Congenital Heart Defects and Risk of Epilepsy
2016; Lippincott Williams & Wilkins; Volume: 134; Issue: 21 Linguagem: Inglês
10.1161/circulationaha.116.024538
ISSN1524-4539
AutoresMichelle Z. Leisner, Nicolas Madsen, John R. Østergaard, Jessica G. Woo, Bradley S. Marino, Morten Smærup Olsen,
Tópico(s)Cardiovascular Issues in Pregnancy
ResumoHomeCirculationVol. 134, No. 21Congenital Heart Defects and Risk of Epilepsy Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBCongenital Heart Defects and Risk of EpilepsyA Population-Based Cohort Study Michelle Z. Leisner, MPH, Nicolas L. Madsen, MD, MPH, John R. Ostergaard, MD, DMSc, Jessica G. Woo, PhD, Bradley S. Marino, MD, MPP, MSCE and Morten S. Olsen, MD, PhD Michelle Z. LeisnerMichelle Z. Leisner From Department of Clinical Epidemiology (M.Z.L., M.S.O.) and Center for Rare Diseases, Department of Pediatrics (J.R.O.), Aarhus University Hospital, Aarhus N, Denmark; Heart Institute (N.L.M.) and Division of Biostatistics and Epidemiology (J.G.W.), Cincinnati Children's Hospital Medical Center, Cincinnati, OH; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH (N.L.M., J.G.W.); Heart Center at the Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL (B.S.M.); and Department of Pediatrics and Medical Social Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL (B.S.M.). , Nicolas L. MadsenNicolas L. Madsen From Department of Clinical Epidemiology (M.Z.L., M.S.O.) and Center for Rare Diseases, Department of Pediatrics (J.R.O.), Aarhus University Hospital, Aarhus N, Denmark; Heart Institute (N.L.M.) and Division of Biostatistics and Epidemiology (J.G.W.), Cincinnati Children's Hospital Medical Center, Cincinnati, OH; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH (N.L.M., J.G.W.); Heart Center at the Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL (B.S.M.); and Department of Pediatrics and Medical Social Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL (B.S.M.). , John R. OstergaardJohn R. Ostergaard From Department of Clinical Epidemiology (M.Z.L., M.S.O.) and Center for Rare Diseases, Department of Pediatrics (J.R.O.), Aarhus University Hospital, Aarhus N, Denmark; Heart Institute (N.L.M.) and Division of Biostatistics and Epidemiology (J.G.W.), Cincinnati Children's Hospital Medical Center, Cincinnati, OH; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH (N.L.M., J.G.W.); Heart Center at the Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL (B.S.M.); and Department of Pediatrics and Medical Social Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL (B.S.M.). , Jessica G. WooJessica G. Woo From Department of Clinical Epidemiology (M.Z.L., M.S.O.) and Center for Rare Diseases, Department of Pediatrics (J.R.O.), Aarhus University Hospital, Aarhus N, Denmark; Heart Institute (N.L.M.) and Division of Biostatistics and Epidemiology (J.G.W.), Cincinnati Children's Hospital Medical Center, Cincinnati, OH; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH (N.L.M., J.G.W.); Heart Center at the Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL (B.S.M.); and Department of Pediatrics and Medical Social Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL (B.S.M.). , Bradley S. MarinoBradley S. Marino From Department of Clinical Epidemiology (M.Z.L., M.S.O.) and Center for Rare Diseases, Department of Pediatrics (J.R.O.), Aarhus University Hospital, Aarhus N, Denmark; Heart Institute (N.L.M.) and Division of Biostatistics and Epidemiology (J.G.W.), Cincinnati Children's Hospital Medical Center, Cincinnati, OH; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH (N.L.M., J.G.W.); Heart Center at the Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL (B.S.M.); and Department of Pediatrics and Medical Social Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL (B.S.M.). and Morten S. OlsenMorten S. Olsen From Department of Clinical Epidemiology (M.Z.L., M.S.O.) and Center for Rare Diseases, Department of Pediatrics (J.R.O.), Aarhus University Hospital, Aarhus N, Denmark; Heart Institute (N.L.M.) and Division of Biostatistics and Epidemiology (J.G.W.), Cincinnati Children's Hospital Medical Center, Cincinnati, OH; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH (N.L.M., J.G.W.); Heart Center at the Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL (B.S.M.); and Department of Pediatrics and Medical Social Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL (B.S.M.). Originally published22 Nov 2016https://doi.org/10.1161/CIRCULATIONAHA.116.024538Circulation. 