The Crucial Interplay Between the Lungs, Brain, and the Heart to Understand Epilepsy Linked SUDEP: A Literature Review

Graphical Abstract: Abstract: Sudden Unexpected Death in Epilepsy (SUDEP) is a leading cause of mortality among individuals with epilepsy, particularly those with drug-resistant forms. This re-view explores the complex multisystem mechanisms underpinning SUDEP, integrating recent findings on brain, cardiac, and pulmonary dysfunctions. Background/Objectives: The main objective of this review is to elucidate how seizures disrupt critical physiological systems, especially the brainstem, heart, and lungs, contributing to SUDEP, with empha-sis on respiratory control failure and autonomic instability. Methods: We systematically examined literature from experimental models, clinical observations, neuroimaging stud-ies, and genetic analyses. Sources were drawn from recent peer-reviewed publications cataloged in a supplementary reference matrix. Results: SUDEP is frequently preceded by generalized tonic-clonic seizures, which trigger central and obstructive apnea, hypoventi-lation, and cardiac arrhythmias. Brainstem dysfunction, particularly in areas such as the pre-Bötzinger complex and nucleus tractus solitarius, plays a central role. Genetic muta-tions affecting ion channels (e.g., SCN1A, KCNQ1) and neurotransmitter imbalances (no-tably serotonin and GABA) exacerbate autonomic dysregulation. Risk is compounded by prone sleeping position, reduced arousal capacity, and impaired ventilatory responses. Conclusions: SUDEP arises from a cascade of interrelated failures in respiratory and car-diac regulation initiated by seizure activity. Recognition of modifiable risk factors, imple-mentation of monitoring technologies, and targeted therapies such as serotonergic agents may reduce mortality. Multidisciplinary approaches integrating neurology, cardiology, and respiratory medicine are essential for effective prevention strategies.