The

n e w e ng l a n d j o u r na l

of

m e dic i n e

original article

Long-Term Mortality in Childhood-Onset Epilepsy

Matti Sillanp, M.D., Ph.D., and Shlomo Shinnar, M.D., Ph.D.

A BS T R AC T
Background
From the Departments of Pediatric Neurology and Public Health, University of Turku and Turku University Hospital both in Turku, Finland (M.S.); and the Departments of Neurology, Pediatrics, and Epidemiology and Population Health and the Comprehensive Epilepsy Management Center, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY (S.S.). Address reprint requests to Dr. Shinnar at the Comprehensive Epilepsy Management Center, Montefiore Medical Center, 111 E. 210th St., Bronx, NY 10467, or at sshinnar@montefiore.org. N Engl J Med 2010;363:2522-9.
Copyright 2010 Massachusetts Medical Society.

There are few studies on long-term mortality in prospectively followed, well-characterized cohorts of children with epilepsy. We report on long-term mortality in a Finnish cohort of subjects with a diagnosis of epilepsy in childhood.
Methods

We assessed seizure outcomes and mortality in a population-based cohort of 245 children with a diagnosis of epilepsy in 1964; this cohort was prospectively followed for 40 years. Rates of sudden, unexplained death were estimated. The very high autopsy rate in the cohort allowed for a specific diagnosis in almost all subjects.
Results

Sixty subjects died (24%); this rate is three times as high as the expected age- and sex-adjusted mortality in the general population. The subjects who died included 51 of 107 subjects (48%) who were not in 5-year terminal remission (i.e., 5 years seizure-free at the time of death or last follow-up). A remote symptomatic cause of epilepsy (i.e., a major neurologic impairment or insult) was also associated with an increased risk of death as compared with an idiopathic or cryptogenic cause (37% vs. 12%, P<0.001). Of the 60 deaths, 33 (55%) were related to epilepsy, including sudden, unexplained death in 18 subjects (30%), definite or probable seizure in 9 (15%), and accidental drowning in 6 (10%). The deaths that were not related to epilepsy occurred primarily in subjects with remote symptomatic epilepsy. The cumulative risk of sudden, unexplained death was 7% at 40 years overall and 12% in an analysis that was limited to subjects who were not in long-term remission and not receiving medication. Among subjects with idiopathic or cryptogenic epilepsy, there were no sudden, unexplained deaths in subjects younger than 14 years of age.
Conclusions

Childhood-onset epilepsy was associated with a substantial risk of epilepsy-related death, including sudden, unexplained death. The risk was especially high among children who were not in remission. (Funded by the Finnish Epilepsy Research Foundation.)

2522

n engl j med 363;26

nejm.org

december 23, 2010

The New England Journal of Medicine Downloaded from nejm.org on June 11, 2011. For personal use only. No other uses without permission. Copyright 2010 Massachusetts Medical Society. All rights reserved.

Mortality in Childhood-Onset Epilepsy

ew studies have evaluated long-term mortality in well-characterized cohorts of children with epilepsy. With a few notable exceptions,1-3 studies involving adults are usually retrospective.4-11 In pediatric series, the followup is generally 5 to 10 years.12-18 In all series, autopsy confirmation of an absence of other causes of death, which is necessary to confirm sudden, unexplained death in persons with epilepsy,19 is rare. We present mortality data from a cohort of 245 subjects with childhood-onset epilepsy who were followed for 40 years. Rates of autopsy in this cohort were high.

Me thods
Subjects and Study Design

The study population included all children younger than 16 years of age who were living in the catchment area of Turku University Hospital, Turku, Finland, at the end of 1964 and who had epilepsy, which was defined as at least two unprovoked seizures. The subjects were identified from the files of Turku University Hospital, other hospitals and institutions in southern Finland, and private surgeons and from Finlands National Health Service registry, which covers the entire population of that country. Of the 245 patients identified, the majority (223 patients) were seen in Turku University Hospital. In the 1960s, all pediatric patients who had one or more epileptic seizures were referred for inpatient hospital evaluation. The study population has been described previously.20-22 The 245 subjects included 150 subjects with incident cases of epilepsy (61%) whose initial visit for the evaluation of new-onset seizures occurred between 1961 and 1964. The remaining 95 subjects with prevalent cases of epilepsy (39%) were seen before 1961, but they were seen again during the 19611964 study period for active epilepsy (at least one epileptic seizure during the preceding 3 years and a prior diagnosis of epilepsy). Excluded were children who had febrile seizures only or other acute symptomatic seizures and children with a single unprovoked seizure. Also excluded were children with an onset of epilepsy before 1961 who were either in remission or who died before 1961. A follow-up examination was performed every fifth year up to 2002. Data on deaths were obtained from continuous follow-up of the patients

