Hannah C. Glass

Clinical Neonatal Seizures are Independently Associated with Outcome in Infants at Risk for Hypoxic-Ischemic Brain Injury

OBJECTIVE To examine whether neonatal seizures are associated with neurodevelopmental outcomes in infants with hypoxia-ischemia independent of the presence and severity of brain injury seen on magnetic resonance imaging (MRI). STUDY DESIGN We used multivariate regression to examine the independent effect of clinical neonatal seizures and their treatment on neurodevelopment in 77 term newborns at risk for hypoxic-ischemic brain injury. Clinical seizures were recorded prospectively, and high-resolution newborn MRI measured the severity of brain injury. The outcome measure was the Full-Scale Intelligence Quotient (FSIQ) of the Wechsler Preschool and Primary Scale of Intelligence-Revised and neuromotor score at age 4 years. RESULTS After controlling for severity of injury on MRI, the children with neonatal seizures had worse motor and cognitive outcomes compared with those without seizures. The magnitude of effect varied with seizure severity; children with severe seizures had a lower FSIQ than those with mild/moderate seizures (P < .0001). CONCLUSIONS Clinical neonatal seizures in the setting of birth asphyxia are associated with worse neurodevelopmental outcome, independent of the severity of hypoxic-ischemic brain injury. Randomized controlled trials are needed to determine whether differences in seizure treatment can improve outcome.

Homozygous Deletion of the Very Low Density Lipoprotein Receptor Gene Causes Autosomal Recessive Cerebellar Hypoplasia with Cerebral Gyral Simplification

An autosomal recessive syndrome of nonprogressive cerebellar ataxia and mental retardation is associated with inferior cerebellar hypoplasia and mild cerebral gyral simplification in the Hutterite population. An identity-by-descent mapping approach using eight patients from three interrelated Hutterite families localized the gene for this syndrome to chromosome region 9p24. Haplotype analysis identified familial and ancestral recombination events and refined the minimal region to a 2-Mb interval between markers D9S129 and D9S1871. A 199-kb homozygous deletion encompassing the entire very low density lipoprotein receptor (VLDLR) gene was present in all affected individuals. VLDLR is part of the reelin signaling pathway, which guides neuroblast migration in the cerebral cortex and cerebellum. To our knowledge, this syndrome represents the first human lipoprotein receptor malformation syndrome and the second human disease associated with a reelin pathway defect.

Recurrent Postnatal Infections Are Associated With Progressive White Matter Injury in Premature Infants

OBJECTIVE. Our objective was to identify clinical predictors of progressive white matter injury. METHODS. We evaluated 133 infants of <34 weeks of gestation at birth from 2 university hospitals. Infants underwent MRI twice, initially when in stable condition for transport and again at term-equivalent age or before transfer or discharge. Two neuroradiologists who were blinded to the clinical course graded MRI white matter injury severity by using a validated scale. Potential risk factors were extracted from medical charts. RESULTS. Twelve neonates (9.0%) had progressive white matter injury. In the unadjusted analysis of 10 newborns without Candida meningoencephalitis, recurrent culture-positive postnatal infection and chronic lung disease were associated with progressive white matter injury. Exposure to multiple episodes of culture-positive infection significantly increased the risk of progressive white matter injury. Of the 11 neonates with >1 infection, 36.4% (4 infants) had progressive injury, compared with 5.0% (6 infants) of those with ≤1 infection. Of the 35 infants with chronic lung disease, 17.1% (6 infants) had progressive injury, compared with 4.3% (4 infants) of those without chronic lung disease. After adjustment for gestational age at birth, the association between infection and white matter injury persisted, whereas chronic lung disease was no longer a statistically significant risk factor. CONCLUSIONS. Recurrent postnatal infection is an important risk factor for progressive white matter injury in premature infants. This is consistent with emerging evidence that white matter injury is attributable to oligodendrocyte precursor susceptibility to inflammation, hypoxia, and ischemia.

