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Review article

current concepts

Sudden, Unexpected Death in Epilepsy


Orrin Devinsky, M.D.

pilepsy is characterized by both recurrent seizures and clinical uncertainty. Paroxysmal symptoms unpredictably punctuate life. Although most people with epilepsy live full and productive lives, doctors may too readily assure patients that seizures never hurt the brain and are never fatal. Over time, convulsive seizures can progressively impair cognition and behavior and alter brain structure.1 In rare cases, seizures can be fatal. Sudden, unexpected death in epilepsy refers to a death in a patient with epilepsy that is not due to trauma, drowning, status epilepticus, or other known causes but for which there is often evidence of an associated seizure. The event may be unwitnessed, and the person is often found dead in bed. A finding of sudden, unexpected death in epilepsy is definite when clinical criteria are met and autopsy reveals no alternative cause of death, such as stroke, myocardial infarction, or drug intoxication, although there may be evidence of a seizure (e.g., a bitten tongue or pulmonary edema).2 Sudden, unexpected death in epilepsy is probable when clinical criteria are met but there is no autopsy, and it is possible when there is an alternative cause of death or when clinical data are lacking.3 The incidence of sudden, unexpected death in epilepsy is probably underestimated because records and databases are incomplete and because it often goes unrecognized by coroners, medical examiners, and physicians who are unaware of the disorder or its diagnostic criteria. The incidence per 1000 patient-years varies with the sample population, increasing from 0.09 to 2.65 in community samples to 1.2 to 5.9 in tertiary care epilepsy centers to 6.0 to 9.3 among patients evaluated for or treated with surgery or vagus-nerve stimulation for epilepsy (Fig. 1).3-13 The rate of sudden, unexpected death increases with the duration and severity of epilepsy. It is much less common in children than in adults5,9,14; among children with epilepsy who are younger than 14 years of age, cases of sudden, unexpected death are rare and are largely restricted to children who have a major neurologic impairment or a history of a major neurologic insult.5,9,14 Like adults, most children in whom sudden, unexpected death in epilepsy is diagnosed die in bed and have a history of generalized tonicclonic seizure.5 Sudden, unexpected death contributes to the increased mortality among children with disorders associated with both treatment-resistant epilepsy and developmental delay, such as autism, the Dravet syndrome, tuberous sclerosis complex, and chromosome 15q11-13 duplication.9,15,16 The magnitude of the problem of sudden, unexpected death in epilepsy is unrecognized in the medical and lay communities. In a population-based cohort of children with epilepsy who were followed for 40 years, sudden, unexpected death occurred in 9% of patients and accounted for 38% of all deaths.9 Although the epilepsy began in childhood, almost all the deaths occurred in adulthood. Among high-risk patients with major neurologic disorders (e.g., mental retardation or cerebral palsy) or treatment-resistant epilepsy, rates of sudden, unexpected death can exceed 10% per decade.4,9 By comparison, the risk of death from surgery for epilepsy
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From the Department of Neurology, NYU Langone School of Medicine, New York. Address reprint requests to Dr. Devinsky at the Department of Neurology, NYU Langone School of Medicine, 223 E. 34th St., New York, NY 10016, or at od4@nyu.edu. N Engl J Med 2011;365:1801-11.
Copyright 2011 Massachusetts Medical Society.

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Figure 1. Incidence of Sudden, Unexpected Death in Epilepsy According to Population Type. Data are based on the pooled results of 23 studies, cited in Sillanp and Shinnar9 and Tomson et al.11 Numbers in parentheses indicate the number of studies for each population. I bars denote 95% confidence intervals.

is approximately 1 death per 1500 procedures; the monthly risk of death for patients at very high risk for sudden, unexpected death is approximately 1 in 2000.

R isk Fac t or s a nd Mech a nisms


Seizure

Evidence from epidemiologic, observational, clinical, and pathological studies strongly suggests that in most cases, sudden, unexpected death in epilepsy occurs after a seizure, usually a tonic clonic seizure (Table 1). In casecontrol studies, the most consistent risk factor is an increased frequency or recent history of seizure, especially tonicclonic seizure (Table 1).11,12,17,19,34,35 Among patients who have had more than three tonic clonic seizures in the preceding year, the risk of sudden, unexpected death is increased by a factor of more than 8.13 Additional risk factors include lack of treatment with antiepileptic drugs or subtherapeutic levels of such drugs, antiepileptic-drug
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polytherapy, frequent changes in antiepileptic drugs, early adulthood, epilepsy of long duration, and mental retardation (Table 1).11,12,18-20 Among 15 cases of sudden, unexpected death in epilepsy that were witnessed in the community, the death was preceded by a tonicclonic seizure in 12 persons and was postictal in 2; 1 person shouted, Im going to have a seizure, before collapsing.27 Difficulty breathing was observed in 80% of these cases,27 with 70% of patients found in a prone position,18 suggesting that suffocation contributed to their deaths. Half of witnessed cases in children were preceded by a tonicclonic seizure, whereas the other half were preceded by sudden loss of consciousness.5 Seizure can cause apnea or arrhythmia without convulsive activity. In six infants, there were 23 life-threatening events in which hypoxemia and apnea followed seizure recorded on electroencephalography (EEG) and in which other clinical features were subtle or absent.36 The only cardiac change was tachycardia, which supports the theory that a seizureinduced respiratory mechanism may be involved in pediatric cases of sudden, unexpected death in epilepsy.36 There is no definite documentation of an unexpected death that was not preceded by a seizure. Although witnesses have reported deaths that were not observed to be preceded by seizure, such an event has not been captured in the millions of hours of video and ambulatory EEG recordings obtained each year from patients with epilepsy. In separate case reports of 13 patients in epilepsy-monitoring units, 8 died suddenly, and 5 were resuscitated after a life-threatening episode. These cases may not accurately reflect the course of sudden, unexpected death in the community, since most of the patients in the study had treatment-resistant epilepsy and underwent rapid withdrawal of medication. However, recorded cases do provide valuable information on the mechanisms of these deaths. Each of the 13 patients had seizures just before death: 12 had tonicclonic seizures and 1 had complex partial seizures11,21,27-33,37; 10 of the patients had two or more seizures the day before they died, and most of the patients died during sleep. Patients who were successfully resuscitat ed were younger than those who died (mean age, 29 years vs. 43 years); older patients may be more vulnerable to seizure-induced cardiopulmonary or brain dysfunction. Electrocardiography (ECG) was usually performed during video EEG, with the patients respiratory effort assessed through visual

