The occurrence of seizures after ischemic stroke does not influence long-term mortality; a 26-year follow-up study

The occurrence of seizures after ischemic stroke does not influence long-term mortality; a... Objective Epileptic seizures are a common complication after stroke. The relation between occurrence of seizures after stroke and long-term mortality remains elusive. We aimed to assess whether seizures in an early or late phase after ischemic stroke are an independent determinant of long-term mortality. Methods We prospectively included and followed 444 ischemic stroke patients with a first-ever supratentorial brain infarct for at least 2 years after their stroke regarding the occurrence of seizures. The final follow-up for mortality is from April 2015 (follow-up duration 24.5–27.8 years, mean 26.0 years, SD 0.9 years). We compared patients with early-onset seizures with all seizure-free patients, whereas the patients with late-onset seizures were compared with the 1-week survivors without any seizures. We used Cox-regression analyses to correct for possible confounding factors. Results Kaplan–Meier analysis showed significantly higher mortality for the patients with early-onset seizures (p = 0.002) but after correction for known risk factors for (long term) mortality early-onset seizures had no independent influence on long-term mortality (HR 1.09; 95% CI 0.64–1.85). In patients with late-onset seizures, no significant influence from late- onset seizures on long-term mortality was found (univariate p = 0.717; multivariate HR 0.81; 95% CI 0.54–1.20). Conclusion Both early-onset and late-onset seizures do not influence long-term mortality after ischemic stroke. Keywords Seizures · Epilepsy · Brain infarct · Stroke Introduction Epileptic seizures are a common complication after stroke although the risk to develop seizures varies, depending on variables such as stroke type (hemorrhagic vs. ischemic), stroke severity, and cortical involvement [1–7]. Seizures * R. P. W. Rouhl occurring after stoke are divided in early-onset seizures (ES, R.Rouhl@mumc.nl incidence 3.3% of patients) and late-onset seizures (LS, inci- dence 18 in 1000 person years) depending on their time of Department of Neurology, Maastricht University Medical Center, PO Box 5800, 6202 AZ Maastricht, The Netherlands occurrence, with a variable cut-off point in different studies between 24 h and 1 month post-stroke [2, 6, 8, 9]. ES and Department of Neurology, Elisabeth-Tweesteden Hospital, Tilburg, The Netherlands LS differ in their pathophysiology. ES are induced by the acute disruption of the blood–brain barrier and the resultant School for Mental Health and Neurosciences, Maastricht University, Maastricht, The Netherlands hyperexcitatory state, whereas LS are a result of a chronic process called epileptogenesis, which causes gliosis and Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center, Maastricht, formation of epileptogenic networks [10]. Furthermore, LS The Netherlands have a higher recurrence rate than ES [11] and, therefore, LS Academic Center for Epileptology, Maastricht University are considered to have a larger clinical significance. In addi- Medical Center and Kempenhaeghe Center of Expertise tion, according to the guidelines of the International League for Epileptology, Maastricht, The Netherlands for Epilepsy (ILAE), in stroke patients with LS, epilepsy Faculty of Electrical Engineering, University of Technology, may be diagnosed after only one seizure [12]. Eindhoven, The Netherlands Vol.:(0123456789) 1 3 Journal of Neurology In general, patients with epilepsy have a higher mortality We recorded age, gender, clinical infarct syndrome (lacu- risk than people without epilepsy [13]. However, whether nar or cortical syndrome), degree of disability at stroke onset this also applies to stroke patients suffering from post-stroke using the modified Rankin scale (mRS; in the present study seizures remains unclear. Most studies showed a negative used as a surrogate marker for stroke severity), and cardio- relation between ES and mortality when using a univariate vascular risk factors, such as smoking, hypertension, dia- statistical analysis technique; however, this relationship was betes mellitus, and ischaemic heart disease. Clinical infarct lost when using multivariate statistical analysis techniques syndrome was defined as lacunar or cortical infarct follow - [14–18]. Only in two studies by Arboix et al. the relationship ing definitions from the Oxfordshire Community Stroke between early seizures and mortality remained significant Project [23]. The cortical infarct group was subdivided in [19, 20]. We are aware of only one study that studied the a cardioembolic and atherothrombotic group, depending relation between LS and mortality in stroke patients [21]. on the identification of a cardiac embolic source, such as This study in young stroke patients showed that long-term atrial fibrillation (as evidenced by ECG, 24-h heart rhythm mortality was significantly higher in patients with seizures monitoring and/or cardiac echocardiography). We defined than in patients without seizures. hypertension, diabetes mellitus and ischemic heart disease Knowledge of the impact of especially late-onset seizures as described previously [24]. Data concerning the occur- on (long term) mortality in stroke patients is relevant with rence of epileptic seizures were collected prospectively by regard to a possible prophylactic treatment to prevent those one single investigator (EPM van Raak) during a follow-up seizures. period of at least 2 years after inclusion in the Maastricht The aim of the present study was to assess the independ- stroke registry. Seizures during admission were recorded ent effect of ES and LS on the long-term mortality after a by the treating physician and recorded from the charts by first-ever supratentorial brain infarct in a large prospective this investigator. After discharge from the hospital, patients cohort study. were invited for regular follow-up visits at the outpatient clinic every 3–6 months until at least 2 years after the stroke. If patients were unable to attend this visit, the investigator Patients and methods contacted the patient or a close relative or the general prac- titioner by phone. In case the patient was living in a nursing All patients aged 18 years and older with a stroke, admitted home the investigator visited the patients every 6 months. to the neurology department or seen at the outpatient clinic Seizure occurrence was recorded when either a focal or a of Maastricht University Medical Center, are registered in generalized epileptic seizure occurred, excluding other a prospective database; the Maastricht Stroke Registry. For causes of disturbances of consciousness or rhythmic limb the present study, all patients with a first ever supratento- movements, such as syncope due to cardiac arrhythmia or rial brain infarct between July 1st 1987 and September limb shaking TIA’s. The date of all seizures and, if possi- 30th 1990 were included. Brain infarction was defined as ble, the seizure subtypes were registered, as well as eventual the rapid onset of clinical signs of focal cerebral function antiepileptic drug (AED) treatment. In patients with seizures disturbance, lasting longer than 24 h or leading to death, occurring ≤ 1  week after stroke onset, the seizures were with no other apparent cause than that of vascular origin, regarded as ES, even when such a patient continued to have with normal CT or CT showing an area of low attenuation seizures after the first week following the initial stroke. In compatible with the clinical signs and symptoms, or autopsy patients with a first seizure occurring > 1 week after stroke revealing an infarct compatible with the clinical signs and onset, the seizures were regarded as LS, as described by the symptoms. When neither CT nor autopsy were available, most recent guideline from the International League Against we used the Guy’s Hospital Stroke Diagnostic Score (Allen Epilepsy (ILAE) [25]. Only seizures occurring within score) [22] to determine the probability that the stroke was 2 years after the