Seizures and epilepsy in patients with lacunar strokes

Journal of the Neurological Sciences 263 (2007) 75 – 78 www.elsevier.com/locate/jns

Seizures and epilepsy in patients with lacunar strokes J. De Reuck a,⁎, E. Nagy a,c , G. Van Maele b a

c

Stroke Unit, Department of Neurology, University Hospital, De Pintelaan 185, B-9000 Ghent, Belgium b Department of Medical Statistics, University Hospital, De Pintelaan 185, B-9000 Ghent, Belgium 2nd Department of Neurology, Mures County Hospital, Gh. Marinescu street 50, Targu-Mures, Romania Received 14 November 2006; received in revised form 29 May 2007; accepted 8 June 2007 Available online 3 July 2007

Abstract Background: The relation between seizures and small subcortical infarcts is uncertain. The present retrospective study investigates whether differences are observed between patients with and without seizures following a lacunar stroke. Patients and methods: Thirty-seven patients with seizures and a prior history of a lacunar stroke were admitted to the Ghent University Hospital during 2000 and 2005. They were compared to 205 patients, admitted between 2002 and 2004, with an acute lacunar stroke and without epileptic spells on follow-up. Nine out of the 37 patients with seizures and 48 out of the 205 without seizures had a history of recurrent strokes. Results: No differences in vascular risk factors, distribution and frequency of the lacunes, degree of severity of the white matter changes and outcome were observed. On the Mini-Mental State Examination moderate to severe cognitive disturbances were observed in the seizure group and in some patients of the non-seizure group. Conclusions: In the present study we found no evidence that seizures are directly induced by lacunar infarcts. The seizures appear to be part of a more global ongoing cerebral disorder probably leading to cognitive impairment. © 2007 Elsevier B.V. All rights reserved. Keywords: Lacunar infarct; White matter changes; Seizures; Epilepsy; Vascular risk factors; Cognitive impairment

1. Introduction Cerebrovascular disease accounts for more than half of the newly diagnosed cases of epilepsy in the elderly [1]. Not only the presence of cerebral infarcts and hemorrhages but also of vascular risk factors, in the absence of a structural brain lesion, is associated with a higher incidence of seizures in the elderly [2]. In the prospective multi-centre study on “ Seizures After Stroke” the incidence of seizures was found to be 8.6% after an ischemic and 10.6% after a hemorrhagic stroke. In patients with a lacunar stroke only 2.6% was reported [3]. While the risk factors for seizures related to territorial infarcts [4,5] are well known, the relation to lacunar infarcts remains uncertain [6–9]. Fisher [10] even considered his occurrence in a stroke patient as an exclusion criterion for the ⁎ Corresponding author. Tel.: +32 9 2404541; fax: +32 9 2404971. E-mail address: [email protected] (J. De Reuck). 0022-510X/$ - see front matter © 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.jns.2007.06.004

diagnosis of a lacunar infarct. Some authors stated that mainly the associated white matter lesions, seen on computed tomography (CT) scans and on magnetic resonance imaging (MRI), are responsible for the seizures [11–13]. The present retrospective study compares the vascular risk factors, the outcome and the neuroimaging findings in patients with lacunar strokes who develop seizures to those who remain seizure-free. 2. Patients and methods The files of 37 patients, admitted between 2000 and 2005 for seizures and with a prior history of a lacunar stroke, were reviewed. For comparison we used the 205 consecutive patients admitted for an acute lacunar infarct during 2002 and 2004 and who did not develop epileptic spells during a follow-up period, varying from 22 up to 46 months. Nine out of the 37 patients of the former and 48 out of the 205 of the

