Epilepsy, Vagal Nerve Stimulation by the NCP System, Mortality, and Sudden, Unexpected, Unexplained Death

Summary: Purpose: To determine rates of all-cause mortality and of sudden, unexpected, unexplained deaths in epilepsy (SUDEP) in a cohort of individuals treated with the Neuro Cybernetic Prosthesis (NCP) System for intractable epilepsy, and; to contrast the NCP experience with other epilepsy cohorts.
Methods: A cohort of 791 individuals were followed for 1, 335 person-years from implantation. Of the total cohort, 120 individuals had their NCP System devices deactivated. The 15 deaths which occurred during NCP System activation were reviewed for SUDEP by a panel. There were three additional deaths and 242.5 person-years of monitoring after deactivation.
Results: The standardized mortality ratios for NCP System were 5.3, 95% confidence interval (CI) 3.0–8.7; and for the time period after device deactivation, 4.4, 95% CI 0.9–12.8. Six of the deaths during stimulation were considered definite or probable SUDEP and two as possible SUDEP. Seven were not considered to be SUDEP. The incidence of definite/probable SUDEP was 4.5 per 1,000 person-years and 6.0 per 1,000 person-years for definite/probable/possible SUDEP.
Conclusions: The mortality rates and standardized mortality ratios are comparable with studies of young adults with intractable epilepsy who were not treated with NCP System. These SUDEP rates are not significantly different from those reported in the recent studies of lamotrigine (LTG), gabapentin (GBP), and tiagabine (TGB). The higher rates of SUDEP in the NCP System cohort, as compared with recent drug trials, presumably is explained by the selection of relatively higher-risk patients for the NCP System device.     

Epilepsy, vagal nerve stimulation by the NCP system, all-cause mortality, and sudden, unexpected, unexplained death

PURPOSE: This report concerns the 2-year extension of the study of mortality and sudden, unexpected, unexplained death in epilepsy (SUDEP) in the cohort of patients receiving vagal nerve stimulation by the NCP System for the treatment of epilepsy. METHODS: A cohort of 1,819 individuals was followed 3,176.3 person-years from implantation. The 25 deaths that occurred during NCP System activation were reviewed for SUDEP by a panel. RESULTS: The mortality rates were lower [standardized mortality ratio (SMR = 3.6)] with the extended follow-up compared to the previous finding (SMR = 5.3). The SUDEP rates (4.1 vs. 4.5 per 1,000 person-years) were similar to those in the previous study of this cohort. When the vagal nerve stimulation experience is stratified by duration of use, the rate of SUDEP was 5.5 per 1,000 over the first 2 years, but only 1.7 per 1,000 thereafter. CONCLUSIONS: The mortality and SUDEP rates are similar to those reported from clinical trials of new drugs and cohorts of severe epilepsy. The lower SUDEP rates after 2 years of follow-up are intriguing, but require further investigation.     

Community-Based Study of Mortality in Children with Epilepsy

Summary: Summary: We used the records of a statewide pediatric mortality surveillance system to determine mortality rates and causes of death in children with epilepsy. Of the 1,095 children aged 1–14 years who died in the state of Victoria during the study period 1985–1989,93 had a history of epilepsy. Six children (6%) had primary epilepsy, and 87 (94%) had secondary epilepsy. Death was (a) directly attributable to epilepsy in 20 (22%), including 11 with sudden unexplained death, (b) not directly attributable to epilepsy in 59 (63%), and (c) of undetermined cause in 14 (15%). No classifiable death occurred as a direct result of status epilepticus. The average annual mortality rates for children with epilepsy were (a) death from all causes, 30.6 in 10,000 [95% confidence interval (CI) 19.7, 47.51, and (b) death attributable to epilepsy, 6.6 in 10,000 (95% CI 3.7, 11.8). Relative to the all-cause mortality rate in children without epilepsy, the all-cause mortality rate ratios were (a) all children with epilepsy, 13.2 (95% CI 8.5, 20.7); (b) primary epilepsy, 1.1 (95% CI 0.5, 2.6); and (c) secondary epilepsy, 49.7 (95% CI 31.7, 77.9). The mortality rate ratios for secondary epilepsy relative to primary epilepsy were (a) death from all causes, 43.5 (95% CI 19.0, 99.5); and (b) death attributable to epilepsy, 9.0 (95% CI 3.3, 24.8). Epilepsy appeared on the death certificate of only 11 of 20 (55%) children whose deaths were attributable to epilepsy. We conclude that (a) there was an increased risk of death during childhood in children with epilepsy; (b) the risk of death was greatest for children with secondary epilepsy; (c) potentially preventable, epilepsy-related deaths occurred in children with primary epilepsy; (d) sudden unexplained death accounted for at least 12% of deaths; and (e) death certification was deficient with respect to recording of epilepsy.     

