Patterns of brain injury and outcome in term neonates presenting with postnatal collapse A Foran, 1,2 C Cinnante, 3 A Groves, 2 D V Azzopardi, 2 M A Rutherford, 1 F M Cowan 2,4 1 Imaging Sciences Department, Imperial College, London, UK; 2 Department of Paediatrics and Neonatal Medicine, Imperial College, London, UK; 3 Diagnostic and Interventional Neuroradiology Unite, Fondazione Ospedale Maggiore Policlinico Mangiagalli e Regina Elena, Milan, Italy; 4 Department of Neonates, Rotunda Hospital, Dublin, Ireland Correspondence to: Dr F M Cowan, Department of Paediatrics, 5th Floor Hammersmith House, Hammersmith Hospital, Du Cane Road, London W12 0HS, UK; [email protected]Accepted 6 October 2008 Published Online First 3 November 2008 ABSTRACT Objective: To document perinatal events, brain imaging, neurophysiology and clinical outcome in term infants with early postnatal collapse (PNC). Design: Tertiary referral centre, retrospective case review (1993–2006). Patients: Infants born at >36 weeks’ gestation with early (,72 h) PNC. Peri-partum and post-collapse data were collated with clinical, electrophysiological, neuroimaging and autopsy data and neurodevelopmental outcome. Results: Twelve infants were studied; median gestation 39 weeks (36–41), birth weight 3150 g (1930–4010). Ten were born vaginally (including occipitoposterior (1), breech (2), water birth (2), ventouse/forceps (3)), and two by emergency caesarean section. Median Apgar scores were 9 (3–9) and 10 (8–10) at 1 and 5 min; median cord pH was 7.29 (7.18–7.34). All were thought to be well after birth. The median age at PNC was 75 min (10 min to 55 h). All infants required extensive resusci- tation. The median pH after PNC was 6.75 (6.39–7.05). Seven infants became severely encephalopathic, with severely abnormal EEG/aEEG recorded within 12 h. MRI showed acute severe hypoxic–ischaemic injury. All died. One infant showed rapid recovery, had mild encephalo- pathy, and good outcome. Four infants had severe respiratory illness, normal background EEG, and MRI showing slight white matter change (n = 3) or a small infarction (n = 1). All had a good 2-year outcome. Conclusions: In this term cohort, early PNC was generally followed by severe encephalopathy, acute central grey matter injury and poor outcome, or severe respiratory illness, slight white matter change and good outcome. Early EEG and MRI predicted outcome accurately. However, no antepartum, intrapartum or other aetiological factors were identified. Further investigation is needed in larger PNC cohorts. A sudden early postnatal collapse (PNC) in a previously apparently healthy term infant is rare, but has been described and reviewed. 1–5 The inci- dence of such events appears to be 0.03–0.5/1000 live births with a high mortality. 45 Current literature provides only a limited description of the clinical events around the time of collapse and minimal data on electrophysiological or neuroimaging findings. The advent of bedside electrophysiological mon- itoring and the increased availability of MRI allow more detailed study of the aetiology of PNC. After perinatal brain injury, electrophysiological data 6–9 enable global prognostication, and MRI provides detailed information on the pattern of lesions 10 11 and is an excellent predictor of outcome after hypoxic– ischaemic insults and stroke. 12–17 Specific patterns of abnormality are also seen in hypoglycaemia 18 19 and metabolic 20 and infective disorders. 21 The aim of this study was to document the clinical, electrophysiological (EEG or amplitude integrated aEEG), cranial ultrasound (US), MRI and autopsy findings in a cohort of such infants to try to understand the aetiology of collapse and document outcome. PATIENTS AND METHODS Infants >36 weeks’ gestation, inborn or referred to the Hammersmith and Queen Charlotte’s Hospitals (1993–2006) for specialist opinion, who appeared healthy at birth but suffered acute PNC (,72 h after delivery) requiring extensive resusci- tation, were included in the study. Data were extracted from case notes, referral letters and information obtained from parents at the time of admission. Perinatal data included onset and progress of labour, fetal distress, analgesia, acute antepartum or intrapartum events, delivery, gestational age, sex, birth weight, head circumference, Apgar score and cord pH. Postnatal data included presentation, time of collapse, relation to feeding, resuscitation required, post- collapse pH and subsequent clinical course. Cerebral function monitor (aEEG), EEG, US and What is already known on this topic c A small subset of term infants die from postnatal collapse similar to sudden infant death syndrome and often when prone and unsupervised with first-time mothers. c There is little literature detailing the neuroimaging and electrophysiology findings in these infants. What this study adds c Apparently well term neonates presenting with early postnatal collapse appear to divide into two apparently distinct clinical groups. c Those without respiratory disease have severe encephalopathy, brain MRI findings that show severe basal ganglia and thalami injury, and a poor outcome, whereas those with a severe respiratory course have mild to moderate white matter abnormality and a good outcome. c Further study into postnatal collapse is warranted. Original article F168 Arch Dis Child Fetal Neonatal Ed 2009;94:F168–F177. doi:10.1136/adc.2008.140301 group.bmj.com on February 27, 2014 - Published by fn.bmj.com Downloaded from