Incidence (per 1000 person-yr)

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current concepts

Table 1. Risk Factors for and Mechanisms of Sudden, Unexpected Death in Epilepsy.* Risk Factor or Mechanism Epidemiologic Studies Seizure, especially GTCS Frequent seizures, recent seizure, long postictal EEG suppression Terminal seizure Prone position after seizure Postictal breathing problem Postictal cardiac arrhythmia Environment Lack of nighttime supervision or monitoring Location (in bed or sleeping) Antiepileptic-drug therapy Lack of use or subtherapeutic levels Polytherapy Frequent changes in regimen Rapid withdrawal Other factors or mechanisms Early adulthood Early onset of epilepsy Long duration of epilepsy** Neurologic status Intelligence quotient <70 Nonambulatory Major neurologic insult Carbamazepine or lamotrigine Yes Yes Yes Yes No No No No No No No No Yes Yes Yes Yes No No Yes No No Yes Yes Yes No Yes No No Yes No No No No Yes Yes No Yes No Yes Yes Yes Yes Yes Yes No Source of Data Video EEG Yes Yes Yes Yes Yes Yes Witness Yes Yes Yes Yes Yes No

* The term No indicates that there is a lack of evidence for the risk factor or mechanism. EEG denotes electroencephalography, and GTCS generalized tonicclonic seizure. The epidemiologic data were reported by Sillanp and Shinnar,9 Tomson et al.,11,12 Walczak et al.,13 Camfield and Camfield,14 Hitiris et al.,17 Kloster and Engelskjn,18 Nilsson et al.,19 Langan et al.,20 Lhatoo et al.,21 Nei et al.,22 Ryvlin et al.,23 Aurlien et al.,24 Opeskin et al.,25 and Nilsson et al.26 The video EEGs were summarized or reported by Tomson et al.,11 Langan et al.,27 Bateman et al.,28 Bird et al.,29 Espinosa et al.,30 So et al.,31 Tao et al.,32 and Thomas et al.33 The witnessed cases of sudden death were reported by Annegers,3 Donner et al.,5 and Langan et al.27 The addition of treatment with an antiepileptic drug in the preceding 3 months is associated with a lower risk of sudden death.23 Early onset refers to onset before 15 years of age. ** Long duration refers to a duration of more than 15 to 30 years.

inspection. Respiratory problems predominated in 8 patients, who underwent postictal hypoventilation, apnea, cyanosis, inspiratory stridor, laryngospasm, pulmonary edema, or suffocation.11,21,32,33,38 Shutdown of brain function, with severe, diffuse EEG attenuation, was considered the primary cause of death in 2 cases; 1 patient showed no movement while lying prone postictally and had a pulse of 47 beats per minute; an autopsy revealed pulmonary edema.11,29 Cardiac abnormalities, such

as peaked T waves, ST-segment elevation, and asystole, usually followed collapse or, less often, coincided with respiratory problems.11,28-31 Ventricular arrhythmia came close to causing sudden death in 1 patient, who had a convulsion that lasted 4.5 minutes, at which point ventricular tachycardia progressed to fibrillation.30 In 2 patients, multiple mechanisms may have led to sudden death.21,37 The view that terminal seizure plays a role in cases of sudden, unexpected death in epilepsy is
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Increased seizures AEDs or abrupt changes in AEDs Prolonged postictal state Acquired changes in brain function Acquired autonomic dysfunction Genetics

Simple or complex partial seizure

Cardiac arrhythmia Death Hypoventilation or hypoxia

Generalized tonicclonic seizure

Cerebral shutdown Central apnea

Chronic epilepsy

Obstructive apnea Asphyxia Pulmonary edema

Figure 2. Mechanisms of Seizure-Induced Death. Sudden, unexpected death often follows a seizure in patients with chronic epilepsy (orange). Potential risk factors associated with chronic epilepsy (blue) and direct effects from seizures (green, pink, and purple) probably interact in various ways to cause death, which is probably a result of cerebral shutdown, hypoventilation and hypoxia, cardiac arrhythmia, or some combination thereof. AED denotes antiepileptic drug.

