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.     

Sudden Unexplained Death in Epilepsy: Observations from a Large Clinical Development Program

Summary: Purpose: The present study was conducted to determine the rate of sudden unexplained death in epilepsy (SUDEP) in a well-defined cohort of patients included in the lamotrigine (LTG) clinical development database.
Methods: A panel of scientists experienced in the area of SUDEP was assembled and provided with case summaries on all deaths (n = 45) reported during the initial clinical development of LTG. The panel developed a set of criteria for classifying cases as SUDEP (definite or highly probable), possible SUDEP, or non-SUDEP. This classification algorithm was then applied to the LTG cases, and SUDEP rates were calculated using patient-years of exposure as the denominator.
Results: At the time of the study, 4,700 patients (5,747 patient-years of exposure) were included in the worldwide LTG clinical trials database. In this cohort, 45 deaths were reported. Eighteen were judged by the panel to be SUDEP, 6 were defined as possible SUDEP, 20 were judged to be due to other causes (non-SUDEP), and 1 lacked sufficient data from which to make a classification. The overall SUDEP rate (definite/highly probable SUDEP and possible SUDEP combined) was calculated to be 3.5 in 1,000 patient-years of exposure to LTG.
Conclusions: The rate of SUDEP in this cohort of patients was comparable to the rate that would be expected in young adults with severe epilepsy (the subgroup of patients believed to be at highest risk of SUDEP). The data suggest that the rate of SUDEP in the LTG clinical development program is a function of the clinical trial population and is unrelated to drug treatment.     

A study of mortality after temporal lobe epilepsy surgery.

OBJECTIVE: To determine early and late mortality in a cohort of 305 consecutive patients who had temporal lobe epilepsy (TLE) surgery over a 20-year period. METHODS: Survival status, cause of death, and postoperative clinical details of those who died were ascertained in a cohort of 305 patients who had TLE surgery. Mortality was related to postoperative seizure status, operative pathology, and side of resection. RESULTS: The survival status of 299 patients was established. Twenty deaths occurred. Mortality was 1 per 136 person-years, with a standardized mortality ratio (SMR) of 4.5 (95% confidence interval [CI], 3.2 to 6.6). Six deaths were sudden and unexpected (SUDEP). The SUDEP rate was 1 per 455 person-years. The overall death and SUDEP rates were lower than those reported for similar patient populations with chronic epilepsy. Mortality in patients who had right-sided resections for mesial temporal sclerosis (MTS) remained considerably elevated with a mortality rate of 1 per 54 person-years, an SMR of 32.0 (95% CI, 24.7 to 40.5), and a SUDEP rate of 1 per 134 person-years. These patients had significantly lower seizure remission rates than left-sided patients, but the excess mortality was not simply explained by those patients whose partial seizures were uninfluenced by surgery. Patients who died had more severe or convulsive seizures despite an overall reduction in seizure frequency. CONCLUSIONS: The present findings confirm previous reports that TLE surgery lowers but does not normalize the overall mortality associated with chronic epilepsy. In patients with right-sided MTS, however, the postoperative mortality has remained similar to other groups with medically intractable seizures.     

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).     

SUDEP: overview of definitions and review of incidence data.

The classification, occurrence, and predictors of sudden unexpected and unexplained death in individuals with epilepsy (SUDEP) have received considerable attention over the last few years. Specific criteria for the classification of definite, probable, possible, and not SUDEP implemented in United States epidemiologic studies are presented. The incidence of SUDEP in different epilepsy populations is presented. SUDEP is a real phenomenon, because the occurrence of such deaths, especially at relatively young ages, among individuals with epilepsy is far greater (perhaps 40-fold) than among those without epilepsy. SUDEP incidence rates are lower in population-based studies, higher in referral populations and clinical trials of adjunct drugs for complex partial epilepsy, and highest for surgical series. Seizure severity appears to be the strongest risk factor for SUDEP because higher rates are reported from studies of individuals with intractable epilepsy. Other potential risk factors, including sex, seizure etiology, younger age at onset, and partial-onset seizures, are unresolved.     