Sudden Unexpected Death in Epilepsy: A Review of Incidence and Risk Factors

Summary:  Sudden unexpected death in epilepsy (SUDEP) is the most important direct epilepsy-related cause of death. However, SUDEP is rare in patients with new onset epilepsy and in patients in remission. Incidence is about 0.35 cases/1,000 person-years in population-based incidence cohort of epilepsy. Incidence is considerably higher in patients with chronic epilepsy, 1–2/1,000 person-years, and highest with severe, refractory seizures, 3–9/1,000. The highest rates occur from 20 to 40 years. Most SUDEP appears seizure-related. When witnessed, the fatal event generally occurred in association with generalized tonic–clonic seizure. Two recent case–control studies suggest that seizure frequency is the strongest risk factor for SUDEP: relative risk = 23 (95% CI = 3.2–170) for persons with ≥1 seizure during the year of observation versus seizure-free patients. Onset of epilepsy at an early age and long duration of the disorder are other risk factors. Although SUDEP has not been associated with the use of any particular antiepileptic drugs (AEDs), some case–control studies have pointed to an association between SUDEP and polytherapy with AEDs and frequent dose changes independent of seizure frequency. Although recent epidemiological studies have been helpful in identifying patients at risk for SUDEP, providing clues to mechanisms behind SUDEP, no single risk factor is common to all SUDEP, suggesting multiple mechanisms or trigger factors. Seizure control seems of paramount importance to prevent SUDEP. Further large-scale case–control studies are needed to assess the role of AEDs in order to form a basis for treatment strategies aiming at seizure control and prevention of SUDEP.     

Epilepsy‐related mortality is low in children: A 30‐year population‐based study in Olmsted County,MN

Purpose: Epilepsy is a common childhood neurologic disorder, affecting 0.5–1% of children. Increased mortality occurs due to progression of underlying disease, seizure‐related accidents, suicide, status epilepticus, aspiration during seizures, and sudden unexplained death in epilepsy (SUDEP). Previous studies show mortality rates of 2.7–6.9 per 1,000 person‐years. Potential risk factors include poor seizure control, intractable epilepsy, status epilepticus, tonic–clonic seizures, mental retardation, and remote symptomatic cause of epilepsy. Few population‐based studies of mortality and SUDEP in childhood‐onset epilepsy have been published. The purpose of this study is to report mortality and SUDEP from a 30‐year population‐based cohort of children with epilepsy. Methods: The Medical Diagnostic Index of the Rochester Epidemiology Project was searched for all codes related to seizure and convulsion in children living in Olmsted County, Minnesota and of ages birth through 17 years from 1980 through 2009. The medical records of these children were reviewed to identify all those with new‐onset epilepsy, and to abstract other baseline and follow‐up information. Potential risk factors including seizure type, epilepsy syndrome, history of status epilepticus, the presence and severity of neurologic impairment, and epilepsy outcome was reviewed. Epilepsy outcome was characterized by seizure frequency, number of antiseizure medications (antiepileptic drugs, AEDs) used, and number of AEDs failed due to lack of efficacy, and epilepsy intractability at 1 year and 2, 3, 5, 10, 15, and 20 years after epilepsy onset. We followed all children through their most recent visit to determine vital status, cause of death, and whether autopsy was performed. Key Findings: From 1980 to 2009, there were 467 children age birth through 17 years diagnosed with epilepsy while residents of Olmsted County, Minnesota, and who had follow‐up beyond the time of epilepsy diagnosis. Children were followed for a median of 7.87 years after the time of diagnosis (range 0.04–29.49 years) for a total of 4558.5 person‐years. Sixteen (3.4%) of the children died, or 3.51 deaths per 1,000 person‐years. Two deaths were epilepsy related (12.5%) for a rate of 0.44 per 1,000 person‐years. One of these children died of probable SUDEP and one died of aspiration during a seizure. The remaining 14 deaths (87.5%) were caused by other complications of underlying disease. Several risk factors for mortality were found, including abnormal cognition, abnormal neurologic examination, structural/metabolic etiology for epilepsy, and poorly controlled epilepsy. Significance: Although mortality in children with epilepsy was higher than what would be expected in the general pediatric population, death occurred significantly more in children with neurologic impairment and poorly controlled epilepsy. Epilepsy‐related death, including SUDEP, was rare and mortality due to epilepsy alone was similar to the expected mortality in the general population (observed deaths = 2, expected deaths = 1.77; standardized mortality ratio 1.13, 95% confidence interval 0.19–3.73, p = 0.86). By contrast, most children died of complications of the underlying neurologic disease or unrelated disease rather than the epilepsy.     

