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Effects of double-dose statin therapy for the prevention of post-stroke epilepsy: A prospective clinical study

  • Author Footnotes
    1 Yanmei Zhu, Haiyan Gou, Long Ma and Jiahang Sun are contributed equally to this work.
    Yanmei Zhu
    Correspondence
    Corresponding authors at: No. 246, Xuefu Road, Nangang District, Harbin City, Heilongjiang Province, China.
    Footnotes
    1 Yanmei Zhu, Haiyan Gou, Long Ma and Jiahang Sun are contributed equally to this work.
    Affiliations
    The Second Affiliated Hospital of Harbin Medical University, China
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  • Author Footnotes
    1 Yanmei Zhu, Haiyan Gou, Long Ma and Jiahang Sun are contributed equally to this work.
    Haiyan Gou
    Footnotes
    1 Yanmei Zhu, Haiyan Gou, Long Ma and Jiahang Sun are contributed equally to this work.
    Affiliations
    The Second Affiliated Hospital of Harbin Medical University, China
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  • Author Footnotes
    1 Yanmei Zhu, Haiyan Gou, Long Ma and Jiahang Sun are contributed equally to this work.
    Long Ma
    Footnotes
    1 Yanmei Zhu, Haiyan Gou, Long Ma and Jiahang Sun are contributed equally to this work.
    Affiliations
    The Second Hospital of Heilongjiang Province
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  • Author Footnotes
    1 Yanmei Zhu, Haiyan Gou, Long Ma and Jiahang Sun are contributed equally to this work.
    Jiahang Sun
    Footnotes
    1 Yanmei Zhu, Haiyan Gou, Long Ma and Jiahang Sun are contributed equally to this work.
    Affiliations
    The Second Affiliated Hospital of Harbin Medical University, China
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  • Yuting Hou
    Affiliations
    Nanning Second People's Hospital (The Third Affiliated Hospital of Guangxi Medical University
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  • Yunong Li
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    The Second Affiliated Hospital of Harbin Medical University, China
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  • Jia He
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    The Second Affiliated Hospital of Harbin Medical University, China
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  • Yan Chen
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    The Second Affiliated Hospital of Harbin Medical University, China
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  • Yulan Zhu
    Correspondence
    Corresponding authors at: No. 246, Xuefu Road, Nangang District, Harbin City, Heilongjiang Province, China.
    Affiliations
    The Second Affiliated Hospital of Harbin Medical University, China
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  • Author Footnotes
    1 Yanmei Zhu, Haiyan Gou, Long Ma and Jiahang Sun are contributed equally to this work.
Open ArchivePublished:April 14, 2021DOI:https://doi.org/10.1016/j.seizure.2021.04.010

      Highlights

      • Double-dose statin treatment reduces the incidence of post-stroke epilepsy (PSE) during the acute phase of ischemic stroke, which is better than a standard-dose.
      • PSE incidence was higher in patients under 65 years of age, and more males than females were affected.
      • The majority of PSE occurred between 6 and 12 months after the beginning of statin treatment.

      Abstract

      Background

      To determine treatment effects on the incidence of post-stroke epilepsy (PSE) using different doses of statin, a prospective hospital-based cohort study was designed to explore whether a double-dose statin treatment can better prevent the occurrence of PSE.

      Methods

      A total of 1152 patients with newly diagnosed ischemic stroke admitted to our hospital from March to August 2017 were selected, 1033 of whom were followed-up. Patients were divided into two treatment groups:(1) standard-dose (20 mg atorvastatin or 10 mg rosuvastatin,daily oral; 788 patients); and (2) double-dose (40 mg atorvastatin or 20 mg rosuvastatin, daily oral; 245 patients).At 18 months follow-up was conducted to compare the incidence of PSE between groups.

      Results

      In general, in the standard-dose group we observed two cases of early seizure (ES) (0.25%), 22 cases oflate seizure (LS) (2.79%) and 20 cases of PSE (2.54%). In the double-dose group, onepatient had ES (0.41%), two patients had LS (0.82%), and onepatient had PSE (0.41%). The incidence of PSE was significantly lower in the double-dose group as compared to the standard-dose group. There was a higher proportion of PSE in patients younger than 65 years and in males. Three patients had ES; one presented with focal aware seizure (FAS), and two had focal to bilateral tonic-clonic seizure (FBTCS). Among the 21 patients with PSE, there were two cases of FAS, five cases of focal impaired awareness seizure (FIAS), five cases of FBTCS, and nine cases of GTCS, suggesting that partial seizure is the most common type of PSE. Cerebral cortex was involved in 85.75% of cases with PSE, and multiple lobes were involved in 61.9% of cases with PSE.

