Sudden Unexpected Death in Epilepsy - Springer Link

Curr Neurol Neurosci Rep (2010) 10:319–326 DOI 10.1007/s11910-010-0116-4

Sudden Unexpected Death in Epilepsy Maromi Nei & Ryan Hays

Published online: 6 May 2010 # Springer Science+Business Media, LLC 2010

Abstract Sudden unexpected death in epilepsy (SUDEP) is a significant cause of death for people with epilepsy. Recent research suggests that multiple factors may contribute and that both cardiac and respiratory mechanisms are involved. Both human and animal data suggest that specific genetic factors might play a role in some cases. Recent animal data suggest that serotonin might affect respiratory mechanisms and may be involved. Both cardiac and respiratory abnormalities are more likely with generalized tonic–clonic seizures. Uncontrolled epilepsy, particularly with generalized tonic–clonic seizures, appears to be the most highly associated modifiable risk factor for SUDEP. Keywords SUDEP . Epilepsy . Mortality . Cardiac . Pulmonary . Sudden death . Seizure . Epidemiology

Introduction Sudden unexpected death in epilepsy (SUDEP) is a significant cause of mortality for people with epilepsy. SUDEP has been defined as a “sudden, unexpected, witnessed or unwitnessed, nontraumatic and nondrowning death in epilepsy, with or without evidence for a seizure and excluding documented status epilepticus, in which postmortem examination does not show a toxicological or anatomical cause for death” [1]. It accounts for a mean of 17% of deaths in this population [2] M. Nei (*) : R. Hays Jefferson Comprehensive Epilepsy Center, Department of Neurology, Jefferson Medical College, 900 Walnut Street, Suite 200, Philadelphia, PA 19107, USA e-mail: [email protected] R. Hays e-mail: [email protected]

and an even higher proportion of deaths in selected populations of people with epilepsy. The etiology remains elusive, but recent data suggest that both cardiac and respiratory mechanisms likely contribute.

Epidemiology Worldwide, epilepsy is estimated to affect 50 million people, most of whom live in developing countries and therefore may have limited access to medical treatment [3]. In the United States, approximately 2.7 million people have active epilepsy. Patients with epilepsy have mortality rates two to three times higher than that of the general population [4]. This excessive mortality is related partly to the underlying etiology of the epilepsy and partly to the consequences of the seizures themselves. SUDEP is a leading cause of mortality in patients with epilepsy. An analysis of mortality in England and Wales demonstrated SUDEP to be the most common cause of epilepsy-related death [5]. In fact, the risk of sudden death in patients with epilepsy is estimated to be as much as 24 times higher than that of the general population [6, 7]. The reported incidence of SUDEP is quite variable, largely because of differences in patient populations, study design, and the criteria for defining SUDEP. Studies evaluating the incidence of SUDEP among all epilepsy patients within a community report lower incidences (0.13– 2.7/1,000 person-years) than those among more selective populations, such as patients being treated at tertiary referral centers (1.2–5.9/1,000 person-years), those undergoing drug or device trials (3.5–6.0/1,000 person-years), and those being evaluated for epilepsy surgery (as high as 9.3/1,000 person-years) [8]. Such results imply that patients with fewer seizures carry a lower risk of SUDEP.

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Most studies have assessed the incidence of SUDEP in adult patients. Interestingly, there appears to be a lower risk of SUDEP among children. Four studies documented a total of 43 cases of SUDEP in children; the authors estimated the risk of SUDEP in children to range from 0.11 to 0.43 per 1,000 person-years [9–12].

Risk Factors Several risk factors have been identified as potentially correlating with an elevated risk of SUDEP. Earlier, largely observational reports from selective populations (e.g., residents of long-term facilities or cases based on coroner reports) suggested poor medication compliance, male sex, young adult age, and alcoholism as possible risk factors for SUDEP. However, extrapolation of these results to the larger population of epilepsy patients as a whole is difficult, because these reports were generally uncontrolled. Subsequently, larger, case-controlled or cohort-controlled studies have helped clarify some of these risks. Seizure Frequency and Type In one of the largest case-controlled studies of SUDEP, Nilsson et al. [13] evaluated all patients in Stockholm with a diagnosis of epilepsy who had been hospitalized at least once between 1980 and 1989. Within this group of 6,880 patients, 57 cases of probable SUDEP had occurred, of which 91% underwent necropsy. The SUDEP cases were matched against patient controls who had epilepsy and similar demographics to determine relevant risk factors. This analysis demonstrated seizure frequency to be the strongest risk factor for SUDEP, with the relative risk of SUDEP increasing as the annual number of seizures increased. The relative risk of SUDEP was 23 times higher in patients who had experienced any seizures during the prior year than in those who had no seizures during the previous 12 months. Seizure frequency also was demonstrated to be one of the greatest risk factors for SUDEP in several other case-control studies. In controlled studies analyzing the risk of SUDEP relative to seizure type, generalized tonic–clonic seizures conferred the greatest risk [7, 14].