supported by the fact that levels of heat-shock protein 70 in hippocampal neurons are elevated in such cases.39 Seizure can cause pulmonary edema,40,41 which is the most common autopsy finding in such cases.7,17,18 It remains uncertain whether sudden death occurs without a terminal seizure. Excluding cases in which there is a terminal seizure, the rate of sudden, unexpected death among patients with epilepsy may be similar to that in the general population. Determining the precise mechanism of death is difficult, even for cases that were recorded on video EEG. In most cases, there is no monitoring of blood pressure or respiratory function, and the findings on ECG are often restricted to a single channel riddled with artifact. A respiratory disorder such as hypoventilation could go unnoticed while cardiac arrhythmia, which is actually sec1804
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ondary, is considered causative (or vice versa). In addition to cardiorespiratory causes and cerebral shutdown, genetic, drug, metabolic, and environmental factors, as well as multifactorial processes, may contribute to sudden, unexpected death in patients with epilepsy (Fig. 2).
Respiratory Factors

The concept of impaired respiration as a cause of death is supported by data from studies in animals and evidence from most witnessed and recorded instances of sudden, unexpected death in epilepsy (Table 2).27,28-33 Seizure-induced respiratory changes can be lethal and may involve pulmonary dysfunction and suppression of brainstem respiratory and arousal centers.40 In sheep, prolonged seizures cause elevated pressure in the left atrial and pulmonary arteries, pulmonary edenovember 10, 2011

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current concepts

Table 2. Suggested Mechanisms of Impaired Respiration in Sudden, Unexpected Death in Epilepsy (SUDEP). Mechanism Respiratory problems (respiratory arrest, labored breathing, suffocation in prone position, laryngeal spasm) are recorded in most instances of near and actual SUDEP on video EEG. Respiratory problems are reported in most witnessed incidents of SUDEP. Most incidents occur during sleep and patient is usually found prone, supporting suffocation as contributing cause of death. Lack of monitoring increases risk (repositioning and stimulation can improve respiration but cannot relieve arrhythmia). Hypercarbia and hypoxemia are common after seizures. Prolonged generalized EEG suppression is a risk factor (brain stem initiates breathing and arousal; the heart can function autonomously). Infants with seizure-induced life-threatening events have hypoxemia and apnea, not arrhythmias. Pulmonary edema is the most common autopsy finding. Video-EEG recordings infrequently show cardiac problem as primary cause of SUDEP. Source of Data Tomson et al.,11 Langan et al.,27 Bateman et al.,28 Thomas et al.33 Langan et al.27 Kloster and Engelskjn,18 Langan et al.27 Nashef et al.,7 Langan et al.20 Hewertson et al.,36 Bateman et al.28 Lhatoo et al.21 Hewertson et al.36 Nashef et al.,7 Hitiris et al.,17 Kloster and Engelskjn18 Langan et al.,27 Bateman et al.,28 Bird et al.,29 Espinosa et al.,30 So et al.,31 Tao et al.,32 Thomas et al.33

ma, tachycardia, and death from hypoventilation.42 Serotonergic neurons that modulate breathing and arousal may be involved in sudden, unexpected death in epilepsy, as is the case with sudden infant death syndrome.40,43 Some serotonergic neurons stimulate respiratory nuclei in the brain stem, whereas others, activated by hypercapnia, contribute to the ascending arousal system.44 Postictal depression of serotonergic activity can impair respiration and reflexive repositioning if the mouth and nose are obstructed by bedding. In some mouse strains, sound-induced seizure arrests respiration an effect that is reduced by selective serotoninreuptake inhibitors (SSRIs) and 5-HT2C receptor agonists.45 Among patients with epilepsy, use of an SSRI is associated with reduced oxygen desaturation during partial seizure but not during tonic clonic seizure.46
Cerebral Shutdown

ratory effort, possibly from ventilationperfusion inequality, which is caused by right-to-left pulmonary shunting or neurogenic pulmonary edema.47 Sudden, unexpected death has been reported in a patient with epilepsy who had postictal pulmonary edema.36 Postictal hypercapnia can cause severe acidosis that is arrhythmogenic.48 The effects of prolonged postictal EEG suppression, apnea, pulmonary shunting and edema, suffocation in the prone position, impaired arousal to hypercapnia, laryngeal spasm, and respiratory acidosis probably combine and cascade with cardiac factors to cause many cases of sudden, unexpected death in patients with epilepsy (Table 2 and Fig. 2).
Cardiac Factors

Seizure and the postictal state can affect brainstem respiratory centers. Central apneas or hypop neas complicate most seizures.38 In one study, patients with epilepsy who died suddenly had longer periods of postictal generalized EEG suppression than did patients with epilepsy who did not die suddenly.21 Respiration depends on brain-stem activity; prolonged suppression of activity stops respiration. Postictal shutdown of cerebral and brain-stem function may be related to the mechanisms that stop seizures. Postictal hypercapnia and hypoxemia can occur despite increased respi-

Cardiac events are considered to be likely culprits in some instances of sudden, unexpected death in patients with epilepsy.4,11,12,30,48,49 Seizure-induced arrhythmias occur in animals and humans,49,50 but in 13 case studies of near and actual sudden death in patients with epilepsy, only 1 incident was clearly due to a cardiac event.30 Hypoxemia could lower the threshold for cardiac arrhythmias during seizure, especially in patients with channelopathies affecting both brain and cardiac tissue (e.g., long-QT syndrome type 2).51 Mice lacking the Kv1.1 potassium channel have severe seizures and die prematurely, possibly because of cardiac arrhythmias.48 Interictal and ictal cardiovascular changes occur in patients with epilepsy,49,50 in1805

