Mood disorders in children following neonatal hypoxic-ischemic encephalopathy.

BACKGROUND: Few studies on the consequences following newborn hypoxic-ischemic encephalopathy (NHIE) assess the risk of mood disorders (MD), although these are prevalent after ischemic brain injury in adults. OBJECTIVE: To study the presence of MD in children survivors of NHIE. METHODS: 14 children survivors of NHIE treated with hypothermia and without cerebral palsy and 15 healthy children without perinatal complications were studied aged three to six years for developmental status (Ages and Stages Questionnaire 3 [ASQ-3]) and for socio-emotional status (Preschool Symptom Self-Report [PRESS] and Child Behavior Checklist [CBCL] 1.5-5 tests). Maternal depression was assessed using Montgomery-Asberg Depression Rating Scale (MADRS). Socio-economic factors such as parental educational level or monthly income were also studied. RESULTS: NHIE children did not present delay but scored worse than healthy children for all ASQ3 items. NHIE children showed higher scores than healthy children for PRESS as well as for anxious/depressive symptoms and aggressive behavior items of CBCL. In addition, in three NHIE children the CBCL anxious/depressive symptoms item score exceeded the cutoff value for frank pathology (P = 0.04 vs healthy children). There were no differences in the other CBCL items as well as in maternal MADRS or parental educational level or monthly income. Neither ASQ3 scores nor MADRS score or socio-economic factors correlated with PRESS or CBCL scores. CONCLUSIONS: In this exploratory study children survivors of NHIE showed increased risk of developing mood disturbances, in accordance with that reported for adults after brain ischemic insults. Considering the potential consequences, such a possibility warrants further research.

Small molecule biomarkers for neonatal hypoxic ischemic encephalopathy.

Hypoxic Ischemic Encephalopathy (HIE) is one of the most deleterious conditions in the perinatal period and the access to small molecule biomarkers aiding accurate diagnosis and disease staging, progress monitoring, and early outcome prognosis could provide relevant advances towards the development of personalized therapies. The emergence of metabolomics, the "omics" technology enabling the holistic study of small molecules, for biomarker discovery employing different analytical platforms, animal models and study populations has drastically increased the number and diversity of small molecules proposed as candidate biomarkers. However, the use of very few compounds has been implemented in clinical guidelines and authorized medical devices. In this work we review different approaches employed for discovering HIE-related small molecule biomarkers. Their role in associated biochemical disease mechanisms as well as the way towards their translation into the clinical practice are discussed.

Superior Vena Cava Syndrome and Hypoxic Ischemic Encephalopathy Secondary to a Massive, Right-Sided Immature Cervical Teratoma.

Cervical teratomas are a rare form of fetal teratoma that can grow to massive size. Generally, these masses can be surgically excised after birth with excellent physical and functional prognosis because the benign variants respect anatomical borders. The primary complications of these masses are associated with compromise of the trachea and esophagus: upper airway obstruction and polyhydramnios. We report the first documented occurrence of superior vena cava syndrome and hypoxic ischemic encephalopathy associated with a massive, right-sided cervical teratoma. This case highlights that when cervical teratomas are right-sided and sufficiently large, they can extend inferiorly and compromise central venous return to the heart. This unique presentation would likely have required fetal surgical excision to avoid catastrophic cerebral injury.

Early identification of neonatal mild hypoxic-ischemic encephalopathy by amide proton transfer magnetic resonance imaging: A pilot study.

