Review

Development of epilepsy after ischaemic stroke

Asla Pitkänen, Reina Roivainen, Katarzyna Lukasiuk

For about 30% of patients with epilepsy the cause is unknown. Even in patients with a known risk factor for epilepsy, Lancet Neurol 2015
such as ischaemic stroke, only a subpopulation of patients develops epilepsy. Factors that contribute to the risk for Published Online
epileptogenesis in a given individual generally remain unknown. Studies in the past decade on epilepsy in patients November 16, 2015
http://dx.doi.org/10.1016/
with ischaemic stroke suggest that, in addition to the primary ischaemic injury, existing difficult-to-detect microscale
S1474-4422(15)00248-3
changes in blood vessels and white matter present as epileptogenic pathologies. Injury severity, location and type of
Department of Neurobiology,
pathological changes, genetic factors, and pre-injury and post-injury exposure to non-genetic factors (ie, the exposome) A. I. Virtanen Institute for
can divide patients with ischaemic stroke into different endophenotypes with a variable risk for epileptogenesis. Molecular Sciences, University
These data provide guidance for animal modelling of post-stroke epilepsy, and for laboratory experiments to explore of Eastern Finland, Kuopio,
Finland (Prof A Pitkänen PhD);
with increased specificity the molecular `mechanisms, biomarkers, and treatment targets of post-stroke epilepsy in
Department of Neurology,
different circumstances, with the aim of modifying epileptogenesis after ischaemic stroke in individual patients Hyvinkää Hospital, Hyvinkää,
without compromising recovery. Finland (R Roivainen MD); and
The Nencki Institute of
Experimental Biology, Polish
Introduction arterial dissection.12 Ischaemic stroke can occur at any
Academy of Sciences, Warsaw,
In 2013, The Working Group of the International League time during life, with the greatest risk being during the Poland (K Lukasiuk PhD)
Against Epilepsy revised the terminology related to the first week after birth.13 Study results14,15 have shown that Correspondence to:
term epileptogenesis and provided recommendations although ischaemic stroke is more often associated with Prof Asla Pitkänen, A. I. Virtanen
for doing studies of antiepileptogenic treatments.1 elderly adults, it is not uncommon in young adults (aged Institute, University of Eastern
Finland, PO Box 1627,
Epileptogenesis refers to the development and extension 16–49 years), with an incidence of ten to 11 per
FIN-70 211 Kuopio, Finland
of tissue capable of generating spontaneous seizures, 100 000 people per year. The initiation and location of asla.pitkanen@uef.fi
resulting in the development of an epileptic disorder or epileptogenesis after ischaemic stroke can be accurately
progression after the disorder is established. Thus, the defined, allowing the mechanisms of the acquired
new definition takes into account evidence from epileptogenesis to be assessed at different stages of the
preclinical studies showing that epileptogenic epileptogenic process. Development of novel diagnostic
neurobiological processes can continue even after the methods and instruments will allow stroke to be
appearance of spontaneous recurrent seizures.2 In classified by subtype, cause, and confounding factors
addition to unprovoked seizures, epilepsy is often with improved accuracy and specificity, which will
associated with cognitive and behavioural comorbidities advance the accuracy of data collection and analysis.
that arise from the region of the epileptogenic network.3 Most of the experimental data from studies of post-stroke
Because the epileptogenic process seems to be largely epileptogenesis come from models of ischaemic stroke,
dependent on the underlying cause of epilepsy, which provide a scenario for the translation of preclinical
therapeutic approaches need to be tailored according to data to the clinic.
these causes.4 No antiepileptogenic treatments are Interpretation of the available data on human post-
available at present for patients at risk of epilepsy after stroke epileptogenesis is subject to several caveats,
brain injury, emphasising the need to understand cause- including the definitions of so-called early and late
specific mechanisms that can be targeted to combat seizures, which have been variable. The definitions are,
epileptogenesis in individual patients. however, crucial for data analysis and interpretation
Cerebrovascular diseases underlie about 11% of all because the occurrence of a late seizure is required for
cases of epilepsy5 and are heterogeneous with various diagnosis of PSE. An early seizure refers to a seizure
causes. Some cerebrovascular diseases are progressive, occurring during the first week after stroke—ie, the time
causing a spectrum of primary and secondary pathologies period during which seizures are regarded as acute
that can initiate the evolution of epileptogenic networks. symptomatic seizures that are not suggestive of an
Depending on the underlying cerebrovascular disease, enduring predisposition of the brain to generate epileptic
3% to 30% of patients who have had a stroke develop seizures.16,17 A late seizure occurs more than 1 week after
post-stroke epilepsy (PSE).6–10 the stroke.17 This definition is generally agreed to be
In this Review, we discuss the present understanding arbitrary. Other caveats to the interpretation of clinical
of the epileptogenic process after cerebrovascular post-stroke epileptogenesis studies are listed in the panel
diseases, focusing on arterial ischaemic stroke. Ischaemic and figure 1.
stroke is a common epileptogenic cause, accounting for Our aim is to describe new aspects emerging from
up to 9% of incident cases of epilepsy.11 In adults, the research into clinical and experimental PSE, which we
most common causal categories of ischaemic stroke are expect will affect experimental modelling, the
large artery atherosclerosis, cardiogenic emboli, small development of diagnostics, and the discovery of
vessel disease, and other, a diverse category that includes biomarkers and treatment strategies for post-stroke
inflammatory disease, hypercoagulable states, and epileptogenesis.

www.thelancet.com/neurology Published online November 16, 2015 http://dx.doi.org/10.1016/S1474-4422(15)00248-3 1

