Are Variants Causing Cardiac Arrhythmia Risk Factors in Sudden Unexpected Death in Epilepsy?

Abstract

Sudden unexpected death in epilepsy (SUDEP) is the most common cause of premature mortality in individuals with epilepsy. Acute and adaptive changes in heart rhythm in epilepsy implicate cardiac dysfunction as a potential pathogenic mechanism in SUDEP. Furthermore, variants in genes associated with Long QT syndrome (LQTS) have been identified in patients with SUDEP. LQTS is a cardiac arrhythmia condition that causes sudden cardiac death with strong similarities to SUDEP. Here, we discuss the possibility of an additive risk of death due to the functional consequences of a pathogenic variant in an LQTS gene interacting with seizure-mediated changes in cardiac function. Extending this general concept, we propose a hypothesis that common variants in LQTS genes, which cause a subtle impact on channel function and would not normally be considered risk factors for cardiac disease, may increase the risk of sudden death when combined with epilepsy. A greater understanding of the interaction between epilepsy, cardiac arrhythmia, and SUDEP will inform our understanding of SUDEP risk and subsequent potential prophylactic treatment.

Keywords: cardiac arrhythmia; common variants; epilepsy; genetics; ion channels; sudden unexpected death in epilepsy.

Figure 1

Proposed mechanism on how genetic variants associated with cardiac arrhythmia may increase risk of sudden unexpected death in epilepsy (SUDEP). (A) Comparison of surface electrocardiogram (ECG) in various conditions. (1) A normal QT interval in a healthy individual without epilepsy or cardiac arrhythmia (blue). (2) A small shift in the QT interval might occur in a patient with epilepsy during a seizure (purple). (3) A “subclinical” individual carrying a functional variant in a cardiac arrhythmia gene, which only subtly shifts the QT interval (orange). (4) A combination of a “subclinical” variant and a seizure event results in a nonlinear increase in the QT interval, thus increasing the risk of sudden death (red). (B) The increased risk of sudden death that is conferred by harboring a “subclinical” functional variant in a cardiac gene presents itself in the acute context of a seizure, which causes disruption of normal cardiac function. Such cardiac disruption is more likely with longer seizures, seizures with more intense autonomic discharges, and perhaps more violent seizures with more systemic metabolic changes, all effects encapsulated by the term “seizure severity.” This risk is present on every occasion when an affected individual has a seizure.