eMedicine Specialties > Neurology > Seizures and Epilepsy

Sudden Unexpected Death in Epilepsy

Shahin Nouri, MD, Director, Comprehensive Epilepsy Center, Associate Chief, Division of Neurology, New York Methodist Hospital
Marshall Balish, MD, PhD, Assistant Chairman, Assistant Professor, Department of Neurology, Washington Veterans Affairs Medical Center, Georgetown University

Updated: Oct 1, 2009

Introduction

Background

Mortality due to epilepsy is a significant concern. Patients with epilepsy have a mortality rate significantly higher than that of the general population. Standardized mortality rate (SMR) is shown to be 1.6-9.3 times higher in this population.^1,2,3,4,5,6
 
Epilepsy-related causes of death in this population account for 40% of the deaths and include the following:

• Death due to the underlying neurological disorder in symptomatic epilepsy
• Sudden unexpected death in epilepsy (SUDEP)
• Accidents during epileptic attack (ie, trauma, drowning, burning, choking)
• Status epilepticus
• Suicide
• Treatment-related death

SUDEP has been reported in patients with epilepsy since the late 1800s and may account for 8-17% of deaths in this population. SUDEP is defined as sudden, unexpected, nontraumatic, nondrowning death in an individual with epilepsy, witnessed or unwitnessed, in which postmortem examination does not reveal an anatomical or toxicological cause for the death.

In an attempt to standardize the definition of this phenomenon, the US Food and Drug Administration (FDA) and Burroughs-Wellcome developed criteria for SUDEP in 1993. These criteria are now used in most SUDEP studies and are as follows:

• The patient has epilepsy, which is defined as recurrent unprovoked seizures.
• The patient died unexpectedly while in a reasonable state of health.
• The death occurred suddenly (ie, within minutes).
• The death occurred during normal and benign circumstances.
• An obvious medical cause of death could not be determined at autopsy.
• The death was not the direct result of a seizure or status epilepticus.

Notably, evidence of a recent seizure does not exclude the diagnosis of SUDEP as long as death did not occur during the seizure.

To further categorize the cases, they also defined the following:

• Definite SUDEP: Cases meet all criteria and have sufficient descriptions of the circumstances of the death and a postmortem report.
• Probable SUDEP: Cases meet all criteria but lack postmortem data.
• Possible SUDEP: SUDEP cannot be ruled out but evidence is insufficient regarding the circumstances of death and no postmortem report is available.
• Not SUDEP: Other causes of death are established clearly or the circumstances make the diagnosis of SUDEP highly improbable.

Pathophysiology

Autopsy plays the core role in determining the diagnosis of SUDEP. Knowing the circumstances surrounding the death will contribute. Information obtained from family and friends are extremely important. This information, also known as verbal autopsy, is often overlooked.⁷ Autopsy, per the definition, fails to reveal the underlying cause of death; however, several autopsy reports confirm the following findings in the organs of patients with SUDEP.

• Brain: Studies by Kloster et al⁸ and Earnest⁹ and Engelskjon indicated that only 16% of victims had no significant pathologic findings. In addition to the underlying cerebral pathology in patients with symptomatic epilepsy, cerebral edema was reported in the majority of both childhood and adult cases. However, none of the cases showed mass effect due to edema. In addition, signs of hypoxia in the hippocampal area were noticed in a few instances. Sclerosis of the amygdala has been documented in patients with SUDEP; no significant difference in the amygdala is seen in other patients with chronic epilepsy.
• Lungs: The lungs were heavier than expected in all patients in different studies; lung weights were 110-190% of normal in a study by Terrence et al.¹⁰ Mild to moderate pulmonary edema with protein-rich fluid and alveolar hemorrhage were seen in all specimens in this study. Other investigators have confirmed the presence of pulmonary edema per weight and histology in 62-84% of cases.
• Heart: Nonfatal pathologic findings, including fibrosis of the conductive system, have been reported in 33%-40% of patients.
• Liver: Increases in weight and venous congestion, indicating right cardiac failure, were documented in the majority of cases.

All of these findings were more frequent in patients with SUDEP than in other patients with epilepsy.

Mechanisms

Various and overlapping pathophysiological events may contribute to SUDEP in different patients, and the mechanism is probably multifactorial. Respiratory events, including airway obstruction, central apnea, and neurogenic pulmonary edema, are probable terminal events. In addition, cardiac arrhythmia, during both the ictal and interictal periods, leading to arrest and acute cardiac failure plays an important role. Specifically, bradyarrhythmias are shown to be associated with apnea. Antiepileptic medication may be another risk factor. The eMedicine article Epilepsy and the Autonomic Nervous System has discussed these mechanisms in more detail. These interactions can be summarized as the events directly related to seizures (see Media file 1) and the baseline (see Media file 2).

Factors contributing to sudden unexpected death in epilepsy (SUDEP) in seizure.