Erythropoietin for Neuroprotection in Neonatal Encephalopathy: Safety and Pharmacokinetics

OBJECTIVE: To determine the safety and pharmacokinetics of erythropoietin (Epo) given in conjunction with hypothermia for hypoxic-ischemic encephalopathy (HIE). We hypothesized that high dose Epo would produce plasma concentrations that are neuroprotective in animal studies (ie, maximum concentration = 6000–10 000 U/L; area under the curve = 117 000–140 000 U*h/L). METHODS: In this multicenter, open-label, dose-escalation, phase I study, we enrolled 24 newborns undergoing hypothermia for HIE. All patients had decreased consciousness and acidosis (pH < 7.00 or base deficit ≥ 12), 10-minute Apgar score ≤ 5, or ongoing resuscitation at 10 minutes. Patients received 1 of 4 Epo doses intravenously: 250 (N = 3), 500 (N = 6), 1000 (N = 7), or 2500 U/kg per dose (N = 8). We gave up to 6 doses every 48 hours starting at <24 hours of age and performed pharmacokinetic and safety analyses. RESULTS: Patients received mean 4.8 ± 1.2 Epo doses. Although Epo followed nonlinear pharmacokinetics, excessive accumulation did not occur during multiple dosing. At 500, 1000, and 2500 U/kg Epo, half-life was 7.2, 15.0, and 18.7 hours; maximum concentration was 7046, 13 780, and 33 316 U/L, and total Epo exposure (area under the curve) was 50 306, 131 054, and 328 002 U*h/L, respectively. Drug clearance at a given dose was slower than reported in uncooled preterm infants. No deaths or serious adverse effects were seen. CONCLUSIONS: Epo 1000 U/kg per dose intravenously given in conjunction with hypothermia is well tolerated and produces plasma concentrations that are neuroprotective in animals. A large efficacy trial is needed to determine whether Epo add-on therapy further improves outcome in infants undergoing hypothermia for HIE.

Agenesis of the corpus callosum in California 1983–2003: A population‐based study

The objective of this study was to characterize the prevalence, demographic risk factors, and malformations associated with agenesis and hypoplasia of the corpus callosum diagnosed in infancy. Using a large population‐based registry of birth defects, we ascertained 630 cases of agenesis (ACC) and hypoplasia (HCC) of the corpus callosum diagnosed in the first year of life among 3.4 million live births from 1983 to 2003. Infants with destructive lesions or specific complex central nervous system (CNS) malformations (neural tube defects, lissencephaly, and holoprosencephaly) were excluded. Multivariable Poisson regression analysis was used to examine demographic risk factors. The combined prevalence of ACC and HCC was 1.8 per 10,000 live births. Fifty‐two percent of cases were male. Infants with ACC had an almost fourfold higher prevalence among infants born prematurely when compared with children born ≥37 weeks gestation (RR 3.7, 95% CI 2.5–5.3). After adjusting for paternal age, advanced maternal age ≥40 years was associated with ACC in infants with a chromosomal disorder (ACC RR 5.9; 95% CI 1.8–19.3, HCC RR 3.5; 95% CI 0.9–14.1). Paternal age was not significantly associated with ACC after adjusting for maternal age. Callosal anomalies were often seen in the context of a chromosomal abnormality (17.3%) and with accompanying somatic (musculoskeletal 33.5% and cardiac 27.6%) and CNS malformations (49.5%). Callosal anomalies form a clinically significant and relatively frequent group of malformations of the CNS that are associated with increased risk of premature birth, are more common with advanced maternal age and are frequently part of a complex, multisystem disorder.

