CME

Sudden Unexpected Death in Epilepsy: What Does Sleep Have to Do With It?

Department of Neurology, University of New Mexico School of Medicine, MSC10 5620, One University of NM, Albuquerque, NM 87131-0001, USA

E-mail address: MGriggD@salud.unm.edu

Abstract

Sudden unexpected death in epilepsy (SUDEP) is the sudden unexpected death of a seemingly healthy individual with epilepsy. SUDEP is the commonest cause of death directly attributable to epilepsy, and most often occurs at or around the time of a seizure and during sleep. Sleep, respiration, arousal responses, and caudal brainstem serotoninergic neurons probably play roles in SUDEP, but more research is needed to understand these relationships. This article reviews the medical literature on the epidemiology, risk factors, and preventive measures for SUDEP in people with epilepsy, and discusses the roles of sleep, respiration, impaired autonomic functioning, and nocturnal seizures.

Keywords

• Sudden unexpected death in epilepsy • Sleep-related hypoventilation • Cerebral shutdown • Prolonged generalized EEG suppression • Sudden death in sleep

Sudden unexpected death in epilepsy (SUDEP) refers to the sudden unexpected death of a seemingly healthy individual with epilepsy. A recently published article recommending a unified definition and classification for SUDEP defines it as a “sudden, unexpected, witnessed or unwitnessed, nontraumatic and nondrowning death, occurring in benign circumstances, in an individual with epilepsy, with or without evidence for a seizure and excluding documented status epilepticus (seizure duration ≥30 minutes or seizures without recovery in between) in which postmortem examination does not reveal a cause of death.”¹ SUDEP is the commonest cause of death directly attributable to epilepsy, and most often occurs at or around the time of a seizure and during sleep. This article reviews the current medical literature on the epidemiology, risk factors, and preventive measures for SUDEP in people with epilepsy, and also discusses the roles of sleep, respiration, impaired autonomic functioning, and nocturnal seizures in SUDEP.

Epidemiology of death in people with epilepsy

Sudden death is 20 to 40 times more common in people with epilepsy compared with the general population.²^–⁵ Between 8% and 17% of deaths in people with epilepsy are SUDEP (most often in people aged 20–40 years).⁶ The incidence of SUDEP increases 100-fold from 0.09 per 1000 patient-years in prospective-based community samples, 1.2 to 5.9 per 1000 patient-years in tertiary care epilepsy centers, up to 6.0 to 9.3 per 1000 patient-years among patients with medically refractory epilepsies being evaluated for epilepsy surgery.⁵^–⁷

A recently published longitudinal population-based cohort study prospectively followed 245 Finnish children with epilepsy for more than 40 years and found that 24% (n = 60) had died, a rate 3 times higher than for the general population.⁸ Of the 60 deaths, 33 (55%) were related to epilepsy, including sudden unexplained death in 18 subjects (30%), definite or probable seizure in 9 (15%), and accidental drowning in 6 (10%). Epilepsy was not in remission in 48% of the cohort. The cumulative risk of sudden unexplained death was 7% at 40 years overall and 12% in subjects whose epilepsy was not controlled. Most of the deaths occurred in adulthood.

SUDEP most often occurs in bed during the night

SUDEP most often occurs in bed during the night, presumably during sleep, and following a generalized tonic-clonic seizure (GTCS) or complex partial seizure (CPS).⁹^–¹¹ Circumstantial evidence of a recent seizure (tongue laceration, urinary incontinence, disheveled bedroom) was present in 67% of 42 SUDEP deaths, 60% were sleep-related, and 71% of subjects were found lying prone.¹¹ Most of 50 SUDEP deaths occurred in sleep and evidence suggests that a seizure preceded death in 22%.¹² A prospective case-control study of 50 cases of SUDEP and 50 subjects with epilepsy who died of other causes found that the SUDEP group were more likely to be found dead in bed with evidence of a terminal seizure.¹³

Only 11% to 14% of cases of SUDEP are witnessed.¹⁴^–¹⁶ In one study, a GTCS preceded 12 of 15 witnessed SUDEP deaths, 70% were in a prone position, and respiratory difficulties were noted in 80%.¹⁴ Half of witnessed cases of SUDEP were preceded by a GTCS, the rest by a sudden loss of consciousness.¹⁶ SUDEP occurred in sleep in at least 40% of a case series in which sufficient clinical data are available, which is greater than could be expected by chance.¹⁷

