Published Ahead of Print on July 22, 2015 as 10.1212/WNL.

0000000000001814

Statin treatment reduces the risk of

poststroke seizures

Jiang Guo, MD* ABSTRACT

Jian Guo, MD* Objective: To examine the potential efficacy of statin treatment in reducing the risk of poststroke
Jinmei Li, MD seizures.
Muke Zhou, MD
Methods: In this cohort study, patients with a first-ever ischemic stroke and no history of epilepsy
Fengqin Qin, MD
before stroke were enrolled. After a mean follow-up period of 2.5 years, a follow-up assessment
Shihong Zhang, MD
was performed to identify poststroke epilepsy. Logistic regression and Cox regression analyses
Bo Wu, MD
were used to assess the relationship between statin use and poststroke early-onset seizures or
Li He, MD
poststroke epilepsy.
Dong Zhou, MD
Results: Of 1,832 enrolled patients, 63 (3.4%) patients had poststroke early-onset seizures and
91 (5.0%) patients had poststroke epilepsy. Statin use was associated with a lower risk of post-
Correspondence to stroke early-onset seizures (odds ratio [OR] 0.35, 95% confidence interval [CI] 0.20–0.60, p ,
Dr. Zhou: 0.001), and this reduced risk was seen mainly in patients who used a statin only in the acute
zhoudong66@yahoo.de
or Dr. He: phase (OR 0.36, 95% CI 0.20–0.62, p , 0.001). No significant association was found between
heli2003new@126.com statin use and poststroke epilepsy (OR 0.81, 95% CI 0.52–1.26, p 5 0.349). In 63 patients who
presented with early-onset seizures, statin use was associated with reduced risk of poststroke
epilepsy (OR 0.34, 95% CI 0.13–0.88, p 5 0.026).
Conclusions: Statin use, especially in the acute phase, may reduce the risk of poststroke early-
onset seizures. In addition, statin treatment may prevent the progression of initial poststroke
seizure-induced neurodegeneration into chronic epilepsy. Because of the observational nature
of the study, more studies are needed to confirm the results.
Classification of evidence: This study provides Class III evidence that in patients with a first-ever
ischemic stroke, the early use of statins reduces the risk of early poststroke seizures. Neurology®
2015;85:1–7

GLOSSARY
CI 5 confidence interval; ES 5 poststroke early-onset seizures; HDL-C 5 high-density lipoprotein cholesterol; NIHSS 5 NIH
Stroke Scale; OR 5 odds ratio; PSE 5 poststroke epilepsy; TOAST 5 Trial of Org 10172 in Acute Stroke Treatment.

Stroke is a common cause of epilepsy in elderly people, accounting for 45% of seizures starting
after the age of 60 years.1 The management of seizures after a stroke is a difficult issue. Current
guidelines recommend that recurrent seizures following stroke be treated with antiepileptic
drugs2,3; however, the optimal timing of initiation as well as the duration and type of antiep-
ileptic drug therapy are controversial.4 For preventive measures, there is insufficient evidence to
support routine use of prophylactic antiepileptic drugs in newly diagnosed stroke patients.5
Studies on the prevention and treatment of poststroke seizures and epilepsy are lacking, and
more research is needed in this area.
Statins have been widely used in the prevention of stroke for many years. In recent years, stat-
ins have been found to have neuroprotective effects in stroke6 and are recommended as neuro-
protective agents in acute stroke treatment.3 As neuroprotective agents can modify the
epileptogenesis process,7 statins have also been suggested as having anticonvulsant effects in
epilepsy.8–12 However, no study has been conducted to investigate the effect of statins on the risk
Supplemental data
at Neurology.org
*These authors contributed equally to this article.
From the Department of Neurology, West China Hospital of Sichuan University, Chengdu, China.
Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.

