- Email: [email protected]
Prediction of neurodevelopmental outcome in term neonates with hypoxic-ischemic encephalopathy
e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 1 7 ( 2 0 1 3 ) 2 8 8 e2 9 3
Official Journal of the European Paediatric Neurology Society
Original article
Prediction of neurodevelopmental outcome in term neonates with hypoxic-ischemic encephalopathy c, Rabia G. Sezer d,*, Mine O¨zkol e, Muzaffer Polat a, Ays‚e S‚ims‚ek b, Nermin Tansug Pınar Bas‚pınar f, Hasan Tekgu¨l g a
Celal Bayar University School of Medicine, Department of Pediatric Neurology, Manisa, Turkey Celal Bayar University School of Medicine, Department of Pediatrics, Manisa, Turkey c Celal Bayar University School of Medicine, Department of Neonatalogy, Manisa, Turkey d Zeynep Kamil Maternity and Childrens Diseases Training and Research State Hospital, Department of Pediatrics, Istanbul, Turkey e Celal Bayar University School of Medicine, Department of Radiology, Manisa, Turkey f Celal Bayar University School of Medicine, Department of Psyhiatry, Manisa, Turkey g Ege University School of Medicine, Department of Pediatrics, Izmir, Turkey b
article info
abstract
Article history:
Background: Hypoxic ischemic encephalopathy may result in many neurological deficits. It
Received 5 May 2012
is crucial to make early diagnosis and assess the prognosis correctly.
Received in revised form
Aims: We aimed to determine the factors to evaluate the prognosis of hypoxic ischemic
7 November 2012
encephalopathy.
Accepted 17 November 2012
Methods: Electroencephalography, neuroimaging, periodic neurological exams and
Keywords:
twenty five term newborn infants with clinical evidence of hypoxic ischemic
Electroencephalography
encephalopathy.
Hypoxic ischemic encephalopathy
Results: Normal/mildly abnormal neonatal electroencephalography correlated with favor-
Magnetic resonance imaging
able outcome, particularly if neuroimaging was normal. The cranial MRI sensitivity was
Neurodevelopmental outcome
83.3%, while the specificity was 57.9%, the positive predictive value was 38.5%, and the
a developmental test at 44e48 months after discharge from the hospital were performed on
negative predictive value was 91.6%. Moderate/severely abnormal electroencephalography and multifocal/diffuse cortical or deep gray matter lesions correlated with poor outcome. Conclusions: Newborn infants with hypoxic ischemic encephalopathy should be treated in neonatal intensive care units, assessed with periodic neurological examination, electroencephalogram and brain imaging. This would help to initiate early intervention and improve the outcome of patients. ª 2012 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.
¨ stu¨nel Caddesi, 34668 Uskudar, * Corresponding author. Zeynep Kamil Hastanesi, Arakiyeci Haci Mehmet Mah., Op. Dr. Burhanettin U Istanbul, Turkey. Tel.: þ90 2163910680 1434; fax: þ90 2163910677. E-mail address: [email protected] (R.G. Sezer). 1090-3798/$ e see front matter ª 2012 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ejpn.2012.11.004
e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 1 7 ( 2 0 1 3 ) 2 8 8 e2 9 3
1.
Introduction
Despite novel approaches in diagnosis and management, hypoxic ischemic encephalopathy remains a major cause of neonatal death and brain injury. Of all neonates, even in developed countries, 2e5:1000 have brain injuries due to perinatal hypoxia-ischemia, 20%e40% of which develop significant neurologic sequela and developmental defects.1 Consequently, establishing the early diagnosis of suspected cases of perinatal asphyxia and accurately predicting the prognosis are of critical importance. For the optimal management of the cranial trauma prompt resuscitation, meticulous prophylactic, and supportive measures to prevent hyperthermia, and hypoglycemia, management of frequently seen clinical, and prolonged subclinical seizures are required. Recent evidence suggests that therapeutic hypothermia by selective head or whole-body cooling within postnatal 6 h reduces concomitant morbidity, and mortality.2,3 Thus, harmful outcomes can be minimized by administering appropriate therapy and rehabilitation as soon as possible. In the present study, we reviewed the factors that might have an impact on long-term prognosis in cases diagnosed with hypoxic encephalopathy and establish markers that can provide guidance in predicting prognosis.
2.
Materials and methods
2.1.
Study group
Newborns diagnosed with hypoxic ischemic encephalopathy at birth in Celal Bayar University, School of Medicine, Manisa, Turkey or referred to us from other centers and admitted to our neonatal intensive care unit between April 2006 and March 2008 were enrolled in the present study. The study group consisted of 25 cases with gestational ages between 37 and 41 weeks. The inclusion criteria were established as follows: (1) Apgar score <5 at 5 min; (2) metabolic acidosis, pH 7.0 (in fetal umbilical cord blood or in neonatal blood samples obtained on the first day of life); (3) delayed onset of respiration for 5 min; (4) fetal distress (such as abnormal fetal heart rate and meconium stained amniotic fluid); (5) need for assisted ventilation (mask/balloon or intubation); (6) encephalopathy (lethargy/ stupor, hypotonia and abnormal reflexes including an absent or weak suck); (7) presence of convulsions in the first 24 h of life; and (8) multiple organ dysfunction (encephalopathy and the involvement of at least one organ). Patients fulfilling at least two of the clinical findings were enrolled.4,5 The patients enrolled were evaluated regarding the presence of a medical condition in the mother during pregnancy, type of delivery, Apgar scores, birth weight, gender, blood gases, clinical findings, modified Sarnat and Sarnat hypoxic ischemic encephalopathy stage,6 and anticonvulsive therapies administered. Neonates with a gestational age <37 weeks, and neonates with intrauterine infections, trauma, central nervous system abnormalities, chromosomal abnormalities, or metabolic disorders were excluded. None of the neonates were treated with hypothermia.
2.2.
289
Imaging methods
Cranial magnetic resonance imaging (MRI) was performed on 25 newborns admitted to the hospital between 7 and 14 days after their birth. 7MRI was performed on a 1.5-T scanner (Vision; Siemens, Erlangen, Germany) under sedation with oral chloral hydrate (40 mg/kg of body weight). The cranial MRI findings of the patients were classified according to Barkovich: (1) Normal; no pathologies were observed, (2) Mild-moderate involvement; involvement of the cerebral cortex and parasagittal zone (the part of the watershed zone between anterior and medial parts of the cerebral zone and medial and posterior parts of the cerebral zone), (3) Severe involvement; involvement of the brain stem, ventral cerebellar vermis, thalamus, basal ganglia, and perirolandic regions.7
2.3.