PURPOSE: This study aimed to evaluate the amide proton transfer (APT) values in neonates with mild hypoxic-ischemic encephalopathy (HIE) using APT imaging. METHOD: A total of 30 full-term neonates with mild HIE (16 males and 14 females; mean postnatal age 4.2 days, age range 2-7 days) and 12 normal neonates (six males and six females; mean postnatal age 3.3 days, age range 2-5 days) underwent conventional magnetic resonance imaging and APT imaging. APT measurements were performed in multiple regions of interest (ROIs) in the brain. APT values were statistically analyzed to assess for significant differences between the mild HIE and normal neonates in different regions of the brain, and correlation with neonatal gestational age. RESULTS: In 30 neonates with mild HIE, 10% (3/30) of the HIE patients had normal conventional MRI. There were significant differences in APT values of the HIE group in bilateral caudate, bilateral thalamus, bilateral centrum semiovale and left globus pallidus/putamen (p < 0.05), and no statistical difference was observed in right globus pallidus/putamen (p = 0.051) and brainstem (p = 0.073) between the two groups. Furthermore, APT values in bilateral caudate, bilateral globus pallidus/putamen, bilateral thalamus, and brainstem regions (p < 0.05) exhibited positive linear correlations with gestational age in the control group, except for bilateral centrum semiovale (right: Pearson's r = 0.554, p = 0.062; left: Pearson's r = 0.561, p = 0.058). In the mild HIE groups, no significant correlation with gestational age was found in all regions. CONCLUSIONS: APT imaging is a feasible and useful technique with diagnostic capability for neonatal HIE.

Neonatal encephalopathy and hypoxic-ischemic encephalopathy.

Acute hypoxic-ischemic encephalopathy around the time of birth remains a major cause of death and life-long disability. The key insight that led to the modern revival of studies of neuroprotection was that, after profound asphyxia, many brain cells show initial recovery from the insult during a short "latent" phase, typically lasting approximately 6h, only to die hours to days later after a "secondary" deterioration characterized by seizures, cytotoxic edema, and progressive failure of cerebral oxidative metabolism. Studies designed around this framework showed that mild hypothermia initiated as early as possible before the onset of secondary deterioration and continued for a sufficient duration to allow the secondary deterioration to resolve is associated with potent, long-lasting neuroprotection. There is now compelling evidence from randomized controlled trials that mild to moderate induced hypothermia significantly improves survival and neurodevelopmental outcomes in infancy and mid-childhood.

Biomarkers in neonatal hypoxic-ischemic encephalopathy-Review of the literature to date and future directions for research.

The widespread introduction of therapeutic hypothermia as a standard of care in hypoxic-ischemic encephalopathy (HIE) has brought increasing pressure on clinicians to make an early and accurate assessment of the degree of hypoxic injury (HI) that has occurred and the severity of the encephalopathy that will ensue. No single blood-based marker is currently robust enough to detect significant HI or predict outcome. However, research in the field has been active in the last 10 years and we know that HIE is associated with predictable alterations in the expression of a number of inflammatory proteins, neuron-specific proteins, metabolite pathways, and microRNA. These alterations evolve quickly over the first hours and days of life. Predictive power varies depending on the timing of measurement of the biomarker, the sample type, and the case mix of the cohort examined. Combining clinical data with biochemical measurements is currently the most likely path toward improved detection and prediction of outcome in neonatal HIE.

Neonatal hypoxic-ischemic encephalopathy: emerging therapeutic strategies based on pathophysiologic phases of the injury.

Neonatal hypoxic ischemic encephalopathy (HIE) is an important cause of neonatal death and disability. At present, there is no unified standard and specialized treatment method for neonatal HIE. In clinical practice, we have found that a gap remains between preclinical medical research and clinical application in the treatment of neonatal HIE. To promote an organic combination of preclinical research and clinical application, we propose the different phases as intervention targets, based on the pathophysiologic changes in phases I, II, and III of neonatal HIE; moreover, we suggest transformative medicine as a principle that may improve the therapeutic effect by blocking the progression of the disease to an irreversible stage. For instance, in phase I, mild hypothermia, free radical scavenger (erythropoietin, hydrogen-rich saline), excitatory amino acid receptor blocker, and neuroprotective agents should be administered to neonates with moderate/severe HIE; in phase II, following phase I treatment, anti-inflammatory agents, neuroprotective or nerve regeneration agents, and stem cell transplantation should be administered to patients; in phase III, anti-inflammatory agents, neuroprotective or nerve regeneration agents, and stem cell transplantation should be administered to patients. As soon as the patient's condition has stabilized, acupuncture, massage, and rehabilitation training should be performed. Following further study of stem cells, stem cell transplantation is expected to become the most promising therapeutic candidate for treatment of severe neonatal HIE with its sequelae.