Factors contributing to sudden unexpected death in epilepsy (SUDEP) in baseline.

Respiratory

Neurogenic pulmonary edema has been reported following a variety of neurological conditions, including epilepsy. Neurogenic pulmonary edema has been documented in 84% of patients in whom autopsy was done following SUDEP. The underlying mechanism for neurogenic pulmonary edema seems to include a massive alpha-adrenergic response, generalized vasoconstriction, and pulmonary hypertension. In addition, the high protein content of the alveoli is indicative of severe damage to the endothelial membranes leading to increased pulmonary permeability. These findings also indicate that the terminal event lasted longer than a few minutes.

Johnston et al developed an animal model to support this theory.¹³ Status epilepticus was induced by bicuculline infusion in unanesthetized, chronically instrumented sheep; 5 of 13 animals died within 5 minutes. Pulmonary edema, accompanied by increased left atrial and pulmonary artery pressures, was more extensive in animals that died than in animals that survived. Cardiac arrhythmia and pulmonary edema, although present in most cases, did not seem to contribute to their demise. The terminal event in all cases was profound central apnea.

In 60% of cases, the event was related to sleep, which might indicate involvement of a sleep-related event.

Central apnea syndromes are characterized by cessation of spontaneous respiratory drive during sleep. Seizures are known to cause central apnea by direct propagation of the electrical discharge to the respiratory center. Episodes of apnea lasting 10-63 seconds, accompanied by a significant fall in oxygen saturation, have been documented. In addition, cardiac arrest can cause secondary cardiopulmonary arrest. So et al documented a case of near-SUDEP due to postictal apnea.¹⁴ These 2 mechanisms may contribute significantly to the pathophysiology of SUDEP.

Asphyxiation secondary to an obstructive cause has been postulated to play a role in the deaths of patients who were found in a prone position at the time of death. Several investigators reported the prone position more frequently than statistically expected (eg, 81%⁹ , 71%⁸ ). The prone position may affect ventilation by obstructing the upper respiratory tract as well as increasing the chances of aspiration. In addition, cases of laryngeal spasm and stridor after a seizure has subsided have been reported.¹⁵ In unsupervised patients, this might have contributed to death after a seizure.

Cardiac

Cardiac arrhythmias also may play an important role as an underlying mechanism of SUDEP. Fatal arrhythmias can occur both during the ictal attack and interictally. Jackson and his associates first described autonomic symptoms in seizures caused by mesial temporal lobe lesions.¹⁶ Erickson systematically studied ictal ECG changes for the first time.¹⁷ He reported tachycardia, cardiac arrhythmia, and T-wave flattening secondary to a right temporal lobe seizure. Initial bradycardia, followed by tachycardia, was documented in as many as 64% of petit mal and 100% of generalized tonic-clonic seizure attacks. More recent studies, documenting simultaneous EEG and ECG, report tachycardia in 74-92% of complex partial seizures. Persistent bradycardia is less common and is reported in 3-7% of complex partial seizures. Ictal cardiac rhythm and conduction abnormalities have been reported in 5-42% of patients with partial seizures.

Arrhythmias preceding SUDEP have been postulated to be the underlying cause of death. Lathers documented the synchronization of ictal and interictal spikes with cardiac sympathetic activity. Ictal tachycardia has been documented in 83% of seizure attacks, and bradycardia can accompany as many as 4% of seizures. During the attack, patients presented with prolonged decreases in heart rate, which lasted beyond the seizure attack in most cases. The majority of patients had decreased brain perfusion with potentially fatal outcome.

Similar findings have been documented in other studies. The potential mechanism for this is propagation of the electrical activity to the amygdala, which has efferent connections, via the central nuclei, to the cardioregulatory centers in the medulla. Arrhythmia can be a consequence of this event. Massive sympathetic surge during a seizure attack and vagal inhibition might be other potential mechanisms for increased ectopic ventricular activity. Also, extreme vagal stimulation might cause heart blocks.

Cardiac arrhythmia during the interictal state is another potentially fatal condition. The evaluation of autonomic cardiovascular reflexes in patients with epilepsy indicates dysfunction of both sympathetic component and parasympathetic division. Furthermore, hypofunction of the autonomic cardiovascular reflexes is postulated to be more prominent in patients who also were at high risk for SUDEP and in patients with a more refractory seizure disorder.

Decreased heart rate variability is well known to increase the vulnerability of the cardioregulatory centers, leading to an increase in ventricular automaticity and thus to arrhythmias. The mechanism of dysfunction of the autonomic nervous system (ANS) in epileptic seizures may be multifactorial. This is discussed in more detail in the article Epilepsy and the Autonomic Nervous System.

Interictal spikes have been shown to cause arrhythmias in animals. Also, the autonomic control centers may undergo physiological or anatomical alterations. An example of these changes is the interictal hypometabolism seen in the area adjacent to the epileptic foci on positron emission tomographic (PET) scanning studies. In addition, autopsies of patients with SUDEP have shown fibrosis of the cardiac conductive system in 33% of patients. Repetitive exposure to catecholamines is known to cause myocardial fibrosis. These can act, per se, as new foci for cardiac arrhythmias.

