The Neuropathology of Fatal Cerebral Malaria in Malawian Children

We examined the brains of 50 Malawian children who satisfied the clinical definition of cerebral malaria (CM) during life; 37 children had sequestration of infected red blood cells (iRBCs) and no other cause of death, and 13 had a nonmalarial cause of death with no cerebral sequestration. For comparison, 18 patients with coma and no parasitemia were included. We subdivided the 37 CM cases into two groups based on the cerebral microvasculature pathology: iRBC sequestration only (CM1) or sequestration with intravascular and perivascular pathology (CM2). We characterized and quantified the axonal and myelin damage, blood-brain barrier (BBB) disruption, and cellular immune responses and correlated these changes with iRBC sequestration and microvascular pathology. Axonal and myelin damage was associated with ring hemorrhages and vascular thrombosis in the cerebral and cerebellar white matter and brainstem of the CM2 cases. Diffuse axonal and myelin damage were present in CM1 and CM2 cases in areas of prominent iRBC sequestration. Disruption of the BBB was associated with ring hemorrhages and vascular thrombosis in CM2 cases and with sequestration in both CM1 and CM2 groups. Monocytes with phagocytosed hemozoin accumulated within microvessels containing iRBCs in CM2 cases but were not present in the adjacent neuropil. These findings are consistent with a link between iRBC sequestration and intravascular and perivascular pathology in fatal pediatric CM, resulting in myelin damage, axonal injury, and breakdown of the BBB. We examined the brains of 50 Malawian children who satisfied the clinical definition of cerebral malaria (CM) during life; 37 children had sequestration of infected red blood cells (iRBCs) and no other cause of death, and 13 had a nonmalarial cause of death with no cerebral sequestration. For comparison, 18 patients with coma and no parasitemia were included. We subdivided the 37 CM cases into two groups based on the cerebral microvasculature pathology: iRBC sequestration only (CM1) or sequestration with intravascular and perivascular pathology (CM2). We characterized and quantified the axonal and myelin damage, blood-brain barrier (BBB) disruption, and cellular immune responses and correlated these changes with iRBC sequestration and microvascular pathology. Axonal and myelin damage was associated with ring hemorrhages and vascular thrombosis in the cerebral and cerebellar white matter and brainstem of the CM2 cases. Diffuse axonal and myelin damage were present in CM1 and CM2 cases in areas of prominent iRBC sequestration. Disruption of the BBB was associated with ring hemorrhages and vascular thrombosis in CM2 cases and with sequestration in both CM1 and CM2 groups. Monocytes with phagocytosed hemozoin accumulated within microvessels containing iRBCs in CM2 cases but were not present in the adjacent neuropil. These findings are consistent with a link between iRBC sequestration and intravascular and perivascular pathology in fatal pediatric CM, resulting in myelin damage, axonal injury, and breakdown of the BBB. Cerebral malaria (CM) is a serious complication of Plasmodium falciparum infection. Cerebral involvement occurs in approximately 1% of infected individuals and carries a 15% to 20% case-fatality rate, resulting in three-fourths of 1 million to 2 million deaths/year.1World Health Organization, Communicable Diseases ClusterSevere falciparum malaria.Trans R Soc Trop Med Hyg. 2000; 94: S1-S90Abstract Full Text PDF PubMed Google Scholar Young children in sub-Saharan Africa account for 90% of CM-associated deaths. Pediatric CM is a diffuse encephalopathy characterized clinically by deep coma, often associated with clinical or subclinical seizures in the presence of P. falciparum parasitemia. Most children who survive CM appear to fully recover, but 10% to 20% are left with neurological disabilities, most commonly spasticity, ataxia, hemiplegia, speech disorders, and blindness2Murphy S.C. Breman J.G. Gaps in the childhood malaria burden in Africa: cerebral malaria, neurological sequelae, anemia, respiratory distress, hypoglycemia, and complications of pregnancy.Am J Trop Med Hyg. 2001; 64: 57-67PubMed Google Scholar; long-term sequelae, including cognitive impairment and epilepsy, are being identified with increasing frequency in follow-up studies.3John C.C. Bangirana P. Byarugaba J. Opoka R.O. Idro R. Jurek A.M. Wu B. Boivin M.J. Cerebral malaria in children is associated with long-term cognitive impairment.Pediatrics. 