      Conclusion

      Increasing the dose of statin treatment during the acute phase of ischemic stroke reduces the incidence of PSE. Further research is needed to understand the mechanisms underlying the potential preventative effects of statins against PSE.

      Keywords

      1. Introduction

      Stroke is the leading cause of epilepsy and ranks among the top causes of death [
      • Tanaka T.
      • Ihara M.
      Post-stroke epilepsy.
      ]. The overall incidence of post-stroke epilepsy (PSE), which is the main type of newly diagnosed epilepsy in elderly patients, is 3%−45% [
      • Siniscalchi A.
      • Mintzer S.
      Statins for poststroke seizures: the first antiepileptogenic agent?.
      ,
      • Guo J.
      • Guo J.
      • Li J.
      Statin treatment reduces the risk of poststroke seizures.
      ]. Therefore, the diagnosis and treatment of PSE has been extensively investigated.
      Statin is an inhibitor of 3‑hydroxy-3-methyl-glutaryl coenzyme (HMG-CoA) reductase and has been commonly used to treat vascular diseases based on its enhancing effect in cholesterol metabolism. Previous studies have suggested that individuals treated with statin have a lower incidence of epilepsy [
      • Siniscalchi A.
      • Mintzer S.
      Statins for poststroke seizures: the first antiepileptogenic agent?.
      ]. Indeed, recent studies based on animal research have proposed that statin exerts antiepileptogenic effects, whereby it induces an inhibition of the epileptic behavior and apoptosis of neurons [
      • Etminan M.
      • Samii A.
      • Brophy J.M.
      Statin use and risk of epilepsy: a nested case-control study.
      ].Subsequently, it has also been observed in some retrospective clinical studies that the use of statin in patients with newly diagnosed stroke reduced the risk of early seizure (ES) and the progression of PSE-induced injury, especially in the acute phase [
      • Guo J.
      • Guo J.
      • Li J.
      Statin treatment reduces the risk of poststroke seizures.
      ]. Based on these findings, the present study aimed to better understand the efficacy of different doses of statin in the treatment and prevention of ES and PSE. This study has been designed as a prospective hospital-based cohort study, with nonrandomized single blind (data collectors were blind to the content of the study), and a comparative study between the standard-dose group and double-dose group.

      2. Methods

      2.1 Study subjects

      A total of 1152 patients with newly diagnosed ischemic stroke admitted to our hospital, which is a tertiary hospital in the Harbin city, from March to August 2017 were consecutively selected. A total of 1033 patients were followed up, including 660 males and 373 females; 41patients died, and 78 were unable to finish the study. Two neurologists independently evaluated the patients according to the inclusion and exclusion criteria as defined below. If there were differences in the evaluation results, consensus was reached through discussion. The study protocol was approved by the Institutional Ethics Committee of Harbin Medical University, China, and all patients had signed the informed consents. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

      2.2 Inclusion criteria

      • (1)
        First ischemic stroke, which met the diagnostic criteria in the 2014 guidelines for the diagnosis and treatment of acute ischemic stroke in China [
        Chinese Neurology Association
        Guidelines for the diagnosis and treatment of acute ischemic stroke 2014.
        ];
      • (2)
        no previous history of epilepsy;
      • (3)
        age between 18 and 80.

      2.3 Exclusion criteria

      • (1)
        Previous history of stroke or post-operative history of cranial trauma;
      • (2)
        secondary stroke caused by direct head trauma or surgery;
      • (3)
        brain computed tomography (CT) or magnetic resonance imaging (MRI) indicating cerebral hemorrhages, including cerebral parenchymal hemorrhage, primary subarachnoid hemorrhage, subdural hematoma, and intracranial venous thrombosis;
      • (4)
        history of severe mental illness;
      • (5)
        history of drug abuse;
      • (6)
        history of epilepsy prior to the stroke;
      • (7)
        family history of epilepsy
      • (8)
        epileptic seizures due to other causes (including malignant tumors, specific autoimmune diseases, severe electrolyte abnormalities, end-stage renal disease, and severe brain trauma);
      • (9)
        a contraindication or intolerance to statin therapy;
      • (10)
        less than 18 or more than 80 years old;
      • (11)
        patients died or lost during follow-up.

