Pathogenesis of cerebral malaria: New diagnostic tools, biomarkers, and therapeutic approaches

Frontiers in Cellular and Infection Microbiology

Volumn 5, Issue OCT, 2015, Pages

  Sahu, Praveen K ^a   Satpathi, Sanghamitra ^a   Behera, Prativa K ^a   Mishra, Saroj K ^a   Mohanty, Sanjib ^a   Wassmer, Samuel Crocodile ^b,c  

^a ISPAT GENERAL HOSPITAL   (India)

^b NEW YORK UNIVERSITY SCHOOL OF MEDICINE   (United States)

^c UNIVERSITY OF SYDNEY   (Australia)

Author keywords

Cerebral malaria; Diagnostic; New therapies; Pathophysiology; Plasmodium falciparum; Research tools

Indexed keywords

ANGIOPOIETIN 1; ANGIOPOIETIN 2; ANTIOXIDANT; ARTEMISININ; CARBON MONOXIDE; FLUORODEOXYGLUCOSE F 18; GAMMA INTERFERON INDUCIBLE PROTEIN 10; HEME OXYGENASE 1; INTERCELLULAR ADHESION MOLECULE 1; NITRIC OXIDE; OXYGEN; TUMOR NECROSIS FACTOR; BIOLOGICAL MARKER;

BIOLUMINESCENCE; BRAIN MALARIA; CEREBROSPINAL FLUID ANALYSIS; COMPUTER ASSISTED TOMOGRAPHY; ELECTROENCEPHALOGRAPHY; FLUORESCENCE ANGIOGRAPHY; HUMAN; INTRAVITAL MICROSCOPY; NEUROIMAGING; NONHUMAN; NUCLEAR MAGNETIC RESONANCE IMAGING; OPHTHALMOSCOPY; OPTICAL COHERENCE TOMOGRAPHY; PATHOGENESIS; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PLASMODIUM FALCIPARUM; POSITRON EMISSION TOMOGRAPHY; RETINOPATHY; REVIEW; ANIMAL; DIAGNOSTIC TEST; DRUG THERAPY; MALARIA, CEREBRAL; PATHOLOGY; PROCEDURES;

ANIMALS; BIOMARKERS; DIAGNOSTIC TESTS, ROUTINE; DRUG THERAPY; HUMANS; MALARIA, CEREBRAL;

EID: 85006188864     PISSN: None     EISSN: 22352988     Source Type: Journal    
DOI: 10.3389/fcimb.2015.00075     Document Type: Review

References (131)