initial stroke were considered as related to due to infarction. In this way, 20 patients with an Allen the stroke and regarded as post-stroke seizures. Since most score < 4, i.e. with a probability of 90% or more that their stroke-related seizures do occur within 2 years [2, 8, 26], stroke was due to infarction, were also included: 15 of 396 the etiology of a first seizure occurring more than 2 years patients without seizures (3.8%), 3 of 16 patients with ES after stroke is uncertain; therefore, we did not include these (18.8%) and 2 of 32 patients with LS (6.3%). We excluded seizures in the present study. In April 2015, the follow-up patients with previous stroke, clinical signs of cerebellar regarding mortality was conducted retrospectively with end or brain stem stroke, primary intracerebral haemorrhage, date March 31st 2015. This was done by checking the elec- subarachnoid haemorrhage, brain tumour, history of one or tronic patient files in our center and the Dutch Municipal more epileptic seizures or a rare cause of the infarction (e.g. Personal Records Database (BRP), the latter being a formal, vasculitis, arterial dissection, or a hematologic disorder). and reliable national registration of personal details of the 1 3 Journal of Neurology entire population of the Netherlands, including birth date CT imaging) followed by LS. The other patient had clinical and date of death. symptoms of a recurrent stroke and epileptic seizures at the same time, and died before CT scan could be performed. Statistical analysis Fourteen patients with ES (87.5%) were treated with an AED, seven of them were treated with carbamazepine Data analysis was performed using SPSS statistics version and seven with phenytoin. The remaining two patients 23. We compared baseline data with Mann–Whitney U test with ES (12.5%) did not receive AED treatment (they died or chi-square test, whichever was appropriate. We assessed after 9 and 21 days, respectively). Of the 32 patients with mortality using Kaplan–Meier survival curves and deter- LS, 22 patients (68.8%) were treated with an AED (17 of mined differences between survival in stroke patients with them received carbamazepine and 5 phenytoin), whereas ES vs. no seizures and in patients with LS vs. no seizures 10 patients (31.2%) did not receive AED treatment. Six of using a log-rank test. We assessed independent contribu- them experienced only one single seizure and two of them tions to mortality risk with Cox regression analyses with experienced only two focal seizures and were seizure free the covariates age at onset of stroke, gender, infarct type thereafter without treatment. The remaining two patients (atherothrombotic, cardioembolic or lacunar stroke), mRS died soon after their first seizure (one patient on the same as a surrogate marker for stroke severity, hypertension, dia- day, one patient the next day). betes mellitus, ischemic heart disease, and smoking. A p Baseline characteristics are shown in Table 1. Patients value < 0.05 was regarded as statistically significant. with ES were significantly older and had a significantly higher initial mRS than patients without seizures. Patients with LS had a significantly higher initial mRS than the Ethical considerations 1-week survivors without any seizures and their infarct type was different, with significantly more atherothrombotic According to national legislation at the time of registra- strokes and less lacunar strokes in patients with LS. tion, informed consent was not required, as only regularly Follow-up duration was 24.5–27.8 years (mean 26.0 years, acquired patient data were recorded. The study protocol on SD 0.9 years). At the end of the follow-up in April 2015, long-term mortality was approved by the medical research 408 patients had died (91.9%), including all 16 patients with ethics committee of the University hospital Maastricht and ES (100%) and 29 patients with LS (90.6%). Patients with Maastricht University, and the study was conducted with the ES had a significantly shorter survival time than patients ethical standard laid down in the declaration of Helsinki and without any seizures (p = 0.02). Median survival for all 444 its later amendments. patients was 5.2 years (range 1 day–27.7 years), median sur- vival for the 396 patients without seizures was also 5.2 years (range 1 day–27.7 years), whereas median survival for the Results ES group was 2.2 years (range 10 days–13.6 years) and for the LS group 5.3 years (range 16 days–26.8 years). Between July 1st 1987 and September 30th 1990, 475 patients with a first-ever supratentorial brain infarction were registered. For this study on post-stroke seizures and long- Mortality after early‑onset seizures term mortality, we excluded 7 patients with a history of epi- lepsy, 17 with a rare cause of stroke and 7 of whom it was Kaplan–Meier analysis comparing patients with ES (n = 16) not possible to retrieve if and when they died, because they and patients without any seizures (n = 396) showed a sta- were not registered in the BRP anymore due to emigration. tistically significant increase in mortality in patients with Of the 444 remaining patients, 48 had one or more epilep- ES (p = 0.002; Fig. 1). However, Cox regression analysis tic seizures within 2 years following their initial stroke: 16 showed that ES did not influence mortality independently patients (3.6%) had ES and 32 patients (7.2%) suffered from (HR 1.09; 95% CI 0.64–1.85, p = 0.76), but that long-term at least one LS. Five patients with ES continued to have sei- mortality was determined by older age, male gender, dia- zures in the first month after the stroke, whereas in the other betes mellitus, infarct type (cardioembolic strokes having 11 patients seizures were limited to the first week after the higher mortality), stroke severity (higher initial mRS having stroke. Three patients with ES had a recurrent stroke with higher mortality), and smoking status unknown (smoking new clinical symptoms (neurological deficit), followed by status was mostly unknown in older patients with high initial new ES. mRS) (Table 2). Because of the long follow-up interval, we Five out of 32 patients with LS had a recurrent stroke also determined the influence of ES on mortality at inter - with new clinical symptoms before developing seizures. mediate time-intervals, as in the very long-term some risk Four of them had a recurrent brain infarction (proven with factors for mortality may overshadow the effect of ES on 1 3 Journal of Neurology Table 1 Baseline characteristics Total No seizures Early-onset seizures p value 1-week survivors Late-onset seizures p value < 2 years poststroke without seizures < 2 years post- stroke No. of patients 444 (100%) 396 (89.2%) 16 (3.6%) 378 (85.1%) 32 (7.2%) Male gender 235 (52.9%) 212 (53.5%) 10 (62.5%) 0.48 205 (54.2%) 13 (40.6%) 0.14 Age (mean) 70.6 (SD 12.0) 70.4 (SD 12.1) 77.3 (SD 5.7) 0.01 70.0 (SD 12.1) 69.1 (SD 12.5) 0.83 Age (median) 72.0 (range 26–96) 71.5 (range 26–96) 78.0 (range 65–83) 0.01 71 (range 26–94) 73.5 (range 40–87) 0.83 DM 95 (21.4%) 83 (21.0%) 3 (18.8%) 0.83 78 (20.6%) 9 (28.1%) 0.32 Hypertension 203 (45.7%) 182 (46.0%) 8 (50.0%) 0.75 175 (46.3%) 13 (40.6%) 0.54 IHD 101 (22.7%) 87 (22.0%) 6 (37.5%) 0.15 81 (21.4%) 8 (25.0%) 0.64 Smoking yes 149 (33.6%) 133 (33.6%) 4 (25.0%) 0.48 128 (33.9%) 12 (37.5%) 0.68 Smoking unk 38 (8.6%) 33 (8.3%) 3 (18.8%) 0.15 31 (8.2%) 2 (6.3%) 1.00 mRS 1 8 (1.8%) 8 (2.0%) 0 (0.0%) 1.00 8 (2.1%) 0 (0.0%) 1.00 mRS 2 88 (19.8%) 87 (22.0%) 0 (0.0%) 0.03 87 (23.0%) 1 (3.1%) 0.01 mRS 3 118 (26.6%) 105 (26.5%) 3 (18.8%) 0.77 105 (27.8%) 10 (31.3%) 0.68 mRS 4 97 (21.8%) 90 (22.7%) 3 (18.8%) 1.00 90 (23.8%) 4 (12.5%) 0.14 mRS 5 133 (30.0%) 106 (26.8%) 10 (62.5%) 0.00 88 (23.3%) 17 (53.1%) 0.00 Infarct-type AT 174 (39.2%) 147 (37.1%) 6 (37.5%) 0.98 141 (37.3%) 21 (65.6%) 0.00 Infarct-type CE 102 (23.0%) 88 (22.2%) 7 (43.8%) 0.07 76 (20.1%) 7 (21.9%) 0.81 Infarct-type LACI 168 (37.8%) 161 (40.7%) 3 (18.8%) 0.08 161 (42.6%) 4 (12.5%) 0.00 DM diabetes mellitus, IHD ischemic heart disease, Smoking unk smoking status is unknown, mRS modified Rankin scale, AT atherothrombotic infarct type, CE