Editorial: Sudden Death in Epilepsy: Basic and Translational Research

Sudden Unexpected Death in Epilepsy (SUDEP) is an important cause of death in people with epilepsy, especially those with chronic epilepsy. In a UK cohort, SUDEP accounted for 17% of deaths in those with chronic epilepsy (1). The incidence of SUDEP is 0.2 per 1,000 persons per year in children, and 1.0 per 1,000 persons per year inadults (2). The incidence of SUDEP in chronic epilepsy is substantially higher, ranging from 2.64 to as high as 5.95 per 1,000 persons per year (1, 3). In this book genetics, functional imaging, autonomic physiology and clinical risk factors for SUDEP are explored in depth.

Sudden Unexpected Death in Epilepsy (SUDEP) is an important cause of death in people with epilepsy, especially those with chronic epilepsy. In a UK cohort, SUDEP accounted for 17% of deaths in those with chronic epilepsy (1). The incidence of SUDEP is 0.2 per 1,000 persons per year in children, and 1.0 per 1,000 persons per year inadults (2). The incidence of SUDEP in chronic epilepsy is substantially higher, ranging from 2.64 to as high as 5.95 per 1,000 persons per year (1,3). In this book genetics, functional imaging, autonomic physiology and clinical risk factors for SUDEP are explored in depth.

GENETICS
Bagnall et al. provide an elegant and comprehensive review of current knowledge of the genetics and basic mechanisms of SUDEP. Several candidate genes are associated with the risk for SUDEP, especially genes associated with long QT interval and cardiac arrhythmias. These include mutations in potassium channels, specifically KCNQ1 and KCNH2 (see Table 2, Bagnall et al.). Other channelopathies associated with SUDEP are caused by defects in sodium channels, especially SCN1A, SCN2A, SCN5A, and SCN8A (Bagnall et al.). Dravet's syndrome, a form of catastrophic childhood onset epilepsy, is associated with the highest recorded SUDEP incidence (9.

CLINICAL RISK FACTORS
Since the 1990's, researchers have identified risk factors which are associated with an increase in risk for SUDEP. Note that three or more seizures per year and three or more AED's appear twice in the list, indicating that these factors were validated in more than one study cohort (DeGiorgio et al.). Table 1 by DeGiorgio et al. provides detailed information about each of the top 10 leading risk factors associated with SUDEP.
In another chapter, Dlouhy et al. report a case of SUDEP in a 21-month old little girl who suffered febrile seizures. This tragic case should cause us to take a closer look at any association between febrile seizures and SUDEP, and should remind all SUDEP researchers that behind every SUDEP case reported, there is a human person and a family who suffers (Dlouhy et al.). Polytherapy has been implicated as a risk factor for SUDEP, but polytherapy as an independent risk factor is controversial (5). In an in-vivo study, Hulbert et al. found that simultaneous exposure of multiple antiepileptic drugs (carbamazepine, lamotrigine, and levetiracetam) impaired electromechanical coupling in cardiac myocytes. Impaired electromechanical coupling in cardiac myocytes may lead to cardiac arrhythmias (Novak et al.). This finding should lead to a closer evaluation of the risk of multiple AED's in people at risk for SUDEP.

FUNCTIONAL MRI AND FUNCTIONAL CONNECTIVITY
In an elegant functional MRI study (fMRI), Allen et al explored which autonomic structures and networks are abnormal in 32 patients with chronic epilepsy (Allen et al.). Subjects were stratified for risk of SUDEP by age of onset, duration, frequency of generalized tonic-clonic seizures, and nocturnal seizures (Allen et al.). Fourteen subjects were classified as high risk, and 18 were classified as low risk. Those subjects at high risk for SUDEP demonstrated significantly reduced functional connectivity in the thalamus, midbrain, anterior cingulate, putamen and amygdala (Allen et al.). This report provides key evidence of an anatomic and functional defect in key structures which regular sympathetic and parasympathetic activity in patients at risk for SUDEP (Allen et al.).

INFLAMMATION
Inflammation is believed to contribute to epileptogenesis and excitotoxicity (6). For example, the pro-inflammatory cytokine Interleukin Ib (IL-1b) can interact with the NR2B subunit of the NMDA receptor, resulting in calcium influx across the neuronal membrane and increased excitability (6). A causal role of inflammation in SUDEP is unknown (7). Nejm et al. explored whether fish oil containing the anti-inflammatory n-3 fatty acids DHA and EPA could reduce inflammation in the hearts of rats in a pilocarpine model. Their group found that long-term supplementation with fish oil significantly reduced cardiac levels of IL-6 compared with controls (Nejm et al.). The study did not explore the effect of fish oil on IL-6 levels in the brain, but these findings may provide insight into the mechanism of n-3 fatty acids in reducing seizures (8).

SUMMARY
This topic adds to current knowledge of the role of genetics, autonomic networks, autonomic physiology and clinical risk factors for SUDEP. It is our hope that this work will encourage basic and clinical scholarship to advance understanding of the mechanisms that underlie SUDEP, and to spur clinical interventions that can prevent SUDEP.

AUTHOR CONTRIBUTIONS
The author confirms being the sole contributor of this work and approved it for publication.