1. Achtman, A. H., Pilat, S., Law, C. W., Lynn, D. J., Janot, L., Mayer, M. L., et al. (2012). Effective adjunctive therapy by an innate defense regulatory peptide in a preclinical model of severe malaria. Sci. Transl. Med. 4:135ra164. doi: 10.1126/scitranslmed.3003515
2. Adukpo, S., Kusi, K. A., Ofori, M. F., Tetteh, J. K., Amoako-Sakyi, D., Goka, B. Q., et al. (2013). High plasma levels of soluble intercellular adhesion molecule (ICAM)-1 are associated with cerebral malaria. PLoS ONE 8:e84181. doi: 10.1371/journal.pone.0084181
3. Ashley, E. A., Dhorda, M., Fairhurst, R. M., Amaratunga, C., Lim, P., Suon, S., et al. (2014). Spread of artemisinin resistance in Plasmodium falciparum malaria. N. Engl. J. Med. 371, 411-423. doi: 10.1056/NEJMoa1314981
4. Bachmann, J., Burte, F., Pramana, S., Conte, I., Brown, B. J., Orimadegun, A. E., et al. (2014). Affinity proteomics reveals elevated muscle proteins in plasma of children with cerebral malaria. PLoS Pathog. 10:e1004038. doi: 10.1371/journal.ppat.1004038
5. Beare, N. A., Harding, S. P., Taylor, T. E., Lewallen, S., and Molyneux, M. E. (2009). Perfusion abnormalities in children with cerebral malaria and malarial retinopathy. J. Infect. Dis. 199, 263-271. doi: 10.1086/595735
6. Beare, N. A., Southern, C., Chalira, C., Taylor, T. E., Molyneux, M. E., and Harding, S. P. (2004). Prognostic significance and course of retinopathy in children with severe malaria. Arch. Ophthalmol. 122, 1141-1147. doi: 10.1001/archopht.122.8.1141
7. Beare, N. A., Taylor, T. E., Harding, S. P., Lewallen, S., and Molyneux, M. E. (2006). Malarial retinopathy: a newly established diagnostic sign in severe malaria. Am. J. Trop. Med. Hyg. 75, 790-797. doi: 10.1016/j.idcr.2014.10.003
8. Berendt, A. R., Tumer, G. D., and Newbold, C. I. (1994). Cerebral malaria: the sequestration hypothesis. Parasitol. Today 10, 412-414. doi: 10.1016/0169-4758(94)90238-0
9. Bhatt, S., Weiss, D. J., Cameron, E., Bisanzio, D., Mappin, B., Dalrymple, U., et al. (2015). The effect of malaria control on Plasmodium falciparum in Africa between 2000 and 2015. Nature. doi: 10.1038/nature15535
10. Birbeck, G. L., Molyneux, M. E., Kaplan, P. W., Seydel, K. B., Chimalizeni, Y. F., Kawaza, K., et al. (2010). Blantyre Malaria Project Epilepsy Study (BMPES) of neurological outcomes in retinopathy-positive paediatric cerebral malaria survivors: a prospective cohort study. Lancet Neurol. 9, 1173-1181. doi: 10.1016/S1474-4422(10)70270-2
11. Blanco, Y. C., Farias, A. S., Goelnitz, U., Lopes, S., Arrais-Silva, W. W., Carvalho, B. O., et al. (2008). Hyperbaric oxygen prevents early death caused by experimental cerebral malaria. PLoS ONE 3:e3126. doi: 10.1371/journal.pone.0003126
12. Bridges, D. J., Bunn, J., van Mourik, J. A., Grau, G., Preston, R. J., Molyneux, M., et al. (2010). Rapid activation of endothelial cells enables Plasmodium falciparum adhesion to platelet-decorated von Willebrand factor strings. Blood 115, 1472-1474. doi: 10.1182/blood-2009-07-235150
13. Cabrales, P., Martins, Y. C., Ong, P. K., Zanini, G. M., Frangos, J. A., and Carvalho, L. J. (2013). Cerebral tissue oxygenation impairment during experimental cerebral malaria. Virulence 4, 686-697. doi: 10.4161/viru.26348
14. Cabrales, P., Zanini, G. M., Meays, D., Frangos, J. A., and Carvalho, L. J. (2010). Murine cerebral malaria is associated with a vasospasm-like microcirculatory dysfunction, and survival upon rescue treatment is markedly increased by nimodipine. Am. J. Pathol. 176, 1306-1315. doi: 10.2353/ajpath.2010.090691
15. Cabrales, P., Zanini, G. M., Meays, D., Frangos, J. A., and Carvalho, L. J. (2011). Nitric oxide protection against murine cerebral malaria is associated with improved cerebral microcirculatory physiology. J. Infect. Dis. 203, 1454-1463. doi: 10.1093/infdis/jir058
16. Campanella, G. S., Tager, A. M., El Khoury, J. K., Thomas, S. Y., Abrazinski, T. A., Manice, L. A., et al. (2008). Chemokine receptor CXCR3 and its ligands CXCL9 and CXCL10 are required for the development of murine cerebral malaria. Proc. Natl. Acad. Sci. U.S.A. 105, 4814-4819. doi: 10.1073/pnas.0801544105
17. Carter, J. A., Neville, B. G., White, S., Ross, A. J., Otieno, G., Mturi, N., et al. (2004). Increased prevalence of epilepsy associated with severe falciparum malaria in children. Epilepsia 45, 978-981. doi: 10.1111/j.0013-9580.2004.65103.x
