Development of epilepsy after ischaemic stroke

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, such as ischaemic stroke, only a subpopulation of patients develops epilepsy. Factors that contribute to the risk for epileptogenesis in a given individual generally remain unknown. Studies in the past decade on epilepsy in patients with ischaemic stroke suggest that, in addition to the primary ischaemic injury, existing difficult-to-detect microscale changes in blood vessels and white matter present as epileptogenic pathologies. Injury severity, location and type of pathological changes, genetic factors, and pre-injury and post-injury exposure to non-genetic factors (ie, the exposome) can divide patients with ischaemic stroke into different endophenotypes with a variable risk for epileptogenesis. These data provide guidance for animal modelling of post-stroke epilepsy, and for laboratory experiments to explore with increased specificity the molecular `mechanisms, biomarkers, and treatment targets of post-stroke epilepsy in different circumstances, with the aim of modifying epileptogenesis after ischaemic stroke in individual patients without compromising recovery.

Introduction In 2013, The Working Group of the International League Against Epilepsy revised the terminology related to the term epileptogenesis and provided recommendations for doing studies of antiepileptogenic treatments.1 Epileptogenesis refers to the development and extension of tissue capable of generating spontaneous seizures, resulting in the development of an epileptic disorder or progression after the disorder is established. Thus, the new definition takes into account evidence from preclinical studies showing that epileptogenic neurobiological processes can continue even after the appearance of spontaneous recurrent seizures.2 In addition to unprovoked seizures, epilepsy is often associated with cognitive and behavioural comorbidities that arise from the region of the epileptogenic network.3 Because the epileptogenic process seems to be largely dependent on the underlying cause of epilepsy, therapeutic approaches need to be tailored according to these causes.4 No antiepileptogenic treatments are available at present for patients at risk of epilepsy after brain injury, emphasising the need to understand causespecific mechanisms that can be targeted to combat epileptogenesis in individual patients. Cerebrovascular diseases underlie about 11% of all cases of epilepsy5 and are heterogeneous with various causes. Some cerebrovascular diseases are progressive, causing a spectrum of primary and secondary pathologies that can initiate the evolution of epileptogenic networks. Depending on the underlying cerebrovascular disease, 3% to 30% of patients who have had a stroke develop post-stroke epilepsy (PSE).6–10 In this Review, we discuss the present understanding of the epileptogenic process after cerebrovascular diseases, focusing on arterial ischaemic stroke. Ischaemic stroke is a common epileptogenic cause, accounting for up to 9% of incident cases of epilepsy.11 In adults, the most common causal categories of ischaemic stroke are large artery atherosclerosis, cardiogenic emboli, small vessel disease, and other, a diverse category that includes inflammatory disease, hypercoagulable states, and

arterial dissection.12 Ischaemic stroke can occur at any time during life, with the greatest risk being during the first week after birth.13 Study results14,15 have shown that although ischaemic stroke is more often associated with elderly adults, it is not uncommon in young adults (aged 16–49 years), with an incidence of ten to 11 per 100 000 people per year. The initiation and location of epileptogenesis after ischaemic stroke can be accurately defined, allowing the mechanisms of the acquired epileptogenesis to be assessed at different stages of the epileptogenic process. Development of novel diagnostic methods and instruments will allow stroke to be classified by subtype, cause, and confounding factors with improved accuracy and specificity, which will advance the accuracy of data collection and analysis. Most of the experimental data from studies of post-stroke epileptogenesis come from models of ischaemic stroke, which provide a scenario for the translation of preclinical data to the clinic. Interpretation of the available data on human poststroke epileptogenesis is subject to several caveats, including the definitions of so-called early and late seizures, which have been variable. The definitions are, however, crucial for data analysis and interpretation because the occurrence of a late seizure is required for diagnosis of PSE. An early seizure refers to a seizure occurring during the first week after stroke—ie, the time period during which seizures are regarded as acute symptomatic seizures that are not suggestive of an enduring predisposition of the brain to generate epileptic seizures.16,17 A late seizure occurs more than 1 week after the stroke.17 This definition is generally agreed to be arbitrary. Other caveats to the interpretation of clinical post-stroke epileptogenesis studies are listed in the panel and figure 1. Our aim is to describe new aspects emerging from research into clinical and experimental PSE, which we expect will affect experimental modelling, the development of diagnostics, and the discovery of biomarkers and treatment strategies for post-stroke epileptogenesis.