      2.4 Basic information collection

      Patients’ information was extracted from the inpatient medical record system of our hospital. Baseline characteristics of patients (age, sex, hypertension, diabetes status, atrial fibrillation, smoking history, drinking history, conversion to cerebral hemorrhage, total cholesterol, triglycerides, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and National Institutes of Health Stroke Scale (NIHSS) score were recorded on admission or during hospitalization. Trial of Org 10,172 in Acute Stroke Treatment (TOAST)subtype of stroke, hospitalization duration, other laboratory examinations, and CT and/or MRI findings were recorded. The data collectors were blind to the content of the study. Statins were used in the patients in whom stroke was presumed to have originated with atherosclerosis, regardless of LDL-C levels.

      2.5 Group assignment and statin treatment

      Patients who met the inclusion criteria were assigned to one of two treatment groups, standard dose or high dose. Statin dosage was determined by the attending physician in the nonrandomized way in accordance with the patient's clinical condition and relevant guideline. In patients with ischemic stroke due to atherosclerotic stenosis of the large intracranial arteries, double-dose statins are recommended. A total of 788 patients were included in the standard-dose statin treatment group (daily oral doses of 20 mg atorvastatin or 10 mg rosuvastatin), 501 of whom were male, and 287were female. The average age in this group was 60.36±10.66 (range 24 to 80) years. Patients in the second group were treated with double-dose of statin (daily oral doses of 40 mg atorvastatin or 20 mg rosuvastatin), with a total number of 245, 159 of whom were men and 86 were women, aged 60.36 ± 10.81 (range 36 to 80) years. There were no significant differences in basic clinical data between the two groups, such as hypertension, diabetes mellitus status, history of atrial fibrillation, and NIHSS score (P> 0.05). Statin treatment was given in the acute phase of ischemic stroke, which was defined as within three days after stroke onset and continuing for at least three days [
      • Stone N.J.
      • Robinson J.G.
      • Lichtenstein A.H.
      • Bairey Merz C.N.
      • Blum C.B.
      • Eckel R.H.
      • et al.
      2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.
      ].

      2.6 Follow-up

      The follow up was conducted by telephone interviews or face-to-face assessments at the outpatient department for a mean period of 18 months after the treatment.

      2.7 Outcome

      The patients were asked whether they had experienced a seizure-like event or had been diagnosed with epilepsy by doctors after discharge. The main outcomes were the occurrence of ES, late seizure (LS), and PSE. According to the time of onset, seizures after stroke can be divided into ES (onset within seven days after stroke) and LS (onset after seven days after stroke). PSE is defined as two or more unprovoked seizures after acute stroke, and the diagnostic criteria for PSE met the guidelines of the International League Against Epilepsy (ILAE) [
      • Zhang C.
      • Wang X.
      • Wang Y.
      • Zhang J.G.
      • Hu W.
      • Ge M.
      • et al.
      Risk factors for post-stroke seizures: a systematic review and meta-analysis.
      ]. None of the patients were treated with anticonvulsant drugs after the first episode of seizure. The relationship between different doses of statin and the incidence of PSE in the two groups was assessed. Seizures were categorized into focal aware seizure (FAS), focal impaired awareness seizure (FIAS), generalized tonic-clonic seizure (GTCS), and focal to bilateral tonic-clonic (FBTCS).

      2.8 Statistical analyses

      Statistical analyses were performed using SPSS version 19.0 (IBM Corp., Armonk, NY). Means and standard deviation were used for measurement data, and frequency was used for counting data. Independent sample t-test was used to compare data sets. The (corrected) χ2 test or Fisher exact probability method was used to compare categorical data. P values of ≤ 0.05 were considered statistically significant.

