NEJMoa0911610

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original article

T he n e w e n g l a n d j o u r n a l o f medicine

n engl j med 363;26 nejm.org december 23, 20102522

Long-Term Mortality in Childhood-Onset

Epilepsy Matti Sillanpää, M.D., Ph.D., and Shlomo Shinnar, M.D., Ph.D.

From the Departments of Pediatric Neu-rology and Public Health, University of

Turku and Turku University Hospital —both in Turku, Finland (M.S.); and theDepartments of Neurology, Pediatrics,and Epidemiology and Population Healthand the Comprehensive Epilepsy Manage-ment Center, Montefiore Medical Center,Albert Einstein College of Medicine, Bronx,NY (S.S.). Address reprint requests to Dr.Shinnar at the Comprehensive EpilepsyManagement Center, Montefiore MedicalCenter, 111 E. 210th St., Bronx, NY 10467,or at [email protected].

N Engl J Med 2010;363:2522-9.Copyright © 2010 Massachusetts Medical Society.

A B S T RA C T

Background

There are few studies on long-term mortality in prospectively followed, well-charac-

terized 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 analy-

sis 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 chil-

dren who were not in remission. (Funded by the Finnish Epilepsy Research Foundation.)

The New England Journal of Medicine

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8/6/2019 NEJMoa0911610


Mortality in Childhood-Onset Epilepsy

n engl j med 363;26 nejm.org december 23, 2010 2523

Few 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 follow-

up is generally 5 to 10 years.12-18 In all series, au-

topsy 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.

Methods

Subjects and Study Design

The study population included all children young-

er 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 un-

provoked seizures. The subjects were identified

from the f iles of Turku University Hospital, other

hospitals and institutions in southern Finland, and

private surgeons and from Finland’s 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 eval-

uation. 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 sub-

jects with prevalent cases of epilepsy (39%) were

seen before 1961, but they were seen again dur-

ing the 1961−1964 study period for active epilepsy

(at least one epileptic seizure during the preced-

ing 3 years and a prior diagnosis of epilepsy). Ex-cluded 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 ob-

tained from continuous follow-up of the patients

in the intervals between the 5-year examinations.

Detailed information collected about this sub-

group included the date and time of death, the

immediate cause of death, the underlying cause

of death, and autopsy data, when available. Writ-

ten informed consent obtained from all subjects

or their caregivers permitted access to the hospi-

tal f iles in order to abstract data on the last stagesof the disease before death. To ensure full cover-

age 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 avail-

able 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 Univer-

sity of Turku Medical School and University Hos-

pital 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 or-

gans 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 au-

topsy, 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 dys-

trophy with pneumonia; and one, who had mod-

erate cognitive impairment, died after an epilep-tic seizure.

Definitions

Epileptic syndromes, epilepsies, epileptic seizures,

and the causes of seizures were defined accord-

ing 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., cog-




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Th e n e w e n g l a n d j o u r n a l o f medicine


nitive impairment, clinically signif icant develop-

mental delay [developmental quotient <70 in chil-

dren younger than 7 years of age], cerebral palsy,

or autism) or a history of a major neurologic in-

sult (e.g., head trauma, stroke, or meningitis). The

remaining subjects were determined to have cryp-

togenic or idiopathic epilepsy. The classification

of epilepsy was made in all subjects, and the de-

tailed seizure types and epilepsy syndromes in this

cohort have been reported previously.22 These clas-

sifications were determined before the new clas-

sifications 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 def i-

nition by Annegers,19 as sudden death with no

evidence of a seizure and no other identified causeof death, with confirmation of these findings by

autopsy. In almost all cases of sudden, unex-

plained death in a person with epilepsy, pulmo-

nary edema was detected on autopsy. We also ex-

amined 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.

Statistical Analysis

Our statistical methods took into account the time-

dependent 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 per-

formed on the basis of the 2002 Finnish popula-

tion. The product-limit method was used to cal-

culate 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 inter-

vals were calculated with the use of a modifica-

tion of the Greenwood formula.29 Univariate and

multivariate analyses were performed with the use

of the Cox proportional-hazards model, and re-

mission status was treated as a time-dependent covariate.29-31 Rates of death according to remission

status were adjusted for the number of person-

years at risk during the remission period. Rate

ratios with 95% confidence intervals were calcu-

lated with the use of the Cox regression models.

