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ORIGINAL ARTICLE Apgar Scores and Long-Term Risk of Epilepsy Yuelian Sun, Mogens Vestergaard, Carsten Bocker Pedersen, Jakob Christensen, t and Jorn Olsens Background: Low Apgar scores are associated with high risk of 100,000 person-years in industrialized countries. There are neonatal death, cerebral palsy, and mental retardation, but the many causes of epilepsy in childhood, including brain tu association between Apgar scores and long-term risk of epilepsy mors, cerebral palsy, and infections. However, for most of remains unresolved epilepsy cases, no clear antecedents have been identified. Methods. We carried out a population-based cohort study of Studies of twins indicate that both genetic and environmental factors play a role in the etiology of epilepsy. Few studies 1,538, 732 live newborns in Denmark between 1 January 1978 and have evaluated the effect of environmental factors originating 31 December 2002 by using national registers. The Apgar scores at or 5 minutes were recorded by midwives following standardized birth weight, preterm birth, toxemias, vaginal bleeding ng in early life; some, 4. but not all, -o have suggested that low procedures. We obtained information on epilepsy by linking the cohort with the National Hospital Register Cohort members were duration of labor may be part of the etiology of epilepsy followed from birth until onset of epilepsy, death, emigration, or 31 Apgar score evaluates newborns based on 5 signs: heart December 2002. whichever came first rate, respiratory effort, reflex irritability, muscle tone, and skin color during the first minutes of life. Each item is Results: The incidence rate of epilepsy increased consistently with scored with a value of 0, 1, or 2, and a total score of 10 3 and 86 per 100,000 person-years for those with a score of 10, the high risk of neonatal death, cerebral palsy, and mental retar- 5. 8-8.8). The incidence rate ratios of epilepsy associated with low dation. One study has reported a higher risk of epilepsy Apgar scores were particularly high in early childhood but remained among children with low Apgar scores, but did not address high into adulthood. The association did not change after excluding this association in detail children with cerebral palsy, congenital malformations, or a parental The aim of this study was to estimate the association history of epilepsy. between low Apgar scores and epilepsy in childhood and Conclusions: Neonates with a suboptimal ave a early adulthood by using a population-based cohort. An higher risk of epilepsy that lasts into adult life findings association between low Apgar scores and epilepsy would suggest that prenatal or perinatal factors play a larger role in the support the hypothesis that prenatal or perinatal factors play etiology of epilepsy than has previously been recognized. a role in the etiology of epilepsy ( Epidemiology2006;17:296-301) METHODS unprovoked seizures. The incidence rate is high in at\ poPulation Sti sy is a serious brain disorder characterized by recur- tem7 to identify all live newborns in Denmark between 1 hildhood,low in adulthood, and high again late in life. I January 1978 and 31 December 2002. They were followed from birth until the onset of epilepsy, death, emigration, or 31 The overall incidence rates range between 40 and 10 per December 2002, whichever came first. The information on deaths and emigration comes from the Danish Civil Regi Submitted 21 June 2005; accepted 14 October 2005 tration System. All live-born children in Denmark are as- From*The Danish Epidemiology Science Centre, Department of Epidemi- signed a unique personal identification number(civil registry ology, Institute of Public Health, and the tNational Centre for Registe based Research, Uni of Aarhus, Aarhus, Denmark; the #Depart- number), which is stored in the Civil Registration System ment of Neurology and Department of Clinical Pharmacology, Aarhus The civil registry number is used as an identification key to University Hospital, Aarhus, Denmark; and the SSchool of Public Health, individual information in all national registers, and it enables Department of Epidemiology, University of California at Los Angeles, accurate linkage of information between registers at the individual level. The study was approved by the Danish Data This study was supported by the Danish National Research Foundation, the Protection Agency. Epidemiology Science Centre, Assessment of Apgar Scores Department of Epidemiology, of Aarhus, Vennelyst Boule- ard 6. DK-8000 Aarhus C. D Information on Apgar scores was obtained from the mail: ys@soci. au. dk. Copyright o 2006 by Lippincott Williams Wilkins Danish Medical Birth Register. Information on Apgar ISSN:1044-398306/1703-0296 scores at 5 minutes after birth was available during the entire DOI:10.1097/01.ede.000020847847401.b6 study period, but information on Apgar scores at 1 minute Epidemiology Volume 17, Number 3, May 2006 第57页 Copyright o Lippincott Williams Wilkins. Unauthorized reproduction of this article is prohibited

ORIGINAL ARTICLE Apgar Scores and Long-Term Risk of Epilepsy Yuelian Sun,* Mogens Vestergaard,* Carsten Bøcker Pedersen,† Jakob Christensen,‡ and Jørn Olsen§ Background: Low Apgar scores are associated with high risk of neonatal death, cerebral palsy, and mental retardation, but the association between Apgar scores and long-term risk of epilepsy remains unresolved. Methods: We carried out a population-based cohort study of 1,538,732 live newborns in Denmark between 1 January 1978 and 31 December 2002 by using national registers. The Apgar scores at 1 or 5 minutes were recorded by midwives following standardized procedures. We obtained information on epilepsy by linking the cohort with the National Hospital Register. Cohort members were followed from birth until onset of epilepsy, death, emigration, or 31 December 2002, whichever came first. Results: The incidence rate of epilepsy increased consistently with decreasing Apgar scores. The incidence rate of epilepsy was 628 per 100,000 person-years for those with 5-minute Apgar scores of 1 to 3 and 86 per 100,000 person-years for those with a score of 10; the resulting incidence rate ratio was 7.1 (95% confidence interval 5.8 – 8.8). The incidence rate ratios of epilepsy associated with low Apgar scores were particularly high in early childhood but remained high into adulthood. The association did not change after excluding children with cerebral palsy, congenital malformations, or a parental history of epilepsy. Conclusions: Neonates with a suboptimal Apgar score have a higher risk of epilepsy that lasts into adult life. These