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June 06, 2017; 88 (23) Article

Poststroke epilepsy in long-term survivors of primary intracerebral hemorrhage

Anna-Maija Lahti, Pertti Saloheimo, Juha Huhtakangas, Henrik Salminen, Seppo Juvela, Michaela K. Bode, Matti Hillbom, Sami Tetri
First published May 5, 2017, DOI: https://doi.org/10.1212/WNL.0000000000004009
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Abstract

Objective: To identify the incidence and predisposing factors for development of poststroke epilepsy (PSE) after primary intracerebral hemorrhage (PICH) during a long-term follow-up.

Methods: We performed a retrospective study of patients who had had their first-ever PICH between January 1993 and January 2008 in Northern Ostrobothnia, Finland, and who survived for at least 3 months. These patients were followed up for PSE. The associations between PSE occurrence and sex, age, Glasgow Coma Scale (GCS) score on admission, hematoma location and volume, early seizures, and other possible risk factors for PSE were assessed using the Cox proportional hazards regression model.

Results: Of the 615 PICH patients who survived for longer than 3 months, 83 (13.5%) developed PSE. The risk of new-onset PSE was highest during the first year after PICH with cumulative incidence of 6.8%. In univariable analysis, the risk factors for PSE were early seizures, subcortical hematoma location, larger hematoma volume, hematoma evacuation, and a lower GCS score on admission, whereas patients with infratentorial hematoma location or hypertension were less likely to develop PSE (all variables p < 0.05). In multivariable analysis, we found subcortical location (hazard ratio [HR] 2.27, 95% confidence interval [CI] 1.35–3.81, p < 0.01) and early seizures (HR 3.63, 95% CI 1.99–6.64, p < 0.01) to be independent risk factors, but patients with hypertension had a lower risk of PSE (HR 0.54, 0.35–0.84, p < 0.01).

Conclusions: Subcortical hematoma location and early seizures increased the risk of PSE after PICH in long-term survivors, while hypertension seemed to reduce the risk.

GLOSSARY

AED=
antiepileptic drug;
CI=
confidence interval;
GCS=
Glasgow Coma Scale;
ICH=
intracerebral hemorrhage;
PICH=
primary intracerebral hemorrhage;
PSE=
poststroke epilepsy

Epileptic seizures after primary intracerebral hemorrhage (PICH) have been observed in 4.6%–18.5% of patients.1,–,5 They frequently occur within 2 weeks of the stroke,1,2,4,6 and may also be a presenting symptom of PICH.4 Previous studies have identified cortical1,5,7,–,11 and lobar6,12,–,16 hematomas as predictors of seizures and post-ICH epilepsy. In addition, seizures in the acute phase, younger patient age, hematoma evacuation, and cerebral microbleeds have been shown to increase the risk of late seizures (occurring more than 2 weeks after the stroke).1,8,17 Occurrence rates for late seizures or poststroke epilepsy (PSE) after PICH vary from 4.5% to 9.5%, but the follow-up periods have been relatively short, with a mean duration varying from 19.5 months to 2.7 years.1,2,8,11,17

To our knowledge, no long-term studies of the incidence of late seizures or PSE have been published. This justifies further investigations into predictive factors for PSE after PICH. The objectives of this study were to determine the incidence and risk factors for PSE during long-term follow-up among 3-month survivors of PICH within a defined population.

METHODS

Participants.

The study design and methods for acquiring clinical data have been described previously.18,19 We identified all patients diagnosed with ICH among the population of Northern Ostrobothnia, Finland, from January 1993 until January 2008 from the records of Oulu University Hospital. Our hospital treats all patients with acute stroke or stroke-like symptoms in its catchment area (population in 1993–2008: 356,026 to 389,671),20 making our cohort also population-based. Patients not resident in this area were excluded from the study. We also excluded patients with brain tumor, intracranial vascular malformation (including aneurysms), head injury, malignant hematologic disease, hemophilia, or recurrent intracerebral hemorrhage (ICH) as the index stroke. We further excluded 25 patients with epilepsy diagnosed before the occurrence of PICH. A total of 933 patients met the criteria. For this study, we also excluded 313 patients who did not survive for at least 3 months after the PICH. This left 620 patients, 5 of whom did not have reliable data on possible later PSE, because their medical records were unavailable. Thus, we accepted a total of 615 patients for our analysis.

