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June 02, 2015; 84 (22) Article

Epilepsy after aneurysmal subarachnoid hemorrhage

A population-based, long-term follow-up study

Jukka Huttunen, Mitja I. Kurki, Mikael von und zu Fraunberg, Timo Koivisto, Antti Ronkainen, Jaakko Rinne, Juha E. Jääskeläinen, Reetta Kälviäinen, Arto Immonen
First published May 6, 2015, DOI: https://doi.org/10.1212/WNL.0000000000001643
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Abstract

Objective: The aim was to elucidate the incidence and risk factors of epilepsy after subarachnoid hemorrhage (SAH) from saccular intracranial aneurysm (sIA) in a population-based cohort.

Methods: The Kuopio sIA Database (www.uef.fi/ns) includes all unruptured and ruptured sIA cases admitted to the Kuopio University Hospital from its defined catchment population in Eastern Finland. The use of prescribed medicines, including reimbursable antiepileptic drugs, has been entered from the Finnish national registries. The cumulative incidence and independent risk factors of epilepsy and death were analyzed in 876 patients with sIA-SAH admitted from 1995 to 2007. The competing risks analysis was used to correctly estimate the probability of epilepsy, because epilepsy and death after sIA-SAH may share risk factors.

Results: The follow-up ended at death (n = 200) or December 31, 2008; median follow-up time was 76 months. Epilepsy was diagnosed in 113 patients in a median of 8 months after sIA-SAH. Cumulative incidence of epilepsy after sIA-SAH was 8% at 1 year and 12% at 5 years. Thirty-three percent of patients with intracerebral hemorrhage (ICH) >15 cm3 developed epilepsy. In the 876 patients with sIA-SAH, the independent risk factors for epilepsy were ICH >15 cm3, Hunt and Hess grade III–V, and acute seizures.

Conclusions: Cumulative incidence of epilepsy is 12% at 5 years. Epilepsy and 12-month mortality after sIA-SAH share poor Hunt and Hess grading as an independent risk factor. Epilepsy in the 2-week survivors of sIA-SAH is predicted by signs of primary injury in the brain tissue, most notably ICH.

GLOSSARY

AED=
antiepileptic drug;
CI=
confidence interval;
HR=
hazard ratio;
ICH=
intracerebral hemorrhage;
ISAT=
International Subarachnoid Aneurysm Trial;
KUH=
Kuopio University Hospital;
OR=
odds ratio;
SAH=
subarachnoid hemorrhage;
sIA=
saccular intracranial aneurysm;
SII=
Social Insurance Institution

Aneurysmal subarachnoid hemorrhage (SAH), almost always from a rupture of a saccular intracranial aneurysm (sIA), affects the working-age population.1 The reported incidence is 4 to 7 per 100,0002 but is 3 times higher in Finland.3 Along with various degrees of acute or delayed brain injury, sIA-SAH may cause systemic manifestations complicating the management.4 Subsequent mortality is high, 22% at 1 month and 27% at 12 months in our series of 1,657 patients, mainly due to poor condition and signs of brain injury on admission.5

The risk of epilepsy after sIA-SAH has not been studied in large unselected populations. Previous studies report risks from 0.9% to 25%6,7 and independent risk factors such as younger age, hypertension, middle cerebral artery aneurysm, initial loss of consciousness, high amount of cisternal blood, intracerebral hemorrhage (ICH), subdural hemorrhage, acute seizures, rebleeding, and delayed ischemic deficits.8,–,16 The problem of 2 dependent risks, risk factors shared by epilepsy and death, has not been addressed.

The Kuopio sIA Database (www.uef.fi/ns) includes all cases of unruptured and ruptured sIAs admitted to the Kuopio University Hospital (KUH) from its Eastern Finnish catchment population.17 Data on prescribed medicines, hospital diagnoses, and causes of death are included from the national registries.17,–,20 In the present study, we analyzed the cumulative incidence and independent risk factors of epilepsy and death in 876 patients with sIA-SAH from 1994 to 2007, alive at 2 weeks after admission, also applying the competing risks analysis methodology.

METHODS

Catchment population of KUH.

