Ayi K, Conroy A, Serghides L, et al. C5 deficiency and C5a or C5aR blockade protects against cerebral malaria. J Exp Med. 2008;205:1133–43.PubMedPubMedCentral
139.
Serghides L, Kim H, Lu Z, Kain DC, Miller C, Francis RC, et al. Inhaled nitric oxide reduces endothelial activation and parasite accumulation in the brain, and enhances survival in experimental cerebral malaria. PLoS ONE. 2011;6:e27714.PubMedPubMedCentral
140.
Gramaglia I, Sobolewski P, Meays D, Contreras R, Nolan JP, Frangos JA, et al. Low nitric oxide bioavailability contributes to the genesis of experimental cerebral malaria. Nat Med. 2006;12:1417–22.PubMed
141.
Yeo TW, Lampah DA, Gitawati R, Tjitra E, Kenangalem E, McNeil YR, et al. Impaired nitric oxide bioavailability and l-arginine reversible endothelial dysfunction in adults with falciparum malaria. J Exp Med. 2007;204:2693–704.PubMedPubMedCentral
142.
Gramaglia I, Velez J, Chang YS, Caparros-Wanderley W, Combes V, Grau G, et al. Citrulline protects mice from experimental cerebral malaria by ameliorating hypoargininemia, urea cycle changes and vascular leak. PLoS ONE. 2019;14:e0213428.PubMedPubMedCentral
143.
Serghides L, Patel SN, Ayi K, Lu Z, Gowda DC, Liles WC, et al. Rosiglitazone modulates the innate immune response to Plasmodium falciparum infection and improves outcome in experimental cerebral malaria. J Infect Dis. 2009;199:1536–45.PubMed
144.
Serghides L, McDonald CR, Lu Z, Friedel M, Cui C, Ho KT, et al. PPARgamma agonists improve survival and neurocognitive outcomes in experimental cerebral malaria and induce neuroprotective pathways in human malaria. PLoS Pathog. 2014;10:e1003980.PubMedPubMedCentral
145.
Wilson NO, Solomon W, Anderson L, Patrickson J, Pitts S, Bond V, et al. Pharmacologic inhibition of CXCL10 in combination with anti-malarial therapy eliminates mortality associated with murine model of cerebral malaria. PLoS ONE. 2013;8:e60898.PubMedPubMedCentral
146.
Taoufiq Z, Pino P, Ndilimabaka N, Arrouss I, Assi S, Soubrier F, et al. Atorvastatin prevents Plasmodium falciparum cytoadherence and endothelial damage. Malar J. 2011;10:52.PubMedPubMedCentral
147.
Wiese L, Hempel C, Penkowa M, Kirkby N, Kurtzhals JA. Recombinant human erythropoietin increases survival and reduces neuronal apoptosis in a murine model of cerebral malaria. Malar J. 2008;7:3.PubMedPubMedCentral
148.
Du Y, Chen G, Zhang X, Yu C, Cao Y, Cui L. Artesunate and erythropoietin synergistically improve the outcome of experimental cerebral malaria. Int Immunopharmacol. 2017;48:219–30.PubMed
149.
Shabani E, Opoka RO, Idro R, Schmidt R, Park GS, Bangirana P, et al. High plasma erythropoietin levels are associated with prolonged coma duration and increased mortality in children with cerebral malaria. Clin Infect Dis. 2015;60:27–35.PubMed
Metadata
Title
Pathophysiology and neurologic sequelae of cerebral malaria
Authors
Nicoline Schiess
Andres Villabona-Rueda
Karissa E. Cottier
Katherine Huether
James Chipeta
Monique F. Stins
Publication date
01-12-2020
Publisher
BioMed Central
Keywords
Malaria
Plasmodia
Published in
Malaria Journal / Issue 1/2020
Electronic ISSN: 1475-2875
DOI
https://doi.org/10.1186/s12936-020-03336-z

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