A case-control study found that patients with predominantly nocturnal seizures had a greater risk of SUDEP.¹⁵ They compared seizure patterns in a cohort of 154 cases of SUDEP and 616 controls living with epilepsy who had either exclusively diurnal or nocturnal seizures.¹⁵ They found that (1) 86% of SUDEP deaths were unwitnessed and 58% occurred in sleep, (2) SUDEP was 4.4 times more likely to be unwitnessed if it occurred in sleep, and (3) those who died of SUDEP were 3.9 times more likely to have a history of primarily nocturnal seizures compared with the living controls with epilepsy.¹⁵ After correcting for other SUDEP risk factors,¹⁸ nocturnal seizures increased the risk of SUDEP 2.6 times. The investigators argued that nocturnal seizures should be considered an independent risk factor for SUDEP.

SUDEP occurs less often in children than adults.^19,²⁰ A retrospective cohort from the United Kingdom General Practice Database found that the incidence of SUDEP was 3.3 per 10,000 person-years (9/6190).²¹ Most of those who died had severe symptomatic epilepsies. A recently published prospective longitudinal study following 1012 children for approximately 10 years reported that 1.1% (11) had died of SUDEP.¹⁹ Another study by the same group found that nearly all cases of SUDEP occurred in children who had poorly controlled epilepsy.¹⁹

Cases of SUDEP occurring during long-term video-electroencephalographic monitoring

A total of 13 cases of SUDEP or near SUDEP have been reported in patients with medically refractory epilepsy undergoing prolonged inpatient continuous video-electroencephalographic (VEEG) recordings scattered among usually isolated case reports.^5,^14,²²^–²⁷ Eight died suddenly and 5 were successfully resuscitated. All had seizures just before the event, GTCS in 12, CPS in 1. Most died during sleep. Other seizures had occurred during the VEEG recordings in all but only 1 triggered the death or near-death event.

Respiratory problems (postictal hypoventilation, apnea, cyanosis, inspiratory stridor, pulmonary edema, or suffocation) heralded the onset of SUDEP in 8 (although the breathing difficulties were confirmed only by visual observation, not comprehensive respiratory monitoring).^22,²⁶^–²⁸

Electrocardiographic (ECG) abnormalities (such as ST-segment increase, peaked T waves, and asystole) usually followed but less often coincided with the respiratory difficulties.^5,²²^–²⁵ Ventricular tachycardia leading to ventricular fibrillation was observed in 1 patient following a prolonged convulsion lasting 4.5 minutes.²⁴

Two patients had prolonged generalized electroencephalogram suppression (PGES) following seizure(s): it followed a seizure in 1, whereas the other showed no movement lying face down and a heart rate of 47 beats per minute before the PGES appeared.^5,²³ PGES following a generalized convulsion preceded death in a woman undergoing a home ambulatory electroencephalogram (EEG).²⁹

A near-death event in a 20-year-old woman occurred following a convulsion that lasted 56 seconds; her ECG rhythm was normal for 10 seconds after the seizure, then gradually slowed until it stopped 57 seconds later.²⁵ She had a history of a previous cardiac arrest after a CPS without secondary generalization. The investigators argued that her heart stopped as a result of marked suppression of central respiratory effort after a seizure. She had 3 others during the recording that did not cause such a response, showing the intermittent nature of SUDEP events. After a short time, EEG activity became mixed with progressive flattening of the EEG (without any electrical activity). After the EEG cessation, pulse artifact was seen for 2 minutes.

Risk factors for SUDEP

Case-control studies using living people with epilepsy as controls have searched for risk factors for SUDEP.^18,³⁰^–³² The most consistently identified risk factor across studies was frequent GTCS. In one study, a history of more than 3 GTCS per year increased the risk of SUDEP 8-fold.³¹ Active epilepsy (defined as failure to obtain 5-year seizure remission) was the strongest risk of SUDEP in a prospective longitudinal study of patients with childhood-onset epilepsy followed for longer than 40 years.⁸

A recently published study by Hesdorffer and colleagues ³³ pooled data from 4 published case-control studies^18,³⁰^–³² to increase the power to identify risk factors for SUDEP. Risk factors for SUDEP in 289 cases and 958 living controls with epilepsy were (1) more than 3 GTCS per year, (2) taking multiple antiepileptic drugs (AEDs), (3) epilepsy duration, (4) onset of epilepsy in childhood, (5) male gender, and (6) symptomatic epilepsy (related to an identifiable cause). Compared with healthy controls, the risk of SUDEP was 37 times greater in persons with epilepsy onset before age 16 years and 8-fold in those whose epilepsy began at age 16 years or older compared with healthy controls.³³ At highest risk of SUDEP were patients with early onset, medically refractory, symptomatic epilepsy with frequent GTCS, and those taking multiple AEDs. Treatment of epilepsy with only 1 drug (called monotherapy) was protective but statistically significant.

