收稿日期: 2025-08-10
修回日期: 2025-11-01
网络出版日期: 2026-04-28
基金资助
国家自然科学基金(82560401)
Advances in neurological injury and sequelae of cerebral malaria
Received date: 2025-08-10
Revised date: 2025-11-01
Online published: 2026-04-28
Supported by
National Natural Science Foundation of China(82560401)
脑型疟是恶性疟原虫感染最致命的并发症之一，临床多表现为意识障碍或昏迷，外周血可检出无性期疟原虫。该病病死率高达20%，15%~25%的康复者遗留不同程度的长期神经功能障碍，生活质量与社会功能受严重影响。当前研究已明确感染红细胞在脑微血管中的滞留、神经炎症级联反应及血脑屏障破坏是其核心发病机制，但其分子调控网络仍未完全阐明。本综述系统梳理近年来脑型疟发病机制与神经后遗症的研究进展，聚焦中枢神经系统损伤的关键环节，以期为开发靶向性辅助治疗与干预措施提供理论依据。
关键词： 脑型疟; 神经炎症; 血脑屏障; 神经后遗症; 疟疾后神经系统综合征
崔巍巍 , 程洋 . 脑型疟神经损伤与后遗症研究进展[J]. 中国寄生虫学与寄生虫病杂志, 2026 , 44(2) : 296 -304 . DOI: 10.12140/j.issn.1000-7423.2026.02.022
Cerebral malaria is one of the most fatal complications of Plasmodium falciparum infection, characterised clinically by altered consciousness or coma. Asexual P. falciparum parasites can be detected in peripheral blood, after exclusion of other causes of encephalopathy. The mortality rate of this disease can reach up to 20%, with approximately 15%-25% of survivors experiencing varying degrees of long-term neurological dysfunction, significantly impairing quality of life and social functioning. Current research has identified the retention of infected red blood cell in cerebral microvasculature, neuroinflammatory cascades, and blood-brain barrier disruption as core pathogenic mechanisms; however, the molecular regulatory networks underlying these processes remain incompletely elucidated. In this article, we systematically review recent research progress on the pathogenesis and neurological sequelae of cerebral malaria, focusing on key links in central nervous system damage, with the aim of providing a theoretical basis for the development of targeted adjuvant therapies and interventions.
| [1] | Venkatesan P. WHO world malaria report 2024[J]. Lancet Microbe, 2025, 6(4): 101073. |
| [2] | WHO. World malaria report 2025[R]. Geneva: World Health Organization, 2025. |
| [3] | WHO. World malaria report 2024[R]. Geneva: World Health Organization, 2024. |
| [4] | Postels DG, Birbeck GL. Cerebral malaria[J]. Handb Clin Neurol, 2013, 114: 91-102. |
| [5] | Newton PN, Stepniewska K, Dondorp A, et al. Prognostic indicators in adults hospitalized with falciparum malaria in Western Thailand[J]. Malar J, 2013, 12(1): 229. |
| [6] | Vanka R, Nakka VP, Kumar SP, et al. Molecular targets in cerebral malaria for developing novel therapeutic strategies[J]. Brain Res Bull, 2020, 157: 100-107. |
| [7] | Idro R, Jenkins NE, Newton CRJC. Pathogenesis, clinical features, and neurological outcome of cerebral malaria[J]. Lancet Neurol, 2005, 4(12): 827-840. |
| [8] | Duan HX, Zhao S, Xiang JQ, et al. Targeting the CD146/Galectin-9 axis protects the integrity of the blood-brain barrier in experimental cerebral malaria[J]. Cell Mol Immunol, 2021, 18(10): 2443-2454. |
| [9] | Keswani T, Sarkar S, Sengupta A, et al. Role of TGF-β and IL-6 in dendritic cells, Treg and Th17 mediated immune response during experimental cerebral malaria[J]. Cytokine, 2016, 88: 154-166. |
| [10] | Bertin GI, Lavstsen T, Guillonneau F, et al. Expression of the domain cassette 8 Plasmodium falciparum erythrocyte membrane protein 1 is associated with cerebral malaria in Benin[J]. PLoS One, 2013, 8(7): e68368. |
