Demystifying Sudden Unexplained Death in Epilepsy—Are We Close?
Address correspondence and reprint requests to Dr. Elson L. So, Section of Electroencephalography, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, U.S.A.
Summary: The cause of sudden unexplained death in epilepsy (SUDEP) is still elusive, despite multiple studies over the past few decades. This review assesses recent progress in the understanding of risk factors (situations that predispose patients to SUDEP) and terminal events (events immediately associated with death) that potentially contribute to SUDEP. Recent studies strongly support a close relationship between seizure episodes (especially generalized convulsions) and SUDEP. The lethal nature of some seizure-induced cardiorespiratory events has been documented fortuitously in rare patient cases, and these events have been consistently reproduced in SUDEP animal models. Nonetheless, SUDEP likely does not have a single cause, and risk factors identified thus far may vary in importance among persons with epilepsy. In the absence of a complete understanding of the pathophysiologic mechanisms underlying SUDEP, potential preventive measures for high-risk patients are offered for consideration. Seizure control is most important for reducing SUDEP risk. Circumstantial data suggest that heightened supervision of patients with frequent seizures may be beneficial. Relatively simple interventions may be sufficient to interrupt potentially lethal events such as periictal suffocation or apnea. However, application of these preventive measures to all epilepsy patients has not been proven to substantially reduce the rate of SUDEP. Additional clinical and laboratory investigations are needed to identify and confirm pathogenic factors and preventive measures.
Sudden unexplained death in epilepsy (SUDEP) has been defined as “sudden, unexpected, witnessed or unwitnessed, nontraumatic, and nondrowning 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 toxicologic or anatomic cause for death” (1). At the core of this definition are the unexplained processes resulting in sudden death. Discussions about whether the word “unexplained” is more appropriate than “unexpected” have occurred. I prefer to use “unexplained,” which emphasizes that the mystery and the challenge of SUDEP result from a lack of knowledge about the condition. Most unexpected deaths in epilepsy are explainable (e.g., from drowning or trauma), and they do not have the same implications as those of SUDEP. Moreover, the unexpected nature of SUDEP is already conveyed by the word “sudden.”
SUDEP was reviewed by Ficker at this annual course 5 years ago (2). In keeping with the objective and the format of the 2005 annual course, this review provides an update on SUDEP and critically assesses the progress in the understanding of SUDEP and management of patients with high risk of SUDEP.
FINDINGS OF RECENT SUDEP STUDIES
Pathogenesis of SUDEP
The pathogenesis of SUDEP may be considered in the context of risk factors (situations that predispose patients with epilepsy to SUDEP) and terminal events (events immediately associated with death).
Observational data in early and recent studies have shown a close temporal relationship between seizure episodes and SUDEP. A prospective comparison of 50 SUDEP patients and 50 control subjects found that a higher proportion of SUDEP patients died in bed and had a seizure near the time of death (3). In another case-control study, Langan and colleagues (4) compared 154 autopsy-supported SUDEP cases with matched controls (persons with epilepsy in the community). They found that the risk of SUDEP was nearly 14 times higher when there was a history of generalized tonic-clonic seizures in the previous 3 months.
In a multicenter study (5), the number of tonic-clonic seizures was associated with higher risk of SUDEP only in women, but reasons for the sex-based difference were unclear. Recently, immunohistochemistry techniques have been used during postmortem examinations to detect evidence of a seizure near the time of death (6). Significantly more brain specimens from SUDEP patients had positive stain results for heat shock protein 70 in hippocampal neurons than specimens from control subjects. However, the presence of this protein cannot be taken as absolute evidence of a recent seizure. Heat shock protein 70 induction can occur with any neuronal injury, and there was no difference in immunostaining properties of cells from the parahippocampal gyrus region.
Two other SUDEP risk factors identified in the multicenter study (5) were mental retardation and the number of antiepileptic drugs (AEDs) used. Both factors were associated with an increased risk of SUDEP and were independent of seizure frequency. Postictal encephalopathy may be more profound in mentally retarded persons, and neurologic deficits could prevent self-recovery of a safe posture or position during the postictal state. Nonsignificant findings in this study were equally important. In contrast with the findings of a previous report (2), several factors did not increase risk of SUDEP: subtherapeutic serum AED concentration at last visit and cerebral structural lesions.
Nilsson and colleagues (7) compared patients who did or did not have their serum AED levels measured during a 2-year period. They found that the relative risk of SUDEP increased 3.7-fold for patients who did not have AED levels measured. Nonetheless, premortem subtherapeutic serum AED concentrations or the lack of serum AED measurements before death does not necessarily implicate a common factor such as poor medication compliance. No association was found between SUDEP risk and the variation of serum AED concentrations in any one patient over time, but polytherapy, frequent dose changes, and high serum carbamazepine concentrations were associated with increased SUDEP risk. Although the analysis had accounted for seizure frequency, the investigators cautioned that their observations may be due to a state of severe intractable epilepsy. In addition, the “high” carbamazepine concentrations were not excessively high, and they were observed in only five patients (the data analysis indicated wide confidence intervals despite statistically significant relative risk) (8).