One study reported that the risk of SUDEP is increased 8-fold in patients with epilepsy taking 3 or more AEDs (so-called polytherapy) compared with those treated with 1.³⁰ However, AED polytherapy may represent a surrogate marker for medical intractability, not a causative factor.

In the study cited earlier, Hesdorffer and colleagues ³³ found that lamotrigine was associated with a significant increase of SUDEP when prescribed to patients with idiopathic generalized epilepsy (IGE). Another recent study found that 10 (39%) of 26 cases of SUDEP had been treated with lamotrigine (and all but 1 were women).³⁴ The risk of SUDEP was 5-fold greater in women taking lamotrigine compared with those who were not (2.5 vs 0.5 per 1000 patient-years). This association may only represent selection bias because lamotrigine is a preferred AED for women.

How might lamotrigine increase the risk of SUDEP?³⁵ Lamotrigine has the potential to induce cardiac arrhythmias by inhibiting rapid, delayed-rectifier, potassium ion, cardiac current.³⁶ Seizure-induced acidosis, excessively high concentrations of lamotrigine, or concurrent treatment with other drugs that block these potassium currents could add to this risk.³⁶ Hesdorffer and colleagues³⁷ reanalyzed SUDEP data from 3 case-control studies and found no increased risk of SUDEP with any particular AED (given alone or in combination) when they controlled for GTCS frequency.

SUDEP risk is significantly greater in patients with longstanding, severe, medically refractory epilepsy, a history of neurologic insult, and cognitive and/or other neurologic impairments. An intelligence quotient (IQ) of less than 75 points greatly increases the risk of early death by secondary or symptomatic epilepsy.² The cumulative effects of seizures (GTCS or CPS) on brain structure and function may contribute to this increased risk.⁶ Frequent GTCS can progressively damage the brain (especially the hippocampus) and cognition (impairment of short-term memory).^38,³⁹

Most studies confirm that so-called poor compliance with AEDs can increase the risk of SUDEP in adults with epilepsy 3-fold.^40,⁴¹ At least 3 coroner-based forensic studies of SUDEP found subtherapeutic AED level(s) in 57% to 90%.^11,^12,⁴² A study of SUDEP in patients with medically refractory epilepsy enrolled in 112 different AED drug trials found that adding³³ another AED at effective doses reduced SUDEP or near-SUDEP risk 7-fold compared with placebo.⁴³ Box 1 summarizes SUDEP risk factors.

Potential mechanisms for SUDEP

No single mechanism is likely to explain all (possibly even some) cases of SUDEP. Potential mechanisms for SUDEP in an individual patient with epilepsy include (1) ictal cardiac arrhythmias (possibly related to the cardiovascular effects of insular cortex); (2) impaired central ventilatory responses, prolonged apneas, or oxyhemoglobin desaturations triggered by seizures; (3) impaired righting responses following a seizure leading to death by suffocation; (4) central nervous system autonomic instability during or after a seizure; and/or (5) postictal dysfunction of serotonin (5-HT) neurons causing depression of breathing, impaired arousal, and repositioning reflexes.

Cerebral Shutdown and Postictal Generalized EEG Suppression

As mentioned earlier, a seizure may lead to, or be associated with, an electrical shutdown of the brain, which may occur with and/or follow brainstem respiratory suppression, central hypoventilation, cardiac standstill, cardiorespiratory arrest, and death.^6,^23,^27,²⁹ A recent study compared 30 epileptic seizures recorded on VEEG in 10 adults who later died of SUDEP with 92 seizures in 30 matched live controls.²⁷ They found PGES in 50% of 30 seizures in the 10 who later died of SUDEP and 38% of 92 seizures in the control group. PGES was significantly longer in the generalized motor seizures of the SUDEP group. After adjusting for multiple variables, the risk of SUDEP was significantly increased if a PGES lasted longer than 50 seconds; the risk quadrupled if the EEG suppression lasted longer than 80 seconds. The investigators concluded that a PGES lasting longer than 50 seconds may identify patients with epilepsy at risk of SUDEP.

