- Email: [email protected]
Estimation of seizures prevalence in ischemic strokes after thrombolytic therapy
Seizure: European Journal of Epilepsy 62 (2018) 91–94
Contents lists available at ScienceDirect
Seizure: European Journal of Epilepsy journal homepage: www.elsevier.com/locate/seizure
Estimation of seizures prevalence in ischemic strokes after thrombolytic therapy
T
Daphna Nesselrothd, Ronit Gilada,c, Montaser Namneha, Sarit Avishayb, Anda Eilama,
⁎
a
Neurological department, Kaplan Medical Center, Rechovot, Israel Management department, Kaplan Medical Center, Rechovot, Israel c Hebrew university, Jerusalem, Israel d Sackler Medical School, Tel-Aviv University, Israel b
ARTICLE INFO
ABSTRACT
Keywords: Ischemic stroke Thrombolytic therapy Post-stroke seizures
Purpose: Post stroke seizures are a complication that occur in 5-20% of acute ischemic stroke (AIS) patients, cause a reduction in quality of life and a greater burden on the health system. There is not enough data regarding an association between today’s standard of care treatment in AIS: recombinant tissue plasminogen activator (rtPA) and the risk for post stroke seizures. Our aim in this work is to reveal such a connection. Method: A non-randomized retrospective cohort-controlled study of 234 patients, who were hospitalized with acute ischemic stroke at Kaplan Medical Center in the years 2009-2015 and were divided into two different treatment groups: r-tPA and antiaggregant therapy(n = 141) and antiaggregant therapy only (n = 95) was conducted by us. Information regarding demographics, medical history, nature of the event, including NIHSS values on admission, discharge, and post stroke seizures, were obtained for each group. Follow-up was done for one year. Results: During the year of follow-up, 19 patients (8.1%) of the overall cohort, developed seizures: 12 of them (12.6%) belonged to the control group and 7 (5%) to the study group p < 0.05). Results showed a decrease in the risk for developing seizure when treated with r-tpA, comparing to antiaggregants (odds ratio = 0.64). Conclusion: This study suggests there is an association between r-tPA treatment and reduction of the risk for post stroke seizures.
1. Background Epilepsy is a common neurologic disorder which affects about 1% of the U.S. population [1]. Most new cases of epilepsy occur in the elderly, with an annual incidence rate of 240 per 100,000 in people aged 65 and older in the United States [1]. Among patients with new-onset epilepsy, almost 50% of the causes can be explained by an underlying etiology, such as vascular diseases, tumors or metabolic disorders [2]. Around 30–40% of new epilepsy cases among the elderly are accounted for by previous cerebrovascular hemorrhages or ischemic accidents. This makes cerebrovascular strokes the most common cause of secondary epilepsy in adults [3]. The risk of developing post-stroke seizures ranges from 5 to 20% in patients older than 35 years old [4,5]. Risk factors for developing secondary seizures or epilepsy have been well studied [4,6,7]. The stroke characteristics, such as subtype, severity, hemorrhagic transformation and cortical involvement, correlate with the risk of secondary epilepsy.
⁎
A large lesion, severe presentation (higher National Institute of Health stroke score (NIHSS) on admission) and signs of cortical injury, such as dysphasia or visual neglect, all enhance the risk to develop future poststroke epilepsy (PSE) [3,6]. After a stroke, the risk of developing a seizure or (PSE) is 20 times higher in the first year after the event [7]. Post-stroke seizures are classified as ‘early onset’ seizures, if they occur within two weeks after the stroke. The peak incidence of 45% is at 24 h past the cerebrovascular event [17]. If the seizures occur after two weeks, it is classified as a 'late onset’. Late-onset seizures usually occur within the first year after the stroke, and they have a stronger correlation with post-stroke-epilepsy (PSE) [8,9]. Today's standard of care for treating an arterial ischemic stroke (AIS) is early reperfusion with a fibrinolytic antithrombotic factor, such as the recombinant tissue plasminogen activator (r-tPA). The National Institute of Neurological Disorders and Stroke has shown a statistically significant beneficial result in r-tPA treatment compared to placebo
Corresponding author at: Neurology Department, Kaplan Medical Center, 1 Pasternak st, Rechovot, 7661041, Israel. E-mail address: [email protected] (A. Eilam).
