Brainstem Serotonergic Deficiency in Sudden Infant Death Syndrome

Context Sudden infant death syndrome ( SIDS) is postulated to result from abnormalities in brainstem control of autonomic function and breathing during a critical developmental period. Abnormalities of serotonin (5-hydroxytryptamine [5-HT]) receptor binding in regions of the medulla oblongata involved in this control have been reported in infants dying from SIDS. Objective To test the hypothesis that 5-HT receptor abnormalities in infants dying from SIDS are associated with decreased tissue levels of 5-HT, its key biosynthetic enzyme ( tryptophan hydroxylase [TPH2]), or both. Design, Setting, and Participants Autopsy study conducted to analyze levels of 5-HT and its metabolite, 5-hydroxyindoleacetic acid (5-HIAA); levels of TPH2; and 5-HT1A receptor binding. The data set was accrued between 2004 and 2008 and consisted of 41 infants dying from SIDS (cases), 7 infants with acute death from known causes (controls), and 5 hospitalized infants with chronic hypoxia-ischemia. Main Outcome Measures Serotonin and metabolite tissue levels in the raphe obscurus and paragigantocellularis lateralis (PGCL); TPH2 levels in the raphe obscurus; and 5-HT1A binding density in 5 medullary nuclei that contain 5-HT neurons and 5 medullary nuclei that receive 5-HT projections. Results Serotonin levels were 26% lower in SIDS cases (n=35) compared with age-adjusted controls (n=5) in the raphe obscurus(55.4 [95% confidence interval {CI}, 47.2-63.6] vs 75.5 [95% CI, 54.2-96.8] pmol/mg protein, P=.05) and the PGCL (31.4 [ 95% CI, 23.7-39.0] vs 40.0 [95% CI, 20.1-60.0] pmol/mg protein, P=.04). There was no evidence of excessive 5-HT degradation assessed by 5-HIAA levels, 5-HIAA: 5-HT ratio, or both. In the raphe obscurus, TPH2 levels were 22% lower in the SIDS cases (n=34) compared with controls (n=5) (151.2% of standard [ 95% CI, 137.5%-165.0%] vs 193.9% [ 95% CI, 158.6%-229.2%], P=.03). 5-HT1A receptor binding was 29% to 55% lower in 3 medullary nuclei that receive 5-HT projections. In 4 nuclei, 3 of which contain 5-HT neurons, there was a decrease with age in 5-HT1A receptor binding in the SIDS cases but no change in the controls ( age x diagnosis interaction). The profile of 5-HT and TPH2 abnormalities differed significantly between the SIDS and hospitalized groups ( 5-HT in the raphe obscurus: 55.4 [95% CI, 47.2-63.6] vs 85.6 [ 95% CI, 61.8-109.4] pmol/mg protein, P=.02; 5-HT in the PGCL: 31.4 [95% CI, 23.7-39.0] vs 71.1 [95% CI, 49.0-93.2] pmol/mg protein, P=.002; TPH2 in the raphe obscurus: 151.2% [ 95% CI, 137.5%-165.0%] vs 102.6% [ 95% CI, 58.7%-146.4%], P=.04). Conclusion Compared with controls, SIDS was associated with lower 5-HT and TPH2 levels, consistent with a disorder of medullary 5-HT deficiency. JAMA. 2010; 303(5):430-437 www.jama.com