findings suggest that prenatal or perinatal factors play a larger role in the etiology of epilepsy than has previously been recognized. (Epidemiology 2006;17: 296 –301) Epilepsy is a serious brain disorder characterized by recurrent, unprovoked seizures. The incidence rate is high in early childhood, low in adulthood, and high again late in life.1 The overall incidence rates range between 40 and 70 per 100,000 person-years in industrialized countries.2 There are many causes of epilepsy in childhood, including brain tumors, cerebral palsy, and infections. However, for most of epilepsy cases, no clear antecedents have been identified. Studies of twins indicate that both genetic and environmental factors play a role in the etiology of epilepsy.3 Few studies have evaluated the effect of environmental factors originating in early life; some,4,5 but not all,6 –10 have suggested that low birth weight, preterm birth, toxemias, vaginal bleeding, and duration of labor may be part of the etiology of epilepsy. Apgar score evaluates newborns based on 5 signs: heart rate, respiratory effort, reflex irritability, muscle tone, and skin color during the first minutes of life.11 Each item is scored with a value of 0, 1, or 2, and a total score of 10 indicates that the baby is “in the best possible condition.”11 Studies have shown that low Apgar scores are associated with high risk of neonatal death, cerebral palsy, and mental retardation.12–16 One study has reported a higher risk of epilepsy among children with low Apgar scores, but did not address this association in detail.14 The aim of this study was to estimate the association between low Apgar scores and epilepsy in childhood and early adulthood by using a population-based cohort. An association between low Apgar scores and epilepsy would support the hypothesis that prenatal or perinatal factors play a role in the etiology of epilepsy. METHODS Study Population We used data from the Danish Civil Registration System17 to identify all live newborns in Denmark between 1 January 1978 and 31 December 2002. They were followed from birth until the onset of epilepsy, death, emigration, or 31 December 2002, whichever came first. The information on deaths and emigration comes from the Danish Civil Registration System. All live-born children in Denmark are assigned a unique personal identification number (civil registry number), which is stored in the Civil Registration System. The civil registry number is used as an identification key to individual information in all national registers, and it enables accurate linkage of information between registers at the individual level. The study was approved by the Danish Data Protection Agency. Assessment of Apgar Scores Information on Apgar scores was obtained from the Danish Medical Birth Register.18 Information on Apgar scores at 5 minutes after birth was available during the entire study period, but information on Apgar scores at 1 minute Submitted 21 June 2005; accepted 14 October 2005. From *The Danish Epidemiology Science Centre, Department of Epidemiology, Institute of Public Health, and the †National Centre for Registerbased Research, University of Aarhus, Aarhus, Denmark; the ‡Department of Neurology and Department of Clinical Pharmacology, Aarhus University Hospital, Aarhus, Denmark; and the §School of Public Health, Department of Epidemiology, University of California at Los Angeles, Los Angeles, CA. This study was supported by the Danish National Research Foundation, the Danish Medical Research Council (22-02-0363, 22-02-0207), and the Danish Rector’s Conference. Correspondence: Yuelian Sun, The Danish Epidemiology Science Centre, Department of Epidemiology, University of Aarhus, Vennelyst Boulevard 6, DK-8000 Aarhus C, Denmark. E-mail: ys@soci.au.dk. Copyright © 2006 by Lippincott Williams & Wilkins ISSN: 1044-3983/06/1703-0296 DOI: 10.1097/01.ede.0000208478.47401.b6 296 Epidemiology • Volume 17, Number 3, May 2006 第 57 页

Epidemiology. Volume 17, Number 3, May 2006 Apgar Scores and Risk of Epilepsy after birth was accessible only for children born between 1978 and 1996. Midwives recorded Apgar scores after birth TABLE 1. Incidence Rates of Epilepsy According to Selected Characteristics of the Study Population, Denmark, 1978-2002 following standardized procedures. More than 95% of al births in Denmark take place in public hospitals, and mid- ncidence Rat wives report Apgar scores to the registry from the remaining Person-Years No of Persons per 100, 000 home births following the hospital procedures Characteristics at risk With Epilepsy Person-Year Assessment of Epilepsy B Information on epilepsy was obtained from the Na 9,202445 95.0 8,751,255 7717 tional Hospital Register that contains information on all discharges from Danish hospitals since 1977. Outpatients Gestational age(weeks) 305.5 have been included in the register since 1995. Diagnostic Very preterm 146637 information in the National Hospital Register was based on Preterm(33-36) 80,516 he International Classification of Diseases. &th revision Term(37-41) 14,370,16 D-8)from 1977 to 1993, and the International Classifica Posten(≥42) 1,471,843 tion of Diseases, 1 Oth revision(ICD-10) from 1994 to 2002 Cohort members were classified with epilepsy if they had Birth order been hospitalized or had been in outpatient care with a 8,124,750 7548 diagnosis of epilepsy (ICD-8: 345; ICD-10: G40-G41). The 2nd+ 9828950 time of onset of epilepsy was defined as the first day of Multiple birth Single birth 17,533,469 Data Analys Twin or more 419,903 104.3 Unknown The incidence rate ratio of epilepsy was estimated by a Maternal age(years) log-linear Poisson regression model- with the GENMOD 656.046 procedure in SAs version 8.1(SAS institute, Cary, NC). All incidence rate ratios were adjusted for age and its interaction 4,611,950 4528 with sex and for calendar year. Age and calendar year were 25-29 7053,083 treated as time-dependent variables. Age was categorized in 4.165.921 3669 1466.700 from the first birthday to the 19th birthday, and then age intervals of 20-21 and 22-25 as the oldest 2 groups. Calendar Ye 915 year was categorized in a 1-year period from 1978-2002. P 17, 15,855 values were based on likelihood ratio tests and 95% confi dence intervals( CIs)were calculated using Walds test. The 259.1 adjusted score test suggested that the regression models were Uncertain% Unknown not subject to overdispersion 87,508 141.7 17,587,074 RESULTS Parental history of epilepsy Mother 123,468 The study included 1, 538, 732 live-born children. Dur- Fath 100.343 ing 17, 953, 700 person-years of follow up, 16, 455 children Both 6855 were diagnosed with epilepsy corresponding to an average 17,728,284 incidence rate of 91.7 per 100,000 person-years. Table 1 shows the incidence rate of epilepsy according to the selected Congenit formation was suspected but not confirmed. The information about congenital malformation was missing. characteristics of the population The incidence rate of epilepsy increased consistently with decreasing 1-and 5-minute Apgar scores, especially for 5-minute Apgar scores (Table 2). In our study population, 3 at both 1 and 5 minutes had the highest incidence rate ratio 2466(0.16%)had a 5-minute Apgar score of l to 3 and 9047 of 8.03(95%CI=6. 