- Email: [email protected]
Prophylactic Phenobarbital and Whole-Body Cooling for Neonatal Hypoxic-Ischemic Encephalopathy
Prophylactic Phenobarbital and Whole-Body Cooling for Neonatal HypoxicIschemic Encephalopathy Donald F. Meyn, Jr., MD, Jayne Ness, MD, PhD, Namasivayam Ambalavanan, MD, and Waldemar A. Carlo, MD In infants with hypoxic-ischemic encephalopathy, cooling reduces death/neurodevelopmental impairment, whereas prophylactic anticonvulsants may not. This retrospective analysis shows no reduction in neurodevelopmental impairment (23% in prophylactic phenobarbital group vs 45% in controls, P = .3) but fewer clinical seizures in cooled infants who received prophylactic phenobarbital (15% vs 82% P < .0001). (J Pediatr 2010;157:334-6)
H
ypoxic-ischemic encephalopathy (HIE) is an important cause of neonatal morbidity and mortality.1,2 Recent randomized controlled trials have shown that therapeutic hypothermia reduces morbidity and mortality in term infants diagnosed with HIE.3-6 Prophylactic anticonvulsants for the prevention of seizures and the preservation of neurodevelopmental potential have also been investigated.710 The results of these studies are mixed, and a metaanalysis of heterogeneous interventions shows a trend toward improved neurodevelopmental outcome.11 The concurrent use of whole-body cooling and the prophylactic administration of anticonvulsants for synergistic neuroprotection has shown neuroprotective effects in animals.12 Ours is a retrospective study designed to test the hypothesis that prophylactic administration of phenobarbital to infants with HIE undergoing whole-body cooling reduces moderate to severe neurodevelopmental impairment (NDI) or death.
Methods All infants who received whole-body hypothermia at a single, tertiary referral center (University of Alabama at Birmingham) for HIE between 1999 and 2007 were included. The Institutional Review Board at the University of Alabama at Birmingham approved this study. Eligibility and protocols for cooling were taken from criteria developed by the NICHD Neonatal Research Network.3 Once an infant met criteria for hypothermia, the practice of the attending neonatologist determined if prophylactic phenobarbital was given. This consisted of a single 40 mg/kg dose of phenobarbital given at the time cooling was initiated. Seizures were diagnosed on clinical grounds only. Electroencephalograms were not routinely performed. Infants who were not given prophylactic phenobarbital were treated with bolus and maintenance doses of phenobarbital as needed if seizures were clinically suspected. Sedation was not uniformly provided. Patients were classified into 2 groups, based on whether or not they received prophylactic phenobarbital. Follow-up exams were performed by either a developmental pediatrician or by a pediatric neurologist. The parents of infants who did not follow up HIE NDI
Hypoxic-ischemic encephalopathy Neurodevelopmental impairment
were interviewed by telephone, and a recent physical exam was obtained from their primary care pediatrician. All follow-up examiners were blinded to the use of prophylactic phenobarbital. Moderate to severe NDI was defined by the presence of hemiparesis, quadriparesis, blindness, deafness, or need for tube feeding. Univariate analysis included Fisher exact test for categorical values and t tests for continuous variables. Multivariate analysis was performed by backward stepwise regression followed by multiple logistic regression of identified variables using Sigmastat (Jandel Scientific, San Jose, California). Significance was set at .05.