18. Casals-Pascual, C., Idro, R., Gicheru, N., Gwer, S., Kitsao, B., Gitau, E., et al. (2008). High levels of erythropoietin are associated with protection against neurological sequelae in African children with cerebral malaria. Proc. Natl. Acad. Sci. U.S.A. 105, 2634-2639. doi: 10.1073/pnas.0709715105
19. Clark, I. A., and Rockett, K. A. (1994). The cytokine theory of human cerebral malaria. Parasitol. Today 10, 410-412. doi: 10.1016/0169-4758(94)90237-2
20. Claser, C., Malleret, B., Gun, S. Y., Wong, A. Y. W., Chang, Z. W., Teo, P., et al. (2011). CD8+ T cells and IFN-γ mediate the time-dependent accumulation of infected red blood cells in deep organs during experimental cerebral malaria. PLoS ONE 6:e18720. doi: 10.1371/journal.pone.0018720
21. Clemmer, L., Martins, Y., Zanini, G., Frangos, J., and Carvalho, L. (2011). Artemether and artesunate show the highest efficacies in rescuing mice with late-stage cerebral malaria and rapidly decrease leukocyte accumulation in the brain. Antimicrob. Agents Chemother. 55, 1383-1390. doi: 10.1128/AAC.01277-10
22. Combes, V., Taylor, T. E., Juhan-Vague, I., Mège, J.-L., Mwenechanya, J., Tembo, M., et al. (2004). Circulating endothelial microparticles in malawian children with severe falciparum malaria complicated with coma. JAMA 291, 2542-2544. doi: 10.1001/jama.291.21.2542-b
23. Conroy, A. L., Lafferty, E. I., Lovegrove, F. E., Krudsood, S., Tangpukdee, N., Liles, W. C., et al. (2009). Whole blood angiopoietin-1 and-2 levels discriminate cerebral and severe (non-cerebral) malaria from uncomplicated malaria. Malar. J. 8:295. doi: 10.1186/1475-2875-8-295
24. Conroy, A. L., Phiri, H., Hawkes, M., Glover, S., Mallewa, M., Seydel, K. B., et al. (2010). Endothelium-based biomarkers are associated with cerebral malaria in Malawian children: a retrospective case-control study. PLoS ONE 5:e15291. doi: 10.1371/journal.pone.0015291
25. Craig, A. G., Grau, G. E., Janse, C., Kazura, J. W., Milner, D., Barnwell, J. W., et al. (2012). The role of animal models for research on severe malaria. PLoS Pathog. 8:e1002401-e1002401. doi: 10.1371/journal.ppat.1002401
26. Crawley, J., Smith, S., Kirkham, F., Muthinji, P., Waruiru, C., and Marsh, K. (1996). Seizures and status epilepticus in childhood cerebral malaria. QJM 89, 591-597. doi: 10.1093/qjmed/89.8.591
27. Dai, M., Freeman, B., Bruno, F. P., Shikani, H. J., Tanowitz, H. B., Weiss, L. M., et al. (2012). 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. 91, 687-692. doi: 10.1016/j.lfs.2012.07.006
28. Dellavalle, B., Staalsoe, T., Kurtzhals, J. A. L., and Hempel, C. (2013). Investigation of hydrogen sulfide gas as a treatment against P. falciparum, murine cerebral malaria, and the importance of thiolation state in the development of cerebral malaria. PloS ONE 8:e59271. doi: 10.1371/journal.pone.0059271
29. Dondorp, A. M., Fanello, C. I., Hendriksen, I. C., Gomes, E., Seni, A., Chhaganlal, K. D., et al. (2010). Artesunate versus quinine in the treatment of severe falciparum malaria in African children (AQUAMAT): an open-label, randomised trial. Lancet 376, 1647-1657. doi: 10.1016/S0140-6736(10)61924-1
30. Dondorp, A., Nosten, F., Stepniewska, K., Day, N., White, N., and South East Asian Quinine Artesunate Malaria Trial, G. (2005). Artesunate versus quinine for treatment of severe falciparum malaria: a randomised trial. Lancet 366, 717-725. doi: 10.1016/S0140-6736(05)67176-0
31. Dorovini-Zis, K., Schmidt, K., Huynh, H., Fu, W., Whitten, R. O., Milner, D., et al. (2011). The neuropathology of fatal cerebral malaria in malawian children. Am. J. Pathol. 178, 2146-2158. doi: 10.1016/j.ajpath.2011.01.016
32. El-Assaad, F., Combes, V., Grau, G. E. R., and Jambou, R. (2014a). Potential Efficacy of Citicoline as Adjunct Therapy in Treatment of Cerebral Malaria. Antimicrob. Agents Chemother. 58, 602-605. doi: 10.1128/AAC.02591-12
33. El-Assaad, F., Wheway, J., Hunt, N. H., Grau, G., and Combes, V. (2014b). Production, fate and pathogenicity of plasma microparticles in murine cerebral malaria. PLoS Pathog. 10:e1003839. doi: 10.1371/journal.ppat.1003839
34. Ellis, C. G., Jagger, J., and Sharpe, M. (2005). The microcirculation as a functional system. Crit. Care 9(Suppl. 4), S3-S8. doi: 10.1186/cc3751
35. Flannery, E. L., Chatterjee, A. K., and Winzeler, E. A. (2013). Antimalarial drug discovery-approaches and progress towards new medicines. Nat. Rev. Microbiol. 11, 849-862. doi: 10.1038/nrmicro3138
36. Franke-Fayard, B., Djokovic, D., Dooren, M. W., Ramesar, J., Waters, A. P., Falade, M. O., et al. (2008). Simple and sensitive antimalarial drug screening in vitro and in vivo using transgenic luciferase expressing Plasmodium berghei parasites. Int. J. Parasitol. 38, 1651-1662. doi: 10.1016/j.ijpara.2008.05.012