Video-EEG monitoring in newborns with hypoxic-ischemic encephalopathy treated with hypothermia

Background: Therapeutic hypothermia (TH) is becoming standard of care in newborns with hypoxic-ischemic encephalopathy (HIE). The prognostic value of the EEG and the incidence of seizures during TH are uncertain. Objective: To describe evolution of EEG background and incidence of seizures during TH, and to identify EEG patterns predictive for MRI brain injury. Methods: A total of 41 newborns with HIE underwent TH. Continuous video-EEG was performed during hypothermia and rewarming. EEG background and seizures were reported in a standardized manner. Newborns underwent MRI after rewarming. Sensitivity and specificity of EEG background for moderate to severe MRI brain injury was assessed at 6-hour intervals during TH and rewarming. Results: EEG background improved in 49%, remained the same in 38%, and worsened in 13%. A normal EEG had a specificity of 100% upon initiation of monitoring and 93% at later time points. Burst suppression and extremely low voltage patterns held the greatest prognostic value only after 24 hours of monitoring, with a specificity of 81% at the beginning of cooling and 100% at later time points. A discontinuous pattern was not associated with adverse outcome in most patients (73%). Electrographic seizures occurred in 34% (14/41), and 10% (4/41) developed status epilepticus. Seizures had a clinical correlate in 57% (8/14) and were subclinical in 43% (6/14). Conclusions: Continuous video-EEG monitoring in newborns with HIE undergoing TH provides prognostic information about early MRI outcome and accurately identifies electrographic seizures, nearly half of which are subclinical.

Outcomes for extremely premature infants

Premature birth is a significant cause of infant and child morbidity and mortality. In the United States, the premature birth rate, which had steadily increased during the 1990s and early 2000s, has decreased annually for 7 years and is now approximately 11.39%. Human viability, defined as gestational age at which the chance of survival is 50%, is currently approximately 23 to 24 weeks in developed countries. Infant girls, on average, have better outcomes than infant boys. A relatively uncomplicated course in the intensive care nursery for an extremely premature infant results in a discharge date close to the prenatal estimated date of confinement. Despite technological advances and efforts of child health experts during the last generation, the extremely premature infant (less than 28 weeks gestation) and extremely low birth weight infant (<1000 g) remain at high risk for death and disability with 30% to 50% mortality and, in survivors, at least 20% to 50% risk of morbidity. The introduction of continuous positive airway pressure, mechanical ventilation, and exogenous surfactant increased survival and spurred the development of neonatal intensive care in the 1970s through the early 1990s. Routine administration of antenatal steroids during premature labor improved neonatal mortality and morbidity in the late 1990s. The recognition that chronic postnatal administration of steroids to infants should be avoided may have improved outcomes in the early 2000s. Evidence from recent trials attempting to define the appropriate target for oxygen saturation in preterm infants suggests arterial oxygen saturation between 91% and 95% (compared with 85%–89%) avoids excess mortality; however, final analyses of data from these trials have not been published, so definitive recommendations are still pending. The development of neonatal neurocritical intensive care units may improve neurocognitive outcomes in this high-risk group. Long-term follow-up to detect and address developmental, learning, behavioral, and social problems is critical for children born at these early gestational ages.The striking similarities in response to extreme prematurity in the lung and brain imply that agents and techniques that benefit one organ are likely to also benefit the other. Finally, because therapy and supportive care continue to change, the outcomes of extremely low birth weight infants are ever evolving. Efforts to minimize injury, preserve growth, and identify interventions focused on antioxidant and anti-inflammatory pathways are now being evaluated. Thus, treating and preventing long-term deficits must be developed in the context of a “moving target.”

Cerebellar Hemorrhage on Magnetic Resonance Imaging in Preterm Newborns Associated with Abnormal Neurologic Outcome

OBJECTIVE To investigate the relationship between cerebellar hemorrhage in preterm infants seen on magnetic resonance imaging (MRI), but not on ultrasonography, and neurodevelopmental outcome. STUDY DESIGN Images from a cohort study of MRI in preterm newborns were reviewed for cerebellar hemorrhage. The children were assessed at a mean age of 4.8 years with neurologic examination and developmental testing using the Wechsler Preschool and Primary Scale of Intelligence, Third Edition. RESULTS Cerebellar hemorrhage was detected on both ultrasonography and MRI in 3 of the 131 preterm newborns evaluated, whereas smaller hemorrhages were seen only on MRI in 10 newborns (total incidence, 10%). Adjusting for gestational age at birth, intraventricular hemorrhage, and white matter injury, cerebellar hemorrhage detectable solely by MRI was associated with a 5-fold increased odds of abnormal neurologic examination compared with newborns without cerebellar hemorrhage (outcome data in 74%). No association with the Wechsler Preschool and Primary Scale of Intelligence, Third Edition score was found. CONCLUSIONS Cerebellar hemorrhage is not uncommon in preterm newborns. Although associated with neurologic abnormalities, hemorrhage seen only on MRI is associated with much more optimistic outcomes than that visible on ultrasonography.

