Donna M. Ferriero

Selective head cooling with mild systemic hypothermia after neonatal encephalopathy: multicentre randomised trial

BACKGROUND Cerebral hypothermia can improve outcome of experimental perinatal hypoxia-ischaemia. We did a multicentre randomised controlled trial to find out if delayed head cooling can improve neurodevelopmental outcome in babies with neonatal encephalopathy. METHODS 234 term infants with moderate to severe neonatal encephalopathy and abnormal amplitude integrated electroencephalography (aEEG) were randomly assigned to either head cooling for 72 h, within 6 h of birth, with rectal temperature maintained at 34-35 degrees C (n=116), or conventional care (n=118). Primary outcome was death or severe disability at 18 months. Analysis was by intention to treat. We examined in two predefined subgroup analyses the effect of hypothermia in babies with the most severe aEEG changes before randomisation--ie, severe loss of background amplitude, and seizures--and those with less severe changes. FINDINGS In 16 babies, follow-up data were not available. Thus in 218 infants (93%), 73/110 (66%) allocated conventional care and 59/108 (55%) assigned head cooling died or had severe disability at 18 months (odds ratio 0.61; 95% CI 0.34-1.09, p=0.1). After adjustment for the severity of aEEG changes with a logistic regression model, the odds ratio for hypothermia treatment was 0.57 (0.32-1.01, p=0.05). No difference was noted in the frequency of clinically important complications. Predefined subgroup analysis suggested that head cooling had no effect in infants with the most severe aEEG changes (n=46, 1.8; 0.49-6.4, p=0.51), but was beneficial in infants with less severe aEEG changes (n=172, 0.42; 0.22-0.80, p=0.009). INTERPRETATION These data suggest that although induced head cooling is not protective in a mixed population of infants with neonatal encephalopathy, it could safely improve survival without severe neurodevelopmental disability in infants with less severe aEEG changes.

Rat forebrain neurogenesis and striatal neuron replacement after focal stroke

The persistence of neurogenesis in the forebrain subventricular zone (SVZ) of adult mammals suggests that the mature brain maintains the potential for neuronal replacement after injury. We examined whether focal ischemic injury in adult rat would increase SVZ neurogenesis and direct migration and neuronal differentiation of endogenous precursors in damaged regions. Focal stroke was induced in adult rats by 90‐minute right middle cerebral artery occlusion (tMCAO). Cell proliferation and neurogenesis were assessed with bromodeoxyuridine (BrdU) labeling and immunostaining for cell type‐specific markers. Brains examined 10–21 days after stroke showed markedly increased SVZ neurogenesis and chains of neuroblasts extending from the SVZ to the peri‐infarct striatum. Many BrdU‐labeled cells persisted in the striatum and cortex adjacent to infarcts, but at 35 days after tMCAO only BrdU‐labeled cells in the neostriatum expressed neuronal markers. Newly generated cells in the injured neostriatum expressed markers of medium spiny neurons, which characterize most neostriatal neurons lost after tMCAO. These findings indicate that focal ischemic injury increases SVZ neurogenesis and directs neuroblast migration to sites of damage. Moreover, neuroblasts in the injured neostriatum appear to differentiate into a region‐appropriate phenotype, which suggests that the mature brain is capable of replacing some neurons lost after ischemic injury.

Management of Stroke in Infants and Children: A Scientific Statement From a Special Writing Group of the American Heart Association Stroke Council and the Council on Cardiovascular Disease in the Young

PURPOSE The purpose of this statement is to review the literature on childhood stroke and to provide recommendations for optimal diagnosis and treatment. This statement is intended for physicians who are responsible for diagnosing and treating infants, children, and adolescents with cerebrovascular disease. METHODS The Writing Group members were appointed by the American Heart Association Stroke Councils Scientific Statement Oversight Committee. The panel included members with several different areas of expertise. Each of the panels recommendations was weighted by applying the American Heart Association Stroke Councils Levels of Evidence grading algorithm. After being reviewed by panel members, the manuscript was reviewed by 4 expert peer reviewers and by members of the Stroke Council Leadership Committee and was approved by the American Heart Association Science Advisory and Coordinating Committee. We anticipate that this statement will need to be updated in 4 years. RESULTS Evidence-based recommendations are provided for the prevention of ischemic stroke caused by sickle cell disease, moyamoya disease, cervicocephalic arterial dissection, and cardiogenic embolism. Recommendations on the evaluation and management of hemorrhagic stroke also are provided. Protocols for dosing of heparin and warfarin in children are suggested. Also included are recommendations on the evaluation and management of perinatal stroke and cerebral sinovenous thrombosis in children.

