AUTHOR AND EDITOR INFORMATION

Section 1 of 7  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Follow-up
• Multimedia
• References

INTRODUCTION

Section 2 of 7  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Follow-up
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Background

Patients with epilepsy have a mortality rate 2-3 times that of the general population. Epilepsy-related causes of death in this population account for 40% of the deaths and include the following:

• Death due to the underlying disease 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 the following 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, 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 al and Earnest 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. 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% 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

Only a small portion of definite SUDEP cases have been documented as witnessed. Langen et al have reported 15 cases of witnessed SUDEP. Eighty percent of these patients had a seizure immediately before death. Terrence reported 24% and Leetsma reported 38% of witnessed deaths to be an immediate consequence of a seizure attack. Kloster reported evidence of recent seizures (ie, witnessed, oral trauma, cyanosis) in 67% of victims. However, in all witnessed deaths, seizures stopped before death, and in many cases patients regained consciousness. The immediate event before death was respiratory arrest (obstructive and central) in a few witnessed cases. The majority of victims were reported to have difficulty breathing before death. Attempts at cardiopulmonary resuscitation were unsuccessful.

Different 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. Antiepileptic medication may be another risk factor.

The interaction between the autonomic control of the cardiovascular functions and the seizure phenomenon is very complex. This is discussed in more detail in the article Epilepsy and the Autonomic Nervous System.

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. 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. 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% [Earnest, 1992], 71% [Kloster and Engelskjon, 1999]). The prone position may affect ventilation by obstructing the upper respiratory tract as well as increasing the chances of aspiration.

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. Erickson systematically studied ictal ECG changes for the first time. 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. To ascertain the true role of cardiac arrhythmia as an immediate event before death, further investigations must be carried out.

Medications

The subtherapeutic levels of antiepileptic agents in SUDEP patients might be a reflection of poor seizure control or poor compliance. Antiepileptic medications potentially play a role in modification of the ANS 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. 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. Seizure threshold also might diminish, leading to rebound effect and increase in seizure frequency.

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.
• A recent seizure might cause central apnea, often associated with bradyarrhythmias.
• Use of carbamazepines is associated with impaired cardiac regulation and with increased risk of SUDEP.

These interactions can be summarized as the events directly related to seizures (see Image 1) and the baseline (see Image 2).

Frequency

United States

SUDEP accounts for 8-17% of deaths in people with epilepsy. The incidence seems to be higher in younger patients.

• Few studies have investigated the incidence of SUDEP. 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. The incidence of SUDEP is estimated to be 0.35 per 1000 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 1000 person-years of follow-up. This translates to a range of 1 in 370 to 1100 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. They reported an incidence of 5.6 per 1000 person-years of follow-up and an SMR 40 times higher in people with SUDEP than in the general population.

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. SUDEP is very rare in children.

CLINICAL

Section 3 of 7  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Follow-up
• Multimedia
• References

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 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 is a more frequent behavior in patients with SUDEP than in the general population of patients with epilepsy.
• 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 1000 for patients with idiopathic seizures.
  • Generalized seizures, lower age of onset of seizures, duration of seizure disorder longer than 10 years, 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. 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.
• Medications
• • 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
  

  Patient-related	Young (25-35 y) Male Developmentally delayed African American
  Seizure-related	Symptomatic epilepsy Seizure type - Generalized tonic-clonic Younger age of seizure onset Duration of seizure disorder - Longer than 10 y Higher number of seizures Recent seizures
  Treatment-related	Subtherapeutic serum level of antiepileptic medication Higher number of antiepileptic medications Recently changed Other treatment Surgery Higher serum levels of carbamazepine

DIFFERENTIALS

Section 4 of 7  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Follow-up
• Multimedia
• References

FOLLOW-UP

Section 5 of 7  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Follow-up
• Multimedia
• References

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 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. 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.
• 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.

Patient Education

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

MULTIMEDIA

Section 6 of 7  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Follow-up
• Multimedia
• References

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

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

Media file 3:  A combination of factors may contribute to sudden unexpected death in epilepsy (SUDEP).
	View Full Size Image
Media type:  Graph

REFERENCES

Section 7 of 7

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Follow-up
• Multimedia
• References

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Article Last Updated: May 17, 2006