Results Forty-two infants were identified as having received wholebody hypothermia from 1999 to 2007. Twenty of these also received a single dose of prophylactic phenobarbital. The demographic characteristics, reason for delivery, caesarean section rate, Apgar scores, cord pH, initial infant pH, initial base deficit, need for intubation, and median total phenobarbital dose were comparable between the 2 groups (Table I). Infants in the prophylactic phenobarbital group achieved a body temperature of 33.5 C at 3 2 hours after birth, and those in the control group achieved 33.5 C at 5 2 hours (P = .03, Table I). Follow-up data were available for 17 patients in the prophylactic phenobarbital group at 18 to 46 months and 21 patients in the control group at 18 to 49 months. Twenty-three percent of infants in the prophylactic phenobarbital group were found to have moderate to severe NDI or death compared with 45% of control infants (P = .3). Fifteen percent of those who received prophylactic phenobarbital were diagnosed with clinical seizures during their NICU course compared with 82% of control subjects (P < .0001, Table II). Also, those who received prophylactic phenobarbital were discharged less frequently on phenobarbital than those in
From the Department of Pediatrics, Division of Neonatology (D.M., N.A., W.C.) and Division of Neurology (J.N.), University of Alabama at Birmingham, Birmingham, AL Supported by the Dixon Foundation Fellowship Award, Birmingham, AL. The authors declare no conflicts of interest. 0022-3476/$ - see front matter. Copyright ª 2010 Mosby Inc. All rights reserved. 10.1016/j.jpeds.2010.04.005
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Vol. 157, No. 2 August 2010
Table I. Neonatal characteristics
Birth weight (g) Gestational age (wks) Male sex Race White Black Other Emergent cesarian section Outborn Intrapartum complications Abruption Decreased fetal heart tones Vacuum/forceps extraction Uterine rupture Shoulder dystocia Unknown Apgar score <5 1 min 5 min 10 min Cord pH (mean) First infant pH (mean) Base deficit (mmol/L) Time 33.5 C reached (hours after birth) Initial phenobarbital dose (median, mg/kg) Time given (mean hours after birth) Median total phenobarbital dose before discharge (mg/kg)
Table II. Results
Prophylactic phenobarbital and whole-body cooling (n = 20)
Whole-body cooling (n = 22)
No. (%)
No. (%)
3167 643 38 1 11 (55)
3215 835 38 2 9 (40)
.7 .3 .5
6 (30) 9 (45) 5 (25) 15 (75) 10 (50)
10 (45) 11 (50) 1 (5) 17 (77) 16 (73)
.5 .3 .5 .9 .2
4 (20) 9 (45)
8 (36) 7 (31)
.2 .4
3 (15)
4 (18)
.9
2 (10) 2 (10) 0
1 (5) 1 (5) 1 (5)
.5 .5 .9
20 (100) 18 (90) 16 (80) 6.90 0.12 7.10 0.20 16 6.7 32
21 (95) 16 (73) 14 (64) 6.77 0.18 7.09 0.30 16 7.5 52
.2 .3 .6 .2 .7 .8 .03
40 54 40
20
P value
<.0001
5 11
.1
43
.9
the control group (P = .01, Table II). No significant differences were noted in the use of phenobarbital or in the rate of NDI over the 7-year period (data not shown). Further, multivariate analysis identified higher birth weight (odds ratio, 0.998/g; P = .046), higher 5-minute Apgar scores (0.462/point; P = .005), and prophylactic phenobarbital (.069; P = .03) as associated with improved outcome. The multiple logistic regression equation was Logit P = 7.724 – (0.0016)BW (g)) – (0.773)5-minute Apgar) – (2.678)prophylactic phenobarbital). The sensitivity of the model is 85%, the specificity is 91%, and the positive predictive value is 85%.
Discussion This study was undertaken to determine if the addition of phenobarbital to whole-body cooling provided a greater neuroprotective effect. We found that prophylactic phenobarbital combined with whole-body cooling reduced clinically detectable seizures but did not significantly improve neurodevelopmental outcome by univariate analysis, although multivariate analysis suggested that phenobarbital use was associated with better outcome.
Death or moderate to severe NDI at >18 mo Death Seizure in the NICU First seizure in the first 24 hours of life First seizure after the first 24 hours of life Multiple days of seizure Discharged on phenobarbital Days until discharge (mean) Required intubation
Prophylactic phenobarbital and whole-body cooling
Whole-body cooling
No. (%)
No. (%)
4 (23) (n = 17)
P value
9 (42) (n = 21) .3
0 (0) 3 (15) 1 (5)
3 (14) 18 (82) 14 (64)
2 (10)
4 (19)
.3
3 (15) 2 (10)
8 (37) 10 (45)
.1 .01
21 17 17 (77)
.4 .8
17 12 16 (80)
.3 <.0001 <.0001
This study is limited by its retrospective design and small sample size. The 40 mg/kg dose of phenobarbital was based on a study by Hall et al, 7 and the decision to administer it was left to the practice of the attending neonatologist at admission. It is possible that bias exists due to both the practice of the admitting neonatologist and that of subsequent physicians not blinded to the treatment. Also, because electroencephalograms were not routinely performed, infants with electrical but not clinical seizures may have been missed. The findings that more infants in the prophylactic phenobarbital group were in-born and that they achieved a body temperature of 33.5 C 2 hours sooner than control subjects represent potential confounders. Further analysis of the control group revealed no difference in outcome between those cooled less than 3 hours from birth and those cooled from 3 to 6 hours after birth. The use of prophylactic anticonvulsants for neuroprotection in infants with HIE is controversial. The most effective drug, its dose, and the timing of administration are not known, and, although anticonvulsants can cause increased neuronal apoptosis in animal models13-15 neonatal seizures may be associated with worsened NDI.16,17 Treatment of HIE with prophylactic anticonvulsants plus whole-body cooling may disrupt the cascade of injury.12 A large multicenter randomized-controlled trial with long-term neurodevelopmental follow-up is necessary to further test the incremental benefit of prophylactic anticonvulsant therapy in the setting of hypothermia. n Submitted for publication Jun 19, 2009; last revision received Feb 18, 2010; accepted Apr 5, 2010. Reprint requests: Dr Donald F. Meyn, Jr., 9000 Airline Hwy Suite 340, Baton Rouge, LA 70815. E-mail: [email protected].