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

Lancet Neurol 2015 Published Online November 16, 2015 http://dx.doi.org/10.1016/ S1474-4422(15)00248-3 Department of Neurobiology, A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland (Prof A Pitkänen PhD); Department of Neurology, Hyvinkää Hospital, Hyvinkää, Finland (R Roivainen MD); and The Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, Poland (K Lukasiuk PhD) Correspondence to: Prof Asla Pitkänen, A. I. Virtanen Institute, University of Eastern Finland, PO Box 1627, FIN-70 211 Kuopio, Finland [email protected]

1

Review

A

B

C

D

Epidemiology and clinical course of PSE

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

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

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Review

Study type

Number of patients

Age group (mean age)

Patients with PSE at 1 year

Patients with PSE Length of follow-up at the end of (years) follow-up

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%

Lossius et al (2005)†22

Prospective

484

>60 years (76·2)

2·5%

3·1%

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%

··

··

5·5%

3 7–8

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 parietotemporal 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

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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

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 strokeunit study79 applying video-EEG monitoring, nonconvulsive 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 calciumchannel 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-pharmacological 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 symptomatic seizures after ischaemic stroke. The risk of acute seizures is not associated with haemorrhagic transformation 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, longterm 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

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Review

pharmacologically induced seizures and had less neurodegeneration 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

CD40-1 C/T49

CD40 molecule, TNF receptor superfamily member 5

410 patients with ischaemic stroke without epilepsy, 389 patients with PSE

PSE

Frequency of T allele higher in patients with PSE

Rs67150

Mitochondrial aldehyde dehydrogenase 2

240 patients with ischaemic stroke without epilepsy, 225 patients with PSE

PSE

Allele A associated with PSE

ε4 status51

Apolipoprotein E

189 patients with acute ischaemic stroke

BI and MRS at 1 and 3 months

No association with performance in daily living activities or degree of disability or dependence

ε4 status52

Apolipoprotein E

496 patients with ischaemic stroke

MRS within 1 year

No association with degree of disability or dependence

ε4 status53

Apolipoprotein E

657 patients with ischaemic stroke

MRS within 1 year

No association with degree of disability or dependence at 1 year; ε4 genotype is a positive predictor of death within 1 year in men

589C→T54

Interleukin 4

145 patients with ischaemic stroke, 145 controls

Disease relapses, deaths, and BI at 1, 3, and 6 months

589 T allele associated with total ischaemic stroke recurrences; no association with performance in daily living activities or death

589C→VT55

Interleukin 4

145 patients with ischaemic stroke

Disease relapses, deaths, and BI

No association with performance in daily living activities, death, or ischaemic stroke recurrences

308G→A55

TNFα

145 patients with ischaemic stroke

Disease relapses, deaths, and BI

GG genotype associated with reduced odds for impairment in daily living activities or death

174G→C55

Interleukin 6

145 patients with ischaemic stroke

Disease relapses, deaths, and BI

No association with performance in daily living activities, death, or ischaemic stroke recurrences

174G→C56

Interleukin 6

100 patients with ischaemic stroke, 120 controls

MRS and BI at 7 days, 3 and 6 months

GC genotype associated with impaired performance in daily living activities, degree of disability or dependence, and higher mortality

1082G→A54

Interleukin 10

145 patients with ischaemic stroke, 145 controls

Disease relapses, deaths, and BI at 1, 3, and 6 months

1082 GG genotype predicts early stroke progression and impaired performance in daily living activities

1082G→A55

Interleukin 10

145 patients with ischaemic stroke

Disease relapses, deaths, and BI

No association with performance in daily living activities, ischaemic stroke recurrences, or death

1188A→C55

Interleukin 12B

145 patients with ischaemic stroke

Disease relapses, deaths, and BI

No association with performance in daily living activities, ischaemic stroke recurrences, or death

VNTR in intron 257

Interleukin 1 receptor antagonist

391 patients with ischaemic stroke

SSS, BI, and OHS at 7 days, 1 and 3 months, 1 year

IL1RN*2 homozygocity associated with reduced impairment in 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 chemoattractant protein-1 stroke

OHS at 1 months

No association with degree of disability or dependence in daily living activities

12 SNPs59

Insulin-like growth factor 1 844 patients with ischaemic stroke

MRS at 3 and 24 months

rs7136446 allele associated with lower degree of disability or dependence in daily living activities at 24 months post stroke

SNPs in promoter MBL-low and MBL-sufficient allele variants60

MBL2

135 patients with ischaemic or haemorrhagic stroke

MRS and BI at 3 months

MBL-sufficient genotype associated with increased disability and dependence

SNP D105→G60

MBL-associated serine protease

135 patients with ischaemic or haemorrhagic stroke

MRS and BI at 3 months

No association with performance in daily living activities or degree of disability or dependence

196G→A and 270C→T61

Brain-derived growth factor

498 patients with ischaemic and 56 with haemorrhagic stroke

BI and OHS at 1 month

No association with performance in daily living activities or degree of disability or dependence

196G→A and 270C→T61

Brain-derived growth factor

287 patients with ischaemic and 51 with haemorrhagic stroke

BI and RS before and after rehabilitation

Effect of 196 GA+AA genotypes on rehabilitation apparent only in those aged ≤55 years and women

Val158Met62

Catechol-Omethyltransferase

78 patients with ischaemic stroke BI and RMA at the beginning and after 4 weeks and 6 months of rehabilitation

PSE

Other stroke outcomes

Val/Val alleles associated with improved motor functions and ability to do activities of daily living