 Review
A
B
C D
Figure 1: Epileptogenesis or atherogenesis?
(A, B) Magnetic resonance angiography and (C, D) fluid-attenuated inversion recovery MRI taken at 20-month
intervals from a woman with her first ischaemic stroke in the right medial cerebral artery territory at age 54 years
(A, C; orange arrows). The left side of the brain is shown on the right side of the images. She had a maternal family
history of ischaemic stroke, and at the time of the first ischaemic stroke she was treated for hypertension. An
episode of clonic movements in the left limbs was seen during treatment at hospital. Inter-ictal EEG recorded at
the acute phase was interpreted to show epileptiform focal disturbance. Post-stroke epilepsy was diagnosed and
treatment with oxcarbazepine was initiated. Additionally, she was given aspirin–dipyridamole combination. A year
later, a short episode of left-sided numbness re-occurred and the oxcarbazepine dose was increased. 3 months
later, a third similar paroxysm occurred in the right arm, prompting reassessment of the symptom cause. A second
radiological assessment suggested rapid progression of atherosclerosis (B) and a new left medial cerebral artery
infarction (D; green arrows). Additionally, dental caries and periodontal disease were diagnosed as possible factors
contributing to ischaemic stroke.
Panel: Caveats to the interpretation of clinical data related
to post-stroke epileptogenesis
Accuracy of stroke diagnosis
Prevalence of different types of stroke in a given study
population
Definitions of early and late seizures and epilepsy
Follow-up duration
Sample size
Heterogeneity in study designs
Use of univariate versus multivariate statistics for data
analysis
Availability and analysis of CT and MRI scans for diagnosis
and follow-up
Accuracy regarding the location and type of primary lesion
Availability of EEG for detection of epileptiform activity
(seizures and status epilepticus)
Use of antiepileptic drugs or other medications acutely or
during follow-up
2 www.thelancet.com/neurology Published online November 16, 2015 http://dx.doi.org/10.1016/S1474-4422(15)00248-3
Epidemiology and clinical course of PSE
In adult populations, about 70–85% of cerebrovascular
diseases are ischaemic, and most cases of PSE are due to
arterial ischaemic stroke.18 The cumulative occurrence of
PSE after ischaemic stroke in different studies is
summarised in table 1.
The longest population-based follow-up study by
Graham and colleagues9 revealed that the 10-year estimate
of PSE after total anterior circulation infarct was 28·7%,
partial anterior circulation infarct was 13·4%, and posterior
circulation infarct was 4·8%. After ischaemic stroke, the
greatest risk for the first unprovoked post-stroke seizure
was during the first follow-up year (table 1). In a 5-year
follow-up,20 the mean incremental risk of late seizures after
ischaemic stroke was 1·5% per year after the first year.20
Another study23 reported that the annual event risk of
seizures after the first-ever ischaemic stroke is 6·3% after
1 year, 2·4% after 2 years, 1·3% after 3 years, and 0·3%
thereafter. Registry-based data from a case-control study
also suggested that the risk of unprovoked seizure
incidence remains heightened for 7 years after cerebral
infarction, being highest during the first post-stroke year.11
Data from the past 10 years has drawn attention to the
development of PSE in young adults (table 1).
Additionally, in the Rochester ischaemic stroke
population, the absolute risk of late seizures after
ischaemic stroke was similar between patients younger
than 55 years and those older than 75 years.19 The
negligible effect of age on the risk of post-stroke
epileptogenesis was also noted in two more recent
studies.11,22 Caveats also exist regarding the recognition of
seizures in elderly people (aged 60–75 years), in whom
convulsive seizures might be less frequent and seizure
manifestations more difficult to recognise than in
younger people (aged <55 years).26 The diagnostic
investigation is also likely to be more thorough in young
patients with ischaemic stroke than in elderly people,
and the higher survival rates of young people might
underlie the late seizure incidence.
Children have a clearly enhanced risk of post-stroke
epileptogenesis (table 1).27 Although the causes and risk
factors for ischaemic stroke are different in children
compared with adults, the molecular and cellular
environment in the immature brain at the time of stroke
seems to promote PSE development.24,25,27
Epilepsy phenotype
In a group of 20 patients with PSE, Lamy and
colleagues21 reported that the first late seizure was
simple partial in ten patients, complex partial in two,
secondary generalised in six, undetermined in one, and
status epilepticus in one, whereas Lossius and
colleagues22 reported simple or complex partial seizures
in three patients and secondarily generalised seizures
in 12 patients. In a study of 102 young adults, the first
late seizure was a bilateral convulsive seizure in
79 (77%) patients, impairment of consciousness was
 Review

Study type Number Age group (mean age) Patients with PSE at Patients with PSE Length of
of 1 year at the end of follow-up
patients follow-up (years)
So et al (1996)19 Prospective 535 8–99 years (71·6) 3·0% 7·4% 5
Burn et al (1997)20 Retrospective 545 All adult (72·2 years) 4·2% 9·7% 5
Bladin et al (2000)*6 Prospective 1632 All adult (72·7 years) 3·8%; 9 months† ·· ··
Lamy et al (2003)21 Prospective 581 18–55 years (42·5) 3·1% 5·5% 3
Lossius et al (2005)†22 Prospective 484 >60 years (76·2) 2·5% 3·1% 7–8
Roivainen et al (2013)23 Retrospective 995 16–49 years (41·3) 6·9% 11·5% 10
Lee et al (2009)24 Retrospective 75 1 month to 18 years (4·2) ·· 20·0% 2‡
Hsu et al (2014)25 Prospective 94 1 month to 18 years (7·6) 15·0% 21·8% 4·5

The epileptogenic process is most active during the first year when more than 50% of patients who will eventually develop post-stroke epilepsy do so. PSE=post-stroke
epilepsy. *Seizures after 2 weeks from index stroke. †PSE defined as at least two unprovoked seizures. ‡Median follow-up time of total population.