Mortality after Epilepsy Surgery

Summary:  Mortality rates are higher in people with refractory epilepsy than in the general population. We assessed mortality rates in a prospectively followed cohort who had epilepsy surgery, to examine the factors related to mortality and to assess the relationship between seizure control and mortality. Five hundred eighty-three patients were evaluated. Mortality was strongly related to seizure control (p = 0.001), with 18 deaths observed in patients with recurrent seizures (mortality rate = 11.4 per 1,000 person-years) and 1 death in patients with no recurrent seizures (mortality rate = 0.85 deaths per 1,000 person-years). Patients with generalized epilepsy who had corpus callosotomy had a higher mortality rate than patients who had resective or transective surgery. The side of surgery and gender did not influence mortality rates. The standardized mortality ratio was 5.75 for patients with recurrent seizures and was significantly higher for females than males. These data show that the excess mortality associated with refractory epilepsy is eliminated after epilepsy surgery when seizures are abolished and suggest that epilepsy surgery reduces the risk of epilepsy-associated death.     

Sudden Death in Epilepsy: A Study of Incidence in a Young Cohort with Epilepsy and Learning Difficulty

Summary: Sudden death, often seizure related, may occur in patients with epilepsy. Population-based incidence is probably on the order of 1:1,000/year. The incidence is much higher in selected groups, however. We wished to establish the incidence of sudden unexpected death (SUD) in a young cohort with severe epilepsy and learning difficulties. The study cohort included 310 pupils with epilepsy enrolled at a special residential school between April 1970 and April 1993. The follow-up period totaling 4,135 person-years included a period of residence at the school as well as time after leaving. Age and sex standardized overall mortality ratio was 15.9 [95% confidence interval (CI) 10.6–23.0], with 20 of 28 deaths considered epilepsy related. An incidence of sudden death cases of 1:295/year was noted. All 14 sudden deaths occurred when the pupils were not under the close supervision of the school and most were unwitnessed, which has implications for prevention.     

Cardiac Deaths in Epilepsy

Summary: A study of heart disease mortality and morbidity in patients with epilepsy in Rochester, Minnesota, U.S.A., is presented. In a cohort of 725 incident cases of epilepsy followed for approximately 10,000 person-years, 237 deaths and 48 incident cases of ischemic heart disease were noted. Overall, the cohort mortality rate was 2.1 times that of the general population. For those with idiopathic epilepsy, the mortality rate was 1.6 times that of the general population. For ischemic heart disease, the epilepsy cohort experienced a standardized mortality rate (SMR) of 1.6, slightly higher for remote symptomatic than idiopathic epilepsy. For sudden death as the initial manifestation of heart disease, the SMR was 2.3. The ratio was not significantly higher for those with idiopathic epilepsy but was 3.9 for remote symptomatic epilepsy. The findings show much lower incidence rates and relative incidence of sudden death than all of the more recent sudden unexpected death in epilepsy studies. Reasons for this discrepancy are discussed.     

