Neurochemistry International 107 (2017) 219e228

Contents lists available at ScienceDirect

Neurochemistry International
journal homepage: www.elsevier.com/locate/nci

Post-stroke epilepsy
Tomotaka Tanaka*, Masafumi Ihara*
Department of Neurology, National Cerebral and Cardiovascular Center, Osaka, Japan

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

Article history: Post-stroke epilepsy (PSE) is a common complication after stroke, yet treatment options remain limited.
Received 26 September 2016 While many physicians prescribe antiepileptic drugs (AED) for secondary prevention of PSE, it is unclear
Received in revised form which treatments are most effective in the prevention of recurrence of symptoms, or whether such
5 February 2017
therapy is needed for primary prevention. This review discusses the current understanding of epide-
Accepted 6 February 2017
miology, diagnoses, mechanisms, risk factors, and treatments of PSE.
Available online 12 February 2017
© 2017 Elsevier Ltd. All rights reserved.
Keywords:
Post stroke epilepsy
Post stroke seizure
Early seizure
Late seizure
Blood brain barrier
Epileptogenesis

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 219
2. Prevalence of early and late seizure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220
3. New definition and diagnosis of PSE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220
4. Risk factors of PSE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220
5. Mechanism of PSE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 221
5.1. Loss of neurovascular unit integrity/BBB disruption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 222
5.2. Increased release of neurotransmitters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 222
5.3. Ion channel dysfunction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 223
5.4. Alterations in gene expression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 223
6. Treatment of PSE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 223
6.1. Primary prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 224
6.2. Secondary prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 224
7. Perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 226
Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 226
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 226
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 226

1. Introduction

Advances in stroke treatment, including tissue plasminogen

activator and endovascular treatment in the acute phase, have
* Corresponding authors. Division of Neurology, Department of Stroke and Ce- resulted in a dramatic reduction in the mortality rate of stroke.
rebrovascular Diseases, National Cerebral and Cardiovascular Center, 5-7-1 Whilst encouraging, the number of stroke survivors living with
Fujishiro-dai, Suita, Osaka 565-8565, Japan.
disability worldwide has consequently increased. In Canada, the
E-mail address: tanakat@hsp.ncvc.go.jp (T. Tanaka).