https://doi.org/10.1016/j.seizure.2018.09.001 Received 14 April 2018; Received in revised form 2 September 2018; Accepted 4 September 2018 1059-1311/ © 2018 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
Seizure: European Journal of Epilepsy 62 (2018) 91–94
D. Nesselroth et al.
[10,11,15]. This should be the most likely recommended treatment, if the patient arrives at the ER within the 4.5-hour window of opportunity and does not present any contraindication for r-tPA. Treatment with rtPA for ischemic stroke reduces infarct size, but it also increases the risk for hemorrhagic transformation. Seizures have also been described in patients who underwent thrombolytic treatment for acute myocardial infarctions [18]. Previous studies have tried determining the relation between thrombolytic treatment and post-stroke epilepsy or seizures. The overall incidence rate of seizures in patients treated with r-tPA ranges from 4% to 20% [12–14]. Conversely, thrombolytic treatment has been suggested as a relative protective factor from late-onset seizures, by virtue of its beneficial effect on brain tissue reperfusion [14,16]. It is known that r-tPA is a more effective treatment in AIS than anti-platelet agents, allowing for faster reperfusion, and therefore, shortening the ischemia and reducing injury to brain tissue [12]. The aim of the study was to determine the influence of thrombolytic treatment on the risk of developing secondary seizures in patients with acute ischemic stroke. It was also to examine whether the benefits of rtPA treatment reduce the risk of developing post-stroke seizures, too, by examining the incidence rate of those events in post-stroke patients.
identify treatable vascular risk factors and secondary prevention with aspirin, clopidogrel or coumadin is started after the initial acute treatment (according to the suspected etiology of the stroke). For at least two years, all the patients were followed-up and their neurological outcome and appearance of seizures were assessed. The information was collected from Kaplan’s medical files and the hospital’s virtual medical records (OFEK, dB Motion, Hod-Hasharon, Israel) which included a record of the emergency room visits, hospitalizations, and outpatient clinic visits. The data was organized using the Excel (Microsoft, Redmond WA) program and analyzed using SPSS (ver. XXX, IBM, Armonk NY) for data processing. Statistical analysis included a homogeneity test using Pearson's chi-squared test for categorical variables. The primary endpoint was the incidence rate of seizure events after thrombolytic treatment compared to the control group, during one year follow-up, and the correlation between the type of treatment and the risk of developing such seizures. The correlation was calculated using Pearson's chi-squared test, as well as odds ratio and relative risk when there was statistical significance. A t-test and a Mann-Whitney test were used to compare means between the two groups.
2. Patients and methods
A cohort of 236 patients participated in the study, of which 141 patients were treated with r-tPA and formed the study group, and 95 patients, who did not receive r-tPA, were the control group. The two groups shared similar populations of various ethnic groups and similar ages (mean age 68.24 and 66.21, respectively). Risk factors for stroke including smoking, alcohol use, and underlying diseases, such as high blood pressure, diabetes and hyperlipidemia, were also similar in both groups. It is important to note that despite our hope for a similar NIHSS score in both groups, mean admission NIHSS score of the study group was 10.82, significantly higher than the control group’s 5.41 (Z= −3.833, p < 0.001). Our results show a correlation between the location of the lesion and the risk for developing secondary seizures. When there was a cortical involvement of the lesion, a higher risk for post stroke seizures was found. This correlation was statistically significant in the overall cohort (p = 0.028) and the control group (p = 0.035), but not in the study group (p = 0.68) (Table 1). Odds ratio calculation showed that the risk for seizures after a cortical infract is 3.85 times higher in comparison to a sub-cortical infract. A correlation was also found between the incidence of seizures and the severity of the lesion, estimated by the NIHSS score at admission. Patients suffering from severe strokes, with a NIHSS score of 8 or more, were more likely to present with seizures in comparison to patients with mild-moderate strokes, with a NIHSS score of 7 or less (p = 0.05) (Table 2). The calculated odds ratio showed 2.748 times higher risk for developing seizures after a severe stroke. In the one-year follow-up, 19 patients developed seizures, which made the overall seizure rate in this study 8.1%. When divided according to type of treatment, the incidence of seizures in the control group was significantly higher (12.6%) than the study group (5%) (χ² = 4.507, df = 1, p < .05). In calculating odds ratio, a 64% decrease in the risk of developing post stroke seizures shown, when treated with r-tPA, in comparison to other treatments (Table 3). There were no patients with early seizures in these series, and no patient developed status epilepticus during the follow-up period. An EEG was performed on all patients with seizures. Focal or diffuse slowing of the background was found in 80% of the patients, epileptic focal abnormalities (spikes, sharp waves) in 15% and 5% were normal. As mentioned, the NIHSS score at admission (mean 10.82 and 5.41, respectively) and discharge (mean 6.74 and 5.78, respectively) was significantly higher in the study group than in the control group. The within-subjects effects tests revealed a correlation between the type of treatment and the improvement in neurological function, as measured