The Mortality Associated with Epilepsy, with Particular Reference to Sudden Unexpected Death: A Review

Summary: Recent studies indicate that the overall mortality rate for persons with epilepsy is elevated two- or threefold compared with the general population. The standardized mortality ratio (SMR) is greatest in the first few years after diagnosis and in symptomatic epilepsies. Idiopathic epilepsies also have a small increase in SMR. The sudden unexpected death rate in those with epilepsy (SUDEP) depends on the population examined. In the general population of persons with epilepsy, the risk is between 1:500 and 1:1,000 person-years. For those with severe epilepsy or other neurologic impairments, the risk appears to be 1:200 person-years. The risk in children remains uncertain. Estimates of mortality should be borne in mind when patients are counseled about the risks and benefits of various treatment strategies.     

Comparative bioethics in bipolar and epilepsy research.

RATIONALE: AEDs are increasingly evaluated for efficacy in bipolar disorders utilizing double-blind, placebo-controlled, randomized clinical trials (RCTs) as required by the FDA. However, the risk to patients is under-estimated in trial design. Bipolar depression has a significant risk for suicide; bipolar episodes can lead to kindling with increased long-term morbidity; rapid regression may occur during the placebo phase or during dose ranging trials with resultant active suicide status. The associated risks mandate that the ethics of FDA-required protocols are addressed. METHOD: Comparative analysis and literature review of bipolar and epilepsy research designs. RESULTS: In psychiatry, all INDs require RCTs for approval. In epilepsy, AEDs are initially approved as add-on agents only. Once AEDs have demonstrated add-on efficacy, cross-over studies comparing active AEDs, sub-optimal dosing paradigms, new-onset, and pre-surgical inpatient placebo trials are utilized to prove efficacy of the new AED in monotherapy. Ethical considerations to avoid seizures and to minimize risks to subjects have led to newer clinical trial designs. CONCLUSIONS: The FDA initially requires add-on studies with new AEDs due to the risk of seizures during the placebo phase. The author argues that bipolar research warrants similar add-on studies to prove efficacy because the risk of suicide and increased long-term morbidity in the bipolar population is as significant as the risk of seizures in the epilepsy population. Although the number of patients needed to prove statistical efficacy would increase, the safety of such research would also markedly increase. The author further concludes that with the risk of suicide during bipolar research, ethical considerations require increased frequency of patient contact with a significant other co-signing the informed consent for research and serving as a contact for the coordinator.     

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).     

Sudden Unexplained Death Among Subjects with Refractory Epilepsy

Summary: Purpose : To address concerns about possible increases in rates of sudden unexplained death (SUD) after use of new anticonvulsants, more information on the rate of SUD among subjects with refractory epilepsy is needed to provide a comparison.
Methods : We conducted a study to estimate the incidence of SUD among subjects younger than 50 years with refractory epilepsy, by using information from the General Practice Research Database (GPRD) in the United Kingdom. For the purposes of this study, subjects receiving two or more anticonvulsant drugs concurrently were considered to have refractory epilepsy. Potential cases of SUD were identified from the computer records, and clinical records for these subjects were reviewed by two specialists in SUD in epilepsy.
Results : Fifteen subjects (eight male, seven female) of the 4,150 subjects with refractory epilepsy were considered to have definite/probable or possible SUD.
Conclusions : The overall incidence rate of SUD in the population was 2.2 per 1,000 person-years (95% CI, 1.3–3.6). The rate for subjects with highly probable SUD was 1.5 per 1,000 person-years (95% CI, 0.8–2.7).     