cardioembolic infarct type, LACI lacunar infarct type unknown), and cardioembolic infarct type had a significant relation with mortality at all time points, whereas diabetes mellitus and male gender only played a role in the longer follow-up duration (Table 4). Mortality after late‑onset seizures In the analyses on LS, we included 1-week survivors without seizures (n = 378) and patients with LS (n = 32). Eighteen patients without any seizures, who died during the first week following their stroke, were excluded as they were not at risk for developing LS. The Kaplan–Meier analysis showed no significant difference in survival ( p = 0.717; Fig.  2). Cox regression analysis confirmed that LS had no signifi- cant influence on mortality (HR 0.81, 95% CI 0.54–1.20, p = 0.28), but that long-term mortality was determined by the same risk factors as in the analyses on ES: older age, male gender, diabetes mellitus, smoking status unknown Fig. 1 Kaplan–Meier survival curves of patients with early-onset sei- zures (dotted line) vs. all seizure-free patients (black line); p = 0.002 (smoking status was mostly unknown in older patients with high initial mRS), stroke severity (higher initial mRS having higher mortality), and infarct type (cardioembolic strokes having higher mortality) (Table 2). We also determined the mortality. These results are shown in Tables 3 and 4. Uni- variate Kaplan–Meier analyses (Table 3) showed a signifi- influence of LS on mortality at intermediate time-intervals. LS had no significant influence on mortality at all follow- cant relation between ES and mortality at 2, 10 and 26 years after stroke, which was lost in the multivariate Cox regres- up durations (Tables 3, 5). Similar as in the ES group, older age, cardioembolic infarct type and high initial mRS (and sion analyses (Table 4). Older age, high initial mRS (and consequently also the age and mRS-related smoking status consequently also the age and mRS-related smoking status 1 3 Journal of Neurology Table 2 Cox regression results Early-onset seizures Late-onset seizures Hazard ratio (95% CI) p value Hazard ratio (95% CI) p value Early-onset seizures 1.09 (0.64–1.85) 0.76 Late-onset seizures 0.81 (0.54–1.20) 0.28 Older age (per year) 1.09 (1.08–1.10) 0.00 1.09 (1.08–1.11) 0.00 Male gender 1.28 (1.01–1.61) 0.04 1.35 (1.07–1.71) 0.01 DM 1.50 (1.16–1.95) 0.00 1.49 (1.15–1.94) 0.00 IHD 1.17 (0.91–1.50) 0.24 1.09 (0.84–1.42) 0.52 Hypertension 1.11 (0.89–1.37) 0.35 1.10 (0.88–1.36) 0.40 Smoking 0.01 0.00  Smoking vs. non-smoking 1.22 (0.95–1.56) 0.12 1.13 (0.88–1.46) 0.33  Smoking unk vs. non-smoking 1.70 (1.17–2.46) 0.01 1.98 (1.35–2.91) 0.00  Smoking unk vs. smoking 1.39 (0.93–2.11) 0.11 1.75 (1.14–2.68) 0.01 mRS 0.00 0.09  mRS 3 vs. 1 or 2 1.14 (0.82–1.58) 0.44 1.19 (0.86–1.64) 0.30  mRS 4 or 5 vs. 1 or 2 1.58 (1.15–2.16) 0.00 1.40 (1.02–1.91) 0.04  mRS 4 or 5 vs. 3 1.38 (1.08–1.77) 0.01 1.18 (0.92–1.50) 0.20 Infarct type 0.00 0.05  Infarct-type AT vs. LACI 1.12 (0.88–1.43) 0.37 1.12 (0.88–1.43) 0.35  Infarct-type CE vs. LACI 1.63 (1.24–2.14) 0.00 1.43 (1.07–1.92) 0.02  Infarct-type CE vs. AT 1.46 (1.11–1.92) 0.01 1.28 (0.96–1.70) 0.10 Note that all analyses were run two times: once with indicator first and once with indicator last, resulting in three different comparisons to report for the variables smoking, mRS and infarct type DM diabetes mellitus, IHD ischemic heart disease, Smoking unk smoking status is unknown, mRS modified Rankin scale, AT atherothrombotic infarct type, CE cardioembolic infarct type, LACI lacunar infarct type Table 3 Kaplan–Meier p values for both early-onset seizures and themselves as shown in the multivariate analysis. Most late-onset seizures at several time-intervals other studies also found no independent relation between ES and higher mortality [14–18]. The relationship between Early-onset seizures Late- onset ES and mortality remained significant after correction for seizures confounders in studies by Arboix et al. [19, 20]. Stroke patients suffer by definition from a cardiovascular disease 1 year after the stroke 0.15 NA and, therefore, are at an increased risk to develop another 2 years after the stroke 0.04 0.79 cardiovascular disease and consequently have an increased 5 years after the stroke 0.12 0.84 mortality [27]. Given this increased risk of mortality due 10 years after the stroke 0.00 0.76 to vascular disease it is more difficult to distinguish an 26 years after the stroke 0.00 0.72 eventual increase in mortality due to early and late sei- zures, which might explain the conflicting results found unknown) had a significant relation with mortality at all in different studies. In our study, LS had no significant influence on survival time points, whereas diabetes mellitus and male gender only played a role in the longer follow-up duration (Table 5). in univariate nor multivariate analyses. This contrasts with the study by Arntz et al. [21], which showed an increased long-term mortality in patients with stroke at young age and post-stroke epilepsy. The seemingly opposite outcome of Discussion our study can be explained mostly by differences in study population and study design. In the study by Arntz et al. In this study, we showed that both ES and LS did not only younger patients (aged 18–50 years) with a TIA or influence long-term mortality after ischemic stroke. We ischemic stroke were included, and the occurrence of sei- found that patients with ES had a higher mortality; how- zures was determined retrospectively, which may have led ever, this effect was due to the confounding factors (older to a recall bias. Also, all seizures which occurred poststroke age, male gender, diabetes mellitus, infarct type and stroke were included, also when these occurred more than 2 years severity as measured by the mRS) and not to the seizures 1 3 Journal of Neurology 1 3 Table 4 Cox regression results for early-onset seizures at several time-intervals Follow-up 1 year 2 years 5 years 10 years 26 years Hazard ratio (95% CI) p value Hazard ratio (95% CI) p value Hazard ratio (95% CI) p value Hazard ratio (95% CI) p value Hazard ratio (95% CI) p value Early-onset seizures 0.96 (0.41–2.25) 0.93 1.14 (0.54–2.41) 0.72 0.83 (0.43–1.63) 0.59 1.02 (0.59–1.78) 0.93 1.09 (0.64–1.85) 0.76 Older age (per year) 1.06 (1.03–1.09) 0.00 1.06 (1.03–1.08) 0.00 1.07 (1.05–1.09) 0.00 1.08 (1.06–1.09) 0.00 1.09 (1.08–1.10) 0.00 Male gender 1.10 (0.69–1.75) 0.68 1.04 (0.68–1.59) 0.85 1.19 (0.86–1.64) 0.30 1.19 (0.91–1.57) 0.21 1.28 (1.01–1.61) 0.04 DM 1.31 (0.81–2.11) 0.28 1.26 (0.81–1.96) 0.30 1.29 (0.92–1.81) 0.15 1.46 (1.10–1.93) 0.01 1.50 (1.16–1.95) 0.00 IHD 1.42 (0.92–2.18) 0.11 1.23 (0.82–1.85) 0.31 1.05 (0.76–1.45) 0.79 1.15 (0.87–1.52) 0.32 1.17 (0.91–1.50) 0.24 Hypertension 0.97 (0.64–1.49) 0.90 0.96 (0.65–1.41) 0.84 1.02 (0.76–1.37) 0.91 0.97 (0.76–1.24) 0.81 1.11 (0.89–1.37) 0.35 Smoking 0.12 0.16 0.07 0.02 0.01  Smoking vs. non- 1.03 (0.61–1.75) 0.91 1.01 (0.62–1.64) 0.97 1.01 (0.70–1.46) 0.95 1.20 (0.90–1.61) 0.21 1.22 (0.95–1.56) 0.12 smoking  Smoking unknown vs. 1.77 (1.02–3.07) 0.04 1.64 (0.98–2.75) 0.06 1.65 (1.08–2.53) 0.02 1.75 (1.18–2.58) 0.01 1.70 (1.17–2.46) 0.01 non-smoking  Smoking unknown vs. 1.71 (0.87–3.39) 0.12 1.62 (0.86–3.08) 0.14 1.63 (0.98–2.70) 0.06 1.45 (0.93–2.26) 0.10 1.39 (0.93–2.11) 0.11 smoking mRS 0.00 0.00 0.02 0.00 0.00  mRS 3 vs. 1 or 2 1.14 (0.45–2.88) 0.79 1.13 (0.49–2.57) 0.78 1.29 (0.76–2.21) 0.35 1.21 (0.79–1.84) 0.38 1.14 (0.82–1.58) 0.44  mRS 4 or 5 vs. 1 or 2 2.61 (1.12–6.06) 0.03 2.53 (1.20–5.36) 0.02 1.83 (1.11–3.03) 0.02 1.85 (1.25–2.73) 0.00 1.58 (1.15–2.16) 0.00  mRS 4 or 5 vs. 3 2.29 (1.35–3.91) 0.00 2.24 (1.39–3.64) 0.00 1.42 (1.01–1.98) 0.04 1.53 (1.15–2.03) 0.00 1.38 (1.08–1.77) 0.01 Infarct type 0.00 0.00 0.00 0.00 0.00  Infarct-type AT vs. 1.60 (0.93–2.77) 0.09 1.60 (0.98–2.60) 0.06 1.24 (0.88–1.75) 0.23 1.14 (0.86–1.51) 0.36 1.12 (0.88–1.43) 0.37 LACI  Infarct-type CE vs. 3.03 (1.75–5.24) 0.00 2.69 (1.64–4.42) 0.00 1.84 (1.28–2.65) 0.00 1.69 (1.24–2.30) 0.00 1.63 (1.24–2.14) 0.00 LACI  Infarct-type CE vs. AT 1.89 (1.20–2.97) 0.01 1.69 (1.11–2.56) 0.02 1.49 (1.05–2.10) 0.02 1.48 (1.09–2.00) 0.01 1.46 (1.11–1.92) 0.01 Note