Transcript
Patterns of brain injury and outcome in termneonates presenting with postnatal collapse
A Foran,1,2 C Cinnante,3 A Groves,2 D V Azzopardi,2 M A Rutherford,1 F M Cowan2,4
1 Imaging Sciences Department,Imperial College, London, UK;2 Department of Paediatrics andNeonatal Medicine, ImperialCollege, London, UK;3 Diagnostic and InterventionalNeuroradiology Unite,Fondazione Ospedale MaggiorePoliclinico Mangiagalli e ReginaElena, Milan, Italy; 4 Departmentof Neonates, Rotunda Hospital,Dublin, Ireland
Correspondence to:Dr F M Cowan, Department ofPaediatrics, 5th FloorHammersmith House,Hammersmith Hospital, Du CaneRoad, London W12 0HS, UK;[email protected]
Accepted 6 October 2008Published Online First3 November 2008
ABSTRACTObjective: To document perinatal events, brain imaging,neurophysiology and clinical outcome in term infants withearly postnatal collapse (PNC).Design: Tertiary referral centre, retrospective casereview (1993–2006).Patients: Infants born at >36 weeks’ gestation with early(,72 h) PNC. Peri-partum and post-collapse data werecollated with clinical, electrophysiological, neuroimaging andautopsy data and neurodevelopmental outcome.Results: Twelve infants were studied; median gestation39 weeks (36–41), birth weight 3150 g (1930–4010).Ten were born vaginally (including occipitoposterior (1),breech (2), water birth (2), ventouse/forceps (3)), andtwo by emergency caesarean section. Median Apgarscores were 9 (3–9) and 10 (8–10) at 1 and 5 min;median cord pH was 7.29 (7.18–7.34). All were thoughtto be well after birth. The median age at PNC was 75 min(10 min to 55 h). All infants required extensive resusci-tation. The median pH after PNC was 6.75 (6.39–7.05).Seven infants became severely encephalopathic, withseverely abnormal EEG/aEEG recorded within 12 h. MRIshowed acute severe hypoxic–ischaemic injury. All died.One infant showed rapid recovery, had mild encephalo-pathy, and good outcome. Four infants had severerespiratory illness, normal background EEG, and MRIshowing slight white matter change (n = 3) or a smallinfarction (n = 1). All had a good 2-year outcome.Conclusions: In this term cohort, early PNC wasgenerally followed by severe encephalopathy, acutecentral grey matter injury and poor outcome, or severerespiratory illness, slight white matter change and goodoutcome. Early EEG and MRI predicted outcomeaccurately. However, no antepartum, intrapartum or otheraetiological factors were identified. Further investigation isneeded in larger PNC cohorts.
A sudden early postnatal collapse (PNC) in apreviously apparently healthy term infant is rare,but has been described and reviewed.1–5 The inci-dence of such events appears to be 0.03–0.5/1000 livebirths with a high mortality.4 5 Current literatureprovides only a limited description of the clinicalevents around the time of collapse and minimal dataon electrophysiological or neuroimaging findings.
The advent of bedside electrophysiological mon-itoring and the increased availability of MRI allowmore detailed study of the aetiology of PNC. Afterperinatal brain injury, electrophysiological data6–9
enable global prognostication, and MRI providesdetailed information on the pattern of lesions10 11 andis an excellent predictor of outcome after hypoxic–ischaemic insults and stroke.12–17 Specific patterns ofabnormality are also seen in hypoglycaemia18 19 andmetabolic20 and infective disorders.21
The aim of this study was to document theclinical, electrophysiological (EEG or amplitudeintegrated aEEG), cranial ultrasound (US), MRIand autopsy findings in a cohort of such infants totry to understand the aetiology of collapse anddocument outcome.
PATIENTS AND METHODSInfants >36 weeks’ gestation, inborn or referred tothe Hammersmith and Queen Charlotte’sHospitals (1993–2006) for specialist opinion, whoappeared healthy at birth but suffered acute PNC(,72 h after delivery) requiring extensive resusci-tation, were included in the study.
Data were extracted from case notes, referralletters and information obtained from parents atthe time of admission. Perinatal data includedonset and progress of labour, fetal distress,analgesia, acute antepartum or intrapartum events,delivery, gestational age, sex, birth weight, headcircumference, Apgar score and cord pH. Postnataldata included presentation, time of collapse,relation to feeding, resuscitation required, post-collapse pH and subsequent clinical course.Cerebral function monitor (aEEG), EEG, US and
What is already known on this topic
c A small subset of term infants die from postnatalcollapse similar to sudden infant deathsyndrome and often when prone andunsupervised with first-time mothers.
c There is little literature detailing theneuroimaging and electrophysiology findings inthese infants.
