Manuscripts

Sudden unexpected death in epilepsy (SUDEP) is a critical concern for individuals suffering from epilepsy, with respiratory dysfunction playing a significant role in its pathology. Fatal seizures are often characterized by central apnea and hypercapnia (elevated CO2 levels), indicating a failure in ventilatory control. Research has shown that both human epilepsy patients and animal models exhibit a reduced hypercapnic ventilatory response in the interictal (non-seizure) period, suggesting an impaired ability to regulate breathing in response to high CO2 levels. This review examines the role of central chemoreceptors—specifically the retrotrapezoid nucleus, raphe nuclei, nucleus tractus solitarius, locus coeruleus, and hypothalamus in this pathology. These structures are critical for sensing CO2 and maintaining respiratory homeostasis. Emerging evidence also implicates neuropeptidergic pathways within these chemoreceptive regions in SUDEP. Neuropeptides like galanin, pituitary adenylate cyclase-activating peptide (PACAP), orexin, somatostatin, and bombesin-like peptides may modulate chemosensitivity and respiratory function, potentially exacerbating respiratory failure during seizures. Understanding the mechanisms linking central chemoreception, respiratory control, and neuropeptidergic signaling is essential to developing targeted interventions to reduce the risk of SUDEP in epilepsy patients.