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cluding prolongation of the QT interval corrected for heart rate (QTc) during the ictal and interictal periods and shortening of the QTc interval postictally.52-54 Ictal asystole occurs during video EEG in 0.1 to 0.4% of patients, but recurrence is rare after pacemaker implantation.49,55 Patients with epilepsy who die suddenly have rates of cardiac repolarization abnormalities and arrhythmias that are similar to those among other patients with epilepsy,22,53 but sudden death is associated with more severe tachycardia during nocturnal seizures.22 Intense seizures may cause greater activation of the sympathetic nervous system, possibly contributing to cardiopulmonary dysfunction56 and to prolonged suppression of brain activity,38 which can in turn cause apnea and impair arousal while the heart functions independently. Intense seizures may also trigger greater compensatory responses (e.g., elevated adenosine levels), and these responses may contribute to sudden death.57
Other Risk Factors

The severity of epilepsy partly explains some of the risk factors for sudden death, such as tonic clonic seizures, frequent seizures, early onset and long duration of epilepsy, and polytherapy, but some factors probably contribute to the risk of sudden death directly. Tonicclonic seizure is often documented immediately before sudden death, suggesting that seizures are responsible for many cases. The association of early onset and long duration of epilepsy with an increased risk of sudden death suggests that progressive neural changes contribute to the risk. Although polytherapy is a mark of treatment-resistant epilepsy, treatment with three or more antiepileptic drugs has been found to increase the risk of sudden death by a factor of more than 8 after adjustment for seizure frequency.19 However, in randomized, controlled trials involving patients with treatment-resistant epilepsy, the rate of sudden death was increased by a factor of more than 7 among patients who received placebo as compared with those who received an additional antiepileptic drug.23 The effects of the number of drugs taken, the frequency of dose changes, and the recent removal or addition of drugs on the risk of sudden death require further investigation. Sudden, unexpected death in epilepsy usually occurs in chronic, severe cases of epilepsy, often in patients with a history of neurologic insult. Thus, such deaths may result from the cumulative
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effects of seizures compounded by a tonicclonic seizure (i.e., the additive effect of acute injury after chronic injury). Frequent tonicclonic seizures can progressively damage brain structure (e.g., atrophy of the hippocampus) and function (e.g., impairment of short-term memory).1 Since greater interictal autonomic changes occur in patients with chronic epilepsy than in those with recent-onset epilepsy,35 there may also be progressive changes in the brain-stem areas that regulate cardiorespiratory function and arousal. However, sudden death can occur early in the course of epilepsy and in patients who have seizures only rarely. It is not known why sudden death occurs in some patients after only a few seizures, whereas others are spared despite a lifetime of tonic clonic seizures. Genetic susceptibility (e.g., cardiac channelopathy), alcohol use, medication withdrawal, and fever may increase the risk of sudden death after a seizure, but these potential risk factors have not been adequately studied. Regarding genetic susceptibility, mutations in the ionchannel genes expressed in brain and cardiac tissue may underlie susceptibility to epilepsy, brainstem autonomic dysfunction, and cardiac arrhythmias.51 Abnormalities in the serotonergic system have been found in patients with epilepsy or depression and in cases of sudden death.40 Patients with epilepsy who have been treated for depression within the past 12 months have a 40% increase in the risk of death, as compared with those who have not been treated for depression.58 Carbamazepine, which has been associated with sudden death among patients with epilepsy in some studies,11,22 can suppress autonomic functions.59 Lamotrigine is also associated with an increased risk of sudden death among patients with epilepsy in some studies.24,60

Sudden, Une x pec ted, Sei zur e-Induced De ath


In most cases, when sudden death occurs after a seizure, it is more precisely defined as sudden, unexpected, seizure-induced death. Use of this term can be important in helping to make patients and their families aware of the potential danger of seizure and to increase public awareness of the disorder. The phrase sudden, unexpected death in epilepsy communicates the message that some people with epilepsy die unexpectedly for unknown reasons, but sudden death also occurs

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current concepts

in people who are or appear to be healthy and complicates our understanding of many medical disorders. In contrast, the use of the phrase sudden, unexpected, seizure-induced death underscores the fact that seizure is involved in death and thereby lays the path for education about prevention. Sudden, unexpected, seizure-induced death should be considered to be a type of seizure-induced death, along with those due to status epilepticus, drowning, motor-vehicle accidents, trauma, burns, and suicide during a postictal psychosis.

Pr e v en t ion
We do not know how to prevent sudden, unexpected death in epilepsy. No prospective or controlled studies have evaluated interventions to reduce its incidence. Since a tonicclonic seizure precedes most sudden deaths in patients with epilepsy, seizure control and the appropriate use of medication as well as counseling on lifestyle is the focus of prevention (Table 3). The lack of therapeutic levels of antiepileptic drugs, nonadherence to treatment regimens, and frequent changes in regimens are all risk factors for sudden death.9,11,12,19,20,25 For patients who have never been treated with antiepileptic drugs, the risk of sudden death may be more than 20 times as high as that for treated patients.20 A discussion of sudden, unexpected death in epilepsy may be worthwhile for patients with tonicclonic seizures who are beginning an antiepileptic-drug regimen and for patients at high risk for recurrent tonicclonic seizures who are discontinuing such a regimen. Thirty percent of patients with epilepsy have treatment-resistant epilepsy, and these patients who are at high risk for sudden death present the greatest challenge. Frequent changes in multidrug regimens are commonly undertaken to reduce the frequency of seizure or the side effects of medication, but the potential effects of regimen changes on the risk of sudden death are rarely considered and remain unknown. Patients who are free of seizures after surgery for epilepsy have reduced rates of sudden death,8,10,62 with mortality approaching that in the general population. In contrast, patients with postoperative seizures have very high rates of sudden death.62 Patients should be informed about the fundamentals of seizure prevention: observance of a

