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

Matthew P. Rubach, Jackson P. Mukemba, Salvatore M. Florence, Bert K. Lopansri, Keith Hyland, Ryan A. Simmons, Charles Langelier, Sara Nakielny, Joseph L. Derisi, Tsin W. Yeo, Nicholas M. Anstey, J. Brice Weinberg, Esther D. Mwaikambo, Donald L. Granger

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6 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)1432-1441
Number of pages10
JournalJournal of Infectious Diseases
Issue number8
Publication statusPublished - 15 Oct 2021

Bibliographical note

Funding Information:
This study was funded by the US National Institute of Allergy and Infectious Diseases (Grants R01AI041764, R01AI041764, K23AI116869). Additional financial support for this research was provided by the US National Institutes of Health (to J. B. W. and D. L. G.), the US Veterans Affairs Medical Research Service (to J. B. W. and D. L. G.), and the Australian National Health and Medical Research Council (to N. M. A. and T. W. Y.).

Publisher Copyright:
© 2021 The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: [email protected].

Copyright 2021 Elsevier B.V., All rights reserved.


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