MRI Lesions and Infants with Neonatal Encephalopathy. Is the Apgar Score Predictive?

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1 MRI Lesions and Infants with Neonatal Encephalopathy. Is the Apgar Score Predictive? E. Mercuri 1,2 M. Rutherford 1 A. Barnett 1 Chr. Foglia 1 L. Haataja 1,3 S. Counsell 4 F. Cowan 1 L. Dubowitz Abstract Objective: The aim of this study was to establish whether, in fullterm infants presenting with neonatal encephalopathy, the 1 minute Apgar score gives an indication of the presence, site or type of lesions observed on brain MRI in the neonatal period. Participants and Methods: The study cohort included 157fullterm infants who had neurological abnormalities during the first 48 hours after delivery. Infants with developmental, genetic, infective or metabolic diagnoses were excluded from the study. The infants were subdivided according to their 1 minute Apgar score into three groups as follows: Apgar score 0±3 (n = 108/ 157, 69%), 4 ± 7 (n = 29, 19%), 8 ± 10 (n = 21, 12%). Results: Severe and moderate basal ganglia and thalamic (BGT) lesions, with one exception, were only observed in the group with an Apgar score of 3 or below. Minimal BGT lesions were, with one exception, associated with scores below 7and mainly below 3. However, not all the infants with low Apgar scores had BGT lesions and 28% of the patients with Apgar scores below 3 had normal scans or only minimal white matter changes. White matter lesions without BGT involvement were equally distributed in the cohort, irrespective of the Apgar scores. Cerebral infarction and scattered white matter haemorrhages were the most common findings in infants with Apgar scores of 4 and above. The Apgar scores were not always predictive of motor outcome at 2 years but the presence and severity of the sequelae mainly reflected the site and severity of MRI findings. Conclusions: These findings stress the importance of subdividing neonatal encephalopathy into diagnostic categories according to brain lesions if one wishes to study either causative factors or outcome. Key words Neonatal Encephalopathy Apgar Score Cord ph MRI Abbreviations BGT IR MRI MCA NE PLIC SE WM Introduction basal ganglia and thalami inversion recovery magnetic resonance imaging middle cerebral artery neonatal encephalopathy posterior limb of internal capsule spin echo white matter Neonatal encephalopathy is characterised by an abnormal neurological state, with or without seizures, and affects 2 ± 8 per 1000 term infants [3, 24]. The majority of studies in the literature have focused on infants who had neonatal encephalopathy (NE) due to a perinatal hypoxic-ischaemic events [1,13,16, 31, 34], generally associated with low Apgar scores. Recently there have been new reports evaluating the relationship between Apgar Affiliation 1 Department of Paediatrics; Imperial College School of Medicine, Hammersmith Campus, London, United Kindom 2 Department of Child Neurology, Catholic University, Rome, Italy 3 Department of Paediatrics and Child Neurology, Turku University Central Hospital, Turku, Finland 4 Medical Research Council Clinical Sciences Centre, Imperial College School of Medicine, Hammersmith Campus, London, United Kingdom Correspondence Eugenio Mercuri Department of Paediatrics, Hammersmith Hospital Du Cane Road London W12 OHN United Kingdom e.mercuri@ic.ac.uk Received: November 30, 2001 Accepted after Revision: March 24, 2002 Bibliography Neuropediatrics 2002; 33: 150 ±156 Georg Thieme Verlag Stuttgart New York ISSN X

2 Mercuri E et al. MRI Lesions and ¼ Neuropediatrics 2002; 33: 150 ±156 scores and neonatal encephalopathy [10, 23]. An epidemiological study in Katmandu [11] reported that 92% of the infants with neonatal encephalopathy had an Apgar score of 3 or below at 1 minute. A Western-Australian epidemiological study, however, has emphasised that the prevalence of low Apgar scores in neonatal encephalopathy is only 38% or 31% [4]. To some extent this difference may reflect the populations studied or the causes of the encephalopathy. Accurate comparisons, however, are difficult as neither of these studies reported details of the underlying diagnosis or any brain imaging findings in these patients. The reports that do exist relating brain lesions defined on magnetic resonance imaging (MRI) in infants with NE generally deal with infants who have low Apgar scores [5,17, 22,25,29,30, 32] and there are only a few imaging studies looking at infants with neonatal encephalopathy and higher Apgar scores. These have mainly studied infants with seizures [19, 26]. There are no studies looking specifically at the relationship between Apgar scores and brain lesions in neonatal encephalopathy. The aim of this study was to establish whether in full term infants presenting with neonatal encephalopathy the Apgar score might be related to the presence, site or type of specific brain lesion seen on MRI in the neonatal