Since 1977, Neurosurgery of KUH has solely provided full-time acute and elective neurosurgical services for the KUH catchment population in Eastern Finland. The KUH area consists of 4 central hospitals with neurologic units and catchment areas of their own. During the recruitment period of the present study, 1995 to 2007, the geographic area has remained the same. The population has decreased from 882.671 to 842.931. The median age has increased from 37 to 42 years in men and from 40 to 45 years in women, and the proportion of men has remained unchanged at 49%.17

Admission of patients with SAH to KUH.

All cases of SAH diagnosed by spinal tap or CT at the KUH catchment area have been acutely admitted to KUH for angiography and treated if not moribund or very aged. The exact number of patients with SAH who were rejected is not available.

Kuopio Neurosurgery Intracranial Aneurysm Database.

The database (www.uef.fi/ns) includes all cases of unruptured and ruptured intracranial aneurysm patients admitted to KUH since 1980. The database has been prospective since 1990. The database is run by a dedicated full-time nurse coordinator who interviews all new patients. The criterion for familial sIA family is at least 2 affected first-degree relatives.17 The clinical data from the hospital periods and follow-up visits are coded into an extensive list of variables. The use of prescribed medicines (see below), other hospital diagnoses, and causes of death have been entered from the Finnish national registries.17,–,20 The phenotype, genetics, and outcome of Eastern Finnish sIA disease have been analyzed in several studies.21,–,29

Study population of 876 patients with sIA-SAH.

The inclusion criteria were as follows: (1) citizen of Finland and resident of the KUH catchment area at the time of first sIA-SAH between January 1, 1995, and December 31, 2007; (2) verification of sIA(s) by angiography; and (3) alive at 2 weeks after admission.

The exclusion criteria included rupture of an intracranial aneurysm other than a saccular one (e.g., fusiform, traumatic, mycotic), and previous diagnosis of epilepsy (n = 14).

Figure 1 presents the flowchart from the basic to the final study cohort of 876 patients with sIA-SAH.

Figure 1
Figure 1 Flowchart of the study cohort

Flowchart of the identification of patients with epilepsy after subarachnoid hemorrhage from saccular intracranial aneurysm (sIA-SAH) among 1,045 patients admitted alive to the Kuopio University Hospital (KUH) from its Eastern Finnish catchment population between 1995 and 2007. The 113 patients with epilepsy were identified according to the use of antiepileptic drugs (AEDs) from the national registry and the diagnoses were verified by neurologists.

Identification of patients with epilepsy after sIA-SAH.

The Social Insurance Institution (SII) of Finland is an independent social security institution with its own administration and financing, supervised by the Finnish Parliament. The National Health Insurance scheme is part of the Finnish social security system, and it is run by the SII. All permanent residents of Finland are covered under the National Health Insurance scheme. The SII maintains a nationwide registry for all patients who have been granted special reimbursement of medicines, including antiepileptic drugs (AEDs). To be reimbursed at the pharmacy for epilepsy, patients must submit a medical certificate to the SII. The medical certificate must be based on examinations and diagnosis of epilepsy made by a neurologist. The entitlement to special reimbursement of AEDs is granted by SII for noninstitutionalized patients. The following AEDs are reimbursed: carbamazepine, clobazam, clonazepam, fosphenytoin, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, nitrazepam, phenobarbital, phenytoin, pregabalin, rufinamide, sodium valproate, stiripentol, tiagabine, topiramate, vigabatrin, and zonisamide.

The case reports of the 876 patients with sIA-SAH were reviewed for acute seizures, defined as clinically observed seizures within 1 week after the onset of sIA-SAH.30 The data on fully reimbursed AEDs between January 1, 1994, and December 31, 2008, were integrated to the Kuopio sIA Database. The recruitment period between January 1, 1995, and December 31, 2007, allowed data on the use of AEDs for at least 1 year before and after sIA-SAH. We identified 378 AED users among the 876 patients with sIA-SAH (figure 1). Their hospital diagnoses and case reports from all neurology units in the KUH catchment area during the follow-up were reviewed. None was lost to follow-up. In the present study, the criteria for the epilepsy diagnosis after sIA-SAH in the AED users, evaluated by a neurologist(s), followed the current International League Against Epilepsy definition31: (1) at least 2 unprovoked seizures occurring >24 hours apart, or (2) one unprovoked seizure and high probability of further seizures due to, for example, brain infarct, ICH, or status epilepticus (figure 1). Acute seizures within 1 week after the onset of sIA-SAH were not considered as unprovoked seizures.

