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Objective: To determine the association of antenatal magnesium sulfate with cerebellar hemorrhage in a prospective cohort of premature newborns evaluated by magnetic resonance imaging (MRI).Study Design: Cross-sectional analysis of baseline characteristics from a prospective cohort of preterm newborns (<33 weeks gestation) evaluated with 3T-MRI shortly after birth. Exclusion criteria were clinical evidence of a congenital syndrome, congenital infection, or clinical status too unstable for transport to MRI. Antenatal magnesium sulfate exposure was abstracted from the medical records and the indication was classified as obstetric or neuroprotection. Two pediatric neuroradiologists, blinded to the clinical history, scored axial T2-weighted and iron susceptibility MRI sequences for cerebellar hemorrhage. The association of antenatal magnesium sulfate with cerebellar hemorrhage was evaluated using multivariable logistic regression, adjusting for postmenstrual age at MRI and known predictors of cerebellar hemorrhage.Results: Cerebellar hemorrhage was present in 27 of 73 newborns (37%) imaged at a mean ± SD postmenstrual age of 32.4 ± 2 weeks. Antenatal magnesium sulfate exposure was associated with a significantly reduced risk of cerebellar hemorrhage. Adjusting for postmenstrual age at MRI, and predictors of cerebellar hemorrhage, antenatal magnesium sulfate was independently associated in our cohort with decreased cerebellar hemorrhage (OR, 0.18; 95% CI, 0.049-0.65; P = .009).Conclusion: Antenatal magnesium sulfate exposure is independently associated with a decreased risk of MRI-detected cerebellar hemorrhage in premature newborns, which could explain some of the reported neuroprotective effects of magnesium sulfate. [ABSTRACT FROM AUTHOR]

Objectives To determine the rate of magnetic resonance imaging (MRI)-detected noncystic white matter injury (WMI) in a prospective cohort of premature newborns, and to evaluate its associations with changes in clinical predictors of WMI over the study period. Study design A prospective cohort of premature newborns (<33 weeks gestational age) was studied with MRI within 4 weeks of birth and near term-equivalent age. A pediatric neuroradiologist scored the severity of WMI on T1-weighted MRI according to published criteria. WMI was classified as none/mild or moderate/severe. Subjects with severe cystic WMI, periventricular hemorrhagic infarction, or motion artifact on MRI were excluded. Changes in clinical characteristics and predictors of WMI over the study period (1998-2011) were evaluated. Predictors of moderate/severe WMI, including birth year, were evaluated using multivariate logistic regression. Results Among 267 newborns, 45 (17%) had moderate/severe WMI. The rate of moderate/severe WMI decreased over the study period (P = .002, χ² test for trends). On multivariate logistic regression, the odds of moderate/severe WMI decreased by 11% for each birth year of the cohort (OR, 0.89; 95% CI, 0.81-0.98; P = .02). Prolonged exposure to indomethacin also was independently associated with reduced odds of moderate/severe WMI. Conclusion The decreasing burden of MRI-detected moderate/severe noncystic WMI in our cohort of premature newborns is independent over time of changes in the known clinical predictors of WMI. Prolonged exposure to indomethacin is associated with reduced WMI. [ABSTRACT FROM AUTHOR]

Objective: To investigate the contribution of hypoglycemia in the first 24 hours after birth to brain injury in term newborns at risk for neonatal encephalopathy. Study design: A prospective cohort of 94 term neonates born between 1994 and 2010 with early postnatal brain magnetic resonance imaging studies were analyzed for regions of brain injury. Neurodevelopmental outcome was assessed at 1 year of age. Results: Hypoglycemia (glucose <46 mg/dL) in the first 24 hours after birth was detected in 16% of the cohort. Adjusting for potential confounders of early perinatal distress and need for resuscitation, neonatal hypoglycemia was associated with a 3.72-fold increased odds of corticospinal tract injury (P =.047). Hypoglycemia was also associated with 4.82-fold increased odds of 1-point worsened neuromotor score (P =.038) and a 15-point lower cognitive and language score on the Bayley Scales of Infant Development (P =.015). Conclusion: Neonatal hypoglycemia is associated with additional risks in the setting of neonatal encephalopathy with increased corticospinal tract injury and adverse motor and cognitive outcomes. [ABSTRACT FROM AUTHOR]

