Risk of stroke after new-onset seizures

  • David Larsson
    Correspondence
    Corresponding authors at: Department of Neurology, Sahlgrenska University Hospital, Blå stråket 7, 413 45 Gothenburg, Sweden.
    Affiliations
    Institute of Neuroscience and Physiology, Department of Clinical Neuroscience, Sahlgrenska Academy, Gothenburg University, Sweden

    Department of Neurology, Sahlgrenska University Hospital, Gothenburg, Sweden
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  • Bahman Farahmand
    Affiliations
    Epi-Consultant, Stockholm, Sweden
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  • Signild Åsberg
    Affiliations
    Department of Neuroscience, Uppsala University, Sweden
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  • Johan Zelano
    Correspondence
    Corresponding authors at: Department of Neurology, Sahlgrenska University Hospital, Blå stråket 7, 413 45 Gothenburg, Sweden.
    Affiliations
    Institute of Neuroscience and Physiology, Department of Clinical Neuroscience, Sahlgrenska Academy, Gothenburg University, Sweden

    Department of Neurology, Sahlgrenska University Hospital, Gothenburg, Sweden
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Open ArchivePublished:October 05, 2020DOI:https://doi.org/10.1016/j.seizure.2020.09.033

      Highlights

      • Epileptic seizures were associated with an increased risk of subsequent stroke.
      • The risk of stroke was higher early after the onset of seizures.
      • The study includes subgroup analyses, stratified by stroke type, age, and sex.
      • Late-onset seizures may warrant a prompt assessment of vascular risk factors.

      Abstract

      Purpose

      Observational cohort studies have reported a potentially increased risk of stroke in patients with epileptic seizures. Whether late-onset seizures merit primary stroke prophylaxis is not known, and more information on stroke risk is needed for the planning of RCTs. We performed a case-control study based on Swedish national registers to quantify the risk of stroke after epileptic seizures.

      Methods

      Cases ≤100 years of age with a first-ever stroke 2001–2009 were identified through the Swedish Stroke Register, and stroke-free controls (matched for age and sex) were obtained from the Population Register. The National Patient Register provided information on diagnostic codes for seizures, epilepsy and comorbidities. 123 105 stroke cases and 250 506 controls were included.

      Results

      Epileptic seizures prior to index stroke date were detected in 1559 (1.27 %) cases and 1806 (0.72 %) controls, yielding an odds ratio (95 % confidence interval) for stroke of 1.77 (1.65–1.89). ORs were similar in men and women, but higher below the age of 75. An onset of seizures in the year preceding stroke date resulted in a higher risk for stroke (OR = 2.21, 95 % CI = 1.79–2.72) compared to when more than 5 years had passed since the first seizure (OR = 1.57, 95 % CI = 1.43–1.72).

      Conclusion

      A history of epileptic seizures was associated with an increased risk of subsequent stroke. The risk seems to be particularly high in the first year following seizure diagnosis, which supports the notion that unexplained late-onset seizures may merit swift assessment of vascular risk profile. The nature of stroke prevention requires further study.