http://dx.doi.org/10.1016/j.neuint.2017.02.002
0197-0186/© 2017 Elsevier Ltd. All rights reserved.
220 T. Tanaka, M. Ihara / Neurochemistry International 107 (2017) 219e228
number of stroke survivors living with disability is expected to
climb by 80% by 2038 (Krueger et al., 2015). Stroke survivors exhibit
a wide range of neurological, physical and psychological issues,
including: paralysis, muscle stiffness, dysphasia, dysarthria, lan-
guage difficulties, unilateral neglect, numbness and pain, fatigue,
cognitive impairment, depression, and difficulty controlling
emotions.
Post-stroke epilepsy (PSE) has been identified as a significant
clinical issue in stroke survivors. In a total of 34 longitudinal cohort
studies involving over 100,000 patients, the incidence rate of PSE
was approximately 7% (95%CI 0.05e0.09) (Zou et al., 2015). Like-
wise, in individuals aged
65, PSE has been shown to account for
30e49% of all new-onset seizures (Assis et al., 2015; Brodie and
Kwan, 2005; Stefan et al., 2014). The occurrence of PSE has also
been shown to lead to poor prognosis and increased mortality in
post-stroke survivors (Arboix et al., 1996; Bladin et al., 2000;
Labovitz et al., 2001).
PSE has a high recurrence rate. We recently found that PSE
recurred in 30% patients within 360 days (Tanaka et al., 2015) and a
further observational study reported approximately 50% of patients
experienced a recurrence of symptoms during a follow-up period of
47 months (Olsen, 2001). The recurrence of PSE may lead to
heightened anxiety and thus worsen recovery and quality of life in
stroke survivors, making effective treatment vital. While the
aetiopathology of PSE remains unclear, this review introduces
concepts concerning the definition, diagnosis, mechanisms, risk
factors, and treatment for this significant, and growing, public
health issue.
2. Prevalence of early and late seizure
Post-stroke seizure is divided into two categories: early and late,
according to the cutoff time-point, the first week after stroke onset
(ILAE, 1981). Early seizures typically occur within the first few days
after stroke and are also termed ‘acute symptomatic seizures’,
whereas late seizures have a peak within 6e12 months and result
in a higher frequency of stroke (Bladin et al., 2000; Burn et al., 1997;
Hsu et al., 2014; Lamy et al., 2003). The cumulative seizure rate after
stroke has been found to be 6.1% after 1 year, 9.5% after 5 years, and
11.5% after 10 years (Roivainen et al., 2013). In addition, Belcastro
et al. showed non-convulsive status epilepticus (NCSE) was more
frequent (1.67 times) in the early rather than late seizure group
(Belcastro et al., 2014). The lack of obvious clinical manifestations of
seizure means NCSE is difficult to detect in the acute phase of stroke
and continuous electroencephalography (cEEG) is required for
detection. It may therefore be necessary to perform cEEG to
implement appropriate treatment of NCSE after stroke.
The importance in differentiating between early and late seizure
is salient as the occurrence of late seizure results in a higher
recurrence rate. Thus, distinguishing categories of post stroke
seizure can help determine the need for AED treatment. A previous
study found recurrent seizure developed in about 50% of patients
who had experienced late seizures but only in approximately 30% of
patients with early seizures (Olsen, 2001). Furthermore, in our
retrospective study of 104 patients with late seizure after stroke,
29.8% of the patients developed recurrent seizures after a median
follow-up of 362 days (Tanaka et al., 2015).
3. New definition and diagnosis of PSE
A commonly-used definition of epilepsy has been the occur-
rence of two unprovoked seizures, spaced more than 24 h apart
(Fisher et al., 2005). Many clinicians have thus hesitated to use AED
treatment after the first unprovoked seizure after stroke. Further-
more, it has been noted that some individuals who have had
experienced one seizure in combination with other risk factors of
epilepsy have the same high recurrence rate as those who have
experienced more than two seizures.
In 2014, epilepsy was newly defined (Fisher et al., 2014) by the
presence any of the three conditions: (1) at least two unprovoked (or
reflex) seizures occurring greater than 24 h apart; (2) one unprovoked
(or reflex) seizure and a probability of further seizures similar to the
general recurrence risk (at least 60%) after two unprovoked seizures,
occurring over the next 10 years; (3) diagnosis of an epilepsy
syndrome.
Criterion (1) mirrors the old definition of epilepsy. However, (2)
allows the consideration of epilepsy after one seizure, if there is a
high risk of having another seizure. Factors increasing the likeli-
hood of seizure include remote structural lesions, such as other
stroke damage, central nervous system infection, certain types of
traumatic brain injury, diagnosis of a specific epilepsy syndrome, or
the presence of other risk factors.
In PSE the risk of subsequent unprovoked seizure after 10 years
of follow up was 33.0% (95% CI ¼ 20.7e49.9%) for those who
experience first acute symptomatic seizure within 7 days of the
stroke onset and 71.5% (95% CI ¼ 59.7e81.9%) for first unprovoked
seizure in at least more than one week after stroke (Hesdorffer
et al., 2009). A further observational study reported approxi-
mately 50% of patients who had received AED after a first seizure
episode had at least one recurrence during the follow-up period of
47 months (Hauser et al., 1993). Based on the above findings, only a
single unprovoked seizure in stroke patients occurring at least in
one week after stroke may result in PSE diagnosis. By using this
new definition and diagnosing PSE correctly, an appropriate
treatment for PSE patients could be promptly applied, reducing
recurrence rate, and improving management in individuals who
have experienced post stroke seizure.
However, the new definition has generated some controversy as
it has been viewed as applicable for clinical use without sufficient
medical evidence. While a clear differentiation exists between the
new and previous definitions of seizure, increasing knowledge of
PSE will make its application more precise.
4. Risk factors of PSE
Numerous studies have examined risk factors of PSE (Pitkanen
et al., 2015). However, because of high heterogeneity and diffi-
cultly in diagnosis, relatively few predictors of PSE have been
identified (summarized in Table 1).
Most studies have shown the location of cortical infarct region,
especially from middle cerebral artery lesions, influenced PSE
occurrence (Awada et al., 1999). A meta-analysis reported signifi-
cantly increased probability of PSE involving cortical lesions from
the combined analysis of 12 studies (OR ¼ 2.35, 95%CI ¼ 1.87e2.94,
p < 0.01) (Zhang et al., 2014b); stroke severity was also identified as
a significant risk factor.
Many studies have indicated hemorrhagic, rather than ischemic,
stroke is a more likely predictor of PSE (Arntz et al., 2013; Burn
et al., 1997). The mechanisms behind PSE following hemorrhage
are unclear. However, hemosiderin deposits are thought to cause
cerebral irritation leading to seizure (Silverman et al., 2002). Sub-
arachnoid hemorrhage also leads to widespread damage extending
into parenchymal component of cortex, which may increase the
likelihood of PSE.
PSE is associated with higher severity of initial neurologic def-
icits and disability after stroke. Conrad, et al. used the National
Institute of Health Stroke Scale (NIHSS) to measure stroke severity
and found that a higher NIHSS score was significantly associated
with PSE (Conrad et al., 2013), suggesting that severe, critical
strokes tend to involve wider cortical lesions.
 T. Tanaka, M. Ihara / Neurochemistry International 107 (2017) 219e228 221

Table 1
Potential risk factors of PSE.

