Epilepsy Is a Risk Factor for Sudden Cardiac Arrest in the
General Population
Abdennasser Bardai1,2, Robert J. Lamberts3, Marieke T. Blom1, Anne M. Spanjaart1, Jocelyn Berdowski4,
Sebastiaan R. van der Staal1, Henk J. Brouwer5, Rudolph W. Koster4, Josemir W. Sander3,7,
Roland D. Thijs3,6,7, Hanno L. Tan1,4*
1 Heart Failure Research Center, University of Amsterdam, Amsterdam, The Netherlands, 2 Interuniversity Cardiology Institute Netherlands, Utrecht, The Netherlands,
3 SEIN- Epilepsy Institute in The Netherlands Foundation, Heemstede, The Netherlands, 4 Department of Cardiology, University of Amsterdam, Amsterdam, The
Netherlands, 5 Department of General Practice, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands, 6 Department of Neurology, Leiden
University Medical Center, Leiden, The Netherlands, 7 Department of Clinical and Experimental Epilepsy, University College London Institute of Neurology, Queen Square,
London, United Kingdom
Abstract
Background: People with epilepsy are at increased risk for sudden death. The most prevalent cause of sudden death in the
general population is sudden cardiac arrest (SCA) due to ventricular fibrillation (VF). SCA may contribute to the increased
incidence of sudden death in people with epilepsy. We assessed whether the risk for SCA is increased in epilepsy by
determining the risk for SCA among people with active epilepsy in a community-based study.
Methods and Results: This investigation was part of the Amsterdam Resuscitation Studies (ARREST) in the Netherlands. It
was designed to assess SCA risk in the general population. All SCA cases in the study area were identified and matched to
controls (by age, sex, and SCA date). A diagnosis of active epilepsy was ascertained in all cases and controls. Relative risk for
SCA was estimated by calculating the adjusted odds ratios using conditional logistic regression (adjustment was made for
known risk factors for SCA). We identified 1019 cases of SCA with ECG-documented VF, and matched them to 2834 controls.
There were 12 people with active epilepsy among cases and 12 among controls. Epilepsy was associated with a three-fold
increased risk for SCA (adjusted OR 2.9 [95%CI 1.1–8.0.], p = 0.034). The risk for SCA in epilepsy was particularly increased in
young and females.
Conclusion: Epilepsy in the general population seems to be associated with an increased risk for SCA.
Citation: Bardai A, Lamberts RJ, Blom MT, Spanjaart AM, Berdowski J, et al. (2012) Epilepsy Is a Risk Factor for Sudden Cardiac Arrest in the General
Population. PLoS ONE 7(8): e42749. doi:10.1371/journal.pone.0042749
Editor: Stefan Kiechl, Innsbruck Medical University, Austria
Received October 21, 2011; Accepted July 12, 2012; Published August 14, 2012
Copyright: ß 2012 Bardai et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: HLT was supported by the Netherlands Organization for Scientific Research (NWO, grant ZonMW Vici 918.86.616), the Dutch Medicines Evaluation
Board (MEB/CBG), and the National Epilepsy Foundation Netherlands. The Arrest data collection was supported by an unconditional grant from Physio Control
and a grant from the Netherlands Heart Foundation (grant 2006B179). AB was supported by the Netherlands Organization for Scientific Research (NWO, grant
Mozaiek 017.003.084). RDT and JWS are part of the Prevention and Risk Identification of SUDEP Mortatlity Consortium which is funded by the National Institutes of
Health (National Board of Industrial Health/National Institute of Neurological Disorders and Stroke -1P20NS076965-01). The funders had no role in study design,
data collection and analysis, decision to publish, or preparation of the manuscript.
Competing Interests: The authors have declared that no competing interests exist.
* E-mail: h.l.tan@amc.nl
electrical activity, occurring in the brain and heart, respectively
[8–10]. If either epilepsy or SCA results from ion channel
dysfunction, these ion channel isoforms may be expressed both in
brain and heart, as seen in SCN1A, which encodes neuronal
sodium channels [11]. SCN1A mutations cause generalized
seizures with febrile seizures plus [11–13]. Yet, SCN1A protein
products are not only expressed in the brain, but also in the heart
[14–15]. It is thus plausible that dysfunction in such ion channels
may cause both epilepsy and SCA. It has not been proven,
however, that epilepsy is associated with an increased risk for
SCA, as studies aimed at systematically determining the risk for
SCA among people with epilepsy are lacking.