Objective: To hypothesize that detailed examination of early cerebellar volumes in time would distinguish differences in cerebellar growth associated with intraventricular hemorrhage (IVH) and white matter injury in preterm infants. Study design: Preterm newborns at the University of California San Francisco (n = 57) and the University of British Columbia (n = 115) were studied with serial magnetic resonance imaging scans near birth and again at near term-equivalent age. Interactive semi-automated tools were used to determine volumes of the cerebellar hemispheres. Results: Adjusting for supratentorial brain injury, cerebellar hemorrhage, and study site, cerebellar volume increased 1.7 cm3/week postmenstrual age (95% CI, 1.6-1.7; P < .001). More severe supratentorial IVH was associated with slower growth of cerebellar volumes (P < .001). Volumes by 40 weeks were 1.4 cm3 lower in premature infants with grade 1 to 2 IVH and 5.4 cm3 lower in infants with grade 3 to 4 IVH. The same magnitude of decrease was found between ipsilateral and contralateral IVH. No association was found with severity of white matter injury (P = .3). Conclusions: Early effects of decreased cerebellar volume associated with supratentorial IVH in either hemisphere may be a result of concurrent cerebellar injury or direct effects of subarachnoid blood on cerebellar development. [Copyright &y& Elsevier]

Objective: To compare the association between perinatal events and the pattern and extent of brain injury on early magnetic resonance imaging in newborn infants with and without therapeutic hypothermia for hypoxic-ischemic encephalopathy. Study design: We performed a cohort study of 35 treated and 25 nontreated neonates who underwent magnetic resonance imaging. The injury patterns were defined a priori as: normal, watershed, or basal ganglia/thalamus-predominant, as well as a dichotomous outcome of moderate-to-severe versus mild-no injury. Results: Neonates with hypothermia had less extensive watershed and basal ganglia/thalamus injuries and a greater proportion had normal imaging. Therapeutic hypothermia was associated with a decreased risk of both basal ganglia/thalamus injury (relative risk, 0.29; 95% CI, 0.10 to 0.81, P = .01) and moderate-severe injury. Neonates with sentinel events showed a decrease in basal ganglia/thalamus-predominant injury and an increase in normal imaging. All neonates with decreased fetal movements had injury, predominantly watershed, regardless of therapeutic hypothermia. Conclusions: These results validate reports of reduced brain injury after therapeutic hypothermia and suggest that perinatal factors are important indicators of response to treatment. [Copyright &y& Elsevier]

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. [ABSTRACT FROM AUTHOR]

Summary: Neuroprotection is a major health care priority, given the enormous burden of human suffering and financial cost caused by perinatal brain damage. With the advent of hypothermia as therapy for term hypoxic–ischemic encephalopathy, there is hope for repair and protection of the brain after a profound neonatal insult. However, it is clear from the published clinical trials and animal studies that hypothermia alone will not provide complete protection or stimulate the repair that is necessary for normal neurodevelopmental outcome. This review critically discusses drugs used to treat seizures after hypoxia–ischemia in the neonate with attention to evidence of possible synergies for therapy. In addition, other agents such as xenon, N-acetylcysteine, erythropoietin, melatonin and cannabinoids are discussed as future potential therapeutic agents that might augment protection from hypothermia. Finally, compounds that might damage the developing brain or counteract the neuroprotective effects of hypothermia are discussed. [Copyright &y& Elsevier]

The ability to image the newborn brain during development has provided new information regarding the effects of injury on brain development at different vulnerable time periods. Studies in animal models of brain injury correlate beautifully with what is now observed in the human newborn. We now know that injury at term primarily results in grey matter injury while injury in the premature brain predominantly results in a pattern of white matter injury, though recent evidence suggests a blurring of this distinction . These injuries affect how the brain matures subsequently and again, imaging has led to new insights that allow us to match function and structure. This review will focus on these patterns of injury that are so crucially determined by age at insult. In addition, this review will highlight how the brain responds to these insults with changes in connectivity that have profound functional consequences. [Copyright &y& Elsevier]

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. [Copyright &y& Elsevier]

Abstract: Neonatal brain injury is an important cause of death and neurodevelopmental delay. Multiple pathways of oxidant stress, inflammation, and excitotoxicity lead to both early and late phases of cell damage and death. Therapies targeting these different pathways have shown potential in protecting the brain from ongoing injury. More recent therapies, such as growth factors, have demonstrated an ability to increase cell proliferation and repair over longer periods of time. Even though hypothermia, which decreases cerebral metabolism and possibly affects other mechanisms, may show some benefit in particular cases, no widely effective therapeutic interventions for human neonates exist. In this review, we summarize recent findings in neuroprotection and neurogenesis for the immature brain, including combination therapy to optimize repair. [Copyright &y& Elsevier]