High risk Low risk

Stroke type Hemorrhagic stroke Transient ischemic attack

(Arntz et al., 2013; Burn et al., 1997) (De Reuck et al., 2005)
Hemorrhagic transformation
(Leone et al., 2009)
Subarachnoid hemorrhage
(Ukkola and Heikkinen, 1990)
Stroke lesion Cortical involvement Infratentorial
(Silverman et al., 2002) (De Reuck et al., 2005)
Supratentorial
(Leone et al., 2009)
Anterior circulation
(De Reuck et al., 2005)
Middle cerebral artery lesion
(Awada et al., 1999)
Severity of stroke High NIHSS score (Conrad et al., 2013)
Scandinavian Stroke Scale <30
(Lossius et al., 2005)
Modified Rankin scale S3
(Lamy et al., 2003)
Age Younger age
(Graham et al., 2013; Tanaka et al., 2015; Werhahn et al., 2011)
CNS morbidities Early seizure
(Lamy et al., 2003; Roivainen et al., 2013)
Dementia
(Cordonnier et al., 2005)
Small vessel disease
(Maxwell et al., 2013)
Non-CNS morbidities Hypertension (Ohman, 1990; Wang et al., 2013)
Peripheral infections (Wang et al., 2013)
Genetic Rs671 (Mitochondrial aldehyde dehydrogenase 2)
(Yang et al., 2014)
CD40-1 C/T (CD40 molecule, TNF receptor superfamily member 5)
(Zhang et al., 2014a)

Abbreviations: CNS ¼ central nervous system.

