www.thelancet.com Published online July 22, 2013 http://dx.doi.org/10.1016/S0140-6736(13)60899-5 1
Premature mortality in epilepsy and the role of psychiatric
comorbidity: a total population study
Seena Fazel, Achim Wolf, Niklas Långström, Charles R Newton, Paul Lichtenstein
Background Epilepsy is associated with high rates of premature mortality, but the contribution of psychiatric comorbidity
is uncertain. We assessed the prevalence and risks of premature mortality from external causes such as suicide, accidents,
and assaults in people with epilepsy with and without psychiatric comorbidity.
Methods We studied all individuals born in Sweden between 1954 and 2009 with inpatient and outpatient diagnoses
of epilepsy (n=69 995) for risks and causes of premature mortality. Patients were compared with age-matched and
sex-matched general population controls (n=660 869) and unaff ected siblings (n=81 396). Sensitivity analyses were
done to investigate whether these odds diff ered by sex, age, seizure types, comorbid psychiatric diagnosis, and
diff erent time periods after epilepsy diagnosis.
Results 6155 (8.8%) people with epilepsy died during follow-up, at a median age of 34·5 (IQR 21·0–44·0) years with
substantially elevated odds of premature mortality (adjusted odds ratio [aOR] of 11·1 [95% CI 10·6–11·6] compared
with general population controls, and 11·4 [10·4–12·5] compared with unaff ected siblings). Of those deaths, 15·8%
(n=972) were from external causes, with high odds for non-vehicle accidents (aOR 5·5, 95 % CI 4·7–6·5) and suicide
(3·7, 3·3–4·2). Of those who died from external causes, 75·2% had comorbid psychiatric disorders, with strong
associations in individuals with co-occurring depression (13·0, 10·3–16·6) and substance misuse (22·4, 18·3–27·3),
compared with patients with no epilepsy and no psychiatric comorbidity.
Interpretation Reducing premature mortality from external causes of death should be a priority in epilepsy
management. Psychiatric comorbidity plays an important part in the premature mortality seen in epilepsy. The ability
of health services and public health measures to prevent such deaths requires review.
Funding Wellcome Trust, the Swedish Prison and Probation Service, and the Swedish Research Council.
Epilepsy accounts for an estimated 0·7% of the global
burden of disease.1 It aff ects around 70 million people,2
and contributes to over 17 million disability-adjusted
life-years annually.1 Premature mortality is substantial3
and almost half of epilepsy-related deaths occur in those
younger than 55 years, corresponding to standardised
mortality ratios above 10 for hospitalised patients.4
Suicide is associated with up to 5% of all epilepsy
deaths,5 but whether epilepsy is independently associated
with suicide is unclear. One study suggested that epilepsy
is an independent risk factor for suicide after controlling
for psychiatric comorbidity,6 but studies from Canada7 and
the UK8 reported no independent relation. There have also
been confl icting conclusions about whether epilepsy is a
risk factor for suicide when psychiatric comorbidity is not
present.6,7 Clarifi cation would assist national suicide pre-
vention strategies that increasingly focus on high-risk
populations,9,10 particularly if such groups can be identi-
fi ed, and could also inform treatment guidelines.
Other major causes of epilepsy-related deaths are
vehicle and non-vehicle accidents,10,11 which contribute to
up to 16% of deaths.12 Restrictions for drivers with epilepsy
have probably contributed to death rates from motor
vehicle accidents not being signifi cantly higher than that
of the general population in certain countries.7 However,
the role of public health and education measures in
reducing mortality from non-vehicle accidents in patients
with epilepsy is uncertain. In particular, possible asso-
ciations of non-vehicle accidental deaths with psychiatric
disorders need clarifi cation, and previous studies have
not investigated psychiatric comorbidity.11
In our 41-year population study of 69 995 individuals
with epilepsy, we aimed to investigate prevalence and
risks of premature mortality, and to address two specifi c
issues. First, whether epilepsy is independently asso-
ciated with external causes of death. To clarify this, we
compared people with epilepsy with the general
population and unaff ected sibling controls. If there is a
link between epilepsy and death from external causes,
the use of sibling controls enables clarifi cation of whether
this association is consistent with a causal hypothesis or
due to residual confounding, including genetic and early
environmental factors. Second, we investigated the
association of epilepsy with premature mortality in
patients with and without comorbid psychiatric disorders.
We linked several longitudinal, nationwide population
registers in Sweden: the Patient Register (held at the
National Board of Health and Welfare), the Censuses
July 22, 2013
University of Oxford,
Department of Psychiatry,
Warneford Hospital, Warneford
Lane, Headington, Oxford, UK
(S Fazel MD, A Wolf MSc,
Prof C R Newton MD);
Department of Medical
Institutet, Stockholm, Sweden
(Prof N Långström PhD,
Prof P Lichtenstein PhD)
Dr Seena Fazel, University of
Oxford, Department of
Psychiatry, Warneford Hospital,
Warneford Lane, Headington,
Oxford OX3 7JX, UK
www.thelancet.com Published online July 22, 2013 http://dx.doi.org/10.1016/S0140-6736(13)60899-5
from 1970 and 1990 (Statistics Sweden), the Multi-
Generation Register (Statistics Sweden), and the
Cause-of-Death Register (National Board of Health and
Welfare). The Multi-Generation Register connects every
person born in Sweden from 1933 onwards and ever
registered as living in Sweden after 1960 to their
parents.13 For immigrants, similar information exists
for those who became citizens of Sweden before aged
18 years, together with one or both parents. In Sweden,
all residents including immigrants have a unique
ten-digit personal identifi cation number that is used in
all national registers, thus making the linking of data
possible. We selected a cohort of people born between
1954 and 2009, and followed them up for up to 41 years,
from 1969 to the end of follow-up in 2009 (n=7 238 800).