Electroencephalography evaluations
Electroencephalography (EEG) recordings were performed for a minimum duration of 30 min with bipolar and reference electrodes using the 10e20 international system. Reducedelectrode montage with nine electrodes were used in EEG recordings. The patients diagnosed with hypoxic ischemic encephalopathy underwent EEG evaluations in the neonatal period (48e72 h) regardless of the presence of convulsions. Twenty-five patients underwent EEG and the EEG recordings were graded by a pediatric neurologist with using a previously well-described grading system (from Grade 0 to Grade 4) with respect to background activity previously8: (1) Normal EEG recordings (Grade 0); Preserved sleep state modulation and transitions, amplitude (voltage), synchrony, and symmetry appropriate for conceptional age, age-appropriate EEG patterns, (2) Mildly abnormal EEG recordings (Grade 1); Preserved sleep state modulation and transitions, but excessive sharp wave activity, (3) Moderately abnormal EEG recordings (Grade 2); asymmetry (voltage/frequency), excessive discontinuity (<20 s), excessive asynchrony for postconceptional age, dysmaturity for conceptional age (>2 weeks), (4) Severely abnormal EEG recording (Grade 3); electrocerebral inactivity, burst-suppression pattern, lowvoltage undifferentiated background rhythm activity, markedly excessive discontinuity (>20 s) and non-reactive tracings.8e10 Excessive sharp activity was defined as excessive amount of sharp wave activity (>7 activity in 30 s EEG duration) with long duration (>150 msec) and high amplitude (150 mV). Discontinuous EEG is a normal EEG pattern in premature infants. However burst-suppression pattern consisted of a nonreactive discontinuous tracing with long periods of quiescence>20 s in duration interrupted by synchronous or asynchronous bursts of poorly organized background activity. The neurologist who evaluated EEG recordings was blinded to the clinical characteristics of the patients.
2.4.
Neurodevelopmental test
Neurodevelopmental tests were performed by assessing neuromotor development between the 44th and 48th month,
290
e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 1 7 ( 2 0 1 3 ) 2 8 8 e2 9 3
to evaluate long-term prognosis for neonates diagnosed with hypoxic ischemic encephalopathy and discharged from the neonatal intensive care unit, and to determine the relationship between prognosis and electroencephalographic monitoring and imaging methods. The developmental outcomes of infants were assessed by the Denver Developmental Screening Test.11 The test is appropriate for ages between 0 and 72 months, and evaluates fine motor and gross motor skills, language, and adaptive personal/social skills. The developmental outcome scores are set for these four skills and total development. Scores between age-normative values and 20% of those values were considered near-normal. Scores between 20% and 30% of agenormative values were recorded as borderline. Scores higher than age-normative values (>30%) indicate the presence of a significant delay. In our study the patients whose scores were more than >30% of age-normative values according to Denver Developmental Screening Test were considered to have a poor outcome.
2.5.
Neurologic examination
Head circumference, cranial nerve function, muscle strength, muscle tone, coordination, posture, and reflexes were evaluated during the neurologic examination. Motor development was compared to age-normative values. Neurologic functions were classified as normal, mild disability (the presence of an abnormality on examination, which does not lead to a significant impairment in function), moderate disability (abnormality, which leads to functional impairment), and severe disability (severe functional impairment requiring special assistance at all times).12
2.6.
Neurologic outcome
To define the primary neurologic outcome, if any one of the following was established in the patients examined between the 44th and 48th month, it was regarded as a “poor” outcome: moderate or severe motor dysfunction; neurodevelopment disability (Denver scores more than >30% of age-normative values); or post-neonatal seizures. Otherwise, it was regarded as a “favorable” outcome.
2.7.
Statistical analysis
SPSS 13.0 software (SPSS Inc., Chicago, IL, USA) was used for the statistical analysis. Data were presented as the mean standard deviation or as n (%), as applicable. A chi-square test was used to compare categorical variables and a p value of <0.05 was considered significant. The ManneWhitney U test was used to compare numerical variables.
3.
Results
3.1.
Study population
Twenty-five newborns were enrolled in the study (n ¼ 12 boys, n ¼ 13 girls). The gestational ages were between 37 and 41
weeks (median age, 38 weeks). The mean birth weight of the newborns was 3165 734 g (range, 1950e4800 g), and the mean Apgar score at 1 and 5 min was 3.9 2.1 (range, 1e9) and 6.8 2.3 (range, 2e10), respectively. Fifteen neonates (60%) were delivered via the vaginal route, and 10 patients (40%) were delivered via caesarean section.
3.2. Neonatal electroencephalography evaluation and prognosis A significant relationship was determined between abnormal EEG background activity and developmental tests ( p < 0.001, Table 1). When the patients were classified with respect to the EEG background rhythms as normal or abnormal, it was noted that the patients with normal EEG findings had normal neurologic development, while 50% of those with abnormal background rhythms had developmental pathology. All patients with pathologic neurocognitive development had moderate or severe EEG background rhythm abnormalities. However, those with mild background rhythm abnormalities had normal development. All patients with normal development had mild abnormalities (Table 2).
3.3.
Magnetic resonance imaging and prognosis
Of the 12 patients with normal cranial MRI findings, 11 (91.7%) had normal development, while 1 (8.3%) had developmental disability. In contrast, 7 patients (77.8%) with mildmoderate MRI findings had normal development, while 2 (22.2%) had developmental disability. Of those neonates with severe MRI findings, only 1 (25%) had normal development, whereas the remaining 3 (75%) had developmental disability. One patient with diffuse involvement on the cranial MRI died during the neonatal period. The cranial MRI findings were significantly related with the developmental tests ( p ¼ 0.01; Table 1).
Table 1 e Neurodevelopmental outcomes according to EEG recordings and MRI findings. Total Favorable Poor pn (%) outcome n outcome n Value EEG background (n ¼ 25) Normal 13 (52) Mildly abnormal 6 (24) Moderately abnormal 3 (12) Severely abnormal 3 (12) Neuroimaging (MRI) (n ¼ 25) Normal 12 (48) Mildly/moderately 9 (36) abnormal Severely abnormal 4 (16) EEG ¼ Electroencephalography. MRI ¼ Magnetic resonance imaging.
13 6 0 0
0 0 3 3
<0.001
11 7
1 2
0.01
1
3
e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 1 7 ( 2 0 1 3 ) 2 8 8 e2 9 3
Table 2 e The predictive values of the prognostic factors in demonstrating neurodevelopmental outcomes. Sensitivity Specificity EEG background Neuroimaging (MRI) Neurologic examination Apgar score at 1 min
100% 83.3% 83.3% 33.3%
68.4% 57.9% 52.6% 57.9%
PPV
NPV
50% 38.5% 90.9% 20%
100% 91.6% 35.7% 73%
PPV ¼ Positive predictive value. NPV ¼ Negative predictive value. EEG ¼ Electroencephalography. MRI ¼ Magnetic resonance imaging.
3.4.
Modified Sarnat staging and prognosis
Of the 11 neonates in Sarnat stage 1, 10 had normal development (90.9%). Of the 10 neonates in Sarnat stage 2, 7 (70%) had normal development. Of the 4 neonates in Sarnat stage 3, 2 (50%) had normal development. No significant relationship was established with developmental tests ( p ¼ 0.08; Table 3). When the modified Sarnat staging was analyzed in 2 groups as stage 1 and stages 2e3 to examine its effect on development, the sensitivity was 83.3%, the specificity was 52.6%, the negative predictive value was 90.9%, and the positive predictive value was 35.7%.