Objective: To evaluate whether therapeutic hypothermia alters the prognostic value of clinical grading of neonatal encephalopathy. Study design: This study was a secondary analysis of a multicenter study of 234 term infants with neonatal encephalopathy randomized to head cooling for 72 hours starting within 6 hours of birth, with rectal temperature maintained at 34.5°C ± 0.5°C, followed by re-warming for 4 hours, or standard care at 37.0°C ± 0.5°C. Severity of encephalopathy was measured pre-randomization and on day 4, after re-warming, in 177 infants; 31 infants died before day 4, and data were missing for 10 infants. The primary outcome was death or severe disability at 18 months of age. Results: Milder pre-randomization encephalopathy, greater improvement in encephalopathy from randomization to day 4, and cooling were associated with favorable outcome in multivariate binary logistic regression. Hypothermia did not affect severity of encephalopathy at day 4, however, in infants with moderate encephalopathy at day 4, those treated with hypothermia had a significantly higher rate of favorable outcome (31/45 infants, 69%, P = .006) compared with standard care (12/33, 36%). Conclusion: Infants with moderate encephalopathy on day 4 may have a more favorable prognosis after hypothermia treatment than expected after standard care. [Copyright &y& Elsevier]

Objective: To determine the long-term outcome of neonatal dehydration. Study design: We identified 182 newborns who were rehospitalized with dehydration (weight loss ≥12% of birth weight and/or serum sodium ≥150 mEq/L) and 419 randomly selected controls from a cohort of 106,627 term and near-term infants with birth weight ≥2000 g born between 1995 and 1998 in northern California Kaiser Permanente hospitals. Outcomes data were obtained from electronic records, interviews, questionnaire responses, and neurodevelopmental evaluations performed in a masked fashion. Results: Follow-up data to age at least 2 years were available for 173 of 182 children with a history of dehydration (95%) and 372 of 419 controls (89%) and included formal evaluation at a mean age (±standard deviation) of 5.1 ± 0.12 years for 106 children (58%) and 168 children (40%), respectively. None of the cases developed shock, gangrene, or respiratory failure. Neither crude nor adjusted scores on cognitive tests differed significantly between groups. There was no significant difference between groups in the proportion of children with abnormal neurologic examinations or neurologic diagnoses. Frequencies of parental concerns and reported behavior problems also were not significantly different in the 2 groups. Conclusions: Neonatal dehydration in this managed care setting was not associated with adverse neurodevelopmental outcomes in infants born at or near term. [Copyright &y& Elsevier]

Objective: To determine the neurodevelopmental outcome of prematurely born newborns with magnetic resonance imaging (MRI) abnormalities. Study design: A total of 89 prematurely born newborns (median age 28 weeks postgestation) were studied with MRI when stable for transport to MRI (median age, 32 weeks postgestation); 50 newborns were studied again near term age (median age, 37 weeks). Neurodevelopmental outcome was determined at 18 months adjusted age (median) using the Mental Development Index (Bayley Scales Infant Development II) and a standardized neurologic exam. Results: Of 86 neonatal survivors, outcome was normal in 51 (59%), borderline in 22 (26%), and abnormal in 13 (15%). Moderate/severe MRI abnormalities were common on the first (37%) and second (32%) scans. Abnormal outcome was associated with increasing severity of white matter injury, ventriculomegaly, and intraventricular hemorrhage on MRI, as well as moderate/severe abnormalities on the first (relative risk [RR] = 5.6; P = .002) and second MRI studies (RR = 5.3; P = .03). Neuromotor abnormalities on neurologic examination near term age (RR = 6.5; P = .04) and postnatal infection (RR = 4.0; P = .01) also increased the risk for abnormal neurodevelopmental outcome. Conclusions: In premature newborns, brain abnormalities are common on MRI early in life and are associated with adverse neurodevelopmental outcome. [Copyright &y& Elsevier]