The Patient Registers started in 1969; hence we began
our follow-up at that point, which meant that children
diagnosed with epilepsy who died between 1954 and
1968 were not included in the cohort. A sensitivity
analysis addressed whether this aff ected the main
fi ndings. Using the Multi-Generation Register, we also
identifi ed patients with epilepsy who had full siblings
The Regional Ethics Committee at Karolinska Institutet
approved the study (2009/939-31/5). Data were merged
and anonymised by an independent government agency
(Statistics Sweden), and the code linking the personal
identifi cation numbers to the new case numbers was
destroyed immediately after merging. Therefore, in-
formed consent was not required.
Epilepsy was identifi ed through the National Patient
Register, which includes individuals hospitalised
(starting in 1969 but with total national coverage
from 1987) or having outpatient appointments with
specialist physicians (since
Patients with epilepsy had to have had at least one
episode in which the diagnosis was made according to
the International Classifi cation of Diseases (ICD) ICD-8
2001) in Sweden.14
(1969–1986; diagnostic codes 345.00–345.99), ICD-9
(1987–1996; codes 345J, K, L, M, N, P, Q, W, X), or ICD-10
(from 1997 onwards; codes G40.1–G40.9, G41).
Swedish patient register data for diagnoses have good to
excellent validity for a range of disorders, including
neurological conditions such as acute stroke15 and
Guillain-Barré syndrome,16 and psychiatric illnesses such
as bipolar disorder17 and schizophrenia.18 Overall, the
positive predictive value of the inpatient register, in a
recent review, was found to be 85–95% for most
diagnoses.19 Less is known about comorbidity, although
one study found fair to moderate agreement for comorbid
substance misuse in schizophrenia (κ=0·37, standard
error 0·23, p<0·001, corresponding to 68% full
agreement).20 Since only around 1% of hospital
admissions have missing personal identifi cation
numbers,21 the register has been used in various
Data for causes of death were retrieved for all individuals
who died between 1969 and 2009. The Cause of Death
register, based on death certifi cates, covers over 99% of
all deaths.24 We extracted both all-cause mortality data
and separately by ICD chapter, including external causes.
Within external causes, we further examined deaths by
suicide, vehicle and non-vehicle accidents, and assault.
In line with previous work,25 undetermined deaths (ICD
codes Y10-Y34) were included as suicides since their
exclusion would underestimate actual rates.26
Sociodemographic and psychiatric covariates
Mean lifetime disposable income (divided into thirds)
was used as a proxy for income, and used as a dichoto-
mous variable (lowest tertile vs top two tertiles). If this
information was unavailable, family lifetime disposable
income, or parents’ lifetime disposable income was used
instead and similarly divided into tertiles. Single mari-
tal status was defi ned as being unmarried at end of
Patients with epilepsy
unaff ected siblings
Unaff ected sibling
Male, n (%)
Single status, n (%)
Immigrant status, n (%)
Lifetime individual mean disposable income, 1000 SEK (SD)
Median age at diagnosis, years (IQR)
Median age at death, years (IQR)
36 999 (52·9%)
50 099 (71·6%)
348 561 (52·7%)
417 053 (63·1%)
20 125 (3·0%)
22 751 (53·0%)
36 257 (74·9%)
41 786 (51·3%)
56 018 (68·8%)
Data for single status were not available for 1527 individuals with epilepsy and 12 259 matched population controls, 910 patients with epilepsy with sibling controls, and
301 unaff ected sibling controls. Data for individual income were not available for 14 441 individuals with epilepsy, 139 580 matched population controls, 10 548 epilepsy
patients with sibling controls, and 15 948 unaff ected sibling controls. SEK=Swedish krona. IQR=interquartile range.
Table 1: Baseline sociodemographic information for cohorts of individuals with epilepsy and comparison groups
www.thelancet.com Published online July 22, 2013 http://dx.doi.org/10.1016/S0140-6736(13)60899-5 3
follow-up. Immigrant status was defi ned as being born
outside of Sweden. Missing data were not replaced by
imputation or other methods.
Any psychiatric, drug, and alcohol use disorders were
defi ned using inpatient (1969–2009) and outpatient
(2001–09) primary or secondary diagnoses of any
psychiatric condition (ICD-8: 290–315; ICD-9: 290–319;
ICD-10: F00–F99), alcohol or drug use or dependence
(ICD-8: 303, 304; ICD-9: 303, 304, 305.1, 305.9; ICD-10:
F10–F19, except x.5), and depression and related mood
disorders (ICD-8: 296, 298.0, 300.4; ICD-9: 296, 298A,
300E, 311; ICD-10: F32–F39).
For each patient, up to ten general population controls
without any diagnosis of epilepsy were matched
individually by birth year and sex (n=660 869). We esti-
mated the association between having been diagnosed
with epilepsy and causes of death, as per related work
using matched or sibling controls,20,23 using the clogit
command in Stata, version 12 (StataCorp). The clogit
command fi ts conditional (fi xed eff ects) logistic regres-
sion models to matched case-control or cohort groups.
We included three confounders (low income, single, and
immigrant status) on theoretical grounds, based on
related work in severe mental illness,20,27 and also tested
whether they were each independently asso ciated with
either case (epilepsy diagnosis) or con trol and outcome
measures, respectively, in univariate analyses at the 5%
level of signifi cance.28
Sibling control studies
To account for possible familial confounding, we did
additional analyses that used unaff ected full siblings of
patients as controls. In this analysis, we identifi ed as
cases those individuals with epilepsy who also had full
siblings without epilepsy, and these individuals were
compared with their unaff ected full siblings (n=81 396)
using matched conditional logistic regression, and
analyses were adjusted for age and sex.