37. Franke-Fayard, B., Waters, A. P., and Janse, C. J. (2006). Real-time in vivo imaging of transgenic bioluminescent blood stages of rodent malaria parasites in mice. Nat. Protoc. 1, 476-485. doi: 10.1038/nprot.2006.69
38. Fraz, M. M., Remagnino, P., Hoppe, A., Uyyanonvara, B., Rudnicka, A. R., Owen, C. G., et al. (2012). Blood vessel segmentation methodologies in retinal images-a survey. Comput. Methods Progr. Biomed. 108, 407-433. doi: 10.1016/j.cmpb.2012.03.009
39. Frevert, U., Nacer, A., Cabrera, M., Movila, A., and Leberl, M. (2014). Imaging Plasmodium immunobiology in the liver, brain, and lung. Parasitol. Int. 63, 171-186. doi: 10.1016/j.parint.2013.09.013
40. Grant, A. C., Abdel-Baki, S. G., Omurtag, A., Sinert, R., Chari, G., Malhotra, S., et al. (2014). Diagnostic accuracy of microEEG: a miniature, wireless EEG device. Epilepsy Behav. 34, 81-85. doi: 10.1016/j.yebeh.2014.03.015
41. Grau, G. E., Mackenzie, C. D., Carr, R. A., Redard, M., Pizzolato, G., Allasia, C., et al. (2003). Platelet accumulation in brain microvessels in fatal pediatric cerebral malaria. J. Infect. Dis. 187, 461-466. doi: 10.1086/367960
42. Haque, A., Best, S. E., Unosson, K., Amante, F. H., De Labastida, F., Anstey, N. M., et al. (2011). Granzyme B expression by CD8+ T cells is required for the development of experimental cerebral malaria. J. Immunol. 186, 6148-6156. doi: 10.4049/jimmunol.1003955
43. Hawkes, M., Elphinstone, R. E., Conroy, A. L., and Kain, K. C. (2013). Contrasting pediatric and adult cerebral malaria: the role of the endothelial barrier. Virulence 4, 543-555. doi: 10.4161/viru.25949
44. Hawkes, N. (2015). European Medicines Agency approves first malaria vaccine. BMJ 351:h4067. doi: 10.1136/bmj.h4067
45. Hempel, C., Combes, V., Hunt, N. H., Kurtzhals, J. A. L., and Grau, G. E. R. (2011). CNS hypoxia is more pronounced in murine cerebral than noncerebral malaria and is reversed by erythropoietin. Am. J. Pathol. 179, 1939-1950. doi: 10.1016/j.ajpath.2011.06.027
46. Hempel, C., Hyttel, P., Staalso, T., Nyengaard, J. R., and Kurtzhals, J. A. (2012). Erythropoietin treatment alleviates ultrastructural myelin changes induced by murine cerebral malaria. Malar. J. 11:216. doi: 10.1186/1475-2875-11-216
47. Hendriksen, I. C., Mwanga-Amumpaire, J., von Seidlein, L., Mtove, G., White, L. J., Olaosebikan, R., et al. (2012). Diagnosing severe falciparum malaria in parasitaemic African children: a prospective evaluation of plasma PfHRP2 measurement. PLoS Med. 9:e1001297. doi: 10.1371/journal.pmed.1001297
48. Hollestelle, M. J., Donkor, C., Mantey, E. A., Chakravorty, S. J., Craig, A., Akoto, A. O., et al. (2006). von Willebrand factor propeptide in malaria: evidence of acute endothelial cell activation. Br. J. Haematol. 133, 562-569. doi: 10.1111/j.1365-2141.2006.06067.x
49. Huang, L. L., and Hirose, T. (2012). Portable optical coherence tomography in management of vitreoretinal diseases: current developments, indications, and implications. Semin. Ophthalmol. 27, 213-220. doi: 10.3109/08820538.2012.708811
50. Imai, T., Iwawaki, T., Akai, R., Suzue, K., Hirai, M., Taniguchi, T., et al. (2014). Evaluating experimental cerebral malaria using oxidative stress indicator OKD48 mice. Int. J. Parasitol. 44, 681-685. doi: 10.1016/j.ijpara.2014.06.002
51. Imwong, M., Woodrow, C. J., Hendriksen, I. C., Veenemans, J., Verhoef, H., Faiz, M. A., et al. (2015). Plasma concentration of parasite DNA as a measure of disease severity in falciparum malaria. J. Infect. Dis. 211, 1128-1133. doi: 10.1093/infdis/jiu590
52. Jain, V., Armah, H. B., Tongren, J. E., Ned, R. M., Wilson, N. O., Crawford, S., et al. (2008). Plasma IP-10, apoptotic and angiogenic factors associated with fatal cerebral malaria in India. Malar. J. 7:83. doi: 10.1186/1475-2875-7-83
53. Jain, V., Lucchi, N. W., Wilson, N. O., Blackstock, A. J., Nagpal, A. C., Joel, P. K., et al. (2011). Plasma levels of angiopoietin-1 and-2 predict cerebral malaria outcome in Central India. Malar J. 10:383. doi: 10.1186/1475-2875-10-383
54. John, C. C., Kutamba, E., Mugarura, K., and Opoka, R. O. (2010). Adjunctive therapy for cerebral malaria and other severe forms of Plasmodium falciparum malaria. Expert. Rev. Anti. Infect. Ther. 8, 997-1008. doi: 10.1586/eri.10.90