3. Results
This cohort-controlled, retrospective, non-randomized cohort study was conducted on 236 consecutive patients with an acute ischemic stroke admitted to the emergency department at Kaplan Medical Center, between September 2008 and September 2015. This study group was composed of 141 consecutive acute stroke patients treated with IV r-tPA, and 95 patients who did not receive thrombolytic therapy, as a control group and was approved by our institute’s Helsinki Committee for Medical Experiments. Data were collected for the entire cohort including: demographic factors, such as age and gender, and vascular risk factors. Both groups of patients were heterogenic and comprised of patients between 33–100 years old, from various ethnic origins and both sexes. The characteristics of infarct were defined as: type of infarct, location, size, and NIHSS at arrival and discharge. The hospitalization files in the context of the emergence of early epileptic seizures and measures of severity of neurological injury (as reflected by NIHSS) were reviewed. Exclusion criteria included: patients with a history of epilepsy or seizures, use of antiepileptic drugs previous to admission, and a previous underlying disorder with involvement of seizures (metabolic disorders, SOL, etc.). In a paradigm comparable to post-traumatic seizures, an arbitrary cut point of two weeks after the stroke onset was considered to distinguish between early- and late-onset seizures [19,20]. Epilepsy was diagnosed using the description of clinical phenomena concordant with known types of seizures corroborated by relevant EEG findings. A possible underestimation of the real number of focal seizures with impaired awareness might have occurred, but this underestimation is true for both study and control groups. According to the family’s or caregiver’s description, the seizures were classified as focal with preserved awareness (formerly known as simple partial-SP), focal with impaired awareness (formerly known as complex partial- CP) and generalized tonic-clonic (TC), the latter probably being of focal onset with rapid secondary generalization. The acute stroke protocol at our institution includes immediate brain imaging with a non-contrast brain CT and a decision whether the patient is suitable for intravenous thrombolysis or not. Those patients treated with IV r-tPA are closely monitored for 24 h and undergo another brain CT during this period if there is suspicion of neurological worsening as reflected by an increase in their NIHSS. Those who are stable or are improving, undergo another brain CT 24 h after the r-tPA infusion. Afterwards, all patients undergo a thorough work-up to 92
Seizure: European Journal of Epilepsy 62 (2018) 91–94
D. Nesselroth et al.
Table 1 Correlation between the incidence of seizures and the location of the lesion. Incidence of seizures
Location of seizure Sub-cortical
Control
no yes Total no yes Total no yes Total
r-tPA Total
Cortical
Count
Column N %
Count
Column N %
Count
Column N %
30 3 33 32 0 32 62 3 65
90.9% 9.1% 100.0% 100.0% 0.0% 100.0% 95.4% 4.6% 100.0%
21 9 30 65 7 72 86 16 102
70.0% 30.0% 100.0% 90.3% 9.7% 100.0% 84.3% 15.7% 100.0%
51 12 63 97 7 104 148 19 167
81.0% 19.0% 100.0% 93.3% 6.7% 100.0% 88.6% 11.4% 100.0%
evidence regarding the correlation between r-tPA treatment and the incidence of seizures. Moreover, there are several biases that should be taken into consideration. Patients of the control group presented contraindications for r-tPA treatment or arrived at the hospital later than 4.5 h after the event had started, so thus suffered ischemia to the brain for a longer period of time. Therefore, it was thought that the control group would consist of the more severe and complex patients, but then it was discovered that the control group had a lower mean NIHSS score. This might be due to the fact that patients with minor strokes, who did not meet indications for r-tPA, were also included in the control group. The selection bias may have served as a confounder and affected the results. Follow-up was done by reviewing the patients' files, which could lack some information. To reduce information bias, both Kaplan’s medical files were used, as well as the virtual medical records (OFEK), so that the information would be more complete. In this work, an association between intravenous r-tPA treatment in patients with AIS and a decrease in the risk for secondary seizures has been shown. These results suggest another possible beneficial quality of the thrombolytic treatment in stroke patients and maybe another point worth considering while making treatment decisions in AIS patients. A larger multicenter study may overcome our limitations and help better reveal the positive qualities of thrombolytic treatment in AIS.
