YEBEH-06307; No of Pages 5

Epilepsy & Behavior xxx (xxxx) xxx

Contents lists available at ScienceDirect

Epilepsy & Behavior

journal homepage: www.elsevier.com/locate/yebeh

Review

Increased risk of stroke and myocardial infarction in patients with

epilepsy: A systematic review of population-based cohort studies
Francesco Brigo a,b,⁎, Piergiorgio Lochner c, Raffaele Nardone a,d, Paolo Manganotti e, Simona Lattanzi f
a
Division of Neurology, “Franz Tappeiner” Hospital, Merano, Italy
b
Department of Neuroscience, Biomedicine and Movement Science, University of Verona, Verona, Italy
c
Department of Neurology, Saarland University Medical Center, Homburg, Germany
d
Department of Neurology, Christian Doppler Klinik, Paracelsus Medical University, Austria
e
Clinical Unit of Neurology, Department of Medicine, Surgery and Health Sciences, University Hospital and Health Services of Trieste, Trieste, Italy
f
Department of Experimental and Clinical Medicine, Marche Polytechnic University, Ancona, Italy

a r t i c l e i n f o a b s t r a c t

Article history: Objective: The objective of the study was to review the current epidemiological evidence about the relationship
Received 13 March 2019 between epilepsy and increased risk of cardio- and cerebrovascular events.
Revised 7 May 2019 Methods: We systematically searched MEDLINE (from inception to 19th October 2018) to identify population-
Accepted 8 May 2019 based cohort studies evaluating the risk of subsequent stroke or myocardial infarction (MI) in patients with ep-
Available online xxxx
ilepsy without history of prior cerebrovascular disease in comparison with subjects without epilepsy.
Results: A total of 16,641 records were screened, and 6 studies were included. Data on the risk of subsequent
Keywords:
Epidemiology
stroke and MI were provided by five and two studies, respectively. The adjusted hazard ratios (adjHRs) of subse-
Myocardial infarction quent ischemic stroke for patients with epilepsy ranged from 1.09 (95% confidence interval (CI): 1.00–1.19) to
Risk factors 2.85 (95% CI: 2.49–3.26). Two studies assessing the incidence of hemorrhagic stroke showed an increased risk
Seizures in patients with epilepsy (adjHR: 3.30; 95% CI: 2.46–4.43 and adjHR: 2.27; 95% CI: 1.80–2.85). The adjHRs of subse-
Stroke quent MI ranged between 1.09 (95% CI: 1.00 to 1.19) and 1.48 (95% CI: 1.31–1.67). Age, hypertension, MI, diabe-
tes, hyperlipidemia, and arteriosclerosis were significantly associated with the increase in stroke risk. A gradient
between the antiepileptic drug (AED) dose and risk of subsequent stroke was found. In comparison with carba-
mazepine (CBZ), oxcarbazepine (OXC) was associated with an increased risk of stroke and valproate (VPA) with
a reduction in risk of stroke and MI, whereas no significant associations with vascular disease were found for phe-
nobarbital (PB), lamotrigine (LMT), phenytoin (PHT), clonazepam (CLZ), and clobazam (CLB).
Conclusions: Patients with epilepsy are at higher risk of subsequent stroke and MI in comparison with subjects
without epilepsy. Although individual AEDs may carry different risks of cardio- and cerebrovascular disease,
the clinical relevance of the metabolic effects of the enzyme-inducing AEDs is still uncertain.
This article is part of the Special Issue “Seizures & Stroke
© 2019 Elsevier Inc. All rights reserved.