55. Kariuki, S. M., Gitau, E., Gwer, S., Karanja, H. K., Chengo, E., Kazungu, M., et al. (2014). Value of Plasmodium falciparum histidine-rich protein 2 level and malaria retinopathy in distinguishing cerebral malaria from other acute encephalopathies in Kenyan children. J. Infect. Dis. 209, 600-609. doi: 10.1093/infdis/jit500
56. Kawai, S., and Sugiyama, M. (2010). Imaging analysis of the brain in a primate model of cerebral malaria. Acta Trop. 114, 152-156. doi: 10.1016/j.actatropica.2009.04.015
57. Kennan, R. P., Machado, F. S., Lee, S. C., Desruisseaux, M. S., Wittner, M., Tsuji, M., et al. (2005). Reduced cerebral blood flow and N-acetyl aspartate in a murine model of cerebral malaria. Parasitol. Res. 96, 302-307. doi: 10.1007/s00436-005-1349-z
58. Kim, H., Higgins, S., Liles, W. C., and Kain, K. C. (2011). Endothelial activation and dysregulation in malaria: a potential target for novel therapeutics. Curr. Opin. Hematol. 18, 177-185. doi: 10.1097/MOH.0b013e328345a4cf
59. Kumar, S., Wang, E.-H., Pokabla, M. J., and Noecker, R. J. (2012). Teleophthalmology assessment of diabetic retinopathy fundus images: smartphone versus standard office computer workstation. Telemed. J. E Health 18, 158-162. doi: 10.1089/tmj.2011.0089
60. Lacerda-Queiroz, N., Rodrigues, D. H., Vilela, M. C., Rachid, M. A., Soriani, F. M., Sousa, L. P., et al. (2012). Platelet-activating factor receptor is essential for the development of experimental cerebral malaria. Am. J. Pathol. 180, 246-255. doi: 10.1016/j.ajpath.2011.09.038
61. Lee, J. H., Chin, H. S., Chung, M.-H., and Moon, Y. S. (2010). Retinal hemorrhage in Plasmodium vivax malaria. Am. J. Trop. Med. Hyg. 82, 219-222. doi: 10.4269/ajtmh.2010.09-0439
62. Li, Y., Lein, P. J., Liu, C., Bruun, D. A., Giulivi, C., Ford, G. D., et al. (2012). Neuregulin-1 is neuroprotective in a rat model of organophosphate-induced delayed neuronal injury. Toxicol. Appl. Pharmacol. 262, 194-204. doi: 10.1016/j.taap.2012.05.001
63. Lok, J., Zhao, S., Leung, W., Seo, J. H., Navaratna, D., Wang, X., et al. (2012). Neuregulin-1 effects on endothelial and blood-brain barrier permeability after experimental injury. Transl. Stroke Res. 3, 119-124. doi: 10.1007/s12975-012-0157-x
64. Looareesuwan, S., Warrell, D. A., White, N. J., Sutharasamai, P., Chanthavanich, P., Sundaravej, K., et al. (1983). Do patients with cerebral malaria have cerebral oedema? A computed tomography study. Lancet 1, 434-437. doi: 10.1016/S0140-6736(83)91437-X
65. Lovegrove, F. E., Tangpukdee, N., Opoka, R. O., Lafferty, E. I., Rajwans, N., Hawkes, M., et al. (2009). Serum angiopoietin-1 and-2 levels discriminate cerebral malaria from uncomplicated malaria and predict clinical outcome in African children. PLoS ONE 4:e4912. doi: 10.1371/journal.pone.0004912
66. Maamari, R. N., Keenan, J. D., Fletcher, D. A., and Margolis, T. P. (2014). A mobile phone-based retinal camera for portable wide field imaging. Br. J. Ophthalmol. 98, 438-441. doi: 10.1136/bjophthalmol-2013-303797
67. Maccormick, I. J., Beare, N. A., Taylor, T. E., Barrera, V., White, V. A., Hiscott, P., et al. (2014). Cerebral malaria in children: using the retina to study the brain. Brain 137(Pt 8), 2119-2142. doi: 10.1093/brain/awu001
68. Machado, F. S., Desruisseaux, M. S., Kennan, R. P., Hetherington, H. P., Wittner, M., Weiss, L. M., et al. (2006). Endothelin in a murine model of cerebral malaria. Exp. Biol. Med. 231, 1176-1181.
69. Macpherson, G., Warrell, M., White, N., Looareesuwan, S., and Warrell, D. (1985). Human cerebral malaria. A quantitative ultrastructural analysis of parasitized erythrocyte sequestration. Am. J. Pathol. 119, 385.
70. Manzano-Roman, R., and Siles-Lucas, M. (2012). MicroRNAs in parasitic diseases: potential for diagnosis and targeting. Mol. Biochem. Parasitol. 186, 81-86. doi: 10.1016/j.molbiopara.2012.10.001
71. Marsh, K., Forster, D., Waruiru, C., Mwangi, I., Winstanley, M., Marsh, V., et al. (1995). Indicators of life-threatening malaria in African children. N. Engl. J. Med. 332, 1399-1404. doi: 10.1056/NEJM199505253322102
72. Maude, R. J., Dondorp, A. M., Sayeed, A. A., Day, N. P., White, N. J., and Beare, N. A. (2009). The eye in cerebral malaria: what can it teach us? Trans. R. Soc. Trop. Med. Hyg. 103, 661-664. doi: 10.1016/j.trstmh.2008.11.003
73. Maude, R. J., Plewes, K., Dimock, J., and Dondorp, A. M. (2011). Low-cost portable fluorescein angiography. Br. J. Ophthalmol. 95, 1213-1215. doi: 10.1136/bjo.2010.200576
74. Mikita, K., Thakur, K., Anstey, N. M., Piera, K. A., Pardo, C. A., Weinberg, J. B., et al. (2014). Quantification of Plasmodium falciparum histidine-rich protein-2 in cerebrospinal spinal fluid from cerebral malaria patients. Am. J. Trop. Med. Hyg. 91, 486-492. doi: 10.4269/ajtmh.14-0210
