PROJECT SUMMARY Sudden unexpected death in epilepsy (SUDEP) is a significant cause of premature death in childhood-onset epilepsy. Aberrant cerebral, respiratory and cardiac processes are candidate mechanisms underlying SUDEP. In support of cardiac mechanism are the findings of higher risk of sudden cardiac arrest in adults with epilepsy, and inter-ictal and peri-ictal electrocardiographic (ECG) abnormalities suggesting increased cardiac vulnerability that results from myocardial remodeling. The appearance of high-risk arrhythmias with peri-ictal hypoxemia suggests that respiratory derangements can also contribute to the cardiac abnormalities in epilepsy. A longitudinal, population-based study of childhood-onset epilepsy has shown that the cumulative SUDEP risk increases with increasing epilepsy duration, suggesting that there might be progressive changes that contribute to mortality risk in adulthood. Our overarching hypothesis is that cardiac electrical remodeling occurs as function of epilepsy duration and renders the heart vulnerable to stresses such as seizures or respiratory derangements over time, thereby contributing to SUDEP. For this proposal we will prospectively follow a cohort of pediatric epilepsy patients without a known ion channelopathy or cardiac disease, who are managed in a quaternary epilepsy referral center using ECG studies as a surrogate marker. We will obtain yearly ECG studies and collect clinical and laboratory data associated with each ECG. For children enrolled in the study who are hospitalized for a respiratory illness during the study period, we will obtain additional ECGs and collect additional clinical information relating to the hospitalizations. Using multivariable models controlling for potential confounders such as seizure semiology and frequency, number of anti-seizure medications, and other factors identified through univariate analyses, we will investigate whether epilepsy duration is an independent risk factor for abnormal ECG. Using an analogous approach, we will also evaluate whether an intercurrent respiratory illness is an independent risk factor for abnormal ECG, and whether epilepsy duration modifies the likelihood of having an abnormal ECG during an intercurrent respiratory illness.