Cerebrospinal Fluid Pterins, Pterin-Dependent Neurotransmitters, and Mortality in Pediatric Cerebral Malaria

Abstract Background Cerebral malaria (CM) pathogenesis remains incompletely understood. Having shown low systemic levels of tetrahydrobiopterin (BH 4 ), an enzymatic cofactor for neurotransmitter synthesis, we hypothesized that BH 4 and BH 4 -dependent neurotransmitters would likewise be low in cerebrospinal fluid (CSF) in CM. Methods We prospectively enrolled Tanzanian children with CM and children with nonmalaria central nervous system conditions (NMCs). We measured CSF levels of BH 4 , neopterin, and BH 4 -dependent neurotransmitter metabolites, 3- O -methyldopa, homovanillic acid, and 5-hydroxyindoleacetate, and we derived age-adjusted z-scores using published reference ranges. Results Cerebrospinal fluid BH 4 was elevated in CM (n = 49) compared with NMC (n = 51) (z-score 0.75 vs −0.08; P < .001). Neopterin was increased in CM (z-score 4.05 vs 0.09; P < .001), and a cutoff at the upper limit of normal (60 nmol/L) was 100% sensitive for CM. Neurotransmitter metabolite levels were overall preserved. A higher CSF BH 4 /BH 2 ratio was associated with increased odds of survival (odds ratio, 2.94; 95% confidence interval, 1.03–8.33; P = .043). Conclusion Despite low systemic BH 4 , CSF BH 4 was elevated and associated with increased odds of survival in CM. Coma in malaria is not explained by deficiency of BH 4 -dependent neurotransmitters. Elevated CSF neopterin was 100% sensitive for CM diagnosis and warrants further assessment of its clinical utility for ruling out CM in malaria-endemic areas. We hypothesized that central nervous system (CNS) tetrahydrobiopterin deficiency contributes to the pathogenesis of cerebral malaria. Instead, we found cerebrospinal fluid tetrahydrobiopterin was elevated in cerebral malaria relative to other CNS diseases, and increase in tetrahydrobiopterin was associated with survival.