75. Miller, L. H., Ackerman, H. C., Su, X.-Z., and Wellems, T. E. (2013). Malaria biology and disease pathogenesis: insights for new treatments. Nat. Med. 19, 156-167. doi: 10.1038/nm.3073
76. Milner, D. A. Jr., Whitten, R. O., Kamiza, S., Carr, R., Liomba, G., Dzamalala, C., et al. (2014). The systemic pathology of cerebral malaria in African children. Front. Cell Infect. Microbiol. 4:104. doi: 10.3389/fcimb.2014.00104
77. Miranda, A., Vieira, L., Lacerda-Queiroz, N., Souza, A., Rodrigues, D., Vilela, M., et al. (2010). Increased levels of glutamate in the central nervous system are associated with behavioral symptoms in experimental malaria. Braz. J. Med. Biol. Res. 43, 1173-1177. doi: 10.1590/S0100-879X2010007500130
78. Mishra, S. K., and Newton, C. R. (2009). Diagnosis and management of the neurological complications of falciparum malaria. Nat. Rev. Neurol. 5, 189-198. doi: 10.1038/nrneurol.2009.23
79. Mishra, S. K., and Wiese, L. (2009). Advances in the management of cerebral malaria in adults. Curr. Opin. Neurol. 22, 302-307. doi: 10.1097/WCO.0b013e32832a323d
80. Mohanty, S., Mishra, S. K., Patnaik, R., Dutt, A. K., Pradhan, S., Das, B., et al. (2011). Brain swelling and mannitol therapy in adult cerebral malaria: a randomized trial. Clin. Infect. Dis. 53, 349-355. doi: 10.1093/cid/cir405
81. Mohanty, S., Patel, D., Pati, S., and Mishra, S. (2006). Adjuvant therapy in cerebral malaria. Indian J. Med. Res. 124, 245.
82. Moxon, C. A., Heyderman, R. S., and Wassmer, S. C. (2009). Dysregulation of coagulation in cerebral malaria. Mol. Biochem. Parasitol. 166, 99-108. doi: 10.1016/j.molbiopara.2009.03.006
83. Moxon, C. A., Wassmer, S. C., Milner, D. A., Chisala, N. V., Taylor, T. E., Seydel, K. B., et al. (2013). Loss of endothelial protein C receptors links coagulation and inflammation to parasite sequestration in cerebral malaria in African children. Blood 122, 842-851. doi: 10.1182/blood-2013-03-490219
84. Myung, D., Jais, A., He, L., Blumenkranz, M. S., and Chang, R. T. (2014). 3D printed smartphone indirect lens adapter for rapid, high quality retinal imaging. J. Mob. Technol. Med. 3, 9-15. doi: 10.7309/jmtm.3.1.3
85. Nacer, A., Movila, A., Sohet, F., Girgis, N. M., Gundra, U. M., Loke, P., et al. (2014). Experimental cerebral malaria pathogenesis-hemodynamics at the blood brain barrier. PLoS Pathog. 10:e1004528. doi: 10.1371/journal.ppat.1004528
86. Nantakomol, D., Dondorp, A. M., Krudsood, S., Udomsangpetch, R., Pattanapanyasat, K., Combes, V., et al. (2011). Circulating red cell-derived microparticles in human malaria. J. Infect. Dis. 203, 700-706. doi: 10.1093/infdis/jiq104
87. Newton, C. R., Peshu, N., Kendall, B., Kirkham, F. J., Sowunmi, A., Waruiru, C., et al. (1994). Brain swelling and ischaemia in Kenyans with cerebral malaria. Arch. Dis. Child. 70, 281-287. doi: 10.1136/adc.70.4.281
88. Newton, C., Taylor, T., and Whitten, R. (1998). Pathophysiology of fatal falciparum malaria in African children. Am. J. Trop. Med. Hyg. 58, 673-683.
89. Ngoungou, E. B., Dulac, O., Poudiougou, B., Druet-Cabanac, M., Dicko, A., Mamadou Traore, A., et al. (2006). Epilepsy as a consequence of cerebral malaria in area in which malaria is endemic in Mali, West Africa. Epilepsia 47, 873-879.
90. Omurtag, A., and Fenton, A. A. (2012). Assessing diagnostic tests: how to correct for the combined effects of interpretation and reference standard. PLoS ONE 7:e52221. doi: 10.1371/journal.pone.0052221
91. Pai, S., Qin, J., Cavanagh, L., Mitchell, A., El-Assaad, F., Jain, R., et al. (2014). Real-time imaging reveals the dynamics of leukocyte behaviour during experimental cerebral malaria pathogenesis. PLoS Pathog. 10:e1004236. doi: 10.1371/journal.ppat.1004236
92. Pamplona, A., Ferreira, A., Balla, J., Jeney, V., Balla, G., Epiphanio, S., et al. (2007). Heme oxygenase-1 and carbon monoxide suppress the pathogenesis of experimental cerebral malaria. Nat. Med. 13, 703-710. doi: 10.1038/nm1586
93. Pankoui Mfonkeu, J. B., Gouado, I., Fotso Kuate, H., Zambou, O., Amvam Zollo, P. H., Grau, G. E., et al. (2010). Elevated cell-specific microparticles are a biological marker for cerebral dysfunctions in human severe malaria. PLoS ONE 5:e13415. doi: 10.1371/journal.pone.0013415
94. Patankar, T. F., Karnad, D. R., Shetty, P. G., Desai, A. P., and Prasad, S. R. (2002). Adult cerebral malaria: prognostic importance of imaging findings and correlation with postmortem findings. Radiology 224, 811-816. doi: 10.1148/radiol.2243010588