We also did the following subanalyses. First, we investi-
gated categories of epilepsy and classifi ed them into four
types according to the diagnosis at fi rst admission:
complex partial seizures (ICD-8: 345.31; ICD-9: 345M,
345N; ICD-10: G40.2), other partial seizures (ICD-8:
345.30, 345.38, 345.39; ICD-10: G40.0, G40.1), generalised
epilepsy (ICD-8: 345.00, 345.09, 345.10, 345.11; ICD-9:
345J, 345K; ICD-10: G40.3), and other or unspecifi ed
epilepsy (ICD-8: 345.18, 345.19, 345.20, 345.29, 345.32,
345.33, 345.9; ICD-9: 345L, 345P, 345Q, 345W, 345X;
ICD-10: G40.4, G40.5, G40.6, G40.7, G40.8, G40.9, G41).23
Patients, n (%)Controls, n (%)
Any psychiatric diagnosis
Any psychiatric diagnosis
Any psychiatric diagnosis
12 631 (18·0%)
23 067 (3·5%)
15 856 (22·7%)
45 314 (6·9%)
12 543 (1·9%)
16 523 (2·5%)
28 487 (40·7%)
68 381 (10·3%)
18 946 (2·9%)
13 520 (2·0%)
21 913 (3·3%)
Data are number (%) with psychiatric comorbidity. Any psychiatric disorder
includes substance use diagnoses. New diagnoses refer to any psychiatric
diagnoses made after fi rst epilepsy diagnosis.
Table 2: Prevalence of pre-existing, new, and lifetime psychiatric
morbidity in individuals with epilepsy
Deaths in patients
n (% of deaths)
Deaths in controls
n (% of deaths)
ratio (95% CI)
I Certain infectious and parasitic diseases
III Diseases of the blood and blood-forming
organs and certain disorders involving the
IV Endocrine nutritional and metabolic
V Mental and behavioural disorders
VI Diseases of the nervous system
IX Diseases of the circulatory system
X Diseases of the respiratory system
XI Diseases of the digestive system
XIII Diseases of the musculoskeletal system
and connective tissue
XIV Diseases of the genitourinary system
XVI Certain conditions originating in the
XVII Congenital malformations,
deformations, and chromosomal
XVIII Symptoms, signs, and abnormal
clinical and laboratory fi ndings, not
elsewhere classifi ed
Other non-external (chapters VII, VIII, XII,
XX External causes of morbidity and
277 (4·5%) 151 (3·1%)14·2 (11·3–17·9)
449 (7·3%)94 (1·9%)38·1 (27·7–52·5)
106 (1·7%)134 (2·7%)7·2 (5·3–9·8)
7 (0·1%)7 (0·2%) 12·7 (3·0–52·8)
972 (15·8%)2101 (42·9%)3·6 (3·3–4·0)
6155 (100%)4892 (100%)11·1 (10·6–11·6)
Adjusted odds ratios refer to the odds of premature death by ICD chapter in patients with epilepsy compared with
controls matched by sex and birth year, and adjusted by income, and immigrant and single status.
Table 3: Prevalence and odds of premature mortality in epilepsy, by International Classifi cation of
www.thelancet.com Published online July 22, 2013 http://dx.doi.org/10.1016/S0140-6736(13)60899-5
Second, based on International League Against Epilepsy
recommendations of subclassifying epilepsy into clinical
syndromes,29 we undertook a further sensitivity analysis
based solely on ICD-10 codes, based on work using Danish
national registers.30 Third, as an index of severity, we
compared individuals whose fi rst hos pital treatment
episode lasted for 9 days or more (90th percentile) with
the others (inpatients and out patients). Fourth, we
investigated diff erences by diagnostic threshold by com-
paring individuals with one or more diagnoses of epilepsy
with those with two or more diagnoses. Fifth, we compared
individuals with epilepsy by birth order. Finally, deaths by
10-year age-bands were investigated, and we also compared
mortality risks in children who died under the age of
15 years with other ages. We followed STROBE guidelines
We identifi ed 69 995 individuals with epilepsy and
compared them with 660 869 age-matched and sex-
matched controls (table 1). Patients were followed up for
an average of 9 years (interquartile range [IQR]
5–18 years). Rates of psychiatric comorbidity were 18·0%
before diagnosis of epilepsy and 22·7% after diagnosis,
with high rates of depression and substance misuse
(drug and alcohol use disorders; table 2).
6155 (8·8%) patients with epilepsy died before the end
of the follow-up period compared with 4892 (0·7%)
controls. We found a substantially elevated increased
odds for all-cause mortality in individuals with epilepsy
after matching for age and sex (odds ratio 14·1, 95% CI
13·5–14·7), and after adjustment for sociodemographic
confounders (adjusted odds ratio [aOR] 11·1, 95% CI
10·6–11·6). In men, 3786 (10·2%) patients died during
follow-up, compared with 3322 (1·0%) controls
(aOR 10·1, 95% CI 9·5–10·7); in women, 2369 (7·2%)
patients died, compared with 1570 (0·5%) controls
(13·0, 12·0–14·0). Adjusted odds ratios for ICD sub-
categories of mortality were mostly elevated (table 3),
with most deaths in patients with diseases caused by the
same underlying disease process as that leading to
epilepsy. Of these, neoplasms (23·0% of deaths;
aOR 11·2, 95% CI 10·3–12·2), and diseases of the
nervous system (21·3% of deaths; 71, 57–88) were the two
major causes. The next largest category was external
causes (15·8% of deaths). The highest mortality odds
ratio was for conditions originating in the perinatal
period (1·6% of deaths; aOR 126, 95% CI 46–348).