in the intervals between the 5-year examinations. Detailed information collected about this subgroup included the date and time of death, the immediate cause of death, the underlying cause of death, and autopsy data, when available. Written informed consent obtained from all subjects or their caregivers permitted access to the hospital files in order to abstract data on the last stages of the disease before death. To ensure full coverage of all deaths, we also sent a list of the names of all 245 subjects (and their unique identification numbers), except those known to be dead, to the Finnish National Death Register every 5 years and requested a list of deaths and copies of the death certificates. Five subjects migrated out of Finland and were last known to be alive 10, 19, 25, 32, and 36 years after the onset of epilepsy. Complete data until death or January 1, 2003, were available for all the remaining subjects. The median duration of follow-up to the last follow-up contact or death was 40.0 years (range, 2 to 53) among all 245 subjects and 39.5 years (range, 2 to 42) among the 150 subjects with incident cases of epilepsy. The joint ethics review committee of the University of Turku Medical School and University Hospital of Turku approved the study design. Data on autopsies performed for clinical or forensic reasons, or both, were available for this study. The autopsy rate was 70% (42 of 60 deaths) for all deaths in the cohort and 80% (24 of 30 deaths) for incident cases. Full autopsies of all organs were performed, although in a few subjects, a less detailed forensic autopsy was performed. The results of toxicologic screening were obtained in all subjects. Of the six subjects with incident cases of epilepsy who were not examined at autopsy, two had malignant, aggressive carcinoma and permission for an autopsy was not given by the subjects relatives; two had severe cognitive impairment, were completely bedridden, and died of pneumonia; one had progressive muscular dystrophy with pneumonia; and one, who had moderate cognitive impairment, died after an epileptic seizure.
Definitions

Epileptic syndromes, epilepsies, epileptic seizures, and the causes of seizures were defined according to the guidelines for epidemiologic research of the International League Against Epilepsy.23-25 Subjects with remote symptomatic epilepsy had either a major neurologic impairment (e.g., cog2523

n engl j med 363;26

nejm.org

december 23, 2010

The New England Journal of Medicine Downloaded from nejm.org on June 11, 2011. For personal use only. No other uses without permission. Copyright 2010 Massachusetts Medical Society. All rights reserved.

The

n e w e ng l a n d j o u r na l

of

m e dic i n e

Table 1. Mortality among Subjects with Childhood-Onset Epilepsy.* All Subjects (N = 245) 60 23 150 8692 6.90 (5.38.9) 7.33 (5.210.2) 6.41 (4.49.4) 51/60 (85) 9/60 (15) 5 4 Subjects with Idiopathic or Cryptogenic Epilepsy (N = 122) 15 26 1150 4638 3.23 (1.95.4) 2.69 (1.26.0) 3.74 (1.97.2) 11/15 (73) 4/15 (27) 2 2 Subjects with Epilepsy Due to Remote Symptomatic Causes (N = 123) 45 21 149 4054 11.10 (8.314.9) 11.63 (8.016.8) 10.33 (6.416.6) 40/45 (89) 5/45 (11) 3 2

Variable Total deaths no. Age at death yr Median Range No. of person-yr No. of deaths/1000 person-yr (95% CI) All Men Women Remission status at time of death Not in remission no./total no. of deaths (%) In remission no./total no. of deaths (%) Receiving medication no. Not receiving medication no.