2016;134:1689–1691Although neurological morbidity has been consistently described in the congenital heart disease (CHD) population,1 no studies to date have examined the long-term risk of epilepsy in subjects with CHD compared with the general population. Previous studies, which point toward a heightened risk of epilepsy, include a single-center case series without the benefit of a control population and a subsequent population-based case-control study.2,3 Given the known clinical implications of epilepsy in the general population and the unique vulnerabilities of the CHD population, our study aimed to provide the first evaluation with the benefit of complete long-term follow-up to address the hypothesis that CHD is associated with an increased long-term risk of epilepsy.We used data from population-based registries covering all Danish hospitals to identify subjects born and diagnosed with CHD between 1980 and 2010 (CHD diagnosis before 15 years of age). Using the Danish Civil Registration System, we identified 10 individuals from the general population for each CHD subject, matched on sex and birth year. Follow-up was continued until diagnosis of epilepsy, death, emigration, or end of study (December 2010). We computed cumulative incidences and hazard ratios (HRs) of time to hospital-based epilepsy diagnosis, adjusting for birth year and sex. In a sensitivity analysis, epilepsy diagnoses made within the 7 days before surgery and 30 days after surgery were ignored. The study was approved by the Danish Data Protection Agency (record No. 2013-41-1754), whose role is to protect the privacy of individuals whose data are recorded in Danish registries. No informed consent was required for this study.We identified 15 222 CHD subjects (51% male). The overall cumulative incidence of epilepsy in CHD subjects by 15 years of age was 5%. Subjects with CHD born at term without extracardiac defects demonstrated a cumulative incidence of 3% by the same age. The overall HR of epilepsy among patients with CHD compared with the general population cohort was 3.7 (95% confidence interval [CI], 3.2–4.2) before 5 years of age and 2.3 (95% CI: 2.1–2.7) from 5 to 32 years of age (Table). The HRs did not vary substantially according to age at surgery. The risk of epilepsy was most elevated among those who experienced multiple surgeries (having ≥3 surgeries was associated with an HR of 4.8; 95% CI, 2.8–8.2). For any subject with CHD who had not undergone surgery, the overall HR was 3.1 (95% CI, 2.8–3.5), whereas the HR was 2.1 (95% CI, 1.8–2.5) after the exclusion of subjects with extracardiac defects or prematurity. The risk of epilepsy remained elevated even when the analysis was further restricted to those subjects with CHD with mild conditions (receiving no intervention) who were without a history of prematurity and extracardiac defects (HR, 1.8; 95% CI, 1.5–2.3).Table. Hazard Ratios of Epilepsy Among Patients With Congenital Heart Disease Compared With a General Population Cohort Matched on Sex and Year of BirthHazard Ratio (95% CI)*Age of Study Subjects0–4 y5–32 yOverall3.7 (3.2–4.2)2.3 (2.1–2.7)Overall†2.5 (2.0–3.2)1.8 (1.5–2.2)Male3.3 (2.7–4.0)2.2 (1.9–2.7)Female4.2 (3.5–5.1)2.4 (2.0–2.9)Year range of birth 1980–19894.6 (3.1–6.8)2.3 (1.8–2.8) 1990–19994.5 (3.6–5.5)2.1 (1.8–2.6) 2000–20103.0 (2.5–3.7)3.3 (2.4–4.4)Congenital heart disease severity‡ Mild and moderate3.8 (3.2–4.5)2.1 (1.8–2.5) Mild and moderate†2.3 (1.7–3.1)1.7 (1.3–2.1) Severe and univentricular heart3.6 (2.8–4.5)2.8 (2.3–3.4) Severe and univentricular heart†3.1 (2.1–4.5)2.2 (1.6–3.0)*Adjusted for sex and birth year.†Excluding those with extracardiac defects or syndromes and preterm birth.