The odds for external causes of death in individuals
with epilepsy were also elevated (aOR 3·6, 95% CI
3·3–4·0; table 4). For suicide (n=510), the adjusted odds
ratio was 3·7 (95% CI 3·3–4·2). Deaths caused by non-
vehicle accidents (n=362) had the highest odds of death
(aOR 5·5, 95% CI 4 ·7–6·5) among external causes
(table 4). For death by assault (n=30), the adjusted odds
ratio was 2·8 (95% CI 1·6–4·8). In further analyses of
non-vehicle accidents, we found 135 deaths (37·3% of
non-vehicle accidents) due to accidental drug poisoning,
60 (16·6%) due to accidental falls, 55 (15·2%) drowning,
and 112 (30·9%) other and unspecifi ed accidental deaths.
We compared patients with epilepsy (n=48 437) with
their unaff ected siblings (n=81 396) for all-cause mor-
tality, natural causes, and specifi c external causes. All
risk estimates remained raised, including those for
suicide (aOR 2·9, 95% CI 2·4–3·6) and non-vehicle
accidents (6·3, 4·6–8·8; table 4). We found no evidence
of familial confounding for non-vehicle accidents (since
risk estimates were signifi cant and of the same mag-
nitude as with the population controls).
Diff erences in mortality due to any external cause did
not vary by severity and diagnostic thresholds in sensitivity
analyses (table 5). Although odds of death by external
causes were lower in those with two or more diagnoses of
epilepsy, this diff erence was not signifi cant, and con-
fi dence intervals overlapped. We found some evidence for
diff erences by epilepsy types in odds of external cause
mortality. Special epilepsy syndromes (ICD-10 G40.5,
including G40.5L epileptic encephalopathy with con-
tinuous spike-and-wave during sleep) had higher odds of
non-vehicle accidents (aOR 24·2, 95% CI 9·2–63·9) than
other types of epilepsy (table 5). For suicide, women had
higher odds of death (aOR 5·0, 95% CI 4·0–6·3) than
men (3·3, 2·8–3·8; interaction test p=0·002). After
stratifi cation by age groups, we found some evidence of
higher odds ratios of external causes of mortality with
increasing age. We found no diff erences in odds or
prevalence of mortality by birth order. Odds ratios of
external causes were higher in the fi rst 6 months after
Odds ratio for
(aOR [95% CI])
Odds ratio for
with unaff ected
(aOR [95% CI])
Other and unspecifi ed
Data are adjusted odds ratios (aOR) of external deaths compared with population
controls (matched for age and sex, and adjusted for income, and marital and
immigration status) or unaff ected sibling controls (adjusted for age and sex).
Table 4: Risks of premature death in individuals with epilepsy compared
to population controls and unaff ected siblings
See Online for appendix
www.thelancet.com Published online July 22, 2013 http://dx.doi.org/10.1016/S0140-6736(13)60899-5 5
diagnosis of epilepsy (table 5). Sensitivity analyses for all
natural causes of death, and specifi cally for neoplasms
and neurological causes, are shown in the appendix.
There was an increased prevalence of psychiatric dis-
orders in epilepsy patients, and specifi cally for alcohol
and drug use disorders, and depression (table 2).
By epilepsy syndrome, special syndromes had higher
comorbidity (81·3%) than unspecifi ed (45·2%), focal
(36·0%), general ised (29·6%) and other groups. Of those
who died from external causes during follow-up,
External causes Suicide or uncertainVehicle accidents Other accidents
n (% deaths) aOR (95% CI)n (% deaths)aOR (95% CI)n (% deaths)aOR (95% CI) n (% deaths)aOR (95% CI)
No epilepsy (n=660 869)
Male (n=36 999)
Female (n=32 996)
≥1 diagnosis (n=69 995)
≥2 diagnoses (n=48 105)
Less severe (n=62 143)
More severe (n=7852)
Inpatient (n=50 071)
Outpatient only (n=19 924)
Type of seizures*
Complex partial (n=8382)
Other partial (n=5857)
Generalised (n=15 315)
Other and unspecifi ed (n=40 441)
Type of epilepsy†
Focal (n=12 841)
Encephalopathy and mixed (n=1894)
Special syndromes (n=894)
Other epilepsy (n=710)
Unspecifi ed epilepsy (n=29 997)
Age at death
0–15 (n=69 995)
16–25 (n=68 877)
26–35 (n=67 963)
36–45 (n=66 691)
46–56 (n=65 055)
Firstborn (n=21 131)
Not fi rstborn (n=27 306)
No siblings (n=21 558)
0–182 days (n=69 995)
183–365 days (n=69 096)
≥366 days (n=68 592)
2101 (42·9%)1·0 (ref)1058 (21·6%)1·0 (ref) 517 (10·6%)1·0 (ref) 453 (9·3%)1·0 (ref)
·· 27 (2·4%)
% deaths refers to proportion of all deaths for row category which were due to the column cause (eg, of the male deaths in epilepsy, 18·8% were from external causes). Adjusted odds ratios (aOR) report odds of
mortality in individuals with epilepsy compared with general population controls (matched for age and sex, and adjusted for income, and marital and immigration statuses). Suicide category includes
undetermined deaths.*Complex partial (ICD-8: 345.31; ICD-9: 345M, 345N; ICD-10: G40.2); other partial (ICD-8: 345.30, 345.38, 345.39; ICD-10: G40.0, G40.1); generalised (ICD-8: 345.00, 345.09, 345.10,
345.11; ICD-9: 345J, 345K; ICD-10: G40.3); other and unspecifi ed (ICD-8: 345.18, 345.19, 345.20, 345.29, 345.32, 345.33, 345.9; ICD-9: 345L, 345P, 345Q, 345W, 345X; ICD-10: G40.4, G40.5, G40.6, G40.7,
G40.8, G40.9, G41). †Focal (ICD-10: G40.0, G40.1, G40.2); generalised (ICD-10: G40.3); encephalopathy and mixed (ICD-10: G40.4); special syndromes (ICD-10: G40.5); other epilepsy (ICD-10: G40.8);
unspecifi ed epilepsy (ICD-10: G40.6, G40.7, G40.9).