1. Introduction increased risk of a first stroke (ischemic or hemorrhagic) or myocardial

The relationship between stroke and seizures or epilepsy is bidirec-
tional. Stroke is the most common cause of acquired epilepsy among
adults and elderly patients, accounting for approximately 10% of all ep-
ilepsies [1]. There is, however, accruing evidence that otherwise unex-
plained seizures may also represent the first clinical expression of an
underlying occult cerebrovascular disease [2–4] and predict the occur-
rence of clinically overt vascular events.
In this review, we aimed to investigate if patients with epilepsy and
no prior history of clinically overt cerebrovascular disease are at
⁎ Corresponding author at: Department of Neuroscience, Biomedicine and Movement,
University of Verona, Piazzale L.A. Scuro, 10, 37134 Verona, Italy.
E-mail address: dr.francescobrigo@gmail.com (F. Brigo).
infarction (MI), assessing also if the risk differs with respect to the use of
specific antiepileptic drugs (AEDs), particularly enzyme-inducing. Be-
cause of the intrinsic limits of case–control and cross-sectional studies,
which prevent from inferring causality and drawing definitive conclu-
sions, only population-based cohort studies have been considered.
2. Methods
The report of this systematic review was made according to the rec-
ommendations of the Preferred Reporting Items for Systematic Reviews
and Meta-Analyses (PRISMA) statement [5] (Supplementary material 1).
We systematically searched MEDLINE (accessed from PubMed)
from inception to 19th October 2018 to identify retrospective and pro-
spective population-based cohort studies evaluating the risk of

https://doi.org/10.1016/j.yebeh.2019.05.005
1525-5050/© 2019 Elsevier Inc. All rights reserved.