Table 1: Cumulative risk of unprovoked seizure occurrence in ischaemic stroke populations

present in 13 (13%) patients, and motor or autonomic
phenomena were reported in 10 (10%) patients.23
Convulsive seizures are the most frequent seizure type
in childhood PSE.25
On EEG, the most frequent finding is focal slowing
corresponding to the hemispheric side of the infarct.21,28
De Reuck and colleagues28 reported diffuse slowing
(n=15), intermittent rhythmic delta activity (n=17), or
periodic lateralised epileptic discharges (n=4) in
69 patients with subsequent early (n=12) or late (n=57)
seizures whereas similar disturbances in post-stroke
EEG were seen in only 17 of 275 patients who did not
develop post-stroke seizures. A normal post-stroke EEG
was seen in only 6 (9%) of 69 patients who developed
epilepsy compared with 148 (54%) of 275 who did not
enter epileptogenesis.28 Notably, the data in large PSE
studies derives mainly from investigations done during
routine clinical practice. EEG is usually done when the
nature of the post-stroke paroxysmal event is uncertain.
Additionally, interpretation of EEG results is challenging
in patients after they have had a stroke because some
EEG disturbances, such as focal slowing, are often
recorded in patients with stroke21,29 and elderly people.30
Characteristics of epileptogenic ischaemic
stroke
Symptom severity and lesion size
Clinical stroke severity, irrespective of stroke scale used,
is a major factor in the development of PSE.6,9,10,31,32 Total
anterior circulation infarct is a particularly strong risk
factor for post-stroke epileptogenesis compared with
other ischaemic stroke subtypes.9,20,21,23
Lesion location
Extent of cortical involvement is a significant risk factor
for post-stroke epileptogenesis shared by different age
groups with ischaemic stroke.6,21,33 Some evidence
suggests that epileptogenicity also varies depending on
the affected cortical area. Involvement of the parieto-
temporal cortex, supramarginal gyrus, and superior
temporal gyrus seems to be associated with post-stroke
epileptogenesis.6,21,34,35
Subcortical small vessel disease
Lacunar infarctions form about 11% of post-ischaemic
epilepsy.36 Lacunar infarcts are often discussed in the
context of leukoaraiosis, which refers to “white matter
hyperintensity of presumed vascular origin”.37
Leukoaraiosis manifests as round-shaped, isolated, or
confluent lesions of variable size without cavitation.
Typically, leukoaraiosis is localised in the periventricular
areas or deep white matter, or both, and has become
easier to detect because of advances in imaging methods.37
Gasparini and colleagues38 studied patients with epilepsy
with or without a clinically identified stroke event, but for
whom the cause of epileptogenesis was probably vascular,
dividing them into those with large vessel infarct (with or
without leukoaraiosis) and those with leukoaraiosis only.
The leukoaraiosis group consisted of 51% of the
117 patients investigated. Patients with leukoaraiosis
frequently had clinical and EEG signs suggestive of
temporal lobe epilepsy. Patients with large vessel infarct,
however, had signs of frontal lobe epilepsy, corresponding
with a cortical or central localisation of the infarct.
Hypothetical leukoaraiosis-induced damage to temporal
lobe networks was discussed, but occult coexisting
cortical microinfarcts could not be excluded. Accordingly,
a PET study39 revealed reduced cortical blood flow and
oxygen consumption more frequently in patients with
late-onset epilepsy and leukoaraiosis than in patients with
leukoaraiosis who did not have epilepsy. Furthermore,
patients with leukoaraiosis and lacunar infarct with
impaired cognition had a greater risk for PSE than
patients without cognitive impairment.40 Leukoaraiosis is
often associated with small vessel disease, which is more
frequent and more severe in patients with seizures
beginning after age 60 years, with or without clinical
stroke than in patients whose seizures began before age
60 years, suggesting a role for small vessel disease in
epileptogenesis.41

www.thelancet.com/neurology Published online November 16, 2015 http://dx.doi.org/10.1016/S1474-4422(15)00248-3 3

 Review
Seizures as biomarkers for cerebrovascular
disease
Epileptic seizures could be caused by ischaemic stroke,
or be a presenting symptom42,43 or biomarker for it (ie, a
marker of subclinical vascular disease).44 The hypothesis
that late-onset epilepsy is a precursor of impending
stroke was presented as vascular heralding epilepsy.45
Accumulating data lend support to this hypothesis.
A large study46 in the UK reported that late-onset epilepsy
is associated with triple the risk of later stroke. The
study46 reported that vascular risk factors, including
history of myocardial infarction, peripheral vascular
disease, hypertension, total serum cholesterol, and left
ventricular hypertrophy, are related to late-onset epilepsy
through either silent infarcts or non-infarct mechanisms.
The findings are lent support by a meta-analysis
published in 201444 showing that cerebrovascular disease
is often a cause of otherwise unexplained late-onset
epilepsy.44 Furthermore, 20% of seizures occurring in
patients with a previous cerebral infarct are reported to
present clinically as a new stroke.47
Genetic factors
About 30% of all epilepsy syndromes are believed to be of
genetic origin and more than 500 loci are linked to
epilepsy in human beings and mice.48 However, only two
studies49,50 have assessed the contribution of genetics to
the response to injury and consequent epileptogenesis in
patients with stroke (table 2).
Yang and colleagues50 reported that allele A of the rs671
polymorphism in a gene encoding mitochondrial
aldehyde dehydrogenase 2 is associated with PSE and
increases the plasma concentration of aldehyde
dehydrogenase 2 substrate, 4-hydrozynonenal. Zhang
and colleagues49 reported that a CD40-1C/T polymorphism
might be associated with PSE susceptibility. The
proposed mechanisms included raised plasma
concentrations of sCD40L, which is involved in the
inflammatory response.63
Several other genes have been investigated in the
context of ischaemic stroke outcome and the development
of comorbidities (table 2). The available data suggest
that both epileptogenesis and the development of
comorbidities can be modulated by non-overlapping
polymorphisms. At the transcriptomics level, a functional
connectivity seems to exist between many of the genes
that modulate post-ischaemic stroke outcomes (figure 2).
So far, no studies have been done to investigate whether
a given polymorphism will increase the association of
PSE with a specific comorbidity.
Peri-injury exposome as a modulator of
epileptogenesis
The exposome is defined as a measure of all non-genetic
exposures of an individual in a lifetime and how those
exposures relate to health65 (table 3, figure 2). It is
composed of environmental, dietary, lifestyle, and other
4 www.thelancet.com/neurology Published online November 16, 2015 http://dx.doi.org/10.1016/S1474-4422(15)00248-3
environmental factors that interact with our own unique
characteristics, such as genetics, physiology, and
epigenetics, and affects our health and response to
injury.
Table 3 summarises the different components of the
exposome and comorbidities that are temporally related
to the occurrence of stroke and have been investigated in
the context of post-stroke epileptogenesis. These studies
have shown that hyperglycaemia, type 1 or 2 diabetes,
dyslipidaemia, hypertension, cardiovascular morbidities,
peripheral infections, early seizures, depression and use
of antidepressants, use of statins, and pre-existing
dementia might modulate post-stroke epileptogenesis.
One important aspect of the peri-injury exposome is
the effect of acute treatments on post-stroke
epileptogenesis. Acute symptomatic seizures occur in
2–6% of patients after ischaemic stroke.19,21,23,74 Although
identified as a risk factor for late seizures, treatment and
prevention of early seizures after stroke with antiepileptic
drugs does not modulate post-stroke epileptogenesis.21,75,76
Convulsive status epilepticus occurs in about 1% of
patients with ischaemic stroke, and 0·1–0·2% cases
occur during the first week after stroke.70,77,78 In a stroke-
unit study79 applying video-EEG monitoring, non-
convulsive status epilepticus was identified in 3·6% of
patients admitted to hospital for stroke. Although status
epilepticus is thought to be epileptogenic in both
animals and man,80,81 it is not associated with the
development of PSE.70,82 Use of antiepileptic drugs to
control seizures or status epilepticus in the acute phase
has raised concerns about their effect on stroke
recovery.83 Nadeau and colleagues72 assessed the classes
of α1-noradrenergic blockers, α2-noradrenergic agonists,
benzodiazepines, voltage-sensitive sodium-channel
anticonvulsants, and α2δ voltage-sensitive calcium-
channel blockers on the recovery of functional walking,
and reported no significant effects on recovery in a 1-year
follow-up. However, systematic studies with larger
cohorts and assessments of different treatment regimens
are needed. Additionally, the effect of non-pharma-
cological treatment (eg, rehabilitation) on post-stroke
epileptogenesis needs to be investigated.
Two studies84,85 reported an association between
thrombolysis with recombinant tissue plasminogen
activator and an increased likelihood of acute sympto-
matic seizures after ischaemic stroke. The risk of acute
seizures is not associated with haemorrhagic trans-
formation or recanalisation and reperfusion injury, but it
is related to the severity of stroke and the extent of cortical
involvement.85 Irrespective of seizure occurrence, long-
term survival and outcome are improved in patients
receiving thrombolysis.86,87 However, within the
population of patients receiving thrombolysis, PSE is
associated with an unfavourable outcome due to an
unidentified mechanism.88,89 Experimental data suggest
that mice with a deficiency in endogenous tissue
plasminogen activator were less susceptible to
 Review