3.5.
Apgar scores and prognosis
The Apgar scores at 1 min were not significantly related with developmental tests ( p ¼ 0.7) (Table 2). The Apgar scores at 5 min were not significantly related with developmental tests ( p ¼ 0.07); the sensitivity and specificity were 16% and 100%, respectively. These results indicated that the Apgar score at 5 min was more significant than the Apgar score at 1 min, in the assessment of long-term morbidity. Furthermore, the Apgar score at 5 min had rather high specificity (Table 3).
Table 3 e Neurodevelopmental outcomes according to Apgar scores and classification of hypoxic ischemic encephalopathy. Total n (%)
Favorable outcome n
Poor outcome n
pValue
Classification of hypoxic ischemic encephalopathya (n ¼ 25) Stage 1 11 (44) 10 1 0.08 Stage 2 10 (40) 7 3 Stage 3 4 (16) 2 2 Apgar scores at 5 min (n ¼ 25) Apgar scores at 1 (4) 0 1 0.07 5 min 5 Apgar scores at 24 (96) 19 5 5 min > 5 Apgar scores at 1 min (n ¼ 25) Apgar scores at 10 (40) 8 2 0.7 1 min 5 Apgar scores at 15 (60) 11 4 1 min > 5 a Hypoxic ischemic encephalopathy grading according to Levene’s modification of the Sarnat criteria (Evans and Levene, 1999).6
4.
291
Discussion
An accurate prediction of the prognosis in neonates with hypoxic ischemic encephalopathy is critical in terms of family counseling and neuroprotective therapy. However, it is often difficult to establish the severity of the injury and the prognosis since most of the primary injury in hypoxic ischemic encephalopathy occurs ante- and intra-partum. A number of clinical evaluation methods and neurodiagnostic tests are widely used to establish prognosis in hypoxic ischemic encephalopathy. Neonatal neurologic syndrome is of essential importance in indicating the severity of hypoxic ischemic injury and prognosis. Increased risk for sequela is particularly associated with increased severity and duration of neurologic abnormalities.13e16 The classification method of Sarnat and Sarnat has commonly been used to rapidly and correctly establish the severity of hypoxic ischemic encephalopathy.4 It can be suggested that patients with mild hypoxic ischemic encephalopathy are more likely to have better prognosis due to the high negative predictive value (90.9%). The lack of a significant relationship between developmental disability and Sarnat staging can be due to the low number of cases. Since hypoxic ischemic injury is one of the causes of depressed Apgar scores, Apgar scores have long been considered to be correlated with prognosis. However, this approach is flawed because even though the five components of Apgar scoring have equal weight, the impact of each factor on the central nervous system is different. Moreover, a number of factors, such as prematurity, drugs used by the mother, anesthetic agents used during delivery, trauma, infections, cardiopulmonary disorders, and congenital abnormalities affecting the neuromuscular system, may also lead to depressed Apgar scores. Therefore, it has been reported that while the Apgar score reflects a neonate’s condition at that particular moment, it failed to provide sufficient information regarding long-term and permanent implications of intrapartum asphyxia, and was poorly related with prognosis.17,18 Another study reported Apgar scores at 1 and 5 min to be of limited use in terms of establishing neurologic injury.1 We also established no significant relationship between developmental stages and Apgar scores at 1 and 5 min in the present study. Many reports have been published on the diagnostic and prognostic significance of EEGs in hypoxic ischemic encephalopathy.4,19,20 Abnormal EEG background activity has been demonstrated to be a good marker of neurologic sequela for both term and preterm neonates. Abnormal background activity has been described as an excessive discontinuity, burst-suppression pattern, low voltage, and electrocerebral inactivity, which were associated with a poor prognosis.21e23 The burst-suppression pattern was observed in 2 neonates. One of those neonates died and the other neonate developed a severe neurologic deficit. The burst-suppression pattern constitutes only a small proportion of the discontinuous tracing. Therefore, the interburst interval duration is of critical importance as longer intervals indicate a poorer prognosis.24 One of the three neonates with an excessive
292
e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 1 7 ( 2 0 1 3 ) 2 8 8 e2 9 3
discontinuity on EEG, classified as grade 3, died while the remaining 2 neonates had neurologic injuries. Furthermore, neurodevelopmental disability was observed in 2 neonates, classified as grade 2, with a reactive prolonged discontinuous tracing < 20 s. Our results concerning normal development in grade 1 neonates in the present study are consistent with the results reported by Menache et al.24 in 2002, when they reported good prognosis in 24 out of 25 patients with increased sharp wave activity (grade 1 patients) on EEG evaluation. Pressler et al.20 suggested that normal EEG findings in neonates with hypoxic ischemic encephalopathy in the first hours of life could be a very strong prognostic factor. Abnormality in the initial EEG may be observed due to acute brain injury, but these abnormalities can improve with time. Therefore, persistent abnormality in serial EEG may be associated with a poor prognosis.20 Although our EEG recordings were not performed in series and were not carried out in the first 48 h, the grading method we used was determined to be very effective in predicting prognosis. Cranial MRIs have been regarded to be the best imaging method in establishing hypoxic ischemic injury in the neonatal population.21,25,26 A number of scoring systems have been used for pathologic MRI findings, but as they are all rather complex, a simpler scoring system has been sought.27 In the present study, we used the simplified form of the Barkovich’s classification, which is the most commonly used scoring method.7 The optimal time for imaging brain damage with an MRI has been reported to be the first 1e4 weeks before edema and atrophy becomes evident.21 Basal ganglia and thalamic involvement are often accompanied with the involvement of perirolandic cortex and other regions of the cortex and indicate a poor prognosis.28e30 We observed severe developmental disability and microcephaly in three of our patients with basal ganglia involvement and diffuse involvement (basal ganglion and cortex). Only one neonate with diffuse involvement on MRI had normal development. In another study, patients with basal ganglia involvement had the lowest neurocognitive scores while patients with watershed involvement on MRI (mild-moderate involvement) had moderate scores.28 Of the nine neonates with mild-moderate involvement on MRI in the present study, two had developmental disability, but their disability was mild and microcephaly was not observed. A study investigating the relationship between MRI lesions with EEG findings reported that normal MRI and minimal basal ganglia lesions are always associated with a normal EEG rhythm, whereas severe basal ganglia and/or white matter diseases are always accompanied by an abnormal EEG background rhythm. Such abnormalities demonstrate an excessive discontinuity and burst-suppression pattern.21 Gire et al.31 conducted a study on 26 neonates with perinatal asphyxia in France and established diffuse cortical injury and presence of lesions in basal ganglia on MRI to be poor prognostic factors independent of EEG and clinical findings.31 Severe background rhythm abnormalities were observed on the EEG recordings of the three neonates with severe MRI involvement and they all had neurodevelopmental disability. On the other hand, a neonate with severe involvement on MRI was shown to have normal EEG findings. That particular
neonate also had normal neurologic development. Of the nine neonates with mild-moderate involvement on MRI, only two had background rhythm abnormalities on their EEG recordings. Those two neonates had neurodevelopmental disability. When factors with an effect on prognosis in patients with hypoxic ischemic encephalopathy are taken into consideration, classification with modified Sarnat criteria is still of great prognostic significance. The simplified MRI criteria that we have used appear to be practical, convenient, and reliable in establishing the prognosis. The EEG grading method was the most reliable method for establishing the prognosis in neonates with hypoxic ischemic encephalopathy in the present study. There was a significant relationship between poor prognosis with discontinuity and burst-suppression pattern. One limitation of our study was the small sample size. Additional studies with larger sample sizes should be conducted. In conclusion, a careful clinical evaluation, accompanied by specific examinations such as EEG and MRI, will play a major role in establishing prognosis. Consequently, deleterious outcomes can be minimized by rehabilitation and neuroprotective therapies, such as head-cooling and pharmacotherapy, at an early stage.
