Suboptimal postnatal function of brainstem auditory pathway in late preterm infants who do not have major perinatal and postnatal complications.

OBJECTIVES: To examine postnatal functional status of the brainstem auditory pathway in late preterm infants and detect any postnatal auditory abnormality. METHODS: Thirty preterm infants born at 33-36 weeks gestation were studied three months after term. None had major perinatal and postnatal complications to minimize confounding effects. Brainstem auditory evoked responses were recorded with 21-91/s clicks. RESULTS: Compared with postnatal age-matched normal term infants, the late preterm infants did not manifest any major abnormalities in brainstem auditory evoked responses at conventionally used 21/s clicks. At higher click rates, however, the late preterm infants manifested a moderate prolongation in BAER wave V latency. All interpeak intervals tended to be prolonged at higher click rates. The I-V interval was significantly prolonged at 51/s and particularly at 91/s clicks. Both the I-III and III-V intervals were significantly prolonged at 91/s. The late preterm infants also manifested reduced amplitudes of BAER waves III and V at most click rates. CONCLUSION: The central components of the brainstem auditory evoked responses were abnormal at higher click rates three months after term in the late preterm infants. Postnatal brainstem auditory function is suboptimal in late preterm infants without major complications. This suboptimal brainstem auditory function may not be clearly shown at term or an earlier stage, but can be shown later. Late preterm infants, although they may not have major complications, should be followed for later auditory development, providing valuable information for improving postnatal care.

Perinatal brain damage - what the obstetrician needs to know.

Perinatal brain damage is still one of the leading contributors to perinatal death and postnatal disability worldwide. However, the term perinatal brain damage encompasses very different aetiological entities that result in an insult to the developing brain and does not differentiate between the onset, cause and severity of this insult. Hypoxic-ischemic encephalopathy (HIE), intraventricular haemorrhage, periventricular leukomalacia and perinatal stroke are often listed as the major aetiologies of perinatal brain damage. They differ by type and timing of injury, neuropathological and imaging findings and their clinical picture. Along the timeline of neurodevelopment in utero, there appears to be a specific "window of vulnerability" for each type of injury, but clinical overlap does exist. In the past, peripartum acute hypoxia was believed to be the major, if not the only, cause of perinatal brain damage, but intrauterine inflammation, prematurity, chronic hypoxia/growth retardation and genetic abnormalities appear to be at least equally important contributors.

Activation of TRESK background potassium channels by cloxyquin exerts protective effects against excitotoxic-induced brain injury and neuroinflammation in neonatal rats.

We investigated effects of activation of TRESK channels by selective activator cloxyquin on excitotoxic-induced brain injury and neuroinflammation involving brain mast cells and inflammatory cytokines in neonatal rats. Three different doses of cloxyquin (0.2, 1 and 5 mg/kg) were studied in ibotenate-induced perinatal brain injury (PBI) in P5 rat-pups. Cerebral lesions and mast cells in coronal brain sections were evaluated. Concentrations of activin A, IL-1ß, IL-6 and IL-10 in brain homogenates were measured using ELISA. Cloxyquin dose-dependently exerted protective effects against excitotoxic-induced neonatal brain injury and neuroinflammation. TRESK channels may be a promising new target for the treatment of PBIs.

Functional status of brainstem auditory pathway in babies born below 30 week gestation with necrotizing enterocolitis.

OBJECTIVE: Recent studies showed that neonatal necrotizing enterocolitis (NEC) adversely affects the brainstem auditory pathway in babies born at 30-40 week gestation. We compared the functional status of the pathway between babies born below 30 week gestation with NEC and those without NEC for any differences to understand whether NEC also affects the pathway in babies born at a smaller gestation. METHOD: Brainstem auditory evoked response was studied at term in NEC babies born below 30 week gestation. The data obtained were compared with age-matched non-NEC babies for any abnormalities, and then compared with previously reported NEC babies born at 30-34 week gestation for any differences. RESULTS: Although the latencies of waves I and III did not differ significantly between NEC and non-NEC babies, wave V latency in NEC babies was longer than in non-NEC babies at all click rates used. In particular, I-V interpeak interval, reflecting brainstem conduction time, in NEC babies was significant longer than in non-NEC babies. Wave V amplitude and the V/I amplitude ratios in NEC babies was smaller than in non-NEC babies at some click rates. The I-V interval in our NEC babies born below 30 week gestation was longer than in previously reported NEC babies born at 30-34 week gestation at all click rates. CONCLUSION: NEC babies born below 30 week gestation are associated with delayed brainstem conduction time. Functional status of the brainstem auditory pathway in NEC babies born below 30 week gestation is less favorable than that in those with greater gestation.

