Rubach MP

Mukemba JP

Florence SM

Lopansri BK

Hyland K

Simmons RA

Langelier C

Nakielny S

DeRisi JL

Yeo TW

Anstey, Nicholas

Weinberg JB

Mwaikambo ED

Granger DL

2021-10-28

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 non-malaria central nervous system conditions (NMC). We measured CSF levels of BH4, neopterin, and BH4-dependent neurotransmitter metabolites, 3-O-methyldopa, homovanillic acid, and 5-hydroxyindoleacetate, and derived age-adjusted z-scores using published reference ranges. RESULTS: CSF BH4 was elevated in CM (n=49) compared to NMC (n=51) [z-score 0.75 vs. -0.08 (p<0.001)]. Neopterin was increased in CM [z-score 4.05 vs. 0.09 (p<0.001)], and a cut-off 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 (OR 2.94 [1.03-8.33]; p=0.043). 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.

Department of Medicine, Division of Infectious Diseases, Duke University, Durham, NC, United States.

Duke Global Health Institute, Duke University, Durham, NC, United States.

Department of Pediatrics, Hubert Kairuki Memorial University, Dar es Salaam, United Republic of Tanzania.

Department of Medicine, Intermountain Healthcare, Salt Lake City, UT, United States.

Department of Medicine, University of Utah School of Medicine and VA Medical Center, Salt Lake City, UT, United States.

Medical Neurogenetics Laboratories, Atlanta, GA, United States.

Department of Biostatistics, Duke University, Durham, NC, United States.

Department of Medicine, Division of Infectious Diseases, University of California San Francisco, San Francisco, CA, United States.

Chan Zuckerberg Biohub, San Francisco, CA, United States.

Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, CA, United States.

Global and Tropical Health Division, Menzies School of Health Research, Darwin, Australia.

Division of Medicine, Royal Darwin Hospital, Darwin, NT, Australia.

Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore.

Department of Medicine, Duke University and VA Medical Centers, Durham, NC, United States.

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

https://pubmed.ncbi.nlm.nih.gov/33617646/?otool=iaurydwlib

https://hdl.handle.net/10137/11669

Cerebrospinal fluid pterins, pterin-dependent neurotransmitters, and mortality in pediatric cerebral malaria.

Journal Article

Publication