© 2015 American Academy of Neurology 1

ª 2015 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

 of poststroke seizures, even though statins are
used widely in stroke patients. We speculated
that statins might assist in preventing post-
stroke early-onset seizures (ES) or poststroke
epilepsy (PSE) and attempted to verify this
hypothesis in the present study.
METHODS Study population. Patients admitted to the
Department of Neurology at Western China Hospital between
January 2010 and August 2013 were enrolled. Patients with a
first-ever ischemic stroke within 24 hours of symptom onset
and without a history of epilepsy before stroke were selected.
Stroke was defined by World Health Organization criteria as a
sudden focal neurologic deficit persisting longer than 24 hours
and confirmed by brain CT or MRI. Study exclusion criteria were
as follows: (1) patients with primary subarachnoid hemorrhage,
subdural hematoma, intraparenchymal hemorrhage, or intracranial
venous thrombosis; (2) stroke as a result of direct head trauma or
iatrogenic stroke as a consequence of surgery; (3) patients with a
history of severe comorbidities that could lead to seizures
(including malignant neoplasms, specific autoimmune diseases,
severe electrolyte abnormalities, end-stage renal disease, and severe
head trauma); and (4) patients with high-grade carotid stenosis
treated with carotid endarterectomy or endovascular therapy.
Transformation hemorrhage after ischemic stroke was included. A
list of inclusion and exclusion criteria was drawn up and 2
neurologists assessed the patients independently according to this
list, with any discrepancies resolved by discussion.
Standard protocol approvals, registrations, and patient
consents. The study protocol was approved by the Institutional
Ethics Committee of Sichuan University. Written informed con-
sent was obtained from all patients.
Data extraction. Patient information was extracted from a
stroke database established at our hospital. Baseline characteristics
of stroke patients were recorded on admission. When the patient
was discharged, information about stroke subtype, treatment in
hospital, complications, laboratory tests, and CT and/or MRI
findings was recorded. The data collectors were not aware of
the study.
Stroke severity was measured using the NIH Stroke Scale
(NIHSS) score on hospital admission, categorized into mild
(NIHSS , 7), moderate (NIHSS 7–25), and severe (NIHSS .
25). Statins were used in patients whose stroke was presumed to
be of atherosclerotic origin, without consideration of the low-
density lipoprotein cholesterol level.13 Statin use was classified
into 2 phases: before stroke or in the acute phase. Statin treatment
before stroke referred to regular use of statins at least 1 month
before stroke, and statin treatment in the acute phase was defined
as statins initiated within 3 days after stroke onset and continuing
for at least 3 days. The dosage was $20 mg per day for atorvas-
tatin, $40 mg per day for simvastatin, or $10 mg per day for
rosuvastatin.
Follow-up. Patients were followed up by telephone interviews or
face-to-face assessments in the outpatient department for a mean
period of 2.5 years (range 0.4–4.6 years). Patients were asked
whether they had experienced a seizure-like event or had been
diagnosed as having epilepsy by attending physicians after
discharge from the hospital. If a patient was suspected of
having experienced a seizure attack or an event or symptoms
that mimicked seizures, a further face-to-face assessment was
performed to confirm the diagnosis. The interviews were
2 Neurology 85 August 25, 2015
ª 2015 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
conducted by senior neurologists who were completely blinded
to the study.
Outcome. Primary outcomes were ES and PSE. Poststroke seiz-
ures were classified into 2 separate categories according to the tim-
ing of occurrence: acute ES (within 7 days of the stroke) and
unprovoked late-onset seizures (.7 days after the stroke). PSE
was defined as $2 unprovoked late-onset epileptic seizures after
the acute phase of stroke. ES and PSE diagnoses were made
according to guidelines set by the International League Against
Epilepsy.14 Seizures were classified as partial (simple, complex,
and secondary generalized) or generalized.
Statistical analyses. Descriptive data were the median and in-
terquartile range for continuous variables and percentages for cat-
egorical variables. Continuous variables were compared using the
Student t test. Categorical variables were compared using the x2
test or Kruskal–Wallis test, as appropriate. Logistic regression
analyses were used to test the association between statin use
and ES. Cox regression analyses were used to test the association
between statin use and PSE. Significant variables in the univariate
analyses (p , 0.1) and clinically significant variables that may
influence outcomes were entered into regression analyses.
Logistic regression analyses and Cox regression analyses were
also used to test the association between statin treatments in
different periods and ES/PSE. Results of multivariate analyses
are presented as odds ratios (ORs) with 95% confidence inter-
vals (CIs) and p values. All tests were 2-sided and p , 0.05 was
considered significant. SPSS v21.0 (SPSS, Chicago, IL) was
used for all analyses.
RESULTS A total of 1,985 consecutive patients from
the database met the inclusion and exclusion criteria.
Of them, 153 (7.7%) patients were unable to be
traced. There were no differences in baseline charac-
teristics between participants and those patients
who were lost to follow-up. A total of 1,832
patients were finally included in the study, of
whom 1,061 (57.9%) were male. The mean age of
patients was 64.3 years. Fourteen patients used a
statin before stroke only, 1,277 patients used a
statin only in the acute phase, 114 patients used
a statin before stroke and in the acute phase, and
427 patients did not use a statin either before stroke
or in the acute phase (table e-1 on the Neurology®
Web site at Neurology.org). Of the 1,391 patients
who used a statin in the acute phase, 1,341 (96.4%)
used atorvastatin, 11 (0.8%) used simvastatin, and
39 (2.8%) used rosuvastatin. Table 1 depicts the
differences between patients who presented with and
without ES/PSE. Compared with patients who did not
have ES, patients with ES had more severe strokes and
were more likely to have hypertension. Patients with
PSE had more severe strokes and were more likely to
have hypertension and atrial fibrillation.
Among the 63 (3.4%) patients with ES, 21
(33.3%) had a simple partial seizure, 11 (17.5%)
had a complex partial seizure, 7 (11.1%) had a sec-
ondary generalized attack, and 24 (38.1%) had a gen-
eralized seizure (table 2). The majority (36 of 63;
57.1%) of all ES occurred during the first 24 hours
 Table 1 Baseline and clinical characteristics of patients with and without poststroke seizures/epilepsy