references
1. Badr Zahr LK, Purdy I. Brain injury in the infant: the old, the new, and the uncertain. J Perinat Neonatal Nurs 2006;20:163e75. 2. Glass HC, Ferriero DM. Treatment of hypoxic-ischemic encephalopathy in newborns. Curr Treat Options Neurol 2007;9:414e23. 3. Shah PS. Hypothermia: a systematic review and metaanalysis of clinical trials. Semin Fetal Neonatal Med 2010;15:238e46. 4. Sarnat HB, Sarnat MS. Neonatal encephalopathy following fetal distress: a clinical and electroencephalographic study. Arch Neurol 1976;33:696e705. 5. Carter BS, Haverkamp AD, Merenstein GB. The definition of acute perinatal asphyxia. Clin Perinatol 1993;20:287e304. 6. Evans DJ, Levene MI. Hypoxic-ischaemic injury. In: Rennie JM, Robertson NRC, editors. Textbook of neonatology. Edinburgh: Churchill Livingstone; 1999. p. 1231e51. 7. Barkovich AJ. Pediatric neuroimaging. 4th ed. Philadelphia: Lippincott Williams &Wilkins; 2005. p. 226e36. 8. Laroia N, Guillet R, Burchfiel J, McBride MC. EEG background as predictor of electrographic seizures in high risk neonates. Epilepsia 1998;39:545e51. 9. Holmes GL, Lombroso CT. Prognostic value of background patterns in the neonatal EEG. J Clin Neurophysiol 1993;10:323e52. 10. Mizrahi EM. Electroencephalographic-video monitoring in neonates, infants, and children. J Child Neurol 1994;9:46e56. 11. Frankenburg WK, Dodds J, Archer P, Shapiro H, Bresnick B. The Denver II: a major revision and restandardization of the Denver developmental screening test. Pediatrics 1992;89:91e7. 12. Tekgul H, Gauvreau K, Soul J, et al. The current etiologic profile and neurodevelopmental outcome of seizures in term newborn infants. Pediatrics 2006;117:1270e80. 13. Robertson C, Finer N. Term infants with hypoxic-ischemic encephalopathy: outcome at 3.5 years. Dev Med Child Neurol 1985;27:473e84.
e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 1 7 ( 2 0 1 3 ) 2 8 8 e2 9 3
14. Robertson CM, Finer NN. Educational readiness of survivors of neonatal encephalopathy associated with birth asphyxia at term. J Dev Behav Pediatr 1988;9:298e306. 15. Robertson CM, Finer NN, Grace MG. School performance of survivors of neonatal encephalopathy associated with birth asphyxia at term. J Pediatr 1989;114:753e60. 16. Thornberg E, Thiringer K, Odeback A, Milsom I. Birth asphyxia: incidence, clinical course and outcome in a Swedish population. Acta Pediatr 1995;84:927e32. 17. American Academy of Pediatrics, Committee on Fetus and Newborn; American College of Obstetricians and Gynecologists and Committee on Obstetric Practice. The Apgar score. Pediatrics 2006;117:1444e7. 18. Hankins GD, Speer M. Defining the pathogenesis and pathophysiology of neonatal encephalopathy and cerebral palsy. Obstet Gynecol 2003;102:628e36. 19. Sankar MJ, Aqarwal R, Aqqarwal R, Deorari AK, Paul VK. Seizures in the newborn. Indian J Pediatr 2008;75:149e55. 20. Pressler RM, Boylan GB, Morton M, Binnie CD, Rennie JM. Early serial EEG in hypoxic ischaemic encephalopathy. Clin Neurophysiol 2001;112:31e7. 21. Biagioni E, Mercuri E, Rutherford M, et al. Combined use of electroencephalogram and magnetic resonance imaging in full-term neonates with acute encephalopathy. Pediatrics 2001;107:461e8. 22. Holmes G, Rowe J, Hafford J, et al. Prognostic value of the electroencephalogram in neonatal asphyxia. Electroencephalogr Clin Neurophysiol 1982;53:60e72. 23. Grigg-Damberger M, Coker S, Halsey C. Neonatal burst suppression: its developmental significance. Pediatr Neurol 1989;5:84e92.
293
24. Menache CC, Bourgeois BF, Volpe JJ. Prognostic value of neonatal discontinuous EEG. Pediatr Neurol 2002;27:93e101. 25. McArdle CB, Richardson CJ, Hayden CK, Nicholas DA, Amparo EG. Abnormalities of the neonatal brain: MR imaging. Part II. Hypoxic-ischemic brain injury. Radiology 1987;163:395e403. 26. Haataja L, Mercuri E, Guzzetta A, et al. Neurologic examination in infants with hypoxic-ischemic encephalopathy at age 9 to 14 months: use of optimality scores and correlation with magnetic resonance imaging findings. J Pediatr 2001;138:332e7. 27. Jyoti R, O’Neil R, Hurrion E. Predicting outcome in term neonates with hypoxic-ischaemic encephalopathy using simplified MR criteria. Pediatr Radiol 2006;36:38e42. 28. Miller SP, Ramaswamy V, Michelson D, et al. Patterns of brain injury in term neonatal encephalopathy. J Pediatr 2005;146:453e60. 29. Rutherford MA, Pennock JM, Dubowitz LM. Cranial ultrasound and magnetic resonance imaging in hypoxic-ischaemic encephalopathy: a comparison with outcome. Dev Med Child Neurol 1994;36:813e25. 30. Mercuri E, Ricci D, Cowan FM, et al. Head growth in infants with hypoxic-ischemic encephalopathy: correlation with neonatal magnetic resonance imaging. Pediatrics 2000;106:235e43. 31. Gire C, Nicaise C, Roussel M, et al. Hypoxic-ischemic encephalopathy in the full-term newborn. Contribution of electroencephalography and MRI or computed tomography to its prognostic evaluation. Apropos of 26 cases. Neurophysiol Clin 2000;30:97e107.
