Frances Cowan

Mutations in the gene encoding the 3'-5' DNA exonuclease TREX1 cause Aicardi-Goutières syndrome at the AGS1 locus

Aicardi-Goutières syndrome (AGS) presents as a severe neurological brain disease and is a genetic mimic of the sequelae of transplacentally acquired viral infection. Evidence exists for a perturbation of innate immunity as a primary pathogenic event in the disease phenotype. Here, we show that TREX1, encoding the major mammalian 3′ → 5′ DNA exonuclease, is the AGS1 gene, and AGS-causing mutations result in abrogation of TREX1 enzyme activity. Similar loss of function in the Trex1−/− mouse leads to an inflammatory phenotype. Our findings suggest an unanticipated role for TREX1 in processing or clearing anomalous DNA structures, failure of which results in the triggering of an abnormal innate immune response.

Origin and timing of brain lesions in term infants with neonatal encephalopathy

BACKGROUND The role of intrapartum asphyxia in neonatal encephalopathy and seizures in term infants is not clear, and antenatal factors are being implicated in the causal pathway for these disorders. However, there is no evidence that brain damage occurs before birth. We aimed to test the hypothesis that neonatal encephalopathy, early neonatal seizures, or both result from early antenatal insults. METHODS We used brain MRI or post-mortem examination in 351 fullterm infants with neonatal encephalopathy, early seizures, or both to distinguish between lesions acquired antenatally and those that developed in the intrapartum and early post-partum period. We excluded infants with major congenital malformations or obvious chromosomal disorders. Infants were divided into two groups: those with neonatal encephalopathy (with or without seizures), and evidence of perinatal asphyxia (group 1); and those without other evidence of encephalopathy, but who presented with seizures within 3 days of birth (group 2). FINDINGS Brain images showed evidence of an acute insult without established injury or atrophy in 197 (80%) of infants in group 1, MRI showed evidence of established injury in only 2 infants (<1%), although tiny foci of established white matter gliosis, in addition to acute injury, were seen in three of 21 on post-mortem examination. In group 2, acute focal damage was noted in 62 (69%) of infants. Two (3%) also had evidence of antenatal injury. INTERPRETATION Although our results cannot exclude the possibility that antenatal or genetic factors might predispose some infants to perinatal brain injury, our data strongly suggest that events in the immediate perinatal period are most important in neonatal brain injury.

Assessment of neonatal encephalopathy by amplitude-integrated electroencephalography

Objective. To define normal and abnormal patterns, test interobserver variability, and the prognostic accuracy of amplitude-integrated electroencephalography (aEEG) soon after the onset of neonatal encephalopathy. Methods. Consecutive cases of neonatal encephalopathy (n = 56; gestation median, 40; range, 35–42 weeks) and healthy infants (n = 14; gestation median, 40; range, 39–40 weeks) were studied. aEEG was recorded using a cerebral function monitor, at median, 0, range, 0–21 days of age. Of the infants, 24 of the 56 with encephalopathy and all of the normal infants were studied within 12 hours of birth (median, 5; range, 3–12 hours). Forty infants were suspected of having suffered birth asphyxia. Criteria for normal and abnormal patterns were defined and the interobserver variability of these classifications determined. Results were compared with neurodevelopmental outcome assessed at 18 to 24 months of age. aEEG also was compared with a standard EEG and with magnetic resonance imaging. Results. The median upper margin of the widest band of aEEG activity in the control infants was 37.5 μV (range, 30–48 μV), and median lower margin was 8 μV (range, 6.5–11 μV). We classified the aEEG background activity as normal amplitude, the upper margin of band of aEEG activity >10 μV and the lower margin >5 μV; moderately abnormal amplitude, the upper margin of band of aEEG activity >10 μV and the lower margin ≤5 μV; and suppressed amplitude, the upper margin of the band of aEEG activity <10 μV and lower margin <5 μV. Recordings were analyzed further for the presence of seizures, defined as periods of sudden increase in voltage accompanied by a narrowing of the band of aEEG activity. Tests of interobserver variability showed excellent agreement both for assessment of amplitude (κ statistic = 0.85) and for identification of seizures (κ statistic = 0.76) There was a close relationship between the aEEG and subsequent outcome: 19 of 21 infants with a normal aEEG finding were normal on follow-up at 18 to 24 months of age, whereas 27 of 35 infants with a moderately abnormal or suppressed aEEG and/or seizures died or developed neurologic abnormalities. Thus, aEEG predicted outcome with a sensitivity of 0.93, a specificity of 0.70, positive predictive value of 0.77, negative predictive value of 0.90, and the likelihood ratio of a positive result of 3.1 and a negative result of 0.06. For the 24 infants studied within 12 hours of birth, the corresponding results were sensitivity, 1.0; specificity, 0.82; positive predictive value, 0.85; negative predictive value, 1; likelihood ratio of a positive result, 5.5; and likelihood ratio of a negative result, 0.18. Conclusion. The aEEG is a simple but accurate and reproducible clinical tool that could be useful in the assessment of infants with encephalopathy.