Clinical data.

We assessed the clinical condition of every participant on admission with the Glasgow Coma Scale (GCS) score.21 We collected data on previous diseases, blood pressure levels, and medication, including anticoagulants and antiepileptic drugs, from hospital records. We verified the use of antiepileptic medication from the Finnish Social Insurance Institution registry of prescribed medication. If a participant's blood pressure values had repeatedly exceeded 160/90 mm Hg before the index stroke, we defined that participant as hypertensive in accordance with the WHO/International Society of Hypertension statement.22 We also recorded patients on antihypertensive medication as having hypertension. We defined cardiac disease as myocardial infarction, coronary artery disease, heart failure, or atrial fibrillation, and cardiac complications as prior myocardial infarctions, arrhythmias, or heart failure. Thromboembolic complications consisted of deep venous thrombosis and pulmonary embolism. If a patient was using an oral hypoglycemic agent or insulin, we presumed that he or she had diabetes. We defined any patient with the reported ingestion of ethanol exceeding 300 g per week or recurrent visits to the emergency unit under the influence of alcohol as a heavy drinker.

Patient management.

All patients received standard care performed following international recommendations.23 The methods of thromboprophylaxis used have been described earlier.20 Hematoma evacuation was performed by standard craniotomy or by a trepanation when necessary, and external ventricular drainage was sometimes used in cases of intraventricular bleeding or hydrocephalus.19

Neuroradiologic methods.

A CT scan was done in our hospital for all patients on admission to detect ICH. CT scans were analyzed by experienced neuroradiologists, who also measured the locations and volumes of the hemorrhage. The method for measuring hematoma volume has been described previously.20 To discover possible structural abnormalities behind the bleeding, the participants were followed up with brain imaging 2–3 months after the ICH. Aneurysmal bleeding was ruled out immediately on admission by angiography when suspected. All surviving participants who received surgical treatment underwent a postoperative CT or MRI at least once during hospitalization. A follow-up CT scan was performed on 75% of the conservatively treated patients, and some were followed up with MRI. If a patient had a seizure, a new CT scan was performed to rule out the possibility of new stroke. Locations were categorized as subcortical, deep supratentorial (including combined hematomas extending from the putamen into the thalamus or subcortex), infratentorial (cerebellar or pontine), and other locations (primary intraventricular, multiple or large with combined regions).

Outcome measurements.

Oulu University Hospital is the only hospital responsible for diagnosing epilepsy and prescribing antiepileptic drugs in its catchment area. All participants in our cohort who sought treatment for epileptic seizures were treated in our hospital. We identified patients with seizures after the index ICH by reviewing medical charts for the whole cohort at the end of the study period in 2012.

Since there is no definitive way of knowing which seizures in the acute phase are related to the acute brain damage, and which ones are a sign of persisting tendency for epileptic seizures due to possible gliotic scarring after ICH,24 we used a time-based definition for early and late seizures. All seizures occurring at onset or within 14 days of the index ICH requiring antiepileptic medication were defined as early seizures. PSE was diagnosed only in patients who developed a single epileptic seizure or multiple seizures later than 14 days after the onset of PICH. The diagnosis was made according to the definitions given by the International League Against Epilepsy and the International Bureau for Epilepsy.25 We also checked the use of antiepileptic drugs for the whole cohort to ensure that no case of diagnosed PSE was missed. The occurrence of poststroke seizures and the use of antiepileptic medication were also double-checked from the hospital records.

Patients showing good recovery at discharge were not followed up by default, and were assumed to have maintained this state at 3 months after the index ICH unless they had been readmitted. To evaluate the clinical condition of the other patients at 3 months, they were followed up at our outpatient clinic or in the rehabilitation ward of our hospital. At this follow-up visit, the patients were evaluated by a neurologist, or a neurosurgeon in case hematoma evacuation was performed. Death certificates for those who died during follow-up were obtained from both hospital records and the Causes of Death Register maintained by Statistics Finland.

