Sudden Unexpected Death in Epilepsy Last Updated: May 17, 2006
Synonyms and related 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

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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:

• In the US: 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

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):

• 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

Sudden unexplained death in children with epilepsy: a cohort study with an eighteen-year follow-up.

Acta Paediatr.  2005; 94(5):564-7 (ISSN: 0803-5253)

Weber P ; Bubl R ; Blauenstein U ; Tillmann BU ; Lütschg J
Department of Neuropaediatrics, Basel University Children's Hospital, Basel, Switzerland. [e-mail]

AIM: Sudden unexplained death is a significant cause of mortality in adults with epilepsy. Only a few data exist about this risk in childhood. METHODS: Cases of sudden unexplained death in epilepsy (SUDEP) up to the age of 18 y occurring at our hospital between 1984 and 2001 were identified. The incidence rate was calculated on the basis of diagnosed epileptics registered with a statutory disability insurance scheme. Results: Four cases of SUDEP were identified during the 18-y period. The incidence of SUDEP was 4.3 per 10,000 patient-years. All children showed polytherapy-refractory epilepsy, developmental retardation and early-onset epilepsy. Two witnessed cases had shown no previous signs of seizure. CONCLUSION: SUDEP is rare in childhood. Children with uncomplicated epilepsy seem not to be at risk.

1: Drug Saf. 2003;26(10):673-83.
Links

Do antiepileptic drugs play a role in sudden unexpected death in epilepsy?

Walczak T.

MINCEP Epilepsy Care, Minneapolis, Minnesota 55447, USA. [e-mail]

Sudden unexpected death in epilepsy (SUDEP) accounts for approximately 2% of deaths in population-based cohorts of epilepsy, and up to 25% of deaths in cohorts of more severe epilepsy. When it occurs, SUDEP usually follows a generalised tonic-clonic seizure. Unresponsiveness, apnoea, and cardiac arrest occur in SUDEP, rather than the typical gradual recovery. The great majority of tonic-clonic seizures occur without difficulty and how the rare seizure associated with SUDEP differs from others is unknown.Three mechanisms have been proposed for SUDEP: cardiac arrhythmia, neurogenic pulmonary oedema, and postictal suppression of brainstem respiratory centres leading to central apnoea. Recent studies have found that the incidence of SUDEP increases with the severity of epilepsy in the population studied. The duration of epilepsy, number of tonic-clonic seizures, mental retardation, and simultaneous treatment with more than two antiepileptic drugs are independent risk factors for SUDEP. Some studies have reported that carbamazepine use, carbamazepine toxicity, and frequent, rapid changes in carbamazepine levels, may be associated with SUDEP. Other evidence indicates that carbamazepine could potentially increase the risk for SUDEP by causing arrhythmia or by altering cardiac autonomic function. However, this evidence is tenuous and most studies have not found an association between the use of carbamazepine or any other individual antiepileptic drug and SUDEP.There is little information regarding antiepileptic drugs other than phenytoin and carbamazepine. The incidence of SUDEP with gabapentin, tiagabine, and lamotrigine clinical development programmes is in the range found in other populations with refractory epilepsy. This suggests that these individual antiepileptic drugs are no more likely to cause SUDEP than antiepileptic drugs in general.Best current evidence indicates that the risk of SUDEP can be decreased by aggressive treatment of tonic-clonic seizures with as few antiepileptic drugs as necessary to achieve complete control. At present there is no strong reason to avoid any particular antiepileptic drug. Further studies are needed to elucidate the potential role of individual antiepileptic drugs in SUDEP and establish clinical relevance, if any. These studies may be challenging to conduct and interpret because SUDEP is relatively uncommon and large numbers will be necessary to narrow confidence intervals to determine the clinical relevance. Also adjustments will be needed to account for the potent risks associated with other independent factors.

Postictal central apnea as a cause of SUDEP: evidence from near-SUDEP incident.