period. As recent studies have also reported the diagnostic and prognostic value of cord ph in neonatal encephalopathy [18, 27, 33], we also investigated whether the assessment of cord ph might provide additional information. Patients and Methods Ethical permission for this study was obtained from the Hammersmith Hospital Research Ethics Committee. The infants described in this study are part of a large prospective cohort of term infants born at or referred to the Hammersmith Hospital, London, which is a tertiary care referral hospital, for MRI between June 1991 and August The diagnosis of neonatal encephalopathy was made in infants who had convulsions in the first 48 hours and/or showed other neurological abnormalities during the first 48 hours after delivery. Neurological abnormalities included abnormal tone, poor feeding and altered level of consciousness. As part of this study all term infants (gestation age 38 weeks or more) with neonatal encephalopathy have at least one brain MRI performed in the neonatal period between 1 and 4 weeks after delivery and detailed neurodevelopmental follow up at least up to 2 years of age performed in this hospital. Infants who subsequently had been diagnosed as suffering from genetic or metabolic syndromes or who presented with other neonatal complications, such as septicaemia or neonatal meningitis, were excluded from the study. Infants with dysmorphic features or other clinical or brain MRI findings suggesting major congenital malformation were also excluded from the study [12]. We did not exclude infants with minor abnormalities such as undescended testicles, minor hypospadias, or umbilical hernia. Clinical information, including Apgar scores at 1 and at 5 minutes and cord ph, was collected from the neonatal and maternal notes. In this study we decided to use the Apgar scores at 1 minute as the main measure for comparison with other clinical and MRI findings as a proportion of infants with neonatal encephalopathy are intubated before 5 minutes and this makes the interpretation of the 5 minute Apgar score difficult. Apgar scores at 1 minute were subdivided according to the classification suggested by Ellis et al [10] in 3 sub categories: normal (8 ± 10), borderline (4 ±7), abnormal (0 ±3). Magnetic resonance imaging MRI was performed using a 1 Tesla HPQ magnet. All the infants had early brain MRI and serial scans if they survived. The images obtained after the first week after birth (range: 7± 28 days) were used in this study as by this time brain swelling, usually present in the first days after birth, has cleared and the pattern of lesions is more evident. Earlier scans were only used in the infants who died before one week of age. Images were obtained in the transverse plane with T 1 -weighted spin echo (SE 860/20), T 2 -weighted spin echo (SE 3000/120) and age related inversion recovery (IR 3800/30/950) sequences. Images were assessed for abnormal signal intensities by an experienced observer (MAR), blinded to outcome data. The pattern of abnormal signal intensities observed was documented as follows: The posterior limb of the internal capsule (PLIC) was assessed as normal, equivocal or abnormal according to our previously published criteria [22, 30]. The basal ganglia and thalami (BGT) were assessed as normal, minimal, moderate and severe. Minimal: focal abnormalities but normal signal within the PLIC. Moderate: focal abnormalities involving the posterior lentiform nuclei and ventrolateral nuclei of the thalami with equivocal or abnormal signal intensity within the PLIC. Severe: widespread abnormalities in all regions of the basal ganglia and thalami and abnormal signal intensity within the PLIC. White matter abnormalities were documented according to which lobes of the brain were involved, whether there was a haemorrhagic element to the lesion and whether they were subcortical, periventricular or widespread. In some neonates minimal changes of long T 1 and long T 2 in the periventricular white matter are difficult to differentiate from normal appearances and for the purposes of the present study these were not classified as abnormal. Abnormalities in the white matter were described as moderate or severe. Moderate: small focal lesions with a short T 1 and short T 2, consistent with haemorrhage and/or areas with an exaggerated long T 1 and long T 2 but no loss of grey/white matter differentiation. Severe: more marked areas of abnormality with larger haemorrhages or exaggerated long T 1 and T 2 with loss of grey/white matter differentiation, consistent with infarction. The cortical abnormalities consisted of ªhighlightingº with an abnormally high signal on T 1 -weighted images and were graded according to how many cortical sites were involved. The scans were classified according to the predominant pattern observed into: 151

