Sun et al Epidemiology. Volume 17, Number 3, May 2006 consistent with those of the 2 previous studies. 4. 2Our study similar to those of previous studies from other industrialized further showed that changes in Apgar scores from 1 to 5 countries. Some children in our study arbitrarily received an minutes played a role, and we also found an association that Apgar score of zero if they were transferred to another depart persisted into early adulthood. ment immediately after birth(0. 4% for 1-and 0. 2% for 5-minute Apgar score is a nonspecific assessment of the neonates Apgar score) and some children had missing Apgar scores for hortly after birth, and low Apgar scores are not specific to unknown reasons(0.6% for 1- and 1. 1% for 5-minute Apgar birth asphyxia. 24,25Congenital malformations, infections, and score). These children had a slightly higher rate of epilepsy than administration of drugs to the mother can also lead to low those with an Apgar score of 10 scores.-We know of only few studies on the effect of early Our findings call for more research focusing on a fetal perinatal environmental factors and the risk of epilepsy.- and perinatal origin of epilepsy. Potential causal candidates Most of these studies did not find strong associations, -0 but could be infections, maternal lifestyle factors, maternal com- some studies indicate that neonatal encephalopathy, neonatal plications during pregnancy, and factors related to the deliv- seizures, and epilepsy may be related to brain lesions occur- ery process ring the antepartum pe The combination of low Apgar scores and symptoms of neonatal encephalopathy REFERENCES carried an increased risk of a variety of later minor disabili- 1. Hauser WA, AnnegersJF,Kurland LT.Incidence ties, including epilepsy, among children with normal birth I xkms -eiw-res in Rochester, Minesota: 1935-I weights, no congenital malformation, and no major neuro- 2. Sander JW. The epidemiology of epilepsy revisited. Curr Opin Neurol gic abnormalities. Unfortunately, we have no information 2003:16:165-170 bout neonatal encephalopathy to add to these findin 3. Kjeldsen M, Kyvik Ko, Christensen K, et al. Genetic and environmen- The major strengths of our study are the large sample size, tal factors in epilepsy: a population-based study of 11900 Danish twin airs. Epilepsy Res. 2001: 44: 167-178 information on hospitalization, and the fact that data came from 4. been a, ecrdsyinehrodreg, 2 z. study uniform healthcare system that is free of charge for all patients. 5. Lilienfeld AM, Pasamanick B. Association of maternal and fetal factors Children with low Apgar scores may be followed more closely with the development of epilepsy. I. Abnormalities in the prenatal and for adverse outcomes than those with a normal score for a short paranatal periods. JAMA. 1954: 155: 719-724 time after birth, but probably not for months or years. Apgar 6. Nelson kB, Elenberg JH Predisposing and causative factors in child- cores were recorded prospectively and the diagnosis of epilepsy 7. Rocca WA, Sharbrough FW, Hauser WA, et al. Risk factors for gener- was made independently of these scores, making differential alized tonic-clonic seizures: a population-based case-control study in misclassification an unlikely explanation for the association. It is Rochester, Minnesota. Neurology. 1987; 37: 1315-1322 more likely that nondifferential misclassification attenuates the 8. Rocca WA. Sharbrough FW, Hauser WA, et al. Risk factors for absence eizures: a population-based case-control study in Rochester, Minne- true association sota. Neurology. 1987: 37: 1309-1314 The main weakness of the study is that we had limited 9. Rocca WA, Sharbrough FW, Hauser WA, et al. Risk factors for clinical data. Epilepsy is a heterogeneous disorder, and dif- partial seizures: a population-based case-control study. Ann ogies. We were not able to evaluate whether that was the case 101987:21: 22-31 ferent seizure types and syndromes may have different etiol- 10. Leone M, Bottacchi E, Beghi E, et al. Risk factors for a first generalized nic-clonic seizure in adult life. Neurol Sci. 2002: 23: 99-106. for the association with Apgar scores. The information of 11. Apgar V. A proposal for a new method of evaluation of the newborn epilepsy in our study came from ICD codes. The validity of nfant Curr Res Anesth Analg. 