pharmacologically induced seizures and had less neuro-
degeneration when exposed to excitotoxic epileptogenic
insults.90 However, the contribution of treatment with
tissue plasminogen activator on acquired post-stroke
epileptogenesis remains to be explored.
Post-injury cellular pathology
Animal models
Since 2001, several video-EEG studies have reported the
occurrence of seizures in various rodent models of
ischaemic stroke, including cortical photothrombosis,

Gene or locus Study participants Outcome measure Observation

PSE
CD40-1 C/T49 CD40 molecule, TNF 410 patients with ischaemic PSE Frequency of T allele higher in patients with PSE
receptor superfamily stroke without epilepsy,
member 5 389 patients with PSE
Rs67150 Mitochondrial aldehyde 240 patients with ischaemic PSE Allele A associated with PSE
dehydrogenase 2 stroke without epilepsy,
225 patients with PSE
Other stroke outcomes
ε4 status51 Apolipoprotein E 189 patients with acute BI and MRS at 1 and 3 months No association with performance in daily living activities or
ischaemic stroke degree of disability or dependence
ε4 status52 Apolipoprotein E 496 patients with ischaemic MRS within 1 year No association with degree of disability or dependence
stroke
ε4 status53 Apolipoprotein E 657 patients with ischaemic MRS within 1 year No association with degree of disability or dependence at 1 year;
stroke ε4 genotype is a positive predictor of death within 1 year in men
589C→T54 Interleukin 4 145 patients with ischaemic Disease relapses, deaths, and BI at 589 T allele associated with total ischaemic stroke recurrences;
stroke, 145 controls 1, 3, and 6 months no association with performance in daily living activities or death
589C→VT55 Interleukin 4 145 patients with ischaemic Disease relapses, deaths, and BI No association with performance in daily living activities, death,
stroke or ischaemic stroke recurrences
308G→A55 TNFα 145 patients with ischaemic Disease relapses, deaths, and BI GG genotype associated with reduced odds for impairment in
stroke daily living activities or death
174G→C55 Interleukin 6 145 patients with ischaemic Disease relapses, deaths, and BI No association with performance in daily living activities, death,
stroke or ischaemic stroke recurrences
174G→C56 Interleukin 6 100 patients with ischaemic MRS and BI at 7 days, 3 and GC genotype associated with impaired performance in daily
stroke, 120 controls 6 months living activities, degree of disability or dependence, and higher
mortality
1082G→A54 Interleukin 10 145 patients with ischaemic Disease relapses, deaths, and BI at 1082 GG genotype predicts early stroke progression and
stroke, 145 controls 1, 3, and 6 months impaired performance in daily living activities
1082G→A55 Interleukin 10 145 patients with ischaemic Disease relapses, deaths, and BI No association with performance in daily living activities,
stroke ischaemic stroke recurrences, or death
1188A→C55 Interleukin 12B 145 patients with ischaemic Disease relapses, deaths, and BI No association with performance in daily living activities,
stroke ischaemic stroke recurrences, or death
VNTR in intron 257 Interleukin 1 receptor 391 patients with ischaemic SSS, BI, and OHS at 7 days, 1 and IL1RN*2 homozygocity associated with reduced impairment in
antagonist stroke 3 months, 1 year performance in daily living activities, with lower disability or
dependence at 7 days and 1 year; IL1RN*2 allele increases risk of
death
2518A→G58 Monocyte 145 patients with ischaemic OHS at 1 months No association with degree of disability or dependence in daily
chemoattractant protein-1 stroke living activities
12 SNPs59 Insulin-like growth factor 1 844 patients with ischaemic MRS at 3 and 24 months rs7136446 allele associated with lower degree of disability or
stroke dependence in daily living activities at 24 months post stroke
SNPs in promoter MBL-low MBL2 135 patients with ischaemic or MRS and BI at 3 months MBL-sufficient genotype associated with increased disability and
and MBL-sufficient allele haemorrhagic stroke dependence
variants60
SNP D105→G60 MBL-associated serine 135 patients with ischaemic or MRS and BI at 3 months No association with performance in daily living activities or
protease haemorrhagic stroke degree of disability or dependence
196G→A and 270C→T61 Brain-derived growth 498 patients with ischaemic and BI and OHS at 1 month No association with performance in daily living activities or
factor 56 with haemorrhagic stroke degree of disability or dependence
196G→A and 270C→T61 Brain-derived growth 287 patients with ischaemic and BI and RS before and after Effect of 196 GA+AA genotypes on rehabilitation apparent only
factor 51 with haemorrhagic stroke rehabilitation in those aged ≤55 years and women
Val158Met62 Catechol-O- 78 patients with ischaemic stroke BI and RMA at the beginning and Val/Val alleles associated with improved motor functions and
methyltransferase after 4 weeks and 6 months of ability to do activities of daily living
rehabilitation