Statistical analysis.

The clinical variables of the 876 patients with sIA-SAH are presented in table 1. Discrete variables were expressed in proportions and continuous variables in medians, quartiles, and ranges. Groups were compared using the χ2 test or the Mann–Whitney U or Kruskal–Wallis test when appropriate.

View this table:
Table 1

Characteristics of 876 patients alive at 2 weeks after sIA-SAH between 1995 and 2007 and cumulative incidence of epilepsy until the end of 2008 with the competing risks analysis (epilepsy vs death) from a defined Eastern Finnish catchment population

The Kaplan–Meier analysis was used to calculate the cumulative mortality rate after sIA-SAH, and the independent risk factors for death were calculated using the Cox proportional hazards model.

The cumulative incidences of epilepsy after sIA-SAH (figure 2) were calculated with the competing risks analysis method (cmprisk R package), because epilepsy and death after sIA-SAH may share risk factors. Likewise, the independent risk factors for epilepsy after sIA-SAH were calculated by the competing risks cause-specific hazards Cox model32 (table 2). In these analyses, the patients who died within 2 weeks from the rupture of sIA (n = 169) were excluded. Values of p <0.05 were considered significant. SPSS 19.0 for Mac (SPSS, Inc., Chicago, IL) and R program were used.

Figure 2
Figure 2 Epilepsy among 876 patients alive 2 weeks after sIA-SAH

Cumulative incidences of epilepsy among 876 patients alive 2 weeks after subarachnoid hemorrhage from saccular intracranial aneurysm (sIA-SAH), in overall (A) and according to independent risk factors for epilepsy after sIA-SAH, intracerebral hemorrhage (ICH) (B), condition on admission by the Hunt and Hess Scale (C), and the presence or absence of acute seizures within 1 week after sIA-SAH (D).

View this table:
Table 2

Independent risk factors for epilepsy using competing risk (epilepsy vs death) regression analysis in 876 patients alive at 2 weeks after sIA-SAH

Standard protocol approvals, registrations, and patient consents.

The study was approved by the Ethical Committee of the KUH. Data integration from the national registries was performed with the approval from the Ministry of Social Affairs and Health of Finland.

RESULTS

Study population.

Altogether, 876 patients with no previous epilepsy had been alive at 2 weeks after admission for first sIA-SAH to KUH between January 1, 1995, and December 31, 2007 (figure 1). Their follow-up ended at death (n = 200) or December 31, 2008: total follow-up 5,616 person-years and a median follow-up time 76 months. Table 1 presents their characteristics and the variables tested for the competing risks death vs epilepsy after sIA-SAH.

Risk factors of mortality after sIA-SAH in 876 two-week survivors.

The cumulative mortality rate for the 876 two-week survivors was 6% at 1 month since their admission, 9% at 6 months, 11% at 1 year, 12% at 2 years, and 34% at 5 years. The independent risk factors for death were as follows: male sex (hazard ratio [HR] 2.1); 1-year increase in age at diagnosis of sIA-SAH (HR 1.07); ruptured sIA on the basilar artery bifurcation (HR 3.2); intraventricular hemorrhage (HR 1.5); severe hydrocephalus (HR 2.0); Hunt and Hess grade V33 (HR 2.9); and conservative treatment (HR 3.0).

Epilepsy after sIA-SAH.

Of the 876 two-week sIA-SAH survivors, 113 developed epilepsy, seizures since 1 week after sIA-SAH, according to both the AED purchases for epilepsy and the hospital case reports and diagnoses by neurologists (figure 1). Overall, the median time to epilepsy diagnosis was 8 months (quartiles 4 and 17 months). The cumulative incidence of epilepsy after sIA-SAH—with death as the competing risk—was 4% at 6 months after admission, 8% at 1 year, 10% at 2 years, and 12% at 5 years (figure 2A).