1953: 32: 260-267 the epilepsy diagnosis has been assessed according to Inter 12. Drage J, Kenndy C, Schwarz B. The Apgar score as an index of neonatal national League Against Epilepsy criteria in 188 randomly rtality. A report from the collaborative study of cerebral palsy. Obster elected inpatients and outpatients registered with epilepsy in 13. Moster D, Lie RT, Irgens LM, et al. The association of Apgar score with the National Hospital Register. The epilepsy diagnoses met subsequent death and cerebral palsy: A population-based study in term the definition as recurrent, unprovoked epileptic seizures in infants. J Pediatr. 2001: 138: 798-803 153 patients corresponding to a positive predictive value of 14. Thormgren-Jerneck K, Herbst A. Low 5-minute Apgar score: a popula- 81%(95%CI=75-87%), which is comparable with other tion-based register study of 1 million term births. Obstet Gynecol. population-based register studies. Among the 35 persons 15.Casey BM, McIntire DD, Leveno KJ. The continuing value of the Apgar who did not fulfill the criteria, 14 had had a single episode of score for the assessment of newborn infants. N Engl JMed. 2001344 seizures.Thus, our estimate of the positive predictive value is 16. Nelson KB, Ellenberg JH. Apgar scores as predictors of chronic neuro- conservative, because some of these persons will probably logic disability. Pediatrics. 1981: 68: 36-44 develop epilepsy. There were 2 major changes in the hospital 17. Malig C vil registration system in Denmark. Technical Papers register system during the time of follow up. ICD-10 replaced RS.1996;66:1-6 CD-8 in 1994, and outpatients were included in the register 18. Knudsen LB, Olsen J. The Danish Medical Birth Registry. Dan Med system from 1995. The association between Apgar score and 19. Andersen TE, Madsen M, Jorgensen J, et al. The Danish National darde: The Apgar scoring is made by midwives following stan- 20. Breslow NE, Day NE. Statistical methods in cancer research Volume ized procedures, but unfortunately, the interrater reliability II-the design and analysis of cohort studies. IARC Scientific Publica- nons.1987:82. of Apgar score has not been estimated in Denmark. The distri- 21. Clayton D, Hills M. Statistical Models in Epidemiology.Oxford,New bution of 5-minute Apgar score in our study was, however, York, Tokyo: Oxford University Press: 1993 c 2006 Lippincott Williams c wilkins 第61页 Copyright c Lippincott Williams& Wilkins. Unauthorized reproduction of this article is prohibited
consistent with those of the 2 previous studies.14,23 Our study further showed that changes in Apgar scores from 1 to 5 minutes played a role, and we also found an association that persisted into early adulthood. Apgar score is a nonspecific assessment of the neonates shortly after birth, and low Apgar scores are not specific to birth asphyxia.24,25 Congenital malformations, infections, and administration of drugs to the mother can also lead to low scores.26 –29 We know of only few studies on the effect of early perinatal environmental factors and the risk of epilepsy.4 –10 Most of these studies did not find strong associations,6 –10 but some studies indicate that neonatal encephalopathy, neonatal seizures, and epilepsy may be related to brain lesions occurring in the antepartum period.30 –32 The combination of low Apgar scores and symptoms of neonatal encephalopathy carried an increased risk of a variety of later minor disabilities, including epilepsy, among children with normal birth weights, no congenital malformation, and no major neurologic abnormalities.33 Unfortunately, we have no information about neonatal encephalopathy to add to these findings. The major strengths of our study are the large sample size, the long follow-up time, the low loss to follow up, the reliable information on hospitalization, and the fact that data came from a uniform healthcare system that is free of charge for all patients. Children with low Apgar scores may be followed more closely for adverse outcomes than those with a normal score for a short time after birth, but probably not for months or years. Apgar scores were recorded prospectively and the diagnosis of epilepsy was made independently of these scores, making differential misclassification an unlikely