The aim of this study was to establish whether epilepsy is
associated with an increased risk for SCA. Our study was
designed to obtain full coverage in the community, and provide
strict confirmation of epilepsy and SCA. To achieve this, we
Introduction
Epilepsy affects over 50 million individuals worldwide [1]. It is
associated with a 2–3 fold risk of premature mortality compared
with the general population [2]. A substantial proportion of
deaths in epilepsy happen suddenly [3]. If trauma, drowning and
a documented status epilepticus are excluded and autopsy does
not reveal an anatomical or toxicological cause for death, such
deaths are classified as sudden unexpected death in epilepsy
(SUDEP) [4]. In the general population the commonest cause of
sudden death by far is sudden cardiac arrest (SCA) due to
ventricular fibrillation (VF) [5]. It has been postulated that
SUDEP at least in some may result from seizure-related SCA [6].
Various possible causes for an association between epilepsy and
SCA have been proposed (discussed in [7]). For instance, epilepsy
and cardiac arrhythmias are both caused by pathological
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Sudden Cardiac Arrest in Epilepsy
source community as cases, using the HAG-net-AMC database
of general practitioners (GPs). This database contains the
complete medical records of ,60,000 people from a large
group of GPs in the study area [19]. Each case was matched to
up to 5 controls by age, sex, and index date (date of SCA in
cases).
used a mandatory multiple-source notification system for SCA.
This strategy ensured the capture of all SCA cases. Every
medical history was then rigorously reviewed for evidence of
active epilepsy, so that all people with SCA and epilepsy were
identified.
Methods
Definition of active epilepsy and risk factors
Setting and study design
All GP records with the terms ‘‘epilepsy’’ or ‘‘epileptic seizure’’
in the diagnosis list were reviewed by two epileptologists (RDT,
JWS). For all cases and controls, epilepsy was confirmed if the
diagnosis was established by a neurologist, in accordance with
national guidelines [20]. Additional information was requested
from the attending neurologist if needed. Only people with a
diagnosis of active epilepsy were included in the analysis. Active
epilepsy was defined as current treatment with antiepileptic drugs
and seizure within the previous 2 years [21]. For all cases and
controls, the following established risk factors for SCA were
assessed: ischemic cardiovascular disease, heart failure, hypertension, diabetes mellitus, and hypercholesterolemia. This was
established from GP records based on a formal diagnosis, or by
use of medication.
This investigation was conducted in a community-based study
in the Netherlands: the Amsterdam Resuscitation Studies
(ARREST). It was designed to assess the determinants of SCA
in the general community [16–18]. Data were retrieved in the
study period July 2005–January 2010. It was conducted in
accordance with the Declaration of Helsinki. Written informed
consent was obtained from all participants who survived the SCA.
The Ethics Committee of the Academic Medical Center
Amsterdam approved the study and the use of data from people
who died.
Design of ARREST
ARREST is a prospective, community-based study aimed at
establishing the genetic and clinical determinants of SCA in the
population of a contiguous region (urban and rural communities, ,2.4 million inhabitants) of the Netherlands. Details of the
study design are provided elsewhere [16–18]. Briefly, the
ARREST research group prospectively collects data of all
cardiopulmonary resuscitation efforts in collaboration with all
Emergency Medical Services in the region, using a mandatory
multiple-source notification system (consisting of personnel at
emergency dispatch centers, ambulance services and all 14 area
hospitals). This ensures a complete coverage of the study region
and an inclusion rate of .95% of all people with out-of-hospital
SCA [16]. A data collection infrastructure is used that records
all out-of-hospital SCA parameters, from ambulance dispatch to
discharge from the hospital or to death. Case inclusion is as
follows: after each suspected out-of-hospital SCA, the emergency dispatch center notifies the study office (providing information on the place and circumstances of SCA). Ambulance
personnel are mandated to upload ECG recordings to the study
office straight after resuscitation, and to provide appropriate
information (e.g., whether SCA was witnessed, whether basic
life support was provided before arrival of ambulance personnel,
whether the patient died at the resuscitation site or was
transported to a hospital). If an automated external defibrillator
was used, the study center is notified by the dispatch center,
ambulance personnel and the user of the automated external
defibrillator (a label requesting notification after each use is
attached to automated external defibrillators in the study
region). The automated external defibrillator ECG recordings
are retrieved by ARREST personnel after notification. ECG
recordings are used to determine whether VF had occurred.
