Linda S. de Vries

The spectrum of leukomalacia using cranial ultrasound

The spectrum of leukomalacia using cranial ultrasound is discussed. Transient densities not evolving into cystic lesions may represent a mild degree of leukomalacia when persisting for at least a week. A unilateral parenchymal density may be due to bleeding into an ischaemic area, but can also be due to a venous infarction. Cystic leukomalacia can be confidently diagnosed using appropriate equipment and performing sequential scans. A distinction should be made between cysts in the periventricular white matter and cysts in the deep white matter, as the latter carries a higher risk for cerebral visual impairment. Careful ophthalmological examination of these infants will enable us to identify infants with cerebral visual impairment during the first few months of life, allowing the use of special programs aimed at promoting visual development.

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.

Effect of Hypothermia on Amplitude-Integrated Electroencephalogram in Infants With Asphyxia

OBJECTIVES: Amplitude-integrated electroencephalogram (aEEG) at <6 hours is the best single outcome predictor in term infants with perinatal asphyxia at normothermia. Hypothermia has been used to treat those infants and proved to improve their outcome. The objectives of this study were to compare the predictive value of aEEG at <6 hours on outcomes in normothermia- and hypothermia-treated infants and to investigate the best outcome predictor (time to normal trace or sleep–wake cycling [SWC]) in normothermia- and hypothermia-treated infants. METHODS: Seventy-four infants were recruited by using the CoolCap entry criteria, and their outcomes were assessed by using the Bayley Scales of Infant Development II at 18 months. The aEEG was recorded for 72 hours. Patterns and voltages of aEEG backgrounds were assessed. RESULTS: The positive predictive value of an abnormal aEEG pattern at the age of 3 to 6 hours was 84% for normothermia and 59% for hypothermia. Moderate abnormal voltage background at 3 to 6 hours of age did not predict outcome. The recovery time to normal background pattern was the best predictor of poor outcome (96.2% in hypothermia, 90.9% in normothermia). Never developing SWC always predicted poor outcome. Time to SWC was a better outcome predictor for infants who were treated with hypothermia (88.5%) than with normothermia (63.6%). CONCLUSIONS: Early aEEG patterns can be used to predict outcome for infants treated with normothermia but not hypothermia. Infants with good outcome had normalized background pattern by 24 hours when treated with normothermia and by 48 hours when treated with hypothermia.

Long-term cognitive and behavioral consequences of neonatal encephalopathy following perinatal asphyxia: a review

Neonatal encephalopathy (NE) following perinatal asphyxia (PA) is considered an important cause of later neurodevelopmental impairment in infants born at term. This review discusses long-term consequences for general cognitive functioning, educational achievement, neuropsychological functioning and behavior. In all areas reviewed, the outcome of children with mild NE is consistently positive and the outcome of children with severe NE consistently negative. However, children with moderate NE form a more heterogeneous group with respect to outcome. On average, intelligence scores are below those of children with mild NE and age-matched peers, but within the normal range. With respect to educational achievement, difficulties have been found in the domains reading, spelling and arithmetic/mathematics. So far, studies of neuropsychological functioning have yielded ambiguous results in children with moderate NE. A few studies suggest elevated rates of hyperactivity in children with moderate NE and autism in children with moderate and severe NE. Conclusion: Behavioral monitoring is required for all children with NE. In addition, systematic, detailed neuropsychological examination is needed especially for children with moderate NE.

Human parechovirus causes encephalitis with white matter injury in Neonates

To assess the role of human parechoviruses (HPeVs) as a cause of neonatal cerebral infection and to report neuroimaging findings of newborn infants with encephalitis caused by HPeVs.

Cerebral lactate and N-acetyl-aspartate/choline ratios in asphyxiated full-term neonates demonstrated in vivo using proton magnetic resonance spectroscopy.