ES PSE

Variable Yes (n 5 63) No (n 5 1,769) p Value Yes (n 5 91) No (n 5 1,741) p Value

Age, y, mean 6 SD 64.4 6 13.7 61.4 6 16.1 0.086 62.6 6 15.7 64.4 6 13.7 0.315

Sex, male 33 (52.4) 1,028 (58.1) 0.365 45 (49.5) 1,016 (58.4) 0.093

TOAST stroke etiology ,0.001 ,0.001

Large artery atherosclerosis 20 (31.7) 771 (43.6) 32 (35.2) 759 (43.6)

Cardioembolism 17 (27.0) 215 (12.2) 21 (23.1) 211 (12.1)

Small vessel disease 1 (1.6) 260 (14.7) 5 (5.5) 256 (14.7)

Other determined etiology 1 (1.6) 131 (7.4) 3 (3.3) 129 (7.3)

Undetermined etiology 24 (38.1) 392 (22.2) 30 (33.0) 386 (22.2)

NIHSS score ,0.001 0.003

<7 28 (44.4) 1,307 (73.9) 54 (59.3) 1,281 (73.6)

7–25 31 (49.2) 436 (24.6) 35 (38.5) 432 (24.8)

>25 4 (6.3) 26 (1.5) 2 (2.2) 28 (1.6)

Hypertension 28 (44.4) 1,085 (61.3) 0.007 41 (45.1) 1,072 (61.6) 0.002

Diabetes mellitus 14 (22.2) 511 (28.9) 0.250 19 (20.9) 506 (29.1) 0.092

Atrial fibrillation 10 (15.9) 203 (11.5) 0.285 17 (18.7) 196 (11.3) 0.031

Peripheral arterial disease 1 (1.6) 83 (4.7) 0.247 6 (6.6) 78 (4.5) 0.347

Smoking 16 (25.4) 595 (33.6) 0.173 29 (31.9) 582 (33.4) 0.798

Alcohol use 10 (15.9) 320 (18.1) 0.653 13 (14.3) 317 (18.2) 0.343

Hemorrhagic transformation 3 (4.8) 113 (6.4) 0.795 10 (11.0) 106 (6.1) 0.061

Admission lipid level

Triglycerides, mmol/L, mean 6 SD 1.66 6 1.14 1.66 6 1.33 1.000 1.66 6 1.32 1.70 6 1.21 0.813

Total cholesterol, mmol/L, mean 6 SD 4.21 6 0.92 4.43 6 1.10 0.064 4.43 6 1.11 4.29 6 0.91 0.245

HDL cholesterol, mmol/L, mean 6 SD 1.19 6 0.40 1.26 6 0.39 0.148 1.26 6 0.39 1.19 6 0.38 0.080

LDL cholesterol, mmol/L, mean 6 SD 2.54 6 0.91 2.63 6 0.92 0.438 2.62 6 0.92 2.59 6 0.91 0.751

