Sudden unexpected death in epilepsy: risk factors and potential pathomechanisms

Abstract

Sudden unexpected death in epilepsy (SUDEP) is the most common cause of death directly related to epilepsy, and most frequently occurs in people with chronic epilepsy. The main risk factors for SUDEP are associated with poorly controlled seizures, suggesting that most cases of SUDEP are seizure-related events. Dysregulation in cardiac and respiratory physiology, dysfunction in systemic and cerebral circulation physiology, and seizure-induced hormonal and metabolic changes might all contribute to SUDEP. Cardiac factors include bradyarrhythmias and asystole, as well as tachyarrhythmias and alterations to cardiac repolarization. Altered electrolytes and blood pH, as well as the release of catecholamines, modulate cardiac excitability and might facilitate arrhythmias. Respiratory symptoms are not uncommon during seizures and comprise central apnea or bradypnea, and, less frequently, obstruction of the airways and neurogenic pulmonary edema. Alterations to autonomic function, such as a reduction in heart rate variability or disturbed baroreflex sensitivity, can impair the body's capacity to cope with challenging situations of elevated stress, such as seizures. Here, we summarize data on the incidence of and risk factors for SUDEP, and consider the pathophysiological aspects of chronic epilepsy that might lead to sudden death. We suggest that SUDEP is caused by the fatal coexistence of several predisposing and triggering factors.

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“…It has an incidence among epileptic adults between 1:500 and 1:1,000 patient-years 7 . A single mechanism is not established for SUDEP, but evidences suggest that the major domain is cardiovascular dysregulation during and after seizures [8][9][10][11][12] . As these two chronic diseases are very common and have high rates of sudden death, we evaluated what would be the scenario if the same person had both conditions 13 .…”

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“…Now, looking through the prism of Neurology, we know that epilepsy is considered the most common serious neurological condition. Unfortunately, each year about one in a 1000 patients with chronic epilepsy will die suddenly, unexpectedly, and without explanation, even with post-mortem examination 3 . Among neurologists around the world, this phenomenon is called sudden unexplained death in epilepsy (SUDEP).…”

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“…In parallel, a number of associated factors for SUDEP have been reported but the results are not wholly consistent between studies. Thus, the main risk factors evaluated until now include refractoriness of the epileptic condition, presence of generalized tonic-clonic seizures, antiepileptic medication (polytherapy with antiepileptic drugs), young age, duration of the seizure disorder, early onset of epilepsy and winter temperatures 5,6 . Although different mechanisms may play separate roles in different cases 5 , the two major domains of potential mechanisms of SUDEP are autonomic, i.e., respiratory, and cardiovascular 7 .…”

“…Thus, the main risk factors evaluated until now include refractoriness of the epileptic condition, presence of generalized tonic-clonic seizures, antiepileptic medication (polytherapy with antiepileptic drugs), young age, duration of the seizure disorder, early onset of epilepsy and winter temperatures 5,6 . Although different mechanisms may play separate roles in different cases 5 , the two major domains of potential mechanisms of SUDEP are autonomic, i.e., respiratory, and cardiovascular 7 . According to the latter, a significant body of literature suggests that SUDEP has a potential cardiac mechanism, due to repetitive cardiac damage during seizures and due to arrhythmia during seizures, possibly triggered by apnea and/or cerebral autonomic imbalance 8 .…”

“…It is clear that SUDEP is mainly (but not exclusively) a problem for people with chronic uncontrolled epilepsy 12 , but our understanding of the best way to prevent it is still incomplete. Thus, some strategies 13 have been suggested that could be useful in reducing the risk of SUDEP: [1] Good control of seizures; [2] Reduction of stress; [3] Participation in physical activity and sports; [4] Dietary management (e.g., omega-3 supplementation); [5] Supervision at night; [6] Family members' knowledge of cardiopulmonary resuscitation (CPR) techniques and the basics of defibrillator use 13 . On balance, as a complete understanding of all the risk factors, mechanisms, and specific methods to prevent SUDEP is yet to be obtained, caution is really prudent and necessary.…”