References 1. Robertson C, Finer N, Grace M. School performance of survivors of neonatal encephalopathy associated with birth asphyxia at term. J Pediatr 1989;114:753-60. 2. Shankaran S, Woldt E, Koepke T, Bedard M, Nandyal R. Acute neonatal morbidity and long-term central nervous system sequelae of perinatal asphyxia in term infants. Early Hum Dev 1991;25:135-48. 335
THE JOURNAL OF PEDIATRICS
www.jpeds.com
3. Shankaran S, Laptook A, Ehrenkranz R, Tyson J, McDonald S, Donovan E, et al. Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy. N Engl J Med 2005;353:1574-84. 4. Gluckman P, Wyatt J, Azzopardi D, Ballard R, Edwards A, Ferriero D, et al. Selective head cooling with mild systemic hypothermia after neonatal encephalopathy: multicentre randomised trial. Lancet 365: 663-70. 5. Jacobs S, Hunt R, Tarnow-Mordi W, Inder T, Davis P. Cooling for newborns with hypoxic ischaemic encephalopathy. Cochrane Database Syst Rev 2007:CD003311. 6. Azzopardi D, Strohm B, Edwards A, Dyet L, Halliday H, Juszczak E, et al. Moderate hypothermia to treat perinatal asphyxial encephalopathy. N Engl J Med 2009;361:1349-58. 7. Hall R, Hall F, Daily D. High-dose phenobarbital therapy in term newborn infants with severe perinatal asphyxia: a randomized, prospective study with three-year follow-up. J Pediatr 1998;132: 345-8. 8. Ruth V, Virkola K, Paetau R, Raivio K. Early high-dose phenobarbital treatment for prevention of hypoxic-ischemic brain damage in very low birth weight infants. J Pediatr 1988;112:81-6. 9. Singh D, Kumar P, Narang A. A randomized controlled trial of phenobarbital in neonates with hypoxic ischemic encephalopathy. J Matern Fetal Neonatal Med 2005;18:391-5.
336
Vol. 157, No. 2 10. Goldberg R, Moscoso P, Bauer C, Bloom F, Curless R, Burke B, et al. Use of barbiturate therapy in severe perinatal asphyxia: a randomized controlled trial. J Pediatr 1986;109:851-6. 11. Evans D, Levene M, Tsakmakis M. Anticonvulsants for preventing mortality and morbidity in full term newborns with perinatal asphyxia. Cochrane Database Syst Rev 2007:CD001240. 12. Liu Y, Barks J, Xu G, Silverstein F. Topiramate extends the therapeutic window for hypothermia-mediated neuroprotection after stroke in neonatal rats. Stroke 2004;35:1460-5. 13. Bittigau P, Sifringer M, Genz K, Reith E, Pospischil D, Govindarajalu S, et al. Antiepileptic drugs and apoptotic neurodegeneration in the developing brain. Proc Natl Acad Sci U S A 2002;99:15089-94. 14. Kim J, Kondratyev A, Tomita Y, Gale K. Neurodevelopmental impact of antiepileptic drugs and seizures in the immature brain. Epilepsia 2007; 48(Suppl 5):19-26. 15. Ikonomidou C, Bosch F, Miksa M, Bittigau P, Vo¨ckler J, Dikranian K, et al. Blockade of NMDA receptors and apoptotic neurodegeneration in the developing brain. Science 1999;283:70-4. 16. Holmes G. Effects of seizures on brain development: lessons from the laboratory. Pediatr Neurol 2005;33:1-11. 17. Miller S, Weiss J, Barnwell A, Ferriero D, Latal-Hajnal B, FerrerRogers A, et al. Seizure-associated brain injury in term newborns with perinatal asphyxia. Neurology 2002;58:542-8.