Impact of ICH.

The presence and the volume of ICH on acute CT scan, a sign of tearing brain tissue injury, associated significantly with epilepsy after sIA-SAH (table 1). The most frequent sites of ruptured sIA in the 855 treated patients were the anterior communicating artery and the middle cerebral artery bifurcation, and ICH of any volume occurred in 40/262 (15%) and 109/233 (47%) cases, respectively. The cumulative incidences of epilepsy are presented in table 1.

Acute seizures.

Acute seizures, within 1 week since sIA-SAH, occurred in 134 (15%) of the 876 two-week survivors (table 1). Significant anatomical risk factors for acute seizures were intraventricular hemorrhage (odds ratio [OR] 2.9; 95% confidence interval [CI] 1.8–4.6) and ICH (OR 2.1; 95% CI 1.3–3.5), while older age was associated with decreased risk of acute seizures (OR 0.97; 95% CI 0.96–0.99) (data not shown).

Independent risk factors for epilepsy after sIA-SAH.

In multivariate analysis, Hunt and Hess grades III (HR 2.2) and IV–V (HR 2.6), large ICH (≥15 cm3) (HR 1.9), and acute seizure (HR 2.3) remained independent risk factors for epilepsy after sIA-aSAH (table 2). Figure 2, B–D, present the cumulative incidence rates of epilepsy with or without these risk factors.

Microsurgical vs endovascular occlusive therapy of ruptured sIA.

During recruitment from 1995 to 2007, the choice between microsurgical vs endovascular therapy in the KUH Neurovascular Group was influenced by the morphology of the aneurysm, aneurysm neck width, location of the ruptured sIA, and the presence of ICH. In addition, between 1995 and 2000, there was a randomized trial on aneurysm treatment with clipping vs coiling.34 Endovascular therapy was significantly associated with lower incidence of epilepsy (table 1), but this disappeared in the multivariate analysis (table 2). Microsurgical clipping was more often associated with epilepsy because the cases with ICH were more often treated with simultaneous microsurgical clipping and evacuation of ICH.

Patients in good condition on admission.

The risk of epilepsy is significant even in patients with good condition on admission. Of the 876 two-week survivors of sIA-SAH, 266 (30%) had been in good condition (Hunt and Hess grades I and II), and their cumulative epilepsy rates were 6% vs 8% at 5 years, respectively (table 1, figure 2C).

DISCUSSION

Thus far, this is the most comprehensive study of the cumulative incidence and independent risk factors of epilepsy after aneurysmal SAH. This is the largest population-based cohort with sIA verified by 4-vessel angiography as the bleeding source and complete follow-up for the risk of epilepsy as identified by prescribed AED use from the national registry and by neurologists.

The initial mortality in unselected sIA-SAH cohorts is very high, e.g., 11% at 3 days, 22% at 30 days, and 27% at 12 months in our previous analysis of 1,657 patients admitted to our hospital within 24 hours after sIA-SAH.5 In the present study, 169 of the 1,045 patients with sIA-SAH admitted between 1995 and 2007 had died within 2 weeks (figure 1). The risk of epilepsy for the 876 two-week survivors was analyzed, because their probability for extended survival was already high, e.g., 88% at 2 years. The competing risks analysis was used for the cumulative epilepsy rates (table 1, figure 2). The Kaplan–Meier analysis would assume that the censoring of sIA survivors (lost to follow-up) and the probability of epilepsy would be independent of each other. In the present cohort, epilepsy and excess mortality after sIA-SAH share the same risk factors known on admission, most notably acute ICH and poorer condition on admission. The larger the risk of competing risk, the greater the extent of bias.32

The risk of epilepsy is significant even in patients with good condition and cisternal blood as the only sign of SAH on CT scan on admission. Of the 876 two-week survivors of sIA-SAH, 266 (30%) had been in good condition (Hunt and Hess grades I and II). Their cumulative epilepsy rates were 6% vs 8% at 5 years. The presence and volume of ICH on acute CT scan as a sign of tearing irreversible brain tissue injury was the strongest anatomical predictor of epilepsy after sIA-SAH (table 1). Of the 113 patients with epilepsy, 57 presented with ICH on admission. Rupture of sIA in the middle cerebral artery bifurcation was particularly prone (47%) to cause ICH in the adjacent temporal lobe.35

Acute seizures, determined as seizures within 1 week from the rupture of sIA, are also an independent risk factor for epilepsy during follow-up. Previous studies indicate that the increasing amount of blood on acute CT scan predisposes to acute seizures,9,36 implying that primary brain damage causes seizures in the acute phase. Previous studies suggest that acute seizures predict poor outcome,37 but in our study, they were not an independent risk factor for poor outcome at 1 year according to the Glasgow Outcome Scale.