19-10.42)compared with children with (0.59%)of 4 to 6. The average incidence rate of epilepsy an Apgar score of 10 at both measures(Table 3) was 628 per 100,000 person-years for those with 5-minute Incidence rate ratios of epilepsy differed in preterm and Apgar scores of l to 3 and 86 for those with a 5-minute term infants according to 5-minute Apgar scores (P for Apgar score of 10 interaction <0.001). The highest incidence rate ratios were The incidence rate ratios of epilepsy decreased when found among term infants (Table 4). the Apgar score improved from I to 5 minutes. However, the Infants with 5-minute Apgar scores of less than 10 had incidence rate ratios remained higher for infants with low higher incidence rate ratios of epilepsy throughout childhood 1-minute Apgar scores, even if their scores improved to 10 at and early adulthood compared with those with a score of 10 5 minutes compared with children with an Apgar score of 10 The highest incidence rate ratios were found, however, during at both 1 and 5 minutes. Children with Apgar scores of 1 to the first year of life(Fig. 1) o 2006 Lippincott Williams Wilkins 第58页 Copyright c Lippincott Williams& Wilkins. Unauthorized reproduction of this article is prohibited

after birth was accessible only for children born between 1978 and 1996. Midwives recorded Apgar scores after birth following standardized procedures. More than 95% of all births in Denmark take place in public hospitals, and midwives report Apgar scores to the registry from the remaining home births following the hospital procedures. Assessment of Epilepsy Information on epilepsy was obtained from the National Hospital Register that contains information on all discharges from Danish hospitals since 1977.19 Outpatients have been included in the register since 1995. Diagnostic information in the National Hospital Register was based on the International Classification of Diseases, 8th revision (ICD-8) from 1977 to 1993, and the International Classification of Diseases, 10th revision (ICD-10) from 1994 to 2002. Cohort members were classified with epilepsy if they had been hospitalized or had been in outpatient care with a diagnosis of epilepsy (ICD-8: 345; ICD-10: G40 –G41). The time of onset of epilepsy was defined as the first day of contact with the hospital. Data Analysis The incidence rate ratio of epilepsy was estimated by a log-linear Poisson regression model20 with the GENMOD procedure in SAS version 8.1 (SAS institute, Cary, NC). All incidence rate ratios were adjusted for age and its interaction with sex and for calendar year. Age and calendar year were treated as time-dependent variables.21 Age was categorized in 3-month intervals in the first year of life, in 1-year age levels from the first birthday to the 19th birthday, and then age intervals of 20 –21 and 22–25 as the oldest 2 groups. Calendar year was categorized in a 1-year period from 1978 –2002. P values were based on likelihood ratio tests and 95% confi- dence intervals (CIs) were calculated using Wald’s test.21 The adjusted score test suggested that the regression models were not subject to overdispersion.22 RESULTS The study included 1,538,732 live-born children. During 17,953,700 person-years of follow up, 16,455 children were diagnosed with epilepsy corresponding to an average incidence rate of 91.7 per 100,000 person-years. Table 1 shows the incidence rate of epilepsy according to the selected characteristics of the population. The incidence rate of epilepsy increased consistently with decreasing 1- and 5-minute Apgar scores, especially for 5-minute Apgar scores (Table 2). In our study population, 2466 (0.16%) had a 5-minute Apgar score of 1 to 3 and 9047 (0.59%) of 4 to 6. The average incidence rate of epilepsy was 628 per 100,000 person-years for those with 5-minute Apgar scores of 1 to 3 and 86 for those with a 5-minute Apgar score of 10. The incidence rate ratios of epilepsy decreased when the Apgar score improved from 1 to 5 minutes. However, the incidence rate ratios remained higher for infants with low 1-minute Apgar scores, even if their scores improved to 10 at 5 minutes compared with children with an Apgar score of 10 at both 1 and 5 minutes. Children with Apgar scores of 1 to 3 at both 1 and 5 minutes had the highest incidence rate ratio of 8.03 (95% CI 6.19 –10.42) compared with children with an Apgar score of 10 at both measures (Table 3). Incidence rate ratios of epilepsy differed in preterm and term infants according to 5-minute Apgar scores (P for interaction 0.001). The highest incidence rate ratios were found among term infants (Table 4). Infants with 5-minute Apgar scores of less than 10 had higher incidence rate ratios of epilepsy throughout childhood and early adulthood compared with those with a score of 10. The highest incidence rate ratios were found, however, during the first year of life (Fig. 1). TABLE 1. Incidence Rates of Epilepsy According to Selected Characteristics of the Study Population, Denmark, 1978 –2002 Characteristics Person-Years at Risk No. of Persons With Epilepsy Incidence Rate per 100,000 Person-Years Sex Boys 9,202,445 8738 95.0 Girls 8,751,255 7717 88.2 Gestational age (weeks) Very preterm (33) 146,637 448 305.5 Preterm (33–36) 680,516 981 144.2 Term (37–41) 14,370,165 12,721 88.5 Postterm (42) 1,471,843 1356 92.1 Unknown 1,284,540 949 73.9 Birth order 1st 8,124,750 7548 92.9 2nd 9,828,950 8907 90.6 Multiple birth Single birth 17,533,469 16,017 91.4 Twin or more 419,903 438 104.3 Unknown 327 0 0.0 Maternal age (years) 20 656,046 794 121.0 20–24 4,611,950 4528 98.2 25–29 7,053,083 6158 87.3 30–34 4,165,921 3669 88.1 35 1,466,700 1306 89.0 Cerebral palsy Yes 30,915 600 1940.8 No 17,922,785 15,855 88.5 Congenital malformation Yes 250,121 648 259.1 Uncertain* 28,998 40 137.9 Unknown† 87,508 124 141.7 No 17,587,074 15,643 88.9 Parental history of epilepsy Mother 123,468 397 321.5 Father 100,343 221 220.2 Both 1605 11 685.5 Neither 17,728,284 15,826 89.3 *Congenital malformation was suspected but not confirmed. † The information about congenital malformation was missing. Epidemiology • Volume 17, Number 3, May 2006 Apgar Scores and Risk of Epilepsy © 2006 Lippincott Williams & Wilkins 297 第 58 页