95. Penet, M. F., Abou-Hamdan, M., Coltel, N., Cornille, E., Grau, G. E., De Reggi, M., et al. (2008). Protection against cerebral malaria by the low-molecular-weight thiol pantethine. Proc. Natl. Acad. Sci. U.S.A. 105, 1321-1326. doi: 10.1073/pnas.0706867105
96. Penet, M. F., Viola, A., Confort-Gouny, S., Le Fur, Y., Duhamel, G., Kober, F., et al. (2005). Imaging experimental cerebral malaria in vivo: significant role of ischemic brain edema. J. Neurosci. 25, 7352-7358. doi: 10.1523/JNEUROSCI.1002-05.2005
97. Ponsford, M. J., Medana, I. M., Prapansilp, P., Hien, T. T., Lee, S. J., Dondorp, A. M., et al. (2012). Sequestration and microvascular congestion are associated with coma in human cerebral malaria. J. Infect. Dis. 205, 663-671. doi: 10.1093/infdis/jir812
98. Potchen, M. J., Birbeck, G. L., Demarco, J. K., Kampondeni, S. D., Beare, N., Molyneux, M. E., et al. (2010). Neuroimaging findings in children with retinopathy-confirmed cerebral malaria. Eur. J. Radiol. 74, 262-268. doi: 10.1016/j.ejrad.2009.02.010
99. Potchen, M. J., Kampondeni, S. D., Seydel, K. B., Birbeck, G. L., Hammond, C. A., Bradley, W. G., et al. (2012). Acute brain MRI findings in 120 Malawian children with cerebral malaria: new insights into an ancient disease. Am. J. Neuroradiol. 33, 1740-1746. doi: 10.3174/ajnr.A3035
100. Promeneur, D., Lunde, L. K., Amiry-Moghaddam, M., and Agre, P. (2013). Protective role of brain water channel AQP4 in murine cerebral malaria. Proc. Natl. Acad. Sci. U.S.A. 110, 1035-1040. doi: 10.1073/pnas.1220566110
101. Reis, P. A., Comim, C. M., Hermani, F., Silva, B., Barichello, T., Portella, A. C., et al. (2010). Cognitive dysfunction is sustained after rescue therapy in experimental cerebral malaria, and is reduced by additive antioxidant therapy. PLoS Pathog. 6:e1000963. doi: 10.1371/journal.ppat.1000963
102. Rénia, L., Howland, S. W., Claser, C., Gruner, A. C., Suwanarusk, R., Teo, T.-H., et al. (2012). Cerebral malaria: mysteries at the blood-brain barrier. Virulence 3, 193-201. doi: 10.4161/viru.19013
103. Roper, C., Pearce, R., Nair, S., Sharp, B., Nosten, F., and Anderson, T. (2004). Intercontinental spread of pyrimethamine-resistant malaria. Science 305, 1124. doi: 10.1126/science.1098876
104. Sakata, L. M., Deleon-Ortega, J., Sakata, V., and Girkin, C. A. (2009). Optical coherence tomography of the retina and optic nerve-a review. Clin. Exp. Ophthalmol. 37, 90-99. doi: 10.1111/j.1442-9071.2009.02015.x
105. Sayeed, A. A., Maude, R. J., Hasan, M. U., Mohammed, N., Hoque, M. G., Dondorp, A. M., et al. (2011). Malarial retinopathy in Bangladeshi adults. Am. J. Trop. Med. Hyg. 84, 141-147. doi: 10.4269/ajtmh.2011.10-0205
106. Serghides, L., McDonald, C. R., Lu, Z., Friedel, M., Cui, C., Ho, K. T., et al. (2014). PPARγ agonists improve survival and neurocognitive outcomes in experimental cerebral malaria and induce neuroprotective pathways in human malaria. PLoS Pathog. 10:e1003980. doi: 10.1371/journal.ppat.1003980
107. Serghides, L., Patel, S. N., Ayi, K., Lu, Z., Gowda, D. C., Liles, W. C., et al. (2009). Rosiglitazone modulates the innate immune response to Plasmodium falciparum infection and improves outcome in experimental cerebral malaria. J. Infect. Dis. 199, 1536-1545. doi: 10.1086/598222
108. Seydel, K. B., Kampondeni, S. D., Valim, C., Potchen, M. J., Milner, D. A., Muwalo, F. W., et al. (2015). Brain swelling and death in children with cerebral malaria. N. Engl. J. Med. 372, 1126-1137. doi: 10.1056/NEJMoa1400116
109. Smith, J. D., Craig, A. G., Kriek, N., Hudson-Taylor, D., Kyes, S., Fagan, T., et al. (2000). Identification of a Plasmodium falciparum intercellular adhesion molecule-1 binding domain: a parasite adhesion trait implicated in cerebral malaria. Proc. Natl. Acad. Sci. U.S.A. 97, 1766-1771. doi: 10.1073/pnas.040545897
110. Solomon, W., Wilson, N. O., Anderson, L., Pitts, S., Patrickson, J., Liu, M., et al. (2014). Neuregulin-1 attenuates mortality associated with experimental cerebral malaria. J. Neuroinflammation 11. doi: 10.1186/1742-2094-11-9
111. Spaccapelo, R., Janse, C. J., Caterbi, S., Franke-Fayard, B., Bonilla, J. A., Syphard, L. M., et al. (2010). Plasmepsin 4-deficient Plasmodium berghei are virulence attenuated and induce protective immunity against experimental malaria. Am. J. Pathol. 176, 205-217. doi: 10.2353/ajpath.2010.090504