Perinatal Brain Injury: Mechanisms, Prevention, and Outcomes.

Perinatal brain injury may lead to long-term morbidity and neurodevelopmental impairment. Improvements in perinatal care have resulted in the survival of more infants with perinatal brain injury. The effects of hypoxia-ischemia, inflammation, and infection during critical periods of development can lead to a common pathway of perinatal brain injury marked by neuronal excitotoxicity, cellular apoptosis, and microglial activation. Various interventions can prevent or improve the outcomes of different types of perinatal brain injury. The objective of this article is to review the mechanisms of perinatal brain injury, approaches to prevention, and outcomes among children with perinatal brain injury.

Progesterone as a Postnatal Prophylactic Agent for Encephalopathy Caused by Prenatal Hypoxic Ischemic Insult.

Brain damage caused by hypoxic ischemic insult during the perinatal period causes hypoxic ischemic encephalopathies (HIEs). Therapeutic hypothermia is indicated for HIE, but because the therapeutic burden is large for its limited therapeutic effectiveness, another strategy is needed. Progesterone (P4) plays a neuroprotective role through the actions of its metabolite, allopregnanolone (Allo), on P4 receptor, γ-aminobutyric acid type A receptors or both. We examined the therapeutic potential of P4 using a newborn rat model of HIE. Fetal rats were exposed to transient ischemic hypoxia by 30-minute bilateral uterine artery clamping on gestational day 18. After spontaneous birth, newborn pups were subcutaneously injected with P4 (0.10 or 0.01 mg), medroxyprogesterone acetate (MPA; 0.12 mg), or Allo (0.10 mg) through postnatal days (PDs) 1 to 9. Brain damage in the rats was assessed using the rotarod test at PD50. The HIE insult reduced the rats' ability in the rotarod task, which was completely reversed by P4 and Allo, but not by MPA. Histological examination revealed that the HIE insult decreased neuronal (the cortex and the hippocampal CA1 region) and oligodendroglial cell density (the corpus callosum) through PD0 to PD50. The axon fiber density and myelin sheath thickness in the corpus callosum were also reduced at PD50. The time-course study revealed that P4 restored oligodendroglial cells by PD5, which was followed by neuroprotective action of P4 that lasted long over the injection period. These results suggest that P4 protects the neonatal brain from HIE insult via restoration of oligodendroglial cells.

Impacts of therapeutic hypothermia on cardiovascular hemodynamics in newborns with hypoxic-ischemic encephalopathy: a case control study using echocardiography.

PURPOSE: The effects of therapeutic hypothermia (TH) on hemodynamics in newborns with hypoxic-ischemic encephalopathy (HIE) were evaluated. MATERIALS AND METHODS: Thirty-two neonates (gestational age, 39.4 ± 1.3 weeks) who had TH for HIE and echocardiographic hemodynamic assessments during TH and post-TH period were studied. Gestational-age-matched 34 healthy neonates were enrolled for comparison. RESULTS: During TH, patients had significantly decreased left ventricular cardiac output (LVCO), descending aorta blood flow (DABF), and DABF/LVCO ratio, and increased resistive index of DA compared to controls. Upper body blood flow (UBBF) remained unchanged but UBBF/LVCO ratio significantly increased during TH. Urine output decreased significantly during TH and increased after rewarming, and showed significant positive correlation with DABF/LVCO ratio. Sixteen patients (50%) showed hypoxic-ischemic (HI) lesions on brain magnetic resonance imaging (MRI) and had significantly increased UBBF/LVCO ratio during TH compared to patients without HI lesions. Patients with UBBF/LVCO ratio >55% had significantly higher risk of having HI lesions on brain MRI (odds ratio 13.0; 95% CI, 2.4-70.2). CONCLUSIONS: Decrease in cardiac output and descending aorta blood flow, and preferential cerebral redistribution of cardiac output along with an increase in systemic peripheral vascular resistance may affect systemic organ perfusion and cerebral metabolism.

