Volume 69, Issue 4
  • ISSN: 0002-9637
  • E-ISSN: 1476-1645


Cerebral malaria (CM) is a major cause of death in severe malaria. We present quantitative electron microscopic findings of the neuropathologic features in a prospective clinicopathologic study of 65 patients who died of severe malaria in Thailand and Vietnam. Sequestration of parasitized red blood cells (PRBCs) in cerebral microvessels was significantly higher in the brains of patients with CM compared with those with non-cerebral malaria (NCM) in all parts of the brain (cerebrum, cerebellum, and medulla oblongata). There was a hierarchy of sequestration with more in the cerebrum and cerebellum than the brain stem. When cerebral sequestration was compared with the peripheral parasitemia pre mortem, there were 26.6 times more PRBCs in the brain microvasculature than in the peripheral blood. The sequestration index was significantly higher in CM patients (median = 50.7) than in NCM patients (median = 6.9) ( = 0.042). The degree of sequestration of -infected erythrocytes in cerebral microvessels is quantitatively associated with pre-mortem coma.


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  1. Miller L, Good M, Milon G, 1994. Malaria pathogenesis. Science 264 : 1878–1883.
  2. Turner GDH, 1997. Cerebral malaria. Brain Pathol 7 : 569–582.
  3. Ho M, White NJ, 1999. Molecular mechanisms of cytoadherence in malaria. Am J Physiol 276 : C1231–C1242.
  4. World Health Organization, Division of Control of Tropical Diseases, 2000. Severe Falciparum Malaria. Trans R Soc Trop Med Hyg 94 (Suppl) : 1–69.
  5. White N, Ho M, 1992. The pathophysiology of malaria. Adv Parasitol 31 : 83–173.
  6. Marsh K, Foster D, Waruiru C, Mwangi I, Winstanley M, Marsh V, Newton C, Winstanley P, Warn P, Peshu N, Pasvol G, Snow R, 1995. Indicators of life-threatening malaria in African children. N Engl J Med 332 : 1399–1404.
  7. Newton CRJC, Taylor TE, Whitten RO, 1998. Pathophysiology of fatal falciparum malaria in African children. Am J Trop Med Hyg 58 : 673–683.
  8. Aikawa M, Iseki M, Barnwell J, Taylor D, Oo M, Howard R, 1990. The pathology of human cerebral malaria. Am J Trop Med Hyg 43 : 30–37.
  9. Pongponratn E, Riganti M, Punpoowong B, Aikawa M, 1991. Microvascular sequestration of parasitized erythrocytes in human falciparum malaria: a pathological study. Am J Trop Med Hyg 44 : 168–175.
  10. Riganti M, Pongponratn E, Tegoshi T, Looareesuwan S, Punpoowong B, Aikawa M, 1990. Human cerebral malaria in Thailand: a clinicopathological correlation. Immunol Lett 25 : 199–205.
  11. MacPherson GG, Warrell MJ, White NJ, Looareesuwan S, Warrell DA, 1985. Human cerebral malaria: a quantitative ultra-structural analysis of parasitized erythrocyte sequestration. Am J Pathol 119 : 385–401.
  12. Silamut K, Phu NH, Whitty C, Turner GDH, Louwrier K, Mai NTH, Simpson JA, Hien TT, White NJ, 1999. A quantitative analysis of the microvascular sequestration of malaria parasites in the human brain. Am J Pathol 155 : 395–410.
  13. Turner GD, Morrison H, Jones M, Davis TM, Looareesuwan S, Buley ID, Gatter KC, Newbold CI, Pukritayakamee S, Nagachinta B, White NJ, Berendt AR, 1994. An immunohistochemical study of the pathology of fatal malaria: evidence for widespread endothelial activation and a potential role for ICAM-1 in cerebral sequestration. Am J Pathol 145 : 1057–1069.
  14. Brown H, Hien TT, Day N, Mai NT, Chuong LV, Chau TT, Loc PP, Phu NH, Bethell D, Farrar J, Gatter K, White NJ, Turner GDH, 1999. Evidence of blood-brain barrier dysfunction in human cerebral malaria. Neuropathol Appl Neurobiol 25 : 331–340.