Natural History of Brain Lesions in Extremely Preterm Infants Studied With Serial Magnetic Resonance Imaging From Birth and Neurodevelopmental Assessment

OBJECTIVES. The aim was to survey the range of cerebral injury and abnormalities of cerebral development in infants born between 23 and 30 weeks’ gestation using serial MRI scans of the brain from birth, and to correlate those findings with neurodevelopmental outcome after 18 months corrected age. METHODS. Between January 1997 and November 2000, consecutive infants born at <30 weeks’ gestational age underwent serial MRI brain scans from birth until term-equivalent age. Infants were monitored after 18 months of age, corrected for prematurity, with the Griffiths Mental Development Scales and neurologic assessment. RESULTS. A total of 327 MRI scans were obtained from 119 surviving infants born at 23 to 30 weeks of gestation. Four infants had major destructive brain lesions, and tissue loss was seen at term for the 2 survivors. Fifty-one infants had early hemorrhage; 50% of infants with term scans after intraventricular hemorrhage had ventricular dilation. Twenty-six infants had punctate white matter lesions on early scans; these persisted for 33% of infants assessed at term. Early scans showed cerebellar hemorrhagic lesions for 8 infants and basal ganglia abnormalities for 17. At term, 53% of infants without previous hemorrhage had ventricular dilation and 80% of infants had diffuse excessive high signal intensity within the white matter on T2-weighted scans. Complete follow-up data were available for 66% of infants. Adverse outcomes were associated with major destructive lesions, diffuse excessive high signal intensity within the white matter, cerebellar hemorrhage, and ventricular dilation after intraventricular hemorrhage but not with punctate white matter lesions, hemorrhage, or ventricular dilation without intraventricular hemorrhage. CONCLUSIONS. Diffuse white matter abnormalities and post–hemorrhagic ventricular dilation are common at term and seem to correlate with reduced developmental quotients. Early lesions, except for cerebellar hemorrhage and major destructive lesions, do not show clear relationships with outcomes.

Abnormal Magnetic Resonance Signal in the Internal Capsule Predicts Poor Neurodevelopmental Outcome in Infants With Hypoxic-Ischemic Encephalopathy

Objective. The aim of this study was to establish whether abnormal signal intensity in the posterior limb of the internal capsule (PLIC) on magnetic resonance imaging is an accurate predictor of neurodevelopmental outcome at 1 year of age in infants with hypoxic-ischemic encephalopathy (HIE). Methods. We have examined 73 term neonates with HIE between 1 and 17 days after birth with cranial magnetic resonance imaging and related the magnetic resonance imaging findings to neurodevelopmental outcome at 1 year of age. Results. All infants with an abnormal signal intensity in the PLIC developed neurodevelopmental impairment although in 4 infants with very early scans the abnormal signal was not apparent until up to 4 days after birth. A normal signal intensity was associated with a normal outcome in all but 4 cases; 3 of these infants had minor impairments and all had persistent imaging changes within the white matter. The 4th infant with a normal signal intensity on day 2 died before a further image could be obtained. The absence of normal signal predicted abnormal outcome in term infants with HIE with a sensitivity of 0.90, a specificity of 1.0, a positive predictive value of 1.0, and a negative predictive value of 0.87. The test correctly predicted outcome in 93% of infants with grade II HIE, according to the Sarnat system. Applying a Bayesian approach, the predictive probability of the test (the probability that the test would predict an outcome correctly) was distributed with a mean of 0.94 and 95% confidence limits of 0.89 to 1.0. Conclusion. Abnormal signal intensity in the PLIC is an accurate predictor of neurodevelopmental outcome in term infants suffering HIE.