Incidence of sudden unexpected death in epilepsy in community-based cohort in China

ObjectiveSudden unexpected death in epilepsy (SUDEP) is associated with the high premature mortality observed among people with epilepsy. It is, however, considered a rare event in China, probably because of lack of awareness and limitation of studies in the country. We aimed to provide some initial estimation of the burden of SUDEP in China.MethodsWe established a large Chinese community-based cohort of people with epilepsy between January 2010 and December 2011. For any participant who died during follow-up, detailed information on cause of death was obtained using a specifically designed Verbal Autopsy Questionnaire. All cases were reviewed by a multidisciplinary expert panel and reinvestigated if necessary. Sudden unexpected death in epilepsy incidence rates were estimated and case details provided.ResultsThe cohort consisted of 1562 people and during a median 5 years follow-up, 72 deaths were reported. The all-causes death incidence was 11.23 (95% CI 8.86–14.07) per 1000 person-years. Fifteen died suddenly and unexpectedly in a reasonable state of health in the week preceding death. We recorded detailed information of these 15 deaths. Thirteen were considered to be probable SUDEP and two possible SUDEP. The incidence of probable SUDEP was 2.03 (95% CI 1.13–3.38) per 1000 person-years, and the incidence of all suspected (probable and possible) SUDEP was 2.34 (95% CI 1.36–3.77) per 1000 person-years.SignificanceThe incidence of SUDEP was relatively high among Chinese people with epilepsy when compared with that in previous community-based studies from high-income countries. The burden of SUDEP in China requires further assessments.     

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.     

Muerte súbita en epilepsia: casuística de una unidad médica de epilepsia española

IntroductionSudden unexpected death in epilepsy (SUDEP) is the leading cause of death in patients with epilepsy. Most studies concerning this issue have been conducted in central and northern European countries and the United States. We conducted an epidemiologic study of SUDEP at our hospital's epilepsy unit.MethodsThis retrospective cohort study included all epileptic patients aged ≥ 14 years, regardless of epilepsy severity, who were treated at the outpatient epilepsy unit of our hospital between 2000 and 2013. The study included 2,309 patients. Deceased patients were identified using civil records. The cause of death was obtained from death certificates, autopsy reports, hospital reports, general practitioner records, and witnesses of the event. We calculated the incidence and proportional mortality of SUDEP based on our data.ResultsWe identified 7 cases of definite SUDEP (2 patients with SUDEP plus), one case of probable SUDEP, and one case of possible SUDEP. Considering only cases of definite SUDEP, incidence was estimated at 0.44 cases per 1,000 patient-years and proportional mortality at 4.6%. Mean age of patients with definite SUDEP was 38.14 years; 4 were men and 3 were women. Most deaths occurred while patients were in bed and were therefore unwitnessed. Epilepsy in these patients was either remote symptomatic or cryptogenic. All patients but 2 had generalised seizures. None of the patients was in remission.ConclusionsSUDEP incidence and proportional mortality rates in our study are similar to those reported by population studies. This may be due to the fact that we did not select patients by severity. Risk factors for SUDEP in our sample are therefore consistent with those reported in the literature.     

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.     

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.     

Cause-Specific Mortality in Epilepsy: A Cohort Study of More Than 9,000 Patients Once Hospitalized for Epilepsy