Epilepsia.  2000; 41(11):1494-7 (ISSN: 0013-9580)

So EL; Sam MC; Lagerlund TL
Section of Electroencephalography and the Division of Epilepsy, Mayo Clinic and Mayo Medical School, Rochester, Minnesota 55905, USA. [e-mail]

While undergoing video-EEG monitoring, a 20-year-old woman had a 56-second convulsive seizure, after which she developed persistent apnea. The rhythm of the electrocardiogram complexes was unimpaired for approximately 10 seconds, after which it gradually and progressively slowed until it stopped 57 seconds later. Evaluation after successful cardio-respiratory resuscitation showed no evidence of airway obstruction or pulmonary edema. The patient had a previous cardio-respiratory arrest after a complex partial seizure without secondary generalization. Although epileptic seizures are known to be potentially arrhythmogenic to the heart, our observations strongly suggest that one probable mechanism of sudden unexplained death in epilepsy is the marked central suppression of respiratory activity after seizures.

Sudden unexpected death in epilepsy: a series of witnessed deaths.

J Neurol Neurosurg Psychiatry.  2000; 68(2):211-3 (ISSN: 0022-3050)

Langan Y ; Nashef L ; Sander JW
Epilepsy Research Group and Neuroepidemiology Unit, Institute of Neurology, Queen Square, London WC1N 3BG, UK. [e-mail]

OBJECTIVES: Sudden unexpected death in epilepsy (SUDEP) represents a significant category of mortality in the population with chronic epilepsy. A consistent feature is that most of these deaths are unwitnessed. The aim was to identify witnessed deaths, examine the circumstances, and relate these findings to the proposed mechanisms for SUDEP. METHODS: During the course of case ascertainment for a control study on SUDEP, witnessed deaths were identified and the circumstances examined in detail. Cases were notified by coroners, neurologists, and bereaved families. The findings were related to the proposed mechanisms for SUDEP which include central and obstructive apnoea and cardiac arrhythmia. RESULTS: One hundred and thirty five SUDEP cases have been identified to date, of which 15 were witnessed deaths. Twelve deaths were associated with convulsive seizures, one collapse occurred 5 minutes after a generalised seizure, another collapse occurred after an aura and one patient died while in a probable post ictal state. Witnesses reported that 12 of the 15 cases experienced respiratory difficulty. CONCLUSIONS: Most sudden epilepsy deaths are unwitnessed. Where witnessed most occur in association with a seizure and respiratory compromise is a prominent feature. Positioning or stimulation of respiration may be important in the prevention of these deaths.

Postictal central apnea as a cause of SUDEP: evidence from near-SUDEP incident.

Epilepsia.  2000; 41(11):1494-7 (ISSN: 0013-9580)

So EL ; Sam MC ; Lagerlund TL
Section of Electroencephalography and the Division of Epilepsy, Mayo Clinic and Mayo Medical School, Rochester, Minnesota 55905, USA. [e-mail]

While undergoing video-EEG monitoring, a 20-year-old woman had a 56-second convulsive seizure, after which she developed persistent apnea. The rhythm of the electrocardiogram complexes was unimpaired for approximately 10 seconds, after which it gradually and progressively slowed until it stopped 57 seconds later. Evaluation after successful cardio-respiratory resuscitation showed no evidence of airway obstruction or pulmonary edema. The patient had a previous cardio-respiratory arrest after a complex partial seizure without secondary generalization. Although epileptic seizures are known to be potentially arrhythmogenic to the heart, our observations strongly suggest that one probable mechanism of sudden unexplained death in epilepsy is the marked central suppression of respiratory activity after seizures.

Sudden unexpected death in epilepsy: a series of witnessed deaths

Y Langan^a, L Nashef^{b c}, J W A S Sander^a

Sudden unexpected death in epilepsy (SUDEP) represents a significant category of mortality in the population with epilepsy with an estimated minimum of 500 deaths occurring yearly in the United Kingdom.¹ The mechanism of sudden death in epilepsy is unknown but a consistent finding is that most deaths are unwitnessed.^2-6 Information gained from previous studies suggests that most are consequent on a seizure although this view remains controversial.²