Prediction of Outcome in Neonates with Hypoxic-Ischemic Encephalopathy II: Role of Amplitude-Integrated Electroencephalography and Cerebral Oxygen Saturation Measured by Near-Infrared Spectroscopy.

BACKGROUND: Few data have been published on the combined use of amplitude-integrated electroencephalography (aEEG) and near-infrared spectroscopy (NIRS) for outcome prediction in neonates cooled for hypoxic-ischemic encephalopathy (HIE). OBJECTIVE: Our aim was to evaluate the predictive values and the most powerful predictive combinations of single aEEG and NIRS parameters and the respective cut-off values with regard to short-term outcomes in HIE II. METHODS: aEEG and NIRS were prospectively studied at the Medical University of Vienna in the first 102 h of life with regard to magnetic resonance imaging (MRI). Thirty-two neonates diagnosed with HIE II treated with hypothermia were investigated. The measurement period was divided into 6-h epochs. According to MRI, 2 outcome groups were defined and predictive values of aEEG parameters, regional cerebral oxygen saturation (rScO2), and the additional value of both methods combined were studied. Receiver operating curves (ROC) were obtained and area under the curve (AUC) values were calculated. ROC were then used to detect the optimal cut-off points, sensitivity, specificity, positive predictive values, and negative predictive values. RESULTS: At all time epochs, combined parameter scores were more predictive than single parameter scores. The highest AUC were observed between 18 and 60 h of cooling for the aEEG summation score (0.72-0.84) and for (background pattern + seizures) × rScO2 (0.79-0.85). At 42-60 h sensitivity was similar between those 2 scores (87.5-90.0%), but the addition of NIRS to aEEG led to an increase in specificity (from 52.4-59.1% to 72.7-90.5%). CONCLUSIONS: In HIE II, aEEG and NIRS are important predictors of short-term outcome. The combination of both methods improves prognostication. The highest predictive abilities were observed between 18 and 60 h of cooling.

Circulating Dickkopf-1 in hypoxic ischemic neonates.

OBJECTIVE: The current study aimed to determine the serum level of Dickkopf-1 (Dkk-1) in peripheral blood of neonates with hypoxic ischemic encephalopathy (HIE). METHODS: We measured serum levels of Dkk-1 by ELISA in neonates with HIE (n = 20) within 24 h from symptom onset and in healthy controls (n = 20). RESULTS: Dkk-1 serum levels increased significantly in HIE neonates than in healthy control. DKK-1 serum levels increased significantly in HIE neonates with convulsion, using multiple anti-convulsant drugs and those complicated with cranial ultrasound changes. Serum DKK-1 levels increased significantly in severe HIE patients. CONCLUSION: Our study provides for the first time the evidence of releasing Dkk-1 into the circulation of neonates with HIE with higher level in severe degree.

Brain magnetic resonance imaging and outcome after hypoxic ischaemic encephalopathy.

OBJECTIVE: To correlate pattern of injury on neonatal brain magnetic resonance imaging (MRI) with outcome in infants ≥36 + 0 weeks gestation with hypoxic ischaemic encephalopathy. METHODS: Prospective cohort study. Images were blindly reviewed. Children were assessed using a variety of standardised assessments. RESULTS: MRI brain was performed on 88 infants. Follow up was available in 73(83%) infants. Eight of 25(32%) children with normal imaging had below normal assessment scores. Eight infants (12%) had isolated punctate white matter lesions and five of these had abnormal assessment scores. Death and cerebral palsy were seen only in children with imaging scores ≥3 on basal ganglia/thalami (BGT) score or ≥4 on watershed score. No developmental concerns were raised in 3/7(43%) infants with isolated watershed injury. Ten of 13(77%) infants with isolated BGT injury died or developed cerebral palsy. All 23 children with posterior limb of the internal capsule (PLIC) injury displayed developmental difficulties. CONCLUSIONS: Almost one-third of infants with a normal MRI brain may be at risk of developmental problems. Punctate foci of white matter injury are common and not always benign. PLIC involvement is usually associated with neurological sequelae including isolated cognitive deficits. Worst outcomes are associated with basal ganglia injury.