What this study adds
c Apparently well term neonates presenting withearly postnatal collapse appear to divide intotwo apparently distinct clinical groups.
c Those without respiratory disease have severeencephalopathy, brain MRI findings that showsevere basal ganglia and thalami injury, and apoor outcome, whereas those with a severerespiratory course have mild to moderate whitematter abnormality and a good outcome.
c Further study into postnatal collapse iswarranted.
Original article
F168 Arch Dis Child Fetal Neonatal Ed 2009;94:F168–F177. doi:10.1136/adc.2008.140301
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MRI findings, along with results of infective and metabolicinvestigations and autopsy, were assessed.
ImagingCranial US scansFrom 1993 to 2002, US scans were obtained using an AdvancedTechnology Laboratory (ATL) Ultramark-4 mechanical sectorscanner with 5.0 and 7.5 MHz probes (Philips Medical Systems,Best, The Netherlands). Subsequently a Siemens Antaresscanner with a multifrequency transducer (Siemens MedicalSolutions, Bracknell, UK) was used. Scans were printed on high-quality paper (ATL) or stored on disc (Antares). All images wereassessed by an experienced ultrasonographer (FMC).
MRI scansMost infants had a brain MRI scan in the neonatal period.Infants were examined during natural sleep after a feed or weresedated with oral chloral hydrate (30–50 mg/kg). They wore earprotection and were monitored with pulse oximetry andelectrocardiography. A neonatologist experienced in MRI waspresent throughout the scan.
Imaging parametersMRI was performed using a 1.0 T dedicated neonatal magnet(Oxford Magnet Technology/Marconi Medical Systems,Cleveland, Ohio, USA), a 1.5 T Philips Eclipse Scanner or a3.0 T Philips scanner. T1-weighted and T2-weighted sequenceswere acquired in the transverse plane, and T1-weightedsequences in the sagittal plane. Diffusion-weighted imaging(DWI) was not performed for all infants; when available and ofadequate quality, apparent diffusion coefficient maps wereanalysed visually and results recorded. All images were assessedby experienced neuroradiologists (CC and MAR).
Image analysisAll images were assessed for1. normal anatomy and structural development;
2. acute injury, ie, abnormal signal intensity (SI) within basalganglia and thalami (BGT), posterior limb of the internalcapsule (PLIC), brainstem or cortex;
3. evidence of more prolonged/sub-acute problems, ie, whitematter (WM) abnormality/extensive cortical abnormality;
4. haemorrhage, intraparenchymal or extracerebral;
5. evidence of long-standing established injury;
6. unusual patterns of injury or SI suggestive of metabolic orinfective disorders.
OutcomeAt a minimum age of 24 months, surviving infants had astandardised neurological examination,22 23 Griffith neurodeve-lopmental assessment24 and head circumference measure-ment.25 26 Normal outcome was defined as a developmentalquotient (DQ) .85 with normal neurological examination.
Ethics approval for the brain MRI studies from theHammersmith Hospital ethics committee and parental permis-sion were obtained in all cases.
RESULTSInfantsTwelve infants fulfilled the study criteria. All but one werewhite, five were male, one was a twin, and nine were first born.Five were outborn. Table 1 gives details of these infants, alongwith descriptions of perinatal and postnatal events.
Only one infant, a twin, was ,3rd centile for weight, and twowere (9th centile. No infant had a head circumference (9thcentile. No infant had an abnormally low cord pH or persistentlylow Apgar scores, or required major resuscitation at birth. Allinfants were considered healthy, initially stayed with theirmother, and were fed. One infant (case 7) born at 36 weeksweighing 1930 g was admitted at 2 h for grunting. He rapidlyimproved and was tolerating full feeds and ready for discharge tothe postnatal ward at the time of unexpected collapse at 55 h.
Maternal and prelabour dataMedian maternal age was 31 years (range 23–38). Two mothershad documented prior medical problems: one hypothyroidismand one a right-sided hemiplegia first noticed at 16 months ofage and attributed to perinatal problems. Three mothersdeveloped hypertension in the third trimester (33–35 weeks):in two this prompted induction of labour; the third mother didnot require treatment and was normotensive at delivery. Threemothers mentioned concerns about fetal movements but .10kicks were always noted in a 12 h period. One mother (case 5)was involved in a car accident 6 days before delivery; she wasunharmed, and a cardiotocogram (CTG) was reported normal.No other intercurrent illnesses or acute events were notedantenatally.
Labour and delivery-related dataLabour started spontaneously in eight mothers and was inducedin four (table 1); four labours were augmented with syntocinin.Three mothers had epidurals; no mother had a generalanaesthetic.
Three fetuses had documented CTG abnormalities: one hadfetal tachycardia thought to be secondary to maternal fever andtwo had early decelerations. In the other 10 mothers, CTGmonitoring was continuous in seven and intermittent in two (inthe water bath) and reported normal. Information was notavailable for one mother.