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

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A

B Postmenopausal hormone therapy

Exposure to cigarette smoke Hypertension

Inflammation

Substance use

Diabetes

Depression Dementia

Atrial fibrillation

Chil3/Chil4 COMT CSF1R

Depression Alzheimer’s disease diabetes

Cancer

Obesity

Sickle cell disease Carotid artery stenosis Poor diet

Post-stroke epileptogensis

Physical inactivity

Dyslipidaemia

Depression Alzheimer’s disease Substance use

Dementia Diabetes Depression Myocardial infarct Hyperlipidaemia

Post-stroke epileptogenesis Myocardial infarct

FAM49A

CLU

FAP

CD40

GSR

HIVEP3

CAMKK2 BDNF

Diabetes Alzheimer’s disease Myocardial infarct Cancer

IGF1

APP

IL10

IL1RN APOE IL4 APBA2 IL6 Tmsb4x

Diabetes Alzheimer’s disease

ITM2B

TNFAIP8L2

LOC728392 Diabetes

TNF MRC1

Cytokine or growth factor Other

Transcription regulator

Kinase

Transmembrane receptor

Transporter

Enzyme

Peptidase

TLR7

MT-ND4 SOD1 SLC40A1 SLC11A2

Mt1 SCG5

Ion channel

NFATC4

NCDN

RYR3

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 6

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 poststroke 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

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Review

cerebral metabolic rate for oxygen, and no changes in the regional oxygen extraction fraction. These observations are interesting in view of a study published in 2015108 suggesting that patchy microlesions could be indicative of epileptogenic areas. On the basis of epidemiological studies, haemorrhagic stroke seems to be more epileptogenic than ischaemic stroke, with about 10–20% of patients developing PSE after haemorrhagic stroke compared with 2–14% after ischaemic stroke;7,20,32 however, this difference was not confirmed by a meta-analysis published in 2014.10 Haemorrhagic transformation of ischaemic stroke is an independent risk factor for both acute symptomatic seizures and epileptogenesis.23,109 The epileptogenic potential of haemorrhagic transformation might also relate to the associated blood–brain barrier disruption.110,111 Experimental studies provide convincing evidence that increased blood–brain barrier permeability makes the brain prone to seizures.112,113 Gilad and colleagues114 reported a prospective study of 28 patients aged 38–90 years with cortical stroke who developed PSE, and imaged them about 1 year after the index stroke with ⁹⁹mTc-diethylene triamine penta-acetic acid SPECT. Imaging was done within 72 h after the last seizure. In 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,

Association with post-stroke epileptogenesis Life-style factors Smoking10,66

No

Alcohol use*10,23,35,66

Yes/no

Acute metabolic disturbances Acid–base imbalance66

No

Electrolyte imbalance35,66

No

Hyperglycaemia*23,35

Yes

Non-CNS morbidities Diabetes 1 or 2*11,35,66

Yes/no

Dyslipidaemia66

No

Renal insufficiency35,66

No

Hypertension35,66,67,68

Yes/no

Coronary heart disease or myocardial infarction*11,35,66 Yes/no Peripheral infections*23,66

Yes/no

CNS morbidities Early seizures*21,23,33,69

Yes

Status epilepticus within 2 weeks post stroke70

No

Depression or use of antidepressants*23,66

Yes

Dementia71

Yes

Pharmacotherapy 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 timespecific alterations in gene expression patterns in the injured hemisphere after transient middle cerebral

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Age

Lesion

Age at the end of follow-up

Percentage with epilepsy

Seizure frequency Seizure 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 with hypoxia102

P7

Ipsilateral hemisphere

2–12 months

100%

0·09–0·96/24 h

10–240 s

Global hypoxia103

P10

Mossy fibre sprouting in CA3

P175

95%

5·8/h

3–37 s

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 8

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).

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Review

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 epileptogenesis, 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 epileptogenesis 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 drugrefractory 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

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

Contributing factors

Injury-induced temporally 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 Pre-stroke

Post-stroke

Subacute 24 h

Chronic 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).

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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