that all analyses were run two times: once with indicator first and once with indicator last, resulting in three different comparisons to report for the variables smoking, mRS and infarct type DM diabetes mellitus, IHD ischemic heart disease, mRS modified Rankin scale, AT atherothrombotic infarct type, CE cardioembolic infarct type, LACI lacunar infarct type Journal of Neurology seizures were gathered prospectively for two consecutive years by one single investigator. Considerable effort was put into gathering information about the occurrence of possible seizures. Therefore, we think our recall bias is low. Also, we chose to include only patients with first ever supratentorial brain infarct and only seizures which occurred within 2 years after the first-ever stroke, which means only seizures which are likely to be ascribed to the patient’s stroke were taken into account. Furthermore, our long-term mortality follow- up and a statistical analysis with correction for known risk factors for (long term) mortality are major strengths of this study and make it possible to make a firm statement on the relation between poststroke seizures and long term mortality. Our study has some limitations. First, not all patients underwent CT scanning; therefore, some patients may have had a haemorrhagic stroke. Since haemorrhagic stroke Fig. 2 Kaplan–Meier survival curves of patients with late-onset sei- patients have a higher risk of poststroke seizures [2, 32], zures (dotted line) vs. 1-week survivors without any seizures (black line); p = 0.717 patients with haemorrhagic stroke may be overrepresented in our ES group. This might have influenced mortality rates, since mortality is higher in patients with haemor- after the index TIA or stroke. In our study only 33 patients rhagic stroke [33]. However, we believe this effect to be aged ≤ 50 years were included, none of those developed ES, small, as we performed all analyses anew excluding the 20 and only 4 of the younger patients developed LS. These patients without CT-scanning and found the same results four patients all had severe strokes (initial mRS 4 or 5). (data not shown). Second, we used a surrogate marker for Our young stroke patients with LS had a survival of 75% stroke severity, the initial mRS, which actually is an out- after 26 years vs. 79% in our young patients without LS come scale and a crude assessment of function directly (non-significant, data not shown). Mortality in our young after a stroke. As the NIHSS was not available yet at the stroke patients was also not influenced by LS in a tenta- time of inclusion start and no other stroke severity score tive Cox-regression analysis (data not shown). In the study was recorded, we unfortunately could not use a more reli- by Arntz et al. the significant effect of post-stroke seizures able measure for stroke severity. on mortality was only found in patients with mild stroke A third limitation is the difference in group size, where (NIHSS 0–4). They found no significant correlation between the seizure groups are small as compared to the stroke post-stroke seizures and mortality in patients with moderate group, which makes it more difficult to detect a clinically stroke, nor in those with severe stroke. Therefore, our results relevant difference in mortality. Last, our follow-up of in the young stroke patients are in line with the result from 2 years with regard to the development of seizures might the study by Arntz et al., since we also found no correlation have excluded some patients who developed seizures at between LS and long-term mortality in young stroke patients a later time point. Though the incidence of new seizures with severe strokes. more than 2 years after a stroke is low, we will certainly When comparing our data to other studies about inci- have missed some events. dence of seizures in stroke patients, we notice a larger part of The authors of the FUTURE study [21] state that future lacunar stroke in our seizure patients [8, 28]. We hypothesize studies should investigate the role of antiepileptic drugs that these seizures may be caused by microvascular changes in preventing post-stroke epilepsy. However, this would in the brain, including cortical parts of the brain, and not by only be true for the specific young stroke population they the lacunar stroke itself, as also suggested by de Reuck et al. studied, since in our study the relation between LS and and Arboix et al. [29–31]. mortality was not significant. Before starting studies aimed Strengths of our study are our method of selection and at prophylactic treatment with antiepileptic drugs in stroke follow-up. In our study data regarding the occurrence of patients, more effort should be done to elaborate the exact influence of LS in stroke patients, not only with regard to mortality but also concerning the effect on stroke recovery and quality of life [34]. In conclusion, neither ES nor LS have a negative impact on long-term mortality in ischemic stroke patients. Mortal- ity is, therefore, no argument to support the prophylactic 1 3 Journal of Neurology Table 5 Cox regression results for late-onset seizures at several time-intervals Follow-up 2 years 5 years 10 years 26 years Hazard ratio (95% p value Hazard ratio (95% p value Hazard ratio (95% p value Hazard ratio (95% p value CI) CI) CI) CI) Late-onset seizures 0.97 (0.48–1.98) 0.94 0.87 (0.50–1.52) 0.62 0.80 (0.50–1.27) 0.34 0.81 (0.54–1.20) 0.28 Older age (per year) 1.06 (1.03–1.08) 0.00 1.07 (1.05–1.09) 0.00 1.08 (1.06–1.09) 0.00 1.09 (1.08–1.11) 0.00 Male gender 1.33 (0.84–2.11) 0.22 1.38 (0.99–1.94) 0.06 1.29 (0.97–1.71) 0.08 1.35 (1.07–1.71) 0.01 DM 1.17 (0.73–1.89) 0.51 1.22 (0.85–1.73) 0.28 1.47 (1.10–1.96) 0.01 1.49 (1.15–1.94) 0.00 IHD 1.22 (0.78–1.89) 0.39 0.99 (0.70–1.39) 0.95 1.07 (0.80–1.43) 0.65 1.09 (0.84–1.42) 0.52 Hypertension 1.09 (0.73–1.63) 0.69 1.03 (0.76–1.39) 0.85 0.94 (0.73–1.20) 0.61 1.10 (0.88–1.36) 0.40 Smoking 0.06 0.00 0.00 0.00  Smoking vs. non- 0.91 (0.54–1.53) 0.72 0.95 (0.65–1.39) 0.79 1.11 (0.83–1.51) 0.48 1.13 (0.88–1.46) 0.33 smoking  Smoking unknown 1.91 (1.08–3.38) 0.03 2.14 (1.38–3.32) 0.00 2.14 (1.43–3.22) 0.00 1.98 (1.35–2.91) 0.00 vs. non-smoking  Smoking unknown 2.11 (1.04–4.27) 0.04 2.25 (1.33–3.80) 0.00 1.92 (1.21–3.06) 0.01 1.75 (1.14–2.68) 0.01 vs. smoking mRS 0.01 0.13 0.04 0.09  mRS 3 vs. 1 or 2 1.19 (0.54–2.62) 0.67 1.39 (0.82–2.35) 0.23 1.28 (0.84–1.93) 0.25 1.19 (0.86–1.64) 0.30  mRS 4 or 5 vs. 1 2.18 (1.05–4.53) 0.04 1.65 (1.00–2.73) 0.05 1.61 (1.09–2.39) 0.02 1.40 (1.02–1.91) 0.04 or 2  mRS 4 or 5 vs. 3 1.84 (1.13–3.00) 0.02 1.19 (0.85–1.67) 0.30 1.26 (0.95–1.68) 0.10 1.18 (0.92–1.50) 0.20 Infarct type 0.07 0.08 0.05 0.05  Infarct-type AT 1.17 (0.72–1.92) 0.52 1.11 (0.78–1.58) 0.55 1.11 (0.84–1.47) 0.47 1.12 (0.88–1.43) 0.35 vs. LACI  Infarct-type CE 1.82 (1.07–3.10) 0.03 1.55 (1.05–2.30) 0.03 1.50 (1.08–2.09) 0.02 1.43 (1.07–1.92) 0.02 vs. LACI  Infarct-type CE 1.55 (0.95–2.52) 0.08 1.39 (0.96–2.03) 0.08 1.35 (0.98–1.97) 0.07 1.28 (0.96–1.70) 0.10 vs. AT Note that all analyses were run two times: once with indicator first and once with indicator last, resulting in three different comparisons to report for the variables smoking, mRS and infarct type DM diabetes mellitus, IHD ischemic heart disease, mRS modified Rankin scale, AT atherothrombotic infarct type, CE cardioembolic infarct type, LACI lacunar infarct type conducted with the ethical standard laid down in the declaration of use of antiepileptic drugs to prevent seizures in ischemic Helsinki and its later amendments. stroke patients. More research is necessary on the impact of especially LS on mortality, neurologic recovery from Open Access This article is distributed under the terms of the Crea- stroke and quality of life. tive Commons Attribution 4.0 International License (http://creat iveco mmons.or g/licenses/b y/4.0/), which permits unrestricted use, distribu- Compliance with ethical standards tion, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Conflicts of interest JH van Tuijl, EPM van Raak, RJ van Oosten- Creative Commons license, and indicate if changes were made. brugge, AP Aldenkamp and RPW Rouhl report no conflicts of interest regarding the current study. References Ethical standards According to national legislation at the time of reg- istration informed consent was not required, as only regularly acquired patient data were recorded. The study protocol on long-term mortality 1. 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The occurrence of seizures after ischemic stroke does not influence long-term mortality; a 26-year follow-up study