      Keywords

      1. Introduction

      Cerebrovascular disease is a well-known cause of epilepsy. Multiple investigators have also reported that an onset of seizures after middle age can precede stroke [
      • Burn J.
      • Dennis M.
      • Bamford J.
      • Sandercock P.
      • Wade D.
      • Warlow C.
      Epileptic seizures after a first stroke: the Oxfordshire Community Stroke Project.
      ,
      • Barolin G.S.
      The cerebrovascular epilepsies.
      ,
      • Shinton R.A.
      • Gill J.S.
      • Zezulka A.V.
      • Beevers D.G.
      The frequency of epilepsy preceding stroke. Case-control study in 230 patients.
      ,
      • Cleary P.
      • Shorvon S.
      • Tallis R.
      Late-onset seizures as a predictor of subsequent stroke.
      ,
      • Chang C.S.
      • Liao C.H.
      • Lin C.C.
      • Lane H.Y.
      • Sung F.C.
      • Kao C.H.
      Patients with epilepsy are at an increased risk of subsequent stroke: a population-based cohort study.
      ,
      • Wannamaker B.B.
      • Wilson D.A.
      • Malek A.M.
      • Selassie A.W.
      Stroke after adult-onset epilepsy: a population-based retrospective cohort study.
      ,
      • Zelano J.
      • Larsson D.
      • Kumlien E.
      • Asberg S.
      Pre-stroke seizures: a nationwide register-based investigation.
      ,
      • Hsu S.P.C.
      • Yeh C.C.
      • Chou Y.C.
      • et al.
      Stroke risk and outcomes in epilepsy patients: two retrospective cohort studies based on National Health Insurance in Taiwan.
      ] and the term “heraldic seizures” has been suggested [
      • Brigo F.
      • Tezzon F.
      • Nardone R.
      Late-onset seizures and risk of subsequent stroke: a systematic review.
      ]. Several plausible explanations exist; late-onset epileptic seizures may reflect occult cerebrovascular disease, promote isolation and reduced physical activity, or result in treatment with antiepileptic drugs that, in turn, increase cardiovascular risk. Whether late-onset epilepsy should prompt cardiovascular workup and primary prevention of stroke remains uncertain, and there is currently no randomised evidence to guide management. To inform clinical practice and enable reliable randomised controlled trials (RCTs), detailed knowledge is needed on particular patient groups where epileptic seizures reflect an increased risk of stroke. We recently observed that, in relation to reported incidence figures, a relatively high proportion of stroke patients in Sweden had new-onset seizures in the decade preceding stroke date [
      • Zelano J.
      • Larsson D.
      • Kumlien E.
      • Asberg S.
      Pre-stroke seizures: a nationwide register-based investigation.
      ]. To verify this observation with an adequate control group, we performed a population-based case-control study. The aim was to assess the association between epileptic seizures and the risk of subsequent stroke, analyzed by stroke type, age, sex, and time between the first epileptic seizure and stroke.

      2. Methods

      We conducted a population-based case-control study including first-ever stroke cases and randomly selected stroke-free controls. Details on the cohort have been published previously in studies of other risk factors for stroke [
      • Bergman E.M.
      • Henriksson K.M.
      • Asberg S.
      • Farahmand B.
      • Terent A.
      National registry-based case-control study: comorbidity and stroke in young adults.
      ,
      • Asberg S.
      • Eriksson M.
      Statin therapy and the risk of intracerebral haemorrhage: a nationwide observational study.
      ].

      2.1 Data sources

      Sweden has a system of unique personal identity numbers that allows researchers to link data from different registers to a specific individual. Data on stroke, epileptic seizures, demographic factors and comorbidities were obtained from two national registers: the Swedish stroke register (Riksstroke [
      • Riksstroke
      General information [online].
      ]) and the National Patient Register (NPR). A control group from the general population was identified by the governmental bureau Statistics Sweden.
      Riksstroke is one of the largest national quality assessment registers in Sweden. All adult patients admitted to a hospital with a diagnosis of acute ischemic stroke or intracerebral hemorrhage are eligible for the register. Before the introduction of a separate pediatric module, some stroke units had the option to register minors. In 2012, Riksstroke had an estimated coverage of 94 % for acute stroke [
      • Riksstroke
      Evaluations of variables in Riksstroke, the Swedish Stroke Register [online].
      ].
      NPR is managed by the Swedish National Board of Health and Welfare and contains information about all inpatient (1987-) and hospital-based outpatient (2001-) care from both public and private caregivers. It covers information on dates of admission and discharge, and diagnostic coding, based on the International Classification of Diseases 9th and 10th revision (ICD-9/10), for each admission.