Please cite this article as: F. Brigo, P. Lochner, R. Nardone, et al., Increased risk of stroke and myocardial infarction in patients with epilepsy: A
systematic review of..., Epilepsy & Behavior, https://doi.org/10.1016/j.yebeh.2019.05.005
2 F. Brigo et al. / Epilepsy & Behavior xxx (xxxx) xxx
subsequent ischemic and hemorrhagic stroke or MI in patients with ep-
ilepsy without prior cerebrovascular disease compared with subjects
without epilepsy. We used the following search strategy: (“Myocardial
Infarction”[Mesh] OR “Myocardial Ischemia”[Mesh] OR “Peripheral Ar-
terial Disease”[Mesh] OR “Coronary Artery Disease”[Mesh] OR “Myocar-
dial infarction” OR “Myocardial ischemia” OR “Ischemic Heart Disease”
OR “peripheral artery disease” OR “peripheral arterial disease” OR
“Stroke”[Mesh] OR “Cerebrovascular Disorders”[Mesh] OR stroke OR
cerebrovasc*) AND (“Epilepsy”[Mesh] OR epilep* OR “Seizures”[Mesh]
OR seizur*). Case–control studies (including nested ones) were
excluded.
Retrieved items were independently screened and selected for pos-
sible inclusion by two reviewers (FB and PL); any disagreement was re-
solved through discussion or after consulting a third reviewer (RN). The
same reviewers independently extracted the following data: study au-
thors; study period and country; characteristics of study cohort and
control group; adjusted hazard ratio (adjHR) with 95% confidence inter-
val (CI) of stroke and MI.
The methodological quality of included studies was assessed using
the Critical Appraisal Skills Programme (CASP) checklist (questions 1–
6) [6]. Our primary intention was to perform a quantitative synthesis
of studies, using inverse-variance weighted average meta-analyses of
adjusted effects estimates (adjHRs and corresponding CIs and standard
error [SE]) to control for confounding [7].
3. Results
The search strategy yielded 16,641 articles. After reading the title,
abstract, and/or full text, eight studies were initially considered eligible.
Two studies were subsequently excluded: one because it did not pro-
vide results in comparison to a control group [8] and one because
some of its data had been already described in a more comprehensive
report (partly duplicate publication) [9].
Accordingly, six studies were included in the current review [10–15]
(Supplementary material 2).
Despite our primary intention, it was impossible to pool results from
individual studies into a meta-analysis, because of different study de-
signs (prospective or retrospective) and clinical heterogeneity in cohort
and control groups (e.g., age at seizure onset in subjects in the cohort
group). A qualitative synthesis was hence performed.
3.1. Methodological quality of included studies
All included studies addressed a clearly focused issue by specifying
the population and the risk factors studied (epilepsy without prior clin-
ically overt cardio/cerebrovascular disease), and the outcomes consid-
ered (occurrence of a first stroke, ischemic or hemorrhagic). In all
studies, the selected cohort was representative of the population of pa-
tient with epilepsy without previous history of vascular disease, al-
though the age at seizure onset varied considerably across studies
(Table 1). Data on the accuracy of diagnoses of epilepsy, stroke, and
MI in the datasets used for the analyses were explicitly reported only
in one study [11]. In one study, patients newly diagnosed with epilepsy
and who were prescribed AEDs were included to increase the validity of
the diagnoses [12]; however, no data on formal validation of diagnoses
was provided. Only a part of data were validated with medical record in
two further studies [13,14], and in the study by Hsu and colleagues, only
the stroke cases were validated [15]. No details on the validation for the
diagnoses of stroke and epilepsy were provided in the study by Cleary
and coworkers [10].
All studies accounted for the presence of major confounding factors
in the design and/or analysis, by matching and adjusting, and the
follow-up was long enough to detect the occurrence of stroke or MI.
However, adjustments for lifestyle variables (e.g., smoking, physical ac-
tivity, alcohol intake, diet habits) were not made, because of lack of in-
formation in the databases.
Please cite this article as: F. Brigo, P. Lochner, R. Nardone, et al., Increased risk of stroke and myocardial infarction in patients with epilepsy: A
systematic review of..., Epilepsy & Behavior, https://doi.org/10.1016/j.yebeh.2019.05.005
3.2. Risk of subsequent stroke
Five studies provided data on risk of subsequent stroke [10–13,15].
Details of included studies are reported in Table 1.
The risk of subsequent ischemic stroke was higher in patients with
epilepsy than in controls, and adjHRs ranged from 1.09 (95% CI: 1.00–
1.19) to 2.85 (95% CI: 2.49–3.26) [11,12,15]. Two studies assessed the
incidence of subsequent hemorrhagic stroke and showed an increased
risk among patients with epilepsy (adjHRs: 3.30; 95% CI: 2.46–4.43 and
2.27; 95% CI: 1.80–2.85) [12,15].
One study identified comorbidities associated with the increase in
stroke risk: hypertension, MI, diabetes mellitus, hyperlipidemia, and ar-
teriosclerosis; the risk of stroke also increased with increasing age [13].
A gradient between AED dose and the risk of subsequent stroke, ei-
ther of ischemic or hemorrhagic type, has been shown; the AED dose
analyzed was based on the average defined daily dose prescribed by
physicians [12].
One Danish study based on 18,039 patients receiving AED mono-
therapy investigated the risk of subsequent stroke according to individ-
ual AEDs [11]. Compared with carbamazepine (CBZ), oxcarbazepine
(OXC) was associated with an increase (adjHR: 1.21; 95% CI: 1.10–
1.34) and valproate (VPA) with a reduction (adjHR 0.86; 95% CI: 0.76–
0.96) in stroke risk whereas no significant associations were found
with phenobarbital (PB), lamotrigine (LMT), phenytoin (PHT), clonaze-
pam (CLZ), or clobazam (CLB). In addition, AED-treated patients with
epilepsy had a higher risk of ischemic stroke (adjHR: 2.22; 95% CI:
2.09–2.36) compared with nontreated patients (adjHR: 1.09; 95% CI:
1.00–1.19). In comparison with control group, the risk of ischemic
stroke was higher among AED-treated (adjHR: 2.22; 95% CI: 2.09–2.36)
than untreated patients with epilepsy (adjHR: 1.09; 95% CI: 1.00–1.19).
3.3. Risk of subsequent myocardial infarction
One nationwide cohort study conducted in Denmark assessed the
risk of MI in patients with epilepsy: the adjHR for subsequent MI was
1.09 (95% CI: 1.00–1.19) in AED-treated and 1.15 (95% CI: 1.06–1.26)
in untreated patients [11]. A second population-based retrospective co-
hort study performed in South Carolina, USA, showed that patients with
epilepsy aged ≥ 18 years without prior cardiovascular disease had a
higher risk for MI compared with patients with isolated lower extremity
fracture (adjHR: 1.24; 95% CI: 1.10 to 1.39) and subjects with migraine
(adjHR: 1.48; 95% CI: 1.31–1.67) [14].
The aforementioned Danish study investigated also the risk of MI
with individual AEDs used in monotherapy: compared with CBZ, the
use of VPA was associated with a reduced risk of MI (adjHR: 0.72; 95%
CI: 0.59–0.87) whereas no significant associations were found with
any of the other drugs analyzed (PHT, PB, LMT, CLZ, and CLB) [11].
Further details of included studies are shown in Table 2.
4. Discussion
All the studies identified and included in the present review consis-
tently show that patients with epilepsy without a previous clinically
overt cerebrovascular disease are at high risk of subsequent stroke
and MI. The association between epilepsy and vascular disease is
based on the results of large-scale population studies that adequately
selected a representative cohort, accounted for the presence of con-
founding factors in the design and/or analysis, and evaluated the occur-
rence of stroke or MI in a long follow-up. However, none adjusted
results for lifestyle variables (e.g., smoking, physical activity, alcohol in-
take, diet habits), because of lack of information in the databases. How-
ever, despite their consistency across different studies, the results of this
review should be interpreted with caution, mostly because of the pau-
city or even lack of data on the accuracy of diagnoses of epilepsy, stroke,
and MI in the datasets used for the analyses [16]. Although it is likely
that diagnostic sensitivity was high, specificity was less certain,
 F. Brigo et al. / Epilepsy & Behavior xxx (xxxx) xxx 3