2008; 122: e92-e99Crossref PubMed Scopus (214) Google Scholar The pathogenesis of coma in pediatric CM is poorly understood, and it is not known what mechanisms determine the outcome of the illness. Several pathogenetic mechanisms have been proposed, including impaired tissue perfusion because of sequestration of parasitized erythrocytes, immune-mediated injury secondary to host responses to parasite products, and cerebral edema resulting from increased permeability of the blood-brain barrier (BBB).4Brown H. Turner G. Rogerson S. Tembo M. Mwenechanya J. Molyneux M. Taylor T. Cytokine expression in the brain in human cerebral malaria.J Infect Dis. 1999; 180: 1742-1746Crossref PubMed Scopus (155) Google Scholar, 5MacPherson G.G. Warrell M.J. White N.J. Looareesuwan S. Warrell D.A. Human cerebral malaria: a quantitative ultrastructural analysis of parasitized erythrocyte sequestration.Am J Pathol. 1985; 119: 385-401PubMed Google Scholar, 6Medana I.M. Chaudhri G. Chan-Ling T. Hunt N.H. Central nervous system in cerebral malaria: “innocent or in the of 2001; PubMed Scopus Google Scholar The of these mechanisms to the outcome of CM to in patients with CM have the presence of axonal I.M. N.H. J. White N.J. Turner Axonal injury in cerebral J Pathol. Full Text Full Text PDF PubMed Scopus Google Scholar and BBB I.M. Turner Human cerebral malaria and the blood-brain J PubMed Scopus Google Scholar in to the of the and sequestration of P. red blood cells (iRBCs) in brain ring hemorrhages and the of CM in children is from in from to the other the of are not is within cerebral iRBCs with These Turner N.H. P. Looareesuwan S. White N.J. ultrastructural of the brain in fatal Plasmodium falciparum J Trop Med Hyg. Google Scholar and increased expression of the 1 vascular 1 and H. cerebellar expression of and in cerebral Trop Med PubMed Scopus Google Scholar, T. M. M. Human vascular for Plasmodium for 1 and vascular PubMed Scopus Google Scholar, H. M. Looareesuwan S. S. B. White N.J. of the pathology of fatal malaria: for and a for in cerebral sequestration.Am J Pathol. Google Scholar associated expression of the and 1 H. N.H. J. White Turner G. of blood-brain barrier in human cerebral 1999; PubMed Scopus Google Scholar is to associated with increased permeability of the BBB. These are by in of cells from human brain of to iRBCs to of of Plasmodium 1 expression on brain PubMed Scopus Google Scholar both and iRBC the barrier of the Plasmodium the of human blood-brain barrier Infect Dis. PubMed Scopus Google Scholar Several H. Turner G. Rogerson S. Tembo M. Mwenechanya J. Molyneux M. Taylor T. Cytokine expression in the brain in human cerebral malaria.J Infect Dis. 1999; 180: 1742-1746Crossref PubMed Scopus (155) Google Scholar, H. R. and expression in the brain in human cerebral J PubMed Scopus Google Scholar, R. cellular of and in brains of patients who with cerebral malaria.J Infect Dis. 2000; PubMed Scopus Google Scholar, S.C. D.A. Taylor mechanisms of and of Pathol. PubMed Scopus Google Scholar, R. M. R. of the and in children with Plasmodium falciparum malaria and malaria or PubMed Scopus Google Scholar, P. B. Looareesuwan S. R. associated with pathology in the brain tissue of fatal J Trop Med 1999; Google Scholar, P. J. P. of in during Plasmodium falciparum malaria Google Scholar, R. S. P. M. P. Looareesuwan S. of in the of cerebral J Trop Med Hyg. Google Scholar, M. M. of and in Plasmodium falciparum Med PubMed Scopus Google Scholar, H. Looareesuwan S. of and in patients from Plasmodium falciparum PubMed Scopus Google Scholar, C.C. of in children with Plasmodium falciparum PubMed Scopus Google Scholar the of immune responses in CM have both and and and and in and in human CM are not fully in the pathogenesis of pediatric CM is the of tissue injury to nervous system damage and death in of the infected of cerebral sequestration in fatal pediatric CM the presence of parasitized sequestration in patients with CM and of sequestration with microvascular pathology in of these R.O. S. Molyneux the of cerebral malaria by parasite PubMed Scopus Google Scholar children with clinically CM of other The presence of on between and nonmalarial coma during to the in fatal CM, a of the brains of 37 Malawian children with clinically and CM and the findings with in 13 cases of clinically CM P. falciparum but with nonmalarial cause of death and with the findings in 18 children who of nonmalarial of parasitemia. The of the sequestration of parasitized and microvascular pathology are associated with myelin and axonal damage, BBB and responses in