Postnatal functional status of the brainstem auditory pathway in term infants after perinatal hypoxia-ischemia.

OBJECTIVES: To examine postnatal changes in the impaired brainstem auditory pathway in term infants after perinatal hypoxia-ischemia (HI). METHODS: Brainstem auditory evoked response (BAER) was studied at 2-4 months of age in term infants who suffered perinatal HI. The BAER data obtained at various click rates in these infants were compared with those in age-matched normal term controls to detect any abnormalities. RESULTS: The infants after HI showed a slight elevation in BAER threshold. Four (9.8%) infants had threshold elevation. At 21/s clicks, there was a slight decrease in wave I latency, and a slight increase in wave III and V latencies. However, the I-V and I-III intervals in these infants were significantly increased (p < .05 and .05), whereas III-V interval was slightly increased. At higher click rates of 51 and 91/s, all BAER variables showed similar changes, with only small variations. An abnormal increase in the I-V and/or I-III intervals was seen in 4 (9.8%) infants, who were not associated with BAER threshold elevation. CONCLUSIONS: At 2-4 months of age, around 20% of the infants after perinatal HI showed a moderate degree of either peripheral or central impairment of the brainstem auditor pathway. Monitoring postnatal changes could provide valuable information for postnatal care of infants after perinatal HI.

Early diagnosis and treatment of infants with prenatal and perinatal risk factors for brain damage at the neurodevelopmental research unit in Mexico.

Prenatal and perinatal risk factors for perinatal brain damage frequently produce brain injuries in preterm and term infants. The early diagnosis and treatment of these infants, in the period of higher brain plasticity, may prevent the neurological and cognitive sequels that accompany these lesions. The Neurodevelopmental Research Unit at the Institute of Neurobiology of the National Autonomous University of Mexico has taken this endeavor. A multidisciplinary approach is followed. Pediatric, neurologic and rehabilitation clinical studies, MRI, EEG, visual and auditory evoked responses, and Bayley II evaluations are carried out initially. Infants are followed up to 8 years, with periodic appointments for evaluation and treatment. Katona's neurohabilitation method is used for initial diagnosis and treatment. Selective visual and auditory attention are explored from 3 months of age. This method was created in the Unit and, if deficiencies are observed, the method also describes the treatment to avoid subsequent alterations of these processes. Deficiencies in the acquisition of language are evaluated from 4 months of age, implementing treatment through instructions to parents on how they should teach their children to speak. This method has also been developed in the Unit and is in its validation process. In the MRI, we pay special attention to subtle and diffuse patterns, due to the high frequency with which they appear in contemporary cohorts at a national and international level. More than 80% of these infants showed abnormal MRI findings that should be taken into consideration. The outcome of children at 8 years old showed that 78%, 76% and 78% of extremely preterm, very preterm and late preterm, respectively, had a normal neurodevelopment. In term infants, only 69% had a normal neurodevelopment; in this group, the majority of infants had very severe brain lesions. Conclusions: It is necessary to evaluate, at an early age, all newborns with prenatal and perinatal risk factors for brain damage. Special attention should be payed to all premature newborns and those newborns who have been discharged from the intensive care unit.

Feasibility of Umbilical Cord Blood Collection in Neonates at Risk of Brain Damage-A Step Toward Autologous Cell Therapy for a High-risk Population.