Premature mortality of epilepsy in low‐ and middle‐income countries: A systematic review from the Mortality Task Force of the International League Against Epilepsy

To determine the magnitude of risk factors and causes of premature mortality associated with epilepsy in low‐ and middle‐income countries (LMICs). We conducted a systematic search of the literature reporting mortality and epilepsy in the World Bank‐defined LMICs. We assessed the quality of the studies based on representativeness; ascertainment of cases, diagnosis, and mortality; and extracted data on standardized mortality ratios (SMRs) and mortality rates in people with epilepsy. We examined risk factors and causes of death. The annual mortality rate was estimated at 19.8 (range 9.7–45.1) deaths per 1,000 people with epilepsy with a weighted median SMR of 2.6 (range 1.3–7.2) among higher‐quality population‐based studies. Clinical cohort studies yielded 7.1 (range 1.6–25.1) deaths per 1,000 people. The weighted median SMRs were 5.0 in male and 4.5 in female patients; relatively higher SMRs within studies were measured in children and adolescents, those with symptomatic epilepsies, and those reporting less adherence to treatment. The main causes of death in people with epilepsy living in LMICs include those directly attributable to epilepsy, which yield a mean proportional mortality ratio (PMR) of 27.3% (range 5–75.5%) derived from population‐based studies. These direct causes comprise status epilepticus, with reported PMRs ranging from 5 to 56.6%, and sudden unexpected death in epilepsy (SUDEP), with reported PMRs ranging from 1 to 18.9%. Important causes of mortality indirectly related to epilepsy include drowning, head injury, and burns. Epilepsy in LMICs has a significantly greater premature mortality, as in high‐income countries, but in LMICs the excess mortality is more likely to be associated with causes attributable to lack of access to medical facilities such as status epilepticus, and preventable causes such as drowning, head injuries, and burns. This excess premature mortality could be substantially reduced with education about the risk of death and improved access to treatments, including AEDs.     

Sudden Unexplained Death and Injury in Epilepsy

Summary: Seizures may be associated with risk of injury or death. Injuries are common in patients with epilepsy, with up to 30% of patients reporting injuries, most commonly blunt trauma and lacerations. Seizures associated with falls increase the risk of injury, but any seizure that is associated with alteration in consciousness may cause injury. Patients with seizures may injure others, especially by causing motor vehicle accidents. Each state has restrictions on driving, requiring seizure-free intervals that range from 3 to 18 months. Mortality is increased in patients with epilepsy. The standardized mortality ratio is increased two to three times in epilepsy cohorts. Sudden unexplained death in epilepsy (SUDEP) is responsible for 2% to 17% of all deaths in patients with epilepsy, depending on the cohort studied. Population-based studies of SUDEP show a lower overall SUDEP rate compared with clinical trials or epilepsy referral center cohorts. Overall, the risk of sudden death is increased in the epilepsy population by 24 times compared with the general population. Risk factors for SUDEP may include poorly controlled seizures, early onset of epilepsy, and generalized tonic-clonic seizures. The pathophysiology of SUDEP is unknown, but animal data suggest apnea may be the initial factor that results in sudden death.     

Incidence of sudden unexpected death in an adult outpatient cohort with epilepsy at a tertiary referral centre.

Overall mortality, incidence of sudden unexpected death, and cause of death were determined in 601 adult outpatients with epilepsy at a tertiary referral centre. The patients were followed up from 1990 to 30 June 1993. There were 24 deaths among the 601 patients (1849 patient years) with a standardised mortality ratio of 5.1 (95% confidence interval 3.3-7.6) of which 14 were related to epilepsy. Underlying disease of which epilepsy was a symptom accounted for four deaths only. An incidence of sudden deaths (including seizure related) was of the order of 1:200/year. In conclusion, excess mortality in chronic epilepsy is more likely to be related to the epilepsy itself than to underlying pathology. The relatively high incidence of sudden deaths found in this hospital based cohort has important implications for patient management.     

SUDEP in the Netherlands: a retrospective study in a tertiary referral center.