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). References 1 Pitkanen A, Nehlig A, Brooks-Kayal AR, et al. Issues related to development of antiepileptogenic therapies. Epilepsia 2013; 54 (suppl 4): 35–43. 2 Pitkänen A ST. Is epilepsy a progressive disease? Prospects for new therapeutic approaches in temporal lobe epilepsy. Lancet Neurol 2002; 1: 73–81. 3 Kanner AM, Mazarati A, Koepp M. Biomarkers of epileptogenesis: psychiatric comorbidities (?). Neurotherapeutics 2014; 11: 358–72. 4 Pitkanen A, Lukasiuk K. Mechanisms of epileptogenesis and potential treatment targets. Lancet Neurol 2011; 10: 173–86. 5 Hauser WA, Annegers JF, Kurland LT. Incidence of epilepsy and unprovoked seizures in Rochester, Minnesota: 1935–1984. Epilepsia 1993; 34: 453–68. 6 Bladin CF, Alexandrov AV, Bellavance A, et al. Seizures after stroke: a prospective multicenter study. Arch Neurol 2000; 57: 1617–22. 7 Menon B, Shorvon SD. Ischaemic stroke in adults and epilepsy. Epilepsy Res 2009; 87: 1–11. 8 Jungehulsing GJ, Heuschmann PU, Holtkamp M, Schwab S, Kolominsky-Rabas PL. Incidence and predictors of post-stroke epilepsy. Acta Neurol Scand 2013; 127: 427–30. 9 Graham NSN, Crichton S, Koutroumanidis M, Wolfe CD, Rudd AG. Incidence and associations of poststroke epilepsy the prospective South London stroke register. Stroke 2013; 44: 605–11. 10 Zhang C, Wang X, Wang Y, et al. Risk factors for post-stroke seizures: a systematic review and meta-analysis. Epilepsy Res 2014; 108: 1806–16. 11 Adelow C, Andersson T, Ahlbom A, Tomson T. Prior hospitalization for stroke, diabetes, myocardial infarction, and subsequent risk of unprovoked seizures. Epilepsia 2011; 52: 301–07. 12 Adams HP, Biller J. Classification of subtypes of ischemic stroke: history of the trial of org 10 172 in acute stroke treatment classification. Stroke 2015: 114–18. 13 Nelson KB. Is it HIE? And why that matters. Acta Paediatr 2007; 96: 1113–14. 14 Jacobs BS, Boden-Albala B, Lin I-F, Sacco RL. Stroke in the young in the northern Manhattan stroke study. Stroke 2002; 33: 2789–93. 15 Putaala J, Curtze S, Hiltunen S, Tolppanen H, Kaste M, Tatlisumak T. Causes of death and predictors of 5-year mortality in young adults after first-ever ischemic stroke: the Helsinki Young Stroke Registry. Stroke 2009; 40: 2698–703. 16 Teasdale G, Jennett B. Assessment of coma and impaired consciousness. A practical scale. Lancet 1974; 2: 81–84. 17 Beghi E, Carpio A, Forsgren L, et al. Recommendation for a definition of acute symptomatic seizure. Epilepsia 2010; 51: 671–75. 18 Feigin VL, Lawes CMM, Bennett DA, Barker-Collo SL, Parag V. Worldwide stroke incidence and early case fatality reported in 56 population-based studies: a systematic review. Lancet Neurol 2009; 8: 355–69. 19 So EL, Annegers JF, Hauser W, O’Brien PC, Whisnant JP. Population-based study of seizure disorders after cerebral infarction. Neurology 1996; 46: 350–55. 20 Burn J, Dennis M, Bamford J, Sandercock P, Wade D, Warlow C. Epileptic seizures after a first stroke: the Oxfordshire Community Stroke Project. BMJ 1997; 315: 1582–87. 21 Lamy C, Domigo V, Semah F, et al. Early and late seizures after cryptogenic ischemic stroke in young adults. Neurology 2003; 60: 400–04. 22 Lossius MI, Ronning OM, Slapo GD, Mowinckel P, Gjerstad L. Poststroke epilepsy: occurrence and predictors—a long-term prospective controlled study (Akershus Stroke Study). Epilepsia 2005; 46: 1246–51. 23 Roivainen R, Haapaniemi E, Putaala J, Kaste M, Tatlisumak T. Young adult ischaemic stroke related acute symptomatic and late seizures: risk factors. Eur J Neurol 2013; 20: 1247–55.