Only one study has evaluated the ictal tachycardia retrospectively in patients with SUDEP. Nei et al described higher increase in heart rate during seizures in patients who would experience SUDEP in the future when compared with other patients with epilepsy.¹⁸ To ascertain the true role of cardiac arrhythmia as an immediate event before death, further investigations must be carried out.

Autonomic cardiac arrhythmias may contribute significantly to sudden unexpected death in epilepsy (SUDEP):

• Decreased baseline heart rate variability is indicative of impaired autonomic cardiovascular reflexes in epilepsy. This can cause an increase in ventricular automaticity, in turn predisposing to arrhythmias.
• Catecholamine surges during repeated seizures can cause cardiac conduction system fibrosis and arrhythmias. Anatomic and functional changes in the cardiac and pulmonary function are evident and might be direct or indirect consequence of autonomic dysregulation. In particular, foci of fibrotic changes in the myocardium might contribute to arrhythmias.
• A recent seizure might cause central apnea, often associated with bradyarrhythmias.
• Use of carbamazepine is associated with impaired cardiac regulation and with increased risk of SUDEP.

Medications

The subtherapeutic levels of antiepileptic agents in SUDEP patients might be a reflection of poor seizure control or poor compliance. In addition, hair samples of patients with SUDEP revealed greater variability of AED levels than other persons with epilepsy.¹⁹

Antiepileptic medications potentially play a role in modification of the autonomic nervous system functions. In a study of the cardiovascular reflexes in 24 patients with epilepsy, Devinsky et al documented increased heart rate variability that was, at least partially, attributed to carbamazepine.²⁰ Other researchers have reported similar findings.

In addition, withdrawal from medications might have contributed to SUDEP via increasing the vulnerability to cardiac arrhythmia. Kenneback et al have shown a decrease in heart rate variability and increase in ventricular automaticity directly related to the fall in serum levels of carbamazepine.²¹ Seizure threshold also might diminish, leading to rebound effect and increase in seizure frequency.

Frequency

United States

Incidence of SUDEP is expected to be comparable in Northern America and Europe.

International

Although studies on SUDEP are heterogenous in methodology and the accuracy of mortality data available, consistent patterns in incidence are obvious.²² SUDEP accounts for 8-17% of deaths in people with epilepsy.

Statistics on the incidence of SUDEP is obtained mainly from community-based data and patient population-based data. The latter is obtained from hospitals, clinics, and referral centers and is therefore reflective of patients who are more tightly monitored, but probably also have more serve epilepsy. The incidence is estimated to be 0.09-3.5/1,000 patient-year in the community-based studies. A higher incidence of 2-10/1,000 patient-year is reported in population-based studies.^11,23,24,25

In a comprehensive study, Ficker reported the only large population-based study, comparing the incidence of SUDEP in patients with epilepsy to sudden unexplained death in the general population.²⁶ The incidence of SUDEP is estimated to be 0.35 per 1,000 person-years of follow-up. The highest standardized mortality ratio (SMR) of sudden unexpected deaths is estimated to be 24 times higher in persons with epilepsy than in the general population.

Other reports have documented an incidence of 0.5-6 per 1,000 person-years of follow-up. This translates to a range of 1 in 370-1,100 in the general epileptic population. This discrepancy reflects patient selection criteria, different study methods, and analysis methods. As an example, Neuspiel et al evaluated sudden deaths in a population of adolescents aged 14-21 years in Pennsylvania.²⁷ They reported an incidence of 5.6 per 1,000 person-years of follow-up and an SMR 40 times higher in people with SUDEP than in the general population.^12,28,29

Race

African Americans have higher rates of SUDEP than Caucasians.

Sex

Male-to-female ratios as high as 7:4 have been reported.

Age

Most cases of SUDEP have been observed in patients with epilepsy who are in their third to fifth decade (ie, age 20-40 years), with a higher incidence at the younger end of the age range. The average age is estimated to be 28-35 years.

The incidence of SUDEP in children appears the lowest at 0-0.2/1,000.³⁰

Clinical

History

Please see Background.

Physical

Neurologic examination findings are most often normal prior to the terminal episode (presuming the patient is not having a seizure at the time of examination). Neurological abnormalities related to a chronic neurological syndrome may be present. Please see the appropriate eMedicine article with regard to these chronic syndromes.