explanation for the association. It is more likely that nondifferential misclassification attenuates the true association. The main weakness of the study is that we had limited clinical data. Epilepsy is a heterogeneous disorder, and different seizure types and syndromes may have different etiologies. We were not able to evaluate whether that was the case for the association with Apgar scores. The information of epilepsy in our study came from ICD codes. The validity of the epilepsy diagnosis has been assessed according to International League Against Epilepsy criteria34 in 188 randomly selected inpatients and outpatients registered with epilepsy in the National Hospital Register.35 The epilepsy diagnoses met the definition as recurrent, unprovoked epileptic seizures in 153 patients corresponding to a positive predictive value of 81% (95% CI 75– 87%), which is comparable with other population-based register studies.36 Among the 35 persons who did not fulfill the criteria, 14 had had a single episode of seizures. Thus, our estimate of the positive predictive value is conservative, because some of these persons will probably develop epilepsy. There were 2 major changes in the hospital register system during the time of follow up. ICD-10 replaced ICD-8 in 1994, and outpatients were included in the register system from 1995. The association between Apgar score and epilepsy decreased slightly when outpatients were included. The Apgar scoring is made by midwives following standardized procedures, but unfortunately, the interrater reliability of Apgar score has not been estimated in Denmark. The distribution of 5-minute Apgar score in our study was, however, similar to those of previous studies from other industrialized countries.14,33 Some children in our study arbitrarily received an Apgar score of zero if they were transferred to another department immediately after birth (0.4% for 1- and 0.2% for 5-minute Apgar score) and some children had missing Apgar scores for unknown reasons (0.6% for 1- and 1.1% for 5-minute Apgar score). These children had a slightly higher rate of epilepsy than those with an Apgar score of 10. Our findings call for more research focusing on a fetal and perinatal origin of epilepsy. Potential causal candidates could be infections, maternal lifestyle factors, maternal complications during pregnancy, and factors related to the delivery process. REFERENCES 1. Hauser WA, Annegers JF, Kurland LT. Incidence of epilepsy and unprovoked seizures in Rochester, Minnesota: 1935–1984. Epilepsia. 1993;34:453– 468. 2. Sander JW. The epidemiology of epilepsy revisited. Curr Opin Neurol. 2003;16:165–170. 3. Kjeldsen MJ, Kyvik KO, Christensen K, et al. Genetic and environmental factors in epilepsy: a population-based study of 11900 Danish twin pairs. Epilepsy Res. 2001;44:167–178. 4. Degen R. Epilepsy in children. An etiological study based on their obstetrical records. J Neurol. 1978;217:145–158. 5. Lilienfeld AM, Pasamanick B. Association of maternal and fetal factors with the development of epilepsy. I. Abnormalities in the prenatal and paranatal periods. JAMA. 1954;155:719 –724. 6. Nelson KB, Ellenberg JH. Predisposing and causative factors in childhood epilepsy. Epilepsia. 1987;28(suppl 1):S16 –24. 7. Rocca WA, Sharbrough FW, Hauser WA, et al. Risk factors for generalized tonic– clonic seizures: a population-based case– control study in Rochester, Minnesota. Neurology. 1987;37:1315–1322. 8. Rocca WA, Sharbrough FW, Hauser WA, et al. Risk factors for absence seizures: a population-based case– control study in Rochester, Minnesota. Neurology. 1987;37:1309 –1314. 9. Rocca WA, Sharbrough FW, Hauser WA, et al. Risk factors for complex partial seizures: a population-based case– control study. Ann Neurol. 1987;21:22–31. 10. Leone M, Bottacchi E, Beghi E, et al. Risk factors for a first generalized tonic– clonic seizure in adult life. Neurol Sci. 2002;23:99 –106. 11. Apgar V. A proposal for a new method of evaluation of the newborn infant. Curr Res Anesth Analg. 1953;32:260 –267. 12. Drage J, Kenndy C, Schwarz B. The Apgar score as an index of neonatal mortality. A report from the collaborative study of cerebral palsy. Obstet Gynecol. 1964;24:222–230. 13. Moster D, Lie RT, Irgens LM, et al. The association of Apgar score with subsequent death and cerebral palsy: A population-based study in term infants. J Pediatr. 