SCA cases are defined as people who had a cardiac arrest in an
out-of-hospital setting with ECG-documented VF. Patients with
an obvious non-cardiac cause of VF (e.g., trauma, intoxication,
drowning, suicide) or those in whom no ECG-documented VF
was available (these patients typically had asystole or pulseless
electrical activity) are excluded. Medical histories are obtained
from the general practitioner (GP) and from hospital. In the
Netherlands, every individual has a GP who acts as gatekeeper
for medical care. Thus, GPs have a full overview of diagnoses
made by medical specialists. Complete medication histories of
the year preceding SCA are obtained from community
pharmacies. Controls were randomly drawn from the same
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Statistical analysis
The relative risk for SCA associated with epilepsy was estimated
by calculation of the adjusted odds ratios using conditional logistic
regression analyses. Covariates that were univariately associated
with SCA (at a p,0.1 level) were included in the regression
analyses if they changed the point estimate of the association
between active epilepsy and SCA by .5%; the only such
covariates were heart failure and hypercholesterolemia. In
addition, the odds ratio was calculated by including all covariates
that univariately associated with SCA (at a p,0.1 level) in the
multivariate analysis. Subanalyses were performed using multivariate logistic regression, adjusting for age, gender and risk
factors.
Results
We identified 1019 SCA cases with known medical and/or
medication use history prior to the SCA; these cases were matched
to 2834 controls. The mean age was 63.5 years in cases (76.5%
male), and 58.3 years in controls (68.5% male). We confirmed that
the established risk factors for SCA were also associated with SCA
in our study (Table 1). Twelve cases (1.4%) and 12 controls (0.4%)
had a diagnosis of active epilepsy at index date. Epilepsy was
associated with an almost three-fold increased risk for SCA
(adjusted OR 2.9 [95% CI 1.1–8.0], p = 0.034, model 2, Table 2).
Sub-analyses suggests that SCA risk is higher in people with
epilepsy aged ,50 years (N = 4, adjusted ORyoung 4.6, p = 0.210)
compared to patients aged $50 years (N = 8, adjusted ORold 2.4,
p = 0.128), and in females (N = 5, adjusted ORfemales 4.6,
p = 0.044) compared to males (N = 7, adjusted ORmales 2.0,
p = 0.309). Epilepsy characteristics of the cases and controls are
given in Table 3.
Discussion
We provide the first systematically collected evidence from a
community-based study that epilepsy in the general population is
associated with an increased risk for SCA. The major strength of
our study is its community-based design, which ensured that
selection bias was minimal. The inclusion of people with epilepsy
and of SCA was systematic. The point prevalence of active
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Sudden Cardiac Arrest in Epilepsy
information on circumstances surrounding death, concomitant
diseases, and potential confounders.
We found that epilepsy increases SCA risk but that this excess
risk is greater in the young. Given that cardiovascular diseases,
by far the most prevalent causes of SCA [5], is less common in
young persons, this observation supports the notion that
epilepsy is likely to play an important role in SCA risk. Women
also had greater excess risk than men, although in the
population cardiovascular disease is more prevalent among
men.
It is very difficult to study SCA in the general population given
the highly unpredictable way in which it occurs, its short duration
before death ensues, and its dismal survival rate [23]. ECGdocumentation of VF may be the best possible method in a
community-based study to ascertain that SCA was due to cardiac
causes. Thus, the observed association between VF and epilepsy in
ARREST supports the hypothesis that cardiac causes may
contribute to SUDEP. SUDEP most frequently occurs in people
with chronic epilepsy, poor seizure control, antiepileptic drug
polytherapy, young age of onset and a long history of epilepsy
[24]. Case-control studies, eyewitness accounts, and ictal recordings suggest that SUDEP is a peri-ictal event likely triggered by a
convulsive seizure [7].
Our findings may suggest that the risk for SCA from cardiac
causes extends to people with epilepsy patients beyond those with
SUDEP. Firstly, SCA risk is increased in the community, i.e., in
people with less severe forms of epilepsy. Secondly, in the SUDEP
definition, the role of epilepsy as a risk factor for SCA may be
underestimated. For instance, an individual with epilepsy who dies
suddenly and has acute signs of ischemic heart disease at autopsy is
not a SUDEP case, as its definition requires that clear causes for
Table 1. Demographics and distribution of covariates.