Hypoxic ischemic encephalopathy in newborns linked to placental and umbilical cord abnormalities.

OBJECTIVE: Birth asphyxia and hypoxic ischemic encephalopathy (HIE) of the newborn remain serious complications. We present a study investigating if placental or umbilical cord abnormalities in newborns at term are associated with HIE. MATERIALS AND METHODS: A prospective cohort study of the placenta and umbilical cord of infants treated with hypothermia (HT) due to hypoxic brain injury and follow-up at 12 months of age has been carried out. The study population included 41 infants treated for HT whose placentas were submitted for histopathological analysis. Main outcome measures were infant development at 12 months, classified as normal, cerebral palsy, or death. A healthy group of 100 infants without HIE and normal follow-up at 12 months of age were used as controls. RESULTS: A velamentous or marginal umbilical cord insertion and histological abruption was associated with the risk of severe HIE, OR = 5.63, p = 0.006, respectively, OR = 20.3, p = 0.01 (multiple-logistic regression). Velamentous or marginal umbilical cord insertion was found in 39% among HIE cases compared to 7% in controls. CONCLUSIONS: Placental and umbilical cord abnormalities have a profound association with HIE. A prompt examination of the placentas of newborns suffering from asphyxia can provide important information on the pathogenesis behind the incident and contribute to make a better early prognosis.

Neuroimaging in the evaluation of neonatal encephalopathy.

BACKGROUND AND OBJECTIVE: Computed tomography (CT) is still used for neuroimaging of infants with known or suspected neurologic disorders. Alternative neuroimaging options that do not expose the immature brain to radiation include MRI and cranial ultrasound. We aim to characterize and compare the use and findings of neuroimaging modalities, especially CT, in infants with neonatal encephalopathy. METHODS: The Vermont Oxford Network Neonatal Encephalopathy Registry enrolled 4171 infants (≥36 weeks' gestation or treated with therapeutic hypothermia) between 2006 and 2010 who were diagnosed with encephalopathy in the first 3 days of life. Demographic, perinatal, and medical conditions were recorded, along with treatments, comorbidities, and outcomes. The modality, timing, and results of neuroimaging were also collected. RESULTS: CT scans were performed on 933 of 4107 (22.7%) infants, and 100 of 921 (10.9%) of those received multiple CT scans. Compared with MRI, CT provided less detailed evaluation of cerebral injury in areas of prognostic significance, but was more sensitive than cranial ultrasound for hemorrhage and deep brain structural abnormalities. CONCLUSIONS: CT is commonly used for neuroimaging in newborn infants with neonatal encephalopathy despite concerns over potential harm from radiation exposure. The diagnostic performance of CT is inferior to MRI in identifying neonatal brain injury. Our data suggest that using cranial ultrasound for screening, followed by MRI would be more appropriate than CT at any stage to evaluate infants with neonatal encephalopathy.

Hypothermia and neonatal encephalopathy.

Data from large randomized clinical trials indicate that therapeutic hypothermia, using either selective head cooling or systemic cooling, is an effective therapy for neonatal encephalopathy. Infants selected for cooling must meet the criteria outlined in published clinical trials. The implementation of cooling needs to be performed at centers that have the capability to manage medically complex infants. Because the majority of infants who have neonatal encephalopathy are born at community hospitals, centers that perform cooling should work with their referring hospitals to implement education programs focused on increasing the awareness and identification of infants at risk for encephalopathy, and the initial clinical management of affected infants.