Sun et al Epidemiology. Volume 17, Number 3, May 2006 TABLE 2. Incidence Rate Ratios of Epilepsy According to Apgar Scores at 1 and 5 Minutes After Birth, Denmark, 1978-2002 I-Min Apgar Scores Min Apgar Scores Apgar Scores No, of Cases IRR(95% CI) No of cases IRR(95% CD 14,2 987 1.04(1.00-1.09) 1.45(1.35-1.56 1193 1.30(1.22-1.38) 1.89(1.72-2.07 143(1.32-1.55) 221 213 244(2.13-2.78) 1.81(1.69-1.95) 4.22(3.78-4.72) 14(5.798.81) 241(1.97-2.95) 219 208(1.61-2.70) 148(1.26-1.73) 0 1.58(139-1.78) scores were accessible from I January 1978 to 31 December 1996. ar year, age, and sex. APgar scores were registered as zero, including children who were transferred to intensive care immediately after birth. IR indicates incidence rate per 100, 000 person-years: IRR, incidence rate ratio. nce Rate Ratios*(95% CI)of Epilepsy According to Combinations of Apgar Scores at 1 and 5 Min, Denmark, 5-Min Apgar Scores 1-Min Apgar Scores 1-3 4-6 7 0.81(0.37-1.81)1.00 1.52(0.84-2.75)1.20(1.02-141)1.03(0.98-1.08) 1.52(1.15-2.01)1.56(1.36-1.80)1.23(1.15-1.32) 286(1.98-4.15)1.61(1.29201)1.69(1.45-1.96)1.24(1.12-1.38) 401(3.29-4.88)224(1.85-2.72)207(180-2.39)1.70(1.45-1.99)1.31(1.15-1.48) 1-3 803(6.19-10.42)464(3.94-5.4 2.24(1.63-3.08)3.20(2.44-4.19)1.60(1.05-243)165(1.18-232) Reference category. ApRar a (not applicable)indicates the number of person-years at risk was less than 5000, corresponding to fewer than 5 expected cases based on a hypothesis of no association between TABLE 4. Association of 5-Min Apgar Scores With Epilepsy for Babies Born Preterm and Term, Denmark, 1978-2002 Preterm Infants(<37 wk) Term Infants (37-41 wk) 5-Min Apgar Scores No of Cases IRR*(95% Ci) No. of Cases IrR*(95% Ci) 11,416 1.42(1.21-1.67 1.34(1.23-1.46) 1.71(1.41-2.08) 66(1.47-1.88) 1.80(1.38-2.34) 2.37(2.00-281) 75 2.52(1.99-3.18) 441(3.83-5.07) 757 8.68(6.73-11.18) Adjusted for calendar year, age, and sex. Reference category. The association between 5-minute Apgar scores and From 1995 to 2002, 9500 people were diagnosed with epilepsy did not change after excluding infants with cerebral epilepsy, including 1466(15%)only in an inpatient setting, palsy (n= 600), with confirmed or suspected congenital 3443(36%)only in an outpatient setting, and 4591(48%)in malformations(n =812), with parental history of epilepsy both settings. The incidence rates of epilepsy increased when (n= 629), or with any of the 3 ions(Table 5) outpatients were included, especially for children with an 298 c 2006 Lippincott Williams c wilkins 第59页 Copyright c Lippincott Williams& Wilkins. Unauthorized reproduction of this article is prohibited

The association between 5-minute Apgar scores and epilepsy did not change after excluding infants with cerebral palsy (n 600), with confirmed or suspected congenital malformations (n 812), with parental history of epilepsy (n 629), or with any of the 3 conditions (Table 5). From 1995 to 2002, 9500 people were diagnosed with epilepsy, including 1466 (15%) only in an inpatient setting, 3443 (36%) only in an outpatient setting, and 4591 (48%) in both settings. The incidence rates of epilepsy increased when outpatients were included, especially for children with an TABLE 2. Incidence Rate Ratios of Epilepsy According to Apgar Scores at 1 and 5 Minutes After Birth, Denmark, 1978 –2002 Apgar Scores 1-Min Apgar Scores* 5-Min Apgar Scores No. of Cases IR IRR† (95% CI) No. of Cases IR IRR† (95% CI) 10‡ 8998 80 1.00 14,281 86 1.00 9 2606 86 1.04 (1.00–1.09) 791 129 1.45 (1.35–1.56) 8 1193 106 1.30 (1.22–1.38) 441 166 1.89 (1.72–2.07) 7 654 118 1.43 (1.32–1.55) 221 213 2.44 (2.13–2.78) 4–6 819 149 1.81 (1.69–1.95) 319 369 4.22 (3.78–4.72) 1–3 380 286 3.43 (3.10–3.80) 88 628 7.14 (5.79–8.81) 0§ 97 234 2.41 (1.97–2.95) 58 219 2.08 (1.61–2.70) Missing 153 108 1.48 (1.26–1.73) 256 130 1.58 (1.39–1.78) *One-minute Apgar scores were accessible from 1 January 1978 to 31 December 1996. † Adjusted for calendar year, age, and sex. ‡ Reference category. § Apgar scores were registered as zero, including children who were transferred to intensive care immediately after birth. Apgar scores were missing for unknown reasons. IR indicates incidence rate per 100, 000 person-years; IRR, incidence rate ratio. TABLE 3. Incidence Rate Ratios* (95% CI) of Epilepsy According to Combinations of Apgar Scores at 1 and 5 Min, Denmark, 1978 –1996† 1-Min Apgar Scores 5-Min Apgar Scores 1–3 4–6 7 8 9 10 10 NA NA NA NA 0.81 (0.37–1.81) 1.00‡ 9 NA NA NA 1.52 (0.84–2.75) 1.20 (1.02–1.41) 1.03 (0.98–1.08) 8 NA NA NA 1.52 (1.15–2.01) 1.56 (1.36–1.80) 1.23 (1.15–1.32) 7 NA NA 2.86 (1.98–4.15) 1.61 (1.29–2.01) 1.69 (1.45–1.96) 1.24 (1.12–1.38) 4–6 NA 4.01 (3.29–4.88) 2.24 (1.85–2.72) 2.07 (1.80–2.39) 1.70 (1.45–1.99) 1.31 (1.15–1.48) 1–3 8.03 (6.19–10.42) 4.64 (3.94–5.46) 2.24 (1.63–3.08) 3.20 (2.44–4.19) 1.60 (1.05–2.43) 1.65 (1.18–2.32) *Adjusted for calendar year, age and sex. † Data on Apgar scores at one minute were not recorded after 1996. ‡ Reference category. NA (not applicable) indicates the number of person-years at risk was less than 5000, corresponding to fewer than 5 expected cases based on a hypothesis of no association between Apgar score and the risk of epilepsy. TABLE 4. Association of 5-Min Apgar Scores With Epilepsy for Babies Born Preterm and Term, Denmark, 1978 –2002 5-Min Apgar Scores Preterm Infants (<37 wk) Term Infants (37–41 wk) No. of Cases IR IRR* (95% CI) No. of Cases IR IRR* (95% CI) 10† 909 147 1.00 11,416 85 1.00 9 176 207 1.42 (1.21–1.67) 518 117 1.34 (1.23–1.46) 8 118 247 1.71 (1.41–2.08) 257 144 1.66 (1.47–1.88) 7 59 254 1.80 (1.38–2.34) 133 204 2.37 (2.00–2.81) 4–6 75 356 2.52 (1.99–3.18) 197 381 4.41 (3.83–5.07) 1–3 17 423 2.98 (1.84–4.81) 60 757 8.68 (6.73–11.18) *Adjusted for calendar year, age, and sex. † Reference category. Sun et al Epidemiology • Volume 17, Number 3, May 2006 298 © 2006 Lippincott Williams & Wilkins 第 59 页