Role of hypoxia-inducible factor-1 in hypoxia-induced ischemic tolerance in neonatal rat brain.

Hypoxia‐inducible factor‐1 (HIF‐1) is a heterodimer composed of HIF‐1α and HIF‐1β protein subunits. This transcription factor is essential for the activation of hypoxia‐inducible genes like erythropoietin, some glucose transporters, the glycolytic enzymes, and vascular endothelial growth factor. Because HIF‐1 activation may promote cell survival in hypoxic tissues, we studied the effect of hypoxic preconditioning on HIF‐1 expression in neonatal rat brain. Hypoxic preconditioning (8% O2 for 3 hours), a treatment known to protect the newborn rat brain against hypoxic‐ischemic injury, markedly increased HIF‐1α and HIF‐1β expression. To support the role of HIF‐1 in protective preconditioning, we also studied the effect of two other known HIF‐1 inducers, cobalt chloride (CoCl2) and desferrioxamine (DFX), on HIF‐1 expression and neuroprotection in newborn brain. HIF‐1α and HIF‐1β protein levels were markedly increased after intraperitoneal injection of CoCl2 (60 mg/kg) and moderately increased after intraperitoneal injection of DFX (200 mg/kg) 1 to 3 hours after the injections. Preconditioning with CoCl2 or DFX 24 hours before hypoxia‐ischemia afforded 75 and 56% brain protection, respectively, compared with that in vehicle‐injected littermate controls. Thus, HIF‐1 activation could contribute to protective brain preconditioning, which could be used in high‐risk deliveries and other clinical situations. Ann Neurol 2000;48:285–296

Brain development in rodents and humans: Identifying benchmarks of maturation and vulnerability to injury across species.

Hypoxic-ischemic and traumatic brain injuries are leading causes of long-term mortality and disability in infants and children. Although several preclinical models using rodents of different ages have been developed, species differences in the timing of key brain maturation events can render comparisons of vulnerability and regenerative capacities difficult to interpret. Traditional models of developmental brain injury have utilized rodents at postnatal day 7-10 as being roughly equivalent to a term human infant, based historically on the measurement of post-mortem brain weights during the 1970s. Here we will examine fundamental brain development processes that occur in both rodents and humans, to delineate a comparable time course of postnatal brain development across species. We consider the timing of neurogenesis, synaptogenesis, gliogenesis, oligodendrocyte maturation and age-dependent behaviors that coincide with developmentally regulated molecular and biochemical changes. In general, while the time scale is considerably different, the sequence of key events in brain maturation is largely consistent between humans and rodents. Further, there are distinct parallels in regional vulnerability as well as functional consequences in response to brain injuries. With a focus on developmental hypoxic-ischemic encephalopathy and traumatic brain injury, this review offers guidelines for researchers when considering the most appropriate rodent age for the developmental stage or process of interest to approximate human brain development.

Diffusion tensor imaging: serial quantitation of white matter tract maturity in premature newborns.

Magnetic resonance diffusion tensor imaging (DTI) enables the discrimination of white matter pathways before myelination is evident histologically or on conventional MRI. In this investigation, 14 premature neonates with no evidence of white matter abnormalities by conventional MRI were studied with DTI. A custom MR-compatible incubator with a novel high sensitivity neonatal head coil and improved acquisition and processing techniques were employed to increase image quality and spatial resolution. The technical improvements enabled tract-specific quantitative characterization of maturing white matter, including several association tracts and subcortical projection tracts not previously investigated in neonates by MR. Significant differences were identified between white matter pathways, with earlier maturing commissural tracts of the corpus callosum, and deep projection tracts of the cerebral peduncle and internal capsule exhibiting lower mean diffusivity (Dav) and higher fractional anisotropy (FA) than later maturing subcortical projection and association pathways. Maturational changes in white matter tracts included reductions in Dav and increases in FA with age due primarily to decreases in the two minor diffusion eigenvalues (lambda2 and lambda3). This work contributes to the understanding of normal white matter development in the preterm neonatal brain, an important step toward the use of DTI for the improved evaluation and treatment of white matter injury of prematurity.