* CI denotes confidence interval. A remote symptomatic cause of epilepsy indicates epilepsy associated with a major neurologic abnormality or insult. A total of 107 subjects in the study cohort were not in 5-year terminal remission, and 138 were in 5-year terminal remission; of the 138 subjects in 5-year terminal remission, 35 were receiving medication and 103 were not.

nitive impairment, clinically significant developmental delay [developmental quotient <70 in children younger than 7 years of age], cerebral palsy, or autism) or a history of a major neurologic insult (e.g., head trauma, stroke, or meningitis). The remaining subjects were determined to have cryptogenic or idiopathic epilepsy. The classification of epilepsy was made in all subjects, and the detailed seizure types and epilepsy syndromes in this cohort have been reported previously.22 These classifications were determined before the new classifications of epilepsy syndromes26 and are used here for consistency with previous studies. Sudden, unexpected death in a person with epilepsy was defined, in accordance with the definition by Annegers,19 as sudden death with no evidence of a seizure and no other identified cause of death, with confirmation of these findings by autopsy. In almost all cases of sudden, unexplained death in a person with epilepsy, pulmonary edema was detected on autopsy. We also examined the rates of sudden, unexplained death among persons with epilepsy in accordance with the alternative definition by Nashef,27 which includes deaths for which there is evidence of probable or definite seizures, although it excludes deaths in persons with known status epilepticus.
2524
n engl j med 363;26

Statistical Analysis

Our statistical methods took into account the timedependent nature of the mortality data. The rate of death was calculated as the number of deaths divided by the person-years at risk during the study; direct adjustment for age and sex was performed on the basis of the 2002 Finnish population. The product-limit method was used to calculate the risk of death from the onset of epilepsy.28,29 Data on subjects were censored at the time of the last follow-up or on January 1, 2003. Standard errors and 95% confidence intervals were calculated with the use of a modification of the Greenwood formula.29 Univariate and multivariate analyses were performed with the use of the Cox proportional-hazards model, and remission status was treated as a time-dependent covariate.29-31 Rates of death according to remission status were adjusted for the number of personyears at risk during the remission period. Rate ratios with 95% confidence intervals were calculated with the use of the Cox regression models. When the cohort with incident epilepsy and the cohort with prevalent epilepsy were combined, adjustment was made for the left truncation due to the delayed entry of the cohort with prevalent epilepsy.32 A direct age- and sex-adjusted standard
december 23, 2010

nejm.org

The New England Journal of Medicine Downloaded from nejm.org on June 11, 2011. For personal use only. No other uses without permission. Copyright 2010 Massachusetts Medical Society. All rights reserved.

Mortality in Childhood-Onset Epilepsy

Table 2. Causes of Death. All Subjects (N = 245) 60 33/60 (55) 6 4 3 6 18 26 (43) 12 8 2 4 1 Subjects with Idiopathic or Cryptogenic Epilepsy (N = 122) 15 9/15 (60) 0 0 2 0 7 6 (40) 0 2 2 2 0 Subjects with Epilepsy Due to Remote Symptomatic Causes (N = 123)* 45 24/45 (53) 6 4 1 6 11 20 (44) 12 6 0 2 1

Variable Total deaths no. Death related to epilepsy no./total no. of deaths (%) Witnessed seizure no. Status epilepticus no. Probable seizure no. Drowning no. Sudden, unexplained death no. Death not related to epilepsy no./ total no. of deaths (%) Pneumonia no. Cardiovascular disease no. Suicide no. Other cause of death no. Cause of death unknown no.

* A remote symptomatic cause of epilepsy indicates epilepsy associated with a major neurologic abnormality or insult.

mortality ratio was calculated; this was defined as the ratio of the number of deaths observed in the study group to the number that would be expected if the age- and sex-specific rates of death in the study population were the same as those in the general population of the study area from 1945 through 2002.31,33 The standard mortality ratio adjusted for age, sex, and time period was calculated with the use of 5-year periods for 5-year age groups, and 95% confidence intervals were determined. The case fatality rate was defined as the proportion of persons who died during followup. Statistical computations were performed with the use of SAS software, version 9.1.3 (SAS Institute).

abnormality or insult). The median duration of epilepsy before achieving 5-year long-term remission was 17 years (range, 1 to 52) for surviving subjects and 22 years (range, 1 to 50) for those who died during the follow-up period. At the time of the last follow-up contact or death, 110 patients (45%) were in 5-year terminal remission and were not receiving medication, 28 (11%) were in 5-year terminal remission and were receiving medication, and 107 (44%) were not in 5-year remission.
Overall Mortality