      3. Results

      At baseline, no significant differences were observed between standard- and double-dose statin treatment groups in age, sex, hypertension, diabetes status, atrial fibrillation, smoking, drinking, NIHSS score, TOAST classification, hemorrhage transformation, and laboratory examinations, such as total cholesterol, triglycerides, HDL-C and LDL-C (P>0.05) (Table 1).
      Table 1Comparisons of baseline data between the two groups.
      VariableGroupsχ2/tP
      Standard- dose statin (n = 788)Double- dose statin (n = 245)
      Sexmale501(63.58)159 (64.90)0.1410.707
      female287 (36.42)86 (35.10)
      TOAST

      stroke etiology
      SUD605 (76.78)190 (77.55)0.0630.802
      LAA183 (23.22)55 (22.45)
      HypertensionNo320 (40.61)102 (41.63)0.0810.776
      Yes468 (59.39)143 (58.37)
      Diabetes mellitusNo612 (77.66)197 (80.41)0.8280.363
      Yes176 (22.34)48 (19.59)
      Atrial fibrillationNo764 (96.95)237 (96.73)0.0300.862
      Yes24 (3.05)8 (3.27)
      SmokingNo476 (60.41)156 (61.18)0.0480.827
      Yes312 (39.59)99 (38.82)
      Alcohol useNo595 (75.51)180 (73.47)0.4140.520
      Yes193 (24.49)65 (26.53)
      Hemorrhagic transformation#No787 (99.87)243 (99.18)0.142
      Yes1 (0.13)2 (0.82)
      Age60.29 ± 10.6660.36 ± 10.810.0120.991
      NIHSS Score3.92 ± 3.493.94 ± 3.160.0860.931
      Total cholesterol(mmol/L)4.81 ± 1.124.67 ± 1.151.7140.087
      Triglycerides(mmol/L)1.96 ± 1.261.93 ± 1.510.3100.757
      HDL cholesterol(mmol/L)1.31 ± 0.481.31 ± 0.320.0400.968
      LDL cholesterol(mmol/L)2.73 ± 0.892.72 ± 0.830.1360.892
      Average follow-up(months)18.83±1.3718.46 ± 1.240.0830.945
      Note: Fisher exact probability method was used.Data are n (%) unless otherwise indicated.
      Abbreviations:HDL: high-density lipoprotein; LAA:large artery atherosclerosis; LDL: low-density lipoprotein; NIHSS:National Institutes of Health Stroke Scale; SUD: stroke of undetermined etiology; TOAST: Trial of Org 10,172 in Acute Stroke Treatment.
      In general, the incidence of PSE was significantly lower in the double-dose group as compared to the standard-dose group. There was a higher proportion of PSE in patients younger than 65 years and in males. Three patients had ES; one presented with FAS, and two had FBTCS. Among the 21 patients with PSE, there were two cases of FAS, five cases of FIAS, five cases of FBTCS, and nine cases of GTCS, suggesting that partial seizure is the most common type of PSE. Cerebral cortex was involved in 85.75% of cases with PSE, and multiple lobes were involved in 61.9% of cases with PSE.

      3.1 Comparison of PSE incidence between groups

      ES, LS, and PSE occurred in a total of two patients (0.25%),22 patients(2.79%), and 20 patients(2.54%), respectively, in the 788 patients treated with standard dose statin. Among the 245 patients in the double-dose statin group, onepatient (0.41%) had ES, two patients had LS (0.82%), and one patient had PSE (0.41%). There were no statistically significant differences in the incidences of ES and LS between the two groups. In contrast, the incidence of PSE was significantly lower in the double-dose group compared to the standard-dose group (P ˂ 0.05) (Table 2).
      Table 2Comparison of ES, LS, and PSE incidence between the two groups.
      VariableGroupsχ2P
      Standard- dose statin (n = 788)Double- dose statin (n = 245)
      ES#No786 (99.75)244 (99.59)0.557
      Yes2 (0.25)1 (0.41)
      LS*No766 (97.21)243 (99.18)3.2140.073
      Yes22 (2.79)2 (0.82)
      PSE*No768 (97.46)244 (99.59)4.2570.039
      Yes20 (2.54)1 (0.41)
      Note: *corrected χ2test; #Fisher exact probability method.
      Abbreviations: ES: early seizure; LS: late seizure; PSE: post-stroke epilepsy.