Causes

SUDEP has been shown to be associated with the following risk factors (Table 1 below):

• Demographic
  • Most cases of SUDEP have been observed in patients with epilepsy who are in their third to fifth decade. The average age is estimated to be 28-35 years. SUDEP is very rare in children.
  • A male-to-female ratio as high as 7:4 has been reported in most studies.
  • African Americans have higher rates than Caucasians.
• Other patient factors
  • Developmental delay, defined as intelligence quotient score (IQ) less than 70 or delay so severe that formal mental status examination was not possible, is significantly more common in the SUDEP group than in patients with epilepsy who do not experience SUDEP.
  • Excessive alcohol consumption and substance abuse are more frequently documented behaviors in patients with SUDEP than in the general population of patients with epilepsy.
• Circumstances around death
  • A higher proportion of patients were found dead in bed. Either the prone position or sleep-related seizures might have contributed to SUDEP in such cases.
  • Patients who were unsupervised after their seizures had a higher rate of SUDEP.
• Epilepsy
  • Symptomatic seizures are reported in 34-70% of SUDEP cases. Annual risk of SUDEP is estimated to be 1 per 100 for patients with symptomatic seizures and 1 per 1,000 for patients with idiopathic seizures.
  • A recent seizure increases the chances of SUDEP.
  • Generalized seizures, lower age of seizure onset, duration of seizure disorder longer than 10 years, total higher number of tonic-clonic seizures and history of therapeutic surgery for epilepsy are other seizure-related risk factors.
  • Most patients who die of SUDEP had poorly controlled seizure disorder, ie, a higher than average number of seizures per year. Sperling et al showed that in a population of patients with refractory epilepsy who underwent therapeutic surgery, only patients who continued to have seizures were at risk for SUDEP.³¹ No patients who had no further seizures after surgery died.
  • Right-sided mesial temporal seizure seems to carry a greater risk than left-sided mesial temporal seizure.
• Treatment
  • Levels of antiepileptic medications have been shown to be subtherapeutic in most SUDEP cases. This might be an indicator of poor compliance with medications.
  • Patients on multiple antiepileptic drugs had a significantly higher rate of SUDEP than patients with epilepsy who were not on multiple antiepileptic drugs. Also, a questionable role has been attributed to recent sudden changes in medication regimen of patients.
  • Carbamazepine has been the antiepileptic used more frequently among these patients compared with other patients with epilepsy. This might point to a possible role of this medication in death. Some side effects such as cardiac arrhythmias or sedation might be contributing.
• Studies that have compared SUDEP in children to that in adults report that children more often seem to have therapeutic blood levels of antiepileptic medications.

Table 1. Summary of Possible Risk Factors for SUDEP

Differential Diagnoses

Status Epilepticus

Follow-up

Deterrence/Prevention

• Patient education plays a significant role in preventing sudden death. Sufficient information is now available to reassure most patients, identify high-risk patients, and suggest means to reduce risk of sudden unexpected death in epilepsy (SUDEP). The issue of SUDEP needs to be discussed specifically with patients and caregivers. In a recent study, Morton et al surveyed neurologists in the United Kingdom to determine how frequently they discuss SUDEP with their epilepsy patients.³² Only 18 (4.7%) of respondents discussed SUDEP with all of their patients. It is reasonable to assume similar statistics apply to specialists in the United States. Increasing awareness of the caregivers might improve the ease that physicians discuss this possibility with their patients and help prevent this outcome.
• An open discussion with the patient is essential.³³ Each case should be considered individually. Although a better control of seizures can be reached when patient is aware of risks of SUDEP, a disclosure may casually adversely affect the quality of life.
• Optimal seizure management with effective monotherapy seems to be the goal for decreasing the risk for SUDEP. Compliance with medication and avoiding periods of decreased coverage during changes in medication regimens are essential. The importance of avoiding alcohol, drugs, seizure-provoking situations, and high-risk situations (eg, driving, swimming) needs to be emphasized.
• Caregivers need to be trained in acute management of tonic-clonic seizures, including positioning the patients during and after the attack and delivering cardiopulmonary resuscitation. Respiration needs to be monitored during the postictal period. Stimulating the patients postictally also is believed to reduce the chances of apnea. Nashef et al reported that SUDEP was far more common in an outpatient setting than in a group home setting where the staff had received vigorous training in first aid treatment of tonic-clonic seizures.³⁴

Patient Education

For excellent patient education resources, visit eMedicine's Brain and Nervous System Center. Also, see eMedicine's patient education article Epilepsy.

Multimedia

Media file 1: Factors contributing to sudden unexpected death in epilepsy (SUDEP) in seizure.

Media file 2: Factors contributing to sudden unexpected death in epilepsy (SUDEP) in baseline.

Media file 3: A combination of factors may contribute to sudden unexpected death in epilepsy (SUDEP).

References

1. Zielinski JJ. Epilepsy and mortality rate and cause of death. Epilepsia. Jun 1974;15(2):191-201. [Medline].

2. Cockerell OC, Johnson AL, Sander JW, Hart YM, Goodridge DM, Shorvon SD. Mortality from epilepsy: results from a prospective population-based study. Lancet. Oct 1 1994;344(8927):918-21. [Medline].