R e sult s
Characteristics of the Study Population

A total of 245 subjects, 150 with incident cases of epilepsy and 95 with prevalent cases of epilepsy, were included in the study. The median age at the onset of epilepsy was 3 years (range, 0 to 14) among subjects with incident cases of epilepsy and 2 years (range, 0 to 12) among subjects with prevalent cases of epilepsy. A total of 122 subjects had idiopathic or cryptogenic epilepsy, and 123 subjects had remote symptomatic epilepsy (i.e., epilepsy associated with a major neurologic
n engl j med 363;26

During the median follow-up period of 40 years, 60 subjects died, for an overall case fatality rate of 24% and a rate of death of 6.9 per 1000 person-years among all subjects (Table 1). The rates of death among the subjects with incident cases of epilepsy (5.3 per 1000 person-years) and those with prevalent cases (9.6 per 1000 person-years) did not differ significantly, and the two groups were therefore combined. Details on incident cases are included in the Supplementary Appendix, available with the full text of this article at NEJM .org. The age- and sex-adjusted rates of death were 7.2 per 1000 person-years, with standard mortality ratios of 5.5 (95% confidence interval [CI], 4.6 to 6.6) in incident cases and 6.4 (95% CI, 5.9 to 7.0) in the overall cohort; the latter ratio is an estimate and was not adjusted for the delayed entry
december 23, 2010

nejm.org

2525

The New England Journal of Medicine Downloaded from nejm.org on June 11, 2011. For personal use only. No other uses without permission. Copyright 2010 Massachusetts Medical Society. All rights reserved.

The

n e w e ng l a n d j o u r na l

of

m e dic i n e

50

Cumulative Rate of Death

40 Remote symptomatic cause

30

20 Idiopathic or cryptogenic cause

10

10

15

20

25

30

35

40

Years after the Onset of Epilepsy

Figure 1. Cumulative Rate of Death According to Cause of Epilepsy. A remote symptomatic cause indicates epilepsy that is associated with a major neurologic abnormality or insult.

of subjects with prevalent cases of epilepsy. The causes of death and their relationship to remission status and cause of epilepsy are summarized in Tables 1 and 2. The highest rate of death occurred among subjects who were not in 5-year terminal remission; only 4 deaths occurred in the 103 subjects in 5-year terminal remission who were not receiving medication at the time of death or the last follow-up contact (1.5 deaths per 1000 person-years), as compared with 5 deaths in 35 subjects in 5-year remission who were receiving medication (11.8 per 1000 person-years) and 51 deaths in the 107 subjects who were not in 5-year remission (15.9 per 1000 person-years) (P<0.001). As expected, the rates of death were significantly higher among subjects with epilepsy due to remote symptomatic causes (11.1 deaths per 1000 personyears) than among subjects with cryptogenic epilepsy (2.9 per 1000 person-years) and those with idiopathic epilepsy (3.5 per 1000 person-years) (P<0.001) (Fig. 1 and Table 1). More than three quarters of the deaths occurred in subjects who were not in 5-year terminal remission and in the groups with epilepsy due to remote symptomatic causes; these included 21 of the 26 deaths not directly related to epilepsy and 24 of the 33 deaths related to epilepsy. The difference in the rates of death between subjects with epilepsy due to remote symptomatic causes and subjects with idiopathic or cryptogenic epilepsy was significant (11.1 deaths per 1000 person-years vs. 3.2 per 1000 person-years, P<0.001).
2526
n engl j med 363;26

Deaths in childhood occurred primarily in the group of subjects with epilepsy due to remote symptomatic causes and were most often related not to epilepsy but to the underlying disease (Table 1). Deaths due to epilepsy-related causes in subjects with cryptogenic or idiopathic epilepsy occurred primarily in adolescence and adulthood. The risk factors for both overall death and epilepsy-related death are summarized in Table 3. Univariate analysis showed that the hazard ratio for death was significantly increased among subjects who were not in 5-year terminal remission, those with a remote symptomatic cause of epilepsy, and those with a history of status epilepticus. Within the group of patients with remote symptomatic epilepsy, severe cognitive impairment was associated with an increased mortality (rate ratio, 4.1; 95% CI, 2.0 to 8.3; P<0.001). On multivariable analysis, only 5-year terminal remission was significantly associated with the hazard ratio for death. The other variables have previously been shown to be associated with a lack of remission.20-22 Other factors, such as the type of epilepsy (localization-related epilepsy, temporallobe epilepsy, or another type of epilepsy) or cerebral palsy, did not influence the risk of death in the group of subjects with remote symptomatic epilepsy.
Causes of Death