In the multicenter study (5), cerebral structural lesions were not a risk factor for SUDEP, although microscopic examination of brain tissue specimens in another study (9) showed a higher proportion of abnormalities in SUDEP patients than in nonepileptic subjects. These microscopic abnormalities consisted of neuronal clusters, increased perivascular oligodendroglia, gliosis, decreased myelin, and atrophy of the folia. However, the observed abnormalities may be broadly associated with epilepsy and may not be specifically linked with SUDEP.
Autonomic dysfunction is rarely studied as a risk factor for SUDEP. Tinuper and colleagues (10) performed interictal autonomic evaluations in 3 epilepsy patients and 18 control subjects. One of the three patients had a higher resting heart rate and hypersympathetic responses to the Valsalva maneuver and tilt table test. Hilz and colleagues (11) reported that temporal lobectomy stabilized cardiovascular control by reducing the risk of sympathetically mediated tachyarrhythmias and excessive bradycardic counterregulation. Evaluation of interictal autonomic functions before and after temporal lobectomy indicated that there was a reduction of sympathetic cardiovascular modulation and baroreflex sensitivity after surgery. It is not known whether their findings explain the observation by Sperling and colleagues (12) that successful epilepsy surgery reduces the risk of SUDEP for patients with drug-resistant epilepsy.
Cardiac arrhythmia and respiratory dysfunction are suspected to be independent primary mechanisms that can lead to SUDEP. We described a near-SUDEP incident caused by postictal central apnea that was captured on videotape and included electroencephalographic and electrocardiographic monitoring (13). SUDEP events are seldom witnessed, and they are infrequently documented (14). Therefore, this case was a rare opportunity to study the pathophysiology of SUDEP in a clinical setting.
The patient was a 20-year-old woman with persistent postictal apnea without respiratory effort. Previously, she had seizure-related cardiopulmonary distress that required resuscitation, even with self-limited complex partial seizures that did not secondarily generalize. In previous events, her pulse appeared to be strong and regular when postictal respiratory arrest first developed, but the pulse faded as the apnea persisted. During the monitored event, electrocardiography showed that cardiac activity was normal during the initial phase of apnea; thus cardiac arrhythmia was not the primary mechanism initiating events that could have led to SUDEP. Cardiac arrest and marked suppression of electroencephalographic waves occurred after prolonged apnea, but the patient was successfully resuscitated. Evaluation of the patient showed no evidence of respiratory pathway obstruction, pulmonary emboli, pulmonary edema, or myocardial infarction. Subsequent intracranial electrode recording failed to lateralize seizure onset. With phenytoin and phenobarbital treatment, the patient's seizures were well controlled, and near-SUDEP events no longer occurred.
Although the role of central apnea in SUDEP was considered nearly a decade ago, the clinical observation of this patient convincingly established seizure-related central apnea as a potential mechanism for sudden death of persons having seizures. Langan and colleagues (14) reported that respiratory difficulty was terminal for 12 of 15 witnessed SUDEP events. Studies in sheep (15,16) provided additional evidence that central hypoventilation, not cardiac arrhythmia, is a major lethal event in sudden death associated with seizures. Furthermore, in the DBA/2J mouse strain, early occurrence of respiratory arrest preceded sudden death during audiogenic seizures (17).
Compared with seizure-related apnea, seizure-related pulmonary edema is more frequently suspected as a respiratory mechanism of SUDEP (2). Pulmonary edema is a common postmortem finding in SUDEP patients, but it is encountered rarely in non-SUDEP patients. There is a well-documented report of seizure-related pulmonary edema that led eventually to SUDEP (18). An otherwise healthy 18-year-old with juvenile myoclonic epilepsy had survived an episode of severe postictal pulmonary edema. That episode and the subsequent fatal episode were characterized by acidosis, hypoxemia, and radiographic evidence of widespread bilateral pulmonary edema.
Several series document patients with bradycardia or asystole during seizures (2). Recent studies have attempted to determine the rate of ictal bradycardia or asystole among medically intractable epilepsy patients (19–21). In these studies, ictal tachycardia was common among adult and pediatric epilepsy patients, but ictal asystole was rare. Seizures associated with asystole were uniformly partial in onset. Nevertheless, the rarity of ictal asystole in clinical practice does not exclude it as a major mechanism of SUDEP. In a 2-year study with 220,000 patient-hours of electrocardiographic data from implanted loop recorders, 21% of drug-resistant epilepsy patients eventually had ictal bradycardia or asystole that required permanent cardiac pacing (21).