TNF=tumour necrosis factor. PSE=post-stroke epilepsy. BI=Barthel index. MRS=modified Rankin scale. VNTR=variable number tandem repeat. SSS=Scandinavian stroke scale. OHS=Oxford handicap scale.
IL1RN=interleukin 1 receptor antagonist. SNP=single nucleotide polymorphism. MBL=mannose-binding lectin. RS=Rankin score. RMA=Rivermead motor assessment.

Table 2: Polymorphisms associated with outcome after ischaemic stroke

www.thelancet.com/neurology Published online November 16, 2015 http://dx.doi.org/10.1016/S1474-4422(15)00248-3 5

 Review

A B Depression
Exposure to Alzheimer’s disease
Postmenopausal cigarette smoke Post-stroke Substance use
hormone therapy Hypertension epileptogensis
Chil3/Chil4
Inflammation Physical inactivity COMT CSF1R
Depression FAM49A
Alzheimer’s disease CLU FAP
Dyslipidaemia Cancer
diabetes CD40
GSR Diabetes
Obesity Substance use HIVEP3
Dementia CAMKK2 Alzheimer’s disease
Diabetes Diabetes
Depression Depression BDNF Myocardial
IGF1
Sickle cell Myocardial infarct infarct
disease Dementia Hyperlipidaemia APP IL10 Cancer
Carotid artery Post-stroke
stenosis epileptogenesis
IL1RN
Poor diet Myocardial
Atrial infarct APOE
fibrillation IL4
APBA2 Diabetes
IL6 Alzheimer’s
Tmsb4x disease

ITM2B
TNFAIP8L2
LOC728392
Diabetes TNF
MRC1
Cytokine or Transcription regulator TLR7
Kinase MT-ND4
growth factor
SOD1
Transmembrane SLC40A1 Mt1
Other Transporter
receptor SLC11A2
NCDN
SCG5 NFATC4
Ion channel Enzyme RYR3
Peptidase

Post-stroke epileptogenesis Diabetes, Alzheimer’s disease

ALDH2 MBL2

Figure 2: Post-stroke epilepsy and comorbidity interactome

(A) Post-stroke epilepsy is associated with several comorbidities that can precede or be caused by ischaemic stroke (comorbidities according to Goldstein and colleagues64). (B) Functional in-silico
analysis of genes investigated to assess the association of polymorphisms with various outcome measures after ischaemic stroke suggests a substantial number of interactions. Polymorphisms in
aldehyde dehydrogenase 2 and CD40 genes are associated with post-stroke epileptogenesis. Polymorphisms in several other genes are associated with stroke outcomes such as death, ischaemic stroke
recurrence, performance of daily living activities, and disability or dependence. Notably, functional in-silico analysis suggests that many of the investigated genes are associated with the
pathophysiology of comorbidities of post-stroke epilepsy shown in panel A. Amyloid precursor protein is a particularly prominent node for interactions. Red colour indicates the genes in which a
polymorphism affected the outcome. Solid lines indicate direct interactions between proteins encoded by the genes. Dashed lines indicate indirect interactions between proteins encoded by the genes.
Different shapes represent functions of gene products. Gene interactions were analysed using Ingenuity Pathway Analysis software (Qiagen, Venlo, Netherlands) with default settings.

transient medial cerebral artery occlusion, cortical
application of endothelin-1, and hypoxia–ischaemia
models of stroke (table 4). In accordance with human
studies, PSE in rodents can be most successfully produced
by ischaemic lesions involving the cerebral cortex. As
summarised in table 4, post-stroke epileptogenesis seems
to depend more on the type of stroke induction than the
age of the animal at the time of stroke.
Cellular changes associated with epileptogenesis,
such as neurodegeneration, axonal and synaptic
sprouting, neurogenesis, gliogenesis, blood–brain
barrier damage, and inflammatory response, have been
extensively investigated after experimental ischaemic
stroke.104,105 However, very few of these changes have
been linked to increased excitability or epileptogenesis.
Cellular changes in the hippocampus, such as hilar cell
loss or mossy fibre sprouting, do not differentiate
animals with or without epilepsy after photothrombotic
stroke,94 and neither does the amount of iron deposits in
the perilesional cortex, thalamus, or corpus callosum.94
Two studies92,106 reported changes in inhibitory networks
in the perilesional cortex, including changes in the
staining intensity of neuropeptide Y neurons and
GABAA receptor subunits (α1, β1, and γ2S). However,
the contribution of these molecular changes to post-
stroke epileptogenesis remains uncertain. A study by
Paz and colleagues95 suggested that epileptiform activity
caused by photothrombotic stroke in the S1 cortex
can be controlled by optogenetic stimulation of the
thalamocortical pathways.
Human PSE
A CT study by Awada and colleagues107 suggested the
existence of viable islands of spared tissue within the
cortical infarct region associated with PSE. Accordingly, a
PET study47 reported that seizures originate from regions
that are only partly destroyed, with borderline critically
decreased cerebral regional blood flow, a low regional