Curr Neurol Neurosci Rep (2010) 10:319–326

Lack of AEDs Conversely, not being on any medication for seizures also seems to be a risk factor for SUDEP. In the largest casecontrolled study of SUDEP to date, Langan et al. [14] demonstrated that an absence of medication compared with being on one or two AEDs carried an OR of 21.7. Furthermore, a recent open-cohort study evaluating medication use in Florida, Iowa, and New Jersey between 1997 and 2006 demonstrated that noncompliance with AEDs was associated with a more than threefold risk of death (hazard ratio, 3.32) compared with compliance [16••]. However, when AED compliance is assessed by postmortem serum levels, there are conflicting results [17, 18]; this may partly be the result of variability of postmortem drug levels, which, at least for phenytoin, were demonstrated to be unreliable compared with antemortem levels in an experiment in rabbits [19]. Drug Choice Carbamazepine and lamotrigine were associated with a higher risk of SUDEP in some studies [14, 20, 21]. However, other studies failed to demonstrate that any specific AED is associated with a higher rate of SUDEP [13, 22]; therefore, whether any single AED poses a greater risk of SUDEP remains unresolved. Age The aforementioned lower rate of SUDEP in children compared with adults implies that SUDEP is not nearly as common in children. However, some, but not all, studies have demonstrated that earlier age of epilepsy onset is an important risk factor for SUDEP [7, 13, 22, 23]. Additionally, some studies have shown that young adult age carries the highest risk of SUDEP [23, 24]. However, the frequent association between young adult age and SUDEP may be misleading because medical comorbidities in older patients may lead to an incorrect attribution of the cause of death, resulting in an underestimation of the true incidence of SUDEP in the older population. Cognitive Dysfunction

Polytherapy Treatment with more than one antiepileptic drug (AED) also was associated with a higher risk of SUDEP in some series [7, 13, 15]. Although polytherapy may just be reflective of refractory epilepsy, and therefore more frequent seizures, being treated with three simultaneous AEDs compared with monotherapy was associated with an odds ratio (OR) of 8.1, even after adjustment for seizure frequency [13].

There is conflicting literature regarding whether intellectual disability poses a higher risk of SUDEP. Walczak et al. [7] demonstrated that patients with an IQ less than 70 had higher mortality rates than those with an IQ greater than 79; Opeskin et al. [25] also reported higher rates of SUDEP in patients with cognitive dysfunction. However, other reports failed to show a correlation between mental retardation and SUDEP [23, 26].


Sex Most studies have not found gender to be a significant risk factor for SUDEP [7, 23, 24]; nevertheless, Timmings [20] reported that male sex was a risk factor for SUDEP, whereas conversely, Opeskin and Berkovic [26] found female sex to be a risk factor. Time of Year and Environmental Factors Certain environmental factors have been posited as conferring a higher risk of SUDEP. A retrospective review among 835 children with epilepsy being treated at a tertiary referral center in Brazil from 2000 to 2008 identified 10 cases of probable SUDEP. Interestingly, 70% of these cases occurred during a full moon, whereas only two cases occurred during the waxing moon and a single case occurred during the new moon, leading the authors to suggest that a full moon may confer a higher risk of SUDEP [27]. However, this lunar association was not reproduced in an analysis of 409 cases of probable SUDEP in England and Wales [28]. Furthermore, in the latter study, there was no clear relationship between the rates of SUDEP and temperature, season, or month. Finally, Schnabel et al. [29] also demonstrated that there was no association between rates of SUDEP and any specific month or season, or geomagnetic activity.

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patients have recurrent seizures despite treatment with medications; surgery offers hope for seizure freedom in some of these patients with medically refractory epilepsy. Prospective randomized studies examining the impact of surgery on mortality in epilepsy are lacking. However, a few nonrandomized studies examining the effect of surgical treatment on long-term mortality suggested that successfully stopping seizures is associated with a reduction in mortality, even when perioperative morbidity is taken into account [32]. For example, Salanova et al. [33] demonstrated that surgical patients who became seizure-free had a significantly lower mortality rate (standardized mortality ratio [SMR], 1.7; approaching that of the general population), whereas surgical patients with persistent seizures had a much higher mortality (SMR, 7.4). Sperling et al. [34] reported similar results, finding that surgical patients who were seizure-free had a mortality rate of 0.85 per 1,000 person-years (similar to that of the general population), compared with 11.4 per 1,000 person-years in surgical patients who continued to have seizures. However, not all studies demonstrated a positive effect of surgery on the reduction of SUDEP rates, and these differences may be the result of study design, patient population, evaluation techniques, or outcomes [35].