Official Journal of the European Paediatric Neurology Society
Original article
Prediction of neurodevelopmental outcome in term neonates with hypoxic-ischemic encephalopathy c, Rabia G. Sezer d,*, Mine O¨zkol e, Muzaffer Polat a, Ays‚e S‚ims‚ek b, Nermin Tansug Pınar Bas‚pınar f, Hasan Tekgu¨l g a
Celal Bayar University School of Medicine, Department of Pediatric Neurology, Manisa, Turkey Celal Bayar University School of Medicine, Department of Pediatrics, Manisa, Turkey c Celal Bayar University School of Medicine, Department of Neonatalogy, Manisa, Turkey d Zeynep Kamil Maternity and Childrens Diseases Training and Research State Hospital, Department of Pediatrics, Istanbul, Turkey e Celal Bayar University School of Medicine, Department of Radiology, Manisa, Turkey f Celal Bayar University School of Medicine, Department of Psyhiatry, Manisa, Turkey g Ege University School of Medicine, Department of Pediatrics, Izmir, Turkey b
article info
abstract
Article history:
Background: Hypoxic ischemic encephalopathy may result in many neurological deficits. It
Received 5 May 2012
is crucial to make early diagnosis and assess the prognosis correctly.
Received in revised form
Aims: We aimed to determine the factors to evaluate the prognosis of hypoxic ischemic
7 November 2012
encephalopathy.
Accepted 17 November 2012
Methods: Electroencephalography, neuroimaging, periodic neurological exams and
Keywords:
twenty five term newborn infants with clinical evidence of hypoxic ischemic
Electroencephalography
encephalopathy.
Hypoxic ischemic encephalopathy
Results: Normal/mildly abnormal neonatal electroencephalography correlated with favor-
Magnetic resonance imaging
able outcome, particularly if neuroimaging was normal. The cranial MRI sensitivity was
Neurodevelopmental outcome
83.3%, while the specificity was 57.9%, the positive predictive value was 38.5%, and the
a developmental test at 44e48 months after discharge from the hospital were performed on
negative predictive value was 91.6%. Moderate/severely abnormal electroencephalography and multifocal/diffuse cortical or deep gray matter lesions correlated with poor outcome. Conclusions: Newborn infants with hypoxic ischemic encephalopathy should be treated in neonatal intensive care units, assessed with periodic neurological examination, electroencephalogram and brain imaging. This would help to initiate early intervention and improve the outcome of patients. ª 2012 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.
¨ stu¨nel Caddesi, 34668 Uskudar, * Corresponding author. Zeynep Kamil Hastanesi, Arakiyeci Haci Mehmet Mah., Op. Dr. Burhanettin U Istanbul, Turkey. Tel.: þ90 2163910680 1434; fax: þ90 2163910677. E-mail address: [email protected] (R.G. Sezer). 1090-3798/$ e see front matter ª 2012 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ejpn.2012.11.004
e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 1 7 ( 2 0 1 3 ) 2 8 8 e2 9 3
1.
Introduction
Despite novel approaches in diagnosis and management, hypoxic ischemic encephalopathy remains a major cause of neonatal death and brain injury. Of all neonates, even in developed countries, 2e5:1000 have brain injuries due to perinatal hypoxia-ischemia, 20%e40% of which develop significant neurologic sequela and developmental defects.1 Consequently, establishing the early diagnosis of suspected cases of perinatal asphyxia and accurately predicting the prognosis are of critical importance. For the optimal management of the cranial trauma prompt resuscitation, meticulous prophylactic, and supportive measures to prevent hyperthermia, and hypoglycemia, management of frequently seen clinical, and prolonged subclinical seizures are required. Recent evidence suggests that therapeutic hypothermia by selective head or whole-body cooling within postnatal 6 h reduces concomitant morbidity, and mortality.2,3 Thus, harmful outcomes can be minimized by administering appropriate therapy and rehabilitation as soon as possible. In the present study, we reviewed the factors that might have an impact on long-term prognosis in cases diagnosed with hypoxic encephalopathy and establish markers that can provide guidance in predicting prognosis.
2.
Materials and methods
2.1.
Study group
Newborns diagnosed with hypoxic ischemic encephalopathy at birth in Celal Bayar University, School of Medicine, Manisa, Turkey or referred to us from other centers and admitted to our neonatal intensive care unit between April 2006 and March 2008 were enrolled in the present study. The study group consisted of 25 cases with gestational ages between 37 and 41 weeks. The inclusion criteria were established as follows: (1) Apgar score <5 at 5 min; (2) metabolic acidosis, pH 7.0 (in fetal umbilical cord blood or in neonatal blood samples obtained on the first day of life); (3) delayed onset of respiration for 5 min; (4) fetal distress (such as abnormal fetal heart rate and meconium stained amniotic fluid); (5) need for assisted ventilation (mask/balloon or intubation); (6) encephalopathy (lethargy/ stupor, hypotonia and abnormal reflexes including an absent or weak suck); (7) presence of convulsions in the first 24 h of life; and (8) multiple organ dysfunction (encephalopathy and the involvement of at least one organ). Patients fulfilling at least two of the clinical findings were enrolled.4,5 The patients enrolled were evaluated regarding the presence of a medical condition in the mother during pregnancy, type of delivery, Apgar scores, birth weight, gender, blood gases, clinical findings, modified Sarnat and Sarnat hypoxic ischemic encephalopathy stage,6 and anticonvulsive therapies administered. Neonates with a gestational age <37 weeks, and neonates with intrauterine infections, trauma, central nervous system abnormalities, chromosomal abnormalities, or metabolic disorders were excluded. None of the neonates were treated with hypothermia.
2.2.
289
Imaging methods
Cranial magnetic resonance imaging (MRI) was performed on 25 newborns admitted to the hospital between 7 and 14 days after their birth. 7MRI was performed on a 1.5-T scanner (Vision; Siemens, Erlangen, Germany) under sedation with oral chloral hydrate (40 mg/kg of body weight). The cranial MRI findings of the patients were classified according to Barkovich: (1) Normal; no pathologies were observed, (2) Mild-moderate involvement; involvement of the cerebral cortex and parasagittal zone (the part of the watershed zone between anterior and medial parts of the cerebral zone and medial and posterior parts of the cerebral zone), (3) Severe involvement; involvement of the brain stem, ventral cerebellar vermis, thalamus, basal ganglia, and perirolandic regions.7
2.3.
