Sudden unexpected death in epilepsy: epidemiology, mechanisms, and prevention

doi:10.1016/S1474-4422(16)30158-2

The Lancet Neurology

Volume 15, Issue 10, September 2016, Pages 1075-1088

https://doi.org/10.1016/S1474-4422(16)30158-2 Get rights and content

Summary

Sudden unexpected death in epilepsy (SUDEP) can affect individuals of any age, but is most common in younger adults (aged 20–45 years). Generalised tonic-clonic seizures are the greatest risk factor for SUDEP; most often, SUDEP occurs after this type of seizure in bed during sleep hours and the person is found in a prone position. SUDEP excludes other forms of seizure-related sudden death that might be mechanistically related (eg, death after single febrile, unprovoked seizures, or status epilepticus). Typically, postictal apnoea and bradycardia progress to asystole and death. A crucial element of SUDEP is brainstem dysfunction, for which postictal generalised EEG suppression might be a biomarker. Dysfunction in serotonin and adenosine signalling systems, as well as genetic disorders affecting cardiac conduction and neuronal excitability, might also contribute. Because generalised tonic-clonic seizures precede most cases of SUDEP, patients must be better educated about prevention. The value of nocturnal monitoring to detect seizures and postictal stimulation is unproven but warrants further study.

Introduction

People with epilepsy face greatly increased prevalence of premature mortality.1, 2 Seizures—especially focal or generalised onset tonic-clonic seizures—are the most common cause of death among children and adults with epilepsy.2, 3 However, other seizure types, anti-seizure therapies, and comorbid disorders can also increase mortality. The incidence of sudden unexpected death in epilepsy (SUDEP) in young adults (aged 20–45 years) is 27 times higher than sudden death in control populations.⁴ For many epilepsy populations, SUDEP is the leading cause of death, and in the USA it is the second leading neurological cause of total years of potential life lost after stroke.⁵ People with epilepsy also have increased mortality compared with control populations, due to status epilepticus, motor vehicle accidents, falls, drowning, suicide, drug poisoning, assault, and pneumonia.1, 2 SUDEP and other causes of epilepsy-related mortality are an enormous public health problem.

Despite a five times increase in the number of research publications related to SUDEP during the past decade, public health agencies cannot accurately track SUDEP incidence, limiting the opportunity to perform population-based intervention trials. Thus, we do not know whether SUDEP rates are stable, rising, or falling. Furthermore, human SUDEP studies—from physiological, EEG, genetic, neuroimaging, and pathological studies—suffer from inconsistent and inaccurate methods of assessment. We reviewed the scientific literature on SUDEP with a focus on papers addressing epidemiology, mechanisms, and prevention, with the aim of increasing knowledge of SUDEP so that evidence-based guidelines, viable trial protocols, and effective prevention strategies can be developed.

Section snippets

Classification

The research classification for SUDEP is summarised in the panel.⁶ The SUDEP-plus category permits SUDEP diagnosis if all definite or probable criteria are met but a potentially lethal comorbid disorder such as long QT syndrome or severe coronary artery atheroma coexists. The term also recognises that two concurrent mechanisms can lead to SUDEP or that the cause of death cannot be distinguished. Near-SUDEP refers to circumstances in which cardiorespiratory arrest was reversed by resuscitation

Epidemiology

Estimates of SUDEP incidence vary substantially, depending on the population studied, how epilepsy and SUDEP are defined, and methods of determining and recording cause of death. The risk of SUDEP per 1000 people with epilepsy per year ranges from 6·3 to 9·3 in epilepsy surgery candidates or in patients after epilepsy surgery, 1·1 to 5·9 in epilepsy clinic populations—most with large proportions of patients with refractory seizures—and 0·35 to 2·3 in community-based populations (figure 1A).¹⁷

Genetics

Genetic mutations are linked to SUDEP in humans and to postictal death in animal models. Some have been labelled SUDEP genes or their association with cardiac disease has led to conclusions about the mechanism of death. However, genetic disorders and variants—as with other brain disorders that cause epilepsy—could increase SUDEP risk through effects on the following: epilepsy severity (seizure frequency, duration, spread pattern, intensity, and postictal effects); postictal depression of

Pathology

Pathological changes in SUDEP do not explain cause of death but might provide clues regarding pathophysiology. Cardiac and pulmonary abnormalities are common in cases of SUDEP at autopsy. In 52 patients who had SUDEP with histopathological examination, 11 cases (21%) showed mild-to-moderate myocyte hypertrophy and 22 patients (42%) showed varying extents of focal myocardial fibrosis.⁵⁸ All 52 SUDEP cases showed moderate to severe pulmonary congestion and oedema.⁵⁸ Another study reported

Animal models

Knowledge of SUDEP is limited by the few cases recorded during epilepsy monitoring, in which confounds include selection bias for more treatment-resistant cases, antiepileptic drug reduction or discontinuation, and scarcity of data for respiration and blood pressure. Animal models (genetic and other) provide invaluable insights into the mechanisms underlying SUDEP, and allow investigators to explore how specific interventions alter physiological variables and SUDEP risk (table 3).

The postictal state

After

Near-SUDEP

People with epilepsy might develop peri-ictal life-threatening events that require cardiac or respiratory resuscitation. Near-SUDEP can refer to these survivors,54, 71 as well as others who temporarily survive cardiac or respiratory resuscitation (beyond 1 h) but later die (eg, due to hypoxic ischaemic brain damage; panel). Two potential issues arise with this definition. First, the near-SUDEP incidence will be overestimated if resuscitation was unnecessary (ie, whether the resuscitation was

Prevention

Prevention of SUDEP can only be achieved through a co-ordinated effort by neurologists, medical examiners, epidemiologists, public health officials, scientists, and lay individuals. The priorities are a clear and consistent classification of epilepsy-related mortality and SUDEP across disciplines; accurate measures of SUDEP incidence over time; increased awareness of SUDEP among patients, families, and clinicians; understanding of the range of SUDEP mechanisms and translation of this knowledge

Conclusions and future directions

Despite an increase in SUDEP research over the past decade, a number of substantial knowledge gaps still exist, which means prevention strategies cannot be optimised. The public health impact of SUDEP is enormous. Yet, we do not have accurate surveillance to define trends and assess the effects of preventive interventions, nor have we been able to develop a model for predicting risk. However, data have shown that populations of people with epilepsy are at a 27 times higher risk for sudden death

Search strategy and selection criteria

We searched the databases MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, and Embase. The search strategy was limited to English references from Jan 1, 2011, to June 8, 2016, with the search terms “exp mortality/”, “exp epilepsy/”, “1 and 2”, “epilep*.ti,ab.”, “seizure?.ti,ab.”, “4 or 5”, “death?.ti,ab.”, “mortality.mp. or exp Mortality/”, “7 or 8”, “6 and 9”, “SUDEP.ti,ab.”, “exp Epilepsy/mo [Mortality]”, “sudden death.ti,ab”, “exp Death, Sudden/”, “sudden unexplained death.ti,ab”,

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