Evidence for umbilical cord blood (UCB) cell therapies as a potential intervention for neurological diseases is emerging. To date, most existing trials worked with allogenic cells, as the collection of autologous UCB from high-risk patients is challenging. In obstetric emergencies the collection cannot be planned. In preterm infants, late cord clamping and anatomic conditions may reduce the availability. The aim of the present study was to assess the feasibility of UCB collection in neonates at increased risk of brain damage. Infants from four high-risk groups were included: newborns with perinatal hypoxemia, gestational age (GA) ≤30 + 0 weeks and/or birthweight <1,500 g, intrauterine growth restriction (IUGR), or monochorionic twins with twin-to-twin transfusion syndrome (TTTS). Feasibility of collection, quantity and quality of obtained UCB [total nucleated cell count (TNC), volume, sterility, and cell viability], and neonatal outcome were assessed. UCB collection was successful in 141 of 177 enrolled patients (hypoxemia n = 10; GA ≤30 + 0 weeks n = 54; IUGR n = 71; TTTS n = 6). Twenty-six cases were missed. The amount of missed cases per month declined over the time. Volume of collected UCB ranged widely (median: 24.5 ml, range: 5.0-102 ml) and contained a median of 0.77 × 108 TNC (range: 0.01-13.0 × 108). TNC and UCB volume correlated significantly with GA. A total of 10.7% (19/177) of included neonates developed brain lesions. To conclude, collection of UCB in neonates at high risk of brain damage is feasible with a multidisciplinary approach and intensive training. High prevalence of brain damage makes UCB collection worthwhile. Collected autologous UCB from mature neonates harbors a sufficient cell count for potential therapy. However, quality and quantity of obtained UCB are critical for potential therapy in preterm infants. Therefore, for extremely preterm infants alternative cell sources such as UCB tissue should be investigated for autologous treatment options because of the low yield of UCB.

Midkine: The Who, What, Where, and When of a Promising Neurotrophic Therapy for Perinatal Brain Injury.

Midkine (MK) is a small secreted heparin-binding protein highly expressed during embryonic/fetal development which, through interactions with multiple cell surface receptors promotes growth through effects on cell proliferation, migration, and differentiation. MK is upregulated in the adult central nervous system (CNS) after multiple types of experimental injury and has neuroprotective and neuroregenerative properties. The potential for MK as a therapy for developmental brain injury is largely unknown. This review discusses what is known of MK's expression and actions in the developing brain, areas for future research, and the potential for using MK as a therapeutic agent to ameliorate the effects of brain damage caused by insults such as birth-related hypoxia and inflammation.

Long-term therapeutic effects of Katona therapy in moderate-to-severe perinatal brain damage.

AIM: To determine the long-term efficacy of Katona therapy and early rehabilitation of infants with moderate-to-severe perinatal brain damage (PBD). METHODS: Thirty-two participants were recruited (7-16 years) and divided into 3 groups: one Healthy group (n = 11), one group with PBD treated with Katona methodology from 2 months of corrected age, and with long-term follow-up (n = 12), and one group with PBD but without treatment in the first year of life due to late diagnosis of PBD (n = 9). Neuropediatric evaluations, motor evoked potentials (MEPs) and magnetic resonance images (MRI) were made. The PBD groups were matched by severity and topography of lesion. RESULTS: The patients treated with Katona had better motor performance when compared to patients without early treatment (Gross Motor Function Classification System levels; 75% of Katona group were classified in levels I and II and 78% of patients without early treatment were classified in levels III and IV). Furthermore, independent k-means cluster analyses of MRI, MEPs, and neuropediatric evaluations data were performed. Katona and non-treated early groups were classified in the same MRI cluster which is the expected for PBD population patients. However, in MEPs and neuropediatric evaluations clustering, the 67% of Katona group were assigned into Healthy group showing the impact of Katona therapy over the patients treated with it. These results highlight the Katona therapy benefits in early rehabilitation of infants with moderate-to-severe PBD. CONCLUSIONS: Katona therapy and early rehabilitation have an important therapeutic effect in infants with moderate-to-severe PBD by decreasing the severity of motor disability in later stages of life.