Electroencephalography evaluations
Electroencephalography (EEG) recordings were performed for a minimum duration of 30 min with bipolar and reference electrodes using the 10e20 international system. Reducedelectrode montage with nine electrodes were used in EEG recordings. The patients diagnosed with hypoxic ischemic encephalopathy underwent EEG evaluations in the neonatal period (48e72 h) regardless of the presence of convulsions. Twenty-five patients underwent EEG and the EEG recordings were graded by a pediatric neurologist with using a previously well-described grading system (from Grade 0 to Grade 4) with respect to background activity previously8: (1) Normal EEG recordings (Grade 0); Preserved sleep state modulation and transitions, amplitude (voltage), synchrony, and symmetry appropriate for conceptional age, age-appropriate EEG patterns, (2) Mildly abnormal EEG recordings (Grade 1); Preserved sleep state modulation and transitions, but excessive sharp wave activity, (3) Moderately abnormal EEG recordings (Grade 2); asymmetry (voltage/frequency), excessive discontinuity (<20 s), excessive asynchrony for postconceptional age, dysmaturity for conceptional age (>2 weeks), (4) Severely abnormal EEG recording (Grade 3); electrocerebral inactivity, burst-suppression pattern, lowvoltage undifferentiated background rhythm activity, markedly excessive discontinuity (>20 s) and non-reactive tracings.8e10 Excessive sharp activity was defined as excessive amount of sharp wave activity (>7 activity in 30 s EEG duration) with long duration (>150 msec) and high amplitude (150 mV). Discontinuous EEG is a normal EEG pattern in premature infants. However burst-suppression pattern consisted of a nonreactive discontinuous tracing with long periods of quiescence>20 s in duration interrupted by synchronous or asynchronous bursts of poorly organized background activity. The neurologist who evaluated EEG recordings was blinded to the clinical characteristics of the patients.
2.4.
Neurodevelopmental test
Neurodevelopmental tests were performed by assessing neuromotor development between the 44th and 48th month,
290
e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 1 7 ( 2 0 1 3 ) 2 8 8 e2 9 3
to evaluate long-term prognosis for neonates diagnosed with hypoxic ischemic encephalopathy and discharged from the neonatal intensive care unit, and to determine the relationship between prognosis and electroencephalographic monitoring and imaging methods. The developmental outcomes of infants were assessed by the Denver Developmental Screening Test.11 The test is appropriate for ages between 0 and 72 months, and evaluates fine motor and gross motor skills, language, and adaptive personal/social skills. The developmental outcome scores are set for these four skills and total development. Scores between age-normative values and 20% of those values were considered near-normal. Scores between 20% and 30% of agenormative values were recorded as borderline. Scores higher than age-normative values (>30%) indicate the presence of a significant delay. In our study the patients whose scores were more than >30% of age-normative values according to Denver Developmental Screening Test were considered to have a poor outcome.
2.5.
Neurologic examination
Head circumference, cranial nerve function, muscle strength, muscle tone, coordination, posture, and reflexes were evaluated during the neurologic examination. Motor development was compared to age-normative values. Neurologic functions were classified as normal, mild disability (the presence of an abnormality on examination, which does not lead to a significant impairment in function), moderate disability (abnormality, which leads to functional impairment), and severe disability (severe functional impairment requiring special assistance at all times).12
2.6.
Neurologic outcome
To define the primary neurologic outcome, if any one of the following was established in the patients examined between the 44th and 48th month, it was regarded as a “poor” outcome: moderate or severe motor dysfunction; neurodevelopment disability (Denver scores more than >30% of age-normative values); or post-neonatal seizures. Otherwise, it was regarded as a “favorable” outcome.
2.7.
Statistical analysis
SPSS 13.0 software (SPSS Inc., Chicago, IL, USA) was used for the statistical analysis. Data were presented as the mean standard deviation or as n (%), as applicable. A chi-square test was used to compare categorical variables and a p value of <0.05 was considered significant. The ManneWhitney U test was used to compare numerical variables.
3.
Results
3.1.
Study population
Twenty-five newborns were enrolled in the study (n ¼ 12 boys, n ¼ 13 girls). The gestational ages were between 37 and 41
weeks (median age, 38 weeks). The mean birth weight of the newborns was 3165 734 g (range, 1950e4800 g), and the mean Apgar score at 1 and 5 min was 3.9 2.1 (range, 1e9) and 6.8 2.3 (range, 2e10), respectively. Fifteen neonates (60%) were delivered via the vaginal route, and 10 patients (40%) were delivered via caesarean section.
3.2. Neonatal electroencephalography evaluation and prognosis A significant relationship was determined between abnormal EEG background activity and developmental tests ( p < 0.001, Table 1). When the patients were classified with respect to the EEG background rhythms as normal or abnormal, it was noted that the patients with normal EEG findings had normal neurologic development, while 50% of those with abnormal background rhythms had developmental pathology. All patients with pathologic neurocognitive development had moderate or severe EEG background rhythm abnormalities. However, those with mild background rhythm abnormalities had normal development. All patients with normal development had mild abnormalities (Table 2).
3.3.
Magnetic resonance imaging and prognosis
Of the 12 patients with normal cranial MRI findings, 11 (91.7%) had normal development, while 1 (8.3%) had developmental disability. In contrast, 7 patients (77.8%) with mildmoderate MRI findings had normal development, while 2 (22.2%) had developmental disability. Of those neonates with severe MRI findings, only 1 (25%) had normal development, whereas the remaining 3 (75%) had developmental disability. One patient with diffuse involvement on the cranial MRI died during the neonatal period. The cranial MRI findings were significantly related with the developmental tests ( p ¼ 0.01; Table 1).
Table 1 e Neurodevelopmental outcomes according to EEG recordings and MRI findings. Total Favorable Poor pn (%) outcome n outcome n Value EEG background (n ¼ 25) Normal 13 (52) Mildly abnormal 6 (24) Moderately abnormal 3 (12) Severely abnormal 3 (12) Neuroimaging (MRI) (n ¼ 25) Normal 12 (48) Mildly/moderately 9 (36) abnormal Severely abnormal 4 (16) EEG ¼ Electroencephalography. MRI ¼ Magnetic resonance imaging.
13 6 0 0
0 0 3 3
<0.001
11 7
1 2
0.01
1
3
e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 1 7 ( 2 0 1 3 ) 2 8 8 e2 9 3
Table 2 e The predictive values of the prognostic factors in demonstrating neurodevelopmental outcomes. Sensitivity Specificity EEG background Neuroimaging (MRI) Neurologic examination Apgar score at 1 min
100% 83.3% 83.3% 33.3%
68.4% 57.9% 52.6% 57.9%
PPV
NPV
50% 38.5% 90.9% 20%
100% 91.6% 35.7% 73%
PPV ¼ Positive predictive value. NPV ¼ Negative predictive value. EEG ¼ Electroencephalography. MRI ¼ Magnetic resonance imaging.
3.4.
Modified Sarnat staging and prognosis
Of the 11 neonates in Sarnat stage 1, 10 had normal development (90.9%). Of the 10 neonates in Sarnat stage 2, 7 (70%) had normal development. Of the 4 neonates in Sarnat stage 3, 2 (50%) had normal development. No significant relationship was established with developmental tests ( p ¼ 0.08; Table 3). When the modified Sarnat staging was analyzed in 2 groups as stage 1 and stages 2e3 to examine its effect on development, the sensitivity was 83.3%, the specificity was 52.6%, the negative predictive value was 90.9%, and the positive predictive value was 35.7%.