Table 2 Correlation between the incidence of seizures and NIHSS score at admission. NIHSS score at admission
incidence of seizures no
up to 7 8 or more Total
yes
Total
Count
Row N %
Count
Row N %
Count
Row N %
106 108 214
95.5% 88.5% 91.8%
5 14 19
4.5% 11.5% 8.2%
111 122 233
100.0% 100.0% 100.0%
Table 3 Incidence of seizures among stroke patients according to the type of treatment. seizures incidence no
Control group r-tPA Total
Total
yes
Total
Count
Row N %
Count
Row N %
Count
Row N %
83 134 217
87.4% 95.0% 91.9%
12 7 19
12.6% 5.0% 8.1%
95 141 236
100.0% 100.0% 100.0%
by the decrease of NIHSS score during hospitalization. The interaction effect was statistically significant (F (1,219) = 22.993, p < 0.01).
Conflict of interests We don’t have any conflict of interests to declare. Daphna Nesselrot, Ronit Gilad, Montaser Namneh, Sarit Avishay, Anda Eilam.
4. Discussion The overall incidence rate of post-stroke seizures in this study was 8.1%, 5% in the r-tPA treated group and 12.6% in the control group. This association between the treatment type and the risk for post-stroke seizures is statistically significant (p < 0.05). According to our results, the risk for seizures after an acute ischemic stroke is reduced by 66.4% when the patient is treated with r-tPA. The benefit of r-tPA treatment in terms of seizures prevention was also reported in a previous work [14]. It is important to note that the study group had a higher mean NIHSS score, which implies a more severe stroke, and therefore, a higher risk for seizures. Even with that, the results still showed a decrease in the risk for seizures in the study group. A possible explanation for this result is the fast reperfusion which minimizes scar tissue in the brain and thus reduces the risk for complications and seizures. Our research has some limitations: the most important one being its size. This study was not conducted on a large sample, and the results are all from relatively small numbers. The patients were of various ages and ethnicities which should minimize sample bias, but still the small sample size may have an influence on the statistical analysis and the results. In addition, this study is not a randomized double-blind prospective study, thus any causal connection from these results cannot be deduced. Further studies must be completed to infer more conclusive
References [1] Faught E, Richman J, Martin R, Funkhouser E, Foushee R, Kratt P, et al. Incidence and prevalence of epilepsy among older U.S. Medicare beneficiaries. Neurology 2012;78(7):448–53. [2] Tanaka A, Akamatsu N, Shouzaki T, Toyota T, Yamano M, Nakagawa M, et al. Clinical characteristics and treatment responses in new-onset epilepsy in the elderly. Seizure 2013;22(9):772–5. [3] Gilad R. Management of seizures following a stroke: what are the options? Drugs Aging 2012;29(7):533–8. [4] Bladin CF, Alexandrov AV, Bellavance A, Bornstein N, Chambers B, Coté R, et al. Seizures after stroke: a prospective multicenter study. Arch Neurol 2000;57:1617–22. [5] Dávalos A, de Cendra E, Molins A, Ferrandiz M, Lopez-Pousa S, Genís D. Epileptic seizures at the onset of stroke. Cerebrovasc Dis 1992;2:327–31. [6] Graham NS, Crichton S, Koutroumanidis M, Wolfe CD, Rudd AG. Incidence and associations of poststroke epilepsy: the prospective South London Stroke Register. Stroke 2013;44(3):605–11. [7] Assis TM, Bacellar A, Costa G, Nascimento OJ. Mortality predictors of epilepsy and epileptic seizures among hospitalized elderly. Arq Neuropsiquiatr 2015;73(6):510–5. [8] Myint PK, Staufenberg EFA, Sabanathan K. Post-stroke seizure and post-stroke epilepsy. Postgrad Med J 2006;82:568–72. [9] Olsen TS. Post-stroke epilepsy. Curr Atheroscler Rep 2001;3(4):340–4. [10] Liang LJ, Yang JM, Jin XC. Review cocktail treatment, a promising strategy to treat acute cerebral ischemic stroke. Med Gas Res 2016;6(March (1)):33–8.