Cases
Controls
Cases with epilepsy
N = 1019
N = 2834
N = 12
780 (76.5)
1855 (68.5)
7 (58.3)
Sex
Male
Female
239 (23.5)
979 (31.5)
5 (41.7)
63.5 (13.7)
58.3 (14.5)
60.0 (16.0)
Active epilepsy
12 (1.4)
12 (0.4)
Ischemic CVD
443 (43.5)
141 (5.0)
5 (41.7)
CVA or TIA
49 (4.8)
71 (2.5)
1 (8.3)
Mean age, years (SD)
Covariates
Hypertension
529 (51.9)
433 (15.3)
7 (58.3)
Diabetes mellitus
219 (21.5)
294 (10.4)
1 (8.3)
Heart failure
199 (19.5)
29 (1.0)
4 (33.3)
Hypercholesterolemia
290 (28.5)
170 (6.0)
6 (30.0)
Data are expressed as number (%) unless otherwise indicated. CVD,
cardiovascular disease; CVA, cerebrovascular accident; SD, Standard Deviation;
TIA, transient ischemic attack.
doi:10.1371/journal.pone.0042749.t001
epilepsy in our control group was 0.4%. This agrees well with
previous studies on the prevalence of active epilepsy in the general
population and suggests that our study design captured all people
with active epilepsy [22]. The design of the study and access to
GPs’ medical records enabled us to collect comprehensive
Table 2. Epilepsy and risk for sudden cardiac arrest.
OR*(95% CI)
OR** (95% CI)
OR*** (95% CI)
Univariate analysis
p-value
p-value
p-value
p-value
Epilepsy
3.3 (1.4–7.5)
2.8 (0.9–9.0)
2.9 (1.1–8.0)
Not applicable
p = 0.005
p = 0.076
p = 0.034
Ischemic CVD
11.2 (8.8–14.3)
6.7 (5.0–8.8)
9 (7–11.7)
p,0.001
p,0.001
0.8 (0.4–1.6)
Not applicable
P = 0.012
Not applicable
p,0.001
0.8 (0.6–1.1)
1.2 (0.9–1.5)
p,0.001
p = 0.1
p = 0.2
9.9 (5.8–17)
12.9 (7.9–21.1)
p,0.001
p,0.001
2.9 (2.2–3.9)
Not applicable
CVA or TIA
1.7 (1.1–2.5)
p,0.001
p = 0.53
Hypertension
5.8 (4.8–7.0)
3.7 (2.9–4.7)
p,0.001
Diabetes mellitus
Heart failure
Hypercholesterolemia
2.0 (1.6–2.4)
20.5 (13.1–32.1)
5.6 (4.5–7.0)
p,0.001
p,0.001
p,0.001
Abbreviations as in Table 1.
*Odds Ratios estimated with conditional logistic regression, matched on age, sex, and index date.
**Model 1: Odds Ratios estimated with conditional logistic regression, matched on age, sex, and index date, with all covariates that were univariately associated with
SCA (at a p,0.05 level) included in the regression analyses (ischemic cardiovascular disease, CVA or TIA, hypertension, diabetes mellitus, heart failure and
hypercholesterolemia).
***Model 2: Odds Ratios estimated with conditional logistic regression, matched on age, sex, and index date, with covariates that were univariately associated with SCA
(at a p,0.05 level) included in the regression analyses if they changed the point estimate of the association between epilepsy and SCA .5%; the only such covariates
were cardiac ischemia, diabetes, and heart failure.
doi:10.1371/journal.pone.0042749.t002
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Sudden Cardiac Arrest in Epilepsy
death are absent at autopsy [4]. In this person, epilepsy would be
excluded from further consideration as a contributing factor to
sudden death. Yet, epilepsy or its underlying pathophysiologic
mechanisms may have triggered the lethal cardiac arrhythmia if
the susceptibility to SCA was increased by ischemic heart disease
(multiple-hit model). Accordingly, we found that, in SCA cases
with epilepsy, the prevalence of known SCA risk factors was
similar as in SCA cases without epilepsy (Table 1).
While our study supports the notion that SCA by cardiac
arrhythmia may at least in part contribute to sudden death in
epilepsy, it should be stressed that other proposed pathomechanisms, e.g., respiratory depression, cannot be excluded [4].