healthful lifestyle (e.g., avoiding sleep deprivation and excessive consumption of alcohol), adherence to their antiepileptic-drug regimen (e.g., avoiding and identifying missed doses with the use of weekly pill boxes and watch alarms), knowledge of how to make up for missed doses and of factors influencing drug levels, and avoidance of drugs that lower the threshold for seizure. Patients should also be asked whether they have symptoms of nocturnal tonicclonic seizure. For patients who do have nocturnal tonicclonic seizure, bedtime medication doses can be increased and seizuredetection devices (discussed below) considered. Educating persons who live with patients with epilepsy may also help to prevent sudden death. Knowledge of how to perform the appropriate first-aid responses to seizure (repositioning the patient and protecting the airway after a tonic clonic seizure) may prevent death. A casecontrol study of adults showed that as compared with unmonitored controls, patients who were monitored while they slept had a reduced risk of sudden death by a factor of 2.5 if another person older than 10 years of age was in the room and by a factor of 10 if there were frequent nighttime checks or if a sound-monitoring device was used.20 In a study of 14 residents at a special-needs school who had severe epilepsy and died suddenly, all 14 died at home, and most of them were not being monitored.7 None died at school, where they were monitored during sleep by four attendants and an on-call nurse and a sound-monitoring device was used. The manufacturers of several commercial devices state that their products can detect tonicclonic seizure, but very limited data are available on the sensitivity and specificity of these devices for the detection of tonicclonic seizure,63 and there is no evidence that their use prevents sudden death. Patients with nocturnal tonicclonic seizure may want to consider the use of motion-detection devices (e.g., the Emfit monitor [Emfit]) that have a configurable sensing unit that is placed under the mattress and a receiver located in another room with audiovisual alarms. Pulse oximeters and heart-rate monitors may detect seizure-induced hypoxemia and tachycardia. Nonetheless, sudden death occurs in hospitals and other medical environments, despite prompt attempts at resuscitation.11 The effectiveness of strategies intended to prevent sudden death by improving respiration or oxygenation remain unproven. Since many pa1807

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Preventive Strategy Improve adherence to medication regimen; recommend lifestyle modifications regular, restorative sleep and limitation of alcohol consumption; optimize antiepileptic-drug regimen; consider epilepsy surgery, dietary therapy, or neurostimulation Consider use of rescue medications Consider use of benzodiazepine rescue medications; urge patient to seek prompt medical attention when appropriate Educate patient about drug interactions (e.g., oral contraceptives lower lamotrigine levels)61 and the effects of vomiting and diarrhea on drug absorption Rescue medications include clonazepam (oral, dissolving wafer), diazepam (buccal solution or rectal gel), lorazepam (oral tablet or liquid), and midazolam (nasal spray, buccal solution)* A redosing strategy is recommended for missed medications or medications lost to vomiting or severe diarrhea Comment Indications that a patient may be having nocturnal seizures without awareness of them are urinary incontinence, tongue or cheek bites, unusual headaches, muscle soreness, lethargy, or confusion on awakening; ask the patient whether any of these conditions apply Redistribute or increase evening or bedtime medication Develop strategies to ensure adherence to medication regimen, especially evening and bedtime doses Educate the patient about the importance of adhering to medication regimen and observing healthy lifestyle A sound or seizure monitor may be considered, but the sensitivity and specificity of these monitors for seizure detection is uncertain, as is their role in preventing sudden death Drugs that lower the seizure threshold (e.g., phenylephrine, pseudoephedrine, bupropion) should be avoided A redosing strategy is recommended for missed medications or medications lost to vomiting or severe diarrhea Consider dose increase; advise patient to adhere to medication regimen and explain what should be done if medications are missed or if patient has gastrointestinal illness that causes vomiting or diarrhea Optimize and simplify the regimen and avoid frequent changes Recommend that caregivers monitor the patient (e.g., with a sound monitor) Reposition the patient to lie on side or stimulate patient; for apnea or severe hypo ventilation, initiate cardiopulmonary resuscitation Recommend a cardiac monitor or, for patients with life-threatening arrhythmia, a pacemaker Consider use of a seizure monitor Consider use of a seizure or respiratory monitor or lattice pillows

Table 3. Prevention of Sudden, Unexpected Death in Epilepsy.