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D. Nesselroth et al. [11] Saver Jeffrey L, Yafeh Banafsheh. Confirmation of tPA treatment effect by baseline severity-adjusted End Point reanalysis of the NINDS-tPA stroke trials. Stroke 2007;38:414–6. [12] Gravanis Iordanis, Tsirka Stella E. tPA as a therapeutic target in stroke. Expert Opin Ther Targets 2008;12(February (2)). https://doi.org/10.1517/14728222.12.2.159. [13] Couillard P, Almekhlafi MA, Irvine A, Jetté N, Pow J, St Germaine-Smith C, et al. Subacute seizure incidence in thrombolysis-treated ischemic stroke patients. Neurocrit Care 2012;16(2):241–5. [14] Keller Lena, Hobohm Carsten, Zeynalova Samira, Classen Joseph, Baum Petra. Does treatment with t-PA increase the risk of developing epilepsy after stroke? J Neurol 2015;262(10):2364–72. [15] De Reuck J, Van Maele G. Acute ischemic stroke treatment and the occurrence of seizures. Clin Neurol Neurosurg 2010;112(4):328–31.
[16] Berg AT, Millichap JJ. The 2010 revised classification of seizures and epilepsy. Continuum (Minneap Minn) 2013:571–97. [17] Berlet MH, Stambo GW, Kelley M, Van Epps K, Woeste T, Steffen D. Does modern ischemic stroke therapy in a large community-based dedicated stroke center improve clinical outcomes? A two-year retrospective study. J Stroke Cerebrovasc Dis 2014;23(May-June (5)):869–78. [18] Okamoto S, Inatomi Y, Yonehara T, Hashimoto Y, Hirano T, Uchino M. Early seizures after acute ischemic stroke. Rinsho Shinkeigaku 2006;46(May (5)):307–11. [19] Caramelli P, Mutarelli EG, Caramelli B, Pileggi F, Scaff M. Neurological complications after thrombolytic treatment for acute myocardial infarction: emphasis on unprecedented manifestations. Acta Neurol Scand 1992;85(5):331–3. [20] Jennett Bryan. Early traumatic epilepsy: incidence and significance after nonmissile injuries. Arch Neurol 1974;30(5):394–8.
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Contents lists available at ScienceDirect
Seizure: European Journal of Epilepsy journal homepage: www.elsevier.com/locate/seizure
Estimation of seizures prevalence in ischemic strokes after thrombolytic therapy
T
Daphna Nesselrothd, Ronit Gilada,c, Montaser Namneha, Sarit Avishayb, Anda Eilama,
⁎
a
Neurological department, Kaplan Medical Center, Rechovot, Israel Management department, Kaplan Medical Center, Rechovot, Israel c Hebrew university, Jerusalem, Israel d Sackler Medical School, Tel-Aviv University, Israel b
ARTICLE INFO
ABSTRACT
Keywords: Ischemic stroke Thrombolytic therapy Post-stroke seizures
Purpose: Post stroke seizures are a complication that occur in 5-20% of acute ischemic stroke (AIS) patients, cause a reduction in quality of life and a greater burden on the health system. There is not enough data regarding an association between today’s standard of care treatment in AIS: recombinant tissue plasminogen activator (rtPA) and the risk for post stroke seizures. Our aim in this work is to reveal such a connection. Method: A non-randomized retrospective cohort-controlled study of 234 patients, who were hospitalized with acute ischemic stroke at Kaplan Medical Center in the years 2009-2015 and were divided into two different treatment groups: r-tPA and antiaggregant therapy(n = 141) and antiaggregant therapy only (n = 95) was conducted by us. Information regarding demographics, medical history, nature of the event, including NIHSS values on admission, discharge, and post stroke seizures, were obtained for each group. Follow-up was done for one year. Results: During the year of follow-up, 19 patients (8.1%) of the overall cohort, developed seizures: 12 of them (12.6%) belonged to the control group and 7 (5%) to the study group p < 0.05). Results showed a decrease in the risk for developing seizure when treated with r-tpA, comparing to antiaggregants (odds ratio = 0.64). Conclusion: This study suggests there is an association between r-tPA treatment and reduction of the risk for post stroke seizures.