ABSTRACT: The purpose of this study was to test the hypothesis that a high lactate signal and a low N-acetyl-aspartate/choline ratio in neonates with postasphyxial encephalopathy indicated a high chance of an adverse outcome in vivo when proton magnetic resonance spectroscopy was used. Twenty-one full-term asphyxiated neonates were examined at a mean postnatal age of 7.1 d. Five patients died, and five survivors had handicaps. Eleven of the 16 survivors (seven without handicaps and four with handicaps) had a second examination at 3 mo of age. After magnetic resonance imaging, spectra were obtained at 1.5 tesla. A 20-mm-thick slice was selected through the basal ganglia. After optimizing the B-0 field, we used a double spin-echo pulse sequence (90–180-180°) with a time to repeat of 2000 ms and a time to echo of 272 ms. Two-dimensional spectroscopic imaging was performed by 32 ± 32 phase encoding steps in two directions in a 225-mm field of view, resulting in 1-mL volumes, followed by computerized processing. Neuromotor development was examined at 6 wk, 3 mo, and every 3 mo thereafter. Lactate resonances were seen only in the five patients with grade 3 postasphyxial encephalopathy. Lactate was distributed diffusely (n = 4), or localized in areas of infarction (n = 1). N-acetyl-aspartate/choline ratios were significantly lower in the patients with an adverse outcome than in the survivors without handicaps, both neonatally (p < 0.005, Wilcoxons rank sum test) and at 3 mo (p < 0.05). In conclusion, the presence of cerebral lactate and a low N-acetyl-aspartate/choline ratio demonstrated in vivo using proton magnetic resonance spectroscopy in full-term neonates with postasphyxial encephalopathy indicate a poor outcome.

Structural and functional brain development after hydrocortisone treatment for neonatal chronic lung disease

Objective. There is much concern about potential neurodevelopmental impairment after neonatal corticosteroid treatment for chronic lung disease. Dexamethasone is the corticosteroid most often used in this clinical setting, and it has been shown to impair cortical growth among preterm infants. This study evaluated long-term effects of prematurity itself and of neonatal hydrocortisone treatment on structural and functional brain development using three-dimensional MRI with advanced image-processing and neurocognitive assessments. Methods. Sixty children born preterm, including 25 children treated with hydrocortisone and 35 children not treated with hydrocortisone, and 21 children born at term were evaluated, at a mean age of 8 years, with quantitative MRI and neurocognitive assessments (Wechsler Intelligence Scales for Children-Revised [WISC-R]). Automatic image segmentation was used to determine the tissue volumes of cerebral gray matter, white matter, and cerebrospinal fluid. In addition, the volume of the hippocampus was determined manually. WISC-R scores were recorded as mean intelligence scores at evaluation. Neonatal hydrocortisone treatment for chronic lung disease consisted of a starting dose of 5 mg/kg per day tapered over a minimum of 3 weeks. Results. Cerebral gray matter volume was reduced among preterm children (regardless of hydrocortisone treatment), compared with children born at term (preterm: 649 ± 4.4 mL; term: 666 ± 7.3 mL). Birth weight was shown to correlate with gray matter volume at 8 years of age in the preterm group (r = 0.421). Cerebrospinal fluid volume was increased among children born preterm, compared with children born at term (preterm: 228 ± 4.9 mL; term: 206 ± 8.2 mL). Total hippocampal volume tended to be lower among children born preterm, with a more pronounced reduction of hippocampal volume among boys (preterm: 6.1 ± 0.13 mL; term: 6.56 ± 0.2 mL). The WISC-R score was lower for children born preterm, compared with children born at term (preterm: 99.4 ± 12.4; term: 109.6 ± 8.8). Children treated with neonatal hydrocortisone had very similar volumes of gray matter (preterm with hydrocortisone: 650 ± 7.0 mL; preterm without hydrocortisone: 640 ± 5.6 mL), white matter (preterm with hydrocortisone: 503 ± 6.1 mL; preterm without hydrocortisone: 510 ± 4.9 mL), and cerebrospinal fluid (preterm with hydrocortisone: 227 ± 7.4 mL; preterm without hydrocortisone: 224 ± 6.0 mL), compared with untreated infants. The hippocampal volumes were similar in the 2 groups (preterm with hydrocortisone: 5.92 ± 0.15 mL; preterm without hydrocortisone: 5.81 ± 0.12 mL). The WISC-R score assessments were within the normal range for both groups, with no difference between the groups (preterm with hydrocortisone: 100.8 ± 13; preterm without hydrocortisone: 98.6 ± 12.3). Conclusions. Prematurity is associated with mild brain structural differences that persist at 8 years of age, with associated lower scores in neurocognitive assessments. The data suggest that perinatal hydrocortisone given at the described dosage has no long-term effects on either neurostructural brain development or neurocognitive outcomes.