3.5.
Apgar scores and prognosis
The Apgar scores at 1 min were not significantly related with developmental tests ( p ¼ 0.7) (Table 2). The Apgar scores at 5 min were not significantly related with developmental tests ( p ¼ 0.07); the sensitivity and specificity were 16% and 100%, respectively. These results indicated that the Apgar score at 5 min was more significant than the Apgar score at 1 min, in the assessment of long-term morbidity. Furthermore, the Apgar score at 5 min had rather high specificity (Table 3).
Table 3 e Neurodevelopmental outcomes according to Apgar scores and classification of hypoxic ischemic encephalopathy. Total n (%)
Favorable outcome n
Poor outcome n
pValue
Classification of hypoxic ischemic encephalopathya (n ¼ 25) Stage 1 11 (44) 10 1 0.08 Stage 2 10 (40) 7 3 Stage 3 4 (16) 2 2 Apgar scores at 5 min (n ¼ 25) Apgar scores at 1 (4) 0 1 0.07 5 min 5 Apgar scores at 24 (96) 19 5 5 min > 5 Apgar scores at 1 min (n ¼ 25) Apgar scores at 10 (40) 8 2 0.7 1 min 5 Apgar scores at 15 (60) 11 4 1 min > 5 a Hypoxic ischemic encephalopathy grading according to Levene’s modification of the Sarnat criteria (Evans and Levene, 1999).6
4.
291
Discussion
An accurate prediction of the prognosis in neonates with hypoxic ischemic encephalopathy is critical in terms of family counseling and neuroprotective therapy. However, it is often difficult to establish the severity of the injury and the prognosis since most of the primary injury in hypoxic ischemic encephalopathy occurs ante- and intra-partum. A number of clinical evaluation methods and neurodiagnostic tests are widely used to establish prognosis in hypoxic ischemic encephalopathy. Neonatal neurologic syndrome is of essential importance in indicating the severity of hypoxic ischemic injury and prognosis. Increased risk for sequela is particularly associated with increased severity and duration of neurologic abnormalities.13e16 The classification method of Sarnat and Sarnat has commonly been used to rapidly and correctly establish the severity of hypoxic ischemic encephalopathy.4 It can be suggested that patients with mild hypoxic ischemic encephalopathy are more likely to have better prognosis due to the high negative predictive value (90.9%). The lack of a significant relationship between developmental disability and Sarnat staging can be due to the low number of cases. Since hypoxic ischemic injury is one of the causes of depressed Apgar scores, Apgar scores have long been considered to be correlated with prognosis. However, this approach is flawed because even though the five components of Apgar scoring have equal weight, the impact of each factor on the central nervous system is different. Moreover, a number of factors, such as prematurity, drugs used by the mother, anesthetic agents used during delivery, trauma, infections, cardiopulmonary disorders, and congenital abnormalities affecting the neuromuscular system, may also lead to depressed Apgar scores. Therefore, it has been reported that while the Apgar score reflects a neonate’s condition at that particular moment, it failed to provide sufficient information regarding long-term and permanent implications of intrapartum asphyxia, and was poorly related with prognosis.17,18 Another study reported Apgar scores at 1 and 5 min to be of limited use in terms of establishing neurologic injury.1 We also established no significant relationship between developmental stages and Apgar scores at 1 and 5 min in the present study. Many reports have been published on the diagnostic and prognostic significance of EEGs in hypoxic ischemic encephalopathy.4,19,20 Abnormal EEG background activity has been demonstrated to be a good marker of neurologic sequela for both term and preterm neonates. Abnormal background activity has been described as an excessive discontinuity, burst-suppression pattern, low voltage, and electrocerebral inactivity, which were associated with a poor prognosis.21e23 The burst-suppression pattern was observed in 2 neonates. One of those neonates died and the other neonate developed a severe neurologic deficit. The burst-suppression pattern constitutes only a small proportion of the discontinuous tracing. Therefore, the interburst interval duration is of critical importance as longer intervals indicate a poorer prognosis.24 One of the three neonates with an excessive
292
e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 1 7 ( 2 0 1 3 ) 2 8 8 e2 9 3
discontinuity on EEG, classified as grade 3, died while the remaining 2 neonates had neurologic injuries. Furthermore, neurodevelopmental disability was observed in 2 neonates, classified as grade 2, with a reactive prolonged discontinuous tracing < 20 s. Our results concerning normal development in grade 1 neonates in the present study are consistent with the results reported by Menache et al.24 in 2002, when they reported good prognosis in 24 out of 25 patients with increased sharp wave activity (grade 1 patients) on EEG evaluation. Pressler et al.20 suggested that normal EEG findings in neonates with hypoxic ischemic encephalopathy in the first hours of life could be a very strong prognostic factor. Abnormality in the initial EEG may be observed due to acute brain injury, but these abnormalities can improve with time. Therefore, persistent abnormality in serial EEG may be associated with a poor prognosis.20 Although our EEG recordings were not performed in series and were not carried out in the first 48 h, the grading method we used was determined to be very effective in predicting prognosis. Cranial MRIs have been regarded to be the best imaging method in establishing hypoxic ischemic injury in the neonatal population.21,25,26 A number of scoring systems have been used for pathologic MRI findings, but as they are all rather complex, a simpler scoring system has been sought.27 In the present study, we used the simplified form of the Barkovich’s classification, which is the most commonly used scoring method.7 The optimal time for imaging brain damage with an MRI has been reported to be the first 1e4 weeks before edema and atrophy becomes evident.21 Basal ganglia and thalamic involvement are often accompanied with the involvement of perirolandic cortex and other regions of the cortex and indicate a poor prognosis.28e30 We observed severe developmental disability and microcephaly in three of our patients with basal ganglia involvement and diffuse involvement (basal ganglion and cortex). Only one neonate with diffuse involvement on MRI had normal development. In another study, patients with basal ganglia involvement had the lowest neurocognitive scores while patients with watershed involvement on MRI (mild-moderate involvement) had moderate scores.28 Of the nine neonates with mild-moderate involvement on MRI in the present study, two had developmental disability, but their disability was mild and microcephaly was not observed. A study investigating the relationship between MRI lesions with EEG findings reported that normal MRI and minimal basal ganglia lesions are always associated with a normal EEG rhythm, whereas severe basal ganglia and/or white matter diseases are always accompanied by an abnormal EEG background rhythm. Such abnormalities demonstrate an excessive discontinuity and burst-suppression pattern.21 Gire et al.31 conducted a study on 26 neonates with perinatal asphyxia in France and established diffuse cortical injury and presence of lesions in basal ganglia on MRI to be poor prognostic factors independent of EEG and clinical findings.31 Severe background rhythm abnormalities were observed on the EEG recordings of the three neonates with severe MRI involvement and they all had neurodevelopmental disability. On the other hand, a neonate with severe involvement on MRI was shown to have normal EEG findings. That particular
neonate also had normal neurologic development. Of the nine neonates with mild-moderate involvement on MRI, only two had background rhythm abnormalities on their EEG recordings. Those two neonates had neurodevelopmental disability. When factors with an effect on prognosis in patients with hypoxic ischemic encephalopathy are taken into consideration, classification with modified Sarnat criteria is still of great prognostic significance. The simplified MRI criteria that we have used appear to be practical, convenient, and reliable in establishing the prognosis. The EEG grading method was the most reliable method for establishing the prognosis in neonates with hypoxic ischemic encephalopathy in the present study. There was a significant relationship between poor prognosis with discontinuity and burst-suppression pattern. One limitation of our study was the small sample size. Additional studies with larger sample sizes should be conducted. In conclusion, a careful clinical evaluation, accompanied by specific examinations such as EEG and MRI, will play a major role in establishing prognosis. Consequently, deleterious outcomes can be minimized by rehabilitation and neuroprotective therapies, such as head-cooling and pharmacotherapy, at an early stage.
