A Quest for a Histaminergic or Orexinergic Biomarker for Sudden Infant Death Syndrome

Background: This study investigated the role of the Hypocretin/Orexin (Ox) and Histamine (HA) systems-two key regulators of wakefulness-in sudden infant death syndrome (SIDS), a condition characterized by impaired arousal responses during sleep. Methods: Cerebrospinal fluid (CSF) Ox levels were measured in 61 healthy controls, 70 Sudden Unexpected Death Infants (38 SIDS, 32 explained deaths). HA and its metabolite tele-methylhistamine (t-MeHA) were analysed in an additional 46 SUDI (34 SIDS, 12 ED) and 42 controls. Immunocytochemistry was performed on hypothalamic tissue from 11 SIDS and 8 ED cases to assess the number of Ox and HA neurons. Results: CSF Ox levels did not differ globally but were relatively higher in deceased infants aged 2-6 months. HA and t-MeHA levels were significantly elevated in both SIDS and ED cases, likely due to postmortem release. Immunohistochemistry showed increased Ox neurons in SIDS compared to EDs, while HA neurons did not differ. Conclusions: Findings suggest increased Ox activity in SIDS especially within the 2-6 month risk window, potentially reflecting repeated stress or hypoxia prior to death, while HA neurons do not appear involved.