Meyn, Jr. et al
H
ypoxic-ischemic encephalopathy (HIE) is an important cause of neonatal morbidity and mortality.1,2 Recent randomized controlled trials have shown that therapeutic hypothermia reduces morbidity and mortality in term infants diagnosed with HIE.3-6 Prophylactic anticonvulsants for the prevention of seizures and the preservation of neurodevelopmental potential have also been investigated.710 The results of these studies are mixed, and a metaanalysis of heterogeneous interventions shows a trend toward improved neurodevelopmental outcome.11 The concurrent use of whole-body cooling and the prophylactic administration of anticonvulsants for synergistic neuroprotection has shown neuroprotective effects in animals.12 Ours is a retrospective study designed to test the hypothesis that prophylactic administration of phenobarbital to infants with HIE undergoing whole-body cooling reduces moderate to severe neurodevelopmental impairment (NDI) or death.
Methods All infants who received whole-body hypothermia at a single, tertiary referral center (University of Alabama at Birmingham) for HIE between 1999 and 2007 were included. The Institutional Review Board at the University of Alabama at Birmingham approved this study. Eligibility and protocols for cooling were taken from criteria developed by the NICHD Neonatal Research Network.3 Once an infant met criteria for hypothermia, the practice of the attending neonatologist determined if prophylactic phenobarbital was given. This consisted of a single 40 mg/kg dose of phenobarbital given at the time cooling was initiated. Seizures were diagnosed on clinical grounds only. Electroencephalograms were not routinely performed. Infants who were not given prophylactic phenobarbital were treated with bolus and maintenance doses of phenobarbital as needed if seizures were clinically suspected. Sedation was not uniformly provided. Patients were classified into 2 groups, based on whether or not they received prophylactic phenobarbital. Follow-up exams were performed by either a developmental pediatrician or by a pediatric neurologist. The parents of infants who did not follow up HIE NDI
Hypoxic-ischemic encephalopathy Neurodevelopmental impairment
were interviewed by telephone, and a recent physical exam was obtained from their primary care pediatrician. All follow-up examiners were blinded to the use of prophylactic phenobarbital. Moderate to severe NDI was defined by the presence of hemiparesis, quadriparesis, blindness, deafness, or need for tube feeding. Univariate analysis included Fisher exact test for categorical values and t tests for continuous variables. Multivariate analysis was performed by backward stepwise regression followed by multiple logistic regression of identified variables using Sigmastat (Jandel Scientific, San Jose, California). Significance was set at .05.
Results Forty-two infants were identified as having received wholebody hypothermia from 1999 to 2007. Twenty of these also received a single dose of prophylactic phenobarbital. The demographic characteristics, reason for delivery, caesarean section rate, Apgar scores, cord pH, initial infant pH, initial base deficit, need for intubation, and median total phenobarbital dose were comparable between the 2 groups (Table I). Infants in the prophylactic phenobarbital group achieved a body temperature of 33.5 C at 3 2 hours after birth, and those in the control group achieved 33.5 C at 5 2 hours (P = .03, Table I). Follow-up data were available for 17 patients in the prophylactic phenobarbital group at 18 to 46 months and 21 patients in the control group at 18 to 49 months. Twenty-three percent of infants in the prophylactic phenobarbital group were found to have moderate to severe NDI or death compared with 45% of control infants (P = .3). Fifteen percent of those who received prophylactic phenobarbital were diagnosed with clinical seizures during their NICU course compared with 82% of control subjects (P < .0001, Table II). Also, those who received prophylactic phenobarbital were discharged less frequently on phenobarbital than those in
From the Department of Pediatrics, Division of Neonatology (D.M., N.A., W.C.) and Division of Neurology (J.N.), University of Alabama at Birmingham, Birmingham, AL Supported by the Dixon Foundation Fellowship Award, Birmingham, AL. The authors declare no conflicts of interest. 0022-3476/$ - see front matter. Copyright ª 2010 Mosby Inc. All rights reserved. 10.1016/j.jpeds.2010.04.005
334