: BackgroundThe objective was to determine the timing and mechanism of brain injury using preoperative and postoperative magnetic resonance imaging (MRI) and three-dimensional MR spectroscopic imaging (MRSI) in newborns with transposition of the great arteries (TGA) repaired with full-flow cardiopulmonary bypass.: MethodsTen term newborns with TGA undergoing an arterial switch operation were studied with MRI, MRSI, and neurologic examination preoperatively and postoperatively at a median of 5 days (2 to 9 days) and 19 days (14 to 26 days) of age, respectively. Five term historical controls were studied at a median of 4 days (3 to 9 days). Lactate/choline (marker of cerebral oxidative metabolism) and N-acetylaspartate (NAA)/choline (marker of cerebral metabolism and density) were measured bilaterally from the basal ganglia, thalamus, and corticospinal tracts.: ResultsFour TGA newborns had brain injury on the preoperative MRI. The only new lesion detected on the postoperative study was a focal white matter lesion in one newborn with a normal preoperative MRI. The MRSI of age-adjusted lactate/choline was quantitatively higher in newborns with TGA compared with those without heart disease (p < 0.0001), even in newborns without MRI evidence of preoperative brain injury. Lactate/choline decreased after surgery but remained elevated compared with controls. In newborns with TGA, those with preoperative brain injury on MRI had lower NAA/choline globally (p = 0.04) than those with normal preoperative MRI. Five newborns had a decline in NAA/choline from the preoperative to postoperative studies.: ConclusionsAbnormal brain metabolism and injury was observed preoperatively in newborns with TGA. Brain injury is not solely related to the operative course. [Copyright &y& Elsevier]

Selective patterns of cerebral injury are observed after a variety of insults at different ages during development. Distinct populations of cells demonstrate selective vulnerability during these specific developmental stages, which may account for the observed patterns of injury. We review the evidence that injury to preoligodendrocytes and subplate neurons contributes to periventricular white matter injury in preterm infants, whereas thalamic neuronal cell vulnerability and neuronal nitric oxide synthase–expressing striatal interneurons resistance result in deep gray nuclei damage in the term infant. The unique roles of particular mechanisms including oxidative stress, glutamatergic neurotransmission, and programmed cell death are discussed in the context of this selective vulnerability. [Copyright &y& Elsevier]

Objectives: The purpose of our study was to examine the physiologic changes caused by 10 minutes of umbilical cord occlusion in fetal sheep and to determine the correlation between fetal acidemia or cerebral ischemia and hippocampal neuronal damage.Study Design: Thirteen fetal sheep were instrumented and catheterized. Carotid artery blood flow (CaF), fetal mean arterial blood pressure (FMABP), pH, PCO (2), base excess, oxygen saturation (SatO(2)), and PO (2) were monitored throughout the occlusion study. Brain sections were examined for the hippocampal neuronal damage.Results: Our data showed severe ischemia (CaF: 10 +/- 7 mL/min; FMABP: 29 +/- 8 mm Hg) and acidemia (pH: 7.0 +/- 0.05; base excess: -9.9 +/- 2.4 mEq/L) at the end of occlusion. The neuronal damage score had significant correlations with ischemia and also with reperfusion, but not with the acidemic or hypoxic parameters.Conclusion: We demonstrated that the degree of hippocampal damage was correlated with the degree of ischemia and reperfusion. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the association of therapeutic hypothermia with magnetic resonance imaging (MRI) findings and 30-month neurodevelopment in term neonatal encephalopathy.Study Design: Cross-sectional analysis of 30-month neurodevelopment (IQR 19.0-31.4) in a prospective cohort of mild-to-severe neonatal encephalopathy imaged on day 4 (1993-2017 with institutional implementation of therapeutic hypothermia in 2007). MRI injury was classified as normal, watershed, or basal ganglia/thalamus. Abnormal motor outcome was defined as Bayley-II psychomotor developmental index <70, Bayley-III motor score <85 or functional motor deficit. Abnormal cognitive outcome was defined as Bayley-II mental developmental index <70 or Bayley-III cognitive score <85. Abnormal composite outcome was defined as abnormal motor and/or cognitive outcome, or death. The association of therapeutic hypothermia with MRI and outcomes was evaluated with multivariable logistic regression adjusted for propensity to receive therapeutic hypothermia.Results: Follow-up was available in 317 (78%) surviving children, of whom 155 (49%) received therapeutic hypothermia. Adjusting for propensity, therapeutic hypothermia was independently associated with decreased odds of abnormal motor (OR 0.15, 95% CI 0.06-0.40, P < .001) and cognitive (OR 0.11, 95% CI 0.04-0.33, P < .001) outcomes. This association remained statistically significant after adjustment for injury pattern. The predictive accuracy of MRI pattern for abnormal composite outcome was unchanged between therapeutic hypothermia-treated (area under the receiver operating curve 0.76; 95% CI 0.61-0.91) and untreated (area under the receiver operating curve 0.74; 95% CI 0.67-0.81) infants. The negative predictive value of normal MRI was high in therapeutic hypothermia-treated and untreated infants (motor 96% vs 90%; cognitive 99% vs 95%).Conclusions: Therapeutic hypothermia is associated with lower rates of brain injury and adverse 30-month outcomes after neonatal encephalopathy. The predictive accuracy of MRI in the first week of life is unchanged by therapeutic hypothermia. Normal MRI remains reassuring for normal 30-month outcome after therapeutic hypothermia. [ABSTRACT FROM AUTHOR]