patients with fatal We the brains of 50 Malawian children who of clinically CM the Pediatric The clinical the coma coma a with no within 2 of of and of P. falciparum and of other clinically of coma, including These patients were subdivided into groups on the of the of the cerebral CM1 CM2 and CM1 patients had iRBC sequestration within cerebral microvessels other changes on of the CM2 sequestration was associated with the presence of microvascular pathology and on intravascular and perivascular was no of in of the CM1 or CM2 The patients had no sequestration of parasitized in cerebral The of and and and and cerebral secondary to or patients a with CM but cerebral and only with parasitemia. We to a of 18 patients with CM but CM and parasitemia. These patients of coma, had no and were of other These or and and and and coma of for was in cases two and but were no in the was to to the of these patients was We a on patients in the of a and from the of the The was by the of the of of of and of the brains were and in the from the and and were in 10% and in For the white matter and matter from cerebral and and and brainstem and and and were with and were with the for the for the of axonal for the of BBB for the of and for the of and and and for the of were by for by changes in two changes in in and changes in was in for and was for and the were with in for and with the for or and or and in were for 1 with the secondary or to a in and with of and of brain from the of the of the of or for and We quantified by the of hemorrhages in in of the with a a and axonal damage was quantified by the of white matter areas with myelin and and the of with with and associated in in the of the areas with myelin or axonal damage was the and areas of myelin or axonal damage of was by the of in in the and white matter in was quantified by the of in in the The of the was were by and and who were of the clinical or The groups were and had and and analysis of or the were and were B. of Scholar We were in of CM1 with CM2 and with patients cerebral and because to to brain damage of of of the brain white and matter from cerebral and and and brainstem and and and were for CM on of CM1 and CM2 between brain The patients in the groups and were in of and of coma on and The CM1 and CM2 patients on blood on with patients with nonmalarial cerebral and were the of patients with nonmalarial cerebral was into and and were of CM1 CM2 or For the of the the groups of patients on was and on parasitemia to death are were for of the CM1 the CM2 the the parasitemia by patients in the not have parasitemia. for and the For the For coma and to death, and analysis of in a are were for of the CM1 the CM2 the the parasitemia by patients in the not have parasitemia. for and the For the For coma and to death, and analysis of of the brains were in the The brain were with the brain of white and Scholar because are no on brain of The brain of of CM2 cases was increased to the the CM2 had and two had brain the CM1 had increased brain to and had a brain was within the 13 had increased brain to the of the 18 the brain was in it was within the and in the brain was was a of of the and of the in patients with brains of increased the children with a increased brain was in in the two in the in the and in the of the brains of CM2 patients the presence of hemorrhages in the white matter of the cerebral and in the and in the white matter of the including the cerebellar and the cerebral of a CM2 hemorrhages are the white The and are because of of hemorrhages in the white The matter is changes in CM2 The of in the is by microvascular cells are and in the white matter iRBCs and of the is by is of and is associated with the adjacent with iRBC cells and in the cerebral white matter to hemorrhages in and B. often containing iRBCs are by a of in is by a ring of a white blood and and 50 and both CM1 and CM2 most microvessels in the and white matter iRBCs and iRBCs were to the the of the presence or of iRBC cells often with prominent in the CM2 was associated with and intravascular of thrombosis was often associated with of the of the and perivascular characterized by a often containing iRBCs and by a of with ring of and a white blood were a of but not of patients and the cerebral these hemorrhages in the white with to the matter but were in the and were most in the cerebral and by the was no sequestration and no intravascular or perivascular in the and groups. damage was in with of myelin damage were The was characterized by areas of myelin in the perivascular of The of poorly and of myelin