A higher incidence of PSE has been reported in patients aged
<65 years than in patients >85 years (10.7% vs. 1.6%; p < 0.001)
based on 10-year estimates (Graham et al., 2013). Furthermore,
mean monthly seizure frequency has been shown to be higher in
younger cohorts of elderly stroke patients (65e74 years) than their
older counterparts (75e84 years) (Werhahn et al., 2011). Our
retrospective study also demonstrated that younger age (<74 years
old) was associated with recurrent seizure (Tanaka et al., 2015).
Comorbidities, such as hypertension and peripheral infections
(Ohman, 1990; Wang et al., 2013), have been identified but there
has been no consensus on whether such factors play a key role in
epileptogenesis. Family history of seizure strongly correlates with
PSE (Leone et al., 2009), suggesting some degree of genetic
contribution in onset. However, only two studies have identified
genetic factors that contribute to epileptogenesis in stroke patients
(Yang et al., 2014; Zhang et al., 2014a). Therefore, it remains un-
known whether genetic background directly affects epilepto-
genesis, or if gene and environmental factors, such as
comorbidities, interact to induce epileptogenesis.
In 2014, Haapaniemi et al. developed the CAVE score for pre-
dicting late seizures after intracerebral hemorrhage, stratifying the
risk for PSE (Haapaniemi et al., 2014). This score referred to “C” for
cortical involvement, “A” for less than 65 years old, “V” for greater
than 10 ml bleeding volume, and “E” for early seizure within 7 days
after hemorrhage. Each item of the score represents a value of 1
point, and the cumulative risk of late seizure was increased by 0.6%,
3.6%, 9.8%, 34.8%, and 46.2% at 0, 1, 2, 3, and 4 points, respectively.
This score may provide a useful utility in identifying high risk
groups for PSE. However, further studies are needed to validate the
use of the CAVE score in the treatment of stroke survivors.
5. Mechanism of PSE
Once a stroke occurs, neuronal injury may ensue from variety of
causes, such as hypoxia, metabolic dysfunction, global hypo-
perfusion,hyperperfusion, glutamate excitotoxicity, ion channel
dysfunction and blood-brain barrier (BBB) disruption in the acute
phase (Myint et al., 2006; Reddy et al., 2016), leading to early
seizure. However, the mechanisms behind late seizure are different
and may be secondary to gliotic scarring, chronic inflammation,
angiogenesis, neurodegeneration, neurogenesis, axonal and syn-
aptic sprouting, selective neuronal loss, and altered synaptic
plasticity.
Firstly, one must consider stroke location and type. There are
different levels of risk of PSE, depending on the presence or absence
of cortical lesion or hemorrhagic component (Fig. 1). Generally,
cortical lesions hold the highest risk of PSE. However, we have
observed that PSE cases often only present with subcortical stroke
lesions. Some reports have stated cortical microinfarcts may be
related to PSE as subcortical stroke is associated with small vessel
disease, though it is difficult to detect microinfarcts with 1.5 T or 3 T
MRI (Ferlazzo et al., 2016; Gibson et al., 2014; Pitkanen et al., 2015;
Silverman et al., 2002). Felazzo et al. also reported that leukoar-
aiosis may play an important role in PSE, from the involvement of
renin-angiotensin system in the central nervous system (Ferlazzo
et al., 2016).
Recently, other studies have shown subcortical stroke lesions or
white matter hyperintensities may be associated with cortical
changes. One plausible mechanism could involve the disruption of
connecting fiber tracts after subcortical stroke leading to secondary
neurodegeneration in cortical lesions (Duering et al., 2012; Righart
222 T. Tanaka, M. Ihara / Neurochemistry International 107 (2017) 219e228
Fig. 1. This figure describes the cascade of events after the onset of stroke (location and stroke subtypes), neuronal excitotoxicity, and synaptic plasticity/reorganization. Early and
late seizure (epileptogenesis) are featured in this process. Epileptogenesis after stroke is associated with complex, multi-faceted phenomena and factors, but it remains unclear how
such phenomena and factors are fundamentally linked with each other. Of note, in order to understand the cause of PSE, we should consider the mechanisms by distinguishing
between cortical and subcortical lesion of stroke, or presence/absence of hemorrhagic lesion as there are fundamental differences in the mechanisms behind PSE (see text in Section
5).
et al., 2013; Tuladhar et al., 2015). Duering et al. reported the
presence of lacunar infarction in the subcortical white matter
causes focal atrophy in connected cortical areas in CADASIL patients
(Duering et al., 2012). Ihara et al. (2004) also showed a decrease in
cortical benzodiazepine receptors was found in patients with leu-
koaraiosis by measuring [11C]flumazenil positron emission to-
mography (Ihara et al., 2004). Retrograde transsynaptic
degeneration may also result in the deterioration of presynaptic
neurons after postsynaptic cell damage (Patel et al., 2016). Failure in
functional or structural connections between remote ipsilateral and
contralateral cortices may lead to retrograde or transsynaptic
neurodegeneration and even epilepsy after subcortical stroke.
In terms of hemorrhagic stroke or transformation, hemosiderin
deposits are thought to result in increasing neuronal excitability.
Injection of iron resulted in focal epilepsy in rats (Kucukkaya et al.,
1998). Moreover, cortical hemosiderin in brain tumors has been
associated with seizures (Roelcke et al., 2013).
Many phenomena after stroke, such as neuronal excitotoxicity,
lead to early seizure. However, little is known on which of the acute
phenomenon is the most important trigger of epileptogenesis after
stroke (origin of late seizure). Several phenomena have been pro-
posed including: (1) loss of neurovascular/blood-brain barrier
(BBB) integrity, (2) increased release of neurotransmitters, (3) ion
channel dysfunction, and (4) alterations in gene expression (Fig. 1).
5.1. Loss of neurovascular unit integrity/BBB disruption
Among those proposed, BBB disruption has been the most
researched and verified hypothesis (Fig. 2). Disruption of the BBB is
a well-known phenomenon in patients with status epilepticus or
refractory temporal lobe epilepsy; however, it is unclear whether
the phenomenon is a precipitatory factor in epilepsy or whether
the relationship is bidirectional. Indeed, recent progress has indi-
cated that disruption of the BBB acts as both a cause and conse-
quence of epilepsy and has emerged an important factor in the
formation of epileptogenic foci or epileptogenesis.
Dysfunction of the BBB is closely associated with brain injury
from stroke, trauma, and chronic neurodegenerative disorders,
such as Alzheimer's and Parkinson's disease (Lo et al., 2003;
Zlokovic, 2008). Following BBB disruption, albumin enters into
the brain parenchyma, directly binds to transforming growth factor
beta (TGFb) receptor on astrocytes, and subsequently activates
TGFb signaling in astrocytes (Heinemann et al., 2012). Activated
astrocytes reduce the uptake of potassium and glutamate in syn-
aptic cleft through potassium channel Kir4.1 and glutamate
transporters (Cacheaux et al., 2009; David et al., 2009). Increased
extracellular potassium and glutamate induces hyperexcitability of
neurons (Djukic et al., 2007; Inyushin et al., 2010). In addition,
extravasated thrombin also plays an important role in increasing
brain electrical activity and inducing seizure (Lee et al., 1997),
which may be mediated by binding of thrombin to protease-
activated receptor-1 in astrocytes (Maggio et al., 2013). Upregula-
tion of TGFb in neurons has been related to epileptogenesis and
exacerbated excitotoxicity in amygdala-kindled rats (Plata-Salaman
et al., 2000). However, some researchers consider TGFb to have
neuroprotective effect as post stroke TGFb activation increases BBB
integrity (Gliem et al., 2012) and induces the non-inflammatory
immunoglobulin isotypes IgG4 and IgA (Taylor et al., 2006).
Hence, the association between TGFb and epilepsy remains
controversial.
Provoked seizure exacerbates the disruption of BBB and pro-
motes brain inflammation. Astrocytes and microglial cells are
activated, leading to the release of proinflammatory cytokines, such
as interleukin (IL)-1b and high mobility group box 1 (HMGB1), and
reduction in seizure threshold (Kim et al., 2012). Tumor necrosis
factor a (TNFa), IL-6, and IL-1b secreted from activated microgial
cells can cause disruption of the BBB (da Fonseca et al., 2014; Kim
et al., 2012). Moreover, microglial cells may enhance astrocytic
TGFb signaling (Doyle et al., 2010; Kim et al., 2012). Vasogenic ce-
rebral edema, glutamate excitotoxicity, collapse of cell ion gradi-
ents, and mitochondrial dysfunction from seizure or stroke itself
may also contribute to the secondary irreversible persistent dam-
age of brain (gliotic scarring) and induce seizure threshold reduc-
tion. Consequently, it is assumed that this cycle of events
contributes to epileptogenesis after stroke.
5.2. Increased release of neurotransmitters
A large and sustained amounts of glutamate and other neuro-
transmitters, including dopamine and serotonin, are released from
ischemic/hypoxic cells into the extracellular space (Szydlowska and
Tymianski, 2010). Glutamate is a major excitotoxic neurotrans-
mitter and acts through various receptors including alpha-amino-
3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), kainate,
and N-methyl-D-aspartate (NMDA). Excess extracellular glutamate
concentration may inappropriately activate AMPA and NMDA re-
ceptors and damage or kill neurons (Lipton, 1999). This damage is
induced by intracellular inflow of calcium and sodium through the
activated glutamate-gated ion channels and promoted by intra-
cellular hyperosmolarity (Matsuoka and Hossmann, 1982).
 T. Tanaka, M. Ihara / Neurochemistry International 107 (2017) 219e228 223