Impact of tocolysis-intent magnesium sulfate and beta-adrenergic agonists on perinatal brain damage in infants born between 28-36 weeks' gestation.

AIMS: Magnesium sulfate has neuroprotective effects in preterm infants. Whether other antepartum treatments interfere with the neuroprotective actions is not well known. This study aims to explore the impacts of antenatal administration of Magnesium sulfate or beta-2 adrenergic agonists as tocolytic agents on the developing brain in premature infants. METHODS: This is a retrospective cohort study in four tertiary perinatal centers in Japan. We collected data of pregnant women and infants born between 28 and 36 weeks for tocolytic agents, gestational age, sex, antenatal corticosteroid, fetal growth restriction, pathological chorioamnionitis, low umbilical arterial pH values (<7.1), multiple pregnancy, mode of delivery and institutions after excluding clinical chorioamnionitis, non-reassuring fetal status or major anomalies. Tocolytic agents were categorized into four groups: no-tocolysis, magnesium sulfate, beta-2 adrenergic agonists and the combination of them. We conducted multiple comparisons with multivariate analyses using generalized linear regression models to compare the prevalence of a poor perinatal outcome defined as infant's death, brain damage, particularly cerebral palsy and developmental delay. RESULTS: Among 1083 infants, 39% were no-tocolysis, 47% were magnesium sulfate, 41% were beta-2 adrenergic agonists and 27% were combination group, including the duplication. The incidence of poor perinatal outcome was decreased by magnesium sulfate (OR 0.27, 95% CI 0.10-0.72), but not changed significantly by beta-2 adrenergic agonists (OR 1.28, 95% CI 0.63-2.59) or the combination group (OR 2.24, 95% CI 0.67-7.54), compared with the no-tocolysis. CONCLUSION: The combination therapy for tocolysis with beta-2 adrenergic agonists diminished the magnesium sulfate neuroprotective action after adjusting for covariables.

Neuromodulatory Effect of NLRP3 and ASC in Neonatal Hypoxic Ischemic Encephalopathy.

BACKGROUND: Following birth asphyxia there is a robust inflammatory response. NLRP3 is a receptor of the innate immune system. Upon activation, NLRP3 forms an inflammasome together with ASC and procaspase-1 to mediate release of IL-1ß and IL-18. NLRP3 has previously been shown to be upregulated following neonatal hypoxic-ischemic (HI) brain injury in mice, but with no early effect on brain injury. OBJECTIVE: We aimed to evaluate if deficiency of NLRP3 or ASC protects against neonatal HI brain damage 7 days after hypoxia-ischemia. METHODS: C57BL/6J, NLRP3-/-, and ASC-/- mice were subjected to unilateral common carotid artery ligation followed by hypoxia at P9. Brain infarction, apoptosis, and microglial response were evaluated, as well as total RNA sequencing and examination of plasma levels of systemic proinflammatory cytokines. RESULTS: NLRP3-/- mice showed significantly increased brain infarction volumes compared to wild-type (Wt) mice, while ASC-/- mice showed reduced brain infarction volumes after neonatal hypoxia-ischemia. The amount of activated microglia was increased in NLRP3-/- mice, while decreased in ASC-/- mice compared to Wt mice. Total RNA sequencing showed an impaired inflammatory transcriptional response in the hippocampus of NLRP3-/- mice. Plasma levels of IL-1ß and IL-18 were not affected, but TNF was lower in NLRP3-/- and ASC-/- mice compared to Wt mice. CONCLUSION: ASC deficiency is neuroprotective in neonatal HI brain damage in mice, while NLRP3 deficiency increases brain damage.

Exosomes derived from umbilical cord mesenchymal stem cells reduce microglia-mediated neuroinflammation in perinatal brain injury.