Although ictal tachycardia may not be an immediate mechanism leading to SUDEP, it may still be a risk factor. Nei and colleagues (22) compared the electrocardiographic data of 21 definite or probable SUDEP patients with a control group of 43 refractory epilepsy patients. The maximal ictal heart rate of SUDEP patients was faster than that of control subjects (mean heart rate, 149 vs. 126 beats per minute).
Sudep in Children
SUDEP is rarely reported in children. In the past 5 years, only two retrospective series of pediatric SUDEP cases were published. One series (23) consisted of 27 cases retrospectively identified in Ontario, Canada, and the other series (24) consisted of five cases from a comprehensive epilepsy center in Houston, Texas. Incidence figures and risk factors could not be determined reliably in these studies because they lacked information about the general population and did not have a control group. Descriptive data in these series suggest that SUDEP risk factors for adults are also relevant for pediatric patients. However, without using matched-control groups, unique or important risk factors for pediatric SUDEP may not be detected.
The Ontario study (23) estimated the incidence rate of SUDEP in children to be approximately 1–2 deaths per 10,000 patient-years. Our population-based study of SUDEP (25) in Rochester, Minnesota, found a comparable rate of 2.7 deaths per 10,000 person-years in children younger than 14 years. The low population-based rates of SUDEP in children are not surprising, given that we found that the population-based rate was only 4.9 deaths per 10,000 person-years in the age group with the highest risk (15–44 years) (25).
IS SUDEP PREVENTABLE?
Despite multiple investigative studies over the past 2 decades, a comprehensive understanding of SUDEP is still elusive. Multiple risk factors have been identified, although they may vary in importance among patients. Is it worthwhile to develop a program for SUDEP prevention? Lessons could be drawn from sudden infant death syndrome (SIDS) that has attracted greater public attention and scientific investigation. Like SUDEP, SIDS has no unitary explanation (26). Multiple risk factors have been observed, including male gender, prematurity, smoking during pregnancy, winter season, insufficient prenatal care, high parity, prone sleeping position, and certain sleeping environs. In 1992, a coalition of health organizations, including the American Academy of Pediatrics, initiated the “Back to Sleep” campaign, and the incidence of SIDS has decreased by nearly 50%. The campaign urges parents and caregivers to have babies sleep in the supine position. Another important measure is the modification of the crib environs (e.g., removal of soft bedding materials and stuffed toys) to reduce further the risk of suffocation.
A concerted program for SUDEP prevention that is similar to the SIDS campaign may substantially reduce its incidence. Even without precise knowledge of the underlying pathogenic mechanism, SUDEP prevention could start with the identification of the most prominent risk factors and terminal events associated with SUDEP. Eighty percent of witnessed SUDEP events were associated with seizures (14). Nashef and colleagues (27) recommended “heightened supervision” for persons with a high risk of SUDEP. In their recent case-control study, supervision throughout the night was associated independently with reduced risk of SUDEP (odds ratio of 0.4) (4). In the study, supervision was defined as having someone present in the bedroom who was at least 10 years old and had at least average intelligence. Other studies have used respiratory data from electroencephalographic monitoring to show that apnea occurred in 45–60% of partial seizures and 100% of generalized convulsive seizures (28). Apnea lasted up to 70 s, and oxyhemoglobin desaturated to as low as 55% in some patients.
Circumstantial evidence (e.g., the high proportion of SUDEP events that occur during sleep hours or without witnesses) and the lower rates of SUDEP in children (presumably because children are less likely to be alone) support the theory that immediate postictal intervention could prevent some SUDEP events. Relatively simple interventions may be able to stop potentially lethal events such as periictal suffocation or apnea. A recent animal study using the audiogenic seizure mouse model of SUDEP showed that oxygenation reliably prevented death (17). Modification of sleeping position may also prevent SUDEP. As in SIDS, a prone sleeping position may predispose high-risk patients to SUDEP. In a series of 42 SUDEP cases (29), 71% of patients died in the prone position.
The high risk of SUDEP for patients with drug-resistant epilepsy is reduced with successful epilepsy surgery. One study with an average of approximately 4 years of postsurgical follow-up data showed that SUDEP occurred in 6 of 194 patients who had postoperative seizures, but SUDEP did not occur in any of the 199 patients who were postoperatively seizure free (12). Two other studies (30,31) suggested that patients with epilepsy surgery had lower SUDEP risks than patients who did not undergo epilepsy surgery, but a recent review (32) cautioned that the baseline rate of SUDEP assumed for comparison was difficult to determine accurately. Also, patients who did not undergo surgery may have had other factors (independent of their nonsurgical status) that predisposed them to SUDEP, such as severe multifocal epilepsy or inoperable seizure foci at locations associated with cardiac arrhythmias or apneas (e.g., insula, opercular, or fronto-orbital regions).
