Early post-stroke seizures in a sample of Egyptian patients with first-ever stroke
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.236973
Source of Support: None, Conflict of Interest: None
Keywords: Stroke, early seizures, incidence, risk factors, stroke outcome, mortality rate, in-hospital duration of stay
Stroke is considered as the second leading global cause of death and the seventh leading cause of disability world-wide. Previous studies have demonstrated that stroke represents the most common etiology of symptomatic seizures especially in the elderly patients.,, Herman  reported that 5–15% of stroke patients develop seizures within the first 2 years of stroke onset. According to their temporal proximity to stroke onset, post-stroke seizures are classified as early and late onset seizures., Early post-stroke seizures are defined as seizures that occur within 7 days after stroke onset. The occurrence of such seizures has a negative impact on stroke recovery and the quality of life.,,
Risk factors that are responsible for early post-stroke seizures could be distinguished into general and neurological factors. Neurological factors vary across studies and were related to stroke subtype, lesion location,,, and severity of the vascular lesion., Identification of risk factors in different populations is of importance for prevention of these seizures and their adequate treatment. The aim of this study was to identify the risk factors associated with occurrence of early seizures after a first-ever cerebral stroke. In addition, the impact of post-stroke seizures on the in-hospital mortality and short-term outcome was assessed.
This study was conducted at the intensive care and stroke units of the Department of Neurology, Zagazig University Hospitals, Egypt during the period from April 2016 to March 2017. One hundred and fifty patients with first-ever acute stroke, admitted within 24 hours of stroke onset, were enrolled in this study. Stroke was defined according to the World Health Organization criteria  as rapidly developed symptoms and signs of focal disturbance of cerebral function lasting for >24 hours of presumed vascular origin. Informed consent from patients or their relatives were obtained. Early post-stroke seizure was defined according to the International League Against Epilepsy, as a seizure that occured within 7 days of stroke onset. The assessment of the onset of seizures was based on direct observation of seizures by the patient's relative when the seizure occured at home; a reliable description of the seizure by ambulance personnel during transportation or by medical staff and by the observations of the attending neurologist during the hospitalization period were also taken into consideration. This study was approved by the Institutional Review Board (IRB), Faculty of Medicine, Zagazig University, Egypt.
These included (1) causes other than vascular origin such as head trauma, tumors, and central nervous system infections; (2) patients with a prior history of epilepsy; (3) previous history of occurrence of strokes or transient ischemic attacks; (4) patients with subarachnoid hemorrhage and cerebral venous sinus thrombosis; and, (5) patients with metabolic or electrolyte disturbances.
All patients were subjected to a detailed medical and neurological examination. Assessment of stroke severity was conducted using the National Institute of Health Stroke Scale (NIHSS) and was categorized into mild (NIHSS score <8), moderate (NIHSS score 8–14), and severe stroke (NIHSS score ≥15). Functional outcome was assessed at discharge using Barthel index with a score ranging from 0 to 20. Laboratory investigations included the random and 2-h postprandial blood glucose level, lipid profile, liver and kidney functions, and finally serum electrolytes.
Cerebral computed tomography was performed for all patients on admission and was repeated after 7 days for those with an intial negative imaging. The lesion size was determined by measuring the largest diameter of the lesion. Thus, the lesions were categorized as small (<1 cm), medium (1–3 cm), and large (>3 cm) lesions. The lesion type, classified as either 'ischemic' or 'hemorrhagic', was determined according to previously published criteria. The lesion was diagnosed as 'cortical' when the lesion involved the cortex with or without subcortical white matter, whereas the diagnosis of a pure 'subcortical' lesion was made when the lesion involved the internal capsule, basal ganglia, thalamus, brainstem, or cerebellum. Hemorrhagic transformation (HT) was diagnosed by the development of hyperdensity within an area of low attenuation.
The sample size of this study was calculated using an incidence rate of 9%, which was reported in a large prospective multicenter study of seizures in acute stroke. A sample size of 126 was found to achieve a power of 80% at 0.05 alpha level of significance. We recruited 150 patients to increase the power of our study. The calculation was performed using Epi Info 7 (CDC, 2015).
Quantitative variables were expressed as mean ± standard deviation (SD), whereas qualitative variables were expressed as frequencies and percentages. Comparison between groups (with and without seizures) was performed using Student t-test, chi-square test, or Fischer exact test, as deemed appropriate. Significant risk factors that were designated as being associated with the seizure using the univariate analysis were entered in the multivariable regression analysis to identify predictors of early seizures. Measures of association were expressed as odds ratio (OR) and 95% confidence interval (CI). A P value ≤0.05 was considered significant. Data were analyzed using Statistical Package for the Social Sciences [SPSS] statistics (IBM corporation, Armonk, New York), version 20.
This study included 150 patients with first-ever stroke. Their age ranged from 35 to 85 years with a mean age (±standard deviation [SD]) of 60.8 (±12.5) years. They consisted of 102 (68%) male and 48 (32%) female patients. According to their stroke type, there were 32 (21.3%) patients with an intracerebral hemorrhage (ICH), 10 (6.6%) with HT of cerebral infarction, and 108 (72.1%) with an ischemic stroke (IS). Cortical lesions were recorded in 58 (38.7%) patients and large lesions were present in 31 patients (20.6%) of our cohort. On assessment of stroke severity, the NIHSS score on admission was as follows: mean ± SD = 11.9 ± 7.3; 114 (76%) patients had a mild/moderate stroke and 36 (24%) had a severe stroke. Early seizures were observed in 14 (9.3%) patients in the entire cohort; 6 (42.8%) patients developed seizures on the first day of admission, 3 (21.4%) on the second day, 2 (14.3%) on the fourth day, 1 (7.1%) on the fifth day, and 1 (7.1%) on the seventh day.