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Medicine & Public Health; Neurology; Neurosciences; Neuroradiology
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Abstract

Objective Epileptic seizures are a common complication after stroke. The relation between occurrence of seizures after stroke and long-term mortality remains elusive. We aimed to assess whether seizures in an early or late phase after ischemic stroke are an independent determinant of long-term mortality. Methods We prospectively included and followed 444 ischemic stroke patients with a first-ever supratentorial brain infarct for at least 2 years after their stroke regarding the occurrence of seizures. The final follow-up for mortality is from April 2015 (follow-up duration 24.5–27.8 years, mean 26.0 years, SD 0.9 years). We compared patients with early-onset seizures with all seizure-free patients, whereas the patients with late-onset seizures were compared with the 1-week survivors without any seizures. We used Cox-regression analyses to correct for possible confounding factors. Results Kaplan–Meier analysis showed significantly higher mortality for the patients with early-onset seizures (p = 0.002) but after correction for known risk factors for (long term) mortality early-onset seizures had no independent influence on long-term mortality (HR 1.09; 95% CI 0.64–1.85). In patients with late-onset seizures, no significant influence from late- onset seizures on long-term mortality was found (univariate p = 0.717; multivariate HR 0.81; 95% CI 0.54–1.20). Conclusion Both early-onset and late-onset seizures do not influence long-term mortality after ischemic stroke. Keywords Seizures · Epilepsy · Brain infarct · Stroke Introduction Epileptic seizures are a common complication after stroke although the risk to develop seizures varies, depending on variables such as stroke type (hemorrhagic vs. ischemic), stroke severity, and cortical involvement [1–7]. Seizures * R. P. W. Rouhl occurring after stoke are divided in early-onset seizures (ES, R.Rouhl@mumc.nl incidence 3.3% of patients) and late-onset seizures (LS, inci- dence 18 in 1000 person years) depending on their time of Department of Neurology, Maastricht University Medical Center, PO Box 5800, 6202 AZ Maastricht, The Netherlands occurrence, with a variable cut-off point in different studies between 24 h and 1 month post-stroke [2, 6, 8, 9]. ES and Department of Neurology, Elisabeth-Tweesteden Hospital, Tilburg, The Netherlands LS differ in their pathophysiology. ES are induced by the acute disruption of the blood–brain barrier and the resultant School for Mental Health and Neurosciences, Maastricht University, Maastricht, The Netherlands hyperexcitatory state, whereas LS are a result of a chronic process called epileptogenesis, which causes gliosis and Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center, Maastricht, formation of epileptogenic networks [10]. Furthermore, LS The Netherlands have a higher recurrence rate than ES [11] and, therefore, LS Academic Center for Epileptology, Maastricht University are considered to have a larger clinical significance. In addi- Medical Center and Kempenhaeghe Center of Expertise tion, according to the guidelines of the International League for Epileptology, Maastricht, The Netherlands for Epilepsy (ILAE), in stroke patients with LS, epilepsy Faculty of Electrical Engineering, University of Technology, may be diagnosed after only one seizure [12]. Eindhoven, The Netherlands Vol.:(0123456789) 1 3 Journal of Neurology In general, patients with epilepsy have a higher mortality We recorded age, gender, clinical infarct syndrome (lacu- risk than people without epilepsy [13]. However, whether nar or cortical syndrome), degree of disability at stroke onset this also applies to stroke patients suffering from post-stroke using the modified Rankin scale (mRS; in the present study seizures remains unclear. Most studies showed a negative used as a surrogate marker for stroke severity), and cardio- relation between ES and mortality when using a univariate vascular risk factors, such as smoking, hypertension, dia- statistical analysis technique; however, this relationship was betes mellitus, and ischaemic heart disease. Clinical infarct lost when using multivariate statistical analysis techniques syndrome was defined as lacunar or cortical infarct follow - [14–18]. Only in two studies by Arboix et al. the relationship ing definitions from the Oxfordshire Community Stroke between early seizures and mortality remained significant Project [23]. The cortical infarct group was subdivided in [19, 20]. We are aware of only one study that studied the a cardioembolic and atherothrombotic group, depending relation between LS and mortality in stroke patients [21]. on the identification of a cardiac embolic source, such as This study in young stroke patients showed that long-term atrial fibrillation (as evidenced by ECG, 24-h heart rhythm mortality was significantly higher in patients with seizures monitoring and/or cardiac echocardiography). We defined than in patients without seizures. hypertension, diabetes mellitus and ischemic heart disease Knowledge of the impact of especially late-onset seizures as described previously [24]. Data concerning the occur- on (long term) mortality in stroke patients is relevant with rence of epileptic seizures were collected prospectively by regard to a possible prophylactic treatment to prevent those one single investigator (EPM van Raak) during a follow-up seizures. period of at least 2 years after inclusion in the Maastricht The aim of the present study was to assess the independ- stroke registry. Seizures during admission were recorded ent effect of ES and LS on the long-term mortality after a by the treating physician and recorded from the charts by first-ever supratentorial brain infarct in a large prospective this investigator. After discharge from the hospital, patients cohort study. were invited for regular follow-up visits at the outpatient clinic every 3–6 months until at least 2 years after the stroke. If patients were unable to attend this visit, the investigator Patients and methods contacted the patient or a close relative or the general prac- titioner by phone. In case the patient was living in a nursing All patients aged 18 years and older with a stroke, admitted home the investigator visited the patients every 6 months. to the neurology department or seen at the outpatient clinic Seizure occurrence was recorded when either a focal or a of Maastricht University Medical Center, are registered in generalized epileptic seizure occurred, excluding other a prospective database; the Maastricht Stroke Registry. For causes of disturbances of consciousness or rhythmic limb the present study, all patients with a first ever supratento- movements, such as syncope due to cardiac arrhythmia or rial brain infarct between July 1st 1987 and September limb shaking TIA’s. The date of all seizures and, if possi- 30th 1990 were included. Brain infarction was defined as ble, the seizure subtypes were registered, as well as eventual the rapid onset of clinical signs of focal cerebral function antiepileptic drug (AED) treatment. In patients with seizures disturbance, lasting longer than 24 h or leading to death, occurring ≤ 1  week after stroke onset, the seizures were with no other apparent cause than that of vascular origin, regarded as ES, even when such a patient continued to have with normal CT or CT showing an area of low attenuation seizures after the first week following the initial stroke. In compatible with the clinical signs and symptoms, or autopsy patients with a first seizure occurring > 1 week after stroke