In one study it was reported that nine of 37 patients "died as a result of a single seizure or a few seizures in the presence of witnesses".⁵ In another report three of the 12 deaths identified were witnessed with only one having a convulsive seizure before death.⁴ In a prospective study it was found that in 38% or 23 out of 60 cases death was witnessed and a convulsive seizure was seen in 14 of these cases.³ In a series of interviews with self referred bereaved relatives it was found that two of 26 deaths were witnessed² and in a study of SUDEP in the Republic of Ireland in one of 15 cases death was witnessed having being preceded by a generalised seizure.⁷
METHODS

We are carrying out a case-control study on SUDEP and to date 135 cases have been referred by coroners, neurologists via the British Neurological Surveillance Unit (BNSU),⁸ and the charity "Epilepsy Bereaved?" with whose assistance families were interviewed. Fifteen of these cases were witnessed, the circumstances were examined in detail, and the findings related to the proposed mechanisms for sudden death in epilepsy which include central and obstructive apnoea and cardiac arrhythmia.

Sudden unexpected death in epilepsy was defined as: sudden, unexpected, non-traumatic, and non-drowning death in an individual with epilepsy, with or without evidence for a seizure and excluding documented status epilepticus where postmortem examination does not reveal a cause for death.⁹ Background clinical information, postmortem reports, and, where applicable, inquest transcripts were sought for all cases identified. Ethical approval was obtained from the joint medical ethics committee of the National Hospital for Neurology and Neurosurgery and the Institute of Neurology, University College London. Informed consent was obtained from all families before interview.

RESULTS
Nineteen cases were initially considered. Four were excluded, three because the diagnosis of epilepsy was in doubt and one because of previous publicity surrounding the case. In one excluded case, although death was certified as being due to epilepsy it has been subsequently decided that this is unlikely given that the patient's mother and sister have been diagnosed with long QT syndrome.

There were nine men and six women ranging in age from 17 to 47 years with a mean age of 32 years. This group comprises 11% of all cases of sudden death identified to date as part of the case-control study. Nine patients had localisation related epilepsy, two had idiopathic generalised epilepsy, and four had epilepsy of undetermined type. Circumstances of death are described in the table. Of the unwitnessed cases 80 (67%) were found dead in bed, 35 (29%) were found dead elsewhere in the home, and five (4%) were found dead outside the home.

Death occurred in association with a witnessed generalised tonic-clonic seizure in 12 of the 15 cases. In the other three one person shouted "I'm going to have a seizure" before collapsing without having a convulsive seizure. One patient had recovered consciousness after a seizure 5 minutes previously before he suddenly collapsed. A young girl with active epilepsy was found collapsed and incoherent in the street and no obvious convulsion was witnessed; however, she had been incontinent of urine and her mother told bystanders that she had had a fit. It seems likely that she was in a postictal state. Bystanders commenced artificial respiration having noticed that she was no longer breathing but this was unsuccessful. A pulse was palpable at the start of resuscitation but subsequently faded. Resuscitation was attempted in 13 of the 15 cases, immediately by staff or family on the scene in eight cases and in five after paramedics arrived. Three resuscitated people subsequently died having been maintained on ventilators for periods ranging from 12 to 48 hours.

In 12 cases witnesses commented on the fact that the persons concerned had difficulty breathing, the following cases being illustrative examples. As the cases were identified through various sources and the quality of information received varied it is not possible to describe cases in a uniform manner.

A 47 year old man had a history of secondary generalised tonic-clonic seizures after a head injury and subsequent meningitis in 1969. He had not had a seizure for 8 years and was on no antiepileptic medication. He came home early from work with a headache and went to bed. On going to investigate noises from the bedroom his wife found him lying on his side, jerking and with obvious bleeding from his tongue. After a minute or so he suddenly flipped on to his back and the seizing stopped. She noticed that he was blue and was not breathing so she commenced mouth to mouth resuscitation. He apparently began to breathe on his own again and she left the room to telephone for assistance. He was not placed in the recovery position. On her return a few minutes later he was no longer breathing and no pulse was palpable so she restarted cardiopulmonary resuscitation which was continued by the paramedics on their arrival, to no avail. This case suggests central apnoea as a mechanism for SUDEP.

