Cerebrospinal fluid studies in children with cerebral malaria: an excitotoxic mechanism?
The pathogenesis of cerebral malaria is poorly understood. One hypothesis is that activation of microglia and astrocytes in the brain might cause the cerebral symptoms by excitotoxic mechanisms. Cerebrospinal fluid was sampled in 97 Kenyan children with cerebral malaria, 85% within 48 hr of admission. When compared with an age-matched reference range, there were large increases in concentrations of the excitotoxin quinolinic acid (geometric mean ratio cerebral malaria/reference population [95% confidence limits] = 14.1 [9.8-20.4], P < 0.001) and total neopterin (10.9 [9.1-13.0], P < 0.001) and lesser increases in tetra-hydrobiopterin, di-hydrobiopterin, and 5-hydroxyindoleacetic acid. There was no change in tryptophan concentration. In contrast, nitrate plus nitrite concentrations were decreased (geometric mean ratio = 0.45 [0.35-0.59], P < 0.001). There was a graded increment in quinolinic acid concentration across outcome groups of increasing severity. The increased concentration of quinolinic acid suggests that excitotoxic mechanisms may contribute to the pathogenesis of cerebral malaria.
Dobbie
M
M
Institute of Child Health, University College London Medical School, United Kingdom.
Crawley
J
J
Waruiru
C
C
Marsh
K
K
Surtees
R
R
D000962:Antimalarials / Q000627:therapeutic use; D001708:Biopterins / Q000031:analogs & derivatives / Q000134:cerebrospinal fluid; D001921:Brain / Q000469:parasitology*; D002648:Child; D002675:Child, Preschool; D002851:Chromatography, High Pressure Liquid; D004727:Endothelium / Q000469:parasitology; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D006897:Hydroxyindoleacetic Acid / Q000134:cerebrospinal fluid; D007223:Infant; D007630:Kenya; D016779:Malaria, Cerebral / Q000134:cerebrospinal fluid / Q000188:drug therapy / Q000209:etiology* / Q000469:parasitology; D017628:Microglia / Q000469:parasitology; D019798:Neopterin / Q000134:cerebrospinal fluid; D009566:Nitrates / Q000134:cerebrospinal fluid; D009573:Nitrites / Q000134:cerebrospinal fluid; D017378:Quinolinic Acid / Q000134:cerebrospinal fluid*; D014364:Tryptophan / Q000134:cerebrospinal fluid
D000962:Antimalarials; D009566:Nitrates; D009573:Nitrites; D001708:Biopterins; D006897:Hydroxyindoleacetic Acid; D019798:Neopterin; C017226:7,8-dihydrobiopterin; D014364:Tryptophan; C003402:sapropterin; D017378:Quinolinic Acid