The causes of death are listed in Table 2. Among the 60 patients who died, the cause of death was not directly related to the seizure disorder but instead was related to the underlying neurologic problem or to another disease in 26 patients (43%) and was related to the epilepsy in 33 patients (55%); the latter group included sudden, unexplained death in epilepsy in 18 patients (30%), probable or definite seizure in 9 (15%), and accidental drowning in 6 (10%). With the use of the alternative classification of sudden, unexplained death in epilepsy,27 which includes possible or definite seizures as long as the seizures were not status epilepticus, 38% of the deaths were due to sudden, unexplained death in epilepsy, 7% were due to status epilepticus, and 10% were due to accidental drowning.
Sudden, Unexplained Death and EpilepsyRelated Deaths

There were 18 cases of sudden, unexplained death,19 including 15 cases that were confirmed by autopsy. Seven of the subjects with sudden,
december 23, 2010

nejm.org

The New England Journal of Medicine Downloaded from nejm.org on June 11, 2011. For personal use only. No other uses without permission. Copyright 2010 Massachusetts Medical Society. All rights reserved.

Mortality in Childhood-Onset Epilepsy

Table 3. Predictors of Death.* Risk Factor Univariate Analysis Hazard Ratio (95% CI) All deaths Absence of 5-yr terminal remission Remote symptomatic cause of epilepsy Prior status epilepticus Age at onset <2 yr Epilepsy-related deaths Absence of 5-yr terminal remission Remote symptomatic cause of epilepsy Prior status epilepticus Age at onset <2 yr Sudden, unexplained deaths Absence of 5-yr terminal remission Prior status epilepticus Age at onset <2 yr Remote symptomatic cause of epilepsy Localization-related epilepsy 5.2 (1.418.5) 2.8 (1.17.0) 2.1 (0.85.5) 1.9 (0.74.8) 0.8 (0.32.0) 0.01 0.03 0.11 0.20 0.60 5.0 (1.220.1) 2.6 (0.97.5) 1.9 (0.75.2) 0.8 (0.32.4) 0.5 (0.21.5) 0.02 0.07 0.20 0.72 0.21 6.4 (2.218.8) 3.1 (1.46.7) 2.1 (1.14.2) 1.9 (0.963.8) <0.001 0.004 0.03 0.06 4.7 (1.514.9) 1.5 (0.73.6) 1.5 (0.73.0) 1.7 (0.83.5) 0.007 0.31 0.28 0.13 5.3 (2.611.0) 3.4 (1.96.1) 1.9 (1.23.2) 1.4 (0.82.3) <0.001 <0.001 0.01 0.20 4.7 (1.514.9) 1.5 (0.73.6) 1.5 (0.73.0) 1.7 (0.83.5) 0.007 0.31 0.28 0.13 P Value Multivariate Analysis Hazard Ratio (95% CI) P Value

* A Cox proportional-hazards model was used to assess the risk of death associated with an absence of 5-year terminal remission, with remission status treated as a time-dependent covariate. A remote symptomatic cause of epilepsy indicates epilepsy associated with a major neurologic abnormality or insult. CI denotes confidence interval.

unexplained death had idiopathic or cryptogenic epilepsy, and 11 had epilepsy due to remote symptomatic causes. The median age at death among the subjects with sudden, unexplained death was 25 years (range, 4 to 49) overall, 27 years (range, 13 to 48) among subjects with idiopathic or cryptogenic epilepsy, and 23 years (range, 4 to 49) among those with epilepsy due to remote symptomatic causes. Although there were two cases of probable sudden, unexplained death among children 6 and 8 years of age with remote symptomatic epilepsy, all cases of sudden, unexplained death in the group with cryptogenic or idiopathic epilepsy occurred in adolescents and adults (Table 3). With the use of the alternative definition of sudden, unexplained death in epilepsy,27 there were 23 cases, 17 of which were confirmed by autopsy. Over the 40-year follow-up period, the risk of sudden, unexplained death among subjects with epilepsy was 7% (95% CI, 5 to 12) among all subjects and 12% (95% CI, 8 to 20) among those who were not in 5-year terminal remission and who were not receiving medication (Fig. 2). Among subjects with idiopathic or cryptogenic epilepsy,
n engl j med 363;26