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

Review

24 25

26

27 28

29

30 31

32

33

34

35

36

37

38

39

40

41

42

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Lee J-C, Lin K-L, Wang H-S, et al. Seizures in childhood ischemic stroke in Taiwan. Brain Dev 2009; 31: 294–99. Hsu C-J, Weng W-C, Peng SS-F, Lee W-T. Early-onset seizures are correlated with late-onset seizures in children with arterial ischemic stroke. Stroke 2014; 45: 1161–63. Cloyd J, Hauser W, Towne A, et al. Epidemiological and medical aspects of epilepsy in the elderly. Epilepsy Res 2006; 68 (suppl 1): S39–48. Holmes GL, Milh MDM, Dulac O. Maturation of the human brain and epilepsy. Handb Clin Neurol 2012; 107: 135–43. De Reuck J, Goethals M, Claeys I, Van Maele G, De Clerck M. EEG findings after a cerebral territorial infarct in patients who develop early- and late-onset seizures. Eur Neurol 2006; 55: 209–13. Horner S, Ni XS, Duft M, Niederkorn K, Lechner H. EEG, CT and neurosonographic findings in patients with postischemic seizures. J Neurol Sci 1995; 132: 57–60. McBride AE, Shih TT, Hirsch LJ. Video-EEG monitoring in the elderly: a review of 94 patients. Epilepsia 2002; 43: 165–69. Jungehulsing GJ, Heuschmann PU, Holtkamp M, Schwab S, Kolominsky-Rabas PL. Incidence and predictors of post-stroke epilepsy. Acta Neurol Scand 2013; 127: 427–30. Arntz R, Rutten-Jacobs L, Maaijwee N, et al. Post-stroke epilepsy in young adults: a long-term follow-up study. PLoS One 2013; 8: e55498. Hsu C-J, Weng W-C, Peng SS-F, Lee W-T. Early-onset seizures are correlated with late-onset seizures in children with arterial ischemic stroke. Stroke 2014; 45: 1161–63. Heuts-van Raak L, Lodder J, Kessels F. Late seizures following a first symptomatic brain infarct are related to large infarcts involving the posterior area around the lateral sulcus. Seizure 1996; 5: 185–94. Leone MA, Tonini MC, Bogliun G, et al. Risk factors for a first epileptic seizure after stroke: A case control study. J Neurol Sci 2009; 277: 138–42. Benbir G, Ince B, Bozluolcay M. The epidemiology of post-stroke epilepsy according to stroke subtypes. Acta Neurol Scand 2006; 114: 8–12. Wardlaw JM, Smith EE, Biessels GJ, et al. Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration. Lancet Neurol 2013; 12: 822–38. Gasparini S, Ferlazzo E, Beghi E, et al. Epilepsy associated with Leukoaraiosis mainly affects temporal lobe: a casual or causal relationship? Epilepsy Res 2015; 109: 1–8. De Reuck JL. Evidence for chronic ischaemia in the pathogenesis of vascular dementia: from neuroPATH to neuroPET. Acta Neurol Belg 1996; 96: 228–31. De Reuck J, De Clerck M, Van Maele G. Vascular cognitive impairment in patients with late-onset seizures after an ischemic stroke. Clin Neurol Neurosurg 2006; 108: 632–37. Maxwell H, Hanby M, Parkes LM, Gibson LM, Coutinho C, Emsley HC. Prevalence and subtypes of radiological cerebrovascular disease in late-onset isolated seizures and epilepsy. Clin Neurol Neurosurg 2013; 115: 591–96. Giroud M, Gras P, Fayolle H, Andre N, Soichot P, Dumas R. Early seizures after acute stroke: a study of 1,640 cases. Epilepsia 1994; 35: 959–64. Chadehumbe MA, Khatri P, Khoury JC, et al. Seizures are common in the acute setting of childhood stroke: a population-based study. J Child Neurol 2009; 24: 9–12. Brigo F, Tezzon F, Nardone R. Late-onset seizures and risk of subsequent stroke: a systematic review. Epilepsy Behav 2014; 31: 9–12. Cocito L, Favale E, Reni L. The frequency, characteristics and prognosis of epileptic seizures at the onset of stroke. J Neurol Neurosurg Psychiatry 1989; 52: 292. Cleary P, Shorvon S, Tallis R. Late-onset seizures as a predictor of subsequent stroke. Lancet 2004; 363: 1184–86. De Reuck JL. Stroke-related seizures and epilepsy. Neurol Neurochir Pol 2007; 41: 144–49. Noebels J. Pathway-driven discovery of epilepsy genes. Nat Neurosci 2015; 18: 344–50. Zhang B, Chen M, Yang H, Wu T, Song C, Guo R. Evidence for involvement of the CD40/CD40L system in post-stroke epilepsy. Neurosci Lett 2014; 567: 6–10.

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65 66 67 68

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Yang H, Song Z, Yang G-P, et al. The ALDH2 rs671 polymorphism affects post-stroke epilepsy susceptibility and plasma 4-HNE levels. PLoS One 2014; 9: e109634. McCarron MO, Muir KW, Nicoll JA, et al. Prospective study of apolipoprotein E genotype and functional outcome following ischemic stroke. Arch Neurol 2000; 57: 1480–84. Sarzynska-Dlugosz I, Gromadzka G, Baranska-Gieruszczak M, Ciesielska A, Czlonkowska A. APOE does not predict poor outcome 1 year after ischemic stroke. Neurol Res 2007; 29: 64–69. Gromadzka G, Baranska-Gieruszczak M, Sarzynska-Dlugosz I, Ciesielska A, Czlonkowska A. The APOE polymorphism and 1-year outcome in ischemic stroke: genotype-gender interaction. Acta Neurol Scand 2007; 116: 392–98. Marousi S, Ellul J, Antonacopoulou A, Gogos C, Papathanasopoulos P, Karakantza M. Functional polymorphisms of interleukin 4 and interleukin 10 may predict evolution and functional outcome of an ischaemic stroke. Eur J Neurol 2011; 18: 637–43. Marousi S, Antonacopoulou A, Kalofonos H, Papathanasopoulos P, Karakantza M, Ellul J. Functional inflammatory genotypes in ischemic stroke: could we use them to predict age of onset and long-term outcome? Stroke Res Treat 2011; 2011: 792923. Chakraborty B, Chowdhury D, Vishnoi G, Goswami B, Kishore J, Agarwal S. Interleukin-6 gene -174 G/C promoter polymorphism predicts severity and outcome in acute ischemic stroke patients from north India. J Stroke Cerebrovasc Dis 2013; 22: 683–89. Gromadzka G, Sarzynska-Dlugosz I, Czlonkowska A. IL1RN intron 2 polymorphism caused by variable number tandem repeats is associated with 1-year outcome in patients with ischaemic stroke. J Neurol Neurosurg Psychiatry 2007; 78: 183–86. Giannakopoulou E, Ragia G, Marousi S, Ellul J, Manolopoulos VG, Tavridou A. Association of monocyte chemoattractant protein-1 -2518A>G polymorphism with occurrence, severity, and outcome in ischemic stroke. Neurol Sci Off J Ital Neurol Soc Ital Soc Clin Neurophysiol 2013; 34: 1315–20. Aberg ND, Olsson S, Aberg D, et al. Genetic variation at the IGF1 locus shows association with post-stroke outcome and to circulating IGF1. Eur J Endocrinol 2013; 169: 759–65. Cervera A, Planas AM, Justicia C, et al. Genetically-defined deficiency of mannose-binding lectin is associated with protection after experimental stroke in mice and outcome in human stroke. PLoS One 2010; 5: e8433. Mirowska-Guzel D, Gromadzka G, Czlonkowski A, Czlonkowska A. BDNF -270 C>T polymorphisms might be associated with stroke type and BDNF -196 G>A corresponds to early neurological deficit in hemorrhagic stroke. J Neuroimmunol 2012; 249: 71–75. Liepert J, Heller A, Behnisch G, Schoenfeld A. Catechol-O-methyltransferase polymorphism influences outcome after ischemic stroke: a prospective double-blind study. Neurorehabil Neural Repair 2013; 27: 491–96. Antoniades C, Bakogiannis C, Tousoulis D, Antonopoulos AS, Stefanadis C. The CD40/CD40 ligand system: linking inflammation with atherothrombosis. J Am Coll Cardiol 2009; 54: 669–77. Goldstein LB, Adams R, Alberts MJ, et al. Primary prevention of ischemic stroke: a guideline from the American Heart Association/ American Stroke Association Stroke Council: cosponsored by the Atherosclerotic Peripheral Vascular Disease Interdisciplinary Working Group; Cardiovascular Nursing Council; Clinical Cardiology Council; Nutrition, Physical Activity, and Metabolism Council; and the Quality of Care and Outcomes Research Interdisciplinary Working Group: the American Academy of Neurology affirms the value of this guideline. Stroke 2006; 37: 1583–633. Wild CP. The exposome: from concept to utility. Int J Epidemiol 2012; 41: 24–32. Wang G, Jia H, Chen C, et al. Analysis of risk factors for first seizure after stroke in Chinese patients. Biomed Res Int 2013; 2013: 702871. Ng SK, Hauser WA, Brust JC, Susser M. Hypertension and the risk of new-onset unprovoked seizures. Neurology 1993; 43: 425–28. Forsgren L, Bucht G, Eriksson S, Bergmark L. Incidence and clinical characterization of unprovoked seizures in adults: a prospective population-based study. Epilepsia 1996; 37: 224–29. Fox CK, Glass HC, Sidney S, Lowenstein DH, Fullerton HJ. Acute seizures predict epilepsy after childhood stroke. Ann Neurol 2013; 74: 249–56.