references
1. Badr Zahr LK, Purdy I. Brain injury in the infant: the old, the new, and the uncertain. J Perinat Neonatal Nurs 2006;20:163e75. 2. Glass HC, Ferriero DM. Treatment of hypoxic-ischemic encephalopathy in newborns. Curr Treat Options Neurol 2007;9:414e23. 3. Shah PS. Hypothermia: a systematic review and metaanalysis of clinical trials. Semin Fetal Neonatal Med 2010;15:238e46. 4. Sarnat HB, Sarnat MS. Neonatal encephalopathy following fetal distress: a clinical and electroencephalographic study. Arch Neurol 1976;33:696e705. 5. Carter BS, Haverkamp AD, Merenstein GB. The definition of acute perinatal asphyxia. Clin Perinatol 1993;20:287e304. 6. Evans DJ, Levene MI. Hypoxic-ischaemic injury. In: Rennie JM, Robertson NRC, editors. Textbook of neonatology. Edinburgh: Churchill Livingstone; 1999. p. 1231e51. 7. Barkovich AJ. Pediatric neuroimaging. 4th ed. Philadelphia: Lippincott Williams &Wilkins; 2005. p. 226e36. 8. Laroia N, Guillet R, Burchfiel J, McBride MC. EEG background as predictor of electrographic seizures in high risk neonates. Epilepsia 1998;39:545e51. 9. Holmes GL, Lombroso CT. Prognostic value of background patterns in the neonatal EEG. J Clin Neurophysiol 1993;10:323e52. 10. Mizrahi EM. Electroencephalographic-video monitoring in neonates, infants, and children. J Child Neurol 1994;9:46e56. 11. Frankenburg WK, Dodds J, Archer P, Shapiro H, Bresnick B. The Denver II: a major revision and restandardization of the Denver developmental screening test. Pediatrics 1992;89:91e7. 12. Tekgul H, Gauvreau K, Soul J, et al. The current etiologic profile and neurodevelopmental outcome of seizures in term newborn infants. Pediatrics 2006;117:1270e80. 13. Robertson C, Finer N. Term infants with hypoxic-ischemic encephalopathy: outcome at 3.5 years. Dev Med Child Neurol 1985;27:473e84.
e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 1 7 ( 2 0 1 3 ) 2 8 8 e2 9 3
14. Robertson CM, Finer NN. Educational readiness of survivors of neonatal encephalopathy associated with birth asphyxia at term. J Dev Behav Pediatr 1988;9:298e306. 15. Robertson CM, Finer NN, Grace MG. School performance of survivors of neonatal encephalopathy associated with birth asphyxia at term. J Pediatr 1989;114:753e60. 16. Thornberg E, Thiringer K, Odeback A, Milsom I. Birth asphyxia: incidence, clinical course and outcome in a Swedish population. Acta Pediatr 1995;84:927e32. 17. American Academy of Pediatrics, Committee on Fetus and Newborn; American College of Obstetricians and Gynecologists and Committee on Obstetric Practice. The Apgar score. Pediatrics 2006;117:1444e7. 18. Hankins GD, Speer M. Defining the pathogenesis and pathophysiology of neonatal encephalopathy and cerebral palsy. Obstet Gynecol 2003;102:628e36. 19. Sankar MJ, Aqarwal R, Aqqarwal R, Deorari AK, Paul VK. Seizures in the newborn. Indian J Pediatr 2008;75:149e55. 20. Pressler RM, Boylan GB, Morton M, Binnie CD, Rennie JM. Early serial EEG in hypoxic ischaemic encephalopathy. Clin Neurophysiol 2001;112:31e7. 21. Biagioni E, Mercuri E, Rutherford M, et al. Combined use of electroencephalogram and magnetic resonance imaging in full-term neonates with acute encephalopathy. Pediatrics 2001;107:461e8. 22. Holmes G, Rowe J, Hafford J, et al. Prognostic value of the electroencephalogram in neonatal asphyxia. Electroencephalogr Clin Neurophysiol 1982;53:60e72. 23. Grigg-Damberger M, Coker S, Halsey C. Neonatal burst suppression: its developmental significance. Pediatr Neurol 1989;5:84e92.
293
24. Menache CC, Bourgeois BF, Volpe JJ. Prognostic value of neonatal discontinuous EEG. Pediatr Neurol 2002;27:93e101. 25. McArdle CB, Richardson CJ, Hayden CK, Nicholas DA, Amparo EG. Abnormalities of the neonatal brain: MR imaging. Part II. Hypoxic-ischemic brain injury. Radiology 1987;163:395e403. 26. Haataja L, Mercuri E, Guzzetta A, et al. Neurologic examination in infants with hypoxic-ischemic encephalopathy at age 9 to 14 months: use of optimality scores and correlation with magnetic resonance imaging findings. J Pediatr 2001;138:332e7. 27. Jyoti R, O’Neil R, Hurrion E. Predicting outcome in term neonates with hypoxic-ischaemic encephalopathy using simplified MR criteria. Pediatr Radiol 2006;36:38e42. 28. Miller SP, Ramaswamy V, Michelson D, et al. Patterns of brain injury in term neonatal encephalopathy. J Pediatr 2005;146:453e60. 29. Rutherford MA, Pennock JM, Dubowitz LM. Cranial ultrasound and magnetic resonance imaging in hypoxic-ischaemic encephalopathy: a comparison with outcome. Dev Med Child Neurol 1994;36:813e25. 30. Mercuri E, Ricci D, Cowan FM, et al. Head growth in infants with hypoxic-ischemic encephalopathy: correlation with neonatal magnetic resonance imaging. Pediatrics 2000;106:235e43. 31. Gire C, Nicaise C, Roussel M, et al. Hypoxic-ischemic encephalopathy in the full-term newborn. Contribution of electroencephalography and MRI or computed tomography to its prognostic evaluation. Apropos of 26 cases. Neurophysiol Clin 2000;30:97e107.