In two other cases breathing difficulty was likely to be obstructive. A 34 year old man woke up feeling unwell, came downstairs, and had a generalised tonic-clonic seizure. He then collapsed across his mother's Zimmer frame with his throat resting across the bar.

In another case an 18 year old woman collapsed in a convulsive seizure and landed under the sink. On their arrival the ambulance crew reported that she was cyanosed and asystolic and it was considered that her airway was compromised due to the position in which she lay.

Discussion

Various mechanisms have been proposed for sudden death in epilepsy. Apnoea was a frequent finding in a study of ictal cardiorespiratory variables at the telemetry unit of the National Hospital for Neurology and Neurosurgery.¹⁰ This hypoventilation, which was primarily central in nature, occurred in the context of both generalised and partial seizures. Obstructive apnoea occurred less commonly in this study but it is likely that in the controlled environment of the telemetry unit, where nursing intervention is likely to minimise airway compromise, the contribution of obstructive apnoea, whether instrinsic or extrinisic, to SUDEP may be underestimated.

An important role for hypoventilation is supported by an animal model in which seizures are chemically induced in sheep, some of whom die. In the animals who die during a seizure a precipitous drop in the partial pressure of oxygen occurs along with a concomitant rise in pulmonary artery and left atrial pressures resulting in pulmonary oedema. In this animal model care was taken to ensure that airway patency was maintained.¹¹ This model of SUDEP is consistent with the observation that pulmonary oedema, in itself thought insufficient to cause death, is a frequent finding and almost a pathological hallmark for sudden death in epilepsy.¹² Of note in relation to the role of apnoea are the findings of a study of SUDEP in a residential school for children with epilepsy and learning difficulties. The children were closely supervised by experienced staff while at school, including at night. No cases were witnessed during the period of the study, suggesting that attention to the recovery of the person after a seizure and positioning or stimulating if necessary may have a role in the prevention of SUDEP.¹³

The development of apnoea during a seizure does not exclude a role for cardiac arrhythmia as a mechanism in SUDEP. Clinical observations of seizures associated with severe cardiac arrhythmias have been reported, mainly sinus arrest and bradycardia. In most of these cases the epileptic focus was located in the temporal lobes.^14-17

Bradyarrhythmias, often transient, have also been noted to occur in the presence of apnoea.¹⁰ Proposed mechanisms for this transient bradycardia include a direct effect of the seizure discharge or a response to apnoea mediated by the cardiorespiratory reflex.¹⁸ Sinus tachycardia is a common accompaniment to seizures¹⁹ but evidence of the occurrence of malignant tacharrhythmias is limited.²⁰ Prolongation of the QT interval has been postulated to occur in sudden death. Investigators have found some evidence of ictal prolongation of the QT and Qtc intervals but not beyond the normal ranges.²¹ It has already been noted that cases of prolonged QT syndrome may be misdiagnosed as epilepsy.²² A recent study which examined cardiac pathology in SUDEP cases found evidence of perivascular and interstitial fibrosis along with reversible myocyte vacuolisation. The control group, in whom such abnormalities were not detected, did not include those with epilepsy dying of other causes and thus the relevance of these findings is unclear.²³

To conclude, in this series, the largest collection of sudden deaths to date, only 11% of deaths were witnessed and most of these occurred in association with a seizure. The account of these deaths support the view that both central and obstructive apnoea play important parts in the genesis of SUDEP, with most witnesses stating that the victims experienced breathing difficulties. Airway obstruction seemed to be a significant factor in at least two cases and it is therefore possible that deaths presently categorised as SUDEP occur through various mechanisms. Although resuscitation was unsuccessful in the cases described most sudden deaths remain unwitnessed. One possible explanation for this is that where seizures are witnessed and recovery is monitored timely assistance by positioning of the patient or stimulation of respiration may prevent a fatal outcome in some cases. This raises the important issue of supervision, which will be examined in the case-control study. Given the association of most witnessed deaths with convulsive seizures, and the previous findings of circumstantial and physical evidence suggestive of seizures in unwitnessed cases,² it is likely that optimisation of seizure control is also important in the prevention of these deaths.