Potential Mechanisms of SUDEP Alcoholism Respiratory Data Although earlier observational reports suggested that alcoholism may be a risk factor for SUDEP, subsequent case-controlled studies failed to reproduce that finding [13, 15]. Supervision Few studies have identified factors that protect against SUDEP. However, an interesting finding from a casecontrolled study was that regular checks during the night, use of a listening device, or sharing the bedroom was associated with a decreased risk of SUDEP [14]. This decrease may be related to stimulation or positioning that might prevent seizure-associated respiratory compromise [30].

Attempts at Seizure Reduction Given the correlation between uncontrolled seizures and SUDEP, it has been postulated that decreasing the seizure frequency might lower the rate of SUDEP and other seizure-related causes of mortality. Indeed, there is some evidence that controlling seizures with medications may lower the risk of SUDEP [13, 31]. However, at least 35% of

Most witnessed SUDEP cases occur after a seizure, and respiratory difficulties often are reported around the time of death in these cases [30]. Recent data from Bateman et al. [36•] suggest that ictal apnea and hypopnea may be quite common and occur in focal seizures with or without secondary generalization, although generalized tonic–clonic seizures are more likely to cause pronounced abnormalities. The same investigators found that ictal apnea may be closely linked to contralateral spread of temporal lobe seizures [37]. So et al. [38] reported a case of near-SUDEP in which the patient had postical central apnea, which responded to cardiopulmonary resuscitation. Animal studies recently revealed intriguing data regarding the possible roles oxygenation and serotonin may play in seizure-induced apnea. Venit et al. [39] found that oxygenation prevented sudden death in a strain of mice that typically exhibit seizure-associated respiratory arrest. In the same mouse strain, another study found that a serotonin reuptake inhibitor reduced respiratory arrest at doses that did not reduce seizure severity [40]. Abnormal serotonin receptor expression in this mouse strain may be responsible for these mice’s susceptibility to respiratory arrest and sudden death [41], which may explain why

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serotonin uptake inhibitors may be effective in preventing death in these animals. Additional investigation is needed to assess the possible role of such treatment in humans. Ictal Cardiac Data Because seizures precede most deaths in witnessed SUDEP, much research has focused on the peri-ictal cardiac rhythm. Seizure-related cardiac rate and rhythm abnormalities occur commonly [42]. Sinus tachycardia occurs during most seizures; rarely, ictal bradycardia and asystole also may occur [43]. Other abnormalities, including supraventricular tachycardia, atrial fibrillation, and junctional rhythms, have been reported in patients undergoing video-electroencephalographic (EEG)/electrocardiographic (ECG) monitoring [44, 45]. Repolarization abnormalities, including T wave inversions and ST segment depression or elevation, also may occur. Potentially serious rhythm or repolarization abnormalities occurred in 14% of patients undergoing video-EEG monitoring for refractory focal epilepsy in one series [44]. At times, the seizure-induced arrhythmia may long outlast the seizure itself, raising concern regarding potential clinical consequences even after the seizure [42]. Ictal asystole has been postulated as one possible mechanism of SUDEP. Only 0.27% of 6,825 patients who underwent video-EEG monitoring had ictal asystole in one study [43]. However, long-term ECG monitoring in patients with refractory focal epilepsy revealed that ictal bradycardia or asystole may occur more commonly than previously suspected, occurring in seven of 19 patients and thought to be sufficiently severe to warrant cardiac pacemaker placement in four [46]. At this time, the clinical criteria for pacemaker placement, except in clear cases of seizureinduced asystole and syncope, and its utility in preventing SUDEP are still uncertain. In one series, none of the six patients who had pacemaker placement for ictal asystole had evidence of pacemaker activation over a mean of 5 years of follow-up [47]. However, one caveat in interpreting these data is that because of pacemaker limitations, information regarding rare pacing activations may be unavailable upon interrogation; thus, the absolute lack of pacing cannot be readily excluded. Cardiac Data in SUDEP and Near-SUDEP Although several types of cardiac rate and rhythm abnormalities may occur, malignant rhythms with high mortality, such as ventricular tachycardia, appear rare. There were two cases of ventricular tachyarrhythmias occurring at the time of SUDEP, but one occurred in a patient with a prior known myocardial infarction and active angina in association with a convulsive seizure at the time