Severe neonatal parechovirus infection and similarity with enterovirus infection

Background: Enteroviruses (EV) are an important cause of neonatal disease including hepatitis, meningoencephalitis, and myocarditis that can lead to death or severe long-term sequelae. Less is known about severe neonatal infection caused by the parechoviruses (PeV) of which type 1 (PeV1) and type 2 (PeV2) were previously known as echovirus 22 and echovirus 23. They belong to the same family of Picornaviridae as the EV. Of the PeV, so far only PeV3 has been associated in 2 recent reports with severe neonatal infection including involvement of central nervous system. Methods: We compared the clinical signs, diagnosis, laboratory data, cerebral imaging, and neurodevelopmental outcome of 11 neonates with PeV infection with 21 infants with EV infection treated in our hospital between 1994 and 2006. The diagnosis of EV infection or PeV infection was confirmed by a positive EV and/or PeV real time-polymerase chain reaction on blood, cerebrospinal fluid, (CSF) or stool or a viral culture of stool, nasopharyngeal swab, and/or CSF. Results: The 32 infants presented with sepsis-like illness and the most frequent signs were: fever, seizures, irritability, rash, and feeding problems. All patients received antibiotic treatment. Eleven of 21 infants infected with EV and 7 of 11 infants infected with PeV were full-term. Differentiation between the infants infected with EV and PeV on the basis of fever, irritability, rash, and seizures was not possible. Myocarditis was exclusively seen in 4 patients infected by EV. Eight of 11 patients with a PeV infection had meningoencephalitis of whom only 1 infant developed pleocytosis in the CSF. Serum C-reactive protein and CSF protein values were significantly higher in infants with EV infection than in those with PeV infection. Cerebral imaging of all infants with EV or PeV cerebral infection showed mild to severe white matter abnormalities. In 1 infant with EV infection and 3 infants with PeV infection, neurodevelopmental delay occurred. Mortality and long-term sequelae were mainly associated with myocarditis in the infants who were infected with EV (4 of 21). Conclusions: It is not possible to distinguish neonatal PeV from EV infection on the basis of clinical signs. Neonates with PeV or EV infection present with sepsis-like illness and the most frequent signs are fever, seizures, irritability, rash, and feeding problems.

tRNA splicing endonuclease mutations cause pontocerebellar hypoplasia

Pontocerebellar hypoplasias (PCH) represent a group of neurodegenerative autosomal recessive disorders with prenatal onset, atrophy or hypoplasia of the cerebellum, hypoplasia of the ventral pons, microcephaly, variable neocortical atrophy and severe mental and motor impairments. In two subtypes, PCH2 and PCH4, we identified mutations in three of the four different subunits of the tRNA-splicing endonuclease complex. Our findings point to RNA processing as a new basic cellular impairment in neurological disorders.

Automatic Segmentation of MR Brain Images With a Convolutional Neural Network

Automatic segmentation in MR brain images is important for quantitative analysis in large-scale studies with images acquired at all ages. This paper presents a method for the automatic segmentation of MR brain images into a number of tissue classes using a convolutional neural network. To ensure that the method obtains accurate segmentation details as well as spatial consistency, the network uses multiple patch sizes and multiple convolution kernel sizes to acquire multi-scale information about each voxel. The method is not dependent on explicit features, but learns to recognise the information that is important for the classification based on training data. The method requires a single anatomical MR image only. The segmentation method is applied to five different data sets: coronal T2-weighted images of preterm infants acquired at 30 weeks postmenstrual age (PMA) and 40 weeks PMA, axial T2-weighted images of preterm infants acquired at 40 weeks PMA, axial T1-weighted images of ageing adults acquired at an average age of 70 years, and T1-weighted images of young adults acquired at an average age of 23 years. The method obtained the following average Dice coefficients over all segmented tissue classes for each data set, respectively: 0.87, 0.82, 0.84, 0.86, and 0.91. The results demonstrate that the method obtains accurate segmentations in all five sets, and hence demonstrates its robustness to differences in age and acquisition protocol.Automatic segmentation in MR brain images is important for quantitative analysis in large-scale studies with images acquired at all ages. This paper presents a method for the automatic segmentation of MR brain images into a number of tissue classes using a convolutional neural network. To ensure that the method obtains accurate segmentation details as well as spatial consistency, the network uses multiple patch sizes and multiple convolution kernel sizes to acquire multi-scale information about each voxel. The method is not dependent on explicit features, but learns to recognise the information that is important for the classification based on training data. The method requires a single anatomical MR image only. The segmentation method is applied to five different data sets: coronal T2-weighted images of preterm infants acquired at 30 weeks postmenstrual age (PMA) and 40 weeks PMA, axial T2-weighted images of preterm infants acquired at 40 weeks PMA, axial T1-weighted images of ageing adults acquired at an average age of 70 years, and T1-weighted images of young adults acquired at an average age of 23 years. The method obtained the following average Dice coefficients over all segmented tissue classes for each data set, respectively: 0.87, 0.82, 0.84, 0.86, and 0.91. The results demonstrate that the method obtains accurate segmentations in all five sets, and hence demonstrates its robustness to differences in age and acquisition protocol.