Fig. 2. The BBB can be disrupted by damage to endothelial cells in stroke, and serum proteins are extravasated: for instance, albumin binds to TGFb receptors on astrocytes, and
subsequently activates TGFb signaling. This response causes downregulation of potassium channel Kir4.1 and glutamate transporters, which increase Kþ and glutamate in the
extracellular space (synaptic cleft). Elevation in extracellular Kþ may directly enhance neuronal excitability and excess glutamate may lead to seizure. Activated astrocytes and
microglial cells release IL-1b, and high mobility group box 1 (HMGB1), leading to decreased seizure threshold in neurons. Activated microglial cells also increase BBB permeability
and interact with astrocytes through inflammatory cytokines, such as IL-1b, IL-6, TNFa and TGFb. Thrombin may bind to PAR-1 in astrocytes, subsequently leading to neuronal
excitability. The negative cascade of events could explain epileptogenesis after stroke. See text for details.
Abbreviations; BBB ¼ blood brain barrier; IL ¼ interleukin; TNFa ¼ tumor necrosis factor a; TGFbR ¼ transforming growth factor b receptor; HMGB-1 ¼ High Mobility Group Box 1;
PAR-1 ¼ protease-activated receptor-1.

Glutamate has been also known to produce epileptiform discharges 5.4. Alterations in gene expression
in surviving neurons. Although there are few studies regarding
potential roles of other transmitters in post-stroke seizure, dopa- Alterations in gene expression after stroke are associated with
mine and serotonin seem to contribute to the control of seizures changes in neuroprotection, synaptic plasticity, regulation of
arising in the limbic system or hippocampus (Bozzi and Borrelli, neuronal excitability, as well as glial scar formation, which may
2013; Lanfumey and Hamon, 2000). jointly lead to epileptogenesis (Pitkanen et al., 2015). Lu et al.
(2004) revealed that ischemia upregulated genes mediating
inflammation, cell death, cytoskeletal functions and metabolism in
5.3. Ion channel dysfunction
a rat model of permanent middle cerebral artery occlusion (Lu et al.,
2004). Another study showed differential alterations in gene
In rodent models, stroke can result in changes in ion channels
expression between the infarct core and surrounding area (Ramos-
within one day post stroke (Kamp et al., 2012; Lu et al., 2004).
Cejudo et al., 2012). Alterations in gene expression may be associ-
Neuronal function depends on homeostatic balance in sodium,
ated with impairments in immune response and neuronal plas-
potassium and calcium ions. If the ion channels are damaged, nerve
ticity, which may lead to seizure.
signals misfire and may enhance the excitatory function in the
The mechanisms mentioned above do not operate indepen-
central nervous system. Increase in intracellular calcium and so-
dently but intertwine in a complex manner to induce structural and
dium due to stroke injury may also lower the seizure threshold for
functional changes in neuronal networks, leading to persistent
depolarization (Silverman et al., 2002). In experimental studies,
epileptogenesis. Although such mechanisms have not been
increased extracellular potassium causes neuronal depolarization
completely clarified, gaining further insights into such pathways
and promotes seizure (Amedee et al., 1997). In terms of inhibitory
may lead to prevention strategies against epileptogenesis or
functions, gamma-aminobutyric acid (GABA) is a major inhibitory
recurrence of PSE. For an overview of experimental PSE models, one
neurotransmitter in the cerebral cortex, regulating neuronal exci-
may also refer to recently published review (Reddy et al., 2016).
tation (Treiman, 2001). Reduced excitability of GABAergic inhibi-
tory interneurons after stroke leads to neuronal instability and
hyperexcitability. Down-regulation of GABA receptors may also 6. Treatment of PSE
lead to elevated excitability of neuronal networks (Cacheaux et al.,
2009). From the perspective of PSE treatment, preventive measures
224 T. Tanaka, M. Ihara / Neurochemistry International 107 (2017) 219e228
may be divided into two categories: primary and secondary. The
first early or late seizure itself is a risk of seizure recurrence, and
early seizure is a risk factor for late seizure. We therefore describe
primary and secondary prevention strategies for seizure below.
Primary prevention is defined as the prevention of the first seizure
after stroke, while the secondary prevention is defined as the
prevention of the following seizure.
6.1. Primary prevention
American Heart Association guidelines have shown that pro-
phylactic administration of AED are not recommended for stroke
survivors in the prevention of seizure (Winstein et al., 2016). This is
due to a lack of reliable randomized control trials for the prevention
of treatment of seizures after stroke and reports that prophylactic
AED therapy may be associated with poorer outcomes (Messe et al.,
2009; Naidech et al., 2005, 2009; Zelano, 2016). Gilad et al. reported
that valproic acid (VPA) monotherapy did not prevent the occur-
rence of late seizures compared with placebo in patients with
spontaneous, non-aneurysmal, intracerebral hemorrhage (Gilad
et al., 2011).
However, the lack of success in prophylactic AED therapy trials
may be due to the use of older generation treatments in most
studies. Recently, several animal studies have reported levetir-
acetam (LEV) possesses antiepileptogenic effects (Loscher et al.,