3 Fig.1 Mild basal ganglia lesions. Inversion recovery sequence (IR 860/ 30/9500). There are bilateral abnormal signal intensities in the lateral lentiform nuclei (short arrow). The signal intensity from myelin within the posterior limb of the internal capsule is normal (long arrow). Fig. 2 Moderate white matter abnormalities. T 1 -weighted spin echo sequence (SE 860/20). There are several foci of high signal intensity within the white matter consistent with haemorrhage (arrows). The image is slightly rotated. 152 Fig. 3 Severe basal ganglia lesions withsubcortical white matter abnormalities. T 1 - weighted spin echo sequence (SE 860/20). There is extensive abnormal signal intensity in the lentiform nuclei (long arrow) and in the region of the ventro lateral nuclei of the thalami (short arrow). There is loss of the normal signal intensity from myelin in the posterior limb of the internal capsule. Subcortical white matter abnormalities were most prominent around the central sulcus (not shown). Fig. 4 Severe basal ganglia lesions and severe white matter abnormalities. T 1 -weighted spin echo sequence (SE 860/20). There is complete loss of grey white matter differentiation consistent withearly infarction. There is a loss of the normal signal intensity from myelin within the posterior limb of the internal capsule (arrow). There is extensive high signal intensity around the surface of the brain consistent with subarachnoid haemorrhage. There is loss of the normal detail within the basal ganglia and thalami with a slightly high signal intensity throughout the lentiform nuclei. This signal intensity became more abnormal during the following week. a) Normal: normal basal ganglia and thalami, white matter and cortex. All the infants in this group had shown brain swelling on the early scans performed in the first days of life. b) Minimal basal ganglia and thalami: focal abnormalities in the basal ganglia and thalami, normal PLIC and normal white matter and cortex (Fig.1). c) Moderate white matter: focal abnormalities in the white matter with or without cortical involvement but with normal basal ganglia, thalami and PLIC (Fig. 2). d) Moderate basal ganglia and thalami: focal abnormalities in the basal ganglia and thalami, equivocal or abnormal PLIC, with or without cortical highlighting. e) Moderate white matter and basal ganglia and thalami: focal abnormalities in the white matter and mild or moderate abnormalities in the basal ganglia and thalami with or without cortical involvement. f) Severe white matter: multifocal abnormalities with or without white matter haemorrhage with normal basal ganglia and thalami and PLIC. g) Severe basal ganglia and thalami with subcortical white matter: widespread abnormalities in the basal ganglia and thalami always with abnormal PLIC with focal abnormalities in the subcortical white matter and in the cortex (Fig. 3). h) Severe basal ganglia and thalami with diffuse white matter: widespread abnormalities in the basal ganglia and thalami with abnormal PLIC with widespread abnormalities in the white matter and cortex (Fig. 4). Mercuri E et al. MRI Lesions and ¼ Neuropediatrics 2002; 33: 150±156

4 100 MRI findings and Apgar scores Apgar scores Percent (%) Basal ganglia White matter Infarct Normal scans Percent (%) at 1 and 5 min. 0 3 at 1 min. but>3at5min CP/died Normal outcome Fig. 5 Correlation between Apgar scores at 1 minute and pattern of lesion on brain MRI. Fig. 6 Correlation between Apgar scores at 5 minutes and outcome in the children with low Apgar scores at 1 minute. i) Arterial infarction: Evidence of infarction with loss of grey/ white matter differentiation and abnormally long T 1 and T 2 within the territory of one artery. Usually unilateral middle cerebral artery with or without involvement of ipsilateral basal ganglia, thalamus and/or internal capsule. j) Borderzone or parasagittal infarction: Bilateral areas of white matter infarction in more than one arterial territory. May be asymmetrical, usually with no or minimal basal ganglia and thalami involvement. Neurodevelopmental outcome Twenty-eight children died, 50 had cerebral palsy and 79 had no cerebral palsy at 2 years. Correlation between Apgar scores, cord ph and MRI findings Of the 108 children who had Apgar scores equal or below 3, 68 had BGT lesions with or without white matter involvement, 10 had only white matter involvement, three had cerebral infarction and 27had a normal MRI. Mercuri E et al. MRI Lesions and ¼ Neuropediatrics 2002; 33: 150 ±156 Neurodevelopmental outcome All the children were considered abnormal if they had signs of cerebral palsy by two years of age. Developmental difficulties other than those related to the motor domain are not included in this outcome data. Results Of the 191 infants who presented with neonatal encephalopathy at 38 weeks of gestation or more, fourteen had incomplete data (9 had no 1 minute Apgar scores recorded and 5 had late MRI scans) and 3 were unavailable for follow up. Nine were excluded because