Clinically silent preoperative brain injuries do not worsen with surgery in neonates with congenital heart disease.

OBJECTIVE Preoperative brain injury, particularly stroke and white matter injury, is common in neonates with congenital heart disease. The objective of this study was to determine the risk of hemorrhage or extension of preoperative brain injury with cardiac surgery. METHODS This dual-center prospective cohort study recruited 92 term neonates, 62 with transposition of the great arteries and 30 with single ventricle physiology, from 2 tertiary referral centers. Neonates underwent brain magnetic resonance imaging scans before and after cardiac surgery. RESULTS Brain injury was identified in 40 (43%) neonates on the preoperative magnetic resonance imaging scan (median 5 days after birth): stroke in 23, white matter injury in 21, and intraventricular hemorrhage in 7. None of the brain lesions presented clinically with overt signs or seizures. Preoperative brain injury was associated with balloon atrial septostomy (P = .003) and lowest arterial oxygen saturation (P = .007); in a multivariable model, only the effect of balloon atrial septostomy remained significant when adjusting for lowest arterial oxygen saturation. On postoperative magnetic resonance imaging in 78 neonates (median 21 days after birth), none of the preoperative lesions showed evidence of extension or hemorrhagic transformation (0/40 [95% confidence interval: 0%-7%]). The presence of preoperative brain injury was not a significant risk factor for acquiring new injury on postoperative magnetic resonance imaging (P = .8). CONCLUSIONS Clinically silent brain injuries identified preoperatively in neonates with congenital heart disease, including stroke, have a low risk of progression with surgery and cardiopulmonary bypass and should therefore not delay clinically indicated cardiac surgery. In this multicenter cohort, balloon atrial septostomy remains an important risk factor for preoperative brain injury, particularly stroke.

Quantitative Fiber Tracking Analysis of the Optic Radiation Correlated with Visual Performance in Premature Newborns

BACKGROUND AND PURPOSE: Many prematurely born neonates have abnormalities of vision or visual processing. This study tests the hypothesis that a correlation exists between the microstructure of the optic radiation and visual performance in premature neonates. MATERIALS AND METHODS: Diffusion tensor imaging (DTI) was performed on 36 premature neonates ranging in age from 29 to 41 weeks of gestational age (GA) at time of MR imaging. DTI fiber tracking methods were developed to delineate the optic radiations and segment the tract into anterior, middle, and posterior regions. Structural development and spatial heterogeneity in the delineated optic radiations were quantitatively assessed with diffusion tensor parameters including fractional anisotropy (FA), directionally averaged diffusivity (Dav), parallel diffusivity (λ1), and transverse diffusivity (λ⊥). Visual maturity of the preterm neonates at the time of MR imaging was assessed with a visual fixation task. Regression analysis was used to examine the relationship between neonatal visual performance and the microstructure of the optic radiation. RESULTS: Fractional anisotropy within the optic radiation was observed to increase with GA (P < .0001). Dav, parallel diffusivity, and transverse diffusivity within the optic radiation each decreased with GA (P < .0003, P < .02, and P < .0001, respectively). The anterior segment of the optic radiation exhibited higher FA and lower Dav, parallel diffusivity, and transverse diffusivity (P < .005 each) than within the middle and posterior segments. Optic radiation fractional anisotropy correlated significantly with scores from the visual fixation tracking assessment, independent of GA (P < .006). CONCLUSIONS: This study detected a significant link between the tissue architecture of the optic radiation and visual function in premature neonates.