1. Background Epilepsy is a common neurologic disorder which affects about 1% of the U.S. population [1]. Most new cases of epilepsy occur in the elderly, with an annual incidence rate of 240 per 100,000 in people aged 65 and older in the United States [1]. Among patients with new-onset epilepsy, almost 50% of the causes can be explained by an underlying etiology, such as vascular diseases, tumors or metabolic disorders [2]. Around 30–40% of new epilepsy cases among the elderly are accounted for by previous cerebrovascular hemorrhages or ischemic accidents. This makes cerebrovascular strokes the most common cause of secondary epilepsy in adults [3]. The risk of developing post-stroke seizures ranges from 5 to 20% in patients older than 35 years old [4,5]. Risk factors for developing secondary seizures or epilepsy have been well studied [4,6,7]. The stroke characteristics, such as subtype, severity, hemorrhagic transformation and cortical involvement, correlate with the risk of secondary epilepsy.
⁎
A large lesion, severe presentation (higher National Institute of Health stroke score (NIHSS) on admission) and signs of cortical injury, such as dysphasia or visual neglect, all enhance the risk to develop future poststroke epilepsy (PSE) [3,6]. After a stroke, the risk of developing a seizure or (PSE) is 20 times higher in the first year after the event [7]. Post-stroke seizures are classified as ‘early onset’ seizures, if they occur within two weeks after the stroke. The peak incidence of 45% is at 24 h past the cerebrovascular event [17]. If the seizures occur after two weeks, it is classified as a 'late onset’. Late-onset seizures usually occur within the first year after the stroke, and they have a stronger correlation with post-stroke-epilepsy (PSE) [8,9]. Today's standard of care for treating an arterial ischemic stroke (AIS) is early reperfusion with a fibrinolytic antithrombotic factor, such as the recombinant tissue plasminogen activator (r-tPA). The National Institute of Neurological Disorders and Stroke has shown a statistically significant beneficial result in r-tPA treatment compared to placebo
Corresponding author at: Neurology Department, Kaplan Medical Center, 1 Pasternak st, Rechovot, 7661041, Israel. E-mail address: [email protected] (A. Eilam).
https://doi.org/10.1016/j.seizure.2018.09.001 Received 14 April 2018; Received in revised form 2 September 2018; Accepted 4 September 2018 1059-1311/ © 2018 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
Seizure: European Journal of Epilepsy 62 (2018) 91–94
D. Nesselroth et al.
[10,11,15]. This should be the most likely recommended treatment, if the patient arrives at the ER within the 4.5-hour window of opportunity and does not present any contraindication for r-tPA. Treatment with rtPA for ischemic stroke reduces infarct size, but it also increases the risk for hemorrhagic transformation. Seizures have also been described in patients who underwent thrombolytic treatment for acute myocardial infarctions [18]. Previous studies have tried determining the relation between thrombolytic treatment and post-stroke epilepsy or seizures. The overall incidence rate of seizures in patients treated with r-tPA ranges from 4% to 20% [12–14]. Conversely, thrombolytic treatment has been suggested as a relative protective factor from late-onset seizures, by virtue of its beneficial effect on brain tissue reperfusion [14,16]. It is known that r-tPA is a more effective treatment in AIS than anti-platelet agents, allowing for faster reperfusion, and therefore, shortening the ischemia and reducing injury to brain tissue [12]. The aim of the study was to determine the influence of thrombolytic treatment on the risk of developing secondary seizures in patients with acute ischemic stroke. It was also to examine whether the benefits of rtPA treatment reduce the risk of developing post-stroke seizures, too, by examining the incidence rate of those events in post-stroke patients.
identify treatable vascular risk factors and secondary prevention with aspirin, clopidogrel or coumadin is started after the initial acute treatment (according to the suspected etiology of the stroke). For at least two years, all the patients were followed-up and their neurological outcome and appearance of seizures were assessed. The information was collected from Kaplan’s medical files and the hospital’s virtual medical records (OFEK, dB Motion, Hod-Hasharon, Israel) which included a record of the emergency room visits, hospitalizations, and outpatient clinic visits. The data was organized using the Excel (Microsoft, Redmond WA) program and analyzed using SPSS (ver. XXX, IBM, Armonk NY) for data processing. Statistical analysis included a homogeneity test using Pearson's chi-squared test for categorical variables. The primary endpoint was the incidence rate of seizure events after thrombolytic treatment compared to the control group, during one year follow-up, and the correlation between the type of treatment and the risk of developing such seizures. The correlation was calculated using Pearson's chi-squared test, as well as odds ratio and relative risk when there was statistical significance. A t-test and a Mann-Whitney test were used to compare means between the two groups.