of congenital malformation (2) or genetic (2), viral (3) or metabolic (2) syndromes. A further eight infants were excluded because they had been enrolled in an intervention trial (hypotermia) [2]. The final cohort consisted of 157infants. Apgar scores and cord ph The Apgar scores at 1 minute were equal or below 3 in 108, between 4 and 7in 29 and above 7in 20 infants. Umbilical cord ph measurements were available in 104 of the 157infants. This was equal or above 7in 48 and below 7in 56. MRI Severe BGT lesions with or without white matter lesions were seen in 44 infants, moderate BGT lesions, with or without white matter lesions in 15 and mild BGT lesions in 14. White matter lesions without involvement of the basal ganglia were reported in 22 cases, and were severe in 7and moderate in 15. Cerebral infarction was observed in 27infants, this was arterial in 23 and borderzone in 4. Normal scans or minimal white matter changes were seen 35 infants. Of the 29 children who had Apgar scores between 4 and 7, four had BGT lesions, five had white matter lesions, 13 had cerebral infarction and seven had a normal MRI. Of the 20 children who had scores above 7, one had BGT lesions, seven had white matter lesions, 11 had arterial infarction and one had a normal MRI. A low cord ph (< 7.0) was found in 48 of the 72 infants (68%) with Apgar scores below 3 in whom cord ph was available, in 7of the 23 (31%) with Apgar scores between 4 and 7, and in none of the infants with Apgar above 7. Details of the distribution of cord ph in the cohort subdivided according to Apgar scores and MRI findings are shown in Table 1. Apgar scores, cord ph, MRI findings and outcome Tables 1 and 2 show details of the correlation between Apgar scores, cord ph and outcome. The sensitivity of Apgar scores and cord ph for predicting outcome was 0.79 and 0.65 respectively. Specificity was 0.39 for the Apgar scores and 0.53 for cord ph. The number of MRI subgroups was too big to allow any meaningful statistical analysis. Apgar scores at 5 minutes and outcome in infants with low Apgar scores at 1 minute Of the 108 infants who had Apgar scores equal or below 3 at 1 minute, 45 still showed low Apgar scores at 5 minutes and 63 had scores above 3. Fig. 6 shows the distribution of normal and abnormal outcome in the 2 subgroups. 153

5 Table 1 Correlation between Apgar scores at 1 minute, Phand lesions 0 (n = 29) 1 (n = 28) 2 (n = 30) 3 (n = 21) 4 (n = 9) 5 (n = 10) 6 (n = 5) 7 (n = 5) 8 (n = 6) 9 (n = 14) Severe BGT (n = 14) Severe BGT (n = 30) Mod BGT (n = 8) Mod BGT (n = 7) Min BGT (n = 14) Sev WM (n = 7) Mod WM (n = 15) MCA infarcts (n = 23) Parasagittal (n = 4) Normal/ min WM (n = 35) JJ ±±± J ±JJ QlJ±± ±±±±±± Q ± mq m ljjj JJJ ±± JJ± mjjj ±±± m Ql J± mj± ± ±±± Jl l J mmml mml± J J m± m J ll± ± m ± m ± m l± J± m ± ± ± mm±± mqj± mmql JJ ± m ll mm mm± m ml± mm±± mmm ±±±± mmlj JJJJ J±± ml ml mjj±± mjjj m mm m BGT = basal ganglia and thalami; WM = white matter; MCA = middle cerebral artery; min = minimal; mod = moderate; m =>7.1;Q = 7.0 ± 7.1; l = 6.91±6.99; J = 6.9; ± = not available 154 Table 2 Correlation between Apgar scores at 1 minute, outcome and lesions Severe BG n Severe BG nnnn nnn 9999 nn n nn9 99nn9 n9 Mod BG n &n nn nnn Mod BG n nnn nn n Min BG & &&&& &n&& & n &n & Sev WM n n&& n n n Mod WM & & && && & && & & &&&&& MCA infarcts & nn nn n&& & &n& n&&n &n&&& nn Parasagittal && n& Normal/ min &&&& &&&&& && &&&&& &&&&& & &&&&& &&&& & && & BGT = basal ganglia and thalami; WM = white matter; MCA = middle cerebral artery; min = minimal; mod = moderate; & = normal outcome; n = cerebral palsy; 9 = died Mercuri E et al. MRI Lesions and ¼ Neuropediatrics 2002; 33: 150±156

6 Mercuri E et al. MRI Lesions and ¼ Neuropediatrics 2002; 33: 150 ±156 Discussion Our study confirms previous observations that not all the infants with neonatal encephalopathy have low Apgar scores [6, 7,15]. Nearly a third of the infants with neonatal encephalopathy in our cohort had scores of 4 and above; 19% had scores between 4 and 7and 12% above 7. This observation holds true even though in our cohort we deliberately excluded infants with a cause for their encephalopathy that was clearly antenatal or infective in origin with established abnormality on MRI brain scan or associated with major congenital malformations. Using MR imaging during the neonatal period we have shown that the pattern of lesions in patients with low Apgar scores was different from that found in patients with higher Apgar scores. Cerebral infarction, either in an arterial territory or parasagittal distribution, and scattered haemorrhages in association with moderate white matter changes, were the most common findings in infants with Apgar scores of 4 and above. White matter lesions without BGT involvement were equally distributed in the groups with low and higher Apgar scores. In contrast, severe and moderate BGT lesions, with one exception, were only observed