2001;138:798 – 803. 14. Thorngren-Jerneck K, Herbst A. Low 5-minute Apgar score: a population-based register study of 1 million term births. Obstet Gynecol. 2001;98:65–70. 15. Casey BM, McIntire DD, Leveno KJ. The continuing value of the Apgar score for the assessment of newborn infants. N Engl J Med. 2001;344: 467– 471. 16. Nelson KB, Ellenberg JH. Apgar scores as predictors of chronic neurologic disability. Pediatrics. 1981;68:36 – 44. 17. Malig C. The civil registration system in Denmark. Technical Papers IIVRS. 1996;66:1– 6. 18. Knudsen LB, Olsen J. The Danish Medical Birth Registry. Dan Med Bull. 1998;45:320 –323. 19. Andersen TF, Madsen M, Jorgensen J, et al. The Danish National Hospital Register. Dan Med Bull. 1999;46:263–268. 20. Breslow NE, Day NE. Statistical methods in cancer research Volume II—the design and analysis of cohort studies. IARC Scientific Publications. 1987;82. 21. Clayton D, Hills M. Statistical Models in Epidemiology. Oxford, New York, Tokyo: Oxford University Press; 1993. Sun et al Epidemiology • Volume 17, Number 3, May 2006 300 © 2006 Lippincott Williams & Wilkins 第 61 页
Epidemiology. Volume 17, Number 3, May 2006 Apgar Scores and Risk of Epile 22. Breslow NE. Generalized linear models: checking assumptions and 30. Okumura A, Watanabe K, Negoro T, et al. MRI findings in patients with lengthening conclusions. Statistica Applicata. 1996; 8: 23-41 symptomatic localization-related epilepsies beginning in infancy and 23. Sidenvall R, Heijbel J, Blomquist HK, et al. An incident case-control arly childhood Seizure. 2000: 9: 566-571 study of first unprovoked afebrile seizures in children: a population- 31. Leth H, Toft PB, Herning M, et al. Neonatal seizures associated with nd perinatal risk factors, Epilepsia. 2001: 42: 126 ral lesions shown by magnetic resonance imaging. Arch Dis Chi Fetal Neonatal Ed. 1997: 77: F105-110 24. Nelson KB. Defining hypoxic-ischemic birth events. Dev Med Child 32. Blackwell SC, Refuerzo JS, Wolfe HM, et al. The relationship between euro.2003:45:71-72 nucleated red blood cell counts and early-onset neonatal seizures. A J 25. Use and abuse of the Apgar score. Committee on Fetus and Newbor Obstet gyneco.2000;182:1452-1457 American Academy of Pediatrics, and Committee on Obstetric Practice, 33. Moster D, Lie RT, Markestad T Joint association of Apgar merican College of Obstetricians and Gynecologists. Pediatrics. 1996 early neonatal symptoms with minor disabilities at school age. Arch Dis Child fetal neonatal ed 2002: 86: F16-21 26. Alexander JM, McIntire DM, Leveno K. Chorioamnionitis and the 34. Proposal for revised classificatio prognosis for term infants. Obstet Gynecol. 1999 94: 274-278 Commission on Classification and Terminology of the International 27. Kallen B Neonate charact ate pregnancy. Arch Pediatr Adolesc Med. 2004: 158: 312-316 35. Christensen J, Vestergaard M, Petersen MG, et al. Epilepsy in Denmark 28. Linhart Y, Bashiri A, Maymon E, et al. Congenital anomalies are cidence, prevalence and validation of diagnosis [Abstract. Epilepsia. tal mortality in 2005:46upl6):S386 reterm birth. Eur J Obstet Gynecol Reprod Biol. 2000; 90: 43-49 36. Tomson T, Forsgren L. Mortality studies in epilepsy. In: Jallon P, Berg 29. Alexander GR, Himes JH, Kaufman RB, et al. A United States national reference for fetal growth. Obstet Gynecol. 1996: 87: 163-168 Libbey Eyrotext Ltd; 2003: 12- o 2006 Lippincott Williams Wilkins 第62页 Copyright c Lippincott Williams& Wilkins. Unauthorized reproduction of this article is prohibited
22. Breslow NE. Generalized linear models: checking assumptions and strengthening conclusions. Statistica Applicata. 1996;8:23– 41. 23. Sidenvall R, Heijbel J, Blomquist HK, et al. An incident case– control study of first unprovoked afebrile seizures in children: a populationbased study of pre- and perinatal risk factors. Epilepsia. 2001;42:1261– 1265. 24. Nelson KB. Defining hypoxic–ischemic birth events. Dev Med Child Neurol. 2003;45:71–72. 25. Use and abuse of the Apgar score. Committee on Fetus and Newborn, American Academy of Pediatrics, and Committee on Obstetric Practice, American College of Obstetricians and Gynecologists. Pediatrics. 1996; 98:141–142. 