Statistical methods.

Statistical analysis was performed using IBM (Armonk, NY) SPSS Statistics version 22.0 for Windows. To describe baseline and clinical data, we tested the associations between categorical variables using the Pearson χ2 test, and between categorical and continuous or ordinal variables using the t test for independent samples or the Mann-Whitney U test. Univariable correlations of continuous variables were tested with Spearman rank (rs) correlation coefficients.

For the Kaplan-Meier analysis and both univariable and multivariable Cox proportional hazards regression analyses, we followed up each patient until the occurrence of PSE, death, or the last contact. We used the Kaplan-Meier product-limit method to determine the cumulative incidence of PSE, and the curves between the groups were compared with the log-rank test. The average annual incidence was calculated by dividing the number of first PSE episodes by the number of person-years in the follow-up.

We used the Cox proportional hazards regression with a forward stepwise procedure (entry if p < 0.05) and Wald statistics was used to determine hazard ratios and 95% confidence intervals (CI) for several variables in predicting PSE. We tested the following variables in univariable Cox regression models: sex, age, GCS score, hematoma size, intraventricular extension of the hematoma, hematoma location, surgical hematoma evacuation, prior ischemic stroke, heavy drinking, hypertension, diabetes, cardiac disease, cardiac complications, thromboembolic complications, warfarin use, and immediate and early seizures. All the variables that predicted higher risk of PSE (p < 0.05) in the univariable analysis were included in the multivariable analysis and adjusted for sex and age. The test of significance was based on changes in the log (partial) likelihood. We considered a 2-tailed p value of less than 0.05 statistically significant.

Standard protocol approvals, registrations, and patient consents.

The protocol was approved by the ethics committee of the Northern Ostrobothnia Hospital District.

RESULTS

Of the 615 long-term survivors, 83 (13.5%) developed PSE during follow-up. The follow-up times of individual patients ranged from 3 months to 19.9 years, with a median of 6.4 years, and the total follow-up time was 4,416 person-years. The risk of developing PSE was highest in the first 2 years after PICH. The cumulative incidence was 6.9% (95% CI 5.0%–8.9%) at 1 year and 9.1% (95% CI 6.8%–11.4%) at 2 years after the index ICH. After the first 2 years of higher incidence, fewer new cases of PSE were observed during the following years (figure, A). Only one case of PSE was observed after 12 years of follow-up. The average annual incidence was 1.9 cases of PSE per year. No statistically significant differences for the baseline characteristics of age, warfarin medication, sex, heavy drinking after the index ICH, previous diabetes, or cardiac disease were found between the groups. Hypertension was more common among patients without PSE (table 1).

Figure
Figure Kaplan-Meier curves show proportion of patients without poststroke epilepsy

(A) All patients. (B) Patients by hematoma location (difference between groups p < 0.001).

View this table:
Table 1

Baseline characteristics

The clinical characteristics, including radiologic parameters, are shown in table 2. Patients who developed PSE had larger hematomas, presented more often with early seizures, and more frequently had their hematoma located subcortically. Surgical hematoma evacuation was also performed to these patients more frequently than on those who did not develop PSE. An infratentorial location of the hematoma was significantly less common in patients who developed PSE. Patients with PSE also had lower GCS scores on admission than those without PSE.

View this table:
Table 2

Clinical characteristics

A multivariable Cox regression analysis showed only subcortical location, early seizures, and nonhypertensive blood pressure status to predict PSE (table 3). Kaplan-Meier curves for PSE appearance in patients with subcortical hematoma vs other locations are shown in the figure, B.

View this table:
Table 3

Risk factors for poststroke epilepsy (PSE) after primary intracerebral hemorrhage

We found out that patients without hypertension seemed to develop PSE more often than those with hypertension. When stratified for hematoma location, this correlation remained statistically significant only in the group with subcortical ICH (table 4). There were only 2 cases of PSE in the infratentorial group, and therefore the correlation could not be assessed separately for these patients. The correlation remained statistically significant in the subcortical group also when we combined the categories of treated and untreated hypertension.