1.	Nashef L, Brown S. Epilepsy and sudden death. Lancet 1996;348:1324-1325[Medline].
2.	Nashef L, Garner S, Sander JWAS, et al. Circumstances of death in sudden death in epilepsy: interviews of bereaved relatives. J Neurol Neurosurg Psychiatry 1998;64:349-352[Abstract/Free Full Text].
3.	Leestma JE, Walczak T, Hughes JR, et al. A prospective study on sudden unexpected death in epilepsy. Ann Neurol 1989;26:195-203[Medline].
4.	Lip GY, Brodie MJ. Sudden death in epilepsy: an avoidable outcome? J R Soc Med 1992;85:609-611[Abstract].
5.	Terrence CF Jr, Wisotzkey HM, Perper JA. Unexpected, unexplained death in epileptic patients. Neurology 1975;25:594-598[Abstract/Free Full Text].
6.	Nashef L, Sander JW. Sudden unexpected deaths in epilepsy: where are we now? Seizure 1996;5:235-238[Medline].
7.	Langan Y. The incidence of sudden unexpected death in epilepsy in South Dublin and Wicklow. Seizure 1998;7:355-358[Medline].
8.	Cockerell OC, Gupta S, Catchpole M, et al. The British neurologial surveillance unit: a nationwide scheme for the ascertainment of rare neurologial disorders. Neuroepidemiology 1995;14:182-187[Medline].
9.	Nashef L. Sudden unexpected death in epilepsy: terminology and definitions. Epilepsia 1997;38:S6-S8.
10.	Nashef L, Walker F, Allen P, et al. Apnoea and bradycardia during epileptic seizures: relation to sudden death in epilepsy. J Neurol Neurosurg Psychiatry 1996;60:297-300[Abstract].
11.	Johnston SC, Horn JK, Valente J, et al. The role of hypoventilation in a sheep model of epileptic sudden death. Ann Neurol 1995;37:531-537[Medline].
12.	Terrence CF, Rao GR, Perper JA. Neurogenic pulmonary edema in unexpected, unexplained death of epileptic patients. Ann Neurol 1981;9:458-464[Medline].
13.	Nashef L, Fish DR, Garner S, et al. Sudden death in epilepsy: a study of incidence in a young cohort with epilepsy and learning difficulty. Epilepsia 1995;36:1187-1194[Medline].
14.	Howell SJ, Blumhardt LD. Cardiac asystole associated with epileptic seizures: a case report with simultaneous EEG and ECG. J Neurol Neurosurg Psychiatry 1989;52:795-798[Abstract].
15.	Fincham RW, Shivapour ET, Leis AA, et al. Ictal bradycardia with syncope: a case report. Neurology 1992;42:2222-2223[Free Full Text].
16.	Dasheiff RM, Dickinson LJ. Sudden unexpected death of epileptic patient due to cardiac arrhythmia after seizure. Arch Neurol 1986;43:194-196[Abstract].
17.	Jallon P. Epilepsie et coeur. Rev Neurol 1997;153:173-184[Medline].
18.	Spyer KM. Central nervous control of the cardiovascular system. In: Bannister R, Mathias CJ, eds. Autonomic failure., 3rd ed. Oxford: Oxford University Press, 1992;55-77.
19.	Blumhardt LD, Smith PEM, Owen L. Electrocardiographic accompaniments of temporal lobe epileptic seizures. Lancet 1986;i:1051-1056.
20.	Keilson MJ, Hauser A, Magrill JP, et al. ECG abnormalities in patients with epilepsy. Neurology 1987;37:1624-1626[Abstract/Free Full Text].
21.	Tavernor SJ, Brown SW, Tavernor RME, et al. Electrocardiograph QT lengthening associated with epileptiform EEG discharges: a role in sudden unexplained death in epilepsy? Seizure 1996;1:79-83.
22.	Ballardie FW, Murphy RP, Davis J. Epilepsy: a presentation of the Romano Ward syndrome. BMJ 1983;24:896-897.
23.	Natelson BH, Suarez RV, Terrence CF, et al. Patients with epilepsy who die suddenly have cardiac disease. Arch Neurol 1998;55:857-860[Abstract/Free Full Text]

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