Sudden unexpected, unexplained death in epilepsy autopsied patients

Sudden unexpected, unexplained death in epilepsy (SUDEP) has been reported to be responsible for 2 to 17% of all deaths in patients with epilepsy. This study was conducted to determine the circumstances of SUDEP and the autopsy findings in these patients. Fifty-three individuals whose cause of death was related to epilepsy were identified and in 30 cases relatives or friends were interviewed about the circumstances of death and other information which allowed to classify the patients as SUDEP or not. The death certificates were also reviewed. We found 20 cases of SUDEP. Most of them were found dead lying on the bed with no evidence of seizure event, and most of them had pulmonary and/or cerebral edema as the cause of death. The incidence and the risk of SUDEP can only be fully ascertained if all sudden deaths had postmortem examination. Consensus in certifying SUDEP cases would allow better accuracy in national mortality rate.     

Sudden unexpected death in epilepsy

Sudden unexpected death in epilepsy (SUDEP) has an incidence ranging between 0.09 and 9 per 1000 patient-years depending on the patient population and the study methodology. It is the commonest cause of death directly attributable to epilepsy, and occurs at or around the time of a seizure. The principal risk factor for SUDEP is poorly controlled generalized tonic-clonic seizures. Other risk factors include polytherapy, male sex, early age at onset of epilepsy, symptomatic etiology, and, possibly, treatment with lamotrigine. The mechanisms underlying SUDEP are poorly understood, but autonomic dysfunction, central apnea, cerebral depression, and cardiac arrthymias have all been described in animal models of SUDEP and during human seizures. Prevention of this fatal event should be aimed at optimizing control of seizures, including prompt referral for consideration of epilepsy surgery. All patients should be told about the risks of SUDEP and informed that complete seizure control appears to be the one proven way of preventing the phenomenon.     

Sudden unexpected death in epilepsy

Mortality in people with epilepsy is two- to three-times that of the general population. This can be attributed to epilepsy itself (epilepsy-related death) or to the underlying cause of the epilepsy. Sudden unexpected death in epilepsy (SUDEP) is the commonest cause of epilepsy-related death. It is a syndrome where a person with epilepsy dies suddenly and no other cause of death is found. There are frequent reports of persons dying alone in their sleep. It is assumed that death occurs following a seizure but since the deaths are often unwitnessed this is only an assumption. The most important risk factor appears to be poor seizure control. Lately, SUDEP has received much public interest, has been the subject of international forums, ethical debates and comprises part of national guidelines on epilepsy management. Despite its high profile, the evidence for specific risk factors and pathophysiology is still not established. Poor incident case reporting, inaccurate death certification and fewer post-mortem examinations have limited the value of epidemiological data on SUDEP. Here, we review the characteristics of SUDEP, its likely risk factors, mechanisms and differential diagnosis, and consider possible strategies for prevention. We also explore the discussion of SUDEP with patients and the management of relatives of SUDEP patients.     

Pediatric experience with sudden unexplained death in epilepsy at a tertiary epilepsy center

Sudden unexplained death in epilepsy is rare in children, and few studies report risk factors. We reviewed our experience with 17 cases of sudden unexplained death in epilepsy to determine risk factors in children. The charts of all patients with onset of epilepsy at less than age 18 years who suffered sudden unexplained death in epilepsy between August 1992 and April 2004 at our epilepsy center were retrospectively reviewed. Deaths were classified as possible, probable, or definite sudden unexplained death in epilepsy. There were seven cases of definite, nine cases of probable, and one case of possible sudden unexplained death in epilepsy. Generalized tonic-clonic seizures and prone position during sleep were found to be major risk factors. Sudden unexplained death in epilepsy in children and adolescents is associated with convulsive seizures, and aggressive treatment of nocturnal generalized tonic-clonic seizures might help lower the occurrence.     

Sudden unexpected death in epilepsy in adults with mental retardation

The medical records of residents of a facility for persons with mental retardation from January 1, 1978, through December 31, 1997, were analyzed to identify incidence of sudden unexpected death for groups of 180 individuals with and 125 without comorbid epilepsy. Eighty deaths were identified, with 55 occurring in the epilepsy group and 25 in the nonepilepsy group. The rate of sudden unexpected death was 1.3 deaths per 1,000 patient years in the nonepilepsy group and 3.6 deaths per 1,000 patient years in the epilepsy group. The risk factors for sudden unexpected death in the epilepsy group were nonambulatory status and poorly controlled seizure disorder (increased seizure rate and increased number of antiepileptic drugs).     