  15. Medana IM, Mai NT, Day NP, Hien TT, Bethell D, Phu NH, Farrar J, White NJ, Turner GD, 2001. Cellular stress and injury responses in the brains of adult Vietnamese patients with fatal Plasmodium falciparum malaria. Neuropathol Appl Neurobiol 27 : 421–433.
  16. Hien TT, Day NPJ, Phu NH, Mai NTH, Chau TTH, Loc PP, Sinh DX, Chuong LV, Vinh H, Waller D, Peto TEA, White NJ, 1996. A controlled trial of artemether or quinine in Vietnamese adults with severe falciparum malaria. N Engl J Med 335 : 76–83.
  17. World Health Organization, Division of Control of Tropical Diseases, 1990. Severe and Complicated Malaria. Trans R Soc Trop Med Hyg 84 : 1–65.
  18. Marchiafava E, Bignami A, 1894. On summer-autumnal malaria fever. Malaria and the parasites of malaria fevers. New Sydenham Soc 150 : 1–234.
  19. Ewing J, 1902. Contribution to the pathological anatomy of malaria fever. J Exp Med 6 : 119–180.
  20. Spitz S, 1946. Pathology of acute falciparum malaria. Mil Med 99 : 555–572.
  21. Clark H, Tomlinson W, 1949. The pathological anatomy of malaria. Boyd MF, ed. Malariology. Philadelphia: W. B. Saunders, 874–903.
  22. Thomas JD, 1971. Clinical and histopathological correlation of cerebral malaria. Trop Geogr Med 23 : 232–238.
  23. Looareesuwan S, Warrell DA, White NJ, Sutharasamai P, Chanthavanich P, Sundaravej K, Juel-Jensen BE, Bunnag D, Harinasuta T, 1983. Do patients with cerebral malaria have cerebral oedema? A computed topography study. Lancet 1 : 434–437.
  24. Looareesuwan S, Wilairatana P, Krishna S, Kendall B, Vanaphan S, Viravan C, White NJ, 1995. Magnetic resonance imaging of the brain in patients with cerebral malaria. Clin Infect Dis 21 : 300–309.
  25. Clark IA, Rockett KA, 1996. Nitric oxide and parasitic disease. Adv Parasitol 37 : 1–56.
  26. Maneerat Y, Viriyavejakul P, Punpoowong B, Jones M, Wilairatana P, Pongponratn E, Turner GDH, Udomsangpetch R, 2000. Inducible nitric oxide synthase expression is increased in the brain in fatal cerebral malaria. Histopathology 37 : 269–277.
  27. Adams S, Brown H, Turner G, 2002. Breaking down the blood-brain barrier: signaling a path to cerebral malaria? Trends Parasitol 18 : 360–366.
  28. el-Shoura SM, al-Amari OM, 1993. Falciparum malaria in naturally infected human patients: II. Ultrastructural alterations to erythrocytes infected with asexual forms. J Morphol 215 : 207–212.
  29. Nagatake T, Thuc HV, Tegoshi T, Rabbege J, Anh K, Aikawa M, 1992. Pathology of falciparum malaria in Vietnam. Am J Trop Med Hyg 47 : 259–264.
  30. Sein K, Maeno Y, Thuc H, Anh T, Aikawa M, 1993. Differential sequestration of parasitized erythrocytes in the cerebrum and cerebellum in human cerebral malaria. Am J Trop Med Hyg 48 : 504–511.
  31. Sein K, Brown AE, Maeno Y, Smith CD, Corcoran KD, Hansukjariya P, Webster HK, Aikawa M, 1993. Sequestration pattern of parasitized erythrocytes in cerebrum, mid-brain, and cerebellum of Plasmodium coatneyi-infected rhesus monkeys (Macaca mulata). Am J Trop Med Hyg 49 : 513–519.
  32. Polder TW, Eling WM, Curfs JH, Jerusalem CR, Wijers-Rouw M, 1992. Ultrastructural changes in the blood-brain barrier of mice infected with Plasmodium berghei. Acta Leiden 60 : 31–46.
  33. Maeno Y, Brown A, Smith C, Tegoshi T, Toyoshima T, Ockenhouse CF, Corcoran KD, Ngampochjana M, Kyle DE, Webster HK, Aikawa M, 1993. A nonhuman primate model for human cerebral malaria: effects of artesunate (qinghaosu derivative) on rhesus monkeys experimentally infected with Plasmodium coatneyi. Am J Trop Med Hyg 49 : 726–734.