Risk Factor

Generalized tonicclonic seizure and uncontrolled seizure

Seizure clusters, prolonged seizure

Fluctuating levels of antiepileptic drugs

Nocturnal seizure
The

Unidentified

Identified

Sleeping alone, especially with history of nocturnal seizure

Breakthrough seizure

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Low levels of antiepileptic drugs

of

Frequent changes in antiepileptic drugs

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Mental retardation, nonambulatory status

Prone position, suffocation after seizure

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Cardiac arrhythmia, asystole

* Rescue medications have a rapid onset and are used to treat prolonged seizure or seizure clusters. The nasal and buccal forms of midazolam have not been approved in the United States. In pregnancy, many drug levels decline; levels should be closely monitored and dose increased to maintain a therapeutic level. The efficacy of seizure and respiratory monitors has not been proved for the detection of seizure or the prevention of sudden, unexpected death in epilepsy. The efficacy of lattice pillows has not been proved for the prevention of suffocation.

current concepts

tients are found prone, some practitioners advocate the use of antisuffocation pillows (e.g., see www.sleep-safe.co.uk) for the prevention of sudden death in epilepsy, but data on their clinical value are lacking. The potential role of oxygen administration during and after a tonicclonic seizure a common practice in hospitals but not in patients homes deserves study. Routine ECG screening of all patients with epilepsy is of uncertain value. Patients with tonic clonic seizure or episodic loss of consciousness who have normal or nonspecific findings on magnetic resonance imaging of the brain and EEG should undergo ECG to rule out the long-QT syndrome, a lethal disorder that mimics epilepsy 64; these patients may also benefit from Holter ECG monitoring to rule out arrhythmia. Misdiagnosis of the long-QT syndrome as epilepsy precludes the use of effective therapy, and the inappropriate administration of antiepileptic drugs can induce arrhythmias.51 One additional preventive step is to discuss sudden, unexpected death in epilepsy with patients a step few physicians initiate because it may cause stress about an uncommon problem for which there is no proven means of prevention. However, most patients with epilepsy and their families want information about sudden death.65,66 Although national guidelines in the United Kingdom recommend that all patients with epilepsy and their families be provided with information about sudden, unexpected death in epilepsy,66 most neurologists cited in the study discuss it only with high-risk patients or when specifically asked.65,66 Guidelines and tools are needed to assist physicians and patients and their families in becoming educated about sudden, unexpected death in epilepsy, and outcome measures
References
1. Hermann B, Seidenberg M, Bell B.

are needed to assess the effectiveness of this education. Patients with risk factors that can be modified such as nonadherence to antiepileptic-drug regimen, tonicclonic seizure, nocturnal seizure, and treatment-resistant epilepsy may benefit most from counseling. When patients ask whether seizures can injure their brain or kill them, a simple no is insufficient. Epilepsy is associated with significant risks of morbidity and death.

F u t ur e Dir ec t ions
Reductions in sudden deaths among patients with epilepsy may be achieved by increasing awareness on the part of the general public and the medical community, improving the prevention and treatment of epilepsy, further developing and encouraging the use of devices that detect seizure and can alert caretakers, improving our understanding of the mechanisms of sudden, unexpected death in epilepsy, and conducting interventional trials to prevent the progression of life-threatening seizure to sudden death. If patients are aware that seizure can be deadly, they may be more motivated to adhere to antiepileptic-drug regimens and to avoid lifestyle choices that increase the likelihood of seizure. Patients with seizures that remain uncontrolled after the administration of two different drug regimens should be referred to an epilepsy center for evaluation. Preventing seizures can be lifesaving.
Dr. Devinsky reports providing expert testimony in legal medical proceedings regarding possible sudden, unexpected death in epilepsy and receiving lecture fees from UCB. No other potential conflict of interest relevant to this article was reported. Disclosure forms provided by the author are available with the full text of this article at NEJM.org. I thank Drs. Daniel Friedman and Ion-Florin Talos and Brigid Staley, M.P.H., for providing invaluable input on earlier versions of the manuscript.

The neurodevelopmental impact of childhood onset temporal lobe epilepsy on brain structure and function and the risk of pro gressive cognitive effects. Prog Brain Res 2002;135:429-38. 2. Nashef L. Sudden unexpected death in epilepsy: terminology and definitions. Epilepsia 1997;38:Suppl:S6-S8. 3. Annegers JF. United States perspective on definitions and classifications. Epilepsia 1997;38:Suppl:S9-S12. 4. Dasheiff RM. Sudden unexpected death in epilepsy: a series from an epilepsy surgery program and speculation on the rela-

tionship to sudden cardiac death. J Clin Neurophysiol 1991;8:216-22. 5. Donner EJ, Smith CR, Snead OC III. Sudden unexplained death in children with epilepsy. Neurology 2001;57:430-4. 6. Ficker D, So E, Shen WK, et al. Population-based study of the incidence of sudden unexplained death in epilepsy. Neurology 1998;51:1270-4. 7. Nashef L, Fish DR, Garner S, Sander JW, Shorvon SD. Sudden death in epilepsy: a study of incidence in a young cohort with epilepsy and learning difficulty. Epilepsia 1995;36:1187-94. 8. Nilsson L, Ahlbom A, Farahmand BY,

Tomson T. Mortality in a population-based cohort of epilepsy surgery patients. Epilepsia 2003;44:575-81. 9. Sillanp M, Shinnar S. Long-term mortality in childhood-onset epilepsy. NEngl J Med 2010;363:2522-9. 10. Sperling MR, Feldman H, Kinman J, Liporace JD, OConnor MJ. Seizure control and mortality in epilepsy. Ann Neurol 1999;46:45-50. 11. Tomson T, Nashef L, Ryvlin P. Sudden unexpected death in epilepsy: current knowledge and future directions. Lancet Neurol 2008;7:1021-31. 12. Tomson T, Walczak T, Sillanpaa M,