Table 1
Characteristics of studies providing data on the risk of subsequent stroke in patients with epilepsy.

Authors Country Study design Study Study cohort Control group Adjusted hazard
period ratio for stroke
(95% confidence
intervals)

Cleary et al., United Nationwide cohort study based on the Not 4709 patients with otherwise 4709 randomly selected controls Stroke (all types)
2004 [10] Kingdom General Practice Research Database explicitly unexplained late-onset (N60 with no history of seizures or 2.89 (2.45–3.41)
(diagnoses and treatments in general reported years) seizures and no history cerebrovascular disease, matched
practice) of cerebrovascular disease for age, sex, and general practice
Olesen et al., Denmark Nationwide cohort study based on Danish January 1, 21,315 AED-treated patients 4,481,132 subjects without Risk for ischemic
2011 [11] National Patient Register (all admission and 1997 to with epilepsy (age ≥10 years) epilepsy and without previous stroke in
discharge diagnoses) and the Danish Register December without previous stroke stroke AED-treated
of Medical Product Statistics (prescription 31, 2006 patients with
register) 27,287 non-AED-treated epilepsy:
patients with epilepsy (age 2.22 (2.09–2.36)
≥10 years) without a previous
stroke Risk for ischemic
stroke in
non-AED-treated
patients with
epilepsy:
1.09 (1.00–1.19)
Chang et al., Taiwan Nationwide cohort study based on 1996–2009 3812 patients newly 15,248 subjects without epilepsy Stroke (all
2014 [12] Longitudinal Health Insurance Database diagnosed with epilepsy in and previous stroke matched for types):
2000–2008, age ≥20 years, sex, age, and comorbidities 2.92 (2.58–3.30)
who were prescribed AEDs (except atrial fibrillation)
Ischemic stroke:
2.85 (2.49–3.26)

Hemorrhagic
stroke:
3.30 (2.46–4.43)
Wannamaker South Population-based retrospective cohort study January 1, 21,035 patients ≥35 years 16,638 subjects without previous Stroke (not
et al., 2015 Carolina, using data from the hospital discharge and 2002 to with otherwise unexplained stroke with isolate lower further
[13] USA emergency department visit dataset December epilepsy and without previous extremity fracture specified):
31, 2011 stroke 1.60 (1.42–1.80)
Hsu et al., Taiwan Retrospective cohort study based on Taiwan's 2000–2008 6746 patients ≥20 years with 26,984 subjects with no epilepsy Stroke (all
2019 [15] National Health Insurance Research Database newly diagnosed epilepsy diagnosis and no history of stroke types):
between 2000 and 2008 and matched for age and sex 2.24 (2.02–2.49)
without previous stroke
Ischemic stroke:
1.91 (1.62–2.26)

Hemorrhagic
stroke:
2.27 (1.80–2.85)