Statin treatment 33 (52.4) 1,372 (77.6) ,0.001 55 (60.4) 1,350 (77.5) ,0.001

Statin use only before stroke 0 (0) 14 (0.8) 0 (0) 14 (0.8)

Statin use only in acute phase 31 (49.2) 1,246 (70.4) 50 (54.9) 1,227 (70.5)

Statin use both before and acutely 2 (3.2) 112 (6.3) 5 (5.5) 109 (6.3)

Abbreviations: ES 5 poststroke early-onset seizures; HDL 5 high-density lipoprotein; LDL 5 low-density lipoprotein; NIHSS 5 NIH Stroke Scale; PSE 5
poststroke epilepsy; TOAST 5 Trial of Org 10172 in Acute Stroke Treatment.
Data are n (%) unless otherwise indicated.

after stroke onset; 17 (27.0%) occurred on days 2–3
and 10 (15.9%) occurred on days 4–7. Table 3 de-
picts the association between statin use in different
periods and risk of ES. Univariate associations
showed that ES were associated with less frequent
use of statins (OR 0.32, 95% CI 0.19–0.53, p ,
0.001). After adjusting for age, Trial of Org 10172
in Acute Stroke Treatment (TOAST) classification,
NIHSS score, hypertension, hemorrhagic transforma-
tion, and total cholesterol, the association still existed
(OR 0.35, 95% CI 0.20–0.60, p , 0.001). Statin
treatment only in the acute phase could reduce the
risk of ES (OR 0.36, 95% CI 0.20–0.62, p , 0.001).
No patients with ES used a statin only before their
stroke, so the effect of statin treatment before stroke
on ES could not be evaluated.
During a mean follow-up of 2.5 years, 91 (5.0%)
patients had PSE. Of these patients, 19 (20.9%) had
mainly simple partial seizures, 15 (16.5%) had mainly
complex partial seizures, 16 (17.6%) had mainly sec-
ondary generalized attacks, and 41 (45.1%) had
mainly generalized seizures. The majority (56 of 91;
61.5%) of patients developed PSE during the first
year; 21 (23.1%) patients developed PSE during the
second year and 14 (15.4%) developed PSE during
the third year or later. None of the patients used anti-
convulsant drugs after the first seizure attack of PSE.
Table 3 depicts the association between statin use in

Neurology 85 August 25, 2015 3

ª 2015 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.