Medically refractory neonatal seizures represent a major therapeutic challenge in neonatal intensive care units. Conventional antiepileptic drugs demonstrate limited efficacy. Previous studies documented a high frequency of off-label drug therapy in neonates. We sought to determine if pediatric neurologists are recommending treatment of neonatal seizures with newer agents, despite a lack of information about their safety or efficacy in this population. Surveys were distributed at the 2007 Annual Meeting of the Child Neurology Society. Responses from 55 pediatric neurologists were analyzed. Seventy-three percent (40/55) recommended treatment of neonatal seizures with one or both of levetiracetam and topiramate; 47% (26/55) recommended levetiracetam; and 55% (30/55) recommended topiramate. Despite an absence of data on neonatal pharmacokinetics of either drug, neurologists made different dosing recommendations for these two drugs (P = 0.003, chi-square test). Respondents considered both agents to be efficacious in the majority of cases; adverse effects were recognized more frequently with topiramate. These results highlight the urgent need for rigorous clinical trials to understand the risks and benefits of new drug therapies for neonatal seizures. [Copyright &y& Elsevier]

Children with neonatal encephalopathy (NE) are at risk for basal ganglia/thalamus (BG/T) and watershed patterns of brain injury. Children with BG/T injury are at high risk for motor impairment in infancy, but the predictive validity of a published rating scale for outcome at age four years is not known. We examined a cohort of children with NE and magnetic resonance imaging (MRI) to examine the relationship between BG/T injury and severity of cerebral palsy (CP) in childhood. Term-born neonates at risk for brain injury due to NE were enrolled from 1993 to 2014 and received MRI within two weeks of birth. Brain injury was scored by a pediatric neuroradiologist. The Gross Motor Function Classification System (GMFCS) level was determined at four years. The relationship between BG/T injury and dichotomized GMFCS (no CP or GMFCS I to II = none/mild versus III to V = moderate/severe CP) was evaluated with logistic regression, and predictive performance was assessed by cross-validated area under the receiver operating characteristic curve (AUROC). Among 174 children, higher BG/T scores were associated with more severe GMFCS level. Clinical predictors had a low AUROC (0.599), compared with that of MRI (0.895). Risk of moderate to severe CP was low (<20%) in all patterns of brain injury except BG/T = 4, which carried a 67% probability (95% confidence interval 36% to 98%) of moderate to severe CP. The BG/T injury score can be used to predict the risk and severity of CP at age four years and thereby inform early developmental interventions. [ABSTRACT FROM AUTHOR]

Objective: To describe the association between electrographically detected seizures and brain injury evaluated by magnetic resonance imaging in newborns treated with hypothermia.Study Design: A total of 56 newborns treated with hypothermia were monitored using video electroencephalography through cooling and rewarming, and then imaged at a median of 5 days. The electroencephalograms were reviewed for indications of seizure and status epilepticus. Moderate-severe injury detected on magnetic resonance imaging was measured using a classification scheme similar to one predicting abnormal outcome in an analogous population.Results: Seizures were recorded in 17 newborns (30%), 5 with status epilepticus. Moderate-severe injury was more common in newborns with seizures (relative risk, 2.9; 95% CI, 1.2-4.5; P=.02), and was present in all 5 newborns with status epilepticus. Newborns with moderate-severe injury had seizures that were multifocal and of later onset, and they were more likely to experience recurrent seizures after treatment with 20 mg/kg phenobarbital. Newborns with only subclinical seizures were as likely to have injury as those with seizures with a clinical correlate (57% vs 60%).Conclusion: Seizures represent a risk factor for brain injury in the setting of therapeutic hypothermia, especially in neonates with status epilepticus, multifocal-onset seizures, and a need for multiple medications. However, 40% of our neonates were spared from brain injury, suggesting that the outcome after seizures is not uniformly poor in children treated with therapeutic hypothermia. [ABSTRACT FROM AUTHOR]