| [11] | Su XZ, Heatwole VM, Wertheimer SP, et al. The large diverse gene family var encodes proteins involved in cytoadherence and antigenic variation of Plasmodium falciparum-infected erythrocytes[J]. Cell, 1995, 82(1): 89-100. |
| [12] | Baruch DI, Pasloske BL, Singh HB, et al. Cloning the P. falciparum gene encoding PfEMP1, a malarial variant antigen and adherence receptor on the surface of parasitized human erythrocytes[J]. Cell, 1995, 82(1): 77-87. |
| [13] | Avril M, Bernabeu M, Benjamin M, et al. Interaction between endothelial protein C receptor and intercellular adhesion molecule 1 to mediate binding of Plasmodium falciparum-infected erythrocytes to endothelial cells[J]. mBio, 2016, 7(4): e00615-e00616. |
| [14] | Tripathi AK, Sullivan DJ, Stins MF. Plasmodium falciparum-infected erythrocytes increase intercellular adhesion molecule 1 expression on brain endothelium through NF-κB[J]. Infect Immun, 2006, 74(6): 3262-3270. |
| [15] | Storm J, Jespersen JS, Seydel KB, et al. Cerebral malaria is associated with differential cytoadherence to brain endothelial cells[J]. EMBO Mol Med, 2019, 11(2): EMMM201809164. |
| [16] | Storm J, Craig AG. Pathogenesis of cerebral malaria-inflammation and cytoadherence[J]. Front Cell Infect Microbiol, 2014, 4: 100. |
| [17] | Penha-Gon?alves C. Genetics of malaria inflammatory responses: a pathogenesis perspective[J]. Front Immunol, 2019, 10: 1771. |
| [18] | Kotepui M, Mala W, Kwankaew P, et al. Distinct cytokine profiles in malaria coinfections: a systematic review[J]. PLoS Negl Trop Dis, 2023, 17(1): e0011061. |
| [19] | Zuniga M, Gomes C, Chen Z, et al. Plasmodium falciparum and TNF-α differentially regulate inflammatory and barrier integrity pathways in human brain endothelial cells[J]. mBio, 2022, 13(5): e01746-e01722. |
| [20] | 沈燕, 李英辉, 王军, 等. 脑型疟小鼠小胶质细胞的活化特征分析[J]. 传染病信息, 2021, 34(1): 32-38. |
| Shen Y, Li YH, Wang J, et al. Analysis of activation characteristics of microglia in cerebral malaria mice[J]. Infect Dis Inf, 2021, 34(1): 32-38. (in Chinese) | |
| [21] | Le?o L, Puty B, Dolabela MF, et al. Association of cerebral malaria and TNF-α levels: a systematic review[J]. BMC Infect Dis, 2020, 20(1): 442. |
| [22] | Schofield L, Grau GE. Immunological processes in malaria pathogenesis[J]. Nat Rev Immunol, 2005, 5(9): 722-735. |
| [23] | Wang Y, Shen Y, Liang J, et al. Neurons upregulate PD-L1 via IFN/STAT1/IRF1 to alleviate damage by CD8+ T cells in cerebral malaria[J]. J Neuroinflammation, 2024, 21(1): 119. |
| [24] | Hunt NH, Ball HJ, Hansen AM, et al. Cerebral malaria: gamma-interferon redux[J]. Front Cell Infect Microbiol, 2014, 4: 113. |
| [25] | Pais TF, Ali H, Moreira da Silva J, et al. Brain endothelial STING1 activation by Plasmodium-sequestered heme promotes cerebral malaria via type I IFN response[J]. Proc Natl Acad Sci USA, 2022, 119(36): e2206327119. |
| [26] | Shafi AM, Végvári á, Zubarev RA, et al. Brain endothelial cells exposure to malaria parasites links type Ⅰ interferon signalling to antigen presentation, immunoproteasome activation, endothelium disruption, and cellular metabolism[J]. Front Immunol, 2023, 14: 1149107. |
| [27] | Kordes M, Matuschewski K, Hafalla JCR. Caspase-1 activation of interleukin-1β (IL-1β) and IL-18 is dispensable for induction of experimental cerebral malaria[J]. Infect Immun, 2011, 79(9): 3633-3641. |