Table 5: Mortality risks after diagnosis with epilepsy, stratifi ed by diagnostic threshold, sex, severity, patient type, epilepsy subtype, age group, birth order, and time after fi rst diagnosis
www.thelancet.com Published online July 22, 2013 http://dx.doi.org/10.1016/S0140-6736(13)60899-5
75% (731 of 972; aOR 10·6, 95% CI 9·2–12·2) had a
lifetime psychiatric diagnosis (including substance
misuse) and, specifi cally, 549 (56%; 22·4, 18·3–27·3) had
a history of substance misuse, and 227 (23%; aOR 13·0,
95% CI 10·3–16·6) had depression (table 6). We found no
diff erences in odds of mortality between psychiatric
disorders diagnosed before epilepsy and those diagnosed
after (data not shown). In those with psychiatric
comorbidity, we found evidence for an association
between epilepsy and external cause mortality (aOR 2·3,
95% CI 1·9–2·8), suicide (2·1, 1·5–2·9), vehicle accidents
(1·9, 1·3–2·6), and non-vehicle accidents (aOR 3·5,
2·5–4·9). In addition, we looked at all natural causes of
death, and the two most common causes (neoplasms,
neurological) and did not fi nd strong associations with
psychiatric comorbidity (appendix).
Our results indicate high rates of premature mortality in
epilepsy, and highlight the substantial contribution of
psychiatric comorbidity to this mortality. The fi ndings
potentially contribute to the clinical management of
epilepsy for neurology, psychiatry, and primary care
services by presenting information on associations with
treatable psychiatric disorders. To our knowledge, this is
the fi rst time that unaff ected sibling controls have been
used to assess mortality in epilepsy (panel).
We report three main fi ndings. First, the adjusted odds
of all-cause mortality, which followed individuals with
epilepsy until they were 56 years old, was 11 compared
with both general population and unaff ected sibling
controls. 16% of all epilepsy deaths were from external
causes, which was the largest category of deaths that was
not clearly related to underlying disease processes (such
as brain tumours and infections). A notable fi nding was
the high risk of death from non-vehicle accidents, with
adjusted odds of death at 5·5 (95% CI 4·7–6·5). Second,
we found evidence that epilepsy is an independent risk
factor for all-cause and external causes of death. This was
most clearly shown when we compared patients with
their unaff ected siblings. For external causes, the odds of
mortality in people with epilepsy were increased at
2·9 for suicide and 3·6 for accidents compared with
unaff ected siblings.
The independent eff ect of epilepsy on suicide contrasts
with some previous research,7,8 but supports another
population study,6 which found an independent eff ect of
epilepsy on external causes of death. We believe our
fi ndings are robust, since our study benefi ted from a
large sample size, various sensitivity analyses, and
External causesSuicide or uncertainVehicle accidentsOther accidents
n (%)aOR (95% CI) n (%)aOR (95% CI) n (%) aOR (95% CI)n (%) aOR (95% CI)
Any psychiatric disorder
No epilepsy, no
No epilepsy, psychiatric
Epilepsy, no psychiatric
No epilepsy, no
No epilepsy, depression
Epilepsy, no depression
No epilepsy, no
No epilepsy, substance
Epilepsy, no substance
1230 (0·2%) 1·0 (ref)488 (0·1%)1·0 (ref)452 (0·1%) 1·0 (ref) 234 (0·1%)1·0 (ref)
871 (1·3%)5·8 (5·2–6·6)570 (0·8%) 9·3 (7·8–11·0)65 (0·1%)1·0 (0·7–1·4) 219 (0·3%)7·5 (5·9–9·6)
241 (0·6%) 2·3 (1·9–2·8)81 (0·2%) 2·1 (1·5–2·9)61 (0·1%) 1·9 (1·3–2·6) 91 (0·2%)3·5 (2·5–4·9)
731 (2·6%) 10·6 (9·2–12·2)429 (1·5%) 14·0 (11·5–17·0) 30 (0·1%)0·9 (0·6–1·5) 271 (1·0%)23·3 (17·4–31·3)
1790 (0·3%) 1·0 (ref) 809 (0·1%) 1·0 (ref)500 (0·1%) 1·0 (ref)411 (0·1%) 1·0 (ref)
1562 (0·2%) 1·0 (ref)759 (0·1%) 1·0 (ref) 477 (0·1%)1·0 (ref) 263 (0·1%)1·0 (ref)
539 (2·8%) 8·6 (7·4–10·0)299 (1·6%)9·4 (7·6–11·6)40 (0·2%) 1·7 (1·1–2·5)190 (1·0%)20·0 (14·3–27·9)
423 (0·7%)2·2 (1·9–2·6) 191 (0·3%)2·2 (1·8–2·6) 68 (0·1%)1·2 (0·9–1·7) 151 (0·2%) 4·2 (3·2–5·4)
549 (6·8%)22·4 (18·3–27·3)319 (4·0%)21·5 (16·6–27·8) 23 (0·3%)3·1 (1·7–5·5) 211 (2·6%)43·3 (28·8–65·1)
Number of deaths in epilepsy and associated controls, stratifi ed by psychiatric diagnoses. % is percentage of deaths from a particular cause within the row sample (eg, of
those with no epilepsy and no psychiatric disorder, 0·2% died from external causes). Adjusted odds ratios (aOR) report odds of morality compared with the reference group.
Suicide category includes undetermined deaths.