Objective: To assess whether birth at <26 weeks gestation is an important predictor of brain microstructure maturation as determined by using diffusion tensor imaging. Study design: We performed serial magnetic resonance imaging and diffusion tensor imaging in 176 infants born at <33 weeks gestation. Diffusion parameters were calculated for white and gray matter regions. Linear regression for repeated measures was used to assess the effect of extremely premature birth on brain maturation. Results: In white matter, fractional anisotropy increased by 0.008 per week (95% CI, 0.007-0.009; P < .0001) and mean diffusivity decreased by 0.021 mm2/sec per week, (95% CI, –0.24–0.018; P < .0001). Birth at <26 weeks was associated with lower white matter fractional anisotropy (–0.01; 95% CI, –0.018–0.003; P = .008), but this effect was eliminated when co-morbid conditions were added to the model. Moderate-severe brain injury was associated with decreased mean white matter fractional anisotropy (–0.012; 95% CI, –0.02–0.004; P = .002). Conclusion: Brain microstructure maturation as measured serially in premature infants is independent of extremely premature birth. Brain injury and co-morbid conditions may be the important determinants of microstructure maturation. [ABSTRACT FROM AUTHOR]

Purpose This study aims to apply neurite orientation dispersion and density imaging (NODDI) to measure white matter microstructural features during early development. Methods NODDI parameters were measured in twelve newborns and thirteen 6-month infants, all with perinatal clinical encephalopathy. Results Between 0 and 6 months, there were significant differences in fractional anisotropy (FA) for all tracts; in neurite density for internal capsules, optic radiations, and splenium; and in orientation dispersion for anterior limb of internal capsule and optic radiations. There were no appreciable differences in NODDI parameters related to outcome. Conclusion NODDI may allow more detailed characterization of microstructural maturation than FA. [ABSTRACT FROM AUTHOR]

Basal ganglia abnormalities on magnetic resonance imaging predict neurodevelopmental impairment in newborns with perinatal depression. We determined the value of a clinical encephalopathy score as a predictor of abnormal magnetic resonance imaging results in newborns with perinatal depression.We assigned a neonatal encephalopathy score to 101 newborns. The encephalopathy score, based on alertness, feeding, tone, respiratory status, reflexes, and seizure activity, was assigned once daily. The maximum score from the first 3 days of life was compared with abnormal magnetic resonance imaging results present globally or solely in the basal ganglia.Eighty-one percent of patients manifested abnormalities on any magnetic resonance imaging sequence, and 37% manifested abnormalities in the basal ganglia alone. The encephalopathy score correlated well with magnetic resonance imaging abnormalities in the basal ganglia (Spearman Rho = 0.335, P < 0.0001). Newborns with mild and severe encephalopathy had likelihood ratios of 0.41 and 7.4, respectively, for abnormal basal ganglia magnetic resonance imaging results. Newborns with moderate encephalopathy (composing 47% of the cohort) manifested basal ganglia abnormalities with a likelihood ratio of 0.785.Severe clinical encephalopathy correlates with abnormal basal ganglia magnetic resonance imaging results, and mild encephalopathy correlates with a normal magnetic resonance imaging result. However, standard clinical criteria do not alter the prior risk of abnormal basal ganglia magnetic resonance imaging results for newborns with moderate encephalopathy. [Copyright &y& Elsevier]

Neonatal brain injury affects thousands of babies each year and may lead to long-term and permanent physical and neurological problems. Currently, therapeutic hypothermia is standard clinical care for term newborns with moderate to severe neonatal encephalopathy. Nevertheless, it is not completely protective, and additional strategies to restore and promote regeneration are urgently needed. One way to ensure recovery following injury to the immature brain is to augment endogenous regenerative pathways. However, novel strategies such as stem cell therapy, gene therapies and nanotechnology have not been adequately explored in this unique age group. In this perspective review, we describe current efforts that promote neuroprotection and potential targets that are unique to the developing brain, which can be leveraged to facilitate neuroregeneration. Unlabelled Image [ABSTRACT FROM AUTHOR]

Highlights: [•] Delineation of the timing of structural maturation and age-dependent behaviors. [•] Impact of hypoxic-ischemic and traumatic injuries on early brain development. [•] Identification of parallels in vulnerability to brain injuries across species. [•] Guidelines for choice of rodent age when modeling human brain injuries. [ABSTRACT FROM AUTHOR]

Abstract: Neonatal seizures are common clinical conditions in both term and preterm neonates, yet no clinical management guidelines for direct care exist. We surveyed 193 international neurologists, neonatologists, and specialists in neonatal neurology or neonatal neurocritical care to assess management practices for seizures in preterm and term neonates. We found high reported rates of electroencephalogram and amplitude-integrated electroencephalogram (aEEG) monitoring to detect neonatal seizures, prevalent use of older anticonvulsant agents, and high rates of neuroimaging. Overall, responses were similar for term and preterm neonates. However, term neonates were likelier to be more heavily investigated, with higher use of magnetic resonance imaging and of electroencephalogram and aEEG monitoring of at-risk neonates. Continuous monitoring and cranial imaging of neonatal seizures now comprise the standard of care in many centers, although management practices vary widely. Early recognition and management of neonatal seizures and possible underlying injury may lead to increased opportunities for stopping seizures, protecting the brain, and improving developmental outcomes in at-risk neonates. The need for collaboration among neonatologists and neurologists is urgent, to address gaps in knowledge regarding management of neonatal seizures in term and preterm neonates. [Copyright &y& Elsevier]