No infant was exposed to a sentinel event. Two mothers, oneof whom had an epidural and one of whom laboured in a waterbath, developed a fever >37.5uC during labour (cases 1 and 10);neither had proven infection. The maximum length ofmembrane rupture was 24 h. The length of the second stage,available for 8/10 infants, was .2 h in four, maximally170 min. The two mothers delivered by caesarean section forbreech presentation were not in 2nd stage.
Seven infants were born by spontaneous vaginal delivery(including one occipitoposterior presentation, two water births),three were born vaginally by forceps, and two by semi-emergencycaesarean section; none was born by elective caesarean section.
Placental information was available for only three infants.The histopathology was normal for one of the infants who hada post-mortem examination, and the placenta was reported tolook normal for two other infants, both of whom also died.
PNC-related dataThe median age at collapse was 75 min (range 10 min to 55 h).All infants required extensive resuscitation including cardio-pulmonary resuscitation and intubation. The median pH afterPNC was 6.75 (range 6.39–7.05) and base deficit 21.7 mmol/l(range 11.3–29.6).
Six infants appeared to collapse while feeding at theirmother’s breast or within minutes of the first breast feed.Two infants were found collapsed having been sleeping withtheir mother. In 10 infants, colour change, pallor or collapse was
Original article
Arch Dis Child Fetal Neonatal Ed 2009;94:F168–F177. doi:10.1136/adc.2008.140301 F169
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noted acutely, and resuscitation was started immediately afterconcerns were raised. One infant (case 2) was found in hermother’s arms while she slept; this infant had no heart ratewhen found, and the time of collapse is unknown but thoughtto be within 1 h. One infant (case 8) was confirmed collapsed20 min after birth and had a slow heart rate at that time;however, the father had been concerned that the infant wasquiet for 10 min before this.
The infants had early electrophysiological monitoring andbrain imaging as part of their clinical assessment. Theyunderwent neurometabolic work-up as individually indicated,the range of investigations including amino acids, organic acids,ammonia, uric acid, urinary sulphite oxidase and blood andcerebrospinal fluid glucose, lactate, pyruvate, amino acids, verylong chain fatty acids and carnitine profile. No result wasdiagnostically positive, although lactate concentrations werehigh in some infants initially but settled. C-reactive proteinconcentrations, blood cultures, virus isolation and PCR, andcongenital infection screens were all normal/negative. No infanthad clinical evidence of congenital malformations includingcongenital heart disease. All echocardiograms obtained (cases 2–4,6, 8, 9, 12) showed normal heart structure. No infant had evidenceof hypoglycaemia, anaemia, clotting or thrombophilic abnorm-ality (full testing carried out in four infants, cases 1, 4, 6 and 8).
The subsequent postnatal course appeared to be most easilydistinguished by the presence or absence of ongoing majorrespiratory disease.
Infants without respiratory disease (cases 1–8)Seven infants (cases 1–7) required ongoing mechanical ventilationbecause of lack of respiratory drive after the collapse. However, allseven required minimal support (maximum positive inspiratorypressure 18 cm H2O, maximum fractional inspiratory oxygen0.30). These seven infants were severely encephalopathic, and allhad an abnormal aEEG or EEG with a burst suppression pattern(n = 3), isoelectric pattern (n = 3) or sustained seizure activity(n = 1) within 24 h of the collapse. Six of these seven were foundbreast feeding in their mother’s arms at the time of collapse. Theirclinical state was consistent with hypoxic–ischaemic encephalo-pathy (HIE) stage 3.27 One infant (case 8) made a very rapidrecovery after PNC, was self-ventilating in air within 10 min, andhad no further respiratory difficulties. She was initially irritable,with high-pitched cry, hypertonic and hyper-reflexic and had oneclinical seizure. An EEG recorded on day 4 had a normalbackground with no electrical seizures seen.
US scansSix of the seven severely encephalopathic infants (cases 1–6) hadcranial US scans on day 1: three were available for review (cases 2–4); two showed mild WM trigonal (cases 1 and 3) and one mildBGT (case 4) echogenicity 2 h after the collapse. The others werereported to be normal. Limited sequential scans were available forthe group, but the pattern appeared to be of a swollen appearanceto the WM on days 2–4 which settled, with BGT abnormalitybecoming increasingly obvious and persisting after day 2. Theinfant who survived to day 36 (case 3) developed smallcaudothalamic cysts. A US scan in case 8 was reported to be normal.