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Rumbach L, Sablot D, Berger E, Tatu L, Vuillier F, Moulin T. Status epilepticus in stroke: report on a hospital-based stroke cohort. Neurology 2000; 54: 350–54. Cordonnier C, Hénon H, Derambure P, Pasquier F, Leys D. Influence of pre-existing dementia on the risk of post-stroke epileptic seizures. J Neurol Neurosurg Psychiatry 2005; 76: 1649–53. Nadeau SE, Lu X, Dobkin B, Wu SS, Dai YE, Duncan PW. A prospective test of the late effects of potentially antineuroplastic drugs in a stroke rehabilitation study. Int J Stroke 2014; 9: 449–56. Guo J, Guo J, Li J, et al. Statin treatment reduces the risk of poststroke seizures. Neurology 2015; 85: 701–07. Szaflarski JP, Rackley AY, Kleindorfer DO, et al. Incidence of seizures in the acute phase of stroke: a population-based study. Epilepsia 2008; 49: 974–81. Temkin NR. Preventing and treating posttraumatic seizures: the human experience. Epilepsia 2009; 50 (suppl 2): 10–13. Trinka E, Brigo F. Antiepileptogenesis in humans: disappointing clinical evidence and ways to move forward. Curr Opin Neurol 2014; 27: 227–35. Labovitz DL, Hauser WA, Sacco RL. Prevalence and predictors of early seizure and status epilepticus after first stroke. Neurology 2001; 57: 200–06. Bateman BT, Claassen J, Willey JZ, et al. Convulsive status epilepticus after ischemic stroke and intracerebral hemorrhage: frequency, predictors, and impact on outcome in a large administrative dataset. Neurocrit Care 2007; 7: 187–93. Belcastro V, Vidale S, Gorgone G, et al. Non-convulsive status epilepticus after ischemic stroke: a hospital-based stroke cohort study. J Neurol 2014; 261: 2136–42. Hesdorffer DC, Logroscino G, Cascino G, Annegers JF, Hauser WA. Risk of unprovoked seizure after acute symptomatic seizure: effect of status epilepticus. Ann Neurol 1998; 44: 908–12. Pitkanen A, Kharatishvili I, Karhunen H, et al. Epileptogenesis in experimental models. Epilepsia 2007; 48 (suppl 2): 13–20. Conrad J, Pawlowski M, Dogan M, Kovac S, Ritter MA, Evers S. Seizures after cerebrovascular events: risk factors and clinical features. Seizure 2013; 22: 275–82. Goldstein LB. Common drugs may influence motor recovery after stroke. The Sygen In Acute Stroke Study Investigators. Neurology 1995; 45: 865–71. De Reuck J, Van Maele G. Acute ischemic stroke treatment and the occurrence of seizures. Clin Neurol Neurosurg 2010; 112: 328–31. Alvarez V, Rossetti AO, Papavasileiou V, Michel P. Acute seizures in acute ischemic stroke: does thrombolysis have a role to play? J Neurol 2013; 260: 55–61. Schmitz ML, Simonsen CZ, Hundborg H, et al. Acute ischemic stroke and long-term outcome after thrombolysis: nationwide propensity score-matched follow-up study. Stroke 2014; 45: 3070–72. Machado C, Pinho J, Alves JN, et al. Five-Year Outcome in Stroke Patients Submitted to Thrombolysis. Stroke 2015; 46: 2312–14. Couillard P, Almekhlafi MA, Irvine A, et al. Subacute seizure incidence in thrombolysis-treated ischemic stroke patients. Neurocrit Care 2012; 16: 241–45. Gensicke H, Seiffge DJ, Polasek AE, et al. Long-term outcome in stroke patients treated with IV thrombolysis. Neurology 2013; 80: 919–25. Tsirka SE, Gualandris A, Amaral DG, Strickland S. Excitotoxin-induced neuronal degeneration and seizure are mediated by tissue plasminogen activator. Nature 1995; 377: 340–44. Kelly KM, Kharlamov A, Hentosz TM, et al. Photothrombotic brain infarction results in seizure activity in aging Fischer 344 and Sprague Dawley rats. Epilepsy Res 2001; 47: 189–203. Liu J, Schmitt KL, Kharlamov EA, Stolarski CJ, Grayson DR, Kelly KM. Quantitative reverse transcription-polymerase chain reaction of GABA(A) alpha1, beta1 and gamma2S subunits in epileptic rats following photothrombotic infarction of neocortex. Epilepsy Res 2002; 52: 85–95. Kharlamov EA, Jukkola PI, Schmitt KL, Kelly KM. Electrobehavioral characteristics of epileptic rats following photothrombotic brain infarction. Epilepsy Res 2003; 56: 185–203. Karhunen H, Bezvenyuk Z, Nissinen J, Sivenius J, Jolkkonen J, Pitkänen A. Epileptogenesis after cortical photothrombotic brain lesion in rats. Neuroscience 2007; 148: 314–24.