Summary: Purpose: We studied overall and cause-specific mortality rates in a large cohort of patients with epilepsy compared with mortality rates of the general population in the same geographic area.
Methods: The cohort consisted of all patients (N = 9,061) aged >15 years admitted with a diagnosis of epilepsy for inpatient care in Stockholm during the years 1980–1989. All patients were followed in the National Cause-of-Death Register, from which the causes of death were obtained, until December 31, 1992. Thus, 53,520 person-years were observed. Mortality rates were compared with those of the general population of Stockholm.
Results: We observed 4,001 deaths in the cohort, compared with an expected number of 1,109 deaths in the general population. This yielded a standardized mortality ratio (SMR) of 3.6 [95% confidence interval (CI) 3.5–3.71] Although highest in the younger patients, the SMR was significantly increased in all age groups. The excess mortality rate in the cohort was due to a wide range of causes of death, including malignant neoplasms [SMR 2.6 (2.4–2.8)], diseases of the circulatory system, [SMR 3.1 (3.0–3.3)], diseases of the respiratory system [SMR 4.0 (3.64.5)], diseases of the digestive system [SMR 5.1 (4.4–5.8)], and injuries and poisoning [SMR 5.6 (5.0–6.3)].
Conclusions: Our results demonstrate that this large subgroup of patients with a diagnosis of epilepsy, once hospitalized and discharged, is a population at risk, with an excess mortality rate due to several different causes.     

Increased risk of sudden unexpected death in epilepsy in females using lamotrigine: a nested, case-control study

Purpose: To estimate the incidence of sudden unexpected death in epilepsy (SUDEP) in Rogaland County, Norway, in the period August 1 1995–July 31 2005, and to investigate whether use of lamotrigine (LTG) was associated with increased risk in female patients or other subgroups. Methods: SUDEP victims were identified from autopsy reports and data from the Norwegian Cause of Death Registry. In all cases where SUDEP was considered as a possible cause of death, the hospital records were also reviewed. For each deceased, at least three living patients with epilepsy were randomly selected as controls. The market share in defined daily doses was collected for each year to estimate the number of patient‐years at risk on each antiepileptic drug. Key Findings: We identified 26 cases of SUDEP: 16 definite, 3 probable, and 7 possible; 15 patients were female and 11 were male. Of these, 10 patients (38.5%) were treated with LTG: 9 of these patients were female. The incidence of SUDEP was estimated as 1.0 per 1,000 patient‐years when all cases were included, and 0.7 per 1,000 patient‐years for definite and probable SUDEP. Seven of 12 (58.3%) of female patients with definite and probable SUDEP and 10 of 41 (24.4%) of controls matched on age and gender were on LTG (p = 0.038). The incidence of definite and probable SUDEP in women on LTG, was estimated as 2.5 per 1,000 patient‐years and 0.5 per 1,000 patient‐years in female who were not taking LTG (p = 0.007). Significance: The incidence of SUDEP was significantly higher among female patients with epilepsy who were being treated with LTG than among female patients with epilepsy who were not taking LTG, and a significantly higher proportion of female SUDEP cases than controls were taking LTG. Our findings may have implications for treatment of epilepsy in female patients.     

Mortality in a population-based cohort of epilepsy surgery patients

PURPOSE: To investigate mortality and especially the incidence of sudden unexpected death in epilepsy (SUDEP) in a population-based cohort of epilepsy surgery patients. METHODS: All patients who underwent epilepsy surgery treatment between January 1990 and December 1998 (surgery patients) or whose presurgical evaluation started, although not leading to an operation, during the same period (nonsurgery patients) were identified through the Swedish National Epilepsy register. All subjects were followed up through the Cause of Death Register until December 1998. Standardized mortality ratios (SMRs) for all causes of death and incidence of SUDEP were calculated. RESULTS: During the study period, 651 surgical operations were carried out on 596 patients (316 male). Of those, 14 patients died (six in SUDEP), rendering a total SMR of 4.9 [95% confidence interval (CI), 2.7-8.3]. SUDEP incidence was 2.4 per 1,000 person years. No major differences were found in SMRs or SUDEP rates between subgroups when stratifying for type of operation and for seizure outcome 2 years after surgery. SMR and SUDEP rates were higher in right-sided temporal lobe resections for gliosis than in left-sided, but the number of deaths was small. Among 212 nonsurgery patients, five died (four in SUDEP). The SMR for all causes was 7.9 (2.6-18.4), and SUDEP incidence, 6.3 per 1,000 person years. CONCLUSIONS: In this large and strictly population-based cohort, SMR for all causes and SUDEP incidence among surgery patients were similar to those of other studies. No differences in overall mortality emerged by seizure outcome, but none of the SUDEP cases was seizure free at the time of death. Four of five deaths in the nonsurgery group occurred during the surgery evaluation period. Mortality appeared to be lower for surgery than for nonsurgery patients, and the interpretation of this finding is discussed.     

