Who to target in sudden unexpected death in epilepsy prevention and how? Risk factors, biomarkers, and intervention study designs

Abstract

SUMMARYThe risk of dying suddenly and unexpectedly is increased 24-to 28-fold among young people with epilepsy compared to the general population, but the incidence of sudden unexpected death in epilepsy (SUDEP) varies markedly depending on the epilepsy population. This article first reviews risk factors and biomarkers for SUDEP with the overall aim of enabling identification of epilepsy populations with different risk levels as a background for a discussion of possible intervention strategies. The by far most important clinical risk factor is frequency of generalized tonic-clonic seizures (GTCS), but nocturnal seizures, early age at onset, and long duration of epilepsy have been identified as additional risk factors. Lack of antiepileptic drug (AED) treatment or, in the context of clinical trials, adjunctive placebo versus active treatment is associated with increased risks. Despite considerable research, reliable electrophysiologic (electrocardiography [ECG] or electroencephalography [EEG]) biomarkers of SUDEP risk remain to be established. This is an important limitation for prevention strategies and intervention studies. There is a lack of biomarkers for SUDEP, and until validated biomarkers are found, the endpoint of interventions to prevent SUDEP must be SUDEP itself. These interventions, be they pharmacologic, seizure-detection devices, or nocturnal supervision, require large numbers. Possible methods for assessing prevention measures include public health community interventions, self-management, and more traditional (and much more expensive) randomized clinical trials.

Research conference summary from the 2014 International Task Force on ATP1A3 -Related Disorders

“…26 Proposed risk factors include the use of multiple anticonvulsants, poor medication compliance, uncontrolled seizures, and the presence of additional neurologic deficits, in addition to epilepsy, among others. 27 …”

The effect of atomoxetine, a selective norepinephrine reuptake inhibitor, on respiratory arrest and cardiorespiratory function in the DBA/1 mouse model of SUDEP

“…Sudden unexpected death in epilepsy (SUDEP) is a major burden on public health (Thurman et al, 2014), as the risk of sudden death in younger patients with epilepsy is increased more than 20-fold (Ficker et al, 1998; Tomson et al, 2016). Clinical and animal studies demonstrate that seizure-induced respiratory arrest (S-IRA) is the primary event leading to death after generalized tonic-clonic seizures in many cases (Bateman et al, 2008; Blum, 2009; Bravo et al, 2015; Buchanan et al, 2014; Faingold et al, 2010; Langan et al, 2000; Pezzella et al, 2009; Ryvlin et al, 2013; So et al, 2000; Zhang et al, 2016), although cardiac dysfunction may also contribute to seizure-induced sudden death (Frasier et al, 2016; Kalume et al, 2013).…”

Could the retrotrapezoid nucleus neurons tell us something about SUDEP?

“…Generally, SUDEP has an incidence rate among adults between 1:500 and 1:1000 patient-years, while in children, SUDEP occurs on average 1:5,000 patient-years [7,8]. Very recent studies suggest that multiple risk factors may contribute to SUDEP, but the most relevant clinical risk factor by far is the presence of uncontrolled generalized tonic-clonic seizures (GTCS) [9].…”