BACKGROUND: Preterm newborns are at high risk of developing neurodevelopmental deficits caused by neuroinflammation leading to perinatal brain injury. Human Wharton's jelly mesenchymal stem cells (hWJ-MSC) derived from the umbilical cord have been suggested to reduce neuroinflammation, in part through the release of extracellular vesicle-like exosomes. Here, we studied whether exosomes derived from hWJ-MSC have anti-inflammatory effects on microglia-mediated neuroinflammation in perinatal brain injury. METHODS: Using ultracentrifugation, we isolated exosomes from hWJ-MSC culture supernatants. In an in vitro model of neuroinflammation, we stimulated immortalized BV-2 microglia and primary mixed glial cells with lipopolysaccharide (LPS) in the presence or absence of exosomes. In vivo, we introduced brain damage in 3-day-old rat pups and treated them intranasally with hWJ-MSC-derived exosomes. RESULTS: hWJ-MSC-derived exosomes dampened the LPS-induced expression of inflammation-related genes by BV-2 microglia and primary mixed glial cells. The secretion of pro-inflammatory cytokines by LPS-stimulated primary mixed glial was inhibited by exosomes as well. Exosomes interfered within the Toll-like receptor 4 signaling of BV-2 microglia, as they prevented the degradation of the NFκB inhibitor IκBα and the phosphorylation of molecules of the mitogen-activated protein kinase family in response to LPS stimulation. Finally, intranasally administered exosomes reached the brain and reduced microglia-mediated neuroinflammation in rats with perinatal brain injury. CONCLUSIONS: Our data suggest that the administration of hWJ-MSC-derived exosomes represents a promising therapy to prevent and treat perinatal brain injury.

Antenatal prevention of cerebral palsy and childhood disability: is the impossible possible?

This review covers our current knowledge of the causes of perinatal brain injury leading to cerebral palsy-like outcomes, and argues that much of this brain damage is preventable. We review the experimental evidence that there are treatments that can be safely administered to women in late pregnancy that decrease the likelihood and extent of perinatal brain damage that occurs because of acute and severe hypoxia that arises during some births, and the additional impact of chronic fetal hypoxia, infection, inflammation, growth restriction and preterm birth. We discuss the types of interventions required to ameliorate or even prevent apoptotic and necrotic cell death, and the vulnerability of all the major cell types in the brain (neurons, astrocytes, oligodendrocytes, microglia, cerebral vasculature) to hypoxia/ischaemia, and whether a pan-protective treatment given to the mother before birth is a realistic prospect.

Influencia del estatus socioeconómico sobre variables cognitivas y electroencefalográficas en escolares con riesgo de daño cerebral / Influence of socioeconomic status on cognitive and electroencephalographic variables school children at risk

Introducción: el estatus socioeconómico puede impactar sobre la cognición y la actividad eléctrica cerebral de los niños, por la influencia que tiene sobre el desarrollo durante etapas tempranas. Objetivo: evaluar la asociación de variables socioeconómicas, con alteraciones cognitivas y electroencefalográficas, en un grupo de niños escolares con riesgo de daño cerebral. Métodos: se estudiaron 42 niños mexicanos, de 6-7 años de edad. Se realizó un estudio socioeconómico a los padres y los niños fueron evaluados mediante la Evaluación Neuropsicológica Infantil (subpruebas de lectura-escritura y escala de signos neurológicos blandos), la Escala de Inteligencia de Wechsler para Niños, la Escala de Conners para Padres-Revisada y un electroencefalograma en diferentes edades. Resultados: con las variables socioeconómicas y, mediante un análisis de conglomerados, se encontraron 3 grupos que mostraban una adecuada diferenciación académica y económica entre sí. Por el método de clasificación basado en regresiones dispersas, se identificaron las variables que diferenciaban significativamente a los 3 grupos: problemas sociales, cognitivos, síntomas inatento, índice TDAH (Trastorno por Déficit de Atención e Hiperactividad, Escala de Conners para Padres-Revisada), lectura de palabras, comprensión en lectura de oraciones, dictado de sílabas, precisión de lectura en voz alta, lectura de sílabas, dictado de no palabras, movimiento de oposición digital, agarre de lápiz (Evaluación Neuropsicológica Infantil) y primer electroencefalograma normal. Conclusiones: el grupo con más desventajas socioeconómicas tuvo un peor desempeño en la lectoescritura y mayor prevalencia de actividad paroxística no epileptiforme; mientras que, el grupo con mayores ventajas socioeconómicas, mostró mejor desempeño en estas habilidades, mayor proporción de electroencefalogramas normales y una tendencia hacia problemas de atención(AU)