Sudden unexpected death in epilepsy in lamotrigine randomized‐controlled trials

Purpose: Nonrandomized studies of the relationship of antiepileptic drugs (AEDs) with sudden unexpected death in epilepsy (SUDEP) may be susceptible to confounding by tonic–clonic seizure frequency, polypharmacy, and other potential risk factors for SUDEP. We evaluated the risk of SUDEP with lamotrigine (LTG) compared to active comparators and placebo in randomized controlled clinical trials conducted by GlaxoSmithKline (GSK) between 1984 and 2009. Methods: Among 7,774 subjects in 42 randomized clinical trials, there were 39 all‐cause deaths. Ten deaths occurred >2 weeks after discontinuation of study medication and were excluded. Narrative summaries of deaths were independently reviewed by three clinical experts (TT, LH, DF), who were blinded to randomized treatment arm. The risk of definite or probable SUDEP was compared between treatment arms for each trial type (placebo‐controlled, active‐comparator, crossover), using exact statistical methods. Key Findings: Of 29 on‐treatment deaths, eight were definite/probable SUDEP, four were possible SUDEP, and 17 were non‐SUDEP. The overall, unadjusted rate of definite/probable SUDEP for LTG was 2.2 events per 1,000‐patient years (95% confidence interval [95% CI] 0.70–5.4). The odds ratios (OR) for on‐treatment, definite/probable SUDEP in LTG arms relative to comparator arms, adjusted for length of exposure and trial, were the following: placebo‐controlled, OR 0.22 (95% CI 0.00–3.14; p = 0.26); active‐comparator, OR 2.18 (95% CI 0.17–117; p = 0.89); and placebo‐controlled cross‐over, OR 1.08 (95% CI 0.00–42.2; p = 1.0). Significance: There was no statistically significant difference in rate of SUDEP between LTG and comparator groups. However, the CIs were wide and a clinically important effect cannot be excluded.     

Mortality in antiepileptic drug development programs

BACKGROUND: Pooled data from New Drug Applications (NDAs) submitted to the U.S. Food and Drug Administration (FDA) provide an opportunity to study the incidence of and risk factors for rare events. OBJECTIVE: To examine the incidence and causes of mortality in patients with epilepsy participating in clinical trials of antiepileptic drugs (AEDs); and to examine the incidence of and risk factors for sudden unexplained death in such patients. METHODS: Exposure data and death narratives were obtained from the NDAs of five recently reviewed AEDs. Deaths were classified as sudden unexplained, accidental, or other cause using the 1993 Burroughs-Wellcome expert panel criteria, and mortality rates were calculated for each category. Add-on trials were analyzed separately from monotherapy initiation trials. RESULTS: Among 9,144 patients in the add-on trial database, the all-cause and sudden unexplained mortality rates were 9.1 and 3.8 deaths per 1,000 person-years (124 and 52 deaths in 13,617.1 person-years of drug exposure). Sixty-five percent of all deaths were related to the underlying epilepsy. Of the examined risk factors, only age was associated with the incidence of sudden unexplained death. Among 1,293 patients in the monotherapy initiation trials, the all-cause and sudden unexplained mortality rates were 7.1 and 0 deaths per 1,000 person-years (7 and 0 deaths in 982.5 person-years of drug exposure). CONCLUSIONS: A large proportion of the deaths in the add-on cohort was attributable to epilepsy-related causes. Mortality due to sudden death in the add-on cohort falls into the high end of the reported range for patients with epilepsy. The difference in mortality due to sudden death between the add-on and monotherapy initiation cohorts suggests that disease severity is the primary determining factor for risk of sudden unexplained death.     