3. Olafsson E, Hauser WA, Gudmundsson G. Long-term survival of people with unprovoked seizures: a population-based study. Epilepsia. Jan 1998;39(1):89-92. [Medline].

4. Loiseau J, Picot MC, Loiseau P. Short-term mortality after a first epileptic seizure: a population-based study. Epilepsia. Oct 1999;40(10):1388-92. [Medline].

5. Lindsten H, Nyström L, Forsgren L. Mortality risk in an adult cohort with a newly diagnosed unprovoked epileptic seizure: a population-based study. Epilepsia. Nov 2000;41(11):1469-73. [Medline].

6. Lhatoo SD, Sander JW. Cause-specific mortality in epilepsy. Epilepsia. 2005;46 Suppl 11:36-9. [Medline].

7. Lathers CM, Schraeder PL. Verbal autopsies and SUDEP. Epilepsy Behav. Apr 2009;14(4):573-6. [Medline].

8. Kloster R, Engelskjon T. Sudden unexpected death in epilepsy (SUDEP): a clinical perspective and a search for risk factors. J Neurol Neurosurg Psychiatry. Oct 1999;67(4):439-44. [Medline].

9. Earnest MP, Thomas GE, Eden RA, et al. The sudden unexplained death syndrome in epilepsy: demographic, clinical, and postmortem features. Epilepsia. Mar-Apr 1992;33(2):310-6. [Medline].

10. Terrence CF, Rao GR, Perper JA. Neurogenic pulmonary edema in unexpected, unexplained death of epileptic patients. Ann Neurol. May 1981;9(5):458-64. [Medline].

11. Langan Y, Nashef L, Sander JW. Case-control study of SUDEP. Neurology. Apr 12 2005;64(7):1131-3. [Medline].

12. Leestma JE, Annegers JF, Brodie MJ, et al. Sudden unexplained death in epilepsy: observations from a large clinical development program. Epilepsia. Jan 1997;38(1):47-55. [Medline].

13. Johnston SC, Horn JK, Valente J, et al. The role of hypoventilation in a sheep model of epileptic sudden death. Ann Neurol. Apr 1995;37(4):531-7. [Medline].

14. So EL, Sam MC, Lagerlund TL. Postictal central apnea as a cause of SUDEP: evidence from near-SUDEP incident. Epilepsia. Nov 2000;41(11):1494-7. [Medline].

15. Tavee J, Morris H 3rd. Severe postictal laryngospasm as a potential mechanism for sudden unexpected death in epilepsy: a near-miss in an EMU. Epilepsia. Dec 2008;49(12):2113-7. [Medline].

16. Jackson JH, Beevor CE. Sudden Unexpected Death in Epilepsy. Brain. 1889;12:346.

17. Erickson T. Cardiac activity during epileptic seizure. Arch Neurol Psych. 1939;41:511-518.

18. Nei M, Ho RT, Abou-Khalil BW. EEG and ECG in sudden unexplained death in epilepsy. Epilepsia. Apr 2004;45(4):338-45. [Medline].

19. Williams J, Lawthom C, Dunstan FD, Dawson TP, Kerr MP, Wilson JF, et al. Variability of antiepileptic medication taking behaviour in sudden unexplained death in epilepsy: hair analysis at autopsy. J Neurol Neurosurg Psychiatry. Apr 2006;77(4):481-4. [Medline].

20. Devinsky O, Price BH, Cohen SI. Cardiac manifestations of complex partial seizures. Am J Med. Feb 1986;80(2):195-202. [Medline].

21. Kenneback G, Ericson M, Tomson T, et al. Changes in arrhythmia profile and heart rate variability during abrupt withdrawal of antiepileptic drugs. Implications for sudden death. Seizure. Oct 1997;6(5):369-75. [Medline].

22. Tellez-Zenteno JF, Ronquillo LH, Wiebe S. Sudden unexpected death in epilepsy: evidence-based analysis of incidence and risk factors. Epilepsy Res. Jun 2005;65(1-2):101-15. [Medline].

23. Mohanraj R, Norrie J, Stephen LJ, Kelly K, Hitiris N, Brodie MJ. Mortality in adults with newly diagnosed and chronic epilepsy: a retrospective comparative study. Lancet Neurol. Jun 2006;5(6):481-7. [Medline].

24. Vlooswijk MC, Majoie HJ, De Krom MC, Tan IY, Aldenkamp AP. SUDEP in the Netherlands: a retrospective study in a tertiary referral center. Seizure. Mar 2007;16(2):153-9. [Medline].

25. Tomson T, Nashef L, Ryvlin P. Sudden unexpected death in epilepsy: current knowledge and future directions. Lancet Neurol. Nov 2008;7(11):1021-31. [Medline].

26. Ficker DM, So EL, Shen WK, et al. Population-based study of the incidence of sudden unexplained death in epilepsy. Neurology. Nov 1998;51(5):1270-4. [Medline].