| [28] | Wang Q, Tang YX, Pan ZY, et al. RNA-seq-based transcriptome analysis of the anti-inflammatory effect of artesunate in the early treatment of the mouse cerebral malaria model[J]. Mol Omics, 2022, 18(8): 716-730. |
| [29] | Orimadegun BE, Faneye AO, Odaibo GN, et al. Apolipoprotein A1 gene polymorphism and its association with TNF-alpha and interleukin-6 levels in uncomplicated Plasmodium falciparum malaria in Nigerian children[J]. Am J Med Sci Med, 2025, 13(1): 1-7. |
| [30] | Kotepui M, Mahittikorn A, Masangkay FR, et al. A systematic review of circulating IP-10/CXCL10 in patients with Plasmodium infections in relation to disease severity[J]. Sci Rep, 2024, 14: 31723. |
| [31] | Campanella GSV, Tager AM, El Khoury JK, et al. Chemokine receptor CXCR3 and its ligands CXCL9 and CXCL10 are required for the development of murine cerebral malaria[J]. Proc Natl Acad Sci USA, 2008, 105(12): 4814-4819. |
| [32] | McNitt SA, Dick JK, Hernandez-Castaneda MA, et al. Phenotype and function of IL-10-producing NK cells in individuals with malaria experience[J]. JCI Insight, 2025, 10(9): e183076. |
| [33] | Kossodo S, Monso C, Juillard P, et al. Interleukin-10 modulates susceptibility in experimental cerebral malaria[J]. Immunology, 1997, 91(4): 536-540. |
| [34] | Barker KR, Lu ZY, Kim H, et al. miR-155 modifies inflammation, endothelial activation and blood-brain barrier dysfunction in cerebral malaria[J]. Mol Med, 2017, 23(1): 24-33. |
| [35] | Rangel G, Teerawattanapong N, Chamnanchanunt S, et al. Candidate microRNAs as biomarkers in malaria infection: a systematic review[J]. Curr Mol Med, 2019, 20(1): 36-43. |
| [36] | Freeman BD, Martins YC, Akide-Ndunge OB, et al. Endothelin-1 mediates brain microvascular dysfunction leading to long-term cognitive impairment in a model of experimental cerebral malaria[J]. PLoS Pathog, 2016, 12(3): e1005477. |
| [37] | Martins YC, Freeman BD, Akide Ndunge OB, et al. Endothelin-1 treatment induces an experimental cerebral malaria-like syndrome in C57BL/6 mice infected with Plasmodium berghei NK65[J]. Am J Pathol, 2016, 186(11): 2957-2969. |
| [38] | Stins MF, Mtaja A, Mulendele E, et al. Inflammation and elevated osteopontin in plasma and CSF in cerebral malaria compared to Plasmodium-negative neurological infections[J]. Int J Mol Sci, 2024, 25(17): 9620.[LinkOut] |
| [39] | Obermeier B, Verma A, Ransohoff RM. The blood-brain barrier[M]. Amsterdam: Elsevier, 2016: 39-59. |
| [40] | Albrecht-Schgoer K, Lackner P, Schmutzhard E, et al. Cerebral malaria: current clinical and immunological aspects[J]. Front Immunol, 2022, 13: 863568. |
| [41] | Lennartz F, Smith C, Craig AG, et al. Structural insights into diverse modes of ICAM-1 binding by Plasmodium falciparum-infected erythrocytes[J]. Proc Natl Acad Sci USA, 2019, 116(40): 20124-20134. |
| [42] | Rastegar-Moghaddam SH, Ebrahimzadeh-Bideskan A, Shahba S, et al. Roles of the miR-155 in neuroinflammation and neurological disorders: a potent biological and therapeutic target[J]. Cell Mol Neurobiol, 2023, 43(2): 455-467. |
| [43] | Seady M, Johnson AJ. CD8+ T cells as drivers of blood-brain barrier disruption[J]. Trends Neurosci, 2025, 48(7): 483-494. |