MRI scansMRI scans were performed at median 4 days (range 1–9) aftercollapse in this group. All seven severely encephalopathic infantshad findings typical of acute severe perinatal hypoxia–ischaemia(fig 1) with swollen featureless appearances and/or abnormal SI inTa
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Original article
Arch Dis Child Fetal Neonatal Ed 2009;94:F168–F177. doi:10.1136/adc.2008.140301 F171
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the BGT and loss of the normal signal from PLIC.17 All also hadbrainstem injury evidenced by swelling and/or loss of the normal SIfrom myelination (fig 1). Four had additional cortical highlightingoften seen with an acute recent hypoxic–ischaemic insult in terminfants. Only two infants had ‘‘slit-like’’ ventricles as a marker ofmore generalised brain swelling; in three infants the ventricles wereof normal size and in two they were mildly dilated.
All infants showed an abnormal appearance to the WMtypically seen with hypoxia–ischaemia with low SI on T1-weighted images and high SI on T2-weighted images. In twoinfants, there were regions of more widespread loss of greymatter (GM)/WM differentiation. One infant had a smallpunctate WM lesion (case 4, fig 2). Six infants had evidence ofextracerebral haemorrhage in the subdural space, three of whomalso had small subdural haemorrhages around the cerebralhemispheres. A small punctate haemorrhagic lesion in thecerebellum was seen in case 3 on day 5 and mild vermis atrophyon day 13. The MRI scan of the mildly encephalopathic infant(case 8) showed a slight but similar WM change to the otherinfants but normal BGT and cortex, but had some extracerebralhaemorrhage in the posterior fossa.
DWI was available for five severely encephalopathic infants.All showed restricted diffusion in the BGT, indicating recent
injury, and, in the three where DWI was acquired at the level ofthe brainstem, there was additional focal restriction within thecorticospinal tracts. In one infant (case 5) imaged on day 9, therestriction was still very marked (fig 1). In a further infant (case1), there was more widespread restricted diffusion involving thecortex and WM.
The imaging appearance in all seven severely encephalopathicinfants was consistent with recent injury around the time ofbirth (figs 1 and 2). None showed changes consistent withinjury established before delivery.
Gadolinium was used for case 1, which enhanced the corticalhighlighting and the abnormal SI in the BGT. Case 2 had protonand phosphorus magnetic resonance spectroscopy, which showeda very high lactate peak, a normal N-acetylaspartate/creatineratio, and a very low inorganic phosphorus/phosphocreatine ratioconsistent with a recent acute severe hypoxic insult.
Outcome (table 2)All seven severely encephalopathic infants died, six within10 days of birth and one at 36 days. After discussion with theirparents, all had intensive care discontinued because of the severeclinical, electrophysiological and neuroimaging findings. Threeinfants had a full autopsy examination, and the findings were
Figure 1 Case 5 imaged on day 9. Toprow: axial T1-weighted images showingabnormally increased signal intensity (SI)in the basal ganglia and thalami (BGT) (A)with abnormally low SI in the posteriorlimb of the internal capsule (arrow). Thereis abnormally increased SI in themesencephalon (B) and in the cortexalong the central sulcus and theinterhemispheric fissure (C). There isabnormally low SI in the white matteradjacent to the abnormal cortex (C).Middle row: axial T2-weighted images.The normal anatomical details in the BGTare lost (A). There is abnormally low SI inthe thalami (A) and the mesencephalon(B). There is also increased SI in thethalami and to a lesser extent theputamen (A). There is some low SI in thecortex of the central sulcus (C) andmultiple foci of abnormally high SI in thesubcortical white matter (C),corresponding to the regions of low SIseen on the T1-weighted images. Bottomrow: axial diffusion-weighted imaging.There is restricted diffusion, seen as lowSI on the apparent diffusion coefficientmaps in the brainstem (A), the internalcapsule (B) and along the central sulcusin the region of the corticospinal tracts(C), marked with arrows.
Original article
F172 Arch Dis Child Fetal Neonatal Ed 2009;94:F168–F177. doi:10.1136/adc.2008.140301
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consistent with the MRI appearances. These were selectiveneuronal cell death of the basal ganglia, thalamus, hippocampusregion and ventral pons (pontosubicular necrosis), dentate andolivary nuclei, and cerebellar cortex with focal necrosis of thebrainstem. No additional information about the cause of deathwas obtained from the autopsy. The infant with mildencephalopathy and mild MRI findings had a normal DQ,neurological examination and head growth at 2 years.
Infants with respiratory disease (cases 9–12)Four infants had ongoing primary respiratory compromise afterthe collapse. All four showed a significant respiratory compo-nent to the acidosis (PCO2 11–20 kPa, base deficit 19–24 mmol/l).
Three infants met diagnostic criteria for persistent pulmonaryhypertension of the newborn (PPHN) with PaO2 6 kPa whenventilated in 100% oxygen, near-normal lung fields, normalcardiac structures and evidence of pulmonary to systemicshunting.28 All three infants required prolonged (.72 h) ventila-tory support and treatment with inotropes and nitric oxide. Twoinfants were referred for, but did not receive, extracorporealmembrane oxygenation (ECMO). One infant (case 12) collapsedat 30 min after birth with evidence of respiratory distresssyndrome but not PPHN; this infant required ventilatory supportfor 72 h and treatment with surfactant. No infant had positivecultures or other evidence of infection.