the risk of sudden, unexplained death19 was 5% (95% CI, 2 to 11) overall, and the risk was 15% (95% CI, 7 to 31) among subjects who were not in 5-year terminal remission and no longer receiving medication. On univariate analysis, the absence of terminal remission and a history of status epilepticus, but not a remote symptomatic cause or a localization-related epilepsy syndrome, were associated with an increased risk of sudden, unexplained death among subjects with epilepsy (Table 3). On multivariate analysis, only the absence of 5-year terminal remission was significantly associated with sudden, unexplained death. The hazard ratios for all epilepsy-related deaths are shown in Table 3. Not surprisingly, these ratios are similar to those of sudden, unexplained death among subjects with epilepsy. According to the alternative Nashef criteria,27 most of the epilepsy-related deaths would qualify as sudden, unexplained death in subjects with epilepsy.

Discussion
The strength of this study is that it involves a cohort that was prospectively followed for 40 years,
december 23, 2010

nejm.org

2527

The New England Journal of Medicine Downloaded from nejm.org on June 11, 2011. For personal use only. No other uses without permission. Copyright 2010 Massachusetts Medical Society. All rights reserved.

The

n e w e ng l a n d j o u r na l

of

m e dic i n e

0.5

Cumulative Risk of Death

0.4

0.3 All epilepsy-related deaths 0.2

0.1 Sudden, unexplained deaths 0.0

10

15

20

25

30

35

40

Years after the Onset of Epilepsy

Figure 2. Cumulative Risk of All Epilepsy-Related Deaths and Sudden, Unexplained Deaths in Subjects with Epilepsy. Data shown are for patients at risk (i.e., receiving medication, with or without 5-year terminal remission).

with complete ascertainment of death and a high rate of autopsy-confirmed causes of death. With the longer follow-up, the epilepsy-related mortality is substantially higher than that reported in the original 1998 study (33% vs. 20%).20 Also, classification of the causes of death with the use of the autopsy data and the more formal definitions of sudden, unexplained death in subjects with epilepsy also greatly increase the number of cases. The reclassification substantially changes the picture of epilepsy-related mortality in this cohort. Frequent causes of death in Finland in persons between birth and 54 years of age in 2002 were accidents (accounting for 24.0 deaths per 100,000 persons), vascular causes (18.0 per 100,000), suicide (13.3 per 100,000), gynecologic cancer (4.0 per 100,000), and congenital malformations (1.6 per 100,000). The increased risk of death associated with childhood-onset epilepsy that we observed was substantial and persisted into adulthood. The increased risk was limited to subjects who were not in terminal remission and those who had another neurologic disability, particularly severe cognitive impairment. The most important risk factor for death from any cause as well as for epilepsyrelated death specifically was the absence of 5-year terminal remission. By definition, epilepsy-related deaths occurred exclusively in subjects who were not in 5-year terminal remission. Univariate analy2528

sis showed that the absence of 5-year terminal remission, a remote symptomatic cause (epilepsy associated with a major neurologic abnormality or previous insult), severe cognitive impairment, and a history of status epilepticus also were significant predictors of death; multivariate analysis showed that only the absence of 5-year terminal remission remained an important predictor. It is somewhat surprising that other factors known to be associated with increased mortality among patients with epilepsy did not emerge as risk factors. Severe cognitive impairment has been associated with an increased risk of sudden, unexplained death among subjects with epilepsy, even after adjustment for seizure frequency in a group with active epilepsy.3,34 The most likely explanation for an absence of this association in our cohort is that the more severely affected children in the symptomatic group were also less likely to have seizure-free remission. Deaths unrelated to seizures occurred primarily in the symptomatic group, and in the group with idiopathic or cryptogenic epilepsy, such deaths occurred at a much older age. We had considerable data on and autopsy confirmation of the majority of epilepsy-related deaths. Depending on which of the two definitions was used,10,18 sudden, unexplained death occurred in up to 9% of the entire cohort. This number, however, included subjects who had been in remission for many years without receiving medication. The risk of sudden, unexplained death among subjects with epilepsy who were not in 5-year terminal remission was substantially higher. Given our 40-year follow-up period, it is likely that we have ascertained most of the cases of sudden, unexplained death that will occur in this cohort, since the peak age period for sudden, unexplained death in patients with epilepsy is generally between 20 and 40 years of age,4,33 and after 50 years of age, it can become difficult to make this classification with certainty. Other studies of childhoodonset epilepsy with shorter periods of follow-up have shown that among children with idiopathic or cryptogenic epilepsy, the rate of death is no different from that in the general population, and in childhood, mortality is increased only among subjects with remote symptomatic epilepsy.5-9 However, in studies involving adults with sudden, unexplained death, the onset of epilepsy in childhood is often a risk factor.34-36 In this study, there were no cases of sudden, unexplained death
december 23, 2010