27. Neuspiel DR, Kuller LH. Sudden and unexpected natural death in childhood and adolescence. JAMA. Sep 13 1985;254(10):1321-5. [Medline].

28. Donner EJ, Smith CR, Snead OC 3rd. Sudden unexplained death in children with epilepsy. Neurology. Aug 14 2001;57(3):430-4. [Medline].

29. Hitiris N, Suratman S, Kelly K, Stephen LJ, Sills GJ, Brodie MJ. Sudden unexpected death in epilepsy: a search for risk factors. Epilepsy Behav. Feb 2007;10(1):138-41. [Medline].

30. Callenbach PM, Westendorp RG, Geerts AT, Arts WF, Peeters EA, van Donselaar CA, et al. Mortality risk in children with epilepsy: the Dutch study of epilepsy in childhood. Pediatrics. Jun 2001;107(6):1259-63. [Medline].

31. Sperling MR, Feldman H, Kinman J, et al. Seizure control and mortality in epilepsy. Ann Neurol. Jul 1999;46(1):45-50. [Medline].

32. Morton B, Richardson A, Duncan S. Sudden unexpected death in epilepsy (SUDEP): don't ask, don't tell?. J Neurol Neurosurg Psychiatry. Feb 2006;77(2):199-202. [Medline].

33. Beran RG, Weber S, Sungaran R, Venn N, Hung A. Review of the legal obligations of the doctor to discuss Sudden Unexplained Death in Epilepsy (SUDEP)--a cohort controlled comparative cross-matched study in an outpatient epilepsy clinic. Seizure. Oct 2004;13(7):523-8. [Medline].

34. Nashef L, Garner S, Sander JW, et al. Circumstances of death in sudden death in epilepsy: interviews of bereaved relatives. J Neurol Neurosurg Psychiatry. Mar 1998;64(3):349-52. [Medline].

35. Annegers JF, Coan SP. SUDEP: overview of definitions and review of incidence data. Seizure. Sep 1999;8(6):347-52. [Medline].

36. Ansakorpi H, Korpelainen JT, Suominen K, et al. Interictal cardiovascular autonomic responses in patients with temporal lobe epilepsy. Epilepsia. Jan 2000;41(1):42-7. [Medline].

37. Bacon GM. On the modes of death in epilepsy. Lancet. 1868;1:555-6.

38. Blumhardt LD, Smith PE, Owen L. Electrocardiographic accompaniments of temporal lobe epileptic seizures. Lancet. May 10 1986;1(8489):1051-6. [Medline].

39. Camfield CS, Camfield PR. Good news-a population based study indicates that SUDEP is very unusual in childhood onset epilepsy. Epilepsia. 1999;40(Suppl 7):159.

40. Camfield P, Camfield C. Sudden unexpected death in people with epilepsy: a pediatric perspective. Semin Pediatr Neurol. Mar 2005;12(1):10-4. [Medline].

41. Cockerell OC. The mortality of epilepsy. Curr Opin Neurol. Apr 1996;9(2):93-6. [Medline].

42. Day SM, Wu YW, Strauss DJ. Causes of death in remote symptomatic epilepsy. Neurology. Jul 26 2005;65(2):216-22. [Medline].

43. Devinsky O, Pacia S, Tatambhotla G. Bradycardia and asystole induced by partial seizures: a case report and literature review. Neurology. Jun 1997;48(6):1712-4. [Medline].

44. Drake ME Jr, Andrews JM, Castleberry CM. Electrophysiologic assessment of autonomic function in epilepsy. Seizure. Apr 1998;7(2):91-6. [Medline].

45. George JR, Davis GG. Comparison of anti-epileptic drug levels in different cases of sudden death. J Forensic Sci. May 1998;43(3):598-603. [Medline].

46. Hennessy MJ, Langan Y, Elwes RD, et al. A study of mortality after temporal lobe epilepsy surgery. Neurology. Oct 12 1999;53(6):1276-83. [Medline].

47. Hitiris N, Mohanraj R, Norrie J, Brodie MJ. Mortality in epilepsy. Epilepsy Behav. May 2007;10(3):363-76. [Medline].

48. Isojarvi JI, Ansakorpi H, Suominen K, et al. Interictal cardiovascular autonomic responses in patients with epilepsy. Epilepsia. Apr 1998;39(4):420-6. [Medline].

49. Langan Y, Nashef L, Sander JW. Sudden unexpected death in epilepsy: a series of witnessed deaths. J Neurol Neurosurg Psychiatry. Feb 2000;68(2):211-3. [Medline].

50. Lathers CM, Schraeder PL, Weiner FL. Synchronization of cardiac autonomic neural discharge with epileptogenic activity: the lockstep phenomenon. Electroencephalogr Clin Neurophysiol. Sep 1987;67(3):247-59. [Medline].

51. Lear-Kaul KC, Coughlin L, Dobersen MJ. Sudden unexpected death in epilepsy: a retrospective study. Am J Forensic Med Pathol. Mar 2005;26(1):11-7. [Medline].