n engl j med 365;19 nejm.org november 10, 2011

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The

n e w e ng l a n d j o u r na l

of

m e dic i n e
et al. Brainstem serotonergic deficiency in sudden infant death syndrome. JAMA 2010; 303:430-7. 44. Buchanan GF, Hodges MR, Richerson GB. Contribution of chemosensitive serotonergic neurons to interactions between the sleep-wake cycle and respiratory control. In: Monti JM, Pandi-Perumal SR, Jacobs BL, Nutt DJ, eds. Serotonin and sleep: molecular, functional and clinical aspects. Basel, Switzerland: Birkhuser Verlag, 2008: 529-54. 45. Uteshev VV, Tupal S, Mhaskar Y, Faingold CL. Abnormal serotonin receptor expression in DBA/2 mice associated with susceptibility to sudden death due to respiratory arrest. Epilepsy Res 2010;88:183-8. 46. Bateman LM, Li CS, Lin TC, Seyal M. Serotonin reuptake inhibitors are associated with reduced severity of ictal hypoxe mia in medically refractory partial epilepsy. Epilepsia 2010;51:2211-4. 47. Seyal M, Bateman LM, Albertson TE, Lin TC, Li CS. Respiratory changes with seizures in localization-related epilepsy: analysis of periictal hypercapnia and airflow patterns. Epilepsia 2010;51:1359-64. 48. Glasscock E, Yoo JW, Chen TT, Klassen TL, Noebels JL. Kv1.1 potassium channel deficiency reveals brain-driven cardiac dysfunction as a candidate mechanism for sudden unexplained death in epilepsy. J Neurosci 2010;30:5167-75. 49. Schuele SU. Effects of seizures on cardiac function. J Clin Neurophysiol 2009; 26:302-8. 50. Devinsky O. Effects of seizures on autonomic and cardiovascular function. Epilepsy Curr 2004;4:43-6. 51. Johnson JN, Hofman N, Haglund CM, Cascino GD, Wilde AA, Ackerman MJ. Identification of a possible pathogenic link between congenital long QT syndrome and epilepsy. Neurology 2009;72: 224-31. 52. Brotherstone R, Blackhall B, McLellan A. Lengthening of corrected QT during epileptic seizures. Epilepsia 2010;51: 221-32. 53. Surges R, Adjei P, Kallis C, et al. Pathologic cardiac repolarization in pharmacoresistant epilepsy and its potential role in sudden unexpected death in epilepsy: a case-control study. Epilepsia 2010; 51:233-42. 54. Surges R, Scott CA, Walker MC. Enhanced QT shortening and persistent tachycardia after generalized seizures. Neurology 2010;74:421-6. 55. Rugg-Gunn FJ, Simister RJ, Squirrell M, Holdright DR, Duncan JS. Cardiac arrhythmias in focal epilepsy: a prospective long-term study. Lancet 2004;364:2212-9. 56. Dnser M, Hasibeder W. Sympathetic overstimulation during critical illness: adverse effects of adrenergic stress. J Intensive Care Med 2009;24:293-316. 57. Shen HY, Li T, Boison D. A novel mouse model for sudden unexpected death in epi-

Sander JW. Sudden unexpected death in epilepsy: a review of incidence and risk factors. Epilepsia 2005;46:Suppl 11:54-61. 13. Walczak TS, Leppik IE, DAmelio M, et al. Incidence and risk factors in sudden unexpected death in epilepsy: a prospective cohort study. Neurology 2001;56:519-25. 14. Camfield P, Camfield C. Special considerations for a first seizure in childhood and adolescence. Epilepsia 2008;49:Suppl 1:40-4. 15. Gillberg C, Billstedt E, Sundh V, Gillberg IC. Mortality in autism: a prospective longitudinal community-based study. J Autism Dev Disord 2010;40:352-7. 16. Le Gal F, Korff CM, Monso-Hinard C, et al. A case of SUDEP in a patient with Dravet syndrome with SCN1A mutation. Epilepsia 2010;51:1915-8. 17. Hitiris N, Suratman S, Kelly K, Stephen LJ, Sills GJ, Brodie MJ. Sudden unexpected death in epilepsy: a search for risk factors. Epilepsy Behav 2007;10:138-41. 18. Kloster R, Engelskjn T. Sudden unexpected death in epilepsy (SUDEP): a clinical perspective and a search for risk factors. J Neurol Neurosurg Psychiatry 1999;67: 439-44. 19. Nilsson L, Farahmand BY, Persson PG, Thiblin I, Tomson T. Risk factors for sudden unexpected death in epilepsy: a casecontrol study. Lancet 1999;353:888-93. 20. Langan Y, Nashef L, Sander JW. Casecontrol study of SUDEP. Neurology 2005; 64:1131-3. 21. Lhatoo SD, Faulkner HJ, Dembny K, Trippick K, Johnson C, Bird JM. An electroclinical case-control study of sudden unexpected death in epilepsy. Ann Neurol 2010;68:787-96. 22. Nei M, Ho RT, Abou-Khalil BW, et al. EEG and ECG in sudden unexplained death in epilepsy. Epilepsia 2004;45:338-45. 23. Ryvlin P, Cucherat M, Rheims S. Risk of sudden unexpected death in epilepsy in patients given adjunctive antiepileptic treatment for refractory seizures: a metaanalysis of placebo-controlled randomised trials. Lancet Neurol 2011 September 19 (Epub ahead of print). 24. Aurlien D, Larsen J, Taubll E, Gjerstad L. Increased incidence of sudden unexpected death in epilepsy (SUDEP) with lamotrigine in Rogaland County, Norway. Epilepsia 2010;51:Suppl 3:136. abstract. 25. Opeskin K, Burke MP, Cordner SM, Berkovic SF. Comparison of antiepileptic drug levels in sudden unexpected deaths in epilepsy with deaths from other causes. Epilepsia 1999;40:1795-8. 26. Nilsson L, Bergman U, Diwan V, Farah mand BY, Persson PG, Tomson T. Antiepileptic drug therapy and its management in sudden unexpected death in epilepsy: a casecontrol study. Epilepsia 2001;42:667-73. 27. Langan Y, Nashef L, Sander JW. Sudden unexpected death in epilepsy: a series of witnessed deaths. J Neurol Neurosurg Psychiatry 2000;68:211-3.