Expression of the Nrf2-system at the blood-CSF barrier is modulated by neonatal inflammation and hypoxia-ischemia.

Transcription factor NF-E2-related factor-2 (Nrf2) is a key regulator of endogenous anti-oxidant systems shown to play a neuroprotective role in the adult by preserving blood-brain barrier function. The choroid plexus, site for the blood-CSF barrier, has been suggested to be particularly important in maintaining brain barrier function in development. We investigated the expression of Nrf2- and detoxification-system genes in choroid plexus following systemic LPS injections, unilateral cerebral hypoxia-ischemia (HI) as well as the combination of LPS and HI (LPS/HI). Plexuses were collected at different time points after LPS, HI and LPS/HI in 9-day old mice. mRNA levels of Nrf2 and many of its target genes were analyzed by quantitative PCR. Cell death was analyzed by caspase-3 immunostaining and TUNEL. LPS caused down-regulation of the Nrf2-system genes while HI increased expression at earlier time points. LPS exposure prior to HI prevented many of the HI-induced gene increases. None of the insults resulted in any apparent cell death to choroidal epithelium. These data imply that the function of the inducible anti-oxidant system in the choroid plexus is down-regulated by inflammation, even if choroid cells are not structurally damaged. Further, LPS prevented the endogenous antioxidant response following HI, suggesting the possibility that the choroid plexus may be at risk if LPS is united with an insult that increases oxidative stress such as hypoxia-ischemia.

Therapeutic hypothermia in the prevention of hypoxic-ischaemic encephalopathy: new categories to be enrolled.

UNLABELLED: Therapeutic hypothermia is now the standard of care for brain injury control in term infants with perinatal hypoxic ischemic encephalopathy (HIE). Accumulated evidence shows a reduction in mortality and long-term neurodevelopmental disability at 12-24 months of age, with more favourable effects in the less severe forms of HIE. Only few trials recruited newborns <36 weeks gestational age, or mild-to-moderate encephalopathy with base deficit (BD) <16. The new categories of patients to be enrolled should include (late) preterm infants, neonates with unexpected postnatal collapse, and newborns with stroke. Preterm HIE: Therapeutic hypothermia shows a good safety profile in clinical studies, and no adverse effects were noted in the preterm fetal animal model. Recently, it has been shown that mild hypothermia in preterm newborns with necrotizing enterocolitis (NEC) and multiple organ dysfunction syndrome (MODS) does not increase mortality, bleeding, infection, or need for inotropes in cooled newborns. A pilot study (NCT00620711) is currently recruiting newborns of > 32 but < 36 weeks gestation with standard criteria for HIE. Postnatal Collapse: The postnatal collapse (PNC) is a rare (0.03-0.5/1000 live births) but life-threatening hypoxic-ischemic event. No clinical trials of therapeutic hypothermia have specifically addressed to PNC. Nevertheless, a beneficial effect of brain cooling is expectable, and it has been proposed to include in brain hypothermia trials the infants with PNC fulfilling the entry criteria for HIE. Stroke: Perinatal arterial ischemic stroke is the most common cause of cerebral palsy (CP) in term and near-term newborn. In a systematic review and meta-analysis of animal studies of focal cerebral ischemia, hypothermia reduced the infarct size by 44%. No specific neuroprotective interventions are available for the management of acute perinatal stroke. Hypothermia may decrease seizures in newborns with encephalopathy and a focal infarct, potentially improving the long-term outcome for these infants. CONCLUDING REMARKS: Future studies of therapeutic hypothermia should include the categories of newborns excluded from the published clinical trials, that is infants <36 weeks gestation, PNC or stroke, or admitted outside of the established 6-hour window, and with encephalopathy not imputable to HIE. New entry criteria will allow significant number of newborns to benefit from the treatment.