Table 6: Associations of external causes of death in epilepsy with psychiatric comorbidity
www.thelancet.com Published online July 22, 2013 http://dx.doi.org/10.1016/S0140-6736(13)60899-5 7
examined familial confounding. Third, patients with epi-
lepsy and psychiatric comorbidity have very high mor-
tality. Specifi cally, individuals with epilepsy and comorbid
depression had an odds ratio for suicide of 23 compared
with non-depressed general population controls, and
those with epilepsy and comorbid substance misuse
of 21. The corresponding odds of suicide in general
popu lation controls with depression but without epilepsy
was 10. For deaths from non-vehicle accidents, there was
a strong association with substance misuse (as suggested
by an increase in odds of mortality of 43 in epilepsy and
comorbid substance misuse, compared with 20 in
general population controls without epilepsy but with
sub stance misuse).
The high odds associated with congenital conditions
and those arising in the perinatal period, such as cerebral
palsy, is not surprising, since these underlying conditions
are associated with the most severe forms of epilepsy. This
mortality risk underlines the importance of preventing
these causes of death during the perinatal period and
perhaps the need to examine interventions to prevent
epileptogenesis in those exposed to perinatal events.
Our fi nding of an 11-fold increase in odds of all-cause
mortality compared with general population controls is
higher than that reported in some other mortality studies,
but consistent with the few studies that have examined
premature mortality. For example, one population study
in Sweden found standardised mortality ratios between
10 and 14 in hospitalised patients aged 15–54 years.4
Furthermore, we reported an increased odds of suicide of
3·7 that is within the range reported in a recent
systematic review.5 Although a few population based
studies have presented data for psychiatric comorbidity,
estimates in our study are within the range of 19–48%
reported in a review article,31 and consistent with the 36%
found in a community survey of patients with epilepsy.32
Additionally, our prevalence of depression of 8·9% is
similar to the 9·6% found in a recent study of
7403 individuals with epilepsy in England.33
Our fi ndings suggest that risks for external causes of
death, and potential treatments to mitigate these risks,
need to be considered in patients with epilepsy. The
importance of identifying, monitoring, and treating
psychiatric comorbidity, discussed recently in an expert
review,34 is underscored by these results. This was most
clearly shown in our fi nding that around three-quarters
of deaths from external causes in the epilepsy cohort
were in patients who had a lifetime psychiatric diagnosis.
In particular, patients with psychiatric comorbidity in the
period immediately after the fi rst diagnosis of epilepsy
represent a high-risk population that might benefi t from
closer monitoring, consultation with liaison psychiatry,
and more intensive treatments. But our results also
highlight the role of other risk factors beyond psychiatric
comorbidity as suicide and accident deaths were in-
creased in those without lifetime co-occurring psych-
iatric disorders. Such risk factors may include more
sensitive measures of disease course and severity than
we were able to investigate, treatment-related factors,5
and direct eff ects of the condition on decision making in
some people.35 Additionally, the importance of other
causes of death is also underlined by our fi ndings;
neurological causes had the highest rates and risks, and
the contribution of sudden unexplained deaths needs
Moreover, our fi ndings highlight the importance of
non-vehicle accidents as a major preventable cause of
death in people with epilepsy. One possible implication
is whether specifi c warnings and patient education,
besides those already given, should be provided to
patients about risks of non-vehicle accidents, including
their link to substance misuse.
Although the relative risks were high, absolute rates of
premature mortality from external causes were 1·4%,
and any changes to clinical practice need to consider how
to identify high-risk populations with low false positive
rates. Nevertheless, as we found around a third of
epilepsy patients had a comorbid psychiatric diagnosis,
and around a tenth had comorbid substance misuse,
clinical epilepsy services could review their liaison with
psychiatric37 and addiction services. The importance of
substance misuse in suicide mortality was at least as
important as depression, but it has not been highlighted
in recent reviews.34 Previous work has examined the role
of alcohol comorbidity in suicide risk,6 but little is known
about comorbid drug use.
There are two main limitations in this study. The fi rst is
that we restricted our cohort to those born between 1954
and 2009. This was done to focus on premature mortality
and so that our fi ndings would not be potentially diluted
by the large mortality eff ects of older people. This
restriction also avoided cohort eff ects with older people,
for whom services and treatments were considerably
diff erent before 1970. Nevertheless, results are confi ned
to premature deaths. A second limitation is that we used
patient registers to identify people with epilepsy, since it
was necessary to use routinely collected data to provide
precision for the fairly rare outcomes investigated.
Syndromal approaches are now recommended to
subclassify epilepsy29 and translating ICD codes into these
syndromes might be subject to some mis classifi cation.30
Nevertheless, using either ICD codes or syndromes,
epilepsies that were not focal or generalised (and described
variously as other or special epileptic syndromes) could
incur higher risk of premature mortality. We used both
outpatient and inpatient data to identify cases, and found
no obvious diff erences in mortality. However, we might be
missing a proportion of patients who never present to
secondary services, although we estimate that this number
would be small for a chronic illness such as epilepsy in a
country with a comprehensive tax-funded health system
such as Sweden, and over an average follow-up of 9 years.
This small missing proportion is likely due to the
longstanding practice for fi rst diagnoses of epilepsy to be
www.thelancet.com Published online July 22, 2013 http://dx.doi.org/10.1016/S0140-6736(13)60899-5
confi rmed by specialist services.38 Nevertheless, under-
sampling of patients with less severe symptoms could
lead to an over estimation of the association with pre-
mature death if individuals with less severe disease are
both less likely to be diagnosed and have fewer co-
morbidities and mortality risks.
We also only studied one country, and the general-
isability to other countries is uncertain. An estimate of
the prevalence of epilepsy based on our sample is
diffi cult, since the 41 year cohort does not lend itself to
such a calculation. However, when extrapolating the
prevalence reported in this cohort to a lifetime prevalence,
we fi nd a similar prevalence estimate to that reported in
other high-income countries.2 Sweden is not dissimilar
to other western European countries in suicide rates39 but
comparative information on death by accidents is limited.