Epidemiology. Volume 17, Number 3, May 2006 Apgar Scores and Risk of Apgar score of 10, whereas incidence rate ratios of children 三细部 with low Apgar score decreased slightly (Table 6) DISCUSSION The incidence rate of epilepsy increased consistently with decreasing 1-and 5-minute Apgar scores for children born at term or born preterm. The incidence rates of epilepsy decreased when the Apgar scores increased from 1 to 5 minutes, but they remained higher than those of children who had an Apgar score of 10 at both measures. The incidence rate ratios of neonates with low 5-minute Apgar score were particularly high in early childhood and continued to be high throughout the study period of up to 25 years. This associa- tion was not confounded by cerebral palsy, congenital mal 345678910 11 12 13 141525 formations, or a parental history of epilepsy Age (years) The association between Apgar scores and epilepsy has FIGURE 1. Incidence rate ratios and 95% Cls of epilepsy for been the subject of few studies. A case-control study indi- children with 5-minute Apgar scores of 1-6 and 7-9 accord- cated that low Apgar score is a risk factor for first unprovoked ing to age. Adjusted for calendar year, age, and sex. The afebrile seizures among children,and one large population reference group consists of children with a 5-minute Apgar based study showed that children with a 5-minute Apgar score of 1o score below 7 had a higher risk of epilepsy. Our results are TABLE 5. Association of 5-Min Apgar Scores With Epilepsy Among Children Without CP, CM, and PHE* Denmark. 1978-2002 Among Children Among Children Without Congenital Without Any of Without Cerebral Palsy ony of adler the 3 Conditions 5-Min Apgar Scores IRRT(95% CD) IRR’(95%CD IRR(95%CD IRRT(95%CI 39(1.29-1.49) 1.42(1.32-1.53) 45(1.35-1.56)1.35(1.24-1.46) 1.79(1.62-1.98) 78(1.61-1.97 1.90(1.72-2.09) 1.68(1.51-1.87) 222(1.93-2.57) 3.46(3.05-3.92) 4.03(3.59-4.54) 4.31(3.85-4.82)3.37(295-3.86) 1-3 59647-75586498573599958(45-751 CP CM. and PHE indicate cerebral palsy, congenital malformation, parental history of epilepsy, respectivel Adjusted for calendar year, age, and ser Reference category. ABLE 6. Association of 5-Min Apgar Scores With Epilepsy, Including and Excluding Outpatients Denmark. 1995-2002 Inpatients and Outpatients Inpatients* 5-Min Apgar Scores No, of Cases IR IRR(95% CD) IRR(95% CD) 91.31.00 57.31.00 432 120.81.28(1.16-1.41) 817135(1.20-1.52) 10.71.87(1.60-2.18) 17641.90(1.57-2.31) 133.2228(1.82-2.85) 32783.52(3.01-4.12) 250.1425(3.55-5.08) 7756.24(4.67-8.33 460.0789(5.71-10.91) ere refer to patients of epilepsy who were ever treated in an inpatient setting during study period. ADjusted for calendar year, age, and fReference category o 2006 Lippincott Williams Wilkins 299 第60页 Copyright c Lippincott Williams& Wilkins. Unauthorized reproduction of this article is prohibited

Apgar score of 10, whereas incidence rate ratios of children with low Apgar score decreased slightly (Table 6). DISCUSSION The incidence rate of epilepsy increased consistently with decreasing 1- and 5-minute Apgar scores for children born at term or born preterm. The incidence rates of epilepsy decreased when the Apgar scores increased from 1 to 5 minutes, but they remained higher than those of children who had an Apgar score of 10 at both measures. The incidence rate ratios of neonates with low 5-minute Apgar score were particularly high in early childhood and continued to be high throughout the study period of up to 25 years. This association was not confounded by cerebral palsy, congenital malformations, or a parental history of epilepsy. The association between Apgar scores and epilepsy has been the subject of few studies. A case– control study indicated that low Apgar score is a risk factor for first unprovoked afebrile seizures among children,23 and one large populationbased study showed that children with a 5-minute Apgar score below 7 had a higher risk of epilepsy.14 Our results are FIGURE 1. Incidence rate ratios and 95% CIs of epilepsy for children with 5-minute Apgar scores of 1– 6 and 7–9 according to age. Adjusted for calendar year, age, and sex. The reference group consists of children with a 5-minute Apgar score of 10. TABLE 5. Association of 5-Min Apgar Scores With Epilepsy Among Children Without CP, CM, and PHE,* Denmark, 1978 –2002 5-Min Apgar Scores Among Children Without Cerebral Palsy Among Children Without Congenital Malformation Among Children Without Parental History of Epilepsy Among Children Without Any of the 3 Conditions IRR† (95% CI) IRR† (95% CI) IRR† (95% CI) IRR† (95% CI) 10‡ 1.00 1.00 1.00 1.00 9 1.39 (1.29–1.49) 1.42 (1.32–1.53) 1.45 (1.35–1.56) 1.35 (1.24–1.46) 8 1.79 (1.62–1.98) 1.78 (1.61–1.97) 1.90 (1.72–2.09) 1.68 (1.51–1.87) 7 2.13 (1.84–2.46) 2.22 (1.93–2.57) 2.46 (2.15–2.82) 1.92 (1.64–2.25) 4–6 3.46 (3.05–3.92) 4.03 (3.59–4.54) 4.31 (3.85–4.82) 3.37 (2.95–3.86) 1–3 5.96 (4.70–7.55) 6.86 (5.49–8.57) 7.35 (5.95–9.09) 5.81 (4.50–7.51) *CP, CM, and PHE indicate cerebral palsy, congenital malformation, parental history of epilepsy, respectively. † Adjusted for calendar year, age, and sex. ‡ Reference category. TABLE 6. Association of 5-Min Apgar Scores With Epilepsy, Including and Excluding Outpatients, Denmark, 1995–2002 5-Min Apgar Scores Inpatients and Outpatients Inpatients* No. of Cases IR IRR† (95% CI) No. of Cases IR IRR† (95% CI) 10‡ 8362 91.3 1.00 5255 57.3 1.00 9 432 120.8 1.28 (1.16–1.41) 293 81.7 1.35 (1.20–1.52) 8 234 153.8 1.65 (1.44–1.87) 169 110.7 1.87 (1.60–2.18) 7 103 176.4 1.90 (1.57–2.31) 78 133.2 2.28 (1.82–2.85) 4–6 159 327.8 3.52 (3.01–4.12) 122 250.1 4.25 (3.55–5.08) 1–3 46 577.5 6.24 (4.67–8.33) 37 460.0 7.89 (5.71–10.91) *Inpatients here refer to patients of epilepsy who were ever treated in an inpatient setting during study period. † Adjusted for calendar year, age, and sex. ‡ Reference category. Epidemiology • Volume 17, Number 3, May 2006 Apgar Scores and Risk of Epilepsy © 2006 Lippincott Williams & Wilkins 299 第 60 页

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

EUROPEAN JOURNAL OF PAEDIATRIC NEUROLOGY I4(20I0)67-72 Patients and methods (for gestational age beyond 42 weeks of gestation). Since the subjects of the study included both term infants and preterm nfants(bom at a wide range of gestational ages), we used their Patients selected for this retrospective region-based survey of gestational age adjusted birth weights as appropriate indica children with CP included 197 children aged 0-12 years tors for intra-uterine growth rather than their actual birth (117 males, 80 females)with CP whose medical records were weights. These birth weights were classified as: small for the Haifa district in Israel (The Clalit Healthcare Services, The gestational age based on Usher McLean intra-uterine growth Bnai-Zion Medical Center, and the Maccabi Healthcare charts. 