Table 2 Classification of poststroke early-onset
seizures and poststroke epilepsy
ES
Partial, n (%)
Simple partial 21 (33.3)
Complex partial 11 (17.5)
Secondary generalized 7 (11.1)
Generalized, n (%) 24 (38.1)
Abbreviations: ES 5 poststroke early-onset seizures;
PSE 5 poststroke epilepsy.
different periods and PSE. Univariate associations
showed that PSE was associated with less frequent
use of statins (OR 0.64, 95% CI 0.42–0.98, p 5
0.041). However, the association did not remain after
adjusting for sex, TOAST classification, NIHSS
score, hypertension, diabetes mellitus, atrial fibrilla-
tion, hemorrhagic transformation, and high-density
lipoprotein cholesterol (HDL-C) (OR 0.81, 95%
CI 0.52–1.26, p 5 0.349). No patients with PSE
used a statin only before their stroke.
Of the 63 patients who presented with ES, 33
(52.4%) patients used a statin regularly (early after
stroke) and 30 (47.6%) patients did not (table 4).
Patients who used a statin were more likely to have
hypertension and a higher level of HDL-C. Among
these patients, 20 (31.7%) developed PSE during
follow-up. After adjusting for age, NIHSS score,
hypertension, hemorrhagic transformation, and
HDL-C, multivariate analyses showed that statin
use could reduce the risk of PSE in patients who
presented with ES (OR 0.34, 95% CI 0.13–0.88,
p 5 0.026).
DISCUSSION The main finding of the study was
that statin use, especially in the acute phase, could
reduce the risk of ES. Moreover, in patients who
had ES, statin treatment could also reduce the risk
of PSE. These results suggest an anticonvulsant effect
of statins in ischemic stroke patients.
Besides lipid-lowering, statins have pleiotropic
neuroprotective effects.15 These neuroprotective ef-
fects can elicit positive outcomes in various neuro-
PSE logic disorders, such as stroke, multiple sclerosis,16
Alzheimer disease,17 and Parkinson disease.18 Two
19 (20.9) studies have investigated the potential anticonvulsant
effect of statins in patients with epilepsy.11,12 One
15 (16.5)
retrospective cohort study showed that statins were
16 (17.6)
associated with a lower likelihood of epilepsy.11 A
41 (45.1)
population-based nested case-control study suggested
that statin use decreased the risk of hospitalization for
epilepsy.12 In the present study, the focus was on PSE
rather than general epilepsy, considering that stroke
accounts for 45% of seizures starting after the age of
60 years1 and statin use is very common in stroke
patients.
Among patients without ES, 77.6% used a statin,
but only 52.4% of patients with ES used a statin,
which was a significant difference even after adjust-
ment for potential confounders. ES are induced by
metabolic and biochemical dysfunction, which is dif-
ferent from late-onset seizures, which are due to dif-
fering pathophysiologic processes.19 Therefore, there
are 3 possible explanations for the results. First, acute
ischemia leads to increased extracellular concentra-
tions of glutamate, which results in epileptiform-
type neuronal discharge of surviving neurons.20
Statins were found to reduce the excitatory effects
of glutamate in a series of experimental studies.21,22
The mechanism underlying this phenomenon, how-
ever, remains incompletely understood. It may be
related to the effect of statins in preventing brain
injury caused by glutamatergic toxicity exacerbation
by increasing cell viability, phospho-Akt levels, and
glutamate uptake22 or by modulating the activity of
NMDA receptors and the dynamics of intracellular
calcium in neuronal cultures exposed to glutamate
excitotoxicity.21 Second, statins can reduce the infarc-
tion volume by anti-inflammatory and antioxidative
effects as well as inhibition of apoptosis of neural
cells,15 and the infarction volume is related to the
number and total duration of depolarizing events23

Table 3 Effect of statin treatment on poststroke early-onset seizures and poststroke epilepsy

ES PSE

Unadjusted Adjusted Unadjusted Adjusted

Statin use OR (95% CI) p OR (95% CI) p OR (95% CI) p OR (95% CI) p

Anytime 0.32 (0.19–0.53) ,0.001 0.35 (0.20–0.60) ,0.001 0.64 (0.42–0.98) 0.041 0.81 (0.52–1.26) 0.349

Prestroke only — — — — — — — —

Acutely only 0.33 (0.20–0.55) ,0.001 0.36 (0.20–0.62) ,0.001 0.65 (0.42–1.01) 0.054 0.82 (0.52–1.28) 0.376

Prestroke and acutely 0.24 (0.06–1.00) 0.051 0.24 (0.05–1.07) 0.061 0.65 (0.26–1.67) 0.356 0.90 (0.34–2.38) 0.837

Abbreviations: CI 5 confidence interval; ES 5 poststroke early-onset seizures; OR 5 odds ratio; PSE 5 poststroke epilepsy.