View this table:
Table 4

Poststroke epilepsy (PSE) and hypertension status

DISCUSSION

Altogether 13.5% of our long-term PICH survivors developed PSE. The incidence rate was highest in the first year after ICH, and although the rate decreased thereafter, it remained stable throughout the period studied, indicating that PSE can also occur years after the ICH. Subcortical hematoma location, early presenting seizures, and nonhypertensive blood pressure status were the only significant predictors for post-ICH epilepsy. A recent meta-analysis showed that cortical involvement and early seizures increase the risk of PSE also in other types of stroke.26

Classifying hematomas by their location is a challenging task, and different definitions of the locations make it difficult to compare the results between studies. In most cases, the category of lobar bleedings also includes ICH involving the cerebral cortex, which makes it difficult to evaluate the true effect of lobar/cortical bleeding site on seizure occurrence.6,7,12,–,16,27 In our study, hematomas located in cortical regions were included in the subcortical category, because the source of bleeding in PICH is often subcortical.

In our cohort, patients with larger hematomas or lower GCS scores on admission, as well as patients who underwent hematoma evacuation, developed late seizures more frequently than others. However, none of these correlations reached statistical significance in the multivariable analysis. In this regard, our results differ from previous studies.5,8,9,11,12,17 These differences between our results and those presented elsewhere may be explained by our longer follow-up time. Our median follow-up period was 6.4 years, whereas the longest average follow-up time in other studies has been 2–2.7 years.8,11,17

In a recent study with 325 participants, Rossi et al.17 did not observe early seizures to be a statistically significant predictor of late seizures, although late seizures did occur somewhat more frequently among those who had had early seizures (26% vs 16%). Sample size might explain the difference between their observations and ours. Also, the number of patients included in many hospital-based studies has been small—even below 300 cases of PICH.1,2,6,12,15,27 This will result in low statistical power and may obscure significant correlations.

Different definitions for early and late seizures are also a confounding factor that should be considered. We set the cutoff point between early and late seizures at 14 days from the occurrence of ICH, as has been done in many previous studies.2,6,28,29 Late-onset seizures have also often been defined as seizures occurring later than 7 days,8,9,11,17 whereupon some seizures provoked by factors associated with the acute event may have been classified as late seizures. The real significance of this confounding factor is difficult to assess, however.

As an interesting discovery, we observed an inverse correlation between PSE and hypertension. It is known that hypertension is a major risk factor for ICH in the deep structures in particular,30 whereas PSE occurs more often in cortical or subcortical ICH. We found that patients with hypertension develop PSE more often only in the subcortical hematoma group, however, so the finding cannot be explained by these location-dependent features. It is possible that some of the subcortical bleedings resulted from amyloid angiopathy or cavernous malformations, since these cannot be reliably excluded by post-ICH CT imaging alone. No statistically or otherwise significant correlation between hypertension and the risk of ICH associated with cavernous malformations has been described, however.31 Cerebral amyloid angiopathy is also associated with lobar hemorrhage, and is a greater risk factor for ICH than hypertension.32 It is also possible that some late seizures were provoked by nonexcessive alcohol consumption. PICH patients may be more predisposed to alcohol-related seizures compared to healthy individuals on account of their brain trauma. Since people with hypertension are more often advised against drinking alcohol, this might in part explain the difference between the groups. It should also be noted that, even though this finding reached statistical significance, the strength of the correlation was rather weak (table 4).

Our study adds to existing knowledge of the predictors of post-ICH epilepsy and should be useful in helping to identify patients who might benefit from prophylactic antiepileptic medication, which is important for achieving both cost-effectiveness and patient safety. The current guidelines of American Heart Association/American Stroke Association and European Stroke Organisation on the management of spontaneous intracerebral hemorrhage do not recommend routine prophylactic use of antiepileptic drugs (AEDs),33,34 since there is no evidence that such prophylaxis will prevent seizures.1,11,35,36 In addition, AEDs have several known side effects, e.g., hyperammonemia with valproate, thrombocytopenia with levetiracetam, and fever and rash with phenytoin.1,2 AED prophylaxis has also been associated with a poorer outcome in some studies,1,35 but not all.37 No randomized controlled trials have been performed regarding AED prophylaxis, however, and confounding by indication in particular must be taken into account when interpreting these results.36,37 Prospective, randomized, controlled studies with adequate sample size will therefore be needed in the future.