Vol. 157, No. 2 August 2010
Table I. Neonatal characteristics
Birth weight (g) Gestational age (wks) Male sex Race White Black Other Emergent cesarian section Outborn Intrapartum complications Abruption Decreased fetal heart tones Vacuum/forceps extraction Uterine rupture Shoulder dystocia Unknown Apgar score <5 1 min 5 min 10 min Cord pH (mean) First infant pH (mean) Base deficit (mmol/L) Time 33.5 C reached (hours after birth) Initial phenobarbital dose (median, mg/kg) Time given (mean hours after birth) Median total phenobarbital dose before discharge (mg/kg)
Table II. Results
Prophylactic phenobarbital and whole-body cooling (n = 20)
Whole-body cooling (n = 22)
No. (%)
No. (%)
3167 643 38 1 11 (55)
3215 835 38 2 9 (40)
.7 .3 .5
6 (30) 9 (45) 5 (25) 15 (75) 10 (50)
10 (45) 11 (50) 1 (5) 17 (77) 16 (73)
.5 .3 .5 .9 .2
4 (20) 9 (45)
8 (36) 7 (31)
.2 .4
3 (15)
4 (18)
.9
2 (10) 2 (10) 0
1 (5) 1 (5) 1 (5)
.5 .5 .9
20 (100) 18 (90) 16 (80) 6.90 0.12 7.10 0.20 16 6.7 32
21 (95) 16 (73) 14 (64) 6.77 0.18 7.09 0.30 16 7.5 52
.2 .3 .6 .2 .7 .8 .03
40 54 40
20
P value
<.0001
5 11
.1
43
.9
the control group (P = .01, Table II). No significant differences were noted in the use of phenobarbital or in the rate of NDI over the 7-year period (data not shown). Further, multivariate analysis identified higher birth weight (odds ratio, 0.998/g; P = .046), higher 5-minute Apgar scores (0.462/point; P = .005), and prophylactic phenobarbital (.069; P = .03) as associated with improved outcome. The multiple logistic regression equation was Logit P = 7.724 – (0.0016)BW (g)) – (0.773)5-minute Apgar) – (2.678)prophylactic phenobarbital). The sensitivity of the model is 85%, the specificity is 91%, and the positive predictive value is 85%.
Discussion This study was undertaken to determine if the addition of phenobarbital to whole-body cooling provided a greater neuroprotective effect. We found that prophylactic phenobarbital combined with whole-body cooling reduced clinically detectable seizures but did not significantly improve neurodevelopmental outcome by univariate analysis, although multivariate analysis suggested that phenobarbital use was associated with better outcome.
Death or moderate to severe NDI at >18 mo Death Seizure in the NICU First seizure in the first 24 hours of life First seizure after the first 24 hours of life Multiple days of seizure Discharged on phenobarbital Days until discharge (mean) Required intubation
Prophylactic phenobarbital and whole-body cooling
Whole-body cooling
No. (%)
No. (%)
4 (23) (n = 17)
P value
9 (42) (n = 21) .3
0 (0) 3 (15) 1 (5)
3 (14) 18 (82) 14 (64)
2 (10)
4 (19)
.3
3 (15) 2 (10)
8 (37) 10 (45)
.1 .01
21 17 17 (77)
.4 .8
17 12 16 (80)
.3 <.0001 <.0001
This study is limited by its retrospective design and small sample size. The 40 mg/kg dose of phenobarbital was based on a study by Hall et al, 7 and the decision to administer it was left to the practice of the attending neonatologist at admission. It is possible that bias exists due to both the practice of the admitting neonatologist and that of subsequent physicians not blinded to the treatment. Also, because electroencephalograms were not routinely performed, infants with electrical but not clinical seizures may have been missed. The findings that more infants in the prophylactic phenobarbital group were in-born and that they achieved a body temperature of 33.5 C 2 hours sooner than control subjects represent potential confounders. Further analysis of the control group revealed no difference in outcome between those cooled less than 3 hours from birth and those cooled from 3 to 6 hours after birth. The use of prophylactic anticonvulsants for neuroprotection in infants with HIE is controversial. The most effective drug, its dose, and the timing of administration are not known, and, although anticonvulsants can cause increased neuronal apoptosis in animal models13-15 neonatal seizures may be associated with worsened NDI.16,17 Treatment of HIE with prophylactic anticonvulsants plus whole-body cooling may disrupt the cascade of injury.12 A large multicenter randomized-controlled trial with long-term neurodevelopmental follow-up is necessary to further test the incremental benefit of prophylactic anticonvulsant therapy in the setting of hypothermia. n Submitted for publication Jun 19, 2009; last revision received Feb 18, 2010; accepted Apr 5, 2010. Reprint requests: Dr Donald F. Meyn, Jr., 9000 Airline Hwy Suite 340, Baton Rouge, LA 70815. E-mail: [email protected].