and associated with prominent sequestration of iRBCs within the of these and of these was associated with of myelin by myelin was a of CM2 cases and the of of diffuse myelin damage were present in both the CM1 and CM2 groups. These areas were in the white matter of the cerebral and and in the white matter of the and brainstem in the CM2 but were only in the white matter of the cerebral and brainstem in the CM1 The areas of diffuse myelin damage were in the cerebral and of the CM2 cases and the areas in the the CM1 the areas of myelin and were in the brainstem and the areas were in the white matter of the cerebral Diffuse myelin damage was the most of myelin pathology and was in cases with or no myelin was not present in or cases. of diffuse myelin were in the cerebral white matter and in the brainstem and of a cases but not in the of damage in the CM1 and CM2 groups. of diffuse myelin damage are present in CM2 to a CM1 patients and are only in the nonmalarial groups. Diffuse axonal injury is present in both CM2 and CM1 with only in the and groups. The areas of axonal damage in the cerebral and cerebellar white by the and permeability to of or is present in the two malaria groups and with no between the two groups. are present in the and deep white matter of brain examined in both CM1 and CM2 with the CM1 the CM2 a of in the cerebral white Axonal injury was by with the for within a of of the axonal in is a and for axonal injury within 2 to S. S. of axonal injury in human PubMed Scopus Google Scholar, M. S. M. Axonal damage by of in 2000; Full Text Full Text PDF PubMed Scopus Google Scholar and T. S. Hunt S. axonal damage in the brain within injury to human PubMed Scopus Google Scholar Axonal is not in the brain by of of axonal injury were The was associated with in CM2 patients and of of and with axonal adjacent to the The of within the were associated with only a between the of the and death The of of axonal damage of being most in the white matter of the cerebral by the of the and the cerebellar white and in the brainstem The of axonal injury of or of with and These areas of axonal injury were not associated with and were in the white matter of the cerebral and cerebellar and in of the and in CM1 and CM2 of diffuse axonal damage was often associated with with iRBCs in the of the and Diffuse axonal injury was not in the and was most in the cerebral and and in the The areas of diffuse axonal damage were in the cerebral and cerebellar white the were present in the Diffuse axonal damage was not to CM2 cases but was present in CM1 both the and of these were in CM1 in CM2 cases cases in the white matter of the Diffuse axonal damage was the most of axonal injury and was present in cases with or no Axonal damage was not present in the of The of axonal damage was characterized by of adjacent to a containing parasitized and and associated was the of axonal injury and was only in CM2 for and diffuse myelin damage often with diffuse axonal were areas of myelin of and axonal injury was associated with myelin The permeability of the BBB was by for a is from the brain by the barrier in PubMed Scopus Google Scholar CM, increased permeability of the BBB was but not associated with vascular of BBB breakdown The was characterized by in with and was to the white matter of the cerebral and in the CM2 cases The of microvessels by in the white matter to a the matter of the cerebral and in CM2 the of BBB was blood with prominent sequestration but in both CM1 and CM2 the the of and and associated vascular were present in CM1 and CM2 cases. of and white matter microvessels was in the and associated vascular changes or intravascular pathology. the of was were no in BBB the groups of the of parasitized in the and brainstem was in the CM2 the CM1 cases The of to was in the white matter in the matter in with the of the in no were consistent in malaria cases was the of immune to the and axonal pathology. of of and were not present in of the 37 cases of are a of CM and a immune to of containing hemozoin were present in the of microvessels in the and white matter of the cerebral and of CM2 were often by the accumulated to most of the of and but not of the into brain tissue and a was with a and Monocytes with phagocytosed were with in the of were in areas of or axonal damage in CM1 or CM2 and only cells were within the vascular in the of a blood in CM1 and CM2 cases. perivascular were present in the brain in of the cases. cells were in a CM2 cases. the not changes of or We the and of in for was diffuse of in the and deep white matter of