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latter group had a history of recurrent strokes. Patients with additional territorial infarcts were excluded from the study. Also, patients with a pre-existing or a family history of epilepsy or with none stroke-related risk factors such as a history of head trauma, birth complications and ethyl or drug abuse were excluded. During the last 6 years 527 patients were admitted with a lacunar stroke to the Neurological Department of the Ghent University Hospital. Description of the seizure episode(s) was gained from the near relatives or the caregivers. Seizure types were classified as recorded from the interview as simple partial or complex partial, with or without secondary generalization, and generalized tonic–clonic spells. Although the latter were most probably partial seizures with rapid secondary generalization, the classification based on the description, given by the relatives or caregivers, was maintained. However, when a Todd's paresis on admission or when focal changes on the post-ictal electroencephalogram (EEG) were present, a focal onset of the seizures was retained. A detailed medical history, including vascular risk factors and previous treatment, was obtained from all patients on admission for their stroke and also on readmission for the occurrence of seizures. Arterial hypertension, hypercholesterolemia and diabetes were retained as risk factors when treatment was needed. All patients had a complete clinical evaluation and underwent a full cardiovascular examination, including routine electrocardiogram (ECG), chest X-ray, routine blood analyses, Doppler sonography of the extracranial arteries, 24- to 72-hour ECG monitoring as well as transesophagial Doppler or transthoracic echography of the heart. A computed tomographic (CT) scan or/and a magnetic resonance imaging (MRI) of the brain was performed in all patients: CT was obtained in 97.3% of the seizure and in 93.7% of the non-seizure group, while MRI was performed in 59.5% of the former and 58.0% of the latter group. The location and the number of lacunes were determined on the CT scan or on the available MRI. To quantify the degree of white matter changes the 3-point scale of Blennow et al. [14] for CT scan and that of Fazekas et al. [15] for MRI were used. A post-ictal EEG, performed within 24 h after the spell, was available in all patients of the seizure group while in the non-seizure group 63.4% underwent an EEG. The same independent EEG specialist was responsible for the inter-

Table 2 Comparison of the location and the number of lacunes, and of the severity of the white matter changes on CT and/or MRI of the brain in the patients with and without seizures Items

Seizure (n = 37)

Non-seizure (n = 205)

P value

Putamino-capsular Internal capsule Thalamus Brainstem Number of lacunes Degree of white matter changes

25 15 8 8 56 0.59

108 71 43 52 274 0.64

0.140 0.509 0.845 0.482 0.167 0.524

pretation and protocol. A Mini-Mental State Examination (MMSE) [16] was taken in all patients of the former and in 29.3% of the latter group. In the non-seizure patients with a lacunar stroke an MMSE was only performed when cognitive impairment was suspected on clinical examination. Modified Rankin (mR) scores on hospital discharge [17] were available in all patients. Statistical analyses were performed with the SPSS statistical package (SPSS Inc., version 14.0). Univariate comparisons of unpaired groups were made with the Fisher's exact test for categorical data. The non-parametric Mann–Whitney U- and the Wilcoxon matched-pairs signed-ranks tests were used to compare continuous variables. The significance level was set at α = 0.05 two-tailed. The MMSE and mR scores are given as medians with interquartile ranges (IQR). 3. Results Simple partial and complex partial seizures with or without secondary generalization occurred respectively in 19 (51.4%) and in 11 (29.7%) patients, and generalized tonic–clonic seizures in 7 (18.9%) patients. The average time of occurrence of the first seizure after the last stroke was 38.3 (SD 39.4) months. No cases of early-onset seizures, accompanying the occurrence of a lacunar stroke were observed. Fourteen (37.8%) patients had recurrent seizures and epilepsy, while 23 (62.2%) had only a single spell. Carbamazepine was the main used anti-epileptic drug (60.7%). Comparison of the seizure with the non-seizure group showed no differences in age (P = 0.321) and gender

Table 1 Percentage comparison of the vascular risk factors in lacunar stroke patients with and without subsequent seizures Items

Seizure (n = 37)

Non-seizure (n = 205)

P value

Arterial hypertension Coronary artery disease Atrial fibrillation Peripheral artery disease Heart valve disease Hypercholesterolemia Diabetes mellitus Smoking

78.4 16.2 16.2 10.8 2.7 32.4 21.6 5.4

75.6 22.9 14.1 8.8 5.9 31.7 30.7 15.1

0.836 0.517 0.799 0.755 0.698 1.0 0.328 0.189

Table 3 Percentage comparison of the type of anti-thrombotic treatment between the patients with and without seizures Items

Seizure (n = 37)

Non-seizure (n = 205)

Aspirin Aspirin + dipyridamole Clopidogrel Aspirin + clopidogrel Coumarin

70.3 2.7 16.2 2.7 8.1

53.2 4.4 22.0 7.8 12.7

P value

0.398

J. De Reuck et al. / Journal of the Neurological Sciences 263 (2007) 75–78 Table 4 Comparison of the number of abnormal versus normal EEG findings in the patients with and without seizures Items

Seizure (n = 37)

Non-seizure (n = 130)

P value

Focal slowing Diffuse slowing Intermittent rhythmic delta activity Periodic lateralized epileptic discharges