Table 1 summarizes preventive strategies for major risk factors and terminal events associated with SUDEP. Early use of an α1-adrenergic blocking agent such as doxazosin mesylate to prevent pulmonary edema was recently proposed (18), but the treatment efficacy has not been determined. A recent study that used the audiogenic seizure DBA/2J mouse model of SUDEP showed that treatment with the serotonergic agent fluoxetine prevented SUDEP in all mice, but 89% of the mice were susceptible to SUDEP after the drug effects faded (33).
Table 1. Potential strategies for preventing SUDEP in high-risk patients
| Uncontrolled epilepsy||Optimize AED treatment, consider epilepsy surgery|
| Generalized tonic–clonic seizures||Optimize AED treatment, consider epilepsy surgery|
| Young adults||Provide prompt medical or surgical treatment|
| Childhood epilepsy onset||Provide prompt medical or surgical treatment|
| Low serum AED concentrations||Improve compliance and monitoring|
| Polytherapy||Reduce AED|
| Frequent AED adjustments||Stabilize regimen|
| Substance abuse||Recommend abstention|
| Mental retardation||Recommend supervision|
| Unsupervised setting||Recommend supervision|
| Seizure occurrence||Recommend supervision; seizure alarm|
| Pulmonary edema||Recommend recognition and treatment|
| Apnea or hypoxia||Recommend pulse oximetry monitor; stimulation; and oxygenation|
| Asystole||Recommend cardiac monitor; pacemaker|
| Suffocation||Reposition patient; modify environment|
Many of the preventive measures listed in Table 1, such as compliance with medication intake and attainment of seizure control, are components of general epilepsy management. However, more complex measures such as direct supervision and cardiorespiratory monitoring are practicable only with high-risk patients. Moreover, implementation of preventive measures requires patients to be educated about their risk of SUDEP. The extent of a clinician's legal obligation to disclose information about SUDEP is unclear. However, recent reviews have discussed how the patient's right to know should be balanced against the need for knowledge about the condition (34,35). I believe that clinicians have an ethical imperative to disclose the risk of SUDEP to their high-risk patients and to discuss the potential preventive measures. Nevertheless, there is no proof that most of the preventive measures reduce the risk of SUDEP substantially. At this point, the consideration of complex preventive measures should not impute a legal obligation to implement them, especially when some measures still lack proof of feasibility and effectiveness in preventing SUDEP.
DEMYSTIFYING SUDEP—THE WORK AHEAD
Improving lay and medical education
SUDEP seldom occurs, and the generally low and diminishing rate of autopsy in the United States hinders the study of SUDEP. Data from every potential case of SUDEP are needed to determine the underlying pathologic mechanisms. Lay and medical communities must understand that a complete postmortem investigation is needed when the cause of death in a person with epilepsy is not obvious. In addition, there should be emphasis on assigning the diagnosis of SUDEP when postmortem data sufficiently and convincingly support it. A recent survey of U.S. coroners and medical examiners showed that SUDEP was not consistently cited as the cause of death, even when criteria for the diagnosis were met (36).
Future SUDEP studies
The following criteria need to be considered when designing future clinical investigations of SUDEP:
- 1Prospective study design. Only prospective studies can address most of the challenges and limitations of previous SUDEP studies. Prospective study design permits hypotheses-driven data collection and analysis. Study data could be collected through usual clinical care activities, with additional information obtained as needed. A data collection program can be used for organizing research data and generating the patient's medical history.
- 2Multicenter or system-wide participation. Because no single center has a sufficient number of SUDEP patients to complete a study within a reasonable period, multicenter participation is required.
- 3Comparison with control subjects. Comparisons can be made in a case-control study or in a cohort study with regression analysis. Purely descriptive case-series (37) are unlikely to yield new information, even with large numbers of SUDEP patients.
- 4Postmortem examinations of all potential SUDEP patients. This is feasible if the scope is limited to patients enrolled in a prospective study and intensive efforts are made to educate the medical examiners and coroners whose jurisdictions cover the patients' residence area. A dedicated forensic protocol must be used when conducting the postmortem investigation.
- 5Provision of study funds to defray autopsy expenses.
Recent SUDEP studies mainly reiterate previous findings, and the cause of SUDEP is still unknown. It is possible that SUDEP does not have a single cause, and risk factors identified thus far may vary in importance among persons with epilepsy. Potential preventive measures must be considered for high-risk patients, although the effect of the measures is not fully understood. The lack of knowledge about SUDEP indicates that continued and concerted efforts to study the phenomenon of SUDEP are needed, with emphasis on prospective multicenter studies and studies using animal models of SUDEP.
Acknowledgement: Editing, proofreading, and reference verification were provided by the Section of Scientific Publications, Mayo Clinic.