References 1. Robertson C, Finer N, Grace M. School performance of survivors of neonatal encephalopathy associated with birth asphyxia at term. J Pediatr 1989;114:753-60. 2. Shankaran S, Woldt E, Koepke T, Bedard M, Nandyal R. Acute neonatal morbidity and long-term central nervous system sequelae of perinatal asphyxia in term infants. Early Hum Dev 1991;25:135-48. 335
THE JOURNAL OF PEDIATRICS
www.jpeds.com
3. Shankaran S, Laptook A, Ehrenkranz R, Tyson J, McDonald S, Donovan E, et al. Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy. N Engl J Med 2005;353:1574-84. 4. Gluckman P, Wyatt J, Azzopardi D, Ballard R, Edwards A, Ferriero D, et al. Selective head cooling with mild systemic hypothermia after neonatal encephalopathy: multicentre randomised trial. Lancet 365: 663-70. 5. Jacobs S, Hunt R, Tarnow-Mordi W, Inder T, Davis P. Cooling for newborns with hypoxic ischaemic encephalopathy. Cochrane Database Syst Rev 2007:CD003311. 6. Azzopardi D, Strohm B, Edwards A, Dyet L, Halliday H, Juszczak E, et al. Moderate hypothermia to treat perinatal asphyxial encephalopathy. N Engl J Med 2009;361:1349-58. 7. Hall R, Hall F, Daily D. High-dose phenobarbital therapy in term newborn infants with severe perinatal asphyxia: a randomized, prospective study with three-year follow-up. J Pediatr 1998;132: 345-8. 8. Ruth V, Virkola K, Paetau R, Raivio K. Early high-dose phenobarbital treatment for prevention of hypoxic-ischemic brain damage in very low birth weight infants. J Pediatr 1988;112:81-6. 9. Singh D, Kumar P, Narang A. A randomized controlled trial of phenobarbital in neonates with hypoxic ischemic encephalopathy. J Matern Fetal Neonatal Med 2005;18:391-5.
336
Vol. 157, No. 2 10. Goldberg R, Moscoso P, Bauer C, Bloom F, Curless R, Burke B, et al. Use of barbiturate therapy in severe perinatal asphyxia: a randomized controlled trial. J Pediatr 1986;109:851-6. 11. Evans D, Levene M, Tsakmakis M. Anticonvulsants for preventing mortality and morbidity in full term newborns with perinatal asphyxia. Cochrane Database Syst Rev 2007:CD001240. 12. Liu Y, Barks J, Xu G, Silverstein F. Topiramate extends the therapeutic window for hypothermia-mediated neuroprotection after stroke in neonatal rats. Stroke 2004;35:1460-5. 13. Bittigau P, Sifringer M, Genz K, Reith E, Pospischil D, Govindarajalu S, et al. Antiepileptic drugs and apoptotic neurodegeneration in the developing brain. Proc Natl Acad Sci U S A 2002;99:15089-94. 14. Kim J, Kondratyev A, Tomita Y, Gale K. Neurodevelopmental impact of antiepileptic drugs and seizures in the immature brain. Epilepsia 2007; 48(Suppl 5):19-26. 15. Ikonomidou C, Bosch F, Miksa M, Bittigau P, Vo¨ckler J, Dikranian K, et al. Blockade of NMDA receptors and apoptotic neurodegeneration in the developing brain. Science 1999;283:70-4. 16. Holmes G. Effects of seizures on brain development: lessons from the laboratory. Pediatr Neurol 2005;33:1-11. 17. Miller S, Weiss J, Barnwell A, Ferriero D, Latal-Hajnal B, FerrerRogers A, et al. Seizure-associated brain injury in term newborns with perinatal asphyxia. Neurology 2002;58:542-8.
Meyn, Jr. et al