revealing an infarct compatible with the clinical signs and onset, the seizures were regarded as LS, as described by the symptoms. When neither CT nor autopsy were available, most recent guideline from the International League Against we used the Guy’s Hospital Stroke Diagnostic Score (Allen Epilepsy (ILAE) [25]. Only seizures occurring within score) [22] to determine the probability that the stroke was 2 years after the initial stroke were considered as related to due to infarction. In this way, 20 patients with an Allen the stroke and regarded as post-stroke seizures. Since most score < 4, i.e. with a probability of 90% or more that their stroke-related seizures do occur within 2 years [2, 8, 26], stroke was due to infarction, were also included: 15 of 396 the etiology of a first seizure occurring more than 2 years patients without seizures (3.8%), 3 of 16 patients with ES after stroke is uncertain; therefore, we did not include these (18.8%) and 2 of 32 patients with LS (6.3%). We excluded seizures in the present study. In April 2015, the follow-up patients with previous stroke, clinical signs of cerebellar regarding mortality was conducted retrospectively with end or brain stem stroke, primary intracerebral haemorrhage, date March 31st 2015. This was done by checking the elec- subarachnoid haemorrhage, brain tumour, history of one or tronic patient files in our center and the Dutch Municipal more epileptic seizures or a rare cause of the infarction (e.g. Personal Records Database (BRP), the latter being a formal, vasculitis, arterial dissection, or a hematologic disorder). and reliable national registration of personal details of the 1 3 Journal of Neurology entire population of the Netherlands, including birth date CT imaging) followed by LS. The other patient had clinical and date of death. symptoms of a recurrent stroke and epileptic seizures at the same time, and died before CT scan could be performed. Statistical analysis Fourteen patients with ES (87.5%) were treated with an AED, seven of them were treated with carbamazepine Data analysis was performed using SPSS statistics version and seven with phenytoin. The remaining two patients 23. We compared baseline data with Mann–Whitney U test with ES (12.5%) did not receive AED treatment (they died or chi-square test, whichever was appropriate. We assessed after 9 and 21 days, respectively). Of the 32 patients with mortality using Kaplan–Meier survival curves and deter- LS, 22 patients (68.8%) were treated with an AED (17 of mined differences between survival in stroke patients with them received carbamazepine and 5 phenytoin), whereas ES vs. no seizures and in patients with LS vs. no seizures 10 patients (31.2%) did not receive AED treatment. Six of using a log-rank test. We assessed independent contribu- them experienced only one single seizure and two of them tions to mortality risk with Cox regression analyses with experienced only two focal seizures and were seizure free the covariates age at onset of stroke, gender, infarct type thereafter without treatment. The remaining two patients (atherothrombotic, cardioembolic or lacunar stroke), mRS died soon after their first seizure (one patient on the same as a surrogate marker for stroke severity, hypertension, dia- day, one patient the next day). betes mellitus, ischemic heart disease, and smoking. A p Baseline characteristics are shown in Table 1. Patients value < 0.05 was regarded as statistically significant. with ES were significantly older and had a significantly higher initial mRS than patients without seizures. Patients with LS had a significantly higher initial mRS than the Ethical considerations 1-week survivors without any seizures and their infarct type was different, with significantly more atherothrombotic According to national legislation at the time of registra- strokes and less lacunar strokes in patients with LS. tion, informed consent was not required, as only regularly Follow-up duration was 24.5–27.8 years (mean 26.0 years, acquired patient data were recorded. The study protocol on SD 0.9 years). At the end of the follow-up in April 2015, long-term mortality was approved by the medical research 408 patients had died (91.9%), including all 16 patients with ethics committee of the University hospital Maastricht and ES (100%) and 29 patients with LS (90.6%). Patients with Maastricht University, and the study was conducted with the ES had a significantly shorter survival time than patients ethical standard laid down in the declaration of Helsinki and without any seizures (p = 0.02). Median survival for all 444 its later amendments. patients was 5.2 years (range 1 day–27.7 years), median sur- vival for the 396 patients without seizures was also 5.2 years (range 1 day–27.7 years), whereas median survival for the Results ES group was 2.2 years (range 10 days–13.6 years) and for the LS group 5.3 years (range 16 days–26.8 years). Between July 1st 1987 and September 30th 1990, 475 patients with a first-ever supratentorial brain infarction were registered. For this study on post-stroke seizures and long- Mortality after early‑onset seizures term mortality, we excluded 7 patients with a history of epi- lepsy, 17 with a rare cause of stroke and 7 of whom it was Kaplan–Meier analysis comparing patients with ES (n = 16) not possible to retrieve if and when they died, because they and patients without any seizures (n = 396) showed a sta- were not registered in the BRP anymore due to emigration. tistically significant increase in mortality in patients with Of the 444 remaining patients, 48 had one or more epilep- ES (p = 0.002; Fig. 1). However, Cox regression analysis tic seizures within 2 years following their initial stroke: 16 showed that ES did not influence mortality independently patients (3.6%) had ES and 32 patients (7.2%) suffered from (HR 1.09; 95% CI 0.64–1.85, p = 0.76), but that long-term at least one LS. Five patients with ES continued to have sei- mortality was determined by older age, male gender, dia- zures in the first month after the stroke, whereas in the other betes mellitus, infarct type (cardioembolic strokes having 11 patients seizures were limited to the first week after the higher mortality), stroke severity (higher initial mRS having stroke. Three patients with ES had a recurrent stroke with higher mortality), and smoking status unknown (smoking new clinical symptoms (neurological deficit), followed by status was mostly unknown in older patients with high initial new ES. mRS) (Table 2). Because of the long follow-up interval, we Five out of 32 patients with LS had a recurrent stroke also determined the influence of ES on mortality at inter - with new clinical symptoms before developing seizures. mediate time-intervals, as in the very long-term some risk Four of them had a recurrent brain infarction (proven with factors for mortality may overshadow the effect of ES on 1 3 Journal of Neurology Table 1 Baseline characteristics Total No seizures Early-onset seizures p value 1-week survivors Late-onset seizures p value < 2 years poststroke without seizures < 2 years post- stroke No. of patients 444 (100%) 396 (89.2%) 16 (3.6%) 378 (85.1%) 32 (7.2%) Male gender 235 (52.9%) 212 (53.5%) 10 (62.5%) 0.48 205 (54.2%) 13 (40.6%) 0.14 Age (mean) 70.6 (SD 12.0) 70.4 (SD 12.1) 77.3 (SD 5.7) 0.01 70.0 (SD 12.1) 69.1 (SD 12.5) 0.83 Age (median) 72.0 (range 26–96) 71.5 (range 26–96) 78.0 (range 65–83) 0.01 71 (range 26–94) 73.5 (range 40–87) 0.83 DM 95 (21.4%) 83 (21.0%) 3 (18.8%) 0.83 78 (20.6%) 9 (28.1%) 0.32 Hypertension 203 (45.7%) 182 (46.0%) 8 (50.0%) 0.75 175 (46.3%) 13 (40.6%) 0.54 IHD 101 (22.7%) 87 (22.0%) 6 (37.5%) 0.15 81 (21.4%) 8 (25.0%) 0.64 Smoking yes 149 (33.6%) 133 (33.6%) 4 (25.0%) 0.48 128 (33.9%) 12 (37.5%) 0.68 Smoking unk 38 (8.6%) 33 (8.3%) 3 (18.8%) 0.15 31 (8.2%) 2 (6.3%) 1.00 mRS 1 8 (1.8%) 8 (2.0%) 0 (0.0%) 1.00 8 (2.1%) 0 (0.0%) 1.00 mRS 2 88 (19.8%) 87 (22.0%) 0 (0.0%) 0.03 87 (23.0%) 1 (3.1%) 0.01 mRS 3 118 (26.6%) 105 (26.5%) 3 (18.8%) 0.77 105 (27.8%) 10 (31.3%) 0.68 mRS 4 97 (21.8%) 90 (22.7%) 3 (18.8%) 1.00 90 (23.8%) 4 (12.5%) 0.14 mRS 5 133 (30.0%) 106 (26.8%) 10 (62.5%) 0.00 88 (23.3%) 17 (53.1%) 0.00 Infarct-type AT 174 (39.2%) 147 (37.1%) 6 (37.5%) 0.98 141 (37.3%) 21 (65.6%) 0.00 Infarct-type CE 102 (23.0%) 88 (22.2%) 7 (43.8%) 0.07 76 (20.1%) 7 (21.9%) 0.81 Infarct-type LACI 168 (37.8%) 161 (40.7%) 3 (18.8%) 0.08 161 (42.6%) 4 (12.5%) 0.00 DM diabetes mellitus, IHD ischemic heart disease, Smoking unk smoking status is unknown, mRS modified Rankin scale, AT atherothrombotic infarct type, CE cardioembolic infarct type, LACI lacunar infarct type unknown), and cardioembolic infarct type had a significant relation with mortality at all time points, whereas diabetes mellitus and male gender only played a role in the longer follow-up duration (Table 4). Mortality after late‑onset seizures In the analyses on LS, we included 1-week survivors without seizures (n = 378) and patients with LS (n = 32). Eighteen patients without any seizures, who died during the first week following their stroke, were excluded as they were not at risk for developing LS. The Kaplan–Meier analysis showed no significant difference in survival ( p = 0.717; Fig.  2). Cox regression analysis confirmed that LS had no signifi- cant influence on mortality (HR 0.81, 95% CI 0.54–1.20, p = 0.28), but that long-term mortality was determined by the same risk factors as in the analyses on ES: older age, male gender, diabetes mellitus, smoking status unknown Fig. 1 Kaplan–Meier survival curves of patients with early-onset sei- zures (dotted line) vs. all seizure-free patients (black line); p = 0.002 (smoking status was mostly unknown in older patients with high initial mRS), stroke severity (higher initial mRS having higher mortality), and infarct type (cardioembolic strokes having higher mortality) (Table 2). We also determined the mortality. These results are shown in Tables 3 and 4. Uni- variate Kaplan–Meier analyses (Table 3) showed a signifi- influence of LS on mortality at intermediate time-intervals. LS had no significant influence on mortality at all follow- cant relation between ES and mortality at 2, 10 and 26 years after stroke, which was lost in the multivariate Cox regres- up durations (Tables 3, 5). Similar as in the ES group, older age, cardioembolic infarct type and high initial mRS (and sion analyses (Table 4). Older age, high initial mRS (and consequently also the age and mRS-related smoking status consequently also the age and mRS-related smoking status 1 3 Journal of Neurology Table 2 Cox regression results Early-onset seizures Late-onset seizures Hazard ratio (95% CI) p value Hazard ratio (95% CI) p value Early-onset seizures 1.09 (0.64–1.85) 0.76 Late-onset seizures 0.81 (0.54–1.20) 0.28 Older age (per year) 1.09 (1.08–1.10) 0.00 1.09 (1.08–1.11) 0.00 Male gender 1.28 (1.01–1.61) 0.04 1.35 (1.07–1.71) 0.01 DM 1.50 (1.16–1.95) 0.00 1.49 (1.15–1.94) 0.00 IHD 1.17 (0.91–1.50) 0.24 1.09 (0.84–1.42) 0.52 Hypertension 1.11 (0.89–1.37) 0.35 1.10 (0.88–1.36) 0.40 Smoking 0.01 0.00  Smoking vs. non-smoking 1.22 (0.95–1.56) 0.12 1.13 (0.88–1.46) 0.33  Smoking unk vs. non-smoking 1.70 (1.17–2.46) 0.01 1.98 (1.35–2.91) 0.00  Smoking unk vs. smoking 1.39 (0.93–2.11) 0.11 1.75 (1.14–2.68) 0.01 mRS 0.00 0.09  mRS 3 vs. 1 or 2 1.14 (0.82–1.58) 0.44 1.19 (0.86–1.64) 0.30  mRS 4 or 5 vs. 1 or 2 1.58 (1.15–2.16) 0.00 1.40 (1.02–1.91) 0.04  mRS 4 or 5 vs. 3 1.38 (1.08–1.77) 0.01 1.18 (0.92–1.50) 0.20 Infarct type 0.00 0.05  Infarct-type AT vs. LACI 1.12 (0.88–1.43) 0.37 1.12 (0.88–1.43) 0.35  Infarct-type CE vs. LACI 1.63 (1.24–2.14) 0.00 1.43 (1.07–1.92) 0.02  Infarct-type CE vs. AT 1.46 (1.11–1.92) 0.01 1.28 (0.96–1.70) 0.10 Note that all analyses were run two times: once with indicator first and once with indicator last, resulting in three different comparisons to report for the variables smoking, mRS and infarct type DM diabetes mellitus, IHD ischemic heart disease, Smoking unk smoking status is unknown, mRS modified Rankin scale, AT atherothrombotic infarct type, CE cardioembolic infarct type, LACI lacunar infarct type Table 3 Kaplan–Meier p values for both early-onset seizures and themselves as shown in the multivariate analysis. Most late-onset seizures at several time-intervals other studies also found no independent relation between ES and higher mortality [14–18]. The relationship between Early-onset seizures Late- onset ES and mortality remained significant after correction for seizures confounders in studies by Arboix et al. [19, 20]. Stroke patients suffer by definition from a cardiovascular disease 1 year after the stroke 0.15 NA and, therefore, are at an increased risk to develop another 2 years after the stroke 0.04 0.79 cardiovascular disease and consequently have an increased 5 years after the stroke 0.12 0.84 mortality [27]. Given this increased risk of mortality due 10 years after the stroke 0.00 0.76 to vascular disease it is more difficult to distinguish an 26 years after the stroke 0.00 0.72 eventual increase in mortality due to early and late sei- zures, which might explain the conflicting results found unknown) had a significant relation with mortality at all in different studies. In our study, LS had no significant influence on survival time points, whereas diabetes mellitus and male gender only played a role in the longer follow-up duration (Table 5). in univariate nor multivariate analyses. This contrasts with the study by Arntz et al. [21], which showed an increased long-term mortality in patients with stroke at young age and post-stroke epilepsy. The seemingly opposite outcome of Discussion our study can be explained mostly by differences in study population and study design. In the study by Arntz et al. In this study, we showed that both ES and LS did not only younger patients (aged 18–50 years) with a TIA or influence long-term mortality after ischemic stroke. We ischemic stroke were included, and the occurrence of sei- found that patients with ES had a higher mortality; how- zures was determined retrospectively, which may have led ever, this effect was due to the confounding factors (older to a recall bias. Also, all seizures which occurred poststroke age, male gender, diabetes mellitus, infarct type and stroke were included, also when these occurred more than 2 years severity as measured by the mRS) and not to the seizures 1 3 Journal of Neurology 1 3 Table 4 Cox regression results for early-onset seizures at several time-intervals Follow-up 1 year 2 years 5 years 10 years 26 years Hazard ratio (95% CI) p value Hazard ratio (95% CI) p value Hazard ratio (95% CI) p value Hazard ratio (95% CI) p value Hazard ratio (95% CI) p value Early-onset seizures 0.96 (0.41–2.25) 0.93 1.14 (0.54–2.41) 0.72 0.83 (0.43–1.63) 0.59 1.02 (0.59–1.78) 0.93 1.09 (0.64–1.85) 0.76 Older age (per year) 1.06 (1.03–1.09) 0.00 1.06 (1.03–1.08) 0.00 1.07 (1.05–1.09) 0.00 1.08 (1.06–1.09) 0.00 1.09 (1.08–1.10) 0.00 Male gender 1.10 (0.69–1.75) 0.68 1.04 (0.68–1.59) 0.85 1.19 (0.86–1.64) 0.30 1.19 (0.91–1.57) 0.21 1.28 (1.01–1.61) 0.04 DM 1.31 (0.81–2.11) 0.28 1.26 (0.81–1.96) 0.30 1.29 (0.92–1.81) 0.15 1.46 (1.10–1.93) 0.01 1.50 (1.16–1.95) 0.00 IHD 1.42 (0.92–2.18) 0.11 1.23 (0.82–1.85) 0.31 1.05 (0.76–1.45) 0.79 1.15 (0.87–1.52) 0.32 1.17 (0.91–1.50) 0.24 Hypertension 0.97 (0.64–1.49) 0.90 0.96 (0.65–1.41) 0.84 1.02 (0.76–1.37) 0.91 0.97 (0.76–1.24) 0.81 1.11 (0.89–1.37) 0.35 Smoking 0.12 0.16 0.07 0.02 0.01  Smoking vs. non- 1.03 (0.61–1.75) 0.91 1.01 (0.62–1.64) 0.97 1.01 (0.70–1.46) 0.95 1.20 (0.90–1.61) 0.21 1.22 (0.95–1.56) 0.12 smoking  Smoking unknown vs. 1.77 (1.02–3.07) 0.04 1.64 (0.98–2.75) 0.06 1.65 (1.08–2.53) 0.02 1.75 (1.18–2.58) 0.01 1.70 (1.17–2.46) 0.01 non-smoking  Smoking unknown vs. 1.71 (0.87–3.39) 0.12 1.62 (0.86–3.08) 0.14 1.63 (0.98–2.70) 0.06 1.45 (0.93–2.26) 0.10 1.39 (0.93–2.11) 0.11 smoking mRS 0.00 0.00 0.02 0.00 0.00  mRS 3 vs. 1 or 2 1.14 (0.45–2.88) 0.79 1.13 (0.49–2.57) 0.78 1.29 (0.76–2.21) 0.35 1.21 (0.79–1.84) 0.38 1.14 (0.82–1.58) 0.44  mRS 4 or 5 vs. 1 or 2 2.61 (1.12–6.06) 0.03 2.53 (1.20–5.36) 0.02 1.83 (1.11–3.03) 0.02 1.85 (1.25–2.73) 0.00 1.58 (1.15–2.16) 0.00  mRS 4 or 5 vs. 3 2.29 (1.35–3.91) 0.00 2.24 (1.39–3.64) 0.00 1.42 (1.01–1.98) 0.04 1.53 (1.15–2.03) 0.00 1.38 (1.08–1.77) 0.01 Infarct type 0.00 0.00 