‡Mild includes the same diagnoses as in the moderate category but without history of intervention. Moderate includes atrial septal defect, ventricular septal defect, coarctation of the aorta, and patent ductus arteriosus. Severe includes tetralogy of Fallot, transposition of the great arteries, and atrioventricular canal defect.Our data indicate that subjects with CHD who did not undergo surgery demonstrate an elevated risk of epilepsy. This finding suggests that nonsurgical factors such as relative fetal hypoxia secondary to abnormal regulation of prenatal cerebral oxygen supply may induce neurodevelopmental changes consistent with studies evaluating fetal oxygen delivery and consumption by fetal magnetic resonance scans. As a result, these subjects have an elevated risk of abnormal neurological outcomes even without any surgical intervention, which may translate to lifelong morbidity, including epilepsy. However, these mechanisms may not pertain to fetuses with all forms of CHD. Other fetal exposures such as maternal epileptic status and in utero exposure to antiepileptic drugs may also partly explain the observed association. The prevalence of CHD among infants born to mothers with epilepsy is 1.5% to 2%, which is greater than the prevalence for infants born to mothers without epilepsy.4 However, the low prevalence of maternal epilepsy in the CHD cohort renders it unlikely that a possible genetic disposition for epilepsy and in utero exposure to antiepileptic drugs were the only mechanisms underpinning the heightened risk of epilepsy in the CHD cohort. In addition, genetic mutations have been identified that are partially associated with the coexistence of CHD and neurodevelopmental disabilities.5 Therefore, there may be an as-yet-undiscovered genetic explanation for the heighted risk of epilepsy in the CHD population.The potential limitations of this observational study must be considered in the interpretation of the results. Because this study is based on population-based data sources with virtually complete follow-up, selection bias should have a minimal impact. Studies report a high positive predictive value of a CHD diagnosis in this data set. Sensitivity analyses indicate that the association between CHD and epilepsy is not explained by misdiagnosed epilepsy arising as a result of postoperative seizure activity. Coupling these results with the expectation that the vast majority of individuals with epilepsy, with or without CHD, are manifesting symptoms that are clinically apparent, it is unlikely that surveillance bias substantially affects our results.This study is novel in that it identifies a higher risk of epilepsy in the adult CHD population with long-term follow-up. Although further studies need to be conducted to validate these findings, it may be prudent to begin with an emphasis on the examination of the mechanisms that may underpin this relationship, especially as it relates to nonsurgical exposures.Michelle Z. Leisner, MPHNicolas L. Madsen, MD, MPHJohn R. Ostergaard, MD, DMScJessica G. Woo, PhDBradley S. Marino, MD, MPP, MSCEMorten S. Olsen, MD, PhDSources of FundingThe study was supported by grants from the Danish Children's Heart Foundation and the Cincinnati Children's Hospital, Heart Institute Research Fund.DisclosuresNone.FootnotesCirculation is available at http://circ.ahajournals.org.Correspondence to: Michelle Z. Leisner, MPH, Department of Clinical Epidemiology, Aarhus University Hospital, Olof Palmes Allé 43-45, 8200, Aarhus N, Denmark. E-mail [email protected]References1. Marino BS, Lipkin PH, Newburger JW, Peacock G, Gerdes M, Gaynor JW, Mussatto KA, Uzark K, Goldberg CS, Johnson WH, Li J, Smith SE, Bellinger DC, Mahle WT; American Heart Association Congenital Heart Defects Committee, Council on Cardiovascular Disease in the Young, Council on Cardiovascular Nursing, and Stroke Council. Neurodevelopmental outcomes in children with congenital heart disease: evaluation and management: a scientific statement from the American Heart Association.Circulation. 2012; 126:1143–1172. doi: 10.1161/CIR.0b013e318265ee8a.LinkGoogle Scholar2. Billett J, Cowie MR, Gatzoulis MA, Vonder Muhll IF, Majeed A. Comorbidity, healthcare utilisation and process of care measures in patients with congenital heart disease in the UK: cross-sectional, population-based study with case-control analysis.Heart. 2008; 94:1194–1199. doi: 10.1136/hrt.2007.122671.CrossrefMedlineGoogle Scholar3. Massin MM, Astadicko I, Dessy H. Noncardiac comorbidities of congenital heart disease in children.Acta Paediatr. 2007; 96:753–755. doi: 10.1111/j.1651-2227.2007.00275.x.CrossrefMedlineGoogle Scholar4. Pennell PB. Pregnancy in the woman with epilepsy: maternal and fetal outcomes.Semin Neurol. 