1998; Russo et al., 2010; Vinogradova and van Rijn, 2008; Yan
et al., 2005). Kim et al. showed LEV inhibited IL-1b inflammatory
responses and reduced reactive gliosis in the hippocampus and
piriform cortex in a rat model of epilepsy (Kim et al., 2010), sug-
gesting it could be an important agent in the prevention of epi-
leptogenesis. Furthermore, in clinical studies, LEV was associated
with improved (Taylor et al., 2011) or neutral (Sheth et al., 2015)
outcomes after intracerebral hemorrhage.
Perampanel is a novel highly selective non-competitive post-
synaptic AMPA glutamate receptor antagonist (Ceolin et al., 2012).
Although no clinical evidence exists for its use in PSE, it is hy-
pothesized to have potential in preventing epileptogenesis by
blocking glutamate excitotoxicity, which plays an important role in
PSE pathogenesis (See Section 5). However, more research is
needed before ascertaining whether such new-generation AED are
useful in the primary prevention of PSE.
Statins are widely used as prophylactic agents for stroke.
Recently, statin administration has been found to reduce the risk of
PSE, especially in the acute phase (Guo et al., 2015). Moreover, other
studies have shown that statin use is associated with a lower
prevalence (Pugh et al., 2009), and reduced risk of hospitalization,
for epilepsy (Etminan et al., 2010). This may be related to the
anticonvulsant, or anti-inflammatory, effects of statins in the pre-
vention of BBB injury. Although not related to PSE, aspirin (Ma et al.,
2012) and rapamycin (Sunnen et al., 2011), which have anti-
inflammatory actions, have been reported to be effective in pre-
venting epileptogenesis in animal experiments. Such anti-
inflammatory drugs may also be effective for PSE but further
investigation should be conducted to explore the possibility.
6.2. Secondary prevention
Although many physicians prescribe AED for secondary pre-
vention of PSE, it is uncertain which AED are the most effective for
the prevention of recurrence of seizure. Most physicians agree that
repeated seizures require AED treatment, as recommended by Eu-
ropean guidelines (European Stroke Initiative Executive et al.,
2003). However, there is no consensus regarding the most effec-
tive class, dose, or duration for the prevention of recurrent PSE. In
2014, we conducted a questionnaire survey to determine the
current status regarding the treatment of PSE in Japan. This was
performed in 189 stroke hospitals, comprising 84 Neurology, 87
Neurosurgery, 13 stroke and 5 other departments. Only 33% of the
hospitals started AED after the first episode of PSE, compared to
88% after the second PSE. In the maintenance phase, the first choice
drugs for PSE were carbamazepine (CBZ) in 44%, VPA in 30% and
LEV in 24% (Fig. 3) Monotherapy using second generation AED had
not been officially approved in Japan during the course of this
survey, despite no consensus existing on AED regimen in Japan. In
the United states, phenytoin (PHT) and gabapentin (GBP) are the
most commonly prescribed AED for the management of epilepsy
(Pugh et al., 2008), while in Europe, CBZ and GBP are the most
commonly prescribed in the elderly (Johnell and Fastbom, 2011).
Previous reports on the clinical efficacy of AED therapies in late
seizure after stroke are summarized in Table 2 (Alvarez-Sabin et al.,
2002; Belcastro et al., 2008; Consoli et al., 2012; Gilad et al., 2007,
2011; Huang et al., 2015; Kutlu et al., 2008; Tanaka et al., 2015;
van Tuijl et al., 2011). Although most studies have some inherent
limitations, such as small number of subjects, no placebo arm, non-
randomization, or retrospective approach, second generation AED,
such as GBP, LEV and lamotrigine (LTG), could be seen as viable
treatments because of the lower rate of recurrent PSE and fewer
side effects.
PSE can also be categorized as partial or focal epilepsy. The 2013
International League Against Epilepsy (ILAE) report suggested CBZ,
LEV, PHT, zonisamide (ZNS) have ‘level A’ evidence, meaning it has
been established as efficacious or effective as an initial mono-
therapy in adults with PSE (Glauser et al., 2013). There have been
several reliable randomized controlled trials in partial epilepsy
patients. In the SANAD trial, the effects of CBZ were compared with
those of GBP, LTG, oxcarbazepine, and topiramate for one year
seizure recurrence. CBZ was shown to be more effective than GBP
(hazard ratio 0.75 [95% CI 0.63e0.90]), and not inferior than LTG
(0.91 [0.77e1.03]) (Marson et al., 2007). They also found LTG was
better tolerated than other drugs. In the KOMET trial on secondary
prevention, LEV was compared with extended-release VPA or
controlled-release CBZ as initial monotherapy among the elderly
patients (>60 years) with two or more unprovoked seizures, where
81.8% participants had focal seizure and 28.7% had at least one
cerebrovascular event (Pohlmann-Eden et al., 2016). After 52
weeks, LEV was superior to other AEDs in terms of time to
Fig. 3. Results of the questionnaire survey on AED treatment in PSE from Japanese
stroke specialists working in 189 hospitals in 2014, comprising of Department of
Neurology (n ¼ 84), Department of Neurosurgery (n ¼ 87), Specialized Stroke Center
(n ¼ 13), and others (n ¼ 5).
Abbreviations: AED ¼ antiepileptic drug; CBZ ¼ carbamazepine; VPA ¼ valproic acid;
LEV ¼ levetiracetam; ZNS ¼ zonisamide; PHT ¼ phenytoin; LTG ¼ lamotrigine;
GBP ¼ gabapentin; TPM ¼ topiramate.
Table 2
Secondary outcomes of late seizure since 2000.