OBJECTIVE: To evaluate risk factors for sudden and unexpected death in epilepsy (SUDEP) in a high-risk population, i.e. patients treated in a Dutch tertiary referral center for epilepsy. METHODS: All patients who died between January 1999 and April 2004 while under treatment of the epilepsy center were identified. Based on clinical data, deaths were classified as definite, probable, possible or non-SUDEP. Potential risk factors were compared in SUDEP cases and non-SUDEP cases. RESULTS: SUDEP incidence was 1.24 per 1000 patient years. SUDEP patients died at a younger age than patients from the control group of non-SUDEP deaths with epilepsy and had an earlier onset of epilepsy. However, the frequently mentioned factors in previous studies, i.e. male sex, generalized tonic-clonic seizures, high seizure frequency, specific AEDs, polytherapy with several AEDs, mental retardation, psychiatric illness and psychotropic comedication, were not found to be correlated with SUDEP. CONCLUSIONS: Even in this high-risk population of patients with refractory epilepsy, treated in a tertiary referral center, SUDEP is not a frequently occurring phenomenon. Specific risk factors could not be identified within an already high-risk population.     

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: a series from an epilepsy surgery program and speculation on the relationship to sudden cardiac death

Sudden unexpected death represents a significant cause of mortality in people with epilepsy. It derives this significance not because it is the most frequent cause of death but because it is apparently a direct consequence of a seizure. The implication is that epilepsy is an inherently lethal disorder. Seven patients who were studied in an epilepsy surgery program died a sudden unexpected death. This incidence of sudden unexpected death was five times higher than the 1-2/1,000 per year reported in the general epilepsy population. Sudden unexpected death shares some of the characteristics associated with sudden cardiac death, which kills 300,000 people in the United States each year. A cardiac arrhythmia, usually ventricular fibrillation, is the most common terminal event for sudden cardiac death and is the leading candidate as the mechanism for sudden unexpected death. Despite this knowledge, little is known on how to identify a high-risk group of patients for sudden death or how these deaths might be prevented.     

Risk of sudden unexpected death in epilepsy in patients given adjunctive antiepileptic treatment for refractory seizures: a meta-analysis of placebo-controlled randomised trials

Background

Sudden unexpected death in epilepsy (SUDEP) represents the main cause of death in patients with refractory epilepsy. No evidence-based intervention to prevent SUDEP exists. We postulated that pooling data from randomised placebo-controlled trials in patients with refractory epilepsy might show a lower incidence of SUDEP in patients receiving antiepileptic drugs (AEDs) at efficacious doses than in those receiving placebo.

Methods

We searched Medline and the Cochrane Library for randomised trials investigating any AED in the add-on treatment of drug-resistant epilepsy in adults. We extracted the number and causes of death in patients allocated to AEDs at doses that were more efficacious than placebo against seizures, AEDs at non-efficacious doses, and placebo. In our primary analysis, we compared the occurrence of definite or probable SUDEP between patients given efficacious AED doses and those given placebo using the Mantel-Haenszel method, with exclusion of trials with no event.

Findings

Data of 33 deaths, including 20 deemed as SUDEP, were extracted from 112 eligible randomised trials. 18 deaths were classified as definite or probable SUDEP and two as possible SUDEP. Definite or probable SUDEP, all SUDEP, and all causes of death were significantly less frequent in the efficacious AED group than in the placebo group, with odds ratios of 0·17 (95% CI 0·05–0·57, p=0·0046), 0·17 (0·05–0·57, p=0·0046), and 0·37 (0·17–0·81, p=0·0131), respectively. Rates of definite or probable SUDEP per 1000 person-years were 0·9 (95% CI 0·2–2·7) in patients who received efficacious AED doses and 6·9 (3·8–11·6) in those allocated to placebo.

Interpretation

Treatment with adjunctive AEDs at efficacious doses may have reduced the incidence of definite or probable SUDEP by more than seven times compared with placebo in patients with previously uncontrolled seizures. This result provides evidence in favour of active treatment revision for patients with refractory epilepsy.

Funding

None.