      2.2 Study population

      All registered stroke events in 2001–2009 (n = 219 407) were identified in Riksstroke by the registry manager Västerbotten County Council. Based on this data, Statistics Sweden provided randomly selected controls from the general population, matched on sex and age at the year of stroke onset (index date). After getting access to the de-identified dataset, we only included cases ≤100 years of age with eligible personal identity numbers (for reliable linkage between registers) and available stroke date. Cases and controls with prior diagnoses of cerebrovascular disease (including stroke), malignant brain tumor, or head injury were excluded. Initially, two controls were selected per case, but the 2:1 ratio was not retained after applying exclusion criteria.

      2.3 Variables and definitions

      Variables were based on occurrence of diagnostic codes in the NPR for: epileptic seizures (ICD-9 345, 780D and ICD-10 G40, G41, R568), cerebrovascular disease (ICD-9 430-438 and ICD-10 I60-I69, G45), malignant brain tumour (ICD-9 191 and ICD-10 C71), head injuries (ICD-9 800-804, 850-854 and ICD-10 S06), hypertension (ICD-9 401 and ICD-10 I10.9), diabetes (ICD-9 250 and ICD-10 E10, E11) and atrial fibrillation (ICD-9 427D and ICD-10 I48) as main or subsidiary diagnoses. To avoid the influence of acute symptomatic seizures, a detected diagnostic code of epileptic seizures in the week preceding the index stroke did not count as exposure. Furthermore, to minimize non-equivalence between cases and controls in the detection of comorbidities, we only used diagnostic codes registered before stroke admission.

      2.4 Statistical analysis

      Odds ratios (OR) and 95 % confidence intervals (CI) for stroke with antecedent epilepsy was calculated using logistic regression models. Adjustments were made for age, sex, hypertension, diabetes mellitus and atrial fibrillation. The analyses were performed in Uppsala, Sweden, using Statistical Analysis System 9.4 for Microsoft Windows (Cary, North Carolina, USA).

      2.5 Ethical permission and data handling

      The study was approved by the regional ethics board in Uppsala, Sweden (approval no 2009/355). The data was de-identified before we were given access to it. All data was stored in Uppsala, Sweden, and has been handled in agreement with the privacy legislation of Sweden.

      2.6 Data accessibility

      The data from the Swedish national registers used in this study are protected by confidentiality laws and cannot be shared by the authors for legal reasons.