Study design Participants Age Interventions Follow-up period Seizure recurrence rate Tolerability Limitations
y ±SD or treatments

(Alvarez-Sabin Prospective 71 (48 ischemic, 63.9 ± 13.3 GBP 30 ± 11.4 months 13/71 (18%) Side effect 27/71 (38%) Small numbers
et al., 2002) Observational 23 hemorrhagic) (900 Discontinuation 2/71 (3%) Not randomized
No placebo arm e1800 mg/day) No placebo arm

T. Tanaka, M. Ihara / Neurochemistry International 107 (2017) 219e228

(Gilad et al., 2007) Prospective 64 ischemic LTG 67.2 ± 2.4 32 LTG 12 months LTG 9/32 (28%) Withdrawal for adverse Small numbers
Randomized CBZ 67.7 ± 2.6 (25 CBZ 18/32 (56%) events No placebo arm
No placebo arm e100 mg/day) P ¼ 0.06 LTG 1/32 (3%) Not double blinded
No double-blinded 32 CBZ CBZ 10/32 (31%)
(100 p ¼ 0.02
e300 mg/day)
(Kutlu et al., 2008) Prospective 34 ischemic 69.8 ± 6.4 34 LEV 17.7 ± 3.4 months 6/34 (18%) Side effect 7/34 (21%) Small numbers
Observational (1000 Discontinuation 1/34 (3%) Not randomized
No placebo arm e2000 mg/day) No placebo arm
(Belcastro et al., 2008) Prospective 35 ischemic 71.9 ± 7.3 35 LEV 18 months 3/35 (9%) Withdrawal for adverse Small numbers
Observational (1000 events 4/35 (11%) Not randomized
No placebo arm e2000 mg/day) No placebo arm
(Consoli et al., 2012) Prospective 106 (79 ischemic, LEV 74.1 ± 11.3 52 LEV 54 weeks LEV 3/52 (6%) Discontinuation Small numbers
Randomized 27 hemorrhagic) CBZ 69.7 ± 13.2 54 CBZ CBZ 8/54 (15%) LEV 3/52 (6%) No placebo arm
No placebo arm p ¼ 0.08 CBZ 4/54 (7%) Not double blinded
No double-blinded Side effect
LEV 17/52 (33%)
CBZ 21/54 (39%)
p ¼ 0.02
(Tanaka et al., 2015) Retrospective 104 (69 ischemic, 72 ± 11.2 23 VPA 362 days (172 VPA 11/23 (48%) N/A Retrospective
Observational 43 hemorrhagic) 22 PHT e552) PHT 4/22 (18%) Small numbers
15 CBZ CBZ 2/15 (13%)
10 Other AED Others 2/10 (20%)
20 Poly AED Poly AED 10/20 (50%)
14 No AED None 2/14 (14%)
(Huang et al., 2015) Retrospective 3622 (1729 ischemic, 60.3 ± 13.1 2507 PHT 100 person- PHT 1.05 (0.95e1.15) N/A Retrospective,
Observational 1893 hemorrhagic) 712 VPA months VPA 0.70 (0.54e0.91) used the diagnostic codes from the database,
157 CBZ CBZ 0.43 (0.22e0.86) excluded seizure recurrence within the first
246 New AED New AED 0.38 (0.21e0.68)/ 3-month period
100 person-months (95%CI)