Another recent study found PGES in 48 (27%) patients who had GTCS when they retrospectively reviewed 470 consecutive VEEG telemetry reports.⁴⁴ The mean duration of PGES was 38 seconds (range 6–69 seconds). They then reviewed VEEG ictal behavior in the patients with PGES (analyzing 1 seizure per subject) and compared them with 12 randomly selected controls. They found that patients with PGES were significantly more likely to lie motionless after the seizure and require simple nursing interventions (suctioning, repositioning, supplemental oxygen).

More research and careful monitoring of ECG and respiration (including tidal volume, respiratory rate, pulse oximeter, and carbon dioxide) is needed to discover which factors precipitate witnessed episodes of SUDEP. PGES, central apnea, pulmonary shunting, pulmonary neurogenic edema, suffocation in the prone position asleep, impaired arousal caused by hypercapnea and sleep, and/or respiratory acidosis may combine in varying degrees and cascade with cardiac factors to cause SUDEP.⁶

Fig. 1 shows an episode of PGES lasting 90 seconds that occurred in a 37-year-old woman with left mesial temporal lobe epilepsy (TLE) while undergoing prolonged VEEG monitoring. She had a cluster of 3 CPS that occurred within 6 hours, 72 hours after withdrawing phenytoin. All were CPS that emanated from her left mesial temporal region; 2 secondarily generalized (lasting 45 and 51 seconds). PGES following the CPS without generalization lasted 8 seconds; and 50 and 90 seconds on the CPS that evolved to generalized convulsions. Note how no suppression of the heart rate occurred despite 90 seconds of PGES.

Fig. 1 (A–E) An episode of PGES lasting 90 seconds recorded in a 37-year-old woman with left mesial temporal lobe epilepsy (TLE) while undergoing prolonged VEEG monitoring. The duration of each figure is 30 seconds. Note that the secondarily generalized seizure ends in (A). Muscle tension artifact is seen in (B) but no EEG activity is observed until the brief bursts in (D). Predominantly δ EEG activity returns in (E). Note how the heart rate continues despite prolonged EEG suppression.

Cardiac Factors Potentially Contributing to SUDEP

Cardiac events have been implicated in some cases of SUDEP.⁴⁵^–⁴⁸ Seizure-induced cardiac arrhythmias occur in animals and humans,^46,⁴⁷ but a malignant cardiac arrhythmia from a partial seizure was the cause of near SUDEP in only 1 of the 13 patients who had SUDEP or near-SUDEP events during long-term VEEG monitoring.²⁴ Seizure-related hypoxemia or acidosis, and/or abnormalities in cardiac potassium currents, could predispose to cardiac arrhythmias.³⁶

Studies in patients with epilepsy show that changes in heart rate and rhythm often accompany or follow seizures, and medically intractable epilepsy over time can be associated with a variety of ECG abnormalities. Interictal and ictal cardiovascular changes have been reported in patients with epilepsy.^46,⁴⁷ Prolonged corrected QT (QTc) intervals during and following seizures, and shortening of the QTc after seizures, have been reported.⁴⁹^–⁵¹ Ictal asystole occurs in 0.1% to 0.4% of patients during VEEG monitoring.⁵²^–⁵⁴

Two studies ⁵⁵ have reported cardiac structural abnormalities in autopsy studies on patients who died of SUDEP. One prospective study found significant myocardial fibrosis in 6 of 15 SUDEP deaths compared with only 1 control who died of other causes.⁵⁵ None had pathologic changes in their cardiac conduction systems. Another case-control autopsy study found perivascular and interstitial fibrosis in 4 of the 7 hearts in the SUDEP group; and none in the 13 controls who died of drug overdose or hanging. The investigators hypothesized that these irreversible cardiac changes result from seizures.

A study by Nei and colleagues ⁵⁶ found that ictal tachycardia was more severe during sleep in patients who later died of SUDEP. They compared VEEG and ECG data in patients who later died of SUDEP with live controls with epilepsy and found that (1) mean heart rates during seizures that occurred in sleep were 149 beats per minute (BPM) in the SUDEP group and 126 BPM in controls; (2) mean increase in heart rate was higher in sleep compared with wake in the cases of SUDEP (78 BPM in sleep, 47 BPM awake), an effect not seen in the controls (52 BPM in sleep, 43 awake); and (3) ictal cardiac repolarization and rhythm abnormalities (atrial fibrillation, ventricular or atrial premature depolarizations, marked sinus arrhythmia, junctional escape, or ST-segment increase) were found in 56% of cases of SUDEP and 39% of the controls.