4 Neurology 85 August 25, 2015

ª 2015 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

 However, there are concerns about the use of tradi-
Table 4 Baseline and outcome differences with and without statin use in
patients presenting with poststroke early-onset seizures
tional antiepileptic drugs due to side effects, poor
tolerance in elderly patients, interaction with antico-
Statin use agulant or antiplatelet therapy, and altered or delayed
functional recovery.28 Because antiepileptic therapy is
Variable Yes (n 5 33) No (n 5 30) p Value
long-term, most neurologists tend to be cautious and
Age, y, mean 6 SD 65.2 6 13.1 57.3 6 18.1 0.051
only initiate treatment after recurrent seizures. Com-
Sex, male 17 (51.5) 16 (53.3) 0.885
pared with traditional antiepileptic drugs, statins have
TOAST stroke etiology 0.155 fewer side effects and drug interactions and are more
Large artery atherosclerosis 14 (42.4) 6 (20) tolerable for elderly patients. Therefore, for patients
Cardioembolism 7 (21.2) 10 (33.3) with first ES for whom treatment is being considered,
Small vessel disease 0 (0) 1 (3.3)
statins may be a potential choice.
Reduction in PSE after statin treatment in patients
Other determined etiology 1 (3.0) 0 (0)
presenting with an acute seizure seems to suggest that
Undetermined etiology 11 (33.3) 13 (43.3)
acute statin treatment can eliminate the need for
NIHSS score 0.055 chronic treatment of epilepsy. Previous studies have
<7 11 (33.3) 17 (56.7) proven that short-term statin treatment in the acute
7–25 19 (57.6) 12 (40) phase of stroke may have neuroprotective effects
>25 3 (9.1) 1 (3.3)
and improve long-term outcomes,6 which is consis-
tent with the current study. Moreover, gliosis is a key
Hypertension 21 (63.6) 7 (23.3) 0.001
factor leading to PSE, and statins have been found to
Diabetes mellitus 10 (30.3) 4 (13.3) 0.106
suppress reactive astrogliosis and neuronal loss,29 the-
Atrial fibrillation 7 (21.2) 3 (10) 0.224 oretically having an effect on PSE. However,
Peripheral arterial disease 0 (0) 1 (3.3) 0.290 although we found a reduction in PSE after statin
Smoking 10 (30.3) 6 (20) 0.348 treatment in patients presenting with an acute seizure,
Alcohol use 5 (15.2) 5 (16.7) 0.869
the results suggest that only a proportion of patients
with ES may not require chronic treatment. For the
Follow-up, mo, mean 6 SD 29.2 6 15.5 26.9 6 15.1 0.550
remaining patients, long-term antiepileptic treatment
Hemorrhagic transformation 1 (3.0) 2 (6.7) 0.498
may still be necessary.
Admission lipid level
Unexpectedly, statins were not found to reduce
Triglycerides, mmol/L, mean 6 SD 1.79 6 1.37 1.53 6 0.83 0.368 the risk of PSE in the present study. This may be
Total cholesterol, mmol/L, mean 6 SD 4.16 6 1.10 4.27 6 0.66 0.640 due to a “dilution effect.” Reduction of PSE in a
HDL cholesterol, mmol/L, mean 6 SD 1.08 6 0.32 1.31 6 0.45 0.022 subset of patients with an acute seizure was found;
LDL cholesterol, mmol/L, mean 6 SD 2.51 6 1.05 2.56 6 0.74 0.844
this is a vulnerable subset, and adding in the rest of
the data drowns out the effect of statins on that sub-
PSE 6 (18.2) 14 (46.7) 0.015
set. The incidence of PSE among patients with acute
Abbreviations: HDL 5 high-density lipoprotein; LDL 5 low-density lipoprotein; NIHSS 5 NIH seizure was 31.7%, whereas the incidence of epilepsy
Stroke Scale; PSE 5 poststroke epilepsy; TOAST 5 Trial of Org 10172 in Acute Stroke
among those who did not have an acute seizure was
Treatment.
Data are n (%) unless otherwise indicated.
only 4.0%. Considering the goal of preventing PSE
with statins, a group of patients who did not require
treatment was treated, which explains why a treat-
and seizure risk.24 Third, statins can reduce the per- ment effect in the whole group cannot be observed.
meability of the blood–brain barrier and brain inflam- None of the patients used anticonvulsant drugs
mation,25 delaying or preventing the development of after a first seizure attack of PSE in this study. This
seizures.26 was due to controversy over initiating anticonvulsant
Another interesting finding was that the risk of therapy after a first poststroke seizure. To date, there
PSE was reduced in patients with ES after statin treat- remains no conclusive evidence.3,28 A previous study
ment. One of the most important issues regarding the stated that the risk of a second seizure after a first
treatment of poststroke seizures is when to start anti- poststroke late-onset seizure varies between 54%
epileptic drugs. Most guidelines recommend that and 66%. These figures are not significantly different
recurrent seizures after stroke be treated, but data from those observed in the general population of pa-
are limited concerning the efficacy of initiating anti- tients who receive no treatment after a first unpro-
convulsants after a first ES.3 Some neurologists start voked seizure and in whom withholding treatment
antiepileptic drugs after a first acute seizure in specific until the second seizure does not appear to be harm-
conditions, considering the increased risk of late- ful.28 In addition to poor tolerance and the adverse
onset seizures and life-threatening status epilepticus.27 effects of antiepileptic drugs in elderly stroke patients