Comparison of findings on cranial ultrasound and magnetic resonance imaging in preterm infants

Objective. To compare findings on hard copies of cranial ultrasound (US) and magnetic resonance imaging (MRI) obtained between birth and term in a group of preterm infants. Participants and Methods. Infants born at or below a gestational age of 30 weeks who underwent cranial US scan and MRI on the same day were eligible for this study. Infants underwent, whenever possible, 3 scans between birth and term. We calculated the predictive probability (PP) of US findings as a predictor of findings on MRI. Results. Sixty-two paired MRI and US studies were performed between birth and term in 32 infants born at a median gestational age of 27 (range: 23–30) weeks and a median birth weight of 918 (530–1710) grams. US predicted some MRI findings accurately: germinal layer hemorrhage (GLH) on US had a PP of 0.8 with a 95% confidence interval of (0.70–0.90) for the presence of GLH on MRI, intraventricular hemorrhage (IVH) on US had a PP of 0.85 (0.76–0.94) for the presence of IVH on MRI, and severe white matter (WM) echogenicity on US had a PP of 0.96 (0.92–1.0) for the presence of WM hemorrhagic parenchymal infarction on MRI. Other MRI changes were less well-predicted: mild or no WM echogenicity on US had a PP of 0.54 (0.41–0.66) for the presence of normal WM signal intensity on MRI, and moderate or severe WM echogenicity on US had a PP of 0.54 (0.42–0.66) for the presence of small petechial WM hemorrhage and/or diffuse excessive high-signal intensity (DEHSI) in the WM on T2-weighted images on MRI. However, mild/moderate or severe WM echogenicity on US scans performed at ≥7 days after birth had a PP of 0.72 (0.58–0.87) for the presence of WM hemorrhage and/or DEHSI on MRI. There were no cases of cystic periventricular leukomalacia. Conclusion. US accurately predicted the presence of GLH, IVH, and hemorrhagic parenchymal infarction on MRI. However, its ability to predict the presence of DEHSI and small petechial hemorrhages in the WM on T2 weighted images is not as good, but improves on scans performed at ≥7 days after birth. In addition, normal WM echogenicity on US is not a good predictor of normal WM signal intensity on MRI.

Magnetic resonance imaging of the brain in a cohort of extremely preterm infants

To define magnetic resonance imaging (MRI) appearances of the brain in extremely preterm infants between birth and term, a sequential cohort of infants born at a gestational age <30 weeks was studied with a dedicated neonatal magnetic resonance scanner. Images of infants (n = 41) with a median gestational age of 27 weeks (range 23 to 29 weeks) were initially obtained at a median age of 2 days (range 1 to 20 days) and then repeatedly studied; 29 (71%) infants had MRI at a median gestational age of 43 weeks (range 38 to 52 weeks) (term MRI). On the initial MRI scan 28 of 41 infants had abnormalities: either intraventricular hemorrhage, germinal layer hemorrhage, ventricular dilatation, or diffuse and excessive high signal intensity in the white matter on T(2)-weighted images. When magnetic resonance images for preterm infants at term gestation were compared with those of infants in the control group born at term, 22 of 29 infants had dilatation of the lateral ventricles, 24 of 29 had squaring of the anterior or posterior horns of the lateral ventricles, 11 of 29 had a widened interhemispheric fissure or extracerebral space, and 22 of 29 had diffuse and excessive high signal intensity in the white matter. There were no cases of cystic periventricular leukomalacia. We conclude that MRI abnormalities are commonly seen in the brain of preterm infants on whom images are obtained within 48 hours of birth and that further abnormalities develop between birth and term. A characteristic appearance of diffuse and excessive high signal intensity in the white matter on T(2)-weighted images is associated with the development of cerebral atrophy and may be a sign of white matter disease. These MRI appearances may help account for the high incidence of neurodevelopmental impairment in extremely preterm infants.