Serial quantitative diffusion tensor MRI of the premature brain: development in newborns with and without injury.

To determine the change over time of the apparent diffusion coefficient (ADC) and relative anisotropy of cerebral water in a cohort of premature newborns serially studied near birth and again near term.

Seizure-associated brain injury in term newborns with perinatal asphyxia

BackgroundThere is controversy over whether seizures, the most common manifestation of neonatal brain injury, may themselves damage the developing brain. ObjectiveTo determine if neonatal seizures are independently associated with brain injury in newborns with perinatal asphyxia. MethodsNinety term neonates were studied with MRI and single-voxel 1H-MRS on median day of life 6 (range 1 to 13 days). The severity of MR abnormality in the 1H-MRS regions of interest was scored using a validated scale. Seizure severity was scored based on seizure frequency and duration, EEG findings, and anticonvulsant administration. Multivariable linear regression tested the independent association of seizure severity with impaired cerebral metabolism measured by lactate/choline and compromised neuronal integrity measured by N-acetylaspartate/choline in both regions. ResultsClinical seizures occurred in 33 of 90 infants (37%). Seizure severity was associated with increased lactate/choline in both the intervascular boundary zone (p < 0.001) and the basal nuclei (p = 0.011) when controlling for potential confounders of MRI abnormalities and amount of resuscitation at birth. Each increase in seizure score was independently associated with a 21% increase in lactate/choline in the intervascular boundary zone (95% CI, 5.1–38.2%) and a 15% increase in the basal nuclei (95% CI, 0.1–31.7%). Seizure severity was independently associated with diminished N-acetylaspartate/choline in the intervascular boundary zone (p = 0.034). ConclusionThe severity of seizures in human newborns with perinatal asphyxia is independently associated with brain injury and is not limited to structural damage detectable by MRI.

Ischemic perinatal stroke : Summary of a workshop sponsored by the national institute of child health and human development and the national institute of neurological disorders and stroke

Ischemic perinatal stroke is a disorder associated with significant long-term neurologic morbidity. With an estimated incidence of 1 in 2300 to 5000 births, stroke is more likely to occur in the perinatal period than at any time in childhood. The incidence of ischemic perinatal stroke ranks second only to that of strokes in the elderly population. Although ischemic perinatal stroke is a well-recognized disorder, many aspects remain to be studied. There is no consensus on its terminology, definition, or classification. Several risk factors have been identified, but their precise roles in causing stroke are not well understood. There are no reliable predictors of ischemic perinatal stroke on which to base prevention or treatment strategies. To review these important issues and propose a research agenda, the National Institute of Child Health and Human Development and the National Institute of Neurological Disorders and Stroke convened a workshop in August 2006. This article provides a summary of the workshop.

Determinants of outcomes after head cooling for neonatal encephalopathy

OBJECTIVE. The goal of this study was to evaluate the role of factors that may determine the efficacy of treatment with delayed head cooling and mild systemic hypothermia for neonatal encephalopathy. METHODS. A total of 218 term infants with moderate to severe neonatal encephalopathy plus abnormal amplitude-integrated electroencephalographic recordings, assigned randomly to head cooling for 72 hours, starting within 6 hours after birth (with the rectal temperature maintained at 34.5 ± 0.5°C), or conventional care, were studied. Death or severe disability at 18 months of age was assessed in a multicenter, randomized, controlled study (the CoolCap trial). RESULTS. Treatment, lower encephalopathy grade, lower birth weight, greater amplitude-integrated electroencephalographic amplitude, absence of seizures, and higher Apgar score, but not gender or gestational age, were associated significantly with better outcomes. In a multivariate analysis, each of the individually predictive factors except for Apgar score remained predictive. There was a significant interaction between treatment and birth weight, categorized as ≥25th or <25th percentile for term, such that larger infants showed a lower frequency of favorable outcomes in the control group but greater improvement with cooling. For larger infants, the number needed to treat was 3.8. Pyrexia (≥38°C) in control infants was associated with adverse outcomes. Although there was a small correlation with birth weight, the adverse effect of greater birth weight in control infants remained significant after adjustment for pyrexia and severity of encephalopathy. CONCLUSIONS. Outcomes after hypothermic treatment were strongly influenced by the severity of neonatal encephalopathy. The protective effect of hypothermia was greater in larger infants.