      3.2 Analysis of sex and age among PSE patients

      Among the 21 patients with PSE, males accounted for 61.9% (13/21), and females accounted for 38.1% (8/21). A total of 66.67% (14/21) was <65 years of age and 33.33% (7/21) were aged >65 years.

      3.3 Seizure type analysis for ES and PSE

      In this study, among the three patients with ES, one patient presented with FAS, and two patients presented with FBTCS. Among the 21 patients with PSE, there were two cases of FAS, five cases of FIAS, five cases of FBTCS, and nine cases of GTCS (Table 3).
      Table 3Seizure type classification of ES and PSE.
      ESPSE
      FAS1(33.33%)2(9.52%)
      FIAS5(23.81%)
      FBTCS2(66.67%)5(23.81%)
      GTCS9(42.86%)
      Abbreviations: FIAS: focal impaired awarenessseizure; ES: early seizure; GTCS: generalized tonic-clonic seizure; FBTCS: focal to bilateral tonic-clonic seizure; PSE: post-stroke epilepsy; FAS: focal aware seizure.

      3.4 Site of stroke in patients with PSE

      Among the 21 patients with PSE, in 18 cases the strokes were located in the cerebral cortex and subcortical structures, accounting for 85.71%, and in three cases the strokes were located only in the subcortical structures, accounting for 14.29% (Table 4).
      Table 4Lesion locations of the stroke of patients with PSE.
      Lesion location of stroke
      cerebral cortex18
      subcortex3

      3.5 Lesion area in patients with PSE

      The number of brain lobes involved in the 21 patients with PSE was analyzed. Eight patients (38.1%) had a lesion involving a single lobe, and 13 patients (61.9%) had lesions involving multiple lobes (Table 5).
      Table 5Area of lesions in patients with PSE.
      Lesion area of stroke
      Involvement of one lobe8
      Involvement two lobes7
      Involvement three lobes or more6

      3.6 Time of episode for ES, LS, and PSE

      All three cases of ES occurred within the first 24 h after stroke onset. Among 23 cases of LS, 3 cases occurred in the first six-month period, 18 cases in the second six-month period, and 2 cases in the third six-month period after stroke. For the 21 patients who presented with PSE, 3 patients developed PSE during the first six-month period after stroke onset, 17 patients during the second six-month period and 1patient during the third six-month period (Table 6).
      Table 6Time of episode for LS and PSE.
      Time of episodeLSPSE
      Within 6 months after stroke3 (13.04%)3(14.29%)
      6–12 months after stroke18 (78.26%)17(80.95%)
      12–18 months after stroke2 (8.70%)1(4.76%)