Finally, some of the causes of death may be prone to
misclassifi cation. Suicide and deaths from undetermined
causes were combined to account for this, but it is
possible that some accidental deaths are in fact suicides.40
Some accidental deaths will also be a direct consequence
of seizures, and therefore the associations with substance
misuse might not be causal. Treatment trials in this
population are necessary to determine the precise role of
substance misuse and other psychiatric disorders on
premature death. We were also unable to examine the
eff ect of psychiatric comorbidity on sudden unexpected
deaths in epilepsy which contribute to around 4% of
deaths in community samples,41 and are defi ned as death
due to sudden and unexplained respiratory failure or
cardiac arrest.36 Future research should examine the
relation between epilepsy, psychiatric comorbidity, and
prescribed medication (particularly selective serotonin
reuptake inhibitors)42 on sudden unexpected deaths.
However, we did examine the association of psychiatric
morbidity with two main causes of natural deaths, namely
cancer and neurological diseases (appendix). We did not
fi nd strong associations with psychiatric comorbidity,
which was not surprising since these underlying causes
of epilepsy are likely to cause death directly.
We found no evidence of familial confounding in all-
cause and external mortality, a somewhat unexpected
fi nding, as previous studies have suggested that familial
(genetic or early environmental) eff ects explain a
substantial part of the association between epilepsy and
violent crime.23 However, it strengthens the hypothesis
that epilepsy is on the causal pathway to premature death.
In summary, psychiatric comorbidity has an important
role in the premature mortality seen in epilepsy.
Reducing premature mortality from external causes of
death should be a priority in epilepsy management.
The ability of health services to prevent such deaths
SF, PL, and CRN conceived and designed the study. AW analysed the
data. SF drafted the report. All authors revised drafts and approved the
fi nal version.
Confl icts of interest
We declare that we have no confl icts of interest.
This study was funded by Wellcome Trust (095806), the Swedish Prison
and Probation Service, and the Swedish Research Council. We thank
Marcus Boman, Karolinska Institutet, for assistance with data extraction
1 Murray C, Vos T, Lozano R, et al. Disability-adjusted life years
(DALYs) for 291 diseases and injuries in 21 regions, 1990–2010:
a systematic analysis for the Global Burden of Disease Study 2010.
Lancet 2013; 380: 2197–223.
2 Ngugi AK, Bottomley C, Kleinschmidt I, Sander JW, Newton CR.
Estimation of the burden of active and life-time epilepsy:
a meta-analytic approach. Epilepsia 2010; 51: 883–90.
3 Sander J, Bell G. Reducing mortality: an important aim of epilepsy
management. J Neurol Neurosurg Psychiatry 2004; 75: 349–51.
4 Nilsson L, Tomson T, Farahmand B, Diwan V, Persson P.
Cause-specifi c mortality in epilepsy: a cohort study of more than
9000 patients once hospitalized for epilepsy. Epilepsia 1997;
5 Bell G, Gaitatzis A, Bell C, Johnson A, Sander J. Suicide in people
with epilepsy: how great is the risk? Epilepsia 2009; 50: 1933–42.
6 Christensen J, Vestergaard N, Mortensen P, Sidenius P, Agerbo E.
Epilepsy and risk of suicide: a population-based case-control study.
Lancet Neurol 2007; 6: 693–98.
7 Kwon C, Liu M, Quan H, Thoo V, Wiebe S, Jetté N. Motor vehicle
accidents, suicides, and assaults in epilepsy: a population-based
study. Neurology 2011; 76: 801–06.
8 Cockerell O, Johnson A, Sander J, Hart Y, Goodridge D, Shorvon S.
Mortality from epilepsy: results from a prospective population-based
study. Lancet 1994; 344: 918.
9 Department of Health. Preventing suicide in England:
a cross-government outcomes strategy to save lives. London:
Department of Health, 2012.
10 US Department of Health and Human Services. National strategy
for suicide prevention: goals and objectives for action. Washington,
DC: US Department of Health and Human Services, 2012.
11 Van Den Broek M, Beghi E. Accidents in patients with epilepsy:
types, circumstances, and complications: a European cohort study.
Epilepsia 2004; 45: 667–72.
Panel: Research in context
We searched Medline for articles comparing mortality in epilepsy to general population
controls and examining the role of psychiatric comorbidity, published up to March 29,
2013, with no language or date restrictions, and with the search terms “epilepsy” and
(“mortality” or “death”) and “psych*”. We also scanned references of key articles.
We identifi ed two population-based case-control studies. A Danish study6
(n=492 suicides) found epilepsy to be a risk factor for suicide independent of increased
risk of psychiatric comorbidity. A Canadian study7 (n=203 fatal and non-fatal accidents,
suicide and suicide attempts, and self-infl icted injuries), however, found no increased risk
of external causes of death in epilepsy after adjusting for comorbidity.
Our study substantially increases the evidence on the contribution of psychiatric morbidity
to mortality in epilepsy. Additionally, for the fi rst time, we examine odds of premature
death in individuals with epilepsy compared with their unaff ected siblings, and fi nd that
they do not diff er signifi cantly from mortality odds in epilepsy compared with general
population controls. This strongly suggests that epilepsy is an independent risk factor for
all-cause and external cause mortality. External causes of death were strongly associated
with psychiatric conditions, and we conclude that premature mortality in epilepsy might be
reduced with improved identifi cation and treatment of these comorbidities.
Articles Download full-text
www.thelancet.com Published online July 22, 2013 http://dx.doi.org/10.1016/S0140-6736(13)60899-5 9
12 Lhatoo SD, Sander J. Cause-specifi c mortality in epilepsy. Epilepsia
2005; 46: 36–39.