52. Lim EC, Lim SH, Wilder-Smith E. Brain seizes, heart ceases: a case of ictal asystole. J Neurol Neurosurg Psychiatry. Oct 2000;69(4):557-9. [Medline].

53. Lip GY, Brodie MJ. Sudden death in epilepsy: an avoidable outcome?. J R Soc Med. Oct 1992;85(10):609-11. [Medline].

54. Massetani R, Strata G, Galli R, et al. Alteration of cardiac function in patients with temporal lobe epilepsy: different roles of EEG-ECG monitoring and spectral analysis of RR variability. Epilepsia. Mar 1997;38(3):363-9. [Medline].

55. Monté CP, Arends JB, Tan IY, Aldenkamp AP, Limburg M, de Krom MC. Sudden unexpected death in epilepsy patients: Risk factors. A systematic review. Seizure. Jan 2007;16(1):1-7. [Medline].

56. Nashef L, Walker F, Allen P, et al. Apnoea and bradycardia during epileptic seizures: relation to sudden death in epilepsy. J Neurol Neurosurg Psychiatry. Mar 1996;60(3):297-300. [Medline].

57. Nei M, Ho RT, Sperling MR. EKG abnormalities during partial seizures in refractory epilepsy. Epilepsia. May 2000;41(5):542-8. [Medline].

58. Nilsson L, Ahlbom A, Farahmand BY, Tomson T. Mortality in a population-based cohort of epilepsy surgery patients. Epilepsia. Apr 2003;44(4):575-81. [Medline].

59. Nilsson L, Bergman U, Diwan V. Antiepileptic drug therapy and its management in sudden unexpected death in epilepsy: a case-control study. Epilepsia. May 2001;42(5):667-73. [Medline].

60. Nilsson L, Farahmand BY, Persson PG, et al. Risk factors for sudden unexpected death in epilepsy: a case-control study. Lancet. Mar 13 1999;353(9156):888-93. [Medline].

61. Nilsson L, Tomson T, Farahmand BY, et al. Cause-specific mortality in epilepsy: a cohort study of more than 9,000 patients once hospitalized for epilepsy. Epilepsia. Oct 1997;38(10):1062-8. [Medline].

62. Novak V, Reeves AL, Novak P, et al. Time-frequency mapping of R-R interval during complex partial seizures of temporal lobe origin. J Auton Nerv Syst. Sep 24 1999;77(2-3):195-202. [Medline].

63. Opeskin K, Harvey AS, Cordner SM, et al. Sudden unexpected death in epilepsy in Victoria. J Clin Neurosci. Jan 2000;7(1):34-7. [Medline].

64. Opeskin K, Thomas A, Berkovic SF. Does cardiac conduction pathology contribute to sudden unexpected death in epilepsy?. Epilepsy Res. Jun 2000;40(1):17-24. [Medline].

65. Schernthaner C, Lindinger G, Potzelberger K, et al. Autonomic epilepsy--the influence of epileptic discharges on heart rate and rhythm. Wien Klin Wochenschr. May 21 1999;111(10):392-401. [Medline].

66. Schraeder PL, Delin K, McClelland RL. Coroner and medical examiner documentation of sudden unexplained deaths in epilepsy. Epilepsy Res. Feb 2006;68(2):137-43. [Medline].

67. Schraeder PL, Lathers CM. Paroxysmal autonomic dysfunction, epileptogenic activity and sudden death. Epilepsy Res. Jan-Feb 1989;3(1):55-62. [Medline].

68. Smith WS, Matthay MA. Evidence for a hydrostatic mechanism in human neurogenic pulmonary edema. Chest. May 1997;111(5):1326-33. [Medline].

69. So EL. Demystifying sudden unexplained death in epilepsy--are we close?. Epilepsia. 2006;47 Suppl 1:87-92. [Medline].

70. Stollberger C, Finsterer J. Cardiorespiratory findings in sudden unexplained/unexpected death in epilepsy (SUDEP). Epilepsy Res. Mar 2004;59(1):51-60. [Medline].

71. Tennis P, Cole TB, Annegers JF, et al. Cohort study of incidence of sudden unexplained death in persons with seizure disorder treated with antiepileptic drugs in Saskatchewan, Canada. Epilepsia. Jan 1995;36(1):29-36. [Medline].

72. Thom M, Griffin B, Sander JW, et al. Amygdala sclerosis in sudden and unexpected death in epilepsy. Epilepsy Res. Oct 1999;37(1):53-62. [Medline].

73. Thom M, Seetah S, Sisodiya S, Koepp M, Scaravilli F. Sudden and unexpected death in epilepsy (SUDEP): evidence of acute neuronal injury using HSP-70 and c-Jun immunohistochemistry. Neuropathol Appl Neurobiol. Apr 2003;29(2):132-43. [Medline].