| [44] | Howland SW, Poh CM, Rénia L. Activated brain endothelial cells cross-present malaria antigen[J]. PLoS Pathog, 2015, 11(6): e1004963. |
| [45] | Riggle BA, Manglani M, Maric D, et al. CD8+ T cells target cerebrovasculature in children with cerebral malaria[J]. J Clin Invest, 2020, 130(3): 1128-1138. |
| [46] | Sorensen EW, Lian J, Ozga AJ, et al. CXCL10 stabilizes T cell-brain endothelial cell adhesion leading to the induction of cerebral malaria[J]. JCI Insight, 2018, 3(8): e98911. |
| [47] | Gun SY, Claser C, Teo TH, et al. Interferon regulatory factor 1 is essential for pathogenic CD8+ T cell migration and retention in the brain during experimental cerebral malaria[J]. Cell Microbiol, 2018, 20(5): e12819. |
| [48] | de Lima RMS, Le?o LKR, Martins LC, et al. Unveiling new perspectives about the onset of neurological and cognitive deficits in cerebral malaria: exploring cellular and neurochemical mechanisms[J]. Front Cell Infect Microbiol, 2025, 15: 1506282. |
| [49] | Hadjilaou A, Brandi J, Riehn M, et al. Pathogenetic mechanisms and treatment targets in cerebral malaria[J]. Nat Rev Neurol, 2023, 19(11): 688-709. |
| [50] | Idro R, Marsh K, John CC, et al. Cerebral malaria: mechanisms of brain injury and strategies for improved neurocognitive outcome[J]. Pediatr Res, 2010, 68(4): 267-274. |
| [51] | Schiess N, Villabona-Rueda A, Cottier KE, et al. Pathophysiology and neurologic sequelae of cerebral malaria[J]. Malar J, 2020, 19(1): 266. |
| [52] | Beniwal P, Joshi J, Kaur S. A comprehensive review of cerebral malaria[J]. J Parasit Dis, 2025, 49(2): 257-272. |
| [53] | Sahu PK, Hoffmann A, Majhi M, et al. Brain magnetic resonance imaging reveals different courses of disease in pediatric and adult cerebral malaria[J]. Clin Infect Dis, 2021, 73(7): e2387-e2396. |
| [54] | Mohanty S, Benjamin LA, Majhi M, et al. Magnetic resonance imaging of cerebral malaria patients reveals distinct pathogenetic processes in different parts of the brain[J]. mSphere, 2017, 2(3): e00193-e00117. |
| [55] | Bangirana P, Idro R, John CC, et al. Rehabilitation for cognitive impairments after cerebral malaria in African children: strategies and limitations[J]. Tropical Med Int Health, 2006, 11(9): 1341-1349. |
| [56] | John CC, Bangirana P, Byarugaba J, et al. Cerebral malaria in children is associated with long-term cognitive impairment[J]. Pediatrics, 2008, 122(1): e92-e99. |
| [57] | Boivin MJ, Bangirana P, Byarugaba J, et al. Cognitive impairment after cerebral malaria in children: a prospective study[J]. Pediatrics, 2007, 119(2): e360-e366. |
| [58] | Bangirana P, Musisi S, Boivin MJ, et al. Malaria with neurological involvement in Ugandan children: effect on cognitive ability, academic achievement and behaviour[J]. Malar J, 2011, 10(1): 334. |
| [59] | Idro R, Kakooza-Mwesige A, Asea B, et al. Cerebral malaria is associated with long-term mental health disorders: a cross sectional survey of a long-term cohort[J]. Malar J, 2016, 15(1): 184. |
| [60] | Bangirana P, Allebeck P, Boivin MJ, et al. Cognition, behaviour and academic skills after cognitive rehabilitation in Ugandan children surviving severe malaria: a randomised trial[J]. BMC Neurol, 2011, 11(1): 96. |
| [61] | Potchen MJ, Birbeck GL, DeMarco JK, et al. Neuroimaging findings in children with retinopathy-confirmed cerebral malaria[J]. Eur J Radiol, 2010, 74(1): 262-268. |