Abstract: The mammalian target of rapamycin (mTOR) exerts neuroprotective effects under hypoxic or ischemic conditions. To explore whether mTOR participates in neuroprotective signaling through regulation of hypoxia-inducible factor-1α (HIF-1α), vascular endothelial growth factor (VEGF) and neuronal apoptosis in developing rat brain with hypoxia–ischemia (HI), we operated on postnatal day 10 rats by ligating the common carotid artery followed by exposure to systemic hypoxia. Brains were collected at various intervals to detect the expression of mTOR, phosphorylated mTOR (p-mTOR), HIF-1α, VEGF and cleaved caspase 3 (CC3), using immunohistochemistry and Western blot analysis. We also used terminal deoxynucleotidyl transferase-mediated dUTP-nick end labeling (TUNEL) to detect neuronal apoptosis. The p-mTOR protein expression increased at 2h after HI, peaked at 8h, lasted 24h, and then dropped to the basal level. Also, the expression of HIF-1α and VEGF was significantly enhanced and peaked at 8h after HI. Up-regulated expression of CC3 was observed at 2h, peaked at 24h, and lasted 72h after HI. Increased neuronal apoptosis is associated with reduced HIF-1α and VEGF expression. Furthermore, pretreatment with rapamycin, a mTOR specific inhibitor, significantly inhibited HIF-1α and VEGF protein after HI. The expression of CC3 and the number of TUNEL-positive cells were up-regulated at 8h and down-regulated at 24h after HI in the rapamycin-treated group. Our findings suggest that mTOR may participate in the regulation of HIF-1α, VEGF and neuronal apoptosis, serving neuroprotective functions after HI in developing rat brain. [Copyright &y& Elsevier]

Abstract: Activation of NMDA receptors (NMDAR) is associated with divergent downstream signaling leading to neuronal survival or death that may be regulated in part by whether the receptor is located synaptically or extrasynaptically. Distinct activation of the MAP kinases ERK and p38 by synaptic and extrasynaptic NMDAR is one of the mechanisms underlying these differences. We have recently shown that the Src family kinases (SFKs) play an important role in neonatal hypoxic–ischemic brain injury by regulating NMDAR phosphorylation. In this study, we characterized the distribution of NMDAR, SFKs and MAP kinases in synaptic and extrasynaptic membrane locations in the postnatal day 7 and adult mouse cortex. We found that the NMDAR, SFKs and phospho-NR2B were predominantly at synapses, whereas striatal-enriched protein tyrosine phosphatase (STEP) and its substrates ERK and p38 were much more concentrated extrasynaptically. NR1/NR2B was the main subunit at extrasynaptic membrane with concomitant NR2B phosphorylation at tyrosine (Y) 1336 in the immature brain. STEP expression increased, while p38 decreased with development in the extrasynaptic membrane. These results suggest that SFKs and STEP are poised to differentially regulate NMDAR-mediated signaling pathways due to their distinct subcellular localization, and thus may contribute to the age-specific differences seen in vulnerability, pathology and consequences of hypoxic–ischemic brain injury. [Copyright &y& Elsevier]

Abstract: Hypoxia-inducible factor-1α (HIF-1α) is a key transciptional regulator of cellular and systemic oxygen homeostasis. Previous studies have shown that the regulation of HIF-1α is involved in the activation of PI3K/Akt pathway in some cells. However, whether this pathway plays a role in modulating HIF-1α in cultured cortical neurons during hypoxia-ischemia (HI) remains unclear. We therefore investigated the relationship between phosphoinositid 3-kinase/Akt (PI3K/Akt) pathway and HIF-1α expression in cultured neurons using an oxygen and glucose deprivation (OGD) model. In this study, cortical neurons cultured in vitro were subjected to OGD for 3h followed by reperfusion. The expressions of HIF-1α, VEGF, total Akt and phosphorelated-Akt (p-Akt) were detected by RT-PCR, Western blot and immunocytochemistry. We found that HIF-1α and VEGF were increased at 4h and peaked at 8h after OGD. Meanwhile, p-Akt increased and peaked at 4h after reperfusion, preceding HIF-1α expression. Pretreatment with wortmannin, a PI3K/Akt pathway inhibitor, significantly inhibited p-Akt expression and further attenuated both transcription and translation of HIF-1α and VEGF. Collectively, our findings suggested that PI3K/Akt signaling pathway might be involved in HIF-1α regulation after OGD in cultured cortical neurons. [Copyright &y& Elsevier]