Abbreviations: SD ¼ standard deviation; N/A ¼ not available; AED ¼ antiepileptic drug; CBZ ¼ carbamazepine; VPA ¼ valproic acid; LEV ¼ levetiracetam; PHT ¼ phenytoin; LTG ¼ lamotrigine; GBP ¼ gabapentin.

225
226 T. Tanaka, M. Ihara / Neurochemistry International 107 (2017) 219e228
treatment withdrawal (0.44 [0.28e0.67]); however, the time to first
seizure was similar between LEV and other AEDs (0.92 [0.63e1.35]).
Werhann et al. conducted a multicenter, double blind, randomized
trial evaluating AED therapy (controlled-release CBZ vs. LEV vs.
LTG) in elderly patients with focal epilepsy (not only stroke pa-
tients; 65.9% participants of this study was PSE) (Werhahn et al.,
2015) showed superior tolerability and higher retention to treat-
ment of LEV or LTG monotherapy compared to controlled-release
CBZ therapy in the management of focal epilepsy in the elderly.
The above results suggest CBZ should not be considered as standard
treatment for partial epilepsy because of low tolerability, though
the initial target dose of CBZ may have been too high for elderly
people (KOMET trial: 600 mg/day, Werhann's trial: 400 mg/day). A
lower target dose of CBZ should lead to lower withdrawal rates,
with well-preserved seizure control. Additionally, CBZ is more
effective than LEV for the treatment of central post-stroke pain
(Shetty, 2013). The next generation AED perampanel has also been
shown to have better clinical efficacy in S65 year-old patients with
PSE (Villanueva et al., 2016).
Elderly stroke survivors tend to have other health-related issues,
such as multiple medical comorbidities, as well as age-associated
alterations in drug metabolism. This is further complicated with
the use of concomitant drugs, which may result in interactions
between medications. In recent years, several studies have
demonstrated that epilepsy patients have a much higher risk of
stroke than the non-epileptic population, perhaps as a result of use
of older generation AED, which may induce stroke (Jin et al., 2016;
Zelano, 2016). Second generation drugs may be considered because
of the lower incidence of side effects and interactions with other
drugs, and the more linear pharmacokinetic profiles of such drugs
compared with older AED (Dewolfe and Szaflarski, 2013). Newer
sodium channel blockers, such as lacosamide, oxcarbazepine, and
eslicarbazepine, result in less drug interactions and could represent
potential treatments for PSE. However, although rare, potential side
effects of second generation drugs, such as psychiatric problems,
should be considered, as they may exacerbate post-stroke
disability. Prospective randomized, double-blind studies are
needed to assess the safest and most efficacious AED in the sec-
ondary prevention of PSE.
7. Perspective
Physicians should always treat stroke survivors with the risk of
PSE in mind. While considerable difficulties exist in designing and
conducting clinical studies of PSE, such as the high heterogeneity of
stroke survivors, further studies are necessary to explore the pri-
mary and secondary prevention of PSE. Recently, connectome
analysis has been used to investigate network abnormalities in
temporal lobe epilepsy (DeSalvo et al., 2014; Liao et al., 2016) or to
predict efficacy of rehabilitation after stroke (Silasi and Murphy,
2014). Connectome analysis may also be useful in predicting who
will develop PSE.
Conflict of interest
The authors declare no conflict of interest.
Acknowledgements
This work was partially supported by the grants-in-aid from
Japan Agency for Medical Research and development, AMED (H28-
16668389, chief investigator: Ihara).
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