  34. Robert C, Peyrol S, Pouvelle B, Gay-Andrieu F, Gysin J, 1996. Ultrastructural aspects of Plasmodium falciparum-infected erythrocyte adherence to endothelial cells of Saimiri brain microvasculature. Am J Trop Med Hyg 54 : 169–177.
  35. Lou J, Donati YRA, Juillard P, Giroud C, Vesin C, Mili N, Grau GE, 1997. Platelets play an important role in TNF-induced microvascular endothelial cell pathology. Am J Pathol 151 : 1397–1405.
  36. Urban BC, Ferguson DJP, Pain A, Willcox N, Phletanski M, Austyn JM, Roberts DJ, 1999. Plasmodium falciparum-infected erythrocytes modulate the maturation of dendritic cells. Nature 400 : 73–77.
  37. Yu W, Yu MC, Young PA, 1974. Ultrastructural changes in the cerebrovascular endothelium induced by a diet high in linoleic acid and deficient in vitamin E. Exp Mol Pathol 21 : 289–299.
  38. Schmahl FW, Schlote W, Urbascher B, Betz E, Heuser D, Hecker H, 1982. Reactions of endothelial cells of cerebral vessels in endotoxic shock. Reichard SM, Adams HR, Reynolds DG, Wolfe RR, eds. Advances in Shock Research. Proceedings of the 5th Annual Conference on Shock. Smugglers Notch, VT: Alan R. Liss, Inc., 192–193.
  39. Oo MM, Than T, 1989. Pathogenesis of ring-haemorrhage in cerebral malaria. Ann Trop Med Parasitol 83 : 555–557.
  40. Oo MM, Aikawa M, Than T, Aye TM, Myint PT, Igarashi I, Schoene WC, 1987. Human cerebral malaria: a pathological study. J Neuropathol Exp Neurol 46 : 223–231.
  41. Boonpucknavig V, Boonpucknavig S, Udomsangpetch R, Nitiyanant P, 1990. An immunofluorescence study of cerebral malaria: a correlation with histopathology. Arch Pathol Lab Med 114 : 1028–1034.
  42. Patnaik JK, Das BS, Mishkra SK, Mohantny S, Satpathy SK, Mohantny D, 1994. Vascular clogging, mononuclear cell margination, and enhanced vascular permeability in the pathogenesis of human cerebral malaria. Am J Trop Med Hyg 51 : 642–647.
  43. Luse SA, Miller LH, 1971. Plasmodium falciparum malaria. Ultrastructure of parasitized erythrocytes in cardiac vessels. Am J Trop Med Hyg 20 : 655–660.
  44. Craig A, Scherf A, 2001. Molecules on the surface of the Plasmodium falciparum infected erythrocyte and their role in malaria pathogenesis and immune evasion. Mol Biochem Parasitol 115 : 129–143.
  45. Aikawa M, Nakamura K, Shiraishi S, Matsumoto Y, Arwati H, Torii M, Ito Y, Takeuchi T, Tandler B, 1996. Membrane knobs of unfixed Plasmodium falciparum infected erythrocytes: new finding as revealed by the atomic force microscopy and surface potential spectroscopy. Exp Parasitol 84 : 339–343.
  46. Aikawa M, 1997. Studies on falciparum malaria with atomic-force and surface-potential microscopes. Ann Trop Med Parasitol 91 : 689–692.
  47. Marchenko S, Sage S, 1993. Electrical properties of resting and acetylcholine-stimulated endothelium in intact aorta. J Physiol 462 : 735–751.
  48. David PH, Handunnetti SM, Leech JH, Gamage P, Mendis KN, 1988. Rosetting: a new cytoadherence property of malaria-infected erythrocytes. Am J Trop Med Hyg 38 : 289–297.
  49. Kaul DK, Roth EF, Nagel RL, Howard RJ, Handunnetti SM, 1991. Rosetting of Plasmodium falciparum infected red blood cells with uninfected red blood cells enhances microvascular obstruction under flow conditions. Blood 78 : 812–819.

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  • Received : 18 Feb 2003
  • Accepted : 30 May 2003

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