Causes and Effects Contributing to Sudden Death in Epilepsy and the Rationale for Prevention and Intervention

Abstract

Sudden unexpected death in epilepsy (SUDEP) claims the lives of one in every thousand epileptic patients each year. Autonomic, cardiac, and respiratory pieces to a mechanistic puzzle have not yet been completely assembled. We propose a single sequence of causes and effects that unifies disparate and competitive concepts into a single algorithm centered on ictal obstructive apnea. Based on detailed animal studies that are sometimes impossible in humans, and striking parallels with a growing body of clinical examples, this framework (1) accounts for the autonomic, cardiac, and respiratory data to date by showing the causal relationships between specific elements, and (2) highlights specific kinds of data that can be used to precisely classify various patient outcomes. The framework also justifies a "near miss" designation to be applied to any cases with evidence of obstructive apnea even, and perhaps especially, in individuals that do not require resuscitation. Lastly, the rationale for preventative oxygen therapy is demonstrated. With better mechanistic understanding of SUDEP, we suggest changes for detection and classification to increase survival rates and improve risk stratification.

Proposed Mechanism-Based Risk Stratification and Algorithm to Prevent Sudden Death in Epilepsy

“…An important step in defining the mechanism of SUDEP came from differentiation of first-order, seizure-induced pathophysiological events from second-order consequences of these first-order derangements ( 17 ). This review develops the arguments in favor of obstructive apnea and discusses potential alternative mechanisms for SUDEP in greater detail.…”

“…The hypoxemia and decreased cardiac output cause the seizure to abort, but the laryngospasm can persist to the point of respiratory arrest (defined as a cessation of attempts to inspire), followed ultimately by cardiac arrest ( 13 , 14 ). Based on the clinical and animal data, respiratory arrest occurs very close in time to the end of seizure activity or the end of a motor convulsion [reviewed in ( 17 )]. This work included a demonstration that early oxygen could significantly delay the time to respiratory arrest, even when available for a relatively short period of time before the onset of obstructive apnea ( 56 ).…”

“…Other work in rats and mice showed that seizure-associated laryngospasm could cause obstructive apnea that may persist to the point of respiratory arrest ( 13 – 15 ). The linkage between preclinical and clinical data was formed by EMG evidence of inspiratory attempts and specific changes in cardiac rhythm ( 14 , 16 , 17 ) [see also Supplemental Data in Ryvlin et al ( 10 )].…”

Utilizing Multimodal Imaging to Visualize Potential Mechanism for Sudden Death in Epilepsy

“…The increased mortality risks include deaths related to status epilepticus, accidents, and sudden unexpected death in epilepsy (SUDEP) [6,7]. One in every thousand patients with epilepsy suffers from SUDEP [8]. With a large population of people (~3.4 million in USA alone) suffering from epilepsy [2], uncovering the underlying mechanism of SUDEP has clinical significance as it accounts for about 4,000 deaths each year in the US alone [9,10].…”

“…Due to the spontaneous nature of most seizure activity it is often hard to study the mechanism of SUDEP as cases occur in otherwise healthy patients with limited or no physiological monitoring prior to death [13]. The limited clinical data suggests SUDEP is initiated by seizure spread in the autonomic nervous system (ANS) [8,12,[14][15][16][17], leading to widespread cardiorespiratory dysfunction and eventually death [13,18,19]. Recent studies have suggested that one potential pathway for such cardiorespiratory dysregulation is linked to laryngospasm due to acid reflux [18][19][20][21].…”