Certification of deaths attributable to epilepsy

OBJECTIVE: To estimate the number of sudden unexpected epilepsy deaths occurring annually in England and Wales in those 16-50 years of age. METHODS: All 1997 death entries mentioning epilepsy as a cause of death in those 16-50 years were examined and classified as sudden unexpected death in epilepsy (SUDEP), other epilepsy related deaths, or non-epilepsy deaths. RESULTS: 612 death entries were obtained with postmortem examination having been performed in 498 cases. Forty four deaths were certified as being attributable to SUDEP and a further 292 deaths were considered to be probable SUDEP cases. CONCLUSION: It is estimated that between 350 and 400 cases of SUDEP occurred in England and Wales in 1997 in those 16-50 years. SUDEP is the commonest category of epilepsy related death and accurate certification of such deaths is vital for the monitoring of trends in mortality.     

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.     

Influence of Epilepsy on Mortality in Mental Retardation: An Epidemiologic Study

Summary: Purpose : A cohort consisting of all persons with known mental retardation (MR) and living in a Swedish province on December 31, 1985, was followed for 7 years (1987–1992) to study the mortality pattern.
Methods : A file of the cohort was linked to the cause-of-death pattern of the general population in the study area.
Results : One hundred twenty-four deaths (8.4%) occurred among the 1,478 persons with MR. Thirty deaths (10.1%) occurred among the 296 persons with epilepsy and MR. The standardized mortality ratio (SMR) in those with only MR was significantly increased as compared with that of the general population: 1.6 [95% confidence interval (CI) 1.3–2.01; MR and epilepsy, 5.0 (CI 3.3–7.5); and MR, epilepsy, and cerebral palsy (CP), 5.8 (CI 3.4–9.7). Mortality was increased both in patients with partial seizures without seizures secondarily generalized (SMR 3.7, CI 1.0–13.6) and in patients with seizures secondarily generalized (5.0, CI 2.3–11.0). The highest mortality occurred in patients who had seizures that were always generalized from the onset: 8.1 (CI 5.7–11.5). Mortality increased with increasing seizure frequency during the year preceding the prevalence date. In patients with epilepsy and MR, pneumonia was the most common cause of death and a seizure was the probable cause of death in 6.7%.
Conclusions : Epilepsy is associated with a significantly increased mortality in persons with MR. The increase is related to seizure type and seizure frequency. Death in persons with epilepsy and MR is seldom directly due to seizures. Other impairments associated with epilepsy and MR are important causes of death.     

Incidence and risk factors in sudden unexpected death in epilepsy: a prospective cohort study

OBJECTIVE: To determine incidence of and risk factors for sudden unexpected death in epilepsy (SUDEP). METHODS: Three epilepsy centers enrolled 4,578 patients and prospectively followed these patients for 16,463 patient-years. The cohort was screened for death annually. Deaths were investigated to determine whether SUDEP occurred. Potential risk factors were compared in SUDEP cases and in controls enrolled contemporaneously at the same center. RESULTS: Incidence of SUDEP was 1.21/1,000 patient-years and was higher among women (1.45/1,000) than men (0.98/1,000). SUDEP accounted for 18% of all deaths. Occurrence of tonic-clonic seizures, treatment with more than two anticonvulsant medications, and full-scale IQ less than 70 were independent risk factors for SUDEP. The number of tonic-clonic seizures was a risk factor only in women. The presence of cerebral structural lesions and use of psychotropic drugs at the last visit were not risk factors for SUDEP in this cohort. Subtherapeutic anticonvulsant levels at the last visit were equally common in the two groups. No particular anticonvulsant appeared to be associated with SUDEP. CONCLUSIONS: These results support the idea that tonic-clonic seizures are an important proximate cause of SUDEP. This information creates a risk profile for SUDEP that may help direct preventative efforts.