Experimental and clinical studies provide clues in support of a
mechanistic link between epilepsy and cardiac arrhythmias
[14,15,25]. The pathological processes that underlie both epilepsy
and SCA may facilitate the occurrence of lethal cardiac
arrhythmias, both in the presence or absence of seizures. In the
majority of our cases (11/12) there was no evidence of seizure
activity preceding SCA. Thus, sudden death in epilepsy may not
be always seizure-related. Firstly, cardiac autonomic function may
be impaired in both epilepsy patients [26–28] and SCA victims
[29–31], and autonomic dysfunction is associated with lethal
cardiac arrhythmias [27]. Secondly, cardiac repolarization disorders (e.g., prolongation or shortening of the QT interval of the
ECG), another established risk factor for fatal cardiac arrhythmias
[32], are found in people with epilepsy [7,33–39]. Thirdly,
variants in genes which encode ion channels that are expressed
both in the brain and the heart may predispose for both epilepsy
and cardiac arrhythmias [11,36,40–43]. Fourthly, anti-epileptic
drugs may increase SCA risk by disturbing heart rhythms. For
instance, they may impede cardiac conduction by blocking cardiac
sodium channels, a mechanism that may trigger lethal arrhythmias
in susceptible individuals, as large randomized placebo-controlled
trials have indicated [44,45]. These drugs may also act centrally
affecting cardiac autonomic control. Lastly, epilepsy characteristics
(type and frequency of seizures, severity of epilepsy) may modulate
the risk for SCA, similar to their reported effects on SUDEP risk
[7,46]. Unfortunately, due to the small number of people with
active epilepsy, we were not able to further detail the causes of
excess SCA risk in epilepsy. This study may, however, serve as a
basis for future studies to address these issues.
In conclusion, we provide the first systematically collected
evidence that epilepsy in the community seems to be associated
with an increased risk for SCA. Future studies must establish the
causes of excess SCA risk in epilepsy.
Table 3. Distribution of epilepsy and cardiovascular
characteristics in cases and controls.
Cases
(n = 12)
Controls
(n = 12)
8 (67%)
5 (42%)
Epilepsy type
Symptomatic
Cryptogenic
2 (16.5%)
4 (33%)
Idiopathic
0 (0%)
2 (17%)
Unknown
2 (16.5%)
1 (8%)
Seizure type1
Convulsive seizures
9
10
Complex partial seizures
3
4
Simple partial seizures
1
1
Absence seizures
1
0
Age at onset of epilepsy, yr (Median, Range)
46.5 (9–79)
42 (6–63)
Duration of epilepsy, yr (Median, Range)
11 (0–52)
17.5 (2–33)
Polytherapy (.1 antiepileptic drug)
Yes
8 (67%)
2 (17%)
No
4 (33%)
10 (83%)
Antiepileptic drug use1
Valproic acid
7
4
Carbamazepine
4
5
Phenytoin
3
2
Phenobarbital
1
1
Topiramate
1
1
Clobazam
1
0
Lamotrigine
0
2
Ischemic heart disease
3 (25%)
2 (17%)
Heart failure
2 (17%)
0 (0%)
Structural heart disease2
3 (25%)
1 (8%)
No history
4 (33%)
9 (75%)
Platelet aggregation inhibitors
5
1
Antihypertensives3
8
2
Antiarrhythmic agents4
1
0
Statins
5
0
History of underlying heart disease
Cardiac medication use
1
Evidence of acute myocardial infarction5
Postmortem6
3
Acknowledgments
Clinical7
8
Not available
4
The authors greatly appreciate the contribution of E.C. Kanters, MD,
Department of General Practice, Academic Medical Center, University of
Amsterdam, The Netherlands; J.P.M. Stroucken, MD, Health Center
Venserpolder, Amsterdam, The Netherlands; F.T.M. Smits, MD, Health
Center Reigersbos, Amsterdam, The Netherlands.
The authors greatly appreciate the contributions of Paulien Homma,
Steffie Beesems, Michiel Hulleman, Esther Landman, and Renate van der
Meer to the data collection, data entry, and patient follow-up at the
Academic Medical Center, and are greatly indebted to the dispatch
centers, ambulance paramedics and first responders of Amsterdam en
Omstreken, Kennemerland and Noord-Holland Noord for their cooperation and support.
1
Some patients had more than one type of seizure/antiepileptic/cardiac drug.
Therefore the number of seizure types/antiepileptic drug used exceeds the total
number of patients.
2
Valve abnormalities and/or aortic coarctation.
3
Diuretics, b-adrenoceptor blockers, calcium channel blockers, angiotensin
converting enzyme inhibitors, angiotensin II receptor antagonists.
4
Amiodaron.
5
Patients may fall in more than one category.
6
Evidence of acute myocardial infarction found during autopsy.
7
Evidence of acute myocardial infarction found during clinical diagnosis and
treatment of the sudden cardiac arrest (ECG, cardiac enzymes, coronary
angiography).
doi:10.1371/journal.pone.0042749.t003
Author Contributions
Analyzed the data: AB RJL MTB AMS JB SvdS HJB RWK JWS RDT
HLT. Wrote the paper: AB RDL MTB JB SvdS HJB RWK JWS RDT
HLT.
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