The mode of occlusive therapy of ruptured sIA, whether microsurgical or endovascular, was not an independent risk factor for epilepsy after sIA-SAH. In the univariate analysis, endovascular treatment was associated with lower incidence of epilepsy. This was most likely because ruptured sIA in the middle cerebral artery bifurcation often caused ICHs and in that case were mainly occluded microsurgically.

A PubMed search identified only 3 original studies on epilepsy after aneurysmal SAH since 2000 with a sizable cohort, flowchart, follow-up time of at least 12 months, methods of gathering follow-up data, proper definition of epilepsy and distinction from acute seizures, and multivariate analyses for independent risk factors for epilepsy.11,13,38 Distinction of sIAs from infrequent fusiform aneurysms was not reported. These 3 studies did not use the competing risks (death vs epilepsy) analysis for the cumulative rate of epilepsy. The overall incidences of epilepsy after aneurysmal SAH are not informative because the survivors are heterogeneous regarding condition on admission, signs of brain injury in neuroimaging and during neurointensive care, and subsequent neurologic morbidity.

In the prospective single-center study, 305 of the 431 patients were alive 1 year after aneurysmal SAH, and 247 of them (58 missing) were analyzed for epilepsy. Only 17 patients with epilepsy were identified: the epilepsy ratio from 17/305 (5.6%) to 17/247 (6.9%).11 In the retrospective single-center study, 217 of the 274 patients with aneurysmal SAH alive at 1 year, all treated by microsurgical clipping, were analyzed for epilepsy during a mean follow-up time of 6.6 years. Only 15 patients with epilepsy were identified: the epilepsy ratio of 15/217 (6.9%).13 In these 2 studies, the cumulative epilepsy rates were not reported, and the identification of independent risk factors for epilepsy was flawed by the small numbers of patients with epilepsy.

In the prospective International Subarachnoid Aneurysm Trial (ISAT),38 2,143 patients with aneurysmal SAH, 1,073 randomized to endovascular treatment and 1,070 to neurosurgery, were studied for epilepsy. Epilepsy was defined as seizures after randomization. Of the 2,143 patients, 88% of patients were WFNS (World Federation of Neurosurgeons) grade 1–2 in both groups; 1,084 patients had anterior cerebral artery aneurysm, 698 patients had internal carotid artery aneurysm, and only 303 (14%) had middle cerebral artery aneurysm. The authors identified 235 patients with epilepsy in a mean follow-up time of 9 years. The cumulative rates of epilepsy at 5 years were 6.4% after endovascular and 9.6% after surgical occlusive therapy. The independent risk factors for epilepsy were thromboembolic complications (HR 5.1), vasospasm (HR 2.1), additional procedures, craniotomy (HR 1.7), middle cerebral artery location of ruptured aneurysm (HR 2.2), age younger than 50 years (HR 1.5), and neurosurgical occlusion of ruptured aneurysm (HR 1.6). In ISAT, study selection was toward patients in good condition with small aneurysm in anterior cerebral artery and internal carotid artery and the study was aimed to compare endovascular vs neurosurgical treatment of SAH in an eligible population. Cumulative incidences of epilepsy at 5 years in ISAT after different treatment modalities are comparable to our results in cumulative incidence of epilepsy after sIA-SAH with patients in good condition on admission.

The strengths derive from the Finnish health care system. Finland is divided into mutually exclusive catchment areas among the 5 university hospitals. This allowed the creation of disease cohorts that are unselected and minimally biased. Very accurate population statistics and a stable population allow long-term follow-up and ensure that few patients are lost to follow-up. Our study is retrospective, but we were able to accurately identify the patients diagnosed with epilepsy by neurologists because of the national registry of fully reimbursed medicines and the case reports from the treating hospitals during the follow-up.