| [62] | Clark DJ, Bond C, Andrews A, et al. Admission clinical and EEG features associated with mortality and long-term neurologic and cognitive outcomes in pediatric cerebral malaria[J]. Neurology, 2023, 101(13): e1307-e1318. |
| [63] | Rosa-Gon?alves P, Ribeiro-Gomes FL, Daniel-Ribeiro CT. Malaria related neurocognitive deficits and behavioral alterations[J]. Front Cell Infect Microbiol, 2022, 12: 829413. |
| [64] | Hora R, Kapoor P, Thind KK, et al. Cerebral malaria-clinical manifestations and pathogenesis[J]. Metab Brain Dis, 2016, 31(2): 225-237. |
| [65] | Guenther G, Muller D, Moyo D, et al. Pediatric cerebral malaria[J]. Curr Trop Med Rep, 2021, 8(2): 69-80. |
| [66] | Song XN, Wei W, Cheng WJ, et al. Cerebral malaria induced by Plasmodium falciparum: clinical features, pathogenesis, diagnosis, and treatment[J]. Front Cell Infect Microbiol, 2022, 12: 939532. |
| [67] | Ghazanfari N, Mueller SN, Heath WR. Cerebral malaria in mouse and man[J]. Front Immunol, 2018, 9: 2016. |
| [68] | Castaldo N, Tascini C, Della Siega P, et al. Clinical presentation and immunological features of post-malaria neurologic syndrome: a case report and review of literature[J]. Malar J, 2020, 19(1): 419. |
| [69] | Trivedi S, Chakravarty A. Neurological complications of malaria[J]. Curr Neurol Neurosci Rep, 2022, 22(8): 499-513. |
| [70] | Mai NTH, Day NP, Van Chuong L, et al. Post-malaria neurological syndrome[J]. Lancet, 1996, 348(9032): 917-921. |
| [71] | Tamzali Y, Demeret S, Haddad E, et al. Post-malaria neurological syndrome: four cases, review of the literature and clarification of the nosological framework[J]. Malar J, 2018, 17(1): 387. |
| [72] | Alawad MJ, Almayoof M, Al bozom A, et al. Post-malaria neurological syndrome (PMNS): a rare case report with brain biopsy findings[J]. BMC Infect Dis, 2023, 23(1): 886. |
| [73] | Riera E, Almuedo A, álvarez-Martínez MJ, et al. Recognizing post-malaria neurological syndrome in travellers: insights from three cases[J]. J Travel Med, 2026, 33: taaf041. |
| [74] | Agarwal N. Post-malaria neurological syndrome manifesting as new onset psychosis with generalized encephalopathy: an analysis of two cases in children[J]. Trop Doct, 2022, 52(1): 168-170. |
| [75] | Panda PK, Sharawat IK, Panda PK. Case report: an adolescent girl with isolated neuropsychiatric features and apparent post-malaria neurological syndrome[J]. Am J Trop Med Hyg, 2020, 102(5): 1030-1032. |
| [76] | Evans OB, Vedanarayanan V. Guillain-barre? syndrome[J]. Pediatr Rev, 1997, 18(1): 10-16. |
| [77] | Kebede MA, Tekle AB, Eshetu MA, et al. Guillain-Barré syndrome following falciparum malaria infection: a case report[J]. BMC Neurol, 2025, 25(1): 37. |
| [78] | Sithinamsuwan P, Sinsawaiwong S, Limapichart K. Guillain- Barre’s syndrome associated with Plasmodium falciparum malaria: role of plasma exchange[J]. J Med Assoc Thai, 2001, 84(8): 1212-1216. |
| [79] | Kanjalkar M, Karnad DR, Narayana RV, et al. Guillain-Barre syndrome following malaria[J]. J Infect, 1999, 38(1): 48-50. |
| [80] | Fischer M, Schmutzhard E. Posterior reversible encephalopathy syndrome[J]. J Neurol, 2017, 264(8): 1608-1616. |