particularly for the diagnosis of seizures, and false positives may have
affected the reliability of estimates [16]. It is, however, worth to notice
that the magnitude of the risk of subsequent stroke is high, ranging
from 9% [11] to 230% [12], and, hence, unlikely to be explained by
miscoding alone.
The high variability in the risks of stroke across the studies may be
due to differences existing in the age of included patients: for instance,
the study reporting an almost 3-fold increased risk of subsequent stroke
included only patients with late-onset (N 60 years) seizures [10]
whereas the study reporting a 60% increased risk included patients
with seizure onset ≥ 35 years, with 20.7% of all cases being under the
age of 46 years [13]. High risks of stroke have been, however, observed
also in studies including young patients [11,12,15], suggesting that the
increased vascular risk may affect every group of age and is not re-
stricted to patients with late-onset seizures [13].
Patients with seizures and without prior history of vascular disease
were also found to be at increased risk of MI, although at a lower degree
than that for subsequent stroke [11,14]. This finding suggests that other-
wise unexplained epilepsy can represent an overall risk factor for vascu-
lar diseases, and not only for stroke. Intriguingly, vascular comorbidities
have been more frequently found in subjects with epilepsy than in con-
trols, suggesting an excess of vascular risk factors in these patients [13].
A cross-sectional study has also shown that patients with late-onset
(≥ 55 years) epilepsy without a previous stroke have a higher
prevalence of hypercholesterolemia and left ventricular hypertrophy
compared with controls [17].
The increased risk of clinically overt stroke or MI in patients with
late-onset epilepsy can be explained by an underlying occult vascular
disease [4]. Subcortical small vessel disease represents a constellation
of endophenotypes carrying different risks for epileptogenesis due to
genetic factors, location, and type of pathological changes, as well as
to the exposure to nongenetic factors (‘exposome’) [18]. Disrupted
corticosubcortical circuits and subsequent imbalance between excit-
ability and inhibitory pathways can predispose patients with small ves-
sel disease to epileptic seizures [19]. Furthermore, the neurovascular
unit dysfunction due to impaired integrity of the blood–brain barrier
could alter cerebral metabolism and/or perfusion increasing the risk of
seizures [2,20]. Finally, in some patients, genetic interactions could ex-
plain the association between vascular comorbidity and otherwise un-
explained seizures [18]. However, drawing definite conclusions on the
causative role of late-onset seizures in subsequent clinically overt vas-
cular disease is still hampered by confounding factors. More specifically,
the coexisting occult cerebrovascular disease, the use of AEDs with neg-
ative metabolic effects, and concomitant underlying age-related
changes in cortical excitability due to neuronal loss and initial cortical
atrophy are interwoven to the point that assessing their own contribu-
tion to the clinical vascular risk would be “like solving a Gordian knot”
[21].

Please cite this article as: F. Brigo, P. Lochner, R. Nardone, et al., Increased risk of stroke and myocardial infarction in patients with epilepsy: A
systematic review of..., Epilepsy & Behavior, https://doi.org/10.1016/j.yebeh.2019.05.005
4 F. Brigo et al. / Epilepsy & Behavior xxx (xxxx) xxx

Table 2
Characteristics of studies providing data on the risk of subsequent myocardial infarction in patients with epilepsy.

Authors Country Study design Study Study cohort Control group Adjusted hazard
period ratio
for myocardial
infarction (95%
confidence
intervals)

Olesen Denmark Nationwide cohort study based on Danish National Patient January 1, 21,315 AED-treated patients 4,481,132 subjects Risk in
et al., Register (all admission and discharge diagnoses) and the 1997 to with epilepsy (age ≥10 years) without epilepsy and AED-treated
2011 Danish Register of Medical Product Statistics (prescription December without previous stroke without previous patients with
[11] register) 31, 2006 stroke epilepsy
27,287 non-AED-treated 1.09 (1.00 to 1.19)
patients with epilepsy (age
≥10 years) without previous Risk in
stroke non-AED-treated
patients with
epilepsy:
1.15
(1.06 to 1.26)
Wilson South Population-based retrospective cohort study using January 1, 39,203 patients with epilepsy 39,090 patients with Compared with
et al., Carolina, statewide hospital and emergency department encounter 2000 to aged N18 years without prior isolated lower patients with
2018 USA data December cardiovascular disease extremity fracture lower extremity
[14] 31, 2013 fracture:
1.24 (1.10 to 1.39)
80,469 persons with
migraine Compared with
persons with
migraine:
1.48 (1.31–1.67)