6 www.thelancet.com/neurology Published online November 16, 2015 http://dx.doi.org/10.1016/S1474-4422(15)00248-3

 Review

cerebral metabolic rate for oxygen, and no changes in the

Association with
regional oxygen extraction fraction. These observations post-stroke
are interesting in view of a study published in 2015108 epileptogenesis
suggesting that patchy microlesions could be indicative Life-style factors
of epileptogenic areas. Smoking10,66 No
On the basis of epidemiological studies, haemorrhagic Alcohol use*10,23,35,66 Yes/no
stroke seems to be more epileptogenic than ischaemic Acute metabolic disturbances
stroke, with about 10–20% of patients developing PSE Acid–base imbalance66 No
after haemorrhagic stroke compared with 2–14% after Electrolyte imbalance35,66 No
ischaemic stroke;7,20,32 however, this difference was not
Hyperglycaemia*23,35 Yes
confirmed by a meta-analysis published in 2014.10
Non-CNS morbidities
Haemorrhagic transformation of ischaemic stroke is an
Diabetes 1 or 2*11,35,66 Yes/no
independent risk factor for both acute symptomatic
Dyslipidaemia66 No
seizures and epileptogenesis.23,109 The epileptogenic
Renal insufficiency35,66 No
potential of haemorrhagic transformation might also
Hypertension35,66,67,68 Yes/no
relate to the associated blood–brain barrier disruption.110,111
Coronary heart disease or myocardial infarction*11,35,66 Yes/no
Experimental studies provide convincing evidence that
Peripheral infections*23,66 Yes/no
increased blood–brain barrier permeability makes the
CNS morbidities
brain prone to seizures.112,113 Gilad and colleagues114
Early seizures*21,23,33,69 Yes
reported a prospective study of 28 patients aged
Status epilepticus within 2 weeks post stroke70 No
38–90 years with cortical stroke who developed PSE, and
imaged them about 1 year after the index stroke with Depression or use of antidepressants*23,66 Yes

⁹⁹mTc-diethylene triamine penta-acetic acid SPECT. Dementia71 Yes

Imaging was done within 72 h after the last seizure. In Pharmacotherapy

86% of patients with PSE, the blood–brain barrier was
disrupted in the known cortical stroke region. This study
also included a historic control group of patients with
stroke without seizures; of these, only 29% had blood–
brain barrier disruption in the cortical stroke region.
Importantly, the study114 reported no difference between
groups with and without PSE for the latency between
stroke and imaging, or for stroke localisation and size.
Perilesional EEG findings do not differ between patients
with and without blood–brain barrier damage,114 and the
reason that seizures do not occur in all patients with
blood–brain barrier damage remains unknown.
Hippocampal sclerosis is a pathological hallmark of
different types of acquired epilepsies, which presents
either as a primary or dual pathology.115 A histological
assessment of hippocampal infarcts revealed that
150 (12%) of 1245 patients who had been autopsied had
hippocampal infarcts; however, after exclusion of cases
with co-existing extrahippocampal pathologies, the
number of patients with hippocampal infarcts who had
epilepsy (5 [4%] of 116) did not differ from those without
hippocampal infarcts (5 [5%] of 96).116 So far, no studies
have specifically assessed hippocampal changes in adult
PSE. Some studies suggest the existence of a critical
time window for the development of hippocampal
sclerosis after childhood cortical infarction,117,118 but the
contribution of hippocampal changes to childhood PSE
remains to be explored.
Post-injury molecular pathology
Molecular analysis of the outcomes of stroke in man is
challenging because of the many patient-related
variables—such as injury subtype, brain areas affected,
Antiepileptic drugs72 No
α1-noradrenergic blockers72 No
α2-noradrenergic agonists72 No
benzodiazepines72 No
α2δ voltage-sensitive calcium-channel blockers72 No
Statins*73 Yes
*Because data derived from ischaemic stroke only are meagre, cohorts reported in
studies shown also include other stroke types.
Table 3: Peri-injury exposome and risk of epileptogenesis after cerebral
stroke
timepoint of sampling, occurrence of seizures and status
epilepticus, and the exposome (particularly drug
treatment)—and the difficulty obtaining representative
control samples. Transcriptomic profiling in animal
models of stroke provides an unbiased insight into
ongoing molecular pathologies that could be exploited
for clinical benefit—eg, for optimisation of treatment of
comorbidities such as status epilepticus—according to
target expression.
Most available data on transcriptome profiling in
animal models of ischaemic stroke describe alterations
in gene expression during the acute phase—ie, within
24 h of stroke. This is the time window when most of
the seizures and status epilepticus occur clinically, and
the patient is being actively treated. Only a few
experimental datasets cover a longer post-stroke time
period that would allow for the assessment of the
temporal sequence of post-stroke molecular
pathologies. Lu and colleagues119 investigated time-
specific alterations in gene expression patterns in the
injured hemisphere after transient middle cerebral

www.thelancet.com/neurology Published online November 16, 2015 http://dx.doi.org/10.1016/S1474-4422(15)00248-3 7

 Review

Age Lesion Age at the end Percentage Seizure frequency Seizure

of follow-up with epilepsy duration
Photothrombosis91 2–30 months Motor cortex, S1 4–8 months 50–75% Multiple 10–90 s
Photothrombosis92 “Young adult” S1 4 months 100% Daily recurrent About 10 s
Photothrombosis93 2 months Sensorimotor cortex 6 months 50% 1/4·6 h 2–3 s
Photothrombosis94 3 months S1 10 months 19% 0·39/day 117 s
Photothrombosis95 P25–30 S1 11 months 60% ·· 10–120 s
Photothrombosis96 P7 Sensorimotor cortex P12, P25 ·· At P25 seizure ··
susceptibility to
pentylenetetrazol
increases
Transient MCAO97 3 months Cortex 12 months 0% NA NA
Transient MCAO98 2·5 months Cortex 6 months 0% NA NA
Transient MCAO99 4 months Cortex 6 months 0% NA NA
Transient MCAO99 20 months Cortex 22 months 100% 1–2/week 6 s to 1 min
Endothelin-1100 8–9 months Cortex, striatum 12 months 3% 0·21/day 78–174 s
Endothelin-1101 P12 Hippocampus 3 months 71% 2·3/24 h 6–18 s
Endothelin-1101 P25 Hippocampus 3 months 92% 1·8/24 h 5–9 s
Unilateral carotid ligation P7 Ipsilateral hemisphere 2–12 months 100% 0·09–0·96/24 h 10–240 s
with hypoxia102
Global hypoxia103 P10 Mossy fibre sprouting in P175 95% 5·8/h 3–37 s
CA3

S1=primary somatosensory cortex. P=postnatal day. MCAO=medial cerebral artery occlusion. NA=not applicable.