On studying the relationship between early seizures and different variables [Table 1] and [Table 2], no relationship could be observed between age, gender, and vascular risk factors on the one hand and the occurrence of early seizures on the other hand. Regarding the stroke subtype, ICH accounted for 50% of patients with early seizures and it carried the highest rate of seizure occurrence in comparison to HT and IS. The second stroke subtype that had a strong relation to early seizures was HT (28.6%). A significant difference related to the presence of early seizures was seen in patients in whom cortical lesions were present versus those without these lesions (P< 0.001). Also, a significant relation was observed between the lesion size and the presence of early seizures (P< 0.05). Patients with early seizures had a significantly higher admission NIHSS score than those without seizures (14.3 ± 7.8 vs. 9.5 ± 6.8, respectively, P < 0.05).
The mean duration ± SD of in-hospital stay was longer in the early seizure group than those without seizures (19.4 ± 6.5 vs. 10.7 ± 4.2 days, respectively). Regarding stroke outcome [Table 3], patients in the early seizure group had more neurological deficits at discharge with their NIHSS score being 12.5 ± 7.2, when compared with the NIHSS score of 6.9 ± 5.8 in stroke patients without seizures. Stroke patients with seizure got lower scores when being scored using the Barthel index (7.5 ± 4.1) compared with 10.5 ± 3.5 in patients without a seizure. The in-hospital mortality rate was five (35.7%) and nine (6.6%) cases in patient with and without seizures, respectively. Within the first 24h of admission, two (40%) mortalities occurred in stroke patients with a seizure compared with none in the stroke patients without a seizure. In the multivariable logistic regression analysis [Table 4], the independent predictors for early seizures were ICH (OR = 3.2), cortical location (OR = 2.8) and a large lesion (OR = 2).
Development of post-stroke seizures has been associated with a poor functional outcome and a high in-hospital mortality rate.,, Epidemiological studies in different nations yielded different sets of risk factors associated with post-stroke seizure. Therefore, the need exists to identify risk factors pertaining to each nation.
This study showed that, in patients with acute first-ever stroke, the incidence of early post-stroke seizures was 9.3%. A similar incidence rate of 8.9% was reported by Bladin et al., who conducted a large prospective multicenter study of post-stroke seizures. In contrast, a study conducted in India had reported a higher incidence rate of 17.9%. On the other hand, other studies reported lower incidences in the range of 1.8–6.3%.,,,, Possible explanations for these different results include different genetic predisposition in different nations, different study designs, and different time windows for defining early seizures (1–30 days). In this study, inclusion of patients within the first 24 h of stroke onset explained our finding of a relatively high incidence rate of post-stroke seizure because 40% of cases were observed within this time window. Previous studies reported that the risk of developing early post-stroke seizures was highest during the first 24 h and tended to decrease thereafter.,
Using multivariable logistic regression analysis, we identified that an ICH, the presence of a cortical lesion, and a large lesion size were the most important risk factors significantly associated with the development of early post-stroke seizures. This result was consistent with the findings of many previous studies ,,,,, demonstrating a strong association between early post-stroke seizures and ICH. In addition, our results demonstrated a significant association between hemorrhagic transformation and occurrence of early seizures, which supports the role of blood extravasation in epileptogenesis. In animal models, blood metabolic products such as hemosiderin were shown to cause cerebral irritation and consequently the development of seizures. In our study, none of the studied vascular risk factors carried an increased risk of development of early seizures, which has been consistent with the findings of many previous studies.,,
Our results demonstrated that cortical lesions increased the risk of early seizures by 2.8-folds. Previous studies demonstrated a consistent positive association between the presence of cortical lesion and the development of post-stroke seizures.,,,,, In general, it was reported that a variety of cortical lesions such as traumatic brain injuries or tumors were also associated with a high risk of developing seizures.,, In animal models, the development of seizures was associated with hyperexcitability caused by cortical damage.
Regarding the relation between the lesion size and the risk of development of early post-stroke seizures, this study showed a significant positive association between both. This result was in agreement with the findings of previous studies.,,, Wang et al., proposed that the lesion size exclusively reflects the severity of stroke. The same authors  demonstrated a positive association between post-stroke seizures and a large lesion size, in which large lesions increased the incidence of seizures by 9.36-folds.
The negative impact of early seizures on stroke outcome has been widely reported, although the pathogenic mechanism is not well understood. Metabolic disturbance in the form of seizure-induced accelerated glucose metabolism and subsequent lactate accumulation was proposed as a candidate pathological pathway for inducing post-stroke brain lesion. Our study provided evidence in support of a positive association between early post-stroke seizures and a poor functional outcome. This was evidenced by the lower Barthel score in stroke patients with seizures compared with patients without seizures. A poor functional outcome was also evidenced by the high incidence of in-hospital mortality rate of 35.7% and a longer in-hospital stay duration of 19.4 ± 6.5 days in the seizure group compared with only 6.6% and 10.7 ± 4.2 days, respectively, in the non-seizure group. In support of our results was the finding of a previous study  in which patients with early seizures had a higher mortality rates than those without seizures (37.9 vs. 14.4%, respectively). Similarly, Labovitz et al., reported a mortality rate of 20% in the early post-stroke seizure group. Further, Bladin et al., Camilo and Goldstein, and Lamy et al. demonstrated that post-stroke seizures were associated with a higher functional disability and mortality.
We observed a high incidence of early seizures after first-ever stroke. Independent risk factors significantly associated with post-stroke seizures were all non-modifiable factors and included ICH, cortical lesions, and large-sized lesions. Early seizures were significantly associated with a poor outcome following the precipitation of a stroke, as well as an increased in-hospital mortality rate and a longer duration of in-hospital stay.
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[Table 1], [Table 2], [Table 3], [Table 4]