2. Patients and methods
A cohort of 236 patients participated in the study, of which 141 patients were treated with r-tPA and formed the study group, and 95 patients, who did not receive r-tPA, were the control group. The two groups shared similar populations of various ethnic groups and similar ages (mean age 68.24 and 66.21, respectively). Risk factors for stroke including smoking, alcohol use, and underlying diseases, such as high blood pressure, diabetes and hyperlipidemia, were also similar in both groups. It is important to note that despite our hope for a similar NIHSS score in both groups, mean admission NIHSS score of the study group was 10.82, significantly higher than the control group’s 5.41 (Z= −3.833, p < 0.001). Our results show a correlation between the location of the lesion and the risk for developing secondary seizures. When there was a cortical involvement of the lesion, a higher risk for post stroke seizures was found. This correlation was statistically significant in the overall cohort (p = 0.028) and the control group (p = 0.035), but not in the study group (p = 0.68) (Table 1). Odds ratio calculation showed that the risk for seizures after a cortical infract is 3.85 times higher in comparison to a sub-cortical infract. A correlation was also found between the incidence of seizures and the severity of the lesion, estimated by the NIHSS score at admission. Patients suffering from severe strokes, with a NIHSS score of 8 or more, were more likely to present with seizures in comparison to patients with mild-moderate strokes, with a NIHSS score of 7 or less (p = 0.05) (Table 2). The calculated odds ratio showed 2.748 times higher risk for developing seizures after a severe stroke. In the one-year follow-up, 19 patients developed seizures, which made the overall seizure rate in this study 8.1%. When divided according to type of treatment, the incidence of seizures in the control group was significantly higher (12.6%) than the study group (5%) (χ² = 4.507, df = 1, p < .05). In calculating odds ratio, a 64% decrease in the risk of developing post stroke seizures shown, when treated with r-tPA, in comparison to other treatments (Table 3). There were no patients with early seizures in these series, and no patient developed status epilepticus during the follow-up period. An EEG was performed on all patients with seizures. Focal or diffuse slowing of the background was found in 80% of the patients, epileptic focal abnormalities (spikes, sharp waves) in 15% and 5% were normal. As mentioned, the NIHSS score at admission (mean 10.82 and 5.41, respectively) and discharge (mean 6.74 and 5.78, respectively) was significantly higher in the study group than in the control group. The within-subjects effects tests revealed a correlation between the type of treatment and the improvement in neurological function, as measured
3. Results
This cohort-controlled, retrospective, non-randomized cohort study was conducted on 236 consecutive patients with an acute ischemic stroke admitted to the emergency department at Kaplan Medical Center, between September 2008 and September 2015. This study group was composed of 141 consecutive acute stroke patients treated with IV r-tPA, and 95 patients who did not receive thrombolytic therapy, as a control group and was approved by our institute’s Helsinki Committee for Medical Experiments. Data were collected for the entire cohort including: demographic factors, such as age and gender, and vascular risk factors. Both groups of patients were heterogenic and comprised of patients between 33–100 years old, from various ethnic origins and both sexes. The characteristics of infarct were defined as: type of infarct, location, size, and NIHSS at arrival and discharge. The hospitalization files in the context of the emergence of early epileptic seizures and measures of severity of neurological injury (as reflected by NIHSS) were reviewed. Exclusion criteria included: patients with a history of epilepsy or seizures, use of antiepileptic drugs previous to admission, and a previous underlying disorder with involvement of seizures (metabolic disorders, SOL, etc.). In a paradigm comparable to post-traumatic seizures, an arbitrary cut point of two weeks after the stroke onset was considered to distinguish between early- and late-onset seizures [19,20]. Epilepsy was diagnosed using the description of clinical phenomena concordant with known types of seizures corroborated by relevant EEG findings. A possible underestimation of the real number of focal seizures with impaired awareness might have occurred, but this underestimation is true for both study and control groups. According to the family’s or caregiver’s description, the seizures were classified as focal with preserved awareness (formerly known as simple partial-SP), focal with impaired awareness (formerly known as complex partial- CP) and generalized tonic-clonic (TC), the latter probably being of focal onset with rapid secondary generalization. The acute stroke protocol at our institution includes immediate brain imaging with a non-contrast brain CT and a decision whether the patient is suitable for intravenous thrombolysis or not. Those patients treated with IV r-tPA are closely monitored for 24 h and undergo another brain CT during this period if there is suspicion of neurological worsening as reflected by an increase in their NIHSS. Those who are stable or are improving, undergo another brain CT 24 h after the r-tPA infusion. Afterwards, all patients undergo a thorough work-up to 92
