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

J Infect Dis. 2021 Oct 28;224(8):1432-1441. doi: 10.1093/infdis/jiab086.


Background: Cerebral malaria (CM) pathogenesis remains incompletely understood. Having shown low systemic levels of tetrahydrobiopterin (BH4), an enzymatic cofactor for neurotransmitter synthesis, we hypothesized that BH4 and BH4-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 BH4, neopterin, and BH4-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 BH4 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 BH4/BH2 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 BH4, CSF BH4 was elevated and associated with increased odds of survival in CM. Coma in malaria is not explained by deficiency of BH4-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.

Keywords: P falciparum; cerebral malaria; neopterin; neurotransmitter; tetrahydrobiopterin.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Biopterins / analogs & derivatives
  • Biopterins / cerebrospinal fluid*
  • Central Nervous System Diseases / cerebrospinal fluid
  • Child
  • Child, Preschool
  • Female
  • Homovanillic Acid / cerebrospinal fluid
  • Humans
  • Hydroxyindoleacetic Acid / cerebrospinal fluid
  • Infant
  • Malaria, Cerebral / cerebrospinal fluid
  • Malaria, Cerebral / mortality*
  • Male
  • Neopterin / cerebrospinal fluid*
  • Neurotransmitter Agents / cerebrospinal fluid*
  • Prospective Studies
  • Pterins / cerebrospinal fluid*
  • Reference Values
  • Tanzania / epidemiology
  • Tyrosine / analogs & derivatives


  • Neurotransmitter Agents
  • Pterins
  • Biopterins
  • Tyrosine
  • Hydroxyindoleacetic Acid
  • Neopterin
  • sapropterin
  • 3-methoxytyrosine
  • Homovanillic Acid