in the group with Apgar scores of 3 or below. Minimal BGT lesions were also more frequently associated with low scores. The association between low Apgar scores and BGT lesions is not surprising as BGT lesions are known to be associated with acute hypoxic insults and low Apgar scores may reflect a recent ongoing acute hypoxic events. However, not all the infants with low Apgar scores had BGT lesions and 28% of the patients in this group had normal scans or only minimal white matter changes. Although several reports have suggested that cord ph is a better marker of acute hypoxic events than the Apgar scores [27, 33], in our cohort the association between low cord ph and basal ganglia lesions was lower (64%) than that found between low Apgar scores and basal ganglia lesions (90%). Low cord phs were found in approximately half of the infants with normal scans and normal ph in infants with severe basal ganglia lesions. These results are at variance with MacLennans suggestion in the recently published consensus report that children should not be diagnosed as having a brain lesion of perinatal origin in the presence of normal cord ph [18]. It is of interest that in our study the infants with low Apgar scores with or without a low cord ph either had severe and mainly BGT damage or near normal scans. In contrast, in the group of infants with higher Apgar scores only one had a normal scan, though the lesions were not as severe as the bilateral BGT lesions seen in the low Apgar group. One possible explanation of this difference is that in the group with higher Apgar scores and cord ph the lesions are probably the result of the combination of factors. We and others have recently reported a significant occurrence of thrombophilic abnormality in infants with neonatal infarction [8, 21]. These abnormalities also occur in those with scattered white matter haemorrhage but are rarely found in the severe group with bilateral basal ganglia lesions (personal observation [28]). It could, therefore, be that a moderate insult, associated with borderline or normal Apgar scores, in the presence of thrombophilic abnormality or other predisposing factors, may lead to focal lesions secondary to thrombosis or embolus. In contrast, in the absence of such factors, the degree of insult required to cause permanent damage needs to be more severe, and will be more likely associated with lower Apgar scores and low cord ph and a different pattern of injury. The BGT are well known to be the most developmentally and metabolically active tissues at term and most susceptible to acute hypoxic insult should it be severe enough. Clearly however, some infants, despite having low Apgar scores did not succumb to long-term damage. Why this should be so and what protects some infants from severe damage is the most important question in this area of research. Although the aim of this paper was not to establish the prognostic value of Apgar scores and cord ph, in agreement with previous studies [9,14] we also found that both the Apgar scores at 1 minute and cord ph were poor predictors of outcome. We also looked at the predictive value of the Apgar scores at 5 minutes in the subgroup who had low scores at 1 minute but although children with better scores (> 3) at 5 minutes tended to have a better outcome than those with persistently low scores (58% versus 43%), both normal and abnormal outcome could still be found in both subgroups. The variability of outcome reflected the variability of lesions on MRI. As previously reported [5,17, 20, 21, 29], we confirmed that moderate and severe basal ganglia lesions were always associated with severe abnormal outcome while normal or near normal scans were always associated with a normal motor outcome at the age of two, irrespective of the Apgar score or cord ph. Further studies are in progress to establish whether these infants show minor neurological signs or other sequelae at school age. In conclusion, this study, for the first time, looks at the pattern of brain lesions in relation to Apgar scores in infants with neonatal encephalopathy. These findings emphasise the importance of subdividing neonatal encephalopathy into diagnostic categories according to lesions if one wishes to study either causative factors or outcome. Acknowledgments This study was supported by grants from ACTION RESEARCH, SCOPE and Medical Research Council. References 1 Adamson SJ, Alessandri LM, Badawi N, Burton PR, Pemberton PJ, Stanley FJ. Predictors of neonatal encephalopathy in full term infants. BMJ 1995; 311: 598±602 2 Azzopardi D, Robertson N, Cowan F, Rutherford M, Rampling M, Edwards D. Pilot study of treatment with whole body hypothermia for neonatal encephalopathy. Pediatrics 2000; 106: 684 ± Badawi N, Kurinczuk JJ, Keogh JM et al. Antepartum risk factors for newborn encephalopathy: the Western Australian case-control study. 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