Seizure: European Journal of Epilepsy 62 (2018) 91–94
D. Nesselroth et al.
Table 1 Correlation between the incidence of seizures and the location of the lesion. Incidence of seizures
Location of seizure Sub-cortical
Control
no yes Total no yes Total no yes Total
r-tPA Total
Cortical
Count
Column N %
Count
Column N %
Count
Column N %
30 3 33 32 0 32 62 3 65
90.9% 9.1% 100.0% 100.0% 0.0% 100.0% 95.4% 4.6% 100.0%
21 9 30 65 7 72 86 16 102
70.0% 30.0% 100.0% 90.3% 9.7% 100.0% 84.3% 15.7% 100.0%
51 12 63 97 7 104 148 19 167
81.0% 19.0% 100.0% 93.3% 6.7% 100.0% 88.6% 11.4% 100.0%
evidence regarding the correlation between r-tPA treatment and the incidence of seizures. Moreover, there are several biases that should be taken into consideration. Patients of the control group presented contraindications for r-tPA treatment or arrived at the hospital later than 4.5 h after the event had started, so thus suffered ischemia to the brain for a longer period of time. Therefore, it was thought that the control group would consist of the more severe and complex patients, but then it was discovered that the control group had a lower mean NIHSS score. This might be due to the fact that patients with minor strokes, who did not meet indications for r-tPA, were also included in the control group. The selection bias may have served as a confounder and affected the results. Follow-up was done by reviewing the patients' files, which could lack some information. To reduce information bias, both Kaplan’s medical files were used, as well as the virtual medical records (OFEK), so that the information would be more complete. In this work, an association between intravenous r-tPA treatment in patients with AIS and a decrease in the risk for secondary seizures has been shown. These results suggest another possible beneficial quality of the thrombolytic treatment in stroke patients and maybe another point worth considering while making treatment decisions in AIS patients. A larger multicenter study may overcome our limitations and help better reveal the positive qualities of thrombolytic treatment in AIS.
Table 2 Correlation between the incidence of seizures and NIHSS score at admission. NIHSS score at admission
incidence of seizures no
up to 7 8 or more Total
yes
Total
Count
Row N %
Count
Row N %
Count
Row N %
106 108 214
95.5% 88.5% 91.8%
5 14 19
4.5% 11.5% 8.2%
111 122 233
100.0% 100.0% 100.0%
Table 3 Incidence of seizures among stroke patients according to the type of treatment. seizures incidence no
Control group r-tPA Total
Total
yes
Total
Count
Row N %
Count
Row N %
Count
Row N %
83 134 217
87.4% 95.0% 91.9%
12 7 19
12.6% 5.0% 8.1%
95 141 236
100.0% 100.0% 100.0%
by the decrease of NIHSS score during hospitalization. The interaction effect was statistically significant (F (1,219) = 22.993, p < 0.01).
Conflict of interests We don’t have any conflict of interests to declare. Daphna Nesselrot, Ronit Gilad, Montaser Namneh, Sarit Avishay, Anda Eilam.
4. Discussion The overall incidence rate of post-stroke seizures in this study was 8.1%, 5% in the r-tPA treated group and 12.6% in the control group. This association between the treatment type and the risk for post-stroke seizures is statistically significant (p < 0.05). According to our results, the risk for seizures after an acute ischemic stroke is reduced by 66.4% when the patient is treated with r-tPA. The benefit of r-tPA treatment in terms of seizures prevention was also reported in a previous work [14]. It is important to note that the study group had a higher mean NIHSS score, which implies a more severe stroke, and therefore, a higher risk for seizures. Even with that, the results still showed a decrease in the risk for seizures in the study group. A possible explanation for this result is the fast reperfusion which minimizes scar tissue in the brain and thus reduces the risk for complications and seizures. Our research has some limitations: the most important one being its size. This study was not conducted on a large sample, and the results are all from relatively small numbers. The patients were of various ages and ethnicities which should minimize sample bias, but still the small sample size may have an influence on the statistical analysis and the results. In addition, this study is not a randomized double-blind prospective study, thus any causal connection from these results cannot be deduced. Further studies must be completed to infer more conclusive
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