the cerebral and and in the and brainstem in CM1 and CM2 cases. were not in the with the of in a cases. The of the CM from to and not with sequestration or myelin or axonal was no between and or areas of axonal or myelin were present a in and of axonal and myelin and were in the white matter was not a of CM because cases and of the 13 cases the was prominent in the cerebral white matter of CM2 CM1 patients and in the cerebral white matter and brainstem of CM1 and CM2 cases in the the brain in a of Malawian children of We the findings with in children who the definition of CM during but had no of parasite sequestration in the cerebral microvasculature and had a nonmalarial cause of death identified a children who with with clinically CM were into groups based on the cerebral on presence of sequestration of iRBCs only sequestration with intravascular and perivascular pathology and of sequestration a to of brain was present in of the CM1 of the CM2 and of the cases. 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Human cerebral malaria: a PubMed Scopus Google Scholar of patients with CM have the presence of cerebral edema in a patients and not a link between brain and fatal Several to cerebral including and increased permeability of the BBB. of in the findings it is is for the pathogenesis of cerebral edema in these CM2 cases by vascular pathology in the of iRBC sequestration in with the presence of and in and of the parasitized microvessels by a of CM, were present only in the CM2 cases and were most in the white matter of the and to a in the and parasitized and often microvessels of These findings are the of damage and to of the and of and the of cells of parasitized or of of brain the of iRBC sequestration have been Turner N.H. P. Looareesuwan S. White N.J. ultrastructural of the brain in fatal Plasmodium falciparum J Trop Med Hyg. 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N.H. J. White N.J. Turner Axonal injury in cerebral J Pathol. Full Text Full Text PDF PubMed Scopus Google Scholar of myelin and axonal damage in and perivascular in intravascular of the microvessels by Disruption of the BBB was present in groups and was associated with a of vascular pathology in of permeability to and microvessels was a of CM2 of BBB is secondary to damage and of the of the and is of the mechanisms to cerebral both CM1 and CM2 of parasitized microvessels associated of the the and the increased permeability of the BBB was and was not associated with vascular pathology. H. Rogerson S. Taylor T. Tembo M. Mwenechanya J. Molyneux M. Turner G. barrier in cerebral malaria in Malawian J Trop Med Hyg. 2001; 64: Google Scholar in Malawian children with CM of for the and with the presence of iRBCs in but was not associated with these in patients with CM by of the H. Turner G. Rogerson S. Tembo M. Mwenechanya J. Molyneux M. Taylor T. 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The immune to Plasmodium falciparum Infect Dis. Full Text Full Text PDF PubMed Scopus Google Scholar and in account for the increased permeability of the BBB in with prominent sequestration in CM1 and CM2 cases and in and cases with of the brain by cells and and cellular immune responses were in CM1 and CM2 The presence of within the of cerebral blood was associated with intravascular and perivascular pathology and the CM2 from the other groups. and to the of the intravascular and not the to the brain The only was the in with to cerebral is by between and have been to in H. cerebellar expression of and in cerebral Trop Med PubMed Scopus Google Scholar, T. M. M. Human vascular for Plasmodium for 1 and vascular PubMed Scopus Google Scholar, N.H. 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M.J. is a of in and PubMed Scopus Google Scholar of cells with of to the and The presence of intravascular the blood a of iRBC sequestration. findings changes in the brain in fatal pediatric of these brain edema and appear not to to malaria and are by nonmalarial fatal including and diffuse axonal and myelin damage, were in children with CM and not in who of a nonmalarial illness. were most prominent and in malaria to within and in the of blood containing hemozoin or of both and of the cells microvessels was prominent these The most damage, commonly associated with of the with and axonal damage was most in to intravascular and changes are in a in or associated and and in and CM are to of malaria coma, brain damage, and We and for with tissue and and with for with and of the and in who in of

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