When the cohort with incident epilepsy and the

cohort with prevalent epilepsy were combined, ad-

justment was made for the left truncation due to

the delayed entry of the cohort with prevalent epi-

lepsy.32 A direct age- and sex-adjusted standard

Table 1. Mortality among Subjects with Childhood-Onset Epilepsy.*

VariableAll Subjects

(N = 245)

Subjects with Idiopathic orCryptogenic Epilepsy

(N = 122)

Subjects with Epilepsy Due toRemote Symptomatic Causes

(N = 123)†

Total deaths — no. 60 15 45

Age at death — yr

Median 23 26 21

Range 1–50 11–50 1–49

No. of person-yr 8692 4638 4054

No. of deaths/1000 person-yr (95% CI)

All 6.90 (5.3–8.9) 3.23 (1.9–5.4) 11.10 (8.3–14.9)

Men 7.33 (5.2–10.2) 2.69 (1.2–6.0) 11.63 (8.0–16.8)

Women 6.41 (4.4–9.4) 3.74 (1.9–7.2) 10.33 (6.4–16.6)

Remission status at time of death‡

Not in remission — no./total no. of deaths (%) 51/60 (85) 11/15 (73) 40/45 (89)

In remission — no./total no. of deaths (%) 9/60 (15) 4/15 (27) 5/45 (11)

Receiving medication — no. 5 2 3Not receiving medication — no. 4 2 2

* 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 sub-

jects in 5-year terminal remission, 35 were receiving medication and 103 were not.




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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 ex-

pected 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 follow-

up. Statistical computations were performed with

the use of SAS software, version 9.1.3 (SAS In-

stitute).

Results

Characteristics of the Study PopulationA 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 sub-

jects had idiopathic or cryptogenic epilepsy, and

123 subjects had remote symptomatic epilepsy

(i.e., epilepsy associated with a major neurologic

abnormality or insult). The median duration of epi-

lepsy before achieving 5-year long-term remission

was 17 years (range, 1 to 52) for surviving sub-

jects 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 medica-

tion, and 107 (44%) were not in 5-year remission.

Overall Mortality

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 per-

son-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 signif icantly, and the two groups

were therefore combined. Details on incident cas-

es 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 mortal-

ity 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 es-

timate and was not adjusted for the delayed entry

Table 2. Causes of Death.

VariableAll Subjects

(N = 245)

Subjects with Idiopathic orCryptogenic Epilepsy

(N = 122)

Subjects with Epilepsy Due toRemote Symptomatic Causes

(N = 123)*

Total deaths — no. 60 15 45

Death related to epilepsy — no./total

no. of deaths (%)

33/60 (55) 9/15 (60) 24/45 (53)

Witnessed seizure — no. 6 0 6

Status epilepticus — no. 4 0 4

Probable seizure — no. 3 2 1

Drowning — no. 6 0 6

Sudden, unexplained death — no. 18 7 11

Death not related to epilepsy — no./total no. of deaths (%)

26 (43) 6 (40) 20 (44)

Pneumonia — no. 12 0 12

Cardiovascular disease — no. 8 2 6

Suicide — no. 2 2 0

Other cause of death — no. 4 2 2

Cause of death unknown — no. 1 0 1

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




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of subjects with prevalent cases of epilepsy. The

causes of death and their relationship to remis-

sion status and cause of epilepsy are summarized

in Tables 1 and 2. The highest rate of death oc-

curred among subjects who were not in 5-year ter-

minal 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 person-

years) than among subjects with cryptogenic epi-

lepsy (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 re-

mote symptomatic causes and subjects with idio-

pathic or cryptogenic epilepsy was significant (11.1

deaths per 1000 person-years vs. 3.2 per 1000 per-

son-years, P<0.001).

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 (Ta-

ble 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 epilep-sy-related death are summarized in Table 3. Uni-

variate 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 asso-

ciated 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 sig-

nificantly associated with the hazard ratio fordeath. The other variables have previously been

shown to be associated with a lack of remis-

sion.20-22 Other factors, such as the type of epi-

lepsy (localization-related epilepsy, temporal-

lobe epilepsy, or another type of epilepsy) or cere-

bral 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, unex-

plained death in epilepsy in 18 patients (30%),

probable or definite seizure in 9 (15%), and ac-

cidental drowning in 6 (10%). With the use of the

alternative classif ication 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 Epilepsy-

Related Deaths

There were 18 cases of sudden, unexplained

death,19 including 15 cases that were confirmed

by autopsy. Seven of the subjects with sudden,

C u m u l a t i v e R a

t e o f D e a t h

50

30

40

20

0

10

0 5 10 15 20 35 4025 30

YearsaftertheOnsetofEpilepsy

Remote symptomatic cause

Idiopathic or cryptogenic cause

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.




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unexplained death had idiopathic or cryptogenic

epilepsy, and 11 had epilepsy due to remote symp-

tomatic 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 cryp-

togenic epilepsy, and 23 years (range, 4 to 49)

among those with epilepsy due to remote symp-

tomatic causes. Although there were two cases of

probable sudden, unexplained death among chil-

dren 6 and 8 years of age with remote symptom-

atic epilepsy, all cases of sudden, unexplained

death in the group with cryptogenic or idiopath-

ic epilepsy occurred in adolescents and adults

(Table 3). With the use of the alternative defini-tion 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,

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 receiv-

ing medication. On univariate analysis, the ab-

sence of terminal remission and a history of sta-

tus 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 ab-

sence of 5-year terminal remission was signifi-

cantly associated with sudden, unexplained death.