13 Statistics Sweden. Flergenerationsregistret 2004: En beskrivning
av innehåll och kvalitet. [The Multi-Generation Register 2004:
a description of content and quality] (in Swedish). Örebro, Sweden:
Statistics Sweden, 2005.
14 Swedish National Board of Health and Welfare. [Patient Register]
(in Swedish). http://www.socialstyrelsen.se/register/
halsodataregister/patientregistret (accessed Nov 21, 2011).
15 Lindblad U, Råstam L, Ranstam J, Peterson M. Validity of register
data on acute myocardial infarction and acute stroke.
Scand J Public Health 1993; 21: 3–9.
16 Jiang G, Pedro-Cuesta J, Fredrikson S. Guillain-Barré syndrome in
South-West Stockholm, 1973–1991, 1. Quality of registered hospital
diagnoses and incidence. Acta Neurol Scand 1995; 91: 109–17.
17 Sellgren C, Landén M, Lichtenstein P, Hultman C, Långström N.
Validity of bipolar disorder hospital discharge diagnoses: fi le review
and multiple register linkage in Sweden. Acta Psychiatr Scand 2011;
18 Ekholm B, Ekholm A, Adolfsson R, et al. Evaluation of diagnostic
procedures in Swedish patients with schizophrenia and related
psychoses. Nord J Psychiatry 2005; 59: 457–64.
19 Ludvigsson J, Andersson E, Ekbom A, et al. External review and
validation of the Swedish national inpatient register.
BMC Public Health 2011; 11: 450.
20 Fazel S, Långström N, Hjern A, Grann M, Lichtenstein P.
Schizophrenia, substance abuse, and violent crime. JAMA 2009;
21 Fazel S, Grann M. The population impact of severe mental illness
on violent crime. Am J Psychiatry 2006; 163: 1397–403.
22 Hjern A, Lindblad F, Vinnerljung B. Suicide, psychiatric illness,
and social maladjustment in intercountry adoptees in Sweden:
a cohort study. Lancet 2002; 360: 443–48.
23 Fazel S, Lichtenstein P, Grann M, Långström N. Risk of violent
crime in individuals with epilepsy and traumatic brain injury:
a 35-year Swedish population study. PLoS Med 2011; 8: e1001150.
24 National Board of Health and Welfare. Cause of death register.
2009 (accessed March 3, 2013).
25 Runeson B, Tidemalm D, Dahlin M, Lichtenstein P, Långström N.
Method of attempted suicide as predictor of subsequent successful
suicide: national long term cohort study. BMJ 2010; published
online July 13. DOI:10.1136/bmj.c3222.
26 Neeleman J, Wessely S. Changes in classifi cation of suicide in
England and Wales: time trends and associations with coroners’
professional backgrounds. Psychol Med 1997; 27: 467–72.
27 Fazel S, Lichtenstein P, Grann M, Goodwin G, Långström N.
Bipolar disorder and violent crime: new evidence from
population-based longitudinal studies and systematic review.
Arch Gen Psychiatry 2010; 67: 931.
28 Klein-Geltink J, Rochon P, Dyer S, Laxer M, Anderson G. Readers
should systematically assess methods used to identify, measure and
analyze confounding in observational cohort studies.
J Clin Epidemiol 2007; 60: 766. e1–e11.
29 Berg A, Berkovic S, Brodie M, et al. Revised terminology and
concepts for organization of seizures and epilepsies: report of the
ILAE Commission on Classifi cation and Terminology, 2005–2009.
Epilepsia 2010; 51: 676–85.
30 Christensen J, Sidenius P. Epidemiology of epilepsy in adults:
implementing the ILAE classifi cation and terminology into
population-based epidemiologic studies. Epilepsia 2012; 53: 14–17.
31 Gaitatzis A, Trimble M, Sander J. The psychiatric comorbidity of
epilepsy. Acta Neurol Scand 2004; 110: 207–20.
32 Tellez–Zenteno JF, Patten SB, Jetté N, Williams J, Wiebe S.
Psychiatric comorbidity in epilepsy: a population-based analysis.
Epilepsia 2007; 48: 2336–44.
33 Rai D, Kerr MP, McManus S, Jordanova V, Lewis G, Brugha TS.
Epilepsy and psychiatric comorbidity: a nationally representative
population-based study. Epilepsia 2012; 53: 1095–103.
34 Bell G, Sander J. Suicide and epilepsy. Curr Opin Neurol 2009;
35 WHO. Preventing suicide: a resource for primary health care
workers. Geneva: World Health Organization, 2000.
36 Shorvon S, Tomson T. Sudden unexpected death in epilepsy. Lancet
2011; 378: 2028–38.
37 Kondziella D, Asztely F. Don’t be afraid to treat depression in
patients with epilepsy! Acta Neurol Scand 2008; 119: 75–80.
38 National Board of Health and Welfare. [Expert report: Epilepsy—
prevalence, management, care organization] (in Swedish).
Stockholm: National Board of Health and Welfare, 1993.
39 Eurostat. Death due to suicide, by sex. Standardised death rate by
100 000 inhabitants. http://epp.eurostat.ec.europa.eu/tgm/table.do?
Jan 11, 2013).
40 Rockett IRH, Thomas BMK. Reliability and sensitivity of suicide
certifi cation in higher-income countries. Suicide Life Threat Behav
1999; 29: 141–49.
41 Tellez-Zenteno JF, Ronquillo LH, Wiebe S. Sudden unexpected
death in epilepsy: evidence-based analysis of incidence and risk
factors. Epilepsy Res 2005; 65: 101–16.
42 Faingold CL, Tupal S, Randall M. Prevention of seizure-induced
sudden death in a chronic SUDEP model by semichronic
administration of a selective serotonin reuptake inhibitor.
Epilepsy Behav 2011; 22: 186–90.