| [81] | Song TJ, Lee KH, Li H, et al. Reversible cerebral vasocon-striction syndrome: a comprehensive systematic review[J]. Eur Rev Med Pharmacol Sci, 2021, 25(9): 3519-3529. |
| [82] | Beuker C, Strunk D, Rawal R, et al. Primary angiitis of the CNS: a systematic review and meta-analysis[J]. Neurol Neuroimmunol Neuroinflamm, 2021, 8(6): e1093. |
| [83] | Bellazreg F, Slama D, Ben Lasfar N, et al. Neurological manifestations following cured malaria: don’t forget post-malaria neurological syndrome[J]. Afr H Sci, 2021, 21(1): 273-276. |
| [84] | Siddig EE, Misbah El-Sadig S, Eltigani HF, et al. Delayed cerebellar ataxia induced by Plasmodium falciparum malaria: a rare complication[J]. Clin Case Rep, 2023, 11(10): e8053. |
| [85] | O’Brien NF, Raees MQ, Wynkoop HJ, et al. Advancing understanding of cerebrovascular hemodynamic perturbations in pediatric cerebral malaria using a modified critical closing pressure evaluation- a prospective, observational study[J]. Neurocritical Care, 2025, 43(2): 493-503. |
| [86] | Hijazi M, Abdalla E, Fadul A, et al. Malaria causing post-infectious cerebellitis, a case report and literature review[J]. Ann Med Surg, 2022, 81: 104462. |
| [87] | Stockman JA Ⅲ. Artesunate versus quinine in the treatment of severe falciparum malaria in African children (AQUAMAT): an open-label, randomised trial[J]. Yearb Pediatr, 2012, 2012: 252-254. |
| [88] | Ogutu BR, Newton CC. Management of seizures in children with falciparum malaria[J]. Trop Doct, 2004, 34(2): 71-75. |
| [89] | Birbeck GL, Herman ST, Capparelli EV, et al. A clinical trial of enteral Levetiracetam for acute seizures in pediatric cerebral malaria[J]. BMC Pediatr, 2019, 19(1): 399. |
| [90] | Konno K, Chibwana S, Takata Y. Intensive physiotherapy with subsequent community-based rehabilitation: two cases of cerebral malaria in rural areas of Malawi[J]. J Phys Ther Sci, 2019, 31(1): 112-115. |
| [91] | 曹伟, 王一, 张熙致, 等. 脑型疟辅助治疗研究进展[J]. 中国寄生虫学与寄生虫病杂志, 2023, 41(3): 361-373, 379. |
| Cao W, Wang Y, Zhang XZ, et al. Research progress in adjunctive therapy of cerebral malaria[J]. Chin J Parasitol Parasit Dis, 2023, 41(3): 361-373, 379. (in Chinese) | |
| [92] | 周珂, 陈宗香, 刘兰军. 疟疾疫苗的研发进展[J]. 中国药科大学学报, 2025, 56(4): 531-538. |
| Zhou K, Chen ZX, Liu LJ. Progress in the development of malaria vaccines[J]. J China Pharm Univ, 2025, 56(4): 531-538. (in Chinese) | |
| [93] | Jensen AR, Adams Y, Hviid L. Cerebral Plasmodium falciparum malaria: the role of PfEMP1 in its pathogenesis and immunity, and PfEMP1-based vaccines to prevent it[J]. Immunol Rev, 2020, 293(1): 230-252. |
| [94] | Patra S, Singh M, Wasnik K, et al. Polymeric nanoparticle based diagnosis and nanomedicine for treatment and development of vaccines for cerebral malaria: a review on recent advancement[J]. ACS Appl Bio Mater, 2021, 4(10): 7342-7365. |
| [95] | Guha SK, Tillu R, Sood A, et al. Single episode of mild murine malaria induces neuroinflammation, alters microglial profile, impairs adult neurogenesis, and causes deficits in social and anxiety-like behavior[J]. Brain Behav Immun, 2014, 42: 123-137. |
| [96] | de Sousa LP, Ribeiro-Gomes FL, de Almeida RF, et al. Immune system challenge improves recognition memory and reverses malaria-induced cognitive impairment in mice[J]. Sci Rep, 2021, 11: 14857. |
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