All four had a normal background cerebral function monitor/EEG, but two (cases 9 and 11) had one documented clinicalseizure, and one (case 9) was irritable and hyperalert in the first1–2 days consistent with HIE stage 127 and one (case 10) wasthought to be floppy.
US scansUS scans were obtained for all four infants on day 1 andsequentially for three; three were available for review. On day 1,one showed diffuse swelling (case 10), one mildly echogenicWM and marked GM/WM contrast (case 11), and one slightlyechogenic cortex adjacent to the interhemispheric fissure, butnormal WM and BGT (case 12). The one that was not reviewedwas reported to be normal. Of the three with early sequentialscans, the WM became more swollen in appearance in two andthe BGT in one; these findings settled in all three. In one (case11), left anterior focal echogenicity was seen on day 6, becomingmore marked on day 7; this infant had an infarct in this regionon MRI. Two infants had later US scans, case 9 on day 17 andcase 10 at 2 months; both showed a slightly increasedextracerebral space, one with mildly echogenic WM and thelater one with deep sulci and mild ventriculomegaly suggestiveof a slight reduction in WM volume. This child also developeddeep caudothalamic notches. One infant (case 12) developedsmall cysts in the caudothalamic notch by day 12.
MRI scansOne infant had an MRI scan on day 18 and at 4 months. Twoinfants had a single MR scan, one each at 2 and 7 months. Oneinfant (case 10) did not have an MR scan but had serial US scans.
The infant with early MRI had some slight WM change withlow SI on T1-weighted images and high SI on T2-weightedimages (fig 3) but normal BGT and PLIC. On a later scan, thischild showed a reduction in WM volume, as did the infantscanned at 7 months. The infant scanned at 2 months had anestablished small frontoparietal infarct in the territory of theleft middle cerebral artery (fig 4), consistent with earlier USfindings. This infant was referred for ECMO; he had two earlynormal US scans, with echogenicity becoming apparent on day6, suggesting a postnatal timing of onset for this lesion. Nohaemorrhage was seen in this group.
Outcome (table 2)All infants in this group had DQs in the normal range (median104, range 90–122). All children were able to walk indepen-dently and had a normal neurological examination; none hadcerebral palsy. Two of the three children with WM change had afall in occipitofrontal circumference centile at follow-up, inkeeping with their US and MRI scans (table 2). The infant withmiddle cerebral artery infarct shows normal development at 2years with no signs of hemiplegia and good head growth.
Figure 2 Case 4 imaged on day 3. Axial T1-weighted images (A), T2-weighted images (B) and apparent diffusion coefficient maps derivedfrom diffusion-weighted images (C) at the level of the basal ganglia (left)and mid-ventricular level (right). There is loss of detail in the basalganglia and thalami and no signal from myelin in the posterior limb of theinternal capsule. There is a small punctate lesion, high signal on T1 andlow signal on T2, in the posterior periventricular white matter on the right(arrow). It shows restricted diffusion (arrow in (C)).
Original article
Arch Dis Child Fetal Neonatal Ed 2009;94:F168–F177. doi:10.1136/adc.2008.140301 F173
group.bmj.com on February 27, 2014 - Published by fn.bmj.comDownloaded from
DISCUSSIONWe report findings on presentation, clinical course, imaging,EEG and outcome of 12 near-term infants with acute severePNC. These infants could be divided into two groups:c Group 1, with a primarily neurological abnormality. All but
one were severely encephalopathic and had severe EEGabnormality and severe damage to the central GM andbrainstem. All these infants died. One infant in this grouphad a mild encephalopathy, and probably represents aspectrum of encephalopathy occurring after collapse, as hasbeen described previously.4
c Group 2, with a primarily respiratory abnormality. Theseinfants had near-normal brain imaging and EEG and anormal outcome.
Extensive metabolic and bacteriological investigation for bothgroups did not reveal any positive results. For both groups,findings from early neonatal electrophysiology and brainimaging aided early prognostication and guided management.
Infants in group 1 showed MRI evidence of recent hypoxic–ischaemic damage affecting the basal ganglia, PLIC andbrainstem, consistent with injury around the time of birth.Information from autopsy was only available in three cases.This is disappointing given the difficulty in defining aetiology,but similar rates have been reported previously,1 where availableautopsy supported the MRI findings. The marked abnormalitiesin the brainstem may represent the severity of the injuryoccurring at collapse or potentially the aetiology of the collapse.Two infants in group 1 had evidence of white matter change onUS scan performed on day 1, suggesting distress before delivery.