Understanding the clinical relevance of the association between ep-
ilepsy and subsequent vascular disease found in the present review is
challenging. In particular, it is highly important to discuss whether oth-
erwise unexplained seizures may be considered a vascular risk factor re-
quiring further investigations and/or treatment and serve as “transient
ischemic attack (TIA) equivalents” to identify patients at high risk of
subsequent vascular events. Notably, the currently available evidence
points to an increased risk of stroke in these patients that is quite similar
to the probability of a first clinically overt stroke in patients with silent
brain infarction [22]. Accordingly, screening these patients for the pres-
ence of vascular risk factors seems reasonable.
The decision to start, or not, preventative treatments remains a more
controversial issue. The decision should rely more on the absolute risk of
stroke and other vascular events, rather than on the existence or extent
of any particular risk factor [16]. In other terms, the cardio/cerebrovas-
cular risk needs to be sufficiently high to warrant the harms potentially
associated with treatment. For instance, aspirin has been recommended
in primary prevention when the risk of a cardiovascular event exceeds
6–10% in a 10-year period (Class I; Level of Evidence A) [23]; its use in
patients with low or moderate risk may expose them to a risk of
major bleeding without significant benefit in reducing the risk of vascu-
lar events [24]. Noteworthy, the risk of a clinically overt stroke in pa-
tients with otherwise unexplained adult-onset epilepsy reached 10%
at 6 years [10], and this may justify a large controlled trial with long-
term follow-up to investigate the use of antiplatelet treatment as pri-
mary prevention. However, the present systematic review shows that
in this population, there is an increased risk also for hemorrhagic stroke,
not only ischemic stroke; hence, safety of antiplatelet treatment admin-
istered as primary prevention remains an open issue, which deserves
further investigation.
The contribution of AEDs to the risk of subsequent vascular disease is
a further issue to discuss. In patients with otherwise unexplained sei-
zures, AEDs might play a synergistic role with the underlying occult vas-
cular disease and amplify the risk of a clinically overt stroke or MI.
Enzyme-inducing AEDs are known to exert detrimental metabolic ef-
fects on surrogate vascular markers, for instance, increasing levels of
low-density lipoprotein (LDL) cholesterol, triglycerides, lipoprotein(a),
C-reactive protein, and homocysteine [25,26]. Furthermore, they can
increase the carotid artery intima media thickness and worsen the ath-
erosclerotic process [27,28] by raising the serum levels of lipids via the
induction of hepatic cytochrome P450 and reducing the cholesterol-
lowering effect of statins through drug–drug pharmacokinetic interac-
tions [29]. The use of AEDs with proatherogenic properties could, at
least partially, explain the higher predisposition to vascular disease,
mostly in patients with earlier onset of epilepsy and longer exposure
to AEDs. Unlike CBZ and other first-generation AEDs, VPA is an en-
zyme-inhibiting drug, and it is not associated with negative metabolic
effects on chemical biomarkers. However, it can favor insulin resistance,
metabolic syndrome, body overweight, and oxidative stress, which, in
turn, can raise the vascular risk [30,31].
Only one study specifically assessed the role of individual AEDs in
the risk of a subsequent vascular event in patients with epilepsy, show-
ing that, in comparison with CBZ, OXC was associated with an increased
risk of stroke and VPA with a reduced risk of stroke and MI [11]. The
choice of CBZ as comparator did not allow to evaluate the risk specifi-
cally associated with this drug. Interestingly, no increased vascular
risk was found with the use of PB or PHT, which are also enzyme-
inducing AEDs; the negative results could be, however, due to the lim-
ited sample size.
Unfortunately, none of the studies included in this review performed
a subgroup analysis according to the enzyme-inducing activity of the
AEDs. A large study conducted in the United Kingdom between 1990
and 2013 in 252,407 patients aged ≥ 18 years treated with AEDs and
without a previous history of stroke showed that the use of enzyme-
inducing AEDs was associated with a slightly increased risk of a subse-
quent ischemic stroke compared with the use of noninducing AEDs
and no effect on MI risk [32]. Conversely, in the same study, a subgroup
analysis performed in 816 patients taking inducing AEDs for treatment
of epilepsy failed to demonstrate any significant association with the
risk of a subsequent ischemic stroke or MI compared with noninducing
drugs [32]. Whether this lack of association is real or due to the small
number of included patients is unknown. The small increase in the
risk of subsequent ischemic stroke found in the entire population sug-
gests that the clinical vascular risk related to the use of inducing AEDs
is lower than expected and makes uncertain whether and to what ex-
tent the negative metabolic effects on surrogate vascular biomarkers