13 For all patients the mode of delivery was classified as Services). Children with CP bon after 1993 were included in normal delivery, instrumental(forceps or vacuum extraction the study. All patients entered the child development centers delivery and cesarean section. This group was further divided prior to age 5, most of them during the first two years of lif into children that were born by elective cesarean section and During the years 2005-2006 when the data on these patients those who were born by an urgent cesarean section due to was collected, the mean age of the patients was7.2+3.0 years, labor complication or acute fetal distress. Apgar score was Range 1.4-12.8 years It should be noted that the data collected defined as high if it was above 7 at one minute or equal to 8 or covered seizures that occurred from birth to 12.8 years. One above at five minutes: as moderate when it was between 4 and hundred and three patients(52.3% were of Jewish ancestry, 88 6 at one minute or between 4 and 7 at ive minutes and as low (44.7%were of Arab ancestry and 6(3.0%)were of other score when it was less than or equal to 3 at one and five evelopmental disorders in this area are referred to these guinity and the presence of neonatal seizures. The research enters, these patients represent the vast majority of the was approved by the Helsinki committee of all the three children with CP in this region. The remaining patients belong agencies collaborating in this study a medical insurance group that did not participate in the Statistics, in 2006 there were 145,000 children(age range 0-13 variables and odds ratio and 95% CI were calculated e test Data analysis was performed using SPSS. Chi-squar study. According to the Government Central Bureau of was used to assess the relationship between categorical years)in the Haifa region which means that the prevalence of In groups with a small number of patients the Fisher Exact CP in the region is at least 1.35: 1000, 95% CI(1.169, 1.548). test was employed. T-test was used to compare continuous Children variables between two independent groups. Multivariate ompared with children with CP without epilepsy logistic regression was used to asses the influence of different The clinical types of CP were divided into five variants sk factors for the development of epilepsy. Odds ratio and hemiplegia, quadriplegia, diplegia, dyskinesia, and ataxia- 95% confidence interval were calculated from the model. All p hypotonia. Whether treated or not, epilepsy was defined as the values were two-sided, and statistical significance was presence of two or more non-febrile seizures beyond the defined as p<0.05 neonatal period. We classified the seizures according to the modified criteria of the International League against Epilepsy into 7 clinical subtypes: infantile spasms, partial seizure (without or with secondary generalization), generalized tonic. 3. Results clonic seizures(GTCS), myoclonic seizures, atonic and/or tonic seizures with or without atypical absences, typical absenc 3.1. Epilepsy, neonatal seizures and seizures and non-classified seizures. In cases where seizures were mixed or changed with time, we referred to the seizure Sixty-five children(33.0%)with CP developed epilepsy.of type at the earliest presentation of the epileptic seizures (but these, thirty two children (49.2%) had their first seizures after the neonatal period). Imaging data such as computed (beyond the neonatal period) during the first 12 months and45 tomography (Cr) and magnetic resonance imaging(MRI) children(69. 2%)had their first seizure during the first two findings were classified as: non-specific atrophy, brain mal formations, primarily gray matter lesions (including infarcts) primanly white matter lesions (including periventricular leu normalimaging. Thinning of the corpus callosum due to white s komalacia), hydrocephalus, intracranial-hemorrhage, and atter atrophy was considered as white matter lesions rather a20 than being a cerebral malformation Cases with non-specific 8 atrophy associated with additional specific changes were classified according to the latter Head size(at time of admis sion to the child development center) was defined as: normo- cephalic, microcephalic (below 2nd percentile),or acrocephalic (above 98th percentile). The gestational age of the patients at birth was classified as: term infants(for gesta- tional age between 38 and 41 weeks), preterm infants(for age(years) a gestational age between 30 and 37 weeks), extreme preterm Fig. 1- The number of patients with epilepsy onset at each (for a gestational age below 30 weeks) and post-term infants 第64°

2. Patients and methods Patients selected for this retrospective region-based survey of children with CP included 197 children aged 0–12 years (117 males, 80 females) with CP whose medical records were retrieved from the three main child development centers of the Haifa district in Israel (The Clalit Healthcare Services, The Bnai-Zion Medical Center, and the Maccabi Healthcare Services). Children with CP born after 1993 were included in the study. All patients entered the child development centers prior to age 5, most of them during the first two years of life. During the years 2005–2006 when the data on these patients was collected, the mean age of the patients was 7.2 3.0 years; Range 1.4–12.8 years. It should be noted that the data collected covered seizures that occurred from birth to 12.8 years. One hundred and three patients (52.3%) were of Jewish ancestry, 88 (44.7%) were of Arab ancestry and 6 (3.0%) were of other origins. Since more than 90% of all the children with neurodevelopmental disorders in this area are referred to these centers, these patients represent the vast majority of the children with CP in this region. The remaining patients belong to a medical insurance group that did not participate in the study. According to the Government Central Bureau of Statistics, in 2006 there were 145,000 children (age range 0–13 years) in the Haifa region which means that the prevalence of CP in the region is at least 1.35:1000, 95% CI (1.169, 1.548). Children who subsequently developed epilepsy were compared with children with CP without epilepsy. The clinical types of CP were divided into five variants: hemiplegia, quadriplegia, diplegia, dyskinesia, and ataxiahypotonia. Whether treated or not, epilepsy was defined as the presence of two or more non-febrile seizures beyond the neonatal period. We classified the seizures according to the modified criteria of the International League against Epilepsy12 into 7 clinical subtypes: infantile spasms, partial seizure (without or with secondary generalization), generalized tonicclonic seizures (GTCS), myoclonic seizures, atonic and/or tonic seizures with or without atypical absences, typical absence seizures and non-classified seizures. In cases where seizures were mixed or changed with time, we referred to the seizure type at the earliest presentation of the epileptic seizures (but after the neonatal period). Imaging data such as computed tomography (CT) and magnetic resonance imaging (MRI) findings were classified as: non-specific