Table 4: Epilepsy phenotype in animal models of ischaemic stroke or hypoxia-ischaemia based on in-vivo EEG recordings

artery occlusion in rats. The data revealed clear dynamic
and coordinated post-stroke transcriptional changes.
For example, transcription factors and heat-shock
proteins were already upregulated at 30 min post
stroke. Upregulation of genes mediating inflammation,
cell death, cytoskeletal functions, and metabolism was
evident at 1 day post stroke. Increased expression of
heat-shock proteins and neurotrophic growth factors
persisted until 7 days post stroke. Downregulation of
ion channels and receptors began at 1 day post stroke,
but some genes remained suppressed for up to 7 days.
Importantly, differentially expressed genes have a
limited overlap at more than one timepoint.119 This
finding was confirmed in a permanent middle cerebral
artery occlusion model in rats, as largely different sets
of genes were upregulated or downregulated at 1 day
and 3 days post stroke.120 Ramos-Cejudo and colleagues120
added another level of complexity by showing
differential alterations in gene expression between the
lesion core and peri-infarct area. These data suggest
that molecular mechanisms induced by ischaemic
stroke have specific spatiotemporal dynamics, starting
with pronounced changes in the regulation of
transcription and culminating in an immune response
and neuronal plasticity.
The regulation mechanisms of mRNA expression after
stroke are not well described. In the past decade studies
have revealed the epigenetic mechanisms involved in the
regulation of post-stroke gene expression, including that
of miRNAs (short non-coding RNAs involved in mRNA
silencing and degradation). Only a few profiling studies
have described miRNA expression at timepoints later
than 1 day after stroke. Gubern and colleagues121 reported
changes in several miRNAs in the cortical ischaemic
tissue at 7 days and 14 days after middle cerebral artery
occlusion, suggesting that regulated miRNAs participate
in brain damage, neuroprotection, synaptic plasticity,
regulation of neuronal excitability, or glial scar formation.
As with mRNA, alterations in miRNA expression are
dynamic after injury.121
Taken together, the findings suggest some similarities
between changes in gene expression after stroke and
those after other brain injuries that trigger
epileptogenesis, especially the dynamic nature of the
alterations and the functional characteristics of genes
whose expression level changes at different timepoints.4,122
Because analyses were done at early post-stroke
timepoints, whether some of the animals developed
epilepsy and whether the molecular changes in those
animals differed from those in non-epileptogenic
animals are unknown. Additionally, many of the studies
were done in models of ischaemic stroke that have not
been shown to result in PSE (adult rats with medial
cerebral artery stroke). Even with these caveats, these
data have implications for the design of treatment
strategies for stroke and its acute manifestations
(eg, seizures and status epilepticus) and chronic
comorbidities (eg, memory impairment) since the given
drug, applied at different post-injury timepoints,
encounters a totally different molecular landscape (target
expression), and therefore the treatment effects might
vary accordingly (figure 3).

8 www.thelancet.com/neurology Published online November 16, 2015 http://dx.doi.org/10.1016/S1474-4422(15)00248-3


