title: Coma in fatal adult human malaria is not caused by cerebral oedema.
abstract: BACKGROUND
  The role of brain oedema in the pathophysiology of cerebral malaria is controversial. Coma associated with severe Plasmodium falciparum malaria is multifactorial, but associated with histological evidence of parasitized erythrocyte sequestration and resultant microvascular congestion in cerebral vessels. To determine whether these changes cause breakdown of the blood-brain barrier and resultant perivascular or parenchymal cerebral oedema, histology, immunohistochemistry and image analysis were used to define the prevalence of histological patterns of oedema and the expression of specific molecular pathways involved in water balance in the brain in adults with fatal falciparum malaria.
  
  
  METHODS
  The brains of 20 adult Vietnamese patients who died of severe malaria were examined for evidence of disrupted vascular integrity. Immunohistochemistry and image analysis was performed on brainstem sections for activation of the vascular endothelial growth factor (VEGF) receptor 2 and expression of the aquaporin 4 (AQP4) water channel protein. Fibrinogen immunostaining was assessed as evidence of blood-brain barrier leakage and perivascular oedema formation. Correlations were performed with clinical, biochemical and neuropathological parameters of severe malaria infection.
  
  
  RESULTS
  The presence of oedema, plasma protein leakage and evidence of VEGF signalling were heterogeneous in fatal falciparum malaria and did not correlate with pre-mortem coma. Differences in vascular integrity were observed between brain regions with the greatest prevalence of disruption in the brainstem, compared to the cortex or midbrain. There was a statistically non-significant trend towards higher AQP4 staining in the brainstem of cases that presented with coma (P = .02).
  
  
  CONCLUSIONS
  Histological evidence of cerebral oedema or immunohistochemical evidence of localised loss of vascular integrity did not correlate with the occurrence of pre-mortem coma in adults with fatal falciparum malaria. Enhanced expression of AQP4 water channels in the brainstem may, therefore, reflect a mix of both neuropathological or attempted neuroprotective responses to oedema formation.
authors.affiliation: Nuffield Department of Clinical Laboratory Sciences, The John Radcliffe Hospital, University of Oxford, Oxford, UK.
authors.forename: Isabelle M
authors.initials: IM
authors.lastname: Medana
authors.forename: Nicholas P J
authors.initials: NP
authors.lastname: Day
authors.forename: Navakanit
authors.initials: N
authors.lastname: Sachanonta
authors.forename: Nguyen T H
authors.initials: NT
authors.lastname: Mai
authors.forename: Arjen M
authors.initials: AM
authors.lastname: Dondorp
authors.forename: Emsri
authors.initials: E
authors.lastname: Pongponratn
authors.forename: Tran T
authors.initials: TT
authors.lastname: Hien
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: White
authors.forename: Gareth D H
authors.initials: GD
authors.lastname: Turner
mesh_terms: D000328:Adult; D000368:Aged; D051401:Aquaporin 4 / Q000032:analysis; D001812:Blood-Brain Barrier / Q000473:pathology / Q000503:physiopathology; D001929:Brain Edema / Q000473:pathology / Q000503:physiopathology; D003128:Coma / Q000209:etiology* / Q000503:physiopathology*; D005260:Female; D005340:Fibrinogen / Q000032:analysis; D006651:Histocytochemistry; D006801:Humans; D007150:Immunohistochemistry; D016779:Malaria, Cerebral / Q000150:complications*; D008297:Male; D008875:Middle Aged; D059906:Neuroimaging; D010963:Plasmodium falciparum / Q000472:pathogenicity*; D042461:Vascular Endothelial Growth Factor A / Q000032:analysis; D055815:Young Adult
chemical_list: C496030:AQP4 protein, human; D051401:Aquaporin 4; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D005340:Fibrinogen