Please cite this article as: F. Brigo, P. Lochner, R. Nardone, et al., Increased risk of stroke and myocardial infarction in patients with epilepsy: A
systematic review of..., Epilepsy & Behavior, https://doi.org/10.1016/j.yebeh.2019.05.005
 F. Brigo et al. / Epilepsy & Behavior xxx (xxxx) xxx
can translate into an increased clinical risk. Although further studies are
needed to draw definitive conclusions, the preferential use of
noninducing AEDs seems reasonable taking into account that patients
with epilepsy generally require medication for years or even for life.
5. Conclusions
The present systematic appraisal of the literature shows that other-
wise unexplained seizures are associated with an increased incidence of
subsequent stroke and MI. It seems, therefore, reasonable to screen
these patients for vascular comorbidities and consider pharmacologic
management of risk factors (e.g., statins or antihypertensive drugs)
and lifestyle changes on the basis of the individual vascular profile.
There is evidence for a relationship between AEDs and stroke, whereas
it is unclear whether AEDs also predispose to MI. Although individual
AEDs may carry different cardio/cerebrovascular risks, the clinical rele-
vance of negative metabolic effects of enzyme-inducing AEDs is still not
completely understood.
Further large, prospective, and high-quality studies, relying on reli-
able databases using validated diagnoses and adjusting for confounding
factors (including lifestyle variables) in the design and/or analysis, are
warranted to draw definite conclusions on the vascular risk related to
epilepsy or the use of specific AEDs.
Declaration of Competing Interest
No funding was received related to the preparation of this article.
Francesco Brigo has received travel support from Eisai; he was one of
the organizers of the “Seizures & Stroke” Congress, held in Gothenburg
from 20th to 22nd February 2019. The remaining authors have no con-
flicts of interest to disclose.
Appendix A. Supplementary data
Supplementary data to this article can be found online at https://doi.
org/10.1016/j.yebeh.2019.05.005.
References
[1] Ferlazzo E, Gasparini S, Beghi E, Sueri C, Russo E, Leo A, et al. Epilepsy in cerebrovas-
cular diseases: review of experimental and clinical data with meta-analysis of risk
factors. Epilepsia 2016;57:1205–14.
[2] Gibson LM, Hanby MF, Al-Bachari SM, Parkes LM, Allan SM, Emsley HC. Late-onset
epilepsy and occult cerebrovascular disease. J Cereb Blood Flow Metab 2014;34:
564–70.
[3] Brigo F, Tezzon F, Nardone R. Late-onset seizures and risk of subsequent stroke: a
systematic review. Epilepsy Behav 2014;31:9–12.
[4] Brigo F, Nardone R. Late-onset seizures: a subclinical cerebrovascular disorder? Ex-
pert Rev Neurother 2017;17:751–3.
[5] Moher D, Liberati A, Tetzlaff J, Altman DG, PRISMA Group. Preferred reporting items
for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 2009;
6:e1000097.
[6] Critical Appraisal Skills Programme. Available online at: https://casp-uk.net/casp-
tools-checklists/
[7] Cochrane Handbook for Systematic Reviews of Interventions. Version 5.1.0.Higgins
JPT, Green S (eds). [Updated 2011] Available online at: http://handbook-5-1.
cochrane.org/
Please cite this article as: F. Brigo, P. Lochner, R. Nardone, et al., Increased risk of stroke and myocardial infarction in patients with epilepsy: A
systematic review of..., Epilepsy & Behavior, https://doi.org/10.1016/j.yebeh.2019.05.005
5
[8] Zelano J, Larsson D, Kumlien E, Åsberg S. Pre-stroke seizures: a nationwide register-
based investigation. Seizure 2017;49:25–9.
[9] Olesen JB, Hansen PR, Abildstrøm SZ, Andersson C, Weeke P, Schmiegelow M, et al.
Valproate attenuates the risk of myocardial infarction in patients with epilepsy: a
nationwide cohort study. Pharmacoepidemiol Drug Saf 2011;20:146–53.
[10] Cleary P, Shorvon S, Tallis R. Late-onset seizures as a predictor of subsequent stroke.