0.00 0.00 0.00  Infarct-type AT vs. 1.60 (0.93–2.77) 0.09 1.60 (0.98–2.60) 0.06 1.24 (0.88–1.75) 0.23 1.14 (0.86–1.51) 0.36 1.12 (0.88–1.43) 0.37 LACI  Infarct-type CE vs. 3.03 (1.75–5.24) 0.00 2.69 (1.64–4.42) 0.00 1.84 (1.28–2.65) 0.00 1.69 (1.24–2.30) 0.00 1.63 (1.24–2.14) 0.00 LACI  Infarct-type CE vs. AT 1.89 (1.20–2.97) 0.01 1.69 (1.11–2.56) 0.02 1.49 (1.05–2.10) 0.02 1.48 (1.09–2.00) 0.01 1.46 (1.11–1.92) 0.01 Note that all analyses were run two times: once with indicator first and once with indicator last, resulting in three different comparisons to report for the variables smoking, mRS and infarct type DM diabetes mellitus, IHD ischemic heart disease, mRS modified Rankin scale, AT atherothrombotic infarct type, CE cardioembolic infarct type, LACI lacunar infarct type Journal of Neurology seizures were gathered prospectively for two consecutive years by one single investigator. Considerable effort was put into gathering information about the occurrence of possible seizures. Therefore, we think our recall bias is low. Also, we chose to include only patients with first ever supratentorial brain infarct and only seizures which occurred within 2 years after the first-ever stroke, which means only seizures which are likely to be ascribed to the patient’s stroke were taken into account. Furthermore, our long-term mortality follow- up and a statistical analysis with correction for known risk factors for (long term) mortality are major strengths of this study and make it possible to make a firm statement on the relation between poststroke seizures and long term mortality. Our study has some limitations. First, not all patients underwent CT scanning; therefore, some patients may have had a haemorrhagic stroke. Since haemorrhagic stroke Fig. 2 Kaplan–Meier survival curves of patients with late-onset sei- patients have a higher risk of poststroke seizures [2, 32], zures (dotted line) vs. 1-week survivors without any seizures (black line); p = 0.717 patients with haemorrhagic stroke may be overrepresented in our ES group. This might have influenced mortality rates, since mortality is higher in patients with haemor- after the index TIA or stroke. In our study only 33 patients rhagic stroke [33]. However, we believe this effect to be aged ≤ 50 years were included, none of those developed ES, small, as we performed all analyses anew excluding the 20 and only 4 of the younger patients developed LS. These patients without CT-scanning and found the same results four patients all had severe strokes (initial mRS 4 or 5). (data not shown). Second, we used a surrogate marker for Our young stroke patients with LS had a survival of 75% stroke severity, the initial mRS, which actually is an out- after 26 years vs. 79% in our young patients without LS come scale and a crude assessment of function directly (non-significant, data not shown). Mortality in our young after a stroke. As the NIHSS was not available yet at the stroke patients was also not influenced by LS in a tenta- time of inclusion start and no other stroke severity score tive Cox-regression analysis (data not shown). In the study was recorded, we unfortunately could not use a more reli- by Arntz et al. the significant effect of post-stroke seizures able measure for stroke severity. on mortality was only found in patients with mild stroke A third limitation is the difference in group size, where (NIHSS 0–4). They found no significant correlation between the seizure groups are small as compared to the stroke post-stroke seizures and mortality in patients with moderate group, which makes it more difficult to detect a clinically stroke, nor in those with severe stroke. Therefore, our results relevant difference in mortality. Last, our follow-up of in the young stroke patients are in line with the result from 2 years with regard to the development of seizures might the study by Arntz et al., since we also found no correlation have excluded some patients who developed seizures at between LS and long-term mortality in young stroke patients a later time point. Though the incidence of new seizures with severe strokes. more than 2 years after a stroke is low, we will certainly When comparing our data to other studies about inci- have missed some events. dence of seizures in stroke patients, we notice a larger part of The authors of the FUTURE study [21] state that future lacunar stroke in our seizure patients [8, 28]. We hypothesize studies should investigate the role of antiepileptic drugs that these seizures may be caused by microvascular changes in preventing post-stroke epilepsy. However, this would in the brain, including cortical parts of the brain, and not by only be true for the specific young stroke population they the lacunar stroke itself, as also suggested by de Reuck et al. studied, since in our study the relation between LS and and Arboix et al. [29–31]. mortality was not significant. Before starting studies aimed Strengths of our study are our method of selection and at prophylactic treatment with antiepileptic drugs in stroke follow-up. In our study data regarding the occurrence of patients, more effort should be done to elaborate the exact influence of LS in stroke patients, not only with regard to mortality but also concerning the effect on stroke recovery and quality of life [34]. In conclusion, neither ES nor LS have a negative impact on long-term mortality in ischemic stroke patients. Mortal- ity is, therefore, no argument to support the prophylactic 1 3 Journal of Neurology Table 5 Cox regression results for late-onset seizures at several time-intervals Follow-up 2 years 5 years 10 years 26 years Hazard ratio (95% p value Hazard ratio (95% p value Hazard ratio (95% p value Hazard ratio (95% p value CI) CI) CI) CI) Late-onset seizures 0.97 (0.48–1.98) 0.94 0.87 (0.50–1.52) 0.62 0.80 (0.50–1.27) 0.34 0.81 (0.54–1.20) 0.28 Older age (per year) 1.06 (1.03–1.08) 0.00 1.07 (1.05–1.09) 0.00 1.08 (1.06–1.09) 0.00 1.09 (1.08–1.11) 0.00 Male gender 1.33 (0.84–2.11) 0.22 1.38 (0.99–1.94) 0.06 1.29 (0.97–1.71) 0.08 1.35 (1.07–1.71) 0.01 DM 1.17 (0.73–1.89) 0.51 1.22 (0.85–1.73) 0.28 1.47 (1.10–1.96) 0.01 1.49 (1.15–1.94) 0.00 IHD 1.22 (0.78–1.89) 0.39 0.99 (0.70–1.39) 0.95 1.07 (0.80–1.43) 0.65 1.09 (0.84–1.42) 0.52 Hypertension 1.09 (0.73–1.63) 0.69 1.03 (0.76–1.39) 0.85 0.94 (0.73–1.20) 0.61 1.10 (0.88–1.36) 0.40 Smoking 0.06 0.00 0.00 0.00  Smoking vs. non- 0.91 (0.54–1.53) 0.72 0.95 (0.65–1.39) 0.79 1.11 (0.83–1.51) 0.48 1.13 (0.88–1.46) 0.33 smoking  Smoking unknown 1.91 (1.08–3.38) 0.03 2.14 (1.38–3.32) 0.00 2.14 (1.43–3.22) 0.00 1.98 (1.35–2.91) 0.00 vs. non-smoking  Smoking unknown 2.11 (1.04–4.27) 0.04 2.25 (1.33–3.80) 0.00 1.92 (1.21–3.06) 0.01 1.75 (1.14–2.68) 0.01 vs. smoking mRS 0.01 0.13 0.04 0.09  mRS 3 vs. 1 or 2 1.19 (0.54–2.62) 0.67 1.39 (0.82–2.35) 0.23 1.28 (0.84–1.93) 0.25 1.19 (0.86–1.64) 0.30  mRS 4 or 5 vs. 1 2.18 (1.05–4.53) 0.04 1.65 (1.00–2.73) 0.05 1.61 (1.09–2.39) 0.02 1.40 (1.02–1.91) 0.04 or 2  mRS 4 or 5 vs. 3 1.84 (1.13–3.00) 0.02 1.19 (0.85–1.67) 0.30 1.26 (0.95–1.68) 0.10 1.18 (0.92–1.50) 0.20 Infarct type 0.07 0.08 0.05 0.05  Infarct-type AT 1.17 (0.72–1.92) 0.52 1.11 (0.78–1.58) 0.55 1.11 (0.84–1.47) 0.47 1.12 (0.88–1.43) 0.35 vs. LACI  Infarct-type CE 1.82 (1.07–3.10) 0.03 1.55 (1.05–2.30) 0.03 1.50 (1.08–2.09) 0.02 1.43 (1.07–1.92) 0.02 vs. LACI  Infarct-type CE 1.55 (0.95–2.52) 0.08 1.39 (0.96–2.03) 0.08 1.35 (0.98–1.97) 0.07 1.28 (0.96–1.70) 0.10 vs. AT Note that all analyses were run two times: once with indicator first and once with indicator last, resulting in three different comparisons to report for the variables smoking, mRS and infarct type DM diabetes mellitus, IHD ischemic heart disease, mRS modified Rankin scale, AT atherothrombotic infarct type, CE cardioembolic infarct type, LACI lacunar infarct type conducted with the ethical standard laid down in the declaration of use of antiepileptic drugs to prevent seizures in ischemic Helsinki and its later amendments. stroke patients. 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Journal of NeurologySpringer Journals

Published: May 29, 2018

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