Figure 3 Case 9 imaged on day 18 (A) and at 4 months (B). (A) AxialT1-weighted (left) and T2-weighted (right) spin-echo images showinglow signal intensity (SI) on the former and patchy high SI on the latter inthe white matter (arrows) in the neonatal period. (B) The later T1-weighted sagittal (left) and T2-weighted (right) axial images show aslightly thin corpus callosum, an increased extracerebral space, and stillsome patchy long T2 in the white matter (arrows).
Tabl
e2
Con
tinue
d
Cas
eN
oA
geat
colla
pse
Age
atM
RI
scan
ECS
Hae
mor
rhag
eLa
tera
lve
ntri
cle
Cor
tex
WM
BG
TP
LIC
BS
Cer
ebel
lum
DW
IO
utco
me
118
h2
mon
ths
q(L
eft)
No
Mild
VM
Left
bran
char
tery
MC
Ain
farc
tion
NN
No
acut
ech
ange
DQ
90
NN
HC
25–5
0th
cent
ile12
35m
in7
mon
ths
NN
oN La
rge
CS
P-C
V
NQ
Vol
ume
NN
NN
N/A
DQ
95
NN
HC
2nd
cent
ile
Abn
,abn
orm
al;A
DC
,app
aren
tdi
ffus
ion
coef
ficie
nt;B
GT,
basa
lgan
glia
/tha
lam
i;B
S,b
rain
stem
;CH
,cor
tical
high
light
ing;
CPH
chor
oid
plex
usha
emor
rhag
e;C
S,c
entr
alsu
lcus
;CS
P-C
V,s
eptu
mpe
lluci
dum
and
cavu
mve
rgae
;CS
T,co
rtic
alsp
inal
trac
t;D
Q,
deve
lopm
enta
lqu
otie
nt;
DW
I,di
ffus
ion
wei
ghte
dim
agin
g;di
ff,
diff
eren
tiatio
n;EC
S,
extr
acer
ebra
lsp
aces
;G
M,
grey
mat
ter;
HC
,hi
ppoc
ampu
s;H
IE,
hypo
xic–
isch
aem
icen
ceph
alop
athy
;I,
insu
la;
IC,
inte
nsiv
eca
re;
IF,
inte
rhem
isph
eric
fissu
re;
MC
A,
mid
dle
cere
bral
arte
ry;
Min
,m
inim
al;
Mod
,m
oder
ate;
N,
norm
al;
N/A
,no
tav
aila
ble;
NN
,no
rmal
neur
olog
ical
exam
;PF
,po
ster
ior
foss
a;PL
IC,
post
erio
rlim
bof
the
inte
rnal
caps
ule;
SD
H,
subd
ural
haem
orrh
age;
SI,
sign
alin
tens
ity;
US
,ul
tras
ound
scan
;V
M,
vent
ricul
omeg
aly;
WM
,w
hite
mat
ter.
Original article
Arch Dis Child Fetal Neonatal Ed 2009;94:F168–F177. doi:10.1136/adc.2008.140301 F175
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WM change tended to become more obvious in the first 3 daysand then lessen, whereas, in those with central GM damage,this became more evident over the first few days after the PNC.Only one infant who had collapsed 10 min after birth had mildBGT echogenicity apparent within 2 h of collapse, suggesting aninsult to this tissue a day or so before delivery.
This study was conducted over a long time period. Whereasimaging techniques have advanced, conventional MRI sequencesand image interpretation in our experience have remainedconsistent, even at different field strengths. Although the adventof DWI has facilitated the early detection of injury, the severity ofdamage in group 1 was readily demonstrated using conventionalMRI scans and was consistent with the clinical and pathologicalfindings and outcome. Where we had DWI findings, theysupported the acute and recent timing of the insult.
All but one infant in the non-respiratory group had posteriorfossa and subdural haemorrhage over the hemispheres (table 2).Most were small, and subdural haemorrhage is reported ininfants born by normal delivery29 and not necessarily attribu-table to excessive birth trauma. No infant had clinical evidenceof clotting problems or disseminated intravascular coagulation,and extensive thrombophilic investigation in four infantsproduced results that were within normal limits. Although thisobservation is of interest, it is not possible to comment furtheron its significance in this small cohort.
The exact timing of injury in these infants is extremely difficultto ascertain. The possibilities are of late antenatal or intrapartumbrainstem injury affecting the baby’s ability to maintain
respiration or a primary airway compromise postnatally. Theclinical, EEG, US and MRI changes for all infants were allconsistent with a perinatal origin. The time from collapse toresuscitation was apparently very short, except for one infant forwhom it could have been as long as 1 h. From this, it seemsunlikely that, in the remaining infants, the injury happened as aresult of the collapse unless perhaps it was accompanied by acomplete cessation of the circulation; however, a heartbeat couldbe heard at the beginning of resuscitation in six infants.