We did not have valid information about epilepsy in the patients permanently institutionalized after sIA-SAH (7 patients, all with Glasgow Outcome Scale score of 2). Their AEDs are not reimbursed but are included in the institution fees, so the overall incidence may be slightly underestimated.

Long-term sIA-SAH survivors present significantly with unexpected neurologic, cognitive, and psychosocial problems39 that may be missed during routine visits to outpatient clinics. Our data on epilepsy will support the clinical practice of post-SAH outpatient clinics that should be organized in dedicated neurocenters. Epilepsy in the 2-week survivors of acute sIA-SAH was predicted by signs of the primary injury in the brain tissue (ICH) on CT scan on admission, the patient's condition on admission reflecting the extent of the primary impact, and acute seizures within 1 week after sIA-SAH, reflecting the patient's individual threshold for seizures. Microsurgical clipping of ruptured sIAs was more often associated with epilepsy than endovascular occlusive therapy because the cases with ICH were more often treated with simultaneous microsurgical clipping and evacuation of ICH.

AUTHOR CONTRIBUTIONS

Dr. Jukka Huttunen: study design, data acquisition, statistical analysis, drafting of the manuscript, funding acquisition. Dr. Mitja I. Kurki: statistical analysis, review of the manuscript. Docent Mikael von und zu Fraunberg: data acquisition, statistical analysis, review of the manuscript. Docent Timo Koivisto: data acquisition, review of the manuscript. Docent Antti Ronkainen: data acquisition, review of the manuscript. Docent Jaakko Rinne: data acquisition, review of the manuscript. Prof. Juha E. Jääskeläinen: study design, study supervision, funding acquisition, review of the manuscript. Prof. Reetta Kälviäinen: study design, study supervision, funding acquisition, review of the manuscript. Dr. Arto Immonen: study design, study supervision, review of the manuscript.

STUDY FUNDING

Supported by the Päivikki and Sakari Sohlberg Foundation, the Kuopio University Hospital, and the UCB Nordic Epilepsy Grant.

DISCLOSURE

J. Huttunen has received funding from the UCB Nordic Epilepsy Grant. M. Kurki reports no disclosures relevant to the manuscript. M. von und zu Fraunberg has received grants from the Kuopio University Hospital. T. Koivisto, A. Ronkainen, and J. Rinne report no disclosures relevant to the manuscript. J. Jääskeläinen has received grants from the Päivikki and Sakari Sohlberg Foundation, the Academy of Finland, and the Kuopio University Hospital. R. Kälviäinen has served on scientific advisory boards for UCB Pharma, Eisai, Lundbeck, GlaxoSmithKline, and Fenno Medical, and has received funding for travel and speaker honoraria from UCB Pharma, Eisai, GlaxoSmithKline, Medtronic, Pfizer, Orion, and Fenno Medical. A. Immonen has received funding for travel and speaker honoraria from UCB Pharma. Go to Neurology.org for full disclosures.

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 2, 2014.
  • Accepted in final form February 20, 2015.

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Letters: Rapid online correspondence

  • Re:Seizures after aneurysmal subarachnoid hemorrhage
    • Jukka M. Huttunen, MD, Kuopio University Hospital
    • Mitja I. Kurki, Boston, USA; Mikael von und zu Fraunberg, Kuopio, Finland;Timo Koivisto, Kuopio, Finland;Antti Ronkainen, Tampere, Finland;Jaakko Rinne, Turku, Finland;Juha E. J??skel?inen, Kuopio, Finland; Reetta K?lvi?inen, Kuopio, Finland; Arto Immonen
    Submitted June 29, 2015
  • Seizures after aneurysmal subarachnoid hemorrhage
    • Nitin K. Sethi, Assistant Professor of Neurology, New York-Presbyterian Hospital, Weill Cornell Medical Center, 525 East 68th Street, New York, NY 100
    • Nitin K Sethi, New York, NY
    Submitted June 15, 2015
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