6 9 8 3

19 13 1 0

0.091 0.001 b0.001 0.002

distribution (P = 0.719): the average age was 72.9 (SD 10.9) years in the former and 70.4 (SD 11.1) years in the latter group with a male predominance respectively of 56.8 and 60%. Median mR scores on discharge were 2.0 (IQR 0.0–4.0) in the patients after the seizure and 2.0 (IQR 1.0–3.0) in the nonseizure group after the stroke (P = 0.420). Median MMSE scores were similar (P = 0.726) and respectively 23.0 (IQR 17.5–27.5) and 23.0 (IQR 18.3–27.0). No statistical differences in vascular risk factors such as arterial hypertension, coronary artery disease, atrial fibrillation, peripheral artery disease, heart valve disease, hypercholesterolemia, diabetes mellitus and smoking were observed between both groups (Table 1). Location and number of the lacunes as well as the severity of the white matter changes were comparable in the seizure and the non-seizure patients (Table 2). The types of anti-thrombotic treatment were not statistically different between both groups (P = 0.398) (Table 3). The EEG changes were significantly different between both groups (Table 4). Normal EEGs were more frequent compared to diffuse slowing (P = 0.001), intermittent rhythmic delta activities (IRDAs) (P b 0.001) and periodic lateralized epileptic discharges (PLEDs) (P = 0.002) in the non-seizure group. The occurrence of focal slowing, on the other hand, was not significantly different compared to the seizure group (P = 0.091). Five patients, classified as having generalized seizures, had diffuse slowing on their post-ictal EEG and 2 had a normal pattern. 4. Discussion The present study does not show differences in vascular risk factors, anti-thrombotic treatment, location and number of lacunes, and severity of white matter changes between the stroke patients with and without subsequent seizures. The distribution of the seizure types and the EEG changes are similar to those of other stroke-related seizures [18]. In view of the controversial data in the literature [6,8,9], no patients with early-onset seizures are observed in our study. The time of occurrence of seizures in relation to the lacunar stroke(s) is highly variable and, on average, longer than for those in relation to territorial infarcts. As the main follow-up period in the non-seizure group is 36 months we cannot exclude that a few patients will still develop very lateonset seizures [19].

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In contrast to previous studies [20,21], we do not observe that hypercholesterolemia is protective against stroke-related seizures. As cortical located infarcts are a main risk factor for strokerelated seizures [3–5] and as in patients with large subcortical infarcts and seizures a cortical involvement has also been demonstrated [22], it seems highly improbable that lacunar infarcts can directly induce epileptic spells. A limitation of this study is that MRI, which is more sensitive than CT for detecting epileptogenic lesions, particularly mesial temporal sclerosis, is only available in less than 60% of our patients. Also no specific epilepsy protocol has been applied [23]. Some studies relate the seizures in patients with smallvessel disease mainly to the presence of the white matter changes [11–13] and one of these explains the occurrence as the result of cortical diaschisis [12]. However, our positron emission tomographic (PET) study has shown that patients with white matter changes and seizures have a more severe decrease of regional cerebral blood flow (rCBF) and regional metabolic rate for oxygen (rCMRO2) in the cerebral cortex, without differences in the cerebral white matter, compared to those without seizures [24]. The changes are more severe than in those with late-onset cryptogenic seizures without cerebrovascular disease [25]. In our PET studies on patients with lacunar infarcts and white matter changes, it was demonstrated that those with vascular cognitive impairment had a more severe decrease of rCBF and rCMRO2 [26] and a more pronounced loss of the vasoreactivity in the cerebral cortex [27]. In the present study the whole group of patients with seizures has on average some degree of cognitive impairment. The fact that the average MMSE score is decreased to the same degree in the patients without seizures can be explained by a bias in selection as this examination was only obtained in 29.3% of this group. The MMSE was only performed in the nonseizure patients who were suspected to have cognitive disturbances. One can suspect that the average score of the whole group would have been much higher. Seizures in patients with lacunar strokes are probably associated to more severe cognitive impairment. Patients with lacunar infarcts have a more prolonged disease course than those with territorial infarcts but the long-term outcome is similar [28–30]. Many lacunes occur without apparent neurological signs [31,32]. Also seizures can promote further cognitive decline [33]. Stroke patients with pre-existing dementia have an increased risk for seizures [34]. The occurrence of seizures in elderly patients has also to be considered as a risk factor for further strokes [35]. Although we do not know the cognitive status of our patients before their stroke and their seizure, it is more probable that both are rather related to cortical involvement (neuronal or vascular?) than to the lacunes themselves. Further studies are needed to investigate whether the seizures in those patients are announcing symptoms of a progressive dementia.

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