Ictal tachycardia accompanies most CPS and GTCS.^52,^56,⁵⁷ Studies have shown that (1) heart rate increases tend to be greater, and other ECG abnormalities more common, with GTCS⁵⁷; (2) ictal tachycardias may be more pronounced with seizures that arise from the temporal lobe⁵⁸^–⁶⁰; (3) increase in heart rate during a seizure correlates with seizure duration.⁵⁸

Other ECG abnormalities are observed in many patients following CPS or GTCS. These abnormalities include longer QT intervals, increased QT dispersion, ST-segment depression, discordant rhythm, and abnormal repolarization.^57,⁶¹ These changes were often transient, not present on ECGs repeated 1 to 9 days later.⁶¹ Potentially serious ECG changes (ST depression or T wave inversion) were observed in 6% of 102 seizures and 10% of 41 patients undergoing VEEG monitoring, and were more likely to occur in generalized seizures.⁵⁷

Ictal bradycardia or ictal asystole are rare manifestations of typical TLE.^51,^52,⁶²^–⁶⁴ Ictal bradycardia was observed in 6% to 8% of patients (and then in only 4%–6% of seizures in an individual patient).^62,⁶³ Ictal asystole is rare. Three large case series reported recording ictal asystole in 0.27% (10/6825),⁵² 0.34% (2/589),⁵³ and 0.4% (5/1244)⁵⁴ of patients with epilepsy undergoing VEEG monitoring.

When ictal asystole occurred in 8 patients with TLE undergoing VEEG monitoring, it developed an average of 42 seconds after seizure onset and resulted in a sudden loss of body tone.⁵² Sudden atonia is not common in TLE and reports of it in a patient with TLE should prompt concern that some of the seizures may be accompanied by ictal asystole. Ictal asystole was found to accompany seizures in 10 (0.2%, median age 50 years, 9 women) of 4500 patients evaluated in a specialized syncope unit; all were temporal in origin.⁶⁵ Eight were subsequently treated with an AED with seizure control; seizures were medically refractory in 2 and required pacemaker implantation. The investigators cautioned that ictal asystole should be considered in patients with recurrent, unexplained, traumatic, and/or convulsive syncope.

Rugg-Gunn and colleagues ⁶⁶ implanted ECG loop recorders in 20 patients with medically refractory focal epilepsies to determine the frequency of neurogenic cardiac arrhythmias. They found that median heart rates exceeded 100 BPM in 16 patients and ictal bradycardia (<40 BPM) occurred in 8 (2.1%) of 377 seizures. Three patients had ictal asystole, and pacemakers were inserted in 4.

Strezelczyk and colleagues ⁶⁴ reviewed their experiences and long-term outcome managing ictal asystole or bradycardia in 16 patients with medically refractory TLE from 4 epilepsy centers. Subjects had TLE for a mean of 18 years, a mean age of 51 years, and had a mean of 8 seizures per month. Two-thirds of reported falls, syncope, or trauma were related to their seizures. Ictal asystole (lasting 3–33 seconds) accompanied 30% (28 episodes) of the 92 seizures in the 16 subjects. An additional 17% of seizures had ictal bradycardia. When either occurred, it resulted in an abrupt complete loss of consciousness, and sudden atonia with falls (unless the patient was reclining in bed). Secondary generalization developed following ictal asystole in 2 patients. Treating these patients with AEDs, and/or epilepsy surgery with/without a cardiac pacemaker, led to resolution of these events in 88% of cases.

Why are these cardiac arrhythmias occurring in people with epilepsy, especially those with TLE? The amygdala has efferent connections to cardioregulatory centers in the medulla. Perhaps excessive vagal stimulation in some patients with epilepsy could lead to profound ictal bradycardia, heart block, and potentially SUDEP.⁴⁸ Seizure-induced hypoxemia or acidosis could predispose to arrhythmias in some patients. Myocardial fibrosis has been found on autopsy in some patients with epilepsy. Recurrent catecholamine surges related to seizures could be the cause, although more research is needed to confirm this.⁵⁵

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Unexpected Death in Epilepsy: What Does Sleep Have to Do With It?