Abstract: HIF-1 is believed to play a critical role in hypoxia/ischemia (H/I) preconditioning protection in neonatal brain. Recently, it has been shown that hydrogen peroxide (H2O2) may contribute to H/I preconditioning in rat primary neurons. We hypothesize that H2O2 produced during H/I preconditioning may increase HIF-1α protein expression and contribute to H/I preconditioning protection in the immature brain. To test this hypothesis, we used 6–8 days in vitro (DIV) primary cortical neurons from embryonic day 16 CD1 mouse brains and preconditioned them with 10min of oxygen and glucose deprivation (OGD) or exogenous H2O2 at doses from 5 to 50μM. Both OGD and low dose H2O2 (15μM) preconditioning provided neuronal protection 24h later against a 2h OGD insult. Cell survival was 34.9±1.8% and 35.8±3.8% with OGD and H2O2 preconditioning respectively vs. 20.0±0.4% without preconditioning (P <0.01). After OGD preconditioning, HIF-1α protein increased at 4h and peaked at 8h, then declined at 18h and increased again to reach another peak at 32h. HIF-1α protein following H2O2 preconditioning increased at 8h and peaked at 32h. For both preconditioning paradigms, HIF-1α expression level declined to baseline at 72h. Our results suggest that low levels of H2O2 may up-regulate HIF-1α protein and thereby mediate H/I preconditioning protection. [Copyright &y& Elsevier]

Periventricular leukomalacia is a risk factor for visual impairment in children born prematurely. The impact of diffuse white-matter injury, as detected on magnetic resonance imaging, on early visual function is unknown. We developed two 5-point visual-gaze scores to analyze the association between this clinical assessment and white-matter injury in 93 premature neonates <34 weeks of gestational age at birth. Older postmenstrual age was associated with higher values of the two gaze scores. Infants with moderate or severe white-matter injury had lower scores than their peers without white-matter injury (0.41 points, 95% confidence interval of 0.13-0.69 for visual fixation score; and 0.70 points, 95% confidence interval of 0.30-1.10 for conjugate score, P < 0.005). Using the results from both scales, a score of ≥9 in an infant examined at ≥36 weeks postmenstrual age predicted normal white matter on magnetic resonance examination, with a sensitivity of 84% and a specificity of 100%. These preliminary findings suggest that white-matter injury affects visual function even before term equivalent postmenstrual age. [Copyright &y& Elsevier]

Standardized approaches to the treatment of neonatal seizures remain undeveloped. We assessed the type and number of anticonvulsants selected, blood levels attained, and postdischarge anticonvulsant treatment of neonatal seizures among five neonatal intensive care units in the United States between 2000-2003. Almost all of the 480 neonates (94%) with seizures were treated, initially with phenobarbital (82%), lorazepam (9%), phenytoin (2%), other anticonvulsants (1%), or a combination of the first two drugs (6%). While the majority of neonates were treated with one drug (59%), the number of anticonvulsants varied (P < 0.0001), as did the peak serum phenobarbital levels (P < 0.0001). The majority (75%) of survivors received anticonvulsant treatment after discharge. These neonates were more likely to have had abnormal electroencephalography or brain imaging, or to have needed a second anticonvulsant, compared with neonates whose drug therapy was discontinued. Anticonvulsant therapy is used in the majority of neonates with seizures, mostly with phenobarbital, and treatment is continued beyond discharge. The observed wide therapeutic variability may reflect a lack of standardized diagnostic and treatment approaches, particularly for seizures refractory to initial phenobarbital therapy. Trials of anticonvulsants with long-term neurodevelopmental follow-up are needed to develop evidence-based treatment guidelines. [Copyright &y& Elsevier]

This report describes the case of an 11-year-old girl with a prior history of epilepsy and multiple episodes of status epilepticus who presented with generalized convulsive status epilepticus and left hemiclonic seizures. Magnetic resonance imaging, including diffusion-weighted sequences and spectroscopy, and neuropathology at autopsy were consistent with excitotoxic neuronal injury to the hippocampus, cortex, thalamus, mammillary bodies, and cerebellum. Review of the literature revealed 11 similar cases that support the hypothesis of excitotoxic neuronal cell death after status epilepticus. [Copyright &y& Elsevier]