The hazard ratios for all epilepsy-related deaths

are shown in Table 3. Not surprisingly, theseratios 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 co-

hort that was prospectively followed for 40 years,

Table 3. Predictors of Death.*

Risk Factor Univariate Analysis Multivariate Analysis

Hazard Ratio(95% CI) P Value

Hazard Ratio(95% CI) P Value

All deaths

Absence of 5-yr terminal remission 5.3 (2.6−11.0) <0.001 4.7 (1.5−14.9) 0.007

Remote symptomatic cause of epilepsy 3.4 (1.9−6.1) <0.001 1.5 (0.7−3.6) 0.31

Prior status epilepticus 1.9 (1.2−3.2) 0.01 1.5 (0.7−3.0) 0.28

Age at onset <2 yr 1.4 (0.8−2.3) 0.20 1.7 (0.8−3.5) 0.13

Epilepsy-related deaths

Absence of 5-yr terminal remission 6.4 (2.2−18.8) <0.001 4.7 (1.5–14.9) 0.007

Remote symptomatic cause of epilepsy 3.1 (1.4−6.7) 0.004 1.5 (0.7−3.6) 0.31

Prior status epilepticus 2.1 (1.1−4.2) 0.03 1.5 (0.7−3.0) 0.28

Age at onset <2 yr 1.9 (0.96−3.8) 0.06 1.7 (0.8−3.5) 0.13

Sudden, unexplained deaths

Absence of 5-yr terminal remission 5.2 (1.4−18.5) 0.01 5.0 (1.2−20.1) 0.02

Prior status epilepticus 2.8 (1.1–7.0) 0.03 2.6 (0.9−7.5) 0.07

Age at onset <2 yr 2.1 (0.8−5.5) 0.11 1.9 (0.7−5.2) 0.20

Remote symptomatic cause of epilepsy 1.9 (0.7−4.8) 0.20 0.8 (0.3−2.4) 0.72

Localization-related epilepsy 0.8 (0.3−2.0) 0.60 0.5 (0.2−1.5) 0.21

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




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with complete ascertainment of death and a high

rate of autopsy-confirmed causes of death. With

the longer follow-up, the epilepsy-related mortal-

ity 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 defini-

tions 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 malfor-

mations (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 in-creased 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 epilepsy-

related 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 analy-

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 sig-

nificant predictors of death; multivariate analy-

sis showed that only the absence of 5-year termi-

nal 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, un-

explained death among subjects with epilepsy,

even after adjustment for seizure frequency in a

group with active epilepsy.3,34 The most likely ex-

planation for an absence of this association in

our cohort is that the more severely affected chil-

dren in the symptomatic group were also less

likely to have seizure-free remission. Deaths un-related to seizures occurred primarily in the symp-

tomatic 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 con-

firmation 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, how-

ever, included subjects who had been in remission

for many years without receiving medication. The

risk of sudden, unexplained death among sub-

jects with epilepsy who were not in 5-year termi-

nal remission was substantially higher. Given our

40-year follow-up period, it is likely that we have

ascertained most of the cases of sudden, unex-

plained 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 classifica-

tion with certainty. Other studies of childhood-

onset epilepsy with shorter periods of follow-uphave 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 child-

hood is often a risk factor.34-36 In this study,

there were no cases of sudden, unexplained death

C u m u l a t i v e R i s k o f D e a t h

0.5

0.3

0.4

0.2

0.0

0.1

0 5 10 15 20 35 4025 30

YearsaftertheOnsetofEpilepsy

All epilepsy-related deaths

Sudden, unexplained deaths

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 with-out 5-year terminal remission).




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among children younger than 14 years of age who

had idiopathic or cryptogenic epilepsy; however,

the risk of sudden, unexplained death and other

epilepsy-related deaths was relatively high among

adults with active epilepsy.

Our data alone do not provide support for ag-

gressive treatment to prevent sudden, unexplained

death in patients with epilepsy. However, studiesof epilepsy surgery in adults with medically re-

fractory partial epilepsy have shown that the rates

of sudden, unexplained death are substantially

lower among those who become seizure-free after

surgery than among those who do not,35 sug-

gesting that the risk is potentially modifiable.

Supported by a grant from the Finnish Epilepsy ResearchFoundation.

Disclosure forms provided by the authors are available withthe full text of this article at NEJM.org.

We thank Hannu Kalimo, M.D., Ph.D., professor of neuropa-thology, and Pekka Saukko, M.D., Ph.D., professor of forensicmedicine, for collecting the autopsy data; Hans Helenius, M.Sc.,

for statistical advice; Olli Kaleva, B.A., for computations; andDale Hesdorffer, Ph.D., for her constructive suggest ions.

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