Introduction: the socioeconomic status can impact on the cognition and electrical brain activity of children due to the influence it has on the development during early stages. Objective: to evaluate the association of socioeconomic variables with cognitive and electroencephalographic alterations, in a group of school children at risk of brain damage. Methods: 42 Mexican children in the ages from 6 to 7 years old were studied. A socioeconomic study was conducted on the parents, and the children were evaluated through the Child Neuropsychological Assessment (reading-writing subtests and the scale of neurological soft signs), the Wechsler´s Intelligence Scale for Children, the Conners´ Scale for Parents-Revised and an electroencephalogram in different ages. Results: with the socioeconomic variables and by means of an analysis of conglomerate, 3 groups were found that showed an adequate academic and economic differentiation among themselves. By the classification method based on scattered regressions were identified variables that significantly differentiated the 3 groups: social and cognitive problems, inattentive symptoms, ADHD (Attention Deficit and Hyperactivity Disorder, Conners Scale for Parents-Revised), reading of words, comprehension in reading of sentences, dictation of syllables, accuracy of reading aloud, reading of syllables, dictation of non words, movement of digital opposition, pencil´s grip (Neuropsychological Evaluation of Children) and first normal electroencephalogram. Conclusions: the group with more socioeconomic disadvantages had a worse performance in reading and writing and a higher prevalence of non-epileptiform paroxysmal activity; whereas, the group with the greatest socioeconomic advantages showed a better performance in these skills, a greater proportion of normal electroencephalograms and a tendency towards attention problems(AU)

Influencia del estatus socioeconómico sobre variables cognitivas y electroencefalográficas en escolares con riesgo de daño cerebral / Influence of socioeconomic status on cognitive and electroencephalographic variables school children at risk

Introducción: el estatus socioeconómico puede impactar sobre la cognición y la actividad eléctrica cerebral de los niños, por la influencia que tiene sobre el desarrollo durante etapas tempranas. Objetivo: evaluar la asociación de variables socioeconómicas, con alteraciones cognitivas y electroencefalográficas, en un grupo de niños escolares con riesgo de daño cerebral. Métodos: se estudiaron 42 niños mexicanos, de 6-7 años de edad. Se realizó un estudio socioeconómico a los padres y los niños fueron evaluados mediante la Evaluación Neuropsicológica Infantil (subpruebas de lectura-escritura y escala de signos neurológicos blandos), la Escala de Inteligencia de Wechsler para Niños, la Escala de Conners para Padres-Revisada y un electroencefalograma en diferentes edades. Resultados: con las variables socioeconómicas y, mediante un análisis de conglomerados, se encontraron 3 grupos que mostraban una adecuada diferenciación académica y económica entre sí. Por el método de clasificación basado en regresiones dispersas, se identificaron las variables que diferenciaban significativamente a los 3 grupos: problemas sociales, cognitivos, síntomas inatento, índice TDAH (Trastorno por Déficit de Atención e Hiperactividad, Escala de Conners para Padres-Revisada), lectura de palabras, comprensión en lectura de oraciones, dictado de sílabas, precisión de lectura en voz alta, lectura de sílabas, dictado de no palabras, movimiento de oposición digital, agarre de lápiz (Evaluación Neuropsicológica Infantil) y primer electroencefalograma normal. Conclusiones: el grupo con más desventajas socioeconómicas tuvo un peor desempeño en la lectoescritura y mayor prevalencia de actividad paroxística no epileptiforme; mientras que, el grupo con mayores ventajas socioeconómicas, mostró mejor desempeño en estas habilidades, mayor proporción de electroencefalogramas normales y una tendencia hacia problemas de atención(AU)