26. Alexander JM, McIntire DM, Leveno KJ. Chorioamnionitis and the prognosis for term infants. Obstet Gynecol. 1999;94:274 –278. 27. Kallen B. Neonate characteristics after maternal use of antidepressants in late pregnancy. Arch Pediatr Adolesc Med. 2004;158:312–316. 28. Linhart Y, Bashiri A, Maymon E, et al. Congenital anomalies are an independent risk factor for neonatal morbidity and perinatal mortality in preterm birth. Eur J Obstet Gynecol Reprod Biol. 2000;90:43– 49. 29. Alexander GR, Himes JH, Kaufman RB, et al. A United States national reference for fetal growth. Obstet Gynecol. 1996;87:163–168. 30. Okumura A, Watanabe K, Negoro T, et al. MRI findings in patients with symptomatic localization-related epilepsies beginning in infancy and early childhood. Seizure. 2000;9:566 –571. 31. Leth H, Toft PB, Herning M, et al. Neonatal seizures associated with cerebral lesions shown by magnetic resonance imaging. Arch Dis Child Fetal Neonatal Ed. 1997;77:F105–110. 32. Blackwell SC, Refuerzo JS, Wolfe HM, et al. The relationship between nucleated red blood cell counts and early-onset neonatal seizures. Am J Obstet Gynecol. 2000;182:1452–1457. 33. Moster D, Lie RT, Markestad T. Joint association of Apgar scores and early neonatal symptoms with minor disabilities at school age. Arch Dis Child Fetal Neonatal Ed. 2002;86:F16 –21. 34. Proposal for revised classification of epilepsies and epileptic syndromes. Commission on Classification and Terminology of the International League Against Epilepsy. Epilepsia. 1989;30:389 –399. 35. Christensen J, Vestergaard M, Petersen MG, et al. Epilepsy in Denmark: incidence, prevalence and validation of diagnosis Abstract. Epilepsia. 2005;46(suppl 6):S386. 36. Tomson T, Forsgren L. Mortality studies in epilepsy. In: Jallon P, Berg AT, Dulac O, et al., eds. Prognosis of Epilepsies. Montrouge: John Libbey Eyrotext Ltd; 2003:12–20. Epidemiology • Volume 17, Number 3, May 2006 Apgar Scores and Risk of Epilepsy © 2006 Lippincott Williams & Wilkins 301 第 62 页
EUROPEAN JOURNAL OF PAEDIATRIC NEUROLOGY I4(20I0)67-72 AEDIATRIC ELSEVIER Official Journal of the European Paediatric Neurology Society Original article Risk factors for epilepsy in children with cerebral palsy Nathanel Zelnik", Muriel Konopnicki, Odeya Bennett-Back Tsofia Castel-Deutsch Emmanuel tirosh The Department of Pediatrics and the Child Development Center, Carmel Medical Center, Rappaport Faculty of Medicine, 7 Michal Street, 34383 Technion, Haifa, Israel bThe Child Development Center, Maccabi Healthcare Services, Haifa, Israel The Child Development Center, Bnai-Zion Medical Center, Rappaport Faculty of Medicine, Technion, Haifa, Israel ARTICLE INF O A BSTRACT The purpose of the study was to identify predictive risk factors for epilepsy among children Received 3 October 2008 with cerebral palsy. We conducted a retrospective study of the clinical characteristics of Received in revised form children with cerebral palsy and epilepsy in comparison to those of children with cerebral 29May2009 palsy without epilepsy. The examined parameters included: the prevalence and the age of Accepted 2 June 2009 onset of the seizures, the clinical subgroup of cerebral palsy and subtype of epileptic seizures. We looked for possible risk factors including the presence of neonatal seizures, Keywords: he imaging findings, the gestational age at delivery, the adjusted birth weight, the mod Epilepsy delivery, the Apgar scores, and the head size as well as the presence of consanguinity palsy Epilepsy occurred in 33% of the studied children. Almost 50% of the epileptic children had their first seizure within the first 12 months of life. Neonatal seizures were strong predictors for epilepsy(p<0.001). Presence of at least one abnormal structural finding (particularly brain atrophy) was also a significant predictor of epilepsy(p< 0.003).Low Apgar score at 5 min after birth and birth at term were also found more frequently among patients with epilepsy, although when adjusted with other risk factors, Apgar score did not reach statistical significance. The mode of delivery, head circumference, adjusted birth weight, gender and ethnic group, consanguineous marriage and prematurity were not found to be risk factors for the occurrence of epilepsy in these children. @2009 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved ntroduction epilepsy was found to be neonatal seizures, 25,, but addi tional data regarding birth history parameters that could During the last decade several publications on the clinical increase the risk for the development of epilepsy in these features of children with both epilepsy and cerebral palsy( cp) children were less consistent9-11 In the present retrospective reported the prevalence and the clinical characteristics of multicenter study we further searched for perinatal and early epilepsy in various forms of CP. It has also been consistently infantile predictive factors that could increase the risk of demonstrated that most of these epilepsies occur at an early epileptogenesis in these children age. -6 The most commonly reported risk factor for later Corresponding author. E-mailaddress:zelnik@netvision.net.il(N.Zelnik) 1090-3798/$-see front matter 2009 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved. doi:10.1016/ j.jpn2009.06.002
Original article Risk factors for epilepsy in children with cerebral palsy Nathanel Zelnika, *, Muriel Konopnickia , Odeya Bennett-Backa , Tsofia Castel-Deutschb , Emmanuel Tiroshc a The Department of Pediatrics and the Child Development Center, Carmel Medical Center, Rappaport Faculty of Medicine, 7 Michal Street, 34383 Technion, Haifa, Israel b The Child Development Center, Maccabi Healthcare Services, Haifa, Israel c The Child Development Center, Bnai-Zion Medical Center, Rappaport Faculty of Medicine, Technion, Haifa, Israel article info Article history: Received 3 October 2008 Received in revised form 29 May 2009 Accepted 2 June 2009 Keywords: Epilepsy Cerebral palsy abstract The purpose of the study was to identify predictive risk factors for epilepsy among children with cerebral palsy. We conducted a retrospective study of the clinical characteristics of children with cerebral palsy and epilepsy in comparison to those of children with cerebral palsy without epilepsy. The examined parameters included: the prevalence and the age of onset of the seizures, the clinical subgroup of cerebral palsy and subtype of epileptic seizures. We looked for possible risk factors including the presence of neonatal seizures, the imaging findings, the gestational age at delivery, the adjusted birth weight, the mode of delivery, the Apgar scores, and the head size as well as the presence of consanguinity. Epilepsy occurred in 33% of the studied children. Almost 50% of the epileptic children had their first seizure within the first 12 months of life. Neonatal seizures were strong predictors for epilepsy ( p < 0.001). Presence of at least one abnormal structural finding (particularly brain atrophy) was also a significant predictor of epilepsy ( p < 0.003). Low Apgar score at 5 min after birth and birth at term were also found more frequently among patients with epilepsy, although when adjusted with other risk factors, Apgar score did not reach statistical significance. The mode of delivery, head circumference, adjusted birth weight, gender and ethnic group, consanguineous marriage and prematurity were not found to be risk factors for the occurrence of epilepsy in these children. ª 2009 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved. 1. Introduction During the last decade several publications on the clinical features of children with both epilepsy and cerebral palsy (CP) reported the prevalence and the clinical characteristics of epilepsy in various forms of CP. It has also been consistently demonstrated that most of these epilepsies occur at an early age.1–6 The most commonly reported risk factor for later epilepsy was found to be neonatal seizures,2,5,7,8 but additional data regarding birth history parameters that could increase the risk for the development of epilepsy in these children were less consistent.9–11 In the present retrospective multicenter study we further searched for perinatal and early infantile predictive factors that could increase the risk of epileptogenesis in these children. * Corresponding author. E-mail address: nzelnik@netvision.net.il (N. Zelnik). Official Journal of the European Paediatric Neurology Society 1090-3798/$ – see front matter ª 2009 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.ejpn.2009.06.002 european journal of paediatric neurology 14 (2010) 67–72 第 63 页