74. Timmings PL. Sudden unexpected death in epilepsy: is carbamazepine implicated?. Seizure. Aug 1998;7(4):289-91. [Medline].

75. Tomson T. Mortality in epilepsy. J Neurol. Jan 2000;247(1):15-21. [Medline].

76. Tomson T, Ericson M, Ihrman C, et al. Heart rate variability in patients with epilepsy. Epilepsy Res. Mar 1998;30(1):77-83. [Medline].

77. Tomson T, Walczak T, Sillanpaa M. Sudden unexpected death in epilepsy: a review of incidence and risk factors. Epilepsia. 2005;46 Suppl 11:54-61. [Medline].

78. Téllez-Zenteno JF, Ronquillo LH, Wiebe S. Sudden unexpected death in epilepsy: evidence-based analysis of incidence and risk factors. Epilepsy Res. Jun 2005;65(1-2):101-15. [Medline].

79. Walczak T. Do antiepileptic drugs play a role in sudden unexpected death in epilepsy?. Drug Saf. 2003;26(10):673-83. [Medline].

80. Walczak TS, Leppik IE, D'Amelio M, Rarick J, So E, Ahman P, et al. Incidence and risk factors in sudden unexpected death in epilepsy: a prospective cohort study. Neurology. Feb 27 2001;56(4):519-25. [Medline].

81. Walczak TS, Leppik IE, D'Amelio M, Rarick J, So E, Ahman P. Incidence and risk factors in sudden unexpected death in epilepsy: a prospective cohort study. Neurology. Feb 27 2001;56(4):519-25. [Medline].

82. Walker F, Fish DR. Recording respiratory parameters in patients with epilepsy. Epilepsia. 1997;38(Suppl 11):41-42.

83. Weber P, Bubl R, Blauenstein U. Sudden unexplained death in children with epilepsy: A cohort study with an eighteen-year follow-up. Acta Paediatr. May 2005;94(5):564-7. [Medline].

Keywords

epilepsy death, SUDEP, antiepileptic medication, antiepileptic drugs, AEDs, cardiac arrhythmia, pulmonary edema, unexpected seizure, apnea, sudden unexpected death in epilepsy, epilepsy, epilepsy-related death

Contributor Information and Disclosures

Author

Shahin Nouri, MD, Director, Comprehensive Epilepsy Center, Associate Chief, Division of Neurology, New York Methodist Hospital
Shahin Nouri, MD is a member of the following medical societies: American Academy of Neurology and American Epilepsy Society
Disclosure: UCB Honoraria Speaking and teaching; Pfizer Honoraria Speaking and teaching

Coauthor(s)

Marshall Balish, MD, PhD, Assistant Chairman, Assistant Professor, Department of Neurology, Washington Veterans Affairs Medical Center, Georgetown University
Disclosure: Nothing to disclose.

Medical Editor

Erasmo A Passaro, MD, Director, Comprehensive Epilepsy Program/Clinical Neurophysiology Lab, Bayfront Medical Center Florida Center for Neurology
Erasmo A Passaro, MD is a member of the following medical societies: American Academy of Neurology, American Academy of Sleep Medicine, American Clinical Neurophysiology Society, American Epilepsy Society, American Medical Association, and American Society of Neuroimaging
Disclosure: Glaxo Smith Kline Honoraria Speaking and teaching; UCB Honoraria Speaking and teaching; Pfizer Honoraria Speaking and teaching; Takeda Honoraria Speaking and teaching

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Jose E Cavazos, MD, PhD, FAAN, Associate Professor with Tenure, Departments of Neurology, Pharmacology, and Physiology, University of Texas Health Science Center at San Antonio; Co-Director, South Texas Comprehensive Epilepsy Center; Director of the Epilepsy Center, Audie L Murphy Veterans Affairs Medical Center
Jose E Cavazos, MD, PhD, FAAN is a member of the following medical societies: American Academy of Neurology, American Clinical Neurophysiology Society, American Epilepsy Society, and Society for Neuroscience
Disclosure: Nothing to disclose.

CME Editor

Selim R Benbadis, MD, Professor, Director of Comprehensive Epilepsy Program, Departments of Neurology and Neurosurgery, University of South Florida School of Medicine, Tampa General Hospital
Selim R Benbadis, MD is a member of the following medical societies: American Academy of Neurology, American Academy of Sleep Medicine, American Clinical Neurophysiology Society, American Epilepsy Society, and American Medical Association
Disclosure: Nothing to disclose.

Chief Editor

Selim R Benbadis, MD, Professor, Director of Comprehensive Epilepsy Program, Departments of Neurology and Neurosurgery, University of South Florida School of Medicine, Tampa General Hospital
Selim R Benbadis, MD is a member of the following medical societies: American Academy of Neurology, American Academy of Sleep Medicine, American Clinical Neurophysiology Society, American Epilepsy Society, and American Medical Association
Disclosure: Nothing to disclose.

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