95

96

97

98

99 100

101

102

103

104 105

106

107 108

109

110

111

112

113

114

115

116 117

Paz JT, Davidson TJ, Frechette ES, et al. Closed-loop optogenetic control of thalamus as a tool for interrupting seizures after cortical injury. Nat Neurosci 2013; 16: 64–70. Brima T, Otáhal J, Mareš P. Increased susceptibility to pentetrazol-induced seizures in developing rats after cortical photothrombotic ischemic stroke at P7. Brain Res 2013; 1507: 146–53. Karhunen H, Pitkänen A, Virtanen T, et al. Long-term functional consequences of transient occlusion of the middle cerebral artery in rats: a 1-year follow-up of the development of epileptogenesis and memory impairment in relation to sensorimotor deficits. Epilepsy Res 2003; 54: 1–10. Kelly KM, Jukkola PI, Kharlamov E a, et al. Long-term video-EEG recordings following transient unilateral middle cerebral and common carotid artery occlusion in Long-Evans rats. Exp Neurol 2006; 201: 495–506. Kelly KM. Stroke. In: Pitkänen A, Schwarzkroin PA, Moshe SL, eds. Models of seizures and epilepsy. Amsterdam: Elsevier, 2006: 501–19. Karhunen H, Nissinen J, Sivenius J, Jolkkonen J, Pitkänen A. A long-term video-EEG and behavioral follow-up after endothelin-1 induced middle cerebral artery occlusion in rats. Epilepsy Res 2006; 72: 25–38. Mátéffyová A, Otáhal J, Tsenov G, Mareš P, Kubová H. Intrahippocampal injection of endothelin-1 in immature rats results in neuronal death, development of epilepsy and behavioral abnormalities later in life. Eur J Neurosci 2006; 24: 351–60. Kadam SD, White AM, Staley KJ, Dudek FE. Continuous electroencephalographic monitoring with radio-telemetry in a rat model of perinatal hypoxia-ischemia reveals progressive post-stroke epilepsy. J Neurosci 2010; 30: 404–15. Rakhade SN, Klein PM, Huynh T, et al. Development of later life spontaneous seizures in a rodent model of hypoxia-induced neonatal seizures. Epilepsia 2011; 52: 753–65. Carmichael ST. Cellular and molecular mechanisms of neural repair after stroke: making waves. Ann Neurol 2006; 59: 735–42. Li S, Overman JJ, Katsman D, et al. An age-related sprouting transcriptome provides molecular control of axonal sprouting after stroke. Nat Neurosci 2010; 13: 1496–504. Kharlamov EA, Kharlamov A, Kelly KM. Changes in neuropeptide Y protein expression following photothrombotic brain infarction and epileptogenesis. Brain Res 2007; 1127: 151–62. Awada A, Omojola MF, Obeid T. Late epileptic seizures after cerebral infarction. Acta Neurol Scand 1999; 99: 265–68. Dachet F, Bagla S, Keren-Aviram G, et al. Predicting novel histopathological microlesions in human epileptic brain through transcriptional clustering. Brain 2015; 138: 356–70. Alberti A, Paciaroni M, Caso V, Venti M, Palmerini F, Agnelli G. Early seizures in patients with acute stroke: frequency, predictive factors, and effect on clinical outcome. Vasc Health Risk Manag 2008; 4: 715–20. Renu A, Amaro S, Laredo C, et al. Relevance of blood–brain barrier disruption after endovascular treatment of ischemic stroke: dual-energy computed tomographic study. Stroke 2015; 46: 673–79. Raabe A, Schmitz AK, Pernhorst K, et al. Cliniconeuropathologic correlations show astroglial albumin storage as a common factor in epileptogenic vascular lesions. Epilepsia 2012; 53: 539–48. Marchi N, Granata T, Ghosh C, Janigro D. Blood-brain barrier dysfunction and epilepsy: pathophysiologic role and therapeutic approaches. Epilepsia 2012; 53: 1877–86. Van Vliet EA, Aronica E, Gorter JA. Blood–brain barrier dysfunction, seizures and epilepsy. Semin Cell Dev Biol 2015; 38: 26–34. Gilad R, Lampl Y, Eilam A, Boaz M, Loyberboim M. SPECT-DTPA as a tool for evaluating the blood–brain barrier in post-stroke seizures. J Neurol 2012; 259: 2041–44. Blumcke I, Coras R, Miyata H, Ozkara C. Defining cliniconeuropathological subtypes of mesial temporal lobe epilepsy with hippocampal sclerosis. Brain Pathol 2012; 22: 402–11. Rauramaa T, Pikkarainen M, Englund E, et al. Cardiovascular diseases and hippocampal infarcts. Hippocampus 2011; 21: 281–87. Squier W, Salisbury H, Sisodiya S. Stroke in the developing brain and intractable epilepsy: effect of timing on hippocampal sclerosis. Dev Med Child Neurol 2003; 45: 580–85.