      2.7 Role of the funding source

      The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

      3. Results

      Overall, 123 105 stroke cases and 250 506 controls were included (Fig. 1).
      Epileptic seizures had occurred in 1559 (1.27 %) of stroke cases and 1806 (0.72 %) of controls (Table 1). Among cases, the highest presence of epileptic seizures (1.21–1.86 %) was seen in those below the age of 75 (Fig. 2), with predominance for ages 45–69 in both men and women. In contrast, epileptic seizures were identified in 0.66 to 0.79 % of controls, relatively evenly distributed in all age groups. Four registered cases were under 18 years of age, and none of them had any seizure diagnoses prior to their stroke. We analyzed the presence of epileptic seizures based on stroke subtypes; an epileptic seizure diagnosis was identified in 1.55 % of cases with intracerebral hemorrhage (ICH) and 1.23 % of cases with acute ischemic stroke (AIS, Fig. 3).
      Table 1Demographics and risk factors of cases and controls. † Intracerebral hemorrhage. ‡ Acute ischemic stroke.
      VariablesCategoriesStroke casesControls
      SeizuresTime seizure to stroke (years)SeizuresTime seizure to index date (years)
      <11–5>5<11–5>5
      NN%%%%NN%%%%
      All12310515591.270.180.340.7525050618060.720.080.180.47
      Age (years)
      Mean73.9573.72
      Categories≤494658861.850.190.541.129805670.680.080.120.48
      50–74504787921.570.200.400.971014447640.730.060.170.50
      ≥75679696811.000.160.290.551362579750.720.090.180.44
      SexMale610398811.440.190.370.8912410210200.820.080.200.54
      Female620666781.090.160.320.611264047860.620.080.160.39
      Stroke typeICH151412351.550.270.400.88313011950.620.060.140.42
      AIS10796413241.230.160.330.7321920516110.730.080.180.47
      Medical history
      Hypertension622477221.160.150.360.65513514930.960.120.250.59
      Diabetes236252891.220.160.360.70194402031.040.130.340.58
      Atrial fibrillation346253761.090.150.320.62280982690.960.110.250.60
      Fig. 2
      Fig. 2Proportion of patients with a history of epileptic seizures prior to stroke (index date), stratified by age and sex.
      Fig. 3
      Fig. 3Proportion of patients with a history of epileptic seizures prior to stroke (index date), stratified by stroke subtype.
      Epileptic seizures were associated with an increased OR (95 % CI) of stroke, 1.77 (1.65–1.89), with approximately the same OR estimates for men and women. The OR for ICH was 2.51 (2.08–3.04), and that of AIS was 1.68 (1.56–1.80). Increased ORs were observed for patients aged 50–74 years (OR = 2.16, 95 % CI = 1.96–2.39) compared to patients aged ≥75 years (OR = 1.40, 95 % CI = 1.27–1.55). The adjusted ORs of stroke associated with epileptic seizures by stroke subtype and stratified by sex and age group are presented in Fig. 4. Adjustments for age, sex and risk factors for stroke did not have any major influence on ORs (Table 2).
      Fig. 4
      Fig. 4Adjusted odds ratios (95 % confidence intervals) for stroke associated with epileptic seizures, stratified by age group, sex and time from seizure onset to stroke (index date).
      Table 2Calculations of crude and adjusted odds ratios for stroke, stratified by time between seizure onset and stroke (index date). † Intracerebral hemorrhage. ‡ Acute ischemic stroke. § Medical history including hypertension, diabetes mellitus and atrial fibrillation.
      Stroke
      AllICHAIS
      VariablesTime seizure to stroke (years)OR95 % CIOR95 % CIOR95 % CI
      CrudeAnytime1.771.65–1.892.512.08–3.041.681.56–1.80
      Age, sex and medical history§1.681.56–1.802.572.10–3.141.571.45–1.70
      Crude>51.611.48–1.762.121.66–2.701.551.41–1.70
      1–51.951.71–2.232.831.92–4.161.861.61–2.14
      <12.271.87–2.754.492.61–7.732.031.65–2.50
      Age, sex and medical history§>51.571.43–1.722.221.72–2.871.481.34–1.64
      1–51.731.50–1.992.581.71–3.881.641.40–1.91
      <12.211.79–2.724.982.83–8.771.941.55–2.44
      We finally studied the impact of a recent first epileptic seizure on the risk of stroke. The adjusted OR was higher when seizure onset occurred in the year before index stroke date (2.21, 95 %CI 1.79–2.72) compared to when more than five years had passed since the first seizure (1.57, 95 %CI 1.43–1.72). A seizure onset between one and five years before stroke was associated with an intermediate OR (1.73, 95 %CI 1.50–1.99). In subjects aged 50–74 years and ≥75 years, the adjusted OR (95 %CI) for stroke following a recent seizure onset (<1 year) was 2.94 (2.07–4.17) and 1.77 (1.35–2.32), respectively.

      3.1 Sensitivity analyses

      We performed two sensitivity analyses regarding exposure. First, we calculated ORs when only diagnostic codes for epilepsy (ICD-10 G40) were counted as exposure, rather than all seizure-related diagnostic codes. Diagnostic codes for epilepsy occurred in 1031 (0.84 %) stroke cases and 1182 (0.47 %) controls. This resulted in a similar estimate for the risk of stroke (1.78, 95 %CI 1.64–1.94) as the main analysis. Additionally, to undermine influence of improved coverage in the NPR in 2001, we limited the study period to 2005–2009. This analysis confirmed the higher adjusted OR for stroke when a first epileptic seizure occurred in the year before stroke (2.74, 95 %CI 1.93–3.86) compared to when a first epileptic seizure occurred >5 years before stroke (1.63, 95 %CI 1.41–1.89).