      4. Discussion

      In this study, we found that the incidence of PSE in patients treated with double-dose statin was lower than in those treated with standard-dose statin, indicating that the antiepileptogenic effect of statin may be positively correlated with dose. Such dose-dependent preventative effects of statin against PSE are in accordance with previous clinical trials [
      • Li Y.
      • Zhang B.
      • Zhang L.
      • Xie D.
      • Li Y.
      Efficacy of statin therapy in post-stroke seizure prophylaxis: clues from an observational study of routine secondary prevention treatment.
      ,
      • Lin F.J.
      • Lin H.W.
      • Ho Y.F.
      Effect of statin intensity on the risk of epilepsy after ischaemicstroke: real-world evidence from population-based health claims.
      ], and have also been observed in patients with intracranial hemorrhage [
      • Lin H.W.
      • Ho Y.F.
      • Lin F.J.
      Statin use associated with lower risk of epilepsy after intracranial hemorrhage: a population-based cohort study.
      ]. Beyond that, we describe for the first-time detailed outcomes of different statin doses, including the time of seizure emergence, the area of lesions, and the sites of stroke.
      In addition, atorvastatin was found to significantly reduce the frequency and amplitude of discharge using electrocorticography, playing an antiepileptogenic role, in a mouse model of epileptic seizures induced by cortical injection of penicillin [
      • Seker F.B.
      • Kilic U.
      • Caglayan B.
      • Ethemoglu M.S.
      • Caglayan A.B.
      • Ekimci N.
      • et al.
      HMG-CoA reductase inhibitor rosuvastatin improves abnormal brain electrical activity via mechanisms involving eNOS.
      ]. The mechanism of action may be related to the fact that statin can improve the integrity of the blood-brain barrier by reducing IgG exosmosis, increase the expression of endothelial nitric oxide synthase mRNA, and reduce the expression of pro-apoptotic p53, Bax, and caspase-3[11]. Statins also exert antiepileptogenic effects by regulating the activity of glycogen synthetase kinase-3 and by reducing moss fiber budding [
      • Lee C.Y.
      • Jaw T.
      • Tseng H.C.
      • Chen I.C.
      • Liou H.H.
      Lovastatin modulates glycogen synthase kinase-3β pathway and inhibits mossy fiber sprouting after pilocarpine-induced status epilepticus.
      ]. In addition, inhibition of astrocyte proliferation and neuron loss by statins may also contribute to the neuroprotective function that reduces the risk of strokes developing into PSE [
      • Li M.Q.
      • Zhang W.W.
      • Chen T.
      • Liu L.
      Protective effects of levetiracetam and simvastatin on pilocarpine-induced epilepsy in rat models.
      ,
      • McFarland A.J.
      • Anoopkumar-Dukie S.
      • Arora D.S.
      Molecular mechanisms underlying the effects of statins in the central nervous system.
      ,
      • Xie C.
      • Sun J.
      • QiaoW Lu D
      • Wei L.
      • Na M.
      • et al.
      Administration of simvastatin after kainic acid-induced status epilepticus restrains chronic temporal lobe epilepsy.
      ].
      In the follow-up of 1033 patients in the present study, the incidences for ES, LS and PSE were 0.29%, 2.1% and 2.03%, respectively, whereas previous studies reported incidences of 2%−4%, 3%−6% and 2%−30%, respectively [
      • Szaflarski J.P.
      • Rackley A.Y.
      • Kleindorfer D.O.
      • Khoury J.
      • Woo D.
      • Miller R.
      • et al.
      Incidence of seizures in the acute phase of stroke: a population-based study.
      ,
      • Renate A.
      • Loes R.J.
      • Noortje M.
      • Schoonderwaldt H.
      • Dorresteijn L.
      • van Dijk E.
      • et al.
      Post-stroke epilepsy in young adults: a long-term follow-Up study.
      ,
      • Jungehulsing G.J.
      • Heuschmann P.U.
      • Holtkamp M.
      • Schwab S.
      • Kolominsky-Rabas P.L.
      Incidence and predictors of post-stroke epilepsy.
      ,
      • Graham N.S.
      • Crichton S.
      • Koutroumanidis M.
      Incidence and associations of poststroke apilepsy: the Prospective South London Stroke Register.
      ]. This disparity may be explained by several reasons. The most obvious reason is that the effect of statin treatment has effectively reduced the incidence of seizures and the risk of developing PSE, as previously reported. Differences may also be explained by a shorter follow-up period in our study. In addition, patients’ location and ethnic background may play a role and cause deviations from other reports. Finally, the identification rate of ES, LS and PSE in our study may be low due to the difficulty in observing seizures by patients or family members, which is the same issue with other studies. In contrast, our finding that male and younger patients (under the age of 65 years) were more likely to develop PSE is consistent with previous studies [
      • Kim H.J.
      • Park K.D.
      • Choi K.G.
      • Lee H.W.
      Clinical predictors of seizure recurrence after the first post-ischemic stroke seizure.
      ].
      In the latest classification of the ILAE from 2017, FAS and FIAS were uniformly defined as focal onsets with awareness or impaired awareness [
      • Fisher R.S.
      • Cross J.H.
      • French J.A.
      • Higurashi N.
      • Hirsch E.
      • Jansen F.E.
      • et al.
      Operational classification of seizure types by the International League against epilepsy: position Paper of the ILAE Commission for Classification and Terminology.