Lancet 2004;363:1184–6.
[11] Olesen JB, Abildstrøm SZ, Erdal J, Gislason GH, Weeke P, Andersson C, et al. Effects of
epilepsy and selected antiepileptic drugs on risk of myocardial infarction, stroke, and
death in patients with or without previous stroke: a nationwide cohort study.
Pharmacoepidemiol Drug Saf 2011;20:964–71.
[12] Chang CS, Liao CH, Lin CC, Lane HY, Sung FC, Kao CH. Patients with epilepsy are at an
increased risk of subsequent stroke: a population-based cohort study. Seizure 2014;
23:377–81.
[13] Wannamaker BB, Wilson DA, Malek AM, Selassie AW. Stroke after adult-onset epi-
lepsy: a population-based retrospective cohort study. Epilepsy Behav 2015;43:93–9.
[14] Wilson DA, Wannamaker BB, Malek AM, Selassie AW. Myocardial infarction after ep-
ilepsy onset: a population-based retrospective cohort study. Epilepsy Behav 2018;
88:181–8.
[15] Hsu SPC, Yeh CC, Chou YC, Shih CC, Hu CJ, Cherng YG, et al. Stroke risk and outcomes
in epilepsy patients: two retrospective cohort studies based on National Health In-
surance in Taiwan. Atherosclerosis 2019;280:147–54.
[16] Sudlow CL. Epilepsy and stroke. Lancet 2004;363:1175–6.
[17] Li X, Breteler MM, de Bruyne MC, Meinardi H, Hauser WA, Hofman A. Vascular deter-
minants of epilepsy: the Rotterdam Study. Epilepsia 1997;38:1216–20.
[18] Pitkänen A, Roivainen R, Lukasiuk K. Development of epilepsy after ischaemic stroke.
Lancet Neurol 2016;15:185–97.
[19] Shinton RA, Gill JS, Zezulka AV, Beevers DG. The frequency of epilepsy preceding
stroke. Case–control study in 230 patients. Lancet 1987;1:11–3.
[20] Gibson LM, Allan SM, Parkes LM, Emsley HC. Occult cerebrovascular disease and
late-onset epilepsy: could loss of neurovascular unit integrity be a viable model?
Cardiovasc Psychiatry Neurol 2011;2011:130406.
[21] Brigo F. Late-onset seizures, underlying etiology and antiepileptic drugs: a Gordian
knot? Seizure 2017;50:12–3.
[22] Gupta A, Giambrone AE, Gialdini G, Finn C, Delgado D, Gutierrez J, et al. Silent brain
infarction and risk of future stroke: a systematic review and meta-analysis. Stroke
2016;47:719–25.
[23] Goldstein LB, Bushnell CD, Adams RJ, Appel LJ, Braun LT, Chaturvedi S, et al. Guide-
lines for the primary prevention of stroke: a guideline for healthcare professionals
from the American Heart Association/American Stroke Association. Stroke 2011;
42:517–84.
[24] McNeil JJ, Wolfe R, Woods RL, Tonkin AM, Donnan GA, Nelson MR, et al. Effect of as-
pirin on cardiovascular events and bleeding in the healthy elderly. N Engl J Med
2018;379:1509–18.
[25] Mintzer S, Skidmore CT, Abidin CJ, Morales MC, Chervoneva I, Capuzzi DM, et al. Ef-
fects of antiepileptic drugs on lipids, homocysteine, and C-reactive protein. Ann
Neurol 2009;65:448–56.
[26] Mintzer S, Trinka E, Kraemer G, Chervoneva I, Werhahn KJ. Impact of carbamaze-
pine, lamotrigine, and levetiracetam on vascular risk markers and lipid-lowering
agents in the elderly. Epilepsia 2018;59:1899–907.
[27] Lopinto-Khoury C, Mintzer S. Antiepileptic drugs and markers of vascular risk. Curr
Treat Options Neurol 2010;12:300–8.
[28] Katsiki N, Mikhailidis DP, Nair DR. The effects of antiepileptic drugs on vascular risk
factors: a narrative review. Seizure 2014;23:677–84.
[29] Mintzer S. Metabolic consequences of antiepileptic drugs. Curr Opin Neurol 2010;
23:164–9.
[30] Isojärvi JI, Laatikainen TJ, Knip M, Pakarinen AJ, Juntunen KT, Myllylä VV. Obesity and
endocrine disorders in women taking valproate for epilepsy. Ann Neurol 1996;39:
579–84.
[31] Verrotti A, Scardapane A, Franzoni E, Manco R, Chiarelli F. Increased oxidative stress
in epileptic children treated with valproic acid. Epilepsy Res 2008;78:171–7.
[32] Renoux C, Dell'Aniello S, Saarela O, Filion KB, Boivin JF. Antiepileptic drugs and the
risk of ischaemic stroke and myocardial infarction: a population-based cohort
study. BMJ Open 2015;5:e008365.