28. Bateman LM, Spitz M, Seyal M. Ictal

hypoventilation contributes to cardiac arrhythmia and SUDEP: report on two deaths in video-EEG-monitored patients. Epilepsia 2010;51:916-20. 29. Bird J, Dembny K, Sandeman D, Butler S. Sudden unexplained death in epilepsy: an intracranially monitored case. Epilepsia 1997;38:Suppl 11:S52-S56. 30. Espinosa PS, Lee JW, Tedrow UB, Bromfield EB, Dworetzky BA. Sudden unexpected near death in epilepsy: malignant arrhythmia from a partial seizure. Neurology 2009;72:1702-3. 31. So EL, Sam MC, Lagerlund TL. Postictal central apnea as a cause of SUDEP: evidence from near-SUDEP incident. Epilepsia 2000;41:1494-7. 32. Tao JX, Qian S, Baldwin M, et al. SUDEP, suspected positional airway obstruction, and hypoventilation in postictal coma. Epilepsia 2010;51:2344-7. 33. Thomas P, Landre E, Suisse G, Brelooin J, Dolisi C, Chatel M. Syncope anoxoischemique par dyspne: le obstructive au cours dune crise partielle complexe temporale droite. Epilepsies 1996;8:339-46. 34. Opeskin K, Berkovic SF. Risk factors for sudden unexpected death in epilepsy: a controlled prospective study based on coroners cases. Seizure 2003;12:456-64. 35. Sevcencu C, Struijk JJ. Autonomic alterations and cardiac changes in epilepsy. Epilepsia 2010;51:725-37. 36. Hewertson J, Poets CF, Samuels MP, Boyd SG, Neville BG, Southall DP. Epileptic seizure-induced hypoxemia in infants with apparent life-threatening events. Pediatrics 1994;94:148-56. 37. Dasheiff RM, Dickinson LJ. Sudden unexpected death of epileptic patient due to cardiac arrhythmia after seizure. Arch Neurol 1986;43:194-6. 38. Bateman LM, Li CS, Seyal M. Ictal hypoxemia in localization-related epilepsy: analysis of incidence, severity and risk factors. Brain 2008;131:3239-45. 39. 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 immuno histochemistry. Neuropathol Appl Neurobiol 2003;29:132-43. 40. Richerson GB, Buchanan GF. The serotonin axis: shared mechanisms in seizures, depression, and SUDEP. Epilepsia 2011; 52:Suppl 1:28-38. 41. Swallow RA, Hillier CE, Smith PE. Sudden unexplained death in epilepsy (SUDEP) following previous seizure-related pulmonary oedema: case report and review of possible preventative treatment. Seizure 2002;11:446-8. 42. Johnston SC, Siedenberg R, Min JK, Jerome EH, Laxer KD. Central apnea and acute cardiac ischemia in a sheep model of epileptic sudden death. Ann Neurol 1997;42:588-94. 43. Duncan JR, Paterson DS, Hoffman JM,

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current concepts
lepsy (SUDEP): role of impaired adenosine clearance. Epilepsia 2010;51:465-8. 58. Ridsdale L, Charlton J, Ashworth M, Richardson MP, Gulliford MC. Epilepsy mortality and risk factors for death in epilepsy: a population-based study. Br J Gen Pract 2011;61:271-8. 59. Persson H, Ericson M, Tomson T. Carbamazepine affects autonomic cardiac control in patients with newly diagnosed epilepsy. Epilepsy Res 2003;57:69-75. 60. Hesdorffer D, Tomson T, Benn E, et al. Combined analysis of risk factors for SUDEP. Epilepsia 2011;52:1150-9.
61. Reddy DS. Clinical pharmacokinetic

interactions between antiepileptic drugs and hormonal contraceptives. Expert Rev Clin Pharmacol 2010;3:183-92. 62. Sperling M, Durhakula S, Scott L, et al. Mortality after epilepsy surgery. Epilepsia 2010;51:Suppl 2:320. abstract. 63. Carlson C, Arnedo V, Cahill M, Devinsky O. Detecting nocturnal convulsions: efficacy of the MP5 monitor. Seizure 2009; 18:225-7. 64. Pacia SV, Devinsky O, Luciano DJ, Vazquez B. The prolonged QT syndrome presenting as epilepsy: a report of two

cases and literature review. Neurology 1994;44:1408-10. 65. Gayatri NA, Morrall MC, Jain V, Kashyape P, Pysden K, Ferrie C. Parental and physician beliefs regarding the provision and content of written sudden unexpected death in epilepsy (SUDEP) information. Epilepsia 2010;51:777-82. 66. Morton B, Richardson A, Duncan S. Sudden unexpected death in epilepsy (SUDEP): dont ask, dont tell? J Neurol Neurosurg Psychiatry 2006;77:199-202.
Copyright 2011 Massachusetts Medical Society.

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