      ]. As we did not obtain electro-encephalograms (EEGs) of the patients during seizure episode in this study, seizures could not be accurately classified according to the latest classification standard. We found that among the three ES cases, one presented as FAS and the other two presented as FBTCS, which is in line with previous studies [
      • O'Connor K.L.
      • Westover M.B.
      • Phillips M.T.
      • Iftimia N.A.
      • Buckley D.A.
      • Ogilvy C.S.
      • et al.
      High risk for seizures following subarachnoid hemorrhage regardless of referral bias.
      ]. Among the 21 patients with PSE, 42.86% presented as GTCS, which is higher than what is mentioned in the literature [
      • O'Connor K.L.
      • Westover M.B.
      • Phillips M.T.
      • Iftimia N.A.
      • Buckley D.A.
      • Ogilvy C.S.
      • et al.
      High risk for seizures following subarachnoid hemorrhage regardless of referral bias.
      ]. This disparity may be due to the lack of clinical and EEG evidence in our study, making it difficult to accurately identify GTCS.
      Among the patients with PSE, 85.71% had an infarction in the cortex, while the other 14.29% had a lesion in the subcortex. These are known to be the sites prone to stroke and associated with PSE [
      • Zhao Y.
      • Li X.
      • Zhang K.
      • Tong T.
      • Cui R.
      The progress of epilepsyafterstroke.
      ]. In addition, in 61.9% of patients, multiple lobes were involved in the stroke, whereas in38.1% of cases only a single lobe was affected. This was also demonstrated by previous studies, which have indicated that the risk of developing epilepsy was elevated in cases where strokes involved multiple lobes, as opposed to those with only a single lobe affected [
      • Kotan D.
      • Deniz O.
      • Aygul R.
      • Yildirim A.
      Acute cerebral ischaemia: relationship between serum and cerebrospinal fluid orexin-A concentration and infarct volume.
      ].
      Our results show that while ES occurred within 24 h after the onset of the stroke, most cases (80.95%) of LS occurred during 6–12 months after stroke. This is similar to the findings of previous investigations [
      • Chung J.M.
      Seizures in the acute stroke setting.
      ,
      • Camilo O.
      • Goldstein L.B.
      Seizures and epilepsy after ischemic stroke.
      ]. Since the duration of the follow-up was limited to 18 months; this may have reduced the incidence of LS in this study.
      The limitations of the present study, including relatively small sample size and short follow-up duration in addition to those already mentioned, raise some expectations for future investigations. Most importantly, we plan to complete a multi-center clinical trial with a larger sample size and an extended follow-up period, which will help to confirm and broaden our current findings in the protection against PSE. Additionally, a recent animal study has claimed that the antiepileptogenic effect of rosuvastatin is not associated with the serum level of cholesterol [
      • Seker F.B.
      • Kilic U.
      • Caglayan B.
      • Ethemoglu M.S.
      • Caglayan A.B.
      • Ekimci N.
      • et al.
      HMG-CoA reductase inhibitor rosuvastatin improves abnormal brain electrical activity via mechanisms involving eNOS.
      ]. It would be interesting and important to investigate a potential correlation between cholesterol levels and the incidence of PSE in humans. There are some shortfalls in the methodology which should be improved in future. For example, EEG evidence will be added in the next study for a more precise interpretation of the onset of the seizure. The statins initiated within the first 72 h after the patients admitted to hospital. However, the intervals between the onset of the stroke and the initiations of statins were not recorded. Most of the patients have continued in taking statins till the last visit for about 18 months. However, the precise period of continuing statin treatment in the two groups were not recorded. In addition, the selection of the two different dose groups were not randomized and biased by the clinical condition. These might also be the limitations to the study.
      In conclusion, this study demonstrated that the preventative effect of statins on the development of PSE is dose-dependent, therefore adding to our understanding to the prevention and treatment of stroke-related epilepsy.

      Data sharing policy

      The authors confirm that the data supporting the findings of this study are available within the article and/or its supplementary materials.

      Funding

      This work was supported by the National Natural Science Foundation of China (Grants No. 81,871,016 ), China Association Against Epilepsy research funding (Grants No. 2,018,015 ) and Innovative Scientific Research Fund for Young and Middle-aged Doctor of Second Affiliated Hospital of Harbin Medical University (Grants No. kycx2018–25 ).

      Ethical publication statement

      We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

      CRediT authorship contribution statement

      Yanmei Zhu: Project administration. Haiyan Gou: Writing – review & editing. Long Ma: Software. Jiahang Sun: Formal analysis. Yuting Hou: Methodology. Yunong Li: Data curtion. Jia He: Validation. Yan Chen: Writing – original draft. Yulan Zhu: Supervision.

      Declaration of Competing Interest

      All authors claim that there are no conflicts of interest.

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