Outstanding questions and future directions
In the past decade, approaches to elucidate the
mechanisms of epileptogenesis have focused on
revealing cause-specific mechanisms.4,126 Despite detailed
cellular analyses of the infarcted cortex in experimental
models, almost no attempts have been made to link
the penumbral cellular reorganisation or molecular
pathology with the development of epileptogenic foci,
even though the limited number of clinical studies point
to the cortex as an epileptogenic area.94,104–106 To identify
the endophenotypes with the highest risk of epilepto-
genesis, improved accuracy of the documentation of the
injury itself and patient-related factors, including
genetics, is needed. In view of the interplay between the
periphery and the CNS, detailed exploration of the effect
of the peri-injury exposome on post-stroke epilepto-
genesis is needed, both in experimental and clinical
studies. Achieving statistical power in endophenotyping
studies will require detailed and accurate data collection
and documentation, often from multiple study sites.
Common data elements have been used in clinics for
many years, and preclinical researchers have recently
taken initiatives to develop common data elements for
harmonising data collection.127
The inherent difficulty in the molecular analysis of
epileptogenesis in human beings is the availability and
sampling of tissue, since the available epileptogenic brain
tissue typically originates from patients who are drug-
refractory and undergoing epilepsy surgery. Additionally,
high-quality control tissue from the corresponding brain
region that has not been affected pathologically is not
available. Sampling of representative tissue from well
characterised relevant animal models of PSE is therefore
indispensable. Another challenge is the dilution of
molecular changes in the epileptogenic microcircuitry by
changes in the surrounding non-epileptogenic tissue.
A combination of electrophysiological methods, such as
high-density EEG arrays accompanied by in-vivo imaging,
will allow for more accurate in-vivo characterisation of
epileptogenic regions, increasing the accuracy of
sampling of epileptogenic changes. New approaches to
the sampling and analysis of molecular changes in
epileptogenic microcircuitries, even in human beings,
were recently presented.108
Another question is the extent to which refinement of
animal models is needed. At present, most studies on the
mechanisms of epileptogenesis or proof-of-concept trials
testing novel antiepileptic drugs are done in status
epilepticus models, in which epilepsy develops in almost
all animals within a period of days to weeks, and seizure
frequency is several per day. These status epilepticus
models are remarkably advantageous compared with
PSE rodent models, in which typically only a few animals
develop epilepsy during the course of weeks to months,
and seizure frequency is low. Although the use of status
epilepticus models is time efficient and cost efficient,
notably, in man, status epilepticus is often associated
www.thelancet.com/neurology Published online November 16, 2015 http://dx.doi.org/10.1016/S1474-4422(15)00248-3
Review
with brain injury such as stroke. Moreover, the highest
risk of epileptogenesis after status epilepticus is in
patients with acute symptomatic status epilepticus.80
Afsar and colleagues128 studied the timing of status
epilepticus in patients with stroke and reported that 5 of
30 episodes of status epilepticus occurred at stroke onset,
15 of 30 within 2 weeks, and 10 of 30 after 2 weeks from
the index stroke. Whether investigators should induce
status epilepticus in a clinically relevant context (ie, after
stroke taking into account the timing of status epilepticus
after stroke) remains to be discussed. In view of data on
the occurrence of PSE after ischaemic stroke at any age,
use of animals with different ages seems relevant in
preclinical research. Additionally, assessment of the
effect of genetic modulators or variable exposomes (eg,
early seizures, status epilepticus, treatments, and
nutrition) should be systematically assessed (figure 3).
About 30 preclinical proof-of-concept pharmacological
studies have provided favourable antiepileptogenesis
Ischaemic
stroke
Seizure focus
Change in brain metabolism, structure, and connectivity
Injury-induced temporally
Contributing factors orchestrated changes in transcriptomics
Chronic exposome
Diabetes
Coronary heart disease
Statins
Depression or use of
antidepressants
Temporary exposome
Alcohol use
Early seizures
Peripheral infections
Polymorphism
ALDH2
CD40
Acute Subacute Chronic
Pre-stroke Post-stroke 24 h 1 week 1 year
Epileptogenesis and development of comorbidities over time since index stroke
Figure 3: Evolution of epileptogenesis and the development of comorbidities after an index stroke and
contribution of genetic factors and the exposome
Components of the exposome deemed to have an effect on epileptogenesis after ischaemic stroke on the basis of
univariate or multivariate analyses are listed in table 4. Exposure to a given factor can precede, co-occur, or follow
the stroke. Additionally, the duration of exposures can vary and differ between patients. For example, on the one
hand, depression and the use of antidepressants might span over the entire peri-injury period (dotted line
expanding throughout the epileptogenic process). On the other hand, 40–98% of acute seizures occur within the
first 48 h post stroke,6,10,21,77,123,124 thus providing the opportunity for short-lasting (minutes) modulation of the
post-injury outcome (short dotted lines represent short-lasting duration). 75% of peripheral infections occur
within the first 3 days post stroke, which can also have a temporary acute-phase modulatory effect on the
outcome.125 Because the exposome varies largely between individuals, its accurate description during data
collection is crucial to reveal the contribution of different factors to the outcome. Moreover, ischaemic stroke
triggers temporally orchestrated waves of molecular changes that can be modulated by the exposome.
Consequently, depending on the timing of administration in a given patient, treatments encounter different
molecular environments within the recipients, which can affect the target expression, and consequently, treatment
effectiveness (eg, treatment of status epilepticus in patients).
9
 Review
Search strategy and selection criteria
We searched all PubMed articles published up to Aug 1, 2015,
with the terms “cerebrovascular disease”, “cerebral stroke”,
“ischemic stroke”, “post-stroke epilepsy”, “epilepsy”, “seizure”,
“epileptogenesis”, “antiepileptogenesis”, and their
combinations. We included data from studies of adults and
children. For genetics, we used the search terms
“polymorphism and post-stroke epilepsy” and
“polymorphism and stroke and outcome”. For
transcriptomics in epileptogenesis, we used the search terms
“microarrays and epileptogenesis” and “transcriptome and
epileptogenesis”. For epigenetics, we used the search term
“epigenetic and epilepsy”. For preclinical treatment trials, we
searched only for studies in which therapy was initiated after
the epileptogenic insult. We also identified articles through
searches of the authors’ own article collections. We only
reviewed articles published in English.
data.129 However, none of these preclinical trials were done
in PSE models. Furthermore, no attempts have been made
to identify biomarkers for post-stroke epileptogenesis.
Even when the data become available, a major concern is
that the successful preclinical trials will not translate to the
clinic.130 To address this concern, the International League
Against Epilepsy and the American Epilepsy Society task
force for advancing preclinical methodology in epilepsy
research published recommendations in 2013 for doing
antiepileptogenesis studies aimed at overcoming the
challenges related to statistically powered assessment of
novel antiepileptogenesis therapies.1,127
Nevertheless, treatments tested in the clinic have not
been vigorously assessed in preclinical models.76 Criteria
for progressing from the laboratory to clinic have been
proposed,1 but the high cost of clinical studies without
available biomarkers to identify the most susceptible
individuals for epileptogenesis and to predict the therapy
response hinder antiepileptogenesis clinical studies.129,131
Attempts have been made to develop algorithms to
predict the risk of PSE after ischaemic or haemorrhagic
stroke on the basis of the clinical characteristics.132,133
Another possibility is that a successful clinical trial in
patients with ischaemic stroke with treatment developed
for an indication other than antiepileptogenesis could
provide a so-called positive control, allowing basic
scientists to verify whether any of the experimental
models predict favourable clinical data, possibly in a
multi-centre standardised setting. Unfortunately, clinical
trials in patients with stroke have not included epilepsy
as an outcome measure. The epilepsy field would be
greatly benefited if present studies searching for
therapies and biomarkers for functional outcomes of
stroke included epilepsy in their design.
Contributors
All authors contributed equally to the conception, design, scientific
literature search, and writing of this Review.
10 www.thelancet.com/neurology Published online November 16, 2015 http://dx.doi.org/10.1016/S1474-4422(15)00248-3
Declaration of interests
We declare no competing interests.
Acknowledgments
This study was supported by the Academy of Finland (AP), ERA-NET
NEURON: TBI Epilepsy (AP), FP7-HEALTH project 602102
(EPITARGET) (AP, KL), PMSE grant W19/7.PR/2014 (KL), and statutory
funds of the Nencki Institute (KL).
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