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Review

118 Salanova V, Markand O, Worth R. Temporal lobe epilepsy: analysis of patients with dual pathology. Acta Neurol Scand 2004; 109: 126–31. 119 Lu X-CM, Williams AJ, Yao C, et al. Microarray analysis of acute and delayed gene expression profile in rats after focal ischemic brain injury and reperfusion. J Neurosci Res 2004; 77: 843–57. 120 Ramos-Cejudo J, Gutierrez-Fernandez M, Rodriguez-Frutos B, et al. Spatial and temporal gene expression differences in core and periinfarct areas in experimental stroke: a microarray analysis. PLoS One 2012; 7: e52121. 121 Gubern C, Camos S, Ballesteros I, et al. miRNA expression is modulated over time after focal ischaemia: up-regulation of miR-347 promotes neuronal apoptosis. FEBS J 2013; 280: 6233–46. 122 Lukasiuk K, Dabrowski M, Adach A, Pitkanen A. Epileptogenesis-related genes revisited. Prog Brain Res 2006; 158: 223–41. 123 Olsen TS. Post-stroke epilepsy. Curr Atheroscler Rep 2001; 3: 340–44. 124 Reith J, Jorgensen HS, Nakayama H, Raaschou HO, Olsen TS. Seizures in acute stroke: predictors and prognostic significance. The Copenhagen Stroke Study. Stroke 1997; 28: 1585–89. 125 Vargas M, Horcajada JP, Obach V, et al. Clinical consequences of infection in patients with acute stroke: is it prime time for further antibiotic trials? Stroke 2006; 37: 461–65. 126 Stables JP, Bertram E, Dudek FE, et al. Therapy discovery for pharmacoresistant epilepsy and for disease-modifying therapeutics: summary of the NIH/NINDS/AES models II workshop. Epilepsia 2003; 44: 1472–78.

127 Galanopoulou AS, Kokaia M, Loeb JA, et al. Epilepsy therapy development: technical and methodologic issues in studies with animal models. Epilepsia 2013; 54 (suppl 4): 13–23. 128 Afsar N, Kaya D, Aktan S, Sykut-Bingol C. Stroke and status epilepticus: stroke type, type of status epilepticus, and prognosis. Seizure 2003; 12: 23–27. 129 Pitkanen A, Engel JJ. Past and present definitions of epileptogenesis and its biomarkers. Neurotherapeutics 2014; 11: 231–41. 130 Green AR. Pharmacological approaches to acute ischaemic stroke: reperfusion certainly, neuroprotection possibly. Br J Pharmacol 2008; 153 (suppl): S325–38. 131 Engel JJ, Pitkanen A, Loeb JA, et al. Epilepsy biomarkers. Epilepsia 2013; 54 (suppl 4): 61–69. 132 Strzelczyk A, Haag A, Raupach H, Herrendorf G, Hamer HM, Rosenow F. Prospective evaluation of a post-stroke epilepsy risk scale. J Neurol 2010; 257: 1322–26. 133 Haapaniemi E, Strbian D, Rossi C, et al. The CAVE score for predicting late seizures after intracerebral hemorrhage. Stroke 2014; 45: 1971–76.

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