atrophy, brain malformations, primarily gray matter lesions (including infarcts), primarily white matter lesions (including periventricular leukomalacia), hydrocephalus, intracranial-hemorrhage, and normal imaging. Thinning of the corpus callosum due to white matter atrophy was considered as white matter lesions rather than being a cerebral malformation. Cases with non-specific atrophy associated with additional specific changes were classified according to the latter. Head size (at time of admission to the child development center) was defined as: normocephalic, microcephalic (below 2nd percentile), or macrocephalic (above 98th percentile). The gestational age of the patients at birth was classified as: term infants (for gestational age between 38 and 41 weeks), preterm infants (for a gestational age between 30 and 37 weeks), extreme preterm (for a gestational age below 30 weeks) and post-term infants (for gestational age beyond 42 weeks of gestation). Since the subjects of the study included both term infants and preterm infants (born at a wide range of gestational ages), we used their gestational age adjusted birth weights as appropriate indicators for intra-uterine growth rather than their actual birth weights. These birth weights were classified as: small for gestational age, appropriate for gestational age, and large for gestational age based on Usher & McLean intra-uterine growth charts.13 For all patients the mode of delivery was classified as: normal delivery, instrumental (forceps or vacuum extraction) delivery and cesarean section. This group was further divided into children that were born by elective cesarean section and those who were born by an urgent cesarean section due to labor complication or acute fetal distress. Apgar score was defined as high if it was above 7 at one minute or equal to 8 or above at five minutes; as moderate when it was between 4 and 6 at one minute or between 4 and 7 at five minutes and as low score when it was less than or equal to 3 at one and five minutes. We also looked in all patients for parental consanguinity and the presence of neonatal seizures. The research was approved by the Helsinki committee of all the three agencies collaborating in this study. Data analysis was performed using SPSS. Chi-square test was used to assess the relationship between categorical variables and odds ratio and 95% CI were calculated. In groups with a small number of patients the Fisher Exact test was employed. T-test was used to compare continuous variables between two independent groups. Multivariate logistic regression was used to asses the influence of different risk factors for the development of epilepsy. Odds ratio and 95% confidence interval were calculated from the model. All p values were two-sided, and statistical significance was defined as p < 0.05. 3. Results 3.1. Epilepsy, neonatal seizures and CP Sixty-five children (33.0%) with CP developed epilepsy. Of these, thirty two children (49.2%) had their first seizures (beyond the neonatal period) during the first 12 months and 45 children (69.2%) had their first seizure during the first two 0 5 10 15 20 25 30 35 0-1 1-2 2-3 3-4 4-5 5-6 6-7 7-8 8-9 9-12 age (years) number of patients Fig. 1 – The number of patients with epilepsy onset at each age (N [ 65). 68 european journal of paediatric neurology 14 (2010) 67–72 第 64 页

EUROPEAN JOURNAL OF PAEDIATRIC NEUROLOGY I4(20I0)67-72 Table 1- The clinical subgroups of CP in the epileptic and the non-epileptic children and their respective type of epilepsy. CP subgroup CP Onl CP Epilepsy(epilepsy subtypes) Total 18(27.7%)infantile spasms 2, partial seizures 9 70(355%) 5, atonic/tonic sz 1, not classified 1] 2. Diplegia 35(265% 7(10.8%)partial seizures 2, GTCS 3, myoclonic sz 1, 42(213% 1 32(49.2%)[infantile spasms 3, partial seizures 6, GTCS 13, onic/tonic sz 5, myoclonic sz 2, not classified 3 13(9.9% 5(7.7%)partial seizures 2, GTCS 1, myoclonic sz 1, 1 5. Dyskinetic/mixed (6.8%) 3(4.6%)infantile spasms 2, atonic/tonic sz 1] 12(6.1%) Total 132(100%) 65(100%)infantile spasms 7, partial seizures 19, GTCS 97(100%) tonic/tonic sz 8, myoclonic sz 4, not classified 51 Abbreviations: CP-cerebral palsy, GTCS- generalized tonic-clonic seizures, and sz- seizures years of life; an additional 16 children had their first seizure 3.3. Birth history between the second and sixth year of age and only 4 children (6.2%)developed their epilepsy beyond 6 years(Fig. 1). The gestational age of the patients at birth was recorded in 190 The clinical subtypes of CP among the epileptic and the (96.4%)of the children with CP In the group of children with non-epileptic patients and the clinical epilepsy subgroups are epilepsy 41(65.1%)were term infants and 20(31.7%)were shown in Table 1, demonstrating that epilepsy was particu- preterm infants(6 of which were extreme preterm). In the larly common in patients with quadriplegia(58.2% VS. 23.2%), group of children without epilepsy 56(44.1%)were term OR=459,95%CI(2.37-891),p<0.001. The mean age infants while 69(54.4% were bom pretermly (34 of which were seizures onset was 1.8+2.0 years. The prevalence of epilepsy extreme preterm). Four children(2 in each group)were post was consistent across ethnic groups(p=0.13)and genders term infants. An increased prevalence of epilepsy was noted (p=0.62). Twenty-seven children with CP had documented in the term infants(p<0.01) neonatal seizures. Twenty two of them( 81.5%)subsequently The mode of delivery was recorded in 178(90.4%)children. had epilepsy, OR=12.99, 95%CI (4.64-36. 43), p<0.001. Out of Normal vaginal delivery was conducted in 29(49.1%)children ninety seven term infants, thirteen children had a history of with epilepsy and 54(45.4%)children without epilepsy neonatal seizures (12 of them subsequently developed Instrumental delivery was conducted in only 6 children with epilepsy), and of the 89 preterm infants, 14 children had epilepsy and 5 children without epilepsy. Caesarian sections neonatal seizures (10 of them subsequently developed were relatively common and performed in 24(40.7%)of chil epilepsy). Most of the children with neonatal seizures who dren with epilepsy(15 of which were urgent) 504%)of later developed epilepsy had quadriplegia(54.5%)and hemi- children without epilepsy (24 of which were urgent). None of plegia(27. 2%). The types of epilepsies that were preceded by these modes of delivery was found as a significant risk factor neonatal seizures were predominantly GTCS (59.0%), partial for developing epilepsy(p=0.2). Urgent caesarian sections seizures(18.2%)and infantile spasms(18.2%). One additional infant had unclassified seizures Table 2- The imaging findings in the epileptic and the non-epileptic children 3. 