EEG and ECG in sudden unexplained death in epilepsy

PURPOSE: Sudden unexpected death in epilepsy (SUDEP) is a major cause of mortality for patients with epilepsy. Cardiac factors may be involved and were evaluated in this study. METHODS: EEG and ECG data for 21 patients with definite (n = 6) or probable (n = 15) SUDEP were compared with data from a group of 43 patients with refractory partial epilepsy. ECG abnormalities and heart rate (HR) changes were correlated with clinical data. RESULTS: Fourteen patients died in their sleep; two were awake. Ictal maximal HR (90 seizures from 16 of 21 patients) was significantly higher in SUDEP (mean, 149 beats/min, BPM) than in comparison patients (mean, 126 BPM; p < 0.001). Greater increases in HR were associated with seizures arising from sleep (78 BPM increase) than from wakefulness (47 BPM; p < 0.001) in SUDEP, as compared with the non-SUDEP group (52 BPM in sleep, 43 BPM in wakefulness; p = 0.27). Ictal cardiac repolarization and rhythm abnormalities occurred in 56% of SUDEP (including two atrial fibrillation, two ventricular premature depolarizations, two marked sinus arrhythmia, two atrial premature depolarizations, one junctional escape, one ST-segment elevation), and 39% of comparison patients (p = 0.39). No specific seizure onset (laterality or lobe) was associated with SUDEP. CONCLUSIONS: This study reveals, for the first time, evidence of increased autonomic stimulation (as measured by HR) associated with seizures, particularly in sleep, in patients with SUDEP, as compared with a clinically similar group of patients with refractory epilepsy.     

Sudden death in epilepsy recorded in ambulatory EEG

A woman with epilepsy died during a seizure and the event was recorded on ambulatory EEG. The circumstances were typical of sudden death in epilepsy (SUDEP). The EEG revealed that the patient had suffered a generalised seizure that abruptly ended with cessation of all cerebral electrical activity. Two other cases recorded on videotelemetry demonstrating similar EEG features were reported in the literature. We postulate that abrupt irreversible cerebral electrical shutdown during a seizure may be the primary mechanism of SUDEP.     

Sudden unexpected death in people with epilepsy: a pediatric perspective

The possibility of sudden unexpected death in people with epilepsy (SUDEP) is very frightening for parents of a child with epilepsy. The mechanism for SUDEP is unclear but is probably most commonly related to postictal respiratory insufficiency. Occasionally the cause is a cardiac arrhythmia induced by a seizure. Even though children with epilepsy have an increased risk of death, SUDEP is very rare (1-2/10,000 patient-years). Nearly all of the mortality in children with epilepsy is related to the underlying neurologic disorder, not the seizures. Normal children with epilepsy do not have an increased risk of death compared with the general population. There is no current proven strategy to prevent SUDEP, although its rarity precludes systematic trials. Common sense approaches include identifying patients with cardiac arrhythmias as the cause of misdiagnosed epilepsy and vigorous attempts to control resistant seizure disorders.     

Sudden unexpected death in epilepsy during cenobamate clinical development

Objective

We assessed mortality, sudden unexpected death in epilepsy (SUDEP), and standardized mortality ratio (SMR) among adults treated with cenobamate during the cenobamate clinical development program.

Methods

We retrospectively analyzed deaths among all adults with uncontrolled focal (focal to bilateral tonic–clonic [FBTC], focal impaired awareness, focal aware) or primary generalized tonic–clonic (PGTC) seizures who received ≥1 dose of adjunctive cenobamate in completed and ongoing phase 2 and 3 clinical studies. In patients with focal seizures from completed studies, median baseline seizure frequencies ranged from 2.8 to 11 seizures per 28 days and median epilepsy duration ranged from 20 to 24 years. Total person-years included all days that a patient received cenobamate during completed studies or up to June 1, 2022, for ongoing studies. All deaths were evaluated by two epileptologists. All-cause mortality and SUDEP rates were expressed per 1000 person-years.

Results

A total of 2132 patients (n = 2018 focal epilepsy; n = 114 idiopathic generalized epilepsy) were exposed to cenobamate for 5693 person-years. Approximately 60% of patients with focal seizures and all patients in the PGTC study had tonic–clonic seizures. A total of 23 deaths occurred (all in patients with focal epilepsy), for an all-cause mortality rate of 4.0 per 1000 person-years. Five cases of definite or probable SUDEP were identified, for a rate of .88 per 1000 person-years. Of the 23 overall deaths, 22 patients (96%) had FBTC seizures, and all 5 of the SUDEP patients had a history of FBTC seizures. The duration of exposure to cenobamate for patients with SUDEP ranged from 130 to 620 days. The SMR among cenobamate-treated patients in completed studies (5515 person-years of follow-up) was 1.32 (95% confidence interval [CI] .84–2.0), which was not significantly different from the general population.

Significance

These data suggest that effective long-term medical treatment with cenobamate may reduce excess mortality associated with epilepsy.