Introduction: the socioeconomic status can impact on the cognition and electrical brain activity of children due to the influence it has on the development during early stages. Objective: to evaluate the association of socioeconomic variables with cognitive and electroencephalographic alterations, in a group of school children at risk of brain damage. Methods: 42 Mexican children in the ages from 6 to 7 years old were studied. A socioeconomic study was conducted on the parents, and the children were evaluated through the Child Neuropsychological Assessment (reading-writing subtests and the scale of neurological soft signs), the Wechsler´s Intelligence Scale for Children, the Conners´ Scale for Parents-Revised and an electroencephalogram in different ages. Results: with the socioeconomic variables and by means of an analysis of conglomerate, 3 groups were found that showed an adequate academic and economic differentiation among themselves. By the classification method based on scattered regressions were identified variables that significantly differentiated the 3 groups: social and cognitive problems, inattentive symptoms, ADHD (Attention Deficit and Hyperactivity Disorder, Conners Scale for Parents-Revised), reading of words, comprehension in reading of sentences, dictation of syllables, accuracy of reading aloud, reading of syllables, dictation of non words, movement of digital opposition, pencil´s grip (Neuropsychological Evaluation of Children) and first normal electroencephalogram. Conclusions: the group with more socioeconomic disadvantages had a worse performance in reading and writing and a higher prevalence of non-epileptiform paroxysmal activity; whereas, the group with the greatest socioeconomic advantages showed a better performance in these skills, a greater proportion of normal electroencephalograms and a tendency towards attention problems(AU)

Brainstem auditory abnormality in extremely premature babies and the impact of neonatal bronchopulmonary dysplasia.

INTRODUCTION: Extremely premature babies, particularly those who have neonatal bronchopulmonary dysplasia, are at risk of brain damage and neurodevelopmental impairment. This study aimed to examine functional status of the brainstem auditory pathway in extremely premature babies and assess the impact of bronchopulmonary dysplasia on function. MATERIAL AND METHODS: Brainstem auditory evoked response was studied at term in babies born at ≤27 weeks of gestation with or without neonatal bronchopulmonary dysplasia. The normal controls were term babies without perinatal problems. RESULTS: Compared with the normal controls, the extremely premature babies showed an elevated response threshold, increased latencies of waves I, III and particularly V. They also showed significantly increased I-V and III-V intervals. The amplitudes of waves I and V were moderately reduced. These abnormalities were clearly more significant in those with bronchopulmonary dysplasia than those without bronchopulmonary dysplasia. A direct comparison between the two groups of extremely premature babies revealed that wave V latency, and I-V and particularly III-V intervals were significantly longer in the babies with bronchopulmonary dysplasia than those without bronchopulmonary dysplasia. CONCLUSIONS: Extremely premature babies have functional impairment of the brainstem auditory pathway. The impairment is clearly more significant in those with bronchopulmonary dysplasia than those without bronchopulmonary dysplasia. Neonatal bronchopulmonary dysplasia and associated unfavorable conditions are major contributors to brainstem auditory impairment in extremely premature babies.

Is the neonatal creatine phosphokinase level a reliable marker for fetal hypoxia?

AIM: The creatine phosphokinase (CPK) level is believed to increase in neonatal peripheral blood after tissue damage, including damage from perinatal hypoxia. However, it is not clear whether it is truly a reliable marker for fetal hypoxia. We investigated the chronological changes in neonatal CPK and the reliability of CPK as a marker for fetal hypoxia. METHODS: Sixty term neonates admitted to the neonatal intensive care unit at Tokyo Women's Medical University Medical Center East from April 2009 to April 2010 were enrolled in this study. We evaluated whether asphyxia and fetal heart rate (FHR) abnormality could predict the neonatal CPK level by using receiver-operator curve analysis. We also compared umbilical cord blood pH levels with neonatal CPK levels. In addition, we investigated factors that influence neonatal CPK in non-asphyxia cases. RESULTS: The median value of CPK peaked on day 1. There were no significant differences in CPK levels regardless of the presence of asphyxia or FHR abnormality. Non-asphyxiated neonates with older gestational ages and amniotic fluid abnormalities had significantly higher levels of CPK. CONCLUSION: Our results indicate that the neonatal CPK level is not an appropriate marker for retrospectively predicting either asphyxia or FHR abnormality. There are influencing factors other than asphyxia that increase neonatal CPK. Therefore, one should be careful when making a diagnosis of perinatal hypoxia based solely on increased levels of neonatal CPK after birth.