n engl j med 363;26

nejm.org

The New England Journal of Medicine Downloaded from nejm.org on June 11, 2011. For personal use only. No other uses without permission. Copyright 2010 Massachusetts Medical Society. All rights reserved.

Mortality in Childhood-Onset Epilepsy

among children younger than 14 years of age who lower among those who become seizure-free after had idiopathic or cryptogenic epilepsy; however, surgery than among those who do not,35 sugthe risk of sudden, unexplained death and other gesting that the risk is potentially modifiable. epilepsy-related deaths was relatively high among adults with active epilepsy. Supported by a grant from the Finnish Epilepsy Research Our data alone do not provide support for ag- Foundation. Disclosure forms provided by the authors are available with gressive treatment to prevent sudden, unexplained the full text of this article at NEJM.org. death in patients with epilepsy. However, studies We thank Hannu Kalimo, M.D., Ph.D., professor of neuropaof epilepsy surgery in adults with medically re- thology, and Pekka Saukko, M.D., Ph.D., professor of forensic medicine, for collecting the autopsy data; Hans Helenius, M.Sc., fractory partial epilepsy have shown that the rates for statistical advice; Olli Kaleva, B.A., for computations; and of sudden, unexplained death are substantially Dale Hesdorffer, Ph.D., for her constructive suggestions.
References
1. Leestma JE, Walczak T, Hughes JR, 12. Brorson LO, Wranne L. Long-term

Kalelkar MB, Teas SS. A prospective study on sudden unexpected death in epilepsy. Ann Neurol 1989;26:195-203. 2. Lhatoo SD, Johnson AL, Goodridge DM, MacDonald BK, Sander JW, Shorvon SD. Mortality in epilepsy in the first 11 to 14 years after diagnosis: multivariate analysis of a long-term, prospective, populationbased cohort. Ann Neurol 2001;49:336-44. 3. Walczak TS, Leppik IE, DAmelio M, et al. Incidence and risk factors in sudden unexpected death in epilepsy: a prospective cohort study. Neurology 2001;56:519-25. 4. Ficker DM, So EL, Shen WK, et al. Population-based study of the incidence of sudden unexplained death in epilepsy. Neurology 1998;51:1270-4. 5. Zielinski JJ. Epilepsy and mortality rate and cause of death. Epilepsia 1974; 15:191-201. 6. Hauser WA, Annegers JF, Elveback LR. Mortality in patients with epilepsy. Epilepsia 1980;21:399-412. 7. Cockerell OC, Johnson AL, Sander JW, Hart YM, Goodridge DM, Shorvon SD. Mortality from epilepsy: results from a prospective population-based study. Lancet 1994;344:918-21. 8. Cockerell OC, Johnson AL, Sander JW, Shorvon SD. Prognosis of epilepsy: a review and further analysis of the first nine years of the British National General Practice Study of Epilepsy, a prospective population-based study. Epilepsia 1997;38:31-46. 9. Derby LE, Tennis P, Jick H. Sudden unexplained death among subjects with refractory epilepsy. Epilepsia 1996;37:931-5. 10. Tennis P, Cole TB, Annegers JF, Leestma JE, McNutt M, Rajput A. Cohort study of incidence of sudden unexplained death in persons with seizure disorder treated with antiepileptic drugs in Saskatchewan, Canada. Epilepsia 1995;36:29-36. 11. Shackleton DP, Westendorp RGJ, Trenit DGA, Vandenbroucke JP. Mortality in patients with epilepsy: 40 years of follow up in a Dutch cohort study. J Neurol Neurosurg Psychiatry 1999;66:636-40.