Neurology 85 August 25, 2015 5

ª 2015 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

 previously discussed, treatment tends to be more con-
servative in China, and patients regularly do not use
antiepileptic drugs after a first poststroke seizure. This
ensures that the effect of statins on PSE will not be
affected by the use of antiepileptic drugs.
Statin treatment only in the acute phase exerted
anticonvulsant effects. In studies using animal mod-
els, treatment with statins before or soon after cerebral
arterial occlusion has been shown to have neuropro-
tective effects.30,31 Therefore, we were prepared to
assess the anticonvulsant effects of statin treatment
before stroke or in the acute phase. However, the
results were not consistent with previous studies. This
may have been due to the small number of patients
who received statin treatment before stroke in the
study.
For the 63 patients who presented with ES, the
average length of exposure to statins was 4.7 days.
Previous studies have suggested that statins exert neu-
roprotective effects rapidly. Many experimental stud-
ies on rats have shown that neuroprotective
pathologic and biochemical changes occur within
24 hours after statin treatment.30 Some clinical stud-
ies have also found that stroke patients have better
clinical outcomes with only a few days of statin expo-
sure,32,33 giving us reason to believe that the exposure
to statins in our study was sufficient to produce anti-
convulsant effects.
The study had 3 main limitations. First, the cate-
gory and dose of statins were not specified in relation
to the risk of poststroke seizure. Studies have sug-
gested that statins may have varying concentrations
in the brain as a result of differing abilities to cross
the blood–brain barrier.15 Hence, the neuroprotective
effects of various statins may be different. In addition,
experimental studies have suggested that the dose of
statins can affect neuroprotective effects.30,34,35 How-
ever, as the number of patients with simvastatin and
rosuvastatin treatment was small in our sample, there
was insufficient data to conduct appropriate subgroup
analyses. Second, the prevalence of seizures after
stroke was low, so the number of seizure events in
the study was low. Due to the relatively small number
of patients who took a statin before stroke, the anti-
convulsant effect of the prestroke use of statins could
not be assessed. In addition, considering the limited
sample size for each type of seizure, the study did not
have enough power to assess the effect of statins on
different clinical features of poststroke seizures.
Third, for those patients with significant carotid ste-
nosis, differentiating the diagnosis from limb-shaking
TIA is difficult. As the study population included
patients with significant carotid stenosis, the potential
for misdiagnosis existed. However, limb-shaking TIA
is a rare manifestation of carotid occlusive disease,36
and with the assessment of professional neurologists,
6 Neurology 85 August 25, 2015
ª 2015 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
the possibility of misdiagnosis should be very low.
Considering these limitations, further investigations
with a larger study cohort and sufficient information
to allow for powerful stratification analyses are needed
to confirm the results.
This study provides initial evidence that statins
may reduce the risk of ES following stroke, particu-
larly if used in the acute phase. In addition, in pa-
tients who present with ES, statin treatment may
reduce the risk of PSE. However, as a consequence
of the observational nature of the study, future trials
with larger sample sizes are needed to validate the
findings.
AUTHOR CONTRIBUTIONS
Drs. Jiang Guo and Jian Guo revised and drafted the manuscript.
Drs. J. Li, F. Qin, S. Zhang, and B. Wu were responsible for the acquisition
and interpretation of data. Dr. M. Zhou was responsible for the data anal-
ysis. Drs. L. He and D. Zhou conceived and designed the study.
STUDY FUNDING
This work was supported by the National Natural Science Foundation of
China (Grants Nos. 81300943, 81071140, 81371529, and 81420108014).
DISCLOSURE
Jiang Guo reports no disclosures relevant to the manuscript. Jian Guo
received grant or research support from the National Natural Science
Foundation of China. J. Li, M. Zhou, F. Qin, S. Zhang, and B. Wu
report no disclosures relevant to the manuscript. L. He received grant
or research support from the National Natural Science Foundation of
China. D. Zhou received grant or research support from the National
Natural Science Foundation of China and serves as an editorial board
member of Neural Regeneration Research and Chinese Journal of Neurology.
Go to Neurology.org for full disclosures.
Received December 6, 2014. Accepted in final form April 28, 2015.
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Neurology 85 August 25, 2015 7
 Statin treatment reduces the risk of poststroke seizures
Jiang Guo, Jian Guo, Jinmei Li, et al.
Neurology published online July 22, 2015
DOI 10.1212/WNL.0000000000001814

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