      4. Discussion

      We report a clear association between seizures and increased risk of subsequent stroke. The highest increase in risk was seen in the first year after new-onset seizures, and an intermediate risk increase was seen in the five years following an incident seizure. On account of the age distribution of our study population, most patients with a recent first seizure have had an onset of epileptic seizures after middle age. Our findings underline the need for rapid cardiovascular assessment of patients with late-onset seizures and more research on appropriate interventions.
      The risk of stroke following epileptic seizures was higher in subjects under the age of 75 years. This is a frequent finding in stroke risk factor studies and may reflect that patients with seizures due to occult cerebrovascular disease develop stroke before they reach higher ages. The largest risk-ratio for stroke was seen in young cases (<50 years), but since stroke is overall rare in this age group this finding is probably confounded by associations between epilepsy and other comorbidities, such as developmental syndromes or long-standing disease.
      Our methodology was register-based, which, for a case-control design, has the significant advantage of minimizing ascertainment as well as recall bias. The data sources are validated registers with good coverage, and our nationwide scope allowed enough power to study age groups as well as stroke subtypes. The random sampling of controls from the Swedish population reduces the risk of selection bias.
      The findings are in line with the existing literature. In 1987, an English study reported a close temporal association between seizures and stroke in three cases [
      • Shinton R.A.
      • Gill J.S.
      • Zezulka A.V.
      • Beevers D.G.
      The frequency of epilepsy preceding stroke. Case-control study in 230 patients.
      ]. Another observational cohort study have compared patients with epilepsy to controls who had suffered lower extremity fractures and described that an onset of stroke between six months and one year after the initial diagnosis occurred in a significantly higher proportion of cases with epilepsy (16.2 %) than controls (10.9 %) [
      • Wannamaker B.B.
      • Wilson D.A.
      • Malek A.M.
      • Selassie A.W.
      Stroke after adult-onset epilepsy: a population-based retrospective cohort study.
      ]. The same study reported a hazard ratio (HR), adjusted for several covariables, of 1.60 (95 %CI 1.42–1.80), which is comparable to our adjusted OR of 1.68 (95 %CI 1.56–1.80) [
      • Wannamaker B.B.
      • Wilson D.A.
      • Malek A.M.
      • Selassie A.W.
      Stroke after adult-onset epilepsy: a population-based retrospective cohort study.
      ]. A British study focused on patients with unexplained epilepsy after the age of 60 and estimated the HR of stroke to be 2.89 (95 %CI 2.45–3.41) [
      • Cleary P.
      • Shorvon S.
      • Tallis R.
      Late-onset seizures as a predictor of subsequent stroke.
      ], which is close to our OR of 2.16 (95 %CI 1.96–2.39) for patients aged 50–74. This difference might reflect either national differences or a reduction in stroke risk in the general population since that investigation. Methodological differences are another possibility, mainly that we required one week between the seizure or epilepsy diagnosis and the stroke date to minimize the influence of acute symptomatic seizures.
      Our study has the limitations normally associated with register-based studies. Some degree of misclassification of exposure is expected among both cases and controls, but the clinical assessment is unlikely to differ between the groups. Since we have not assessed each case individually, the time between the actual seizure and the detected diagnostic code is unknown to us. These misclassifications are considered non-differential and might bias our ORs slightly towards the null, but should not affect our findings in any major way. Furthermore, we lack information about potential confounders, including alcohol use disorders and dementia, and several other factors that influence stroke risk, such as physical activity, body mass index, cholesterol levels, and drugs used in primary stroke prevention. It is uncertain whether these risk factors also influence the occurrence of seizures, thus becoming confounders. Components of the metabolic syndrome are often interlinked, and adjustments for available vascular risk factors, i.e., hypertension and diabetes mellitus, did not have any significant impact on ORs.
      Our findings have potential clinical implications and suggest the increased risk of stroke inferred by late-onset seizure to be of a magnitude warranting intervention. Previously, Cleary et al. reported subsequent stroke in 10 % of patients with new-onset unexplained seizures after 60 years of age, with a median follow-up of approximately 5.3 years (max 13 years) [
      • Cleary P.
      • Shorvon S.
      • Tallis R.
      Late-onset seizures as a predictor of subsequent stroke.
      ]. Based on pre-existing epilepsy among individuals in the Swedish stroke register and national incidence figures, we have calculated that 5–20 % of patients with a first-ever seizure after 50 years of age will suffer stroke within ten years, depending on age group [
      • Zelano J.
      • Larsson D.
      • Kumlien E.
      • Asberg S.
      Pre-stroke seizures: a nationwide register-based investigation.
      ]. There have also been reports of an association between epilepsy and a moderately increased risk of subsequent myocardial infarction [
      • Olesen J.B.
      • Abildstrom S.Z.
      • Erdal J.
      • et al.
      Effects of epilepsy and selected antiepileptic drugs on risk of myocardial infarction, stroke, and death in patients with or without previous stroke: a nationwide cohort study.
      ,
      • Wilson D.A.
      • Wannamaker B.B.
      • Malek A.M.
      • Selassie A.W.
      Myocardial infarction after epilepsy onset: a population-based retrospective cohort study.
      ]. All things considered, risk-factor intervention to modify general vascular risk seems motivated, which is in line with existing guidelines and expert opinions [
      • Brigo F.
      • Tezzon F.
      • Nardone R.
      Late-onset seizures and risk of subsequent stroke: a systematic review.
      ,
      • (SIGN) SIGN
      Diagnosis and management of epilepsy in adults. Edinburgh: (SIGN publication no. 143).
      ].
      The nature of stroke prevention requires further study. Intervention may target smoking, hypertension, physical inactivity, and hyperlipidemia, but the benefits of antiplatelet treatment is less clear. In our material, epileptic seizures were associated with an increased risk of ICH, a finding in agreement with a previous study in which exposure to late-onset seizures was higher in patients suffering ICH than infarction [
      • Zelano J.
      • Larsson D.
      • Kumlien E.
      • Asberg S.
      Pre-stroke seizures: a nationwide register-based investigation.
      ]. Since that observation was also based on the Swedish stroke register, validation in an independent international dataset would be valuable. Hopefully, our findings may be of use in the planning of future RCTs aimed at reducing stroke risk in patients with late-onset seizures.