112. Sugiyama, M., Ikeda, E., Kawai, S., Higuchi, T., Zhang, H., Khan, N., et al. (2004). Cerebral metabolic reduction in severe malaria: fluorodeoxyglucose-positron emission tomography imaging in a primate model of severe human malaria with cerebral involvement. Am. J. Trop. Med. Hyg. 71, 542-545.
113. Tamura, T., Kimura, K., Yuda, M., and Yui, K. (2011). Prevention of experimental cerebral malaria by Flt3 ligand during infection with Plasmodium berghei ANKA. Infect. Immun. 79, 3947-3956. doi: 10.1128/IAI.01337-10
114. Taoufiq, Z., Pino, P., N'dilimabaka, N., Arrouss, I., Assi, S., Soubrier, F., et al. (2011). Atorvastatin prevents Plasmodium falciparum cytoadherence and endothelial damage. Malar. J. 10:52. doi: 10.1186/1475-2875-10-52
115. Taylor, T. E., Fu, W. J., Carr, R. A., Whitten, R. O., Mueller, J. G., Fosiko, N. G., et al. (2004). Differentiating the pathologies of cerebral malaria by postmortem parasite counts. Nat. Med. 10, 143-145. doi: 10.1038/nm986
116. Thakur, K., Vareta, J., Carson, K., Taylor, T., Sullivan, D., and Seydel, K. (2014). Performance of Cerebrospinal Fluid (CSF) Plasmodium falciparum Histidine-Rich Protein-2 (pfHRP-2) in prediction of death in cerebral malaria (S10.007). Neurology 82, S10.007-S010.007.
117. Thumasupapong, S., Tin, T., Sukontason, K., Sawaddichi, C., and Karbwang, J. (1995). Electroencephalography in cerebral malaria. Southeast Asian J. Trop. Med. Public Health 26, 34-37.
118. Tokmak, H., Ergonul, O., Demirkol, O., Cetiner, M., and Ferhanoglu, B. (2014). Diagnostic contribution of 18 F-FDG-PET/CT in fever of unknown origin. Int. J. Infect. Dis. 19, 53-58. doi: 10.1016/j.ijid.2013.10.009
119. Trang, T. T. M., Phu, N. H., Vinh, H., Hien, T. T., Cuong, B. M., Chau, T. T. H., et al. (1992). Acute renal failure in patients with severe falciparum malaria. Clin. Infect. Dis. 15, 874-880. doi: 10.1093/clind/15.5.874
120. Turner, G. D., Morrison, H., Jones, M., Davis, T. M., Looareesuwan, S., Buley, I. D., et al. (1994). An immunohistochemical study of the pathology of fatal malaria: evidence for widespread endothelial activation and a potential role for intercellular adhesion molecule-1 in cerebral sequestration. Am. J. Pathol. 145, 1057.
121. van der Heyde, H. C., Nolan, J., Combes, V., Gramaglia, I., and Grau, G. E. (2006). A unified hypothesis for the genesis of cerebral malaria: sequestration, inflammation and hemostasis leading to microcirculatory dysfunction. Trends Parasitol. 22, 503-508. doi: 10.1016/j.pt.2006.09.002
122. van Meurs, M., Kumpers, P., Ligtenberg, J. J., Meertens, J. H., Molema, G., and Zijlstra, J. G. (2009). Bench-to-bedside review: angiopoietin signalling in critical illness-a future target? Crit Care 13, 207. doi: 10.1186/cc7153
123. Volz, J. C. (2013). Looking through a cranial window: intravital microscopy for in vivo study of cerebral malaria. Virulence 4, 661-663. doi: 10.4161/viru.26802
124. Waknine-Grinberg, J. H., Hunt, N., Bentura-Marciano, A., McQuillan, J. A., Chan, H.-W., Chan, W.-C., et al. (2010). Artemisone effective against murine cerebral malaria. Malar. J. 9:227. doi: 10.1186/1475-2875-9-227
125. Wassmer, S. C., Moxon, C. A., Taylor, T., Grau, G. E., Molyneux, M. E., and Craig, A. G. (2011). Vascular endothelial cells cultured from patients with cerebral or uncomplicated malaria exhibit differential reactivity to TNF. Cell. Microbiol. 13, 198-209. doi: 10.1111/j.1462-5822.2010.01528.x
126. Wassmer, S. C., Taylor, T. E., Rathod, P. K., Mishra, S. K., Mohanty, S., Arevalo-Herrera, M., et al. (2015). Investigating the pathogenesis of severe malaria: a multidisciplinary and cross-geographical approach. Am. J. Trop. Med. Hyg. 93, 42-56. doi: 10.4269/ajtmh.14-0841
127. W.H.O. (2011). World Malaria Report 2010. Geneva.
128. W.H.O. (2014). World Malaria Report 2013. Geneva.
129. Wilson, N. O., Jain, V., Roberts, C. E., Lucchi, N., Joel, P. K., Singh, M. P., et al. (2011). CXCL4 and CXCL10 predict risk of fatal cerebral malaria. Dis. Markers 30, 39-49. doi: 10.1155/2011/828256
130. Zanini, G. M., Cabrales, P., Barkho, W., Frangos, J. A., and Carvalho, L. (2011). Exogenous nitric oxide decreases brain vascular inflammation, leakage and venular resistance during Plasmodium berghei ANKA infection in mice. J. Neuroinflammation 8:66. doi: 10.1186/1742-2094-8-66
131. Zhao, Y., Maccormick, I. J., Parry, D. G., Beare, N. A., Harding, S. P., and Zheng, Y. (2015). Automated detection of vessel abnormalities on fluorescein angiogram in malarial retinopathy. Sci. Rep. 5:11154. doi: 10.1038/srep10425