2002; 22:299–308. doi: 10.1055/s-2002-36649.CrossrefMedlineGoogle Scholar5. Homsy J, Zaidi S, Shen Y, Ware JS, Samocha KE, Karczewski KJ, DePalma SR, McKean D, Wakimoto H, Gorham J, Jin SC, Deanfield J, Giardini A, Porter GA, Kim R, Bilguvar K, López-Giráldez F, Tikhonova I, Mane S, Romano-Adesman A, Qi H, Vardarajan B, Ma L, Daly M, Roberts AE, Russell MW, Mital S, Newburger JW, Gaynor JW, Breitbart RE, Iossifov I, Ronemus M, Sanders SJ, Kaltman JR, Seidman JG, Brueckner M, Gelb BD, Goldmuntz E, Lifton RP, Seidman CE, Chung WK. De novo mutations in congenital heart disease with neurodevelopmental and other congenital anomalies.Science. 2015; 350:1262–1266. doi: 10.1126/science.aac9396.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Castillo-Pinto C, Carpenter J, Donofrio M, Zhang A, Wernovsky G, Sinha P and Harrar D (2021) Incidence and predictors of epilepsy in children with congenital heart disease, Cardiology in the Young, 10.1017/S1047951121003279, 32:6, (918-924), Online publication date: 1-Jun-2022. Hoashi T, Imai K, Okuda N, Komori M, Kurosaki K and Ichikawa H (2022) Intermediate-term outcomes of deferred Norwood strategy, European Journal of Cardio-Thoracic Surgery, 10.1093/ejcts/ezac099 Ikegawa T, Ono S, Yamamoto K, Shimizu M, Yanagi S, Kim K, Ichikawa Y and Ueda H (2021) A retrospective study of perioperative clinical seizures and epilepsy in children after operation for CHD, Cardiology in the Young, 10.1017/S1047951121005011, (1-7) Evers P, Farkas D, Hjorth C, Khoury M, Olsen M and Madsen N (2021) Return to work following adverse cardiovascular events in adults with congenital heart disease, International Journal of Cardiology Congenital Heart Disease, 10.1016/j.ijcchd.2021.100160, 4, (100160), Online publication date: 1-Aug-2021. Goldstein S and Goldstein L (2021) Neurologic complications of congenital heart disease in adults Heart and Neurologic Disease, 10.1016/B978-0-12-819814-8.00011-1, (15-22), . Pulcine E and deVeber G (2021) Neurologic complications of pediatric congenital heart disease Heart and Neurologic Disease, 10.1016/B978-0-12-819814-8.00010-X, (1-13), . Peyvandi S, Fox C and Nash K (2021) Neurologic Complications of Congenital Heart Disease and Cardiac Surgery in Children Aminoff's Neurology and General Medicine, 10.1016/B978-0-12-819306-8.00004-6, (53-63), . Haga T (2020) Characteristics of Patients With Congenital Heart Disease Requiring ICU Admission From Japanese Emergency Departments*, Pediatric Critical Care Medicine, 10.1097/PCC.0000000000002440, 21:12, (e1106-e1112), Online publication date: 1-Dec-2020. Ghosh S, Philip J, Patel N, Munoz-Pareja J, Lopez-Colon D, Bleiweis M and Winesett S (2020) Risk Factors for Seizures and Epilepsy in Children With Congenital Heart Disease, Journal of Child Neurology, 10.1177/0883073820904912, 35:7, (442-447), Online publication date: 1-Jun-2020. Raissadati A, Haukka J, Pätilä T, Nieminen H and Jokinen E (2020) Chronic Disease Burden After Congenital Heart Surgery: A 47‐Year Population‐Based Study With 99% Follow‐Up, Journal of the American Heart Association, 9:9, Online publication date: 5-May-2020. Desnous B, Lenoir M, Doussau A, Marandyuk B, Beaulieu-Genest L, Poirier N, Carmant L and Birca A (2019) Epilepsy and seizures in children with congenital heart disease: A prospective study, Seizure, 10.1016/j.seizure.2018.11.011, 64, (50-53), Online publication date: 1-Jan-2019. Kratzert W and Schwarzenberger J (2019) Sedation in ACHD Intensive Care of the Adult with Congenital Heart Disease, 10.1007/978-3-319-94171-4_8, (131-156), . Kratzert W, Boyd E and Schwarzenberger J (2018) Management of the Critically Ill Adult With Congenital Heart Disease, Journal of Cardiothoracic and Vascular Anesthesia, 10.1053/j.jvca.2017.11.025, 32:4, (1682-1700), Online publication date: 1-Aug-2018. Bagge C, Henderson V, Laursen H, Adelborg K, Olsen M and Madsen N (2018) Risk of Dementia in Adults With Congenital Heart Disease, Circulation, 137:18, (1912-1920), Online publication date: 1-May-2018. November 22, 2016Vol 134, Issue 21 Advertisement Article InformationMetrics © 2016 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.116.024538PMID: 27881510 Manuscript receivedMay 13, 2016Manuscript acceptedSeptember 28, 2016Originally publishedNovember 22, 2016 Keywordscohort studiespopulationepilepsyheart defects, congenitalPDF download Advertisement SubjectsCongenital Heart Disease
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