Abnormal Cortical Development after Premature Birth Shown by Altered Allometric Scaling of Brain Growth

Background We postulated that during ontogenesis cortical surface area and cerebral volume are related by a scaling law whose exponent gives a quantitative measure of cortical development. We used this approach to investigate the hypothesis that premature termination of the intrauterine environment by preterm birth reduces cortical development in a dose-dependent manner, providing a neural substrate for functional impairment. Methods and Findings We analyzed 274 magnetic resonance images that recorded brain growth from 23 to 48 wk of gestation in 113 extremely preterm infants born at 22 to 29 wk of gestation, 63 of whom underwent neurodevelopmental assessment at a median age of 2 y. Cortical surface area was related to cerebral volume by a scaling law with an exponent of 1.29 (95% confidence interval, 1.25–1.33), which was proportional to later neurodevelopmental impairment. Increasing prematurity and male gender were associated with a lower scaling exponent (p < 0.0001) independent of intrauterine or postnatal somatic growth. Conclusions Human brain growth obeys an allometric scaling relation that is disrupted by preterm birth in a dose-dependent, sexually dimorphic fashion that directly parallels the incidence of neurodevelopmental impairments in preterm infants. This result focuses attention on brain growth and cortical development during the weeks following preterm delivery as a neural substrate for neurodevelopmental impairment after premature delivery.

Patterns of cerebral injury and neurodevelopmental outcomes after symptomatic neonatal hypoglycemia.

BACKGROUND. Symptomatic neonatal hypoglycemia may be associated with later neurodevelopmental impairment. Brain injury patterns identified on early MRI scans and their relationships to the nature of the hypoglycemic insult and neurodevelopmental outcomes are poorly defined. METHODS. We studied 35 term infants with early brain MRI scans after symptomatic neonatal hypoglycemia (median glucose level: 1 mmol/L) without evidence of hypoxic-ischemic encephalopathy. Perinatal data were compared with equivalent data from 229 term, neurologically normal infants (control subjects), to identify risk factors for hypoglycemia. Neurodevelopmental outcomes were assessed at a minimum of 18 months. RESULTS. White matter abnormalities occurred in 94% of infants with hypoglycemia, being severe in 43%, with a predominantly posterior pattern in 29% of cases. Cortical abnormalities occurred in 51% of infants; 30% had white matter hemorrhage, 40% basal ganglia/thalamic lesions, and 11% an abnormal posterior limb of the internal capsule. Three infants had middle cerebral artery territory infarctions. Twenty-three infants (65%) demonstrated impairments at 18 months, which were related to the severity of white matter injury and involvement of the posterior limb of the internal capsule. Fourteen infants demonstrated growth restriction, 1 had macrosomia, and 2 had mothers with diabetes mellitus. Pregnancy-induced hypertension, a family history of seizures, emergency cesarean section, and the need for resuscitation were more common among case subjects than control subjects. CONCLUSIONS. Patterns of injury associated with symptomatic neonatal hypoglycemia were more varied than described previously. White matter injury was not confined to the posterior regions; hemorrhage, middle cerebral artery infarction, and basal ganglia/thalamic abnormalities were seen, and cortical involvement was common. Early MRI findings were more instructive than the severity or duration of hypoglycemia for predicting neurodevelopmental outcomes.

Early prognostic indicators of outcome in infants with neonatal cerebral infarction : A clinical, electroencephalogram, and magnetic resonance imaging study

Objective. The aim of this study was to identify prognostic factors in newborns with cerebral infarction. Design. Antenatal and perinatal factors and early clinical, electroencephalogram (EEG), and magnetic resonance imaging (MRI) findings were compared with neurodevelopmental outcome in 24 children with evidence of cerebral infarction on neonatal MRI. Results. Out of 24 infants, 19 had an infarction in the territory of a major cerebral vessel and 5 in the borderzone between cerebral arteries. Neuromotor outcome was normal in 17 and abnormal in 7 infants. Of these 7 infants, 5 infants showed a definite hemiplegia, whereas the other 2 showed some asymmetry of tone or function but no definite hemiplegia. None of the adverse antenatal or perinatal factors was significantly associated with abnormal outcome. Neonatal clinical examination was also not always predictive of the outcome. The extent of the lesion on MRI was a better predictor. In particular, it was the concomitant involvement of hemisphere, internal capsule and basal ganglia that was always associated with an abnormal outcome whereas the involvement of only one or two of the three tended to be associated with a normal outcome. EEG was also very helpful. Abnormal background activity either unilateral or bilateral was found in 6 infants and 5 out of 6 developed hemiplegia. In contrast, the presence of seizure activity in presence of a normal background was not related to abnormal outcome. Conclusions. Early MRI and EEG can help to identify the infants with cerebral infarction who are likely to develop hemiplegia.