prognosis in childhood epilepsy: survival and seizure prognosis. Epilepsia 1987;28: 324-30. 13. Berg AT, Shinnar S, Testa FM, Levy SR, Smith SN, Beckerman B. Mortality in childhood-onset epilepsy. Arch Pediatr Adolesc Med 2004;158:1147-52. 14. Shinnar S, ODell C, Berg AT. Mortality following a first unprovoked seizure in children: a prospective study. Neurology 2005;64:880-2. 15. Callenbach PMC, Westendorp RGJ, Geerts AT, et al. Mortality in children with epilepsy: the Dutch Study of Epilepsy in Childhood. Pediatrics 2001;107:1259-63. 16. Camfield CS, Camfield PR, Veugelers PJ. Death in children with epilepsy: a population-based study. Lancet 2002;359:1891-5. 17. Donner EJ, Smith CR, Snead OC III. Sudden unexplained death in children with epilepsy. Neurology 2001;57:430-4. 18. Nashef L, Fish DR, Garner S, Sander JW, Shorvon SD. Sudden death in epilepsy: a study of incidence in a young cohort with epilepsy and learning difficulty. Epilepsia 1995;36:1187-94. 19. Annegers JF. United States Perspective on Definitions and Classifications. Epilepsia 1997;38:Suppl:S9-S12. 20. Sillanp M, Jalava M, Kaleva O, Shinnar S. Long-term prognosis of seizures with onset in childhood. N Engl J Med 1998;338:1715-22. 21. Sillanp M, Shinnar S. Status epilepticus in a population-based cohort with childhood-onset epilepsy in Finland. Ann Neurol 2002;52:303-10. 22. Sillanp M, Jalava M, Shinnar S. Epilepsy syndromes in patients with childhood-onset seizures in Finland. Pediatr Neurol 1999;21:533-7. 23. Commission on Epidemiology and Prognosis, International League Against Epilepsy. Guidelines for epidemiologic studies on epilepsy. Epilepsia 1993;34:592-6. 24. Commission on Classification and Terminology of the International League Against Epilepsy. Proposal for revised

clinical and electroencephalographic classification of epileptic seizures. Epilepsia 1981;22:489-501. 25. Idem. Proposal for revised classification of epilepsies and epileptic syndromes. Epilepsia 1989;30:389-99. 26. Berg AT, Berkovic SF, Brodie MJ, et al. Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE Commission on Classification and Terminology, 2005-2009. Epilepsia 2010;51:676-85. 27. Nashef L. Sudden unexpected death in epilepsy: terminology and definitions. Epilepsia 1997;38:Suppl:S6-S8. 28. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958;53:457-81. 29. Elandt-Johnson RC, Johnson NL. Survival models and data analysis. New York: John Wiley, 1980:150-80. 30. Cox DR. Regression models and lifetables. J R Stat Soc [B] 1972;34:187-220. 31. Fleiss JL, Levin B, Cho Paik M. Statistical methods for rates and proportions. 3rd ed. Hoboken, NJ: John Wiley, 2003:638. 32. Foreman AJ, Lai GP, Miller DP. Surviving left truncation using PROC PHREG. In: SAS/STAT users guide, version 9. Cary, NC: SAS Institute, 2003. (http://mayoresearch.mayo.edu/mayo/ research/biostat/sasmacros.cfm.) 33. Central Statistical Office of Finland. Statistical yearbook of Finland. 2003. (http://pxweb2.stat.fi/sahkoiset_ julkaisut/vuosikirja2004/2003/vkirja.pdf.) 34. Tomson T, Walczk T, Sillanp M, Sander JW. Sudden unexpected death in epilepsy: a review of incidence and risk factors. Epilepsia 2005;46:Suppl 11:54-61. 35. Sperling MR, Feldman H, Kinman J, Liporace JD, OConnor MJ. Seizure control and mortality in epilepsy. Ann Neurol 1999;46:45-50. 36. Nilsson L, Farahmand BY, Persson PG, Thiblin I, Tomson T. Risk factors for sudden unexpected death in epilepsy: a casecontrol study. Lancet 1999;353:888-93.
Copyright 2010 Massachusetts Medical Society.

n engl j med 363;26

nejm.org

december 23, 2010

2529

The New England Journal of Medicine Downloaded from nejm.org on June 11, 2011. For personal use only. No other uses without permission. Copyright 2010 Massachusetts Medical Society. All rights reserved.