      Funding

      The study was funded by the Swedish state under the agreement between the Swedish government and the country councils, the ALF-agreement (ALF-789921 and 715781), Swedish Society of Medicine , Swedish Society for Medical Research , Felix Neubergh Foundation , Magnus Bergvall Foundation , Gothenburg Medical Society .

      CRediT authorship contribution statement

      David Larsson: Methodology, Visualization, Writing - original draft, Writing - review & editing. Bahman Farahmand: Methodology, Formal analysis, Visualization, Writing - review & editing. Signild Åsberg: Methodology, Data curation, Writing - review & editing. Johan Zelano: Conceptualization, Funding acquisition, Methodology, Writing - original draft, Writing - review & editing.

      Declaration of Competing Interest

      DL reports grants from Sahlgrenska University Hospital/ALF. BF has nothing to disclose. SÅ reports grants from AstraZeneca outside the submitted work. JZ reports grants from Sahlgrenska University Hospital/ALF, Swedish Society of Medicine, Swedish Society for Medical Research, Felix Neubergh Foundation, Magnus Bergvall Foundation, and Gothenburg Medical Society. As an employee of Sahlgrenska University Hospital, he serves as investigator/sub-investigator in clinical trials sponsored by UCB, Bial, SK life science, and GW (no personal compensation). JZ has been a speaker at non-branded educations organized by UCB (honoraria) and Eisai (no personal compensation) outside the submitted work.

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