We acknowledge that none of the infants showed convincingsigns of perinatal asphyxia from the Apgar scores, which werenormal, or from the cord pH values when available. Threeinfants had some fetal CTG concerns, but these were relativelyminor. Of note, however, and in common with infants whodevelop focal arterial ischaemic infarction, few of the group hada simple normal vaginal delivery, and none was delivered byelective caesarean section.30 31
A possible explanation for the PNC was that interference withbrainstem blood flow in the course of labour and delivery gave riseto brainstem injury. Infants with focal hemispheric lesions usuallypresent with seizures some hours after birth and presumablysome hours after the insult. It is possible therefore that infantswith brainstem injury may also have a time lag between injuryand presentation, but in these infants the presentation may beone of collapse rather than focal seizures because of the site oflesion and the period of hypoxia leading to further injury in thebrainstem and basal ganglia. None of the infants who sustainedbrainstem injury regained self-ventilation.
Given that most of the infants collapsed within a few hours ofbirth, it would be very difficult to discriminate between damageoccurring intrapartum and at the time of collapse, using eitherimaging or histopathological methods. The presentation in thegroup with severe neuronal injury seemed often to have a timerelation to feeding—six of these infants were noted to havecollapsed while feeding at their mother’s breast or within minutesof their first breast feed. This may be due to either the infantshaving suffered a mild generalised asphyxia or basal ganglia andbrainstem injury impairing ability to coordinate feeding andrespiration. Previous literature has suggested a primary mechan-ism of inadvertent suffocation in infants with early PNC, which issupported by risk appearing to be higher in first-time parents(nine of our 12 infants were born to primiparous mothers) andwith early skin-to-skin contact.1 Although the benefits of skin-to-skin contact are not disputed,32 some authors have recommendedclose monitoring of parents and infants in the first postnatalhours.1 4 As this was a retrospective study, we do not have cleardocumentation of the infants’ position at the time of collapse;however, in our study only two were found sleeping with theirmothers. The majority with poor outcome were found collapsedduring or immediately after feeding.
Both gestational age and the nature of the asphyxial insulthave a profound effect on the ultimate pattern of injury. It isinteresting that the gestation of these infants was a little lessthan term, median 38 weeks (range 36–41); it has been foundthat acute severe hypoxic–ischaemic injury in more preterminfants tends to affect the lower basal ganglia and brainstem morethan in more mature infants (P Logitharajah, M Rutherford,F Cowan, unpublished work).33
Four infants presented with a severe respiratory illness,requiring ventilation in 100% oxygen, with no evidence of sepsis,metabolic disease or congenital heart disease. These infants didnot generally present in relation to feeding. Two of these fourinfants were delivered in a water bath and an association betweenwater birth and respiratory distress, although controversial, has
Figure 4 Case 11 imaged at 2 months. Axial T1-weighted (left) and T2-weighted (right) images. (A) There is a small infarct in the left parietallobe (arrows). There is mild ventricular dilatation superiorly. (B) Theappearances of the basal ganglia and thalami and posterior limb of theinternal capsule are symmetrical and appropriate for age.
Original article
F176 Arch Dis Child Fetal Neonatal Ed 2009;94:F168–F177. doi:10.1136/adc.2008.140301
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previously been reported.34–36 Two of the four infants had oneclinical seizure (without EEG corroboration) and one hadsymptoms of stage 1 HIE, but none had evidence of severe injuryon MRI and all had normal background EEG. They did, however,have some mild WM change and reduction in WM volume onfollow-up; one infant had a small branch middle cerebral arteryterritory infarct, which was not evident until day 6 on US.37 Itmay be that this was a postnatal event associated with severePPHN. All these children have a good outcome at 2 years,although longer-term surveillance is warranted. Head growth,although in the normal range, was on a lower centile than at birthin two infants, supporting the imaging evidence of mild WMinjury,26 and three of the children also had an increasedextracerebral space. The children may be at risk of attentionand behavioural problems, as has been reported in children withmilder WM injury,38 39 HIE40 or after ECMO.41–43
CONCLUSIONSThis series of infants present a rare but interesting entity, and,although no infant in this cohort was found to have anunderlying metabolic or infective aetiology, investigation forthese disorders is clearly warranted. As with more typicalintrapartum asphyxial presentations, early electrophysiologicalmonitoring and brain imaging (both US and MRI) are useful toguide prognosis and treatment. The outcome for those infantswith early severe neurological problems was uniformly severe.Infants with severe respiratory disease but only mild or noencephalopathy had little evidence of brain injury and a normaldevelopmental outcome. A multicentre study of all infantspresenting with PNC is likely to increase our understanding ofthis rare but important condition.
Funding: This work was supported by Philips Medical Systems (Best, TheNetherlands), the Medical Research Council, the Academy of Medical Sciences, theNIHR Biomedical Research Centre Funding Scheme and the Health Foundation.
Competing interests: None.
Ethics approval: Obtained.
Patient consent: Parental consent obtained.
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Original article
Arch Dis Child Fetal Neonatal Ed 2009;94:F168–F177. doi:10.1136/adc.2008.140301 F177
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