Our study has several strengths. First, our patient follow-up period was significantly longer than in most other instances. Since the incidence of late-onset seizures was highest during the first 2 years after PICH and decreased thereafter, it is unlikely that a significant number of new cases of PSE would have appeared after the termination of our follow-up. Thus, we were able to calculate the cumulative incidence of PSE fairly reliably. Second, our sample of 615 long-term ICH survivors formed a suitably sized population for achieving statistically reliable results. Because in Finland there are no private hospitals treating patients with acute stroke, our results are likely to apply well to the general population. Third, the use of AED prophylaxis was rare in our population, in that only 10% (13 patients) of those among all PICH patients without prior diagnosis of epilepsy who developed seizures after PICH received prophylactic IV AED treatment, as reported previously.18 The confounding effect of AED prophylaxis would therefore have been minimal.

The retrospective design is one limitation in our study, although the execution of a prospective study of similar proportions would have been a challenging undertaking. Due to the setting, there were some confounding factors that we were not able to control for, particularly those concerning treatment and lifestyle. Regarding seizure incidence, the lack of routine continuous EEG monitoring was also a limitation. As many seizures that occur in the acute phase are not manifested as convulsions and are visible only by EEG,10,38 it is likely that we missed some early seizures. This may have led to either underestimation or overestimation of the correlation between early seizures and PSE. It is also possible that we missed some late seizures if a patient did not seek treatment for seizures occurring after 3 months. If a patient contacted primary health care because of seizure-like symptoms, they could also be misdiagnosed to have had nonepileptic seizures. However, all patients in the area who sought treatment and were suspected to have epilepsy were also evaluated in our hospital, and we were able to reliably identify the cases of PSE from the hospital and medication records (Finnish Social Insurance Institution) for these patients.

During a median follow-up of 6.4 years per patient, 13.5% of our participants with a first-ever PICH who had survived for more than 3 months had developed PSE. This event occurred most frequently during the first year after ICH, with the probability of 6.9%, and the incidence decreased thereafter. We found a subcortical location of the hematoma and early seizures to increase the risk of PSE, whereas hypertension was associated with a decreased risk.

AUTHOR CONTRIBUTIONS

Anna-Maija Lahti: drafting and revision of the manuscript, analysis and interpretation of the data. Pertti Saloheimo: acquisition of data, drafting and revision of the manuscript. Juha Huhtakangas: study design, acquisition of data, drafting and revision of the manuscript. Henrik Salminen: acquisition of data. Seppo Juvela: analysis and interpretation of the data, revision of the manuscript. Michaela Bode: analysis and interpretation of the data, assessing radiologic findings, drafting and revision of the manuscript. Matti Hillbom: acquisition of data, revision of the manuscript. Sami Tetri: supervision of the work, acquisition of data, revision of the manuscript.

STUDY FUNDING

No targeted funding reported.

DISCLOSURE

A. Lahti reports no disclosures relevant to the manuscript. P. Saloheimo is an associate editor for the European Journal of Neurology and reports Orion stock ownership. J. Huhtakangas and H. Salminen report no disclosures relevant to the manuscript. S. Juvela is an associate editor for the European Journal of Neurology and a member of the editorial board of Stroke. M. Bode, M. Hillbom, and S. Tetri report no disclosures relevant to the manuscript. Go to Neurology.org for full disclosures.

ACKNOWLEDGMENT

The authors thank Risto Bloigu, MSc, Medical Informatics and Statistics Research Group, University of Oulu, Finland, for statistical counseling.

Footnotes

  • Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.

  • Received November 15, 2016.
  • Accepted in final form March 20, 2017.

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