of death [48]. In the other case, a ventricular rhythm was noted by emergency medical personnel, but the rhythm strip was not available later for confirmation [49]. Recently, however, there was a well-documented case of ventricular tachycardia occurring after a complex partial seizure during video-EEG/ECG monitoring [50•]. If this had occurred outside the hospital, it is highly likely the patient would have died, and her death would have been considered a SUDEP. These data reveal that seizure-induced ventricular arrhythmias may occur. However, although potentially preventive treatment is available, unfortunately there are no known effective and practical ways to screen for this risk in the epilepsy population. Cardiac Repolarization and Heart Rate Prolongation of the QTc interval may increase the risk of ventricular tachyarrhythmias. Recent data reveal that QTc intervals may be significantly prolonged during seizures in SUDEP [51]. In contrast, other studies did not find specific ECG rate, rhythm, or repolarization abnormalities to be more common in SUDEP than in control individuals [49, 52]. However, a greater degree of sympathetic stimulation was associated with seizures in SUDEP than in control patients with refractory focal epilepsy, as assessed by ictal heart rate measures [49]. Such a tendency toward extreme autonomic imbalance during seizures might predispose some individuals to SUDEP risk, as it may increase the likelihood of significant cardiac arrhythmias and/or respiratory compromise. Autonomic Dysfunction In addition to seizure-related autonomic cardiac and respiratory abnormalities, abnormal autonomic function also may be present interictally and may contribute to SUDEP. Heart rate variability, a measure of overall sympathetic and parasympathetic balance, often is diminished in people with epilepsy, particularly those with refractory epilepsy. Decreased heart rate variability has been associated with increased risk of sudden cardiac death in patients with underlying cardiac disease, but its clinical significance in epilepsy is still uncertain. Further investigation is needed to evaluate the significance of such abnormalities in the pathophysiology of SUDEP. AEDs may affect autonomic tone, and these effects may be difficult to distinguish from those of the epilepsy. Carbamazepine might affect autonomic tone in people with temporal lobe epilepsy [53]. Withdrawal of carbamazepine also may increase cardiac sympathetic activity during sleep [54]. Lamotrigine may affect the cardiac rapid delayed rectifier potassium ion current, but it is uncertain whether this medication contributes to the risk of SUDEP [21]. These data, as well as studies of SUDEP cases, suggest a


potential role of specific AEDs in SUDEP via a cardiac mechanism [20, 21], but additional studies are needed in this area to evaluate these findings further.

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abnormalities during seizures associated with sleep, which might increase the risk for SUDEP. Cardiopulmonary Function

Case Reports of SUDEP or Near-SUDEP Case reports of SUDEP or near-SUDEP describe both respiratory and cardiac abnormalities. Central apnea occurred after a convulsive seizure in a patient undergoing video-EEG monitoring [38]. In this case, apnea occurred immediately after the seizure, followed by the gradual onset of bradycardia, then asystole. Cardiopulmonary resuscitation was successful in this case, and a cardiac pacemaker was placed to prevent seizure-associated bradycardia. Near-SUDEP also has been reported to occur in association with laryngospasm [55]. Some reports have noted immediate postictal suppression of the EEG without definite cardiac or respiratory abnormalities at the time of SUDEP and have postulated that primary cerebral shutdown might cause death [56, 57]. However, respiratory and cardiac data in these cases are limited. Alternatively, seizure-related anoxia and/or decreased cardiac output might prevent the typical postictal recovery of cerebral activity, causing persistent suppression of cerebral function and death. Seizure Clusters Several reports highlight the potential risk of seizure clusters in SUDEP. Some cases of SUDEP or nearSUDEP occurred after a cluster of two or more seizures within a few hours of each other [38, 48, 49, 58]. In one study, seizures within clusters caused incremental increases in heart rate that showed a clear cumulative effect with each subsequent seizure, suggesting that autonomic instability during seizure clusters might be particularly high [44]. Sleep SUDEP often occurs in sleep; this may be related to alterations in autonomic function during sleep, positioning, or even lack of observation with subsequent stimulation, which might prevent SUDEP. Variations in heart rate or respiration during sleep might be worsened by seizures or the condition of epilepsy and might explain why SUDEP is more common in this state. Such abnormalities might be exacerbated by accompanying sleep-disordered breathing, which independently appears to increase mortality [59]. EEG data also suggest that patients with SUDEP are more likely than control patients to have a history and/or documentation of seizures arising from sleep [49]. Opherk et al. [45] also found that in patients with refractory epilepsy, there was a trend toward increased ictal ECG