2. Imaging data Imaging CP Only CP Epilepsy Total The imaging findings were available for 148 children which Normal imaging 25(287%10(164%)35(236% encompass 75.1% of all the subjects(Table 2). For 72 patients CT Abnormal Imaging (713%)51(836%)113(764% scans were available, for 48 patients MRI scans were available Non-specific atrophy (4.6%)11(180%)16(10.8% d for 28 patients both CT and MRI scans were available In 49 Grey matter insult 14(161%)17(27.9%)31(210% patients we had no data or they had documented head ultra- (including infarctions) only during early infancy. Abnormal White matter insult 16(18 4(115%)23(155% imaging was more common in CP children with epilepsy as (including PVL) compared to children without epilepsy(p<0.003). Within the Cerebral malformations 10(11. 5%) 7(11.5%) (115% patients with abnormal imaging findings only cerebral atrophy Hydrocephalus 5(5.7%) 5(82% 8(54% was more common in children with epilepsy, than in children Brain Hemorrhage 13(14.9%) 7(11.5%) 20(13. 5% without epilepsy (p<0.012). Children with infarcts and gray (including IVH) matter disease were somewhat more prone to develop epilepsy, Total 87(100%)61(100%)148(100%) the small number of patients in each group these differences did intraventricular Hemorrhage not reach statistical significance 第65页

years of life; an additional 16 children had their first seizure between the second and sixth year of age and only 4 children (6.2%) developed their epilepsy beyond 6 years (Fig. 1). The clinical subtypes of CP among the epileptic and the non-epileptic patients and the clinical epilepsy subgroups are shown in Table 1, demonstrating that epilepsy was particularly common in patients with quadriplegia (58.2% vs. 23.2%), OR ¼ 4.59, 95% CI (2.37–8.91), p < 0.001. The mean age for seizures onset was 1.8 2.0 years. The prevalence of epilepsy was consistent across ethnic groups ( p ¼ 0.13) and genders ( p ¼ 0.62). Twenty-seven children with CP had documented neonatal seizures. Twenty two of them (81.5%) subsequently had epilepsy, OR ¼ 12.99, 95% CI (4.64–36.43), p < 0.001. Out of ninety seven term infants, thirteen children had a history of neonatal seizures (12 of them subsequently developed epilepsy), and of the 89 preterm infants, 14 children had neonatal seizures (10 of them subsequently developed epilepsy). Most of the children with neonatal seizures who later developed epilepsy had quadriplegia (54.5%) and hemiplegia (27.2%). The types of epilepsies that were preceded by neonatal seizures were predominantly GTCS (59.0%), partial seizures (18.2%) and infantile spasms (18.2%). One additional infant had unclassified seizures. 3.2. Imaging data The imaging findings were available for 148 children which encompass 75.1% of all the subjects (Table 2). For 72 patients CT scans were available, for 48 patients MRI scans were available and for 28 patients both CT and MRI scans were available. In 49 patients we had no data or they had documented head ultrasounds that were done only during early infancy. Abnormal imaging was more common in CP children with epilepsy as compared to children without epilepsy ( p < 0.003). Within the patients with abnormal imaging findings only cerebral atrophy was more common in children with epilepsy, than in children without epilepsy ( p < 0.012). Children with infarcts and gray matter disease were somewhat more prone to develop epilepsy, while children with white matter disease were relatively more frequent in the group of CP without epilepsy. However, due to the small number of patients in each group these differences did not reach statistical significance. 3.3. Birth history The gestational age of the patients at birth was recorded in 190 (96.4%) of the children with CP. In the group of children with epilepsy 41 (65.1%) were term infants and 20 (31.7%) were preterm infants (6 of which were extreme preterm). In the group of children without epilepsy 56 (44.1%) were term infants while 69 (54.4%) were born pretermly (34 of which were extreme preterm). Four children (2 in each group) were postterm infants. An increased prevalence of epilepsy was noted in the term infants ( p < 0.01). The mode of delivery was recorded in 178 (90.4%) children. Normal vaginal delivery was conducted in 29 (49.1%) children with epilepsy and 54 (45.4%) children without epilepsy. Instrumental delivery was conducted in only 6 children with epilepsy and 5 children without epilepsy. Caesarian sections were relatively common and performed in 24 (40.7%) of children with epilepsy (15 of which were urgent) and 60 (50.4%) of children without epilepsy (24 of which were urgent). None of these modes of delivery was found as a significant risk factor for developing epilepsy ( p ¼ 0.2). Urgent caesarian sections Table 1 – The clinical subgroups of CP in the epileptic and the non-epileptic children and their respective type of epilepsy. CP subgroup CP Only CP & Epilepsy (epilepsy subtypes) Total 1. Hemiplegia 52 (39.4%) 18 (27.7%) [infantile spasms 2, partial seizures 9, GTCS 5, atonic/tonic sz 1, not classified 1] 70 (35.5%) 2. Diplegia 35 (26.5%) 7 (10.8%) [partial seizures 2, GTCS 3, myoclonic sz 1, atonic/tonic sz 1] 42 (21.3%) 3. Quadriplegia 23 (17.4%) 32 (49.2%) [infantile spasms 3, partial seizures 6, GTCS 13, atonic/tonic sz 5, myoclonic sz 2, not classified 3] 55 (27.9%) 4. Ataxic-Hypotonic 13 (9.9%) 5 (7.7%) [partial seizures 2, GTCS 1, myoclonic sz 1, not classified 1] 18 (9.2%) 5. Dyskinetic/mixed 9 (6.8%) 3 (4.6%) [infantile spasms 2, atonic/tonic sz 1] 12 (6.1%) Total 132 (100%) 65 (100%) [infantile spasms 7, partial seizures 19, GTCS 22, atonic/tonic sz 8, myoclonic sz 4, not classified 5] 197 (100%) Abbreviations: CP – cerebral palsy, GTCS – generalized tonic-clonic seizures, and sz – seizures. Table 2 – The imaging findings in the epileptic and the non-epileptic children. Imaging findings CP Only CP & Epilepsy Total Normal imaging 25 (28.7%) 10 (16.4%) 35 (23.6%) Abnormal Imaging (all findings) 62 (71.3%) 51 (83.6%) 113 (76.4%) Non-specific atrophy 4 (4.6 %) 11 (18.0%) 16 (10.8%) Grey matter insult (including infarctions) 14 (16.1%) 17 (27.9%) 31 (21.0%) White matter insult (including PVL) 16 (18.4%) 4 (11.5%) 23 (15.5%) Cerebral malformations Dysgenesis 10 (11.5%) 7 (11.5%) 17 (11.5%) Hydrocephalus 5 (5.7%) 5 (8.2%) 8 (5.4%) Brain Hemorrhage (including IVH) 13 (14.9%) 7 (11.5%) 20 (13.5%) Total 87 (100%) 61 (100%) 148 (100%) Abbreviations: PVL – Periventricular Leukomalacia, and IVH – Intraventricular Hemorrhage. p < 0.003. european journal of paediatric neurology 14 (2010) 67–72 69 第 65 页

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