Sudden Unexpected Death in Epilepsy (SUDEP): How Do We Prevent This Childhood Tragedy?

Abstract

Epilepsy is associated with 2- to 3-fold increased mortality as compared with the general population. The most common cause of death related to epilepsy is sudden unexpected death in epilepsy (SUDEP).1 SUDEP is defined as follows: a sudden, unexplained, witnessed or unwitnessed, non-traumatic, and non-drowning death in patients with epilepsy, with or without evidence for a seizure and excluding documented status epilepticus, in which postmortem examination does not reveal a toxico-logic or an anatomic cause for death.2 The SUDEP risk in adults with epilepsy (aged >17 years) is 1.2 per 1000 patient years, which is higher than the risk reported in children (0.22 per 1000 patient years).3The pathophysiology of SUDEP is still poorly understood. In the landmark MORTEMUS study,4 all SUDEP cases had a generalized tonic-clonic seizure followed by tachypnea in the postictal phase then generalized EEG suppression and development of bradycardia, apnea, and asystole. Impaired arousal, which is far more common after generalized tonic-clonic seizure than a focal seizure, might reduce reflex recovery responses from cardiorespiratory dysfunction. Postictal generalized EEG suppression (PGES) is a potential biomarker in some studies.4 PGES is associated with greater arousal impairment, respiratory dysfunction, and autonomic dysregulation indicating possible brainstem involvement. Medullary serotonergic neurons are inhibited by seizures, which might contribute to ictal apnea and postictal hypoventilation.5 Another neuromodulator, adenosine, is also important for seizure-induced inhibition of breathing.6 Such data suggest that medications that modulate serotonin, adenosine, or other neurochemical systems might help to reduce SUDEP. Further research is needed in this area.In a recent issue of the Journal of Pediatric Pharmacology and Therapeutics, Wicker and Cole7 reviewed risk factors for SUDEP in children and possible interventions to prevent this catastrophic event. The strongest risk factor is poorly controlled generalized tonic-clonic seizures (GTCSs). Compared with patients who are free from GTCSs, even a “few” GTCSs dramatically increase the risk for SUDEP. Those having 1 to 2 per year have a 5-fold increased risk of SUDEP, and those having 3 or more GTCSs per year have 15-fold increased risk.8 This reinforces the goal to aggressively treat patients with ongoing GTCSs, in an effort to eliminate all of them. Other risk factors for SUDEP include nocturnal seizures, early onset epilepsy, long duration of epilepsy (>15 years) and developmental/intellectual delay. There is significantly increased risk of SUDEP in patients with genetic disorders that cause severe epileptic encephalopathy and drug-resistant epilepsy owing to mutations in SCN1A, SCN2A, SCN8A, and DEPDC5 genes and 15 Q duplication syndrome. In patients with Dravet syndrome, the risk of SUDEP is 15 times higher than for other pediatric epilepsies.9 Initially antiepileptic polypharmacy was thought to be a risk factor, but later studies refuted this when the analysis to control for the frequency of GTCSs was performed.10Achieving effective control of GTCSs, especially nocturnal events, is the mainstay of prevention of SUDEP. Appropriate and optimal pharmacologic treatment and timely consideration of non-pharmacologic approaches like epilepsy surgery, neuromodulation (i.e, vagus nerve stimulation, deep brain stimulation for epilepsy, and responsive neurostimulation11–13), and the ketogenic diet can all be very important in improving seizure control, and thereby preventing or decreasing the likelihood of SUDEP. Improved adherence to antiepileptic medications may reduce the risk of SUDEP by increasing seizure control; however, no studies have directly proven this so far. One strategy to help minimize seizure occurrence, even with an occasional missed dose of medication, is to use antiseizure medications with a long half-life or extended-release products. These would prevent antiseizure medication concentrations from falling to subtherapeutic concentrations (and the associated risk of a seizure), even with a late or forgotten doses, owing to the end-of-dose forgiveness period.14–16In this issue of the Journal, Scorza et al17 present information regarding the use of omega-3 fatty acid in the prevention of SUDEP in children. Dr Scorza has long been a proponent of omega-3 fatty acid supplementation to prevent seizures and thereby reduce the risk of SUDEP. We would agree with the earlier editorial response of Devinsky et al18 discussing this treatment and the need for high-quality studies before general recommendations could be made. Omega-3 fatty acids are very important for brain function in children; however, what is not established is if they can definitively help prevent some cases of SUDEP. Although many nutritional supplements have shown efficacy in animal models of epilepsy, this same proof of efficacy has yet to be established in humans. More research is needed in this area. Scorza et al17 also point out the importance of identifying SUDEP biomarkers that could help to study the effectiveness of different interventions. There are several autonomic biomarkers considered likely candidates, but none have been proven yet.Converging evidence supports that basic first aid provided during or shorty after a convulsive seizure can be lifesaving.4 Nocturnal supervision has been shown to reduce the risk of SUDEP.10 Seizure detection devices like smart watches and undermattress motion sensors may alert caregivers to intervene in a timely manner when a seizure occurs, thus preventing SUDEP. Most of the current devices are designed to detect convulsive seizures, the prime target to prevent SUDEP.19 However, they vary in their degree of effectiveness in detecting these events; some must be worn by the patients (requiring a cooperative patient), while others do not have to be worn, and they have differing levels of false-positive detections. All these factors will be critical in helping a family decide which device may be right for them. This is an area that is continuing to change rapidly owing to improvements in electronics, software, and artificial intelligence support. In the future these devices will likely play a larger role in management of nocturnal convulsive seizures.Most parents of children with epilepsy express a desire to discuss SUDEP with their neurologist at diagnosis. Both the American Academy of Neurology and American Epilepsy Society strongly recommend clinicians inform the parents about the risk and explain the known modifiable risk factors for SUDEP.20Extensive SUDEP research over the last few years has improved our understanding of risk factors, some of which may be modifiable; however, substantial knowledge gaps still exist regarding pathophysiology and effectiveness of interventions. There is a clear need for multiple large-scale, prospective international studies to explore SUDEP pathogenesis, and possible preventive measures. We look forward to ongoing research results that translate into improved care for children, adolescents, and adults at risk for this devastating consequence of living with epilepsy. In the near future we look forward to the day when families of children and adolescents living with epilepsy do not have to fear this outcome as a consequence of a single GTCS.