Both respiratory and cardiac mechanisms likely are involved in SUDEP. Dysfunction of one system can adversely affect the other. Bradycardia and asystole often are preceded by ictal apnea [60]. The case reported by So et al. [38], noted earlier, also described a similar sequence of respiratory cessation, then bradycardia and eventual asystole. Genetic Data Recently, studies have focused on the possibility that a common channelopathy might contribute to both epilepsy and cardiac disease and thus might contribute to the increased incidence of SUDEP via a lethal cardiac arrhythmia. Long QT syndrome is caused by a potassium or sodium channel mutation resulting in ventricular tachyarrhythmias, which may manifest clinically as syncope or sudden death. In one large cohort of 343 unrelated patients with long QT syndrome, 29% were found to have either a personal or family history of possible epilepsy or a personal history of AED use, suggesting that people with long QT syndrome might also be at risk for seizures [61]. This study found that the gene KCNH2, which is responsible for type 2 long QT syndrome and encodes a potassium channel found in hippocampal astrocytes, was more highly associated with a history of possible epilepsy than other long QT genotypes, suggesting that a common mechanism might be responsible for both cardiac disease and seizures. However, confirmatory EEG data were not available in those cases; thus, convulsive syncope, rather than seizures, might have occurred. Goldman et al. [62••] reported both epileptiform and cardiac abnormalities in mutant mice engineered to carry the human KCNQ1 mutation, which causes two types of long QT syndrome in humans, again suggesting that a common channelopathy may cause both seizures and long QT syndrome. Recent case reports also suggest a link between long QT syndrome and epilepsy [63, 64]. Aurlien et al. [64] reported a patient with idiopathic generalized epilepsy who died of SUDEP and had an SCN5A mutation, which has been linked to long QT syndrome. They postulated that this cardiac sodium channel mutation, found on a postmortem examination, also may have caused sudden cardiac death and his epilepsy. Thus, although there now are several cases reporting a possible link between long QT syndrome and epilepsy, definitive data are still lacking to confirm that SUDEP may be caused by a channelopathy. Further research combining genetic testing and detailed neurologic and cardiac clinical

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evaluations are still needed to confirm this link. Treatment options exist, including β-blocker medication and implantable cardiac defibrillators, but additional data are needed to evaluate whether they have a role in SUDEP prevention.


risk as well. More invasive treatments, such as cardiac pacemakers or, possibly, implantable cardiac defibrillators, might be needed in other cases. However, additional studies are needed to further evaluate these potential therapies. At this time, the strongest evidence for SUDEP risk reduction appears to be maximizing seizure control.

Postmortem Data in SUDEP Necropsy findings have been rather nonspecific. Pulmonary edema (suggesting abnormal pulmonary vascular tone or cardiac dysfunction) and/or swelling of other organs (including the brain) have been reported [65, 66]. Microscopic examinations of the heart have reported subendocardial vacuolization (suggesting chronic cardiac injury) [67], possibly as a result of autonomic stimulation from repetitive seizures. Such abnormalities might later serve as a substrate for lethal arrhythmias, particularly in the setting of subsequent seizures. Abnormal microscopic brain findings were more likely in SUDEP than in a nonepileptic control population [68], but it is not clear whether these are specific to SUDEP, as epilepsy controls were not included for comparison. Additionally, one study suggested that there is an elevation of hippocampal heat shock protein 70 in SUDEP patients but not in those who have sudden cardiac death. This finding might hint at an underlying neural mechanism for death (possibly related to a terminal seizure) in patients with SUDEP [69]. Nevertheless, no conclusive causative effect has been elicited from the current postmortem data.

Conclusions SUDEP risk is highly correlated with the condition of having active epilepsy, particularly in patients with generalized tonic–clonic seizures. Although there may be an underlying genetic, functional, or anatomic substrate for SUDEP in some cases, in most cases seizures appear responsible for triggering a cascade of events leading to death. Both respiratory and cardiac abnormalities occur more commonly in longer seizures and in secondarily generalized tonic–clonic seizures [36•, 42, 44, 45, 49]. The increased autonomic abnormalities seen with convulsive seizures may partially explain the increased risk for SUDEP with this seizure type. Seizures in sleep and seizure clusters also may be particularly dangerous. Recent genetic data suggest that a common channelopathy might cause seizures or ventricular tachyarrhythmias, or both, and thus may contribute to sudden death in some individuals. Recent data suggest that relatively simple measures, such as stimulation after a seizure, oxygenation, or serotonin modulation, might have roles in preventing SUDEP. Perhaps prevention of seizure clusters might reduce the

Disclosure No potential conflicts of interest relevant to this article were reported.

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