Matthew P Rubach1,2, Jackson P Mukemba3, Salvatore M Florence3, Bert K Lopansri4,5, Keith Hyland6, Ryan A Simmons2,7, Charles Langelier8,9, Sara Nakielny9, Joseph L DeRisi9,10, Tsin W Yeo11,12,13, Nicholas M Anstey11,12, J Brice Weinberg14, Esther D Mwaikambo3, Donald L Granger5. 1. Department of Medicine, Division of Infectious Diseases, Duke University, Durham, North Carolina, USA. 2. Duke Global Health Institute, Duke University, Durham, North Carolina, USA. 3. Department of Pediatrics, Hubert Kairuki Memorial University, Dar es Salaam, United Republic of Tanzania. 4. Department of Medicine, Intermountain Healthcare, Salt Lake City, Utah, USA. 5. Department of Medicine, University of Utah School of Medicine and VA Medical Center, Salt Lake City, Utah, USA. 6. Medical Neurogenetics Laboratories, Atlanta, Georgia, USA. 7. Department of Biostatistics, Duke University, Durham, North Carolina, USA. 8. Department of Medicine, Division of Infectious Diseases, University of California San Francisco, San Francisco, California, USA. 9. Chan Zuckerberg Biohub, San Francisco, California, USA. 10. Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, California, USA. 11. Global and Tropical Health Division, Menzies School of Health Research, Darwin, Australia. 12. Division of Medicine, Royal Darwin Hospital, Darwin, Northern Territory, Australia. 13. Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore. 14. Department of Medicine, Duke University and VA Medical Centers, Durham, North Carolina, USA.
Abstract
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.
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.
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