Abnormal findings in brainstem auditory evoked response at 36-37weeks of postconceptional age in babies with neonatal chronic lung disease.

AIM: To examine brainstem auditory function at 36-37weeks of postconceptional age in preterm infants who are diagnosed to have neonatal chronic lung disease (CLD). STUDY DESIGN: Preterm infants, born at 31 and less weeks of gestation, were studied at 36-37weeks of postconceptional age when they were diagnosed to have neonatal CLD. Brainstem auditory evoked response (BAER) was recorded and analyzed at different click rates. RESULTS: Compared with healthy controls at the same postconceptional age, the CLD infants showed a slightly increase in BAER wave V latency. However, the I-V, and III-V interpeak intervals in the CLD infants were significantly increased. The III-V/I-III interval ratio was also significantly increased. The amplitudes of BAER waves III and V in the CLD infants tended to be reduced. These BAER findings were similar at all 21, 51 and 91/s clicks, although the abnormalities tended to be more significant at higher than at low click rates. CONCLUSION: At 36-37weeks of postconceptional age, BAER was abnormal in preterm infants who were diagnosed to have neonatal CLD. This suggests that at time when the diagnosis of CLD is made there is functional impairment, reflecting poor myelination, in the brainstem auditory pathway in preterm infants with neonatal CLD.

Reduced wave amplitudes of brainstem auditory response in high-risk babies born at 28-32week gestation.

OBJECTIVE: To examine brainstem auditory electrophysiology in high-risk babies born at 28-32week gestation by analysing the amplitudes of wave components in maximum length sequence brainstem auditory evoked response (MLS BAER). METHODS: 94 preterm babies, ranging in gestation 28-32weeks, with perinatal problems (high-risk) were recruited. The amplitudes of MLS BAER wave components were studied at term age (37-42weeks postconceptional age). RESULTS: Compared with normal term controls, the amplitude in the high-risk preterm babies was significantly smaller at the highest click rate 910/s for wave I (p<0.01), at all 91-910/s for wave III (all p<0.01) and at 455 and 910/s (p<0.05 and 0.01) for wave V. Compared with age-matched low-risk preterm controls, the amplitude was significantly smaller at 455 and 910/s for wave I (p<0.05 and 0.05), 91-910/s for wave III (p<0.05-0.001), and 227-910/s (p<0.05 and 0.01) for wave V. No differences in the V/I and V/III amplitude ratios were found between the high-risk preterm babies and the controls. CONCLUSIONS: The amplitudes of MLS BAER wave components, mainly more central components, were reduced in the high-risk preterm babies born at 28-32week gestation. Electrophysiological activity of the brainstem auditory neuron in such babies is depressed, mainly attributed to or related to the associated perinatal problems.

Environmental enrichment attenuates the blood brain barrier dysfunction induced by the neonatal hypoxia-ischemia.

Environmental enrichment (EE) is considered an efficient neuroprotector against neonatal hypoxia-ischemia (HI). Nevertheless, the mechanisms involved are not yet clear. In this context, the aim of this study was to investigate the effects of neonatal HI and environmental stimulation in the hippocampus of rats at 3 different time points (PND 8, 22 and 60), evaluating some aspects of BBB structure and function. Seven-day-old Wistar rats were divided into four groups: a control group maintained in a standard environment (CTSE), a control group maintained in an enrichment environment (CTEE), an HI group maintained in a standard environment (HISE) and an HI group maintained in an enrichment environment (HIEE). At the 7th postnatal day (PND), rats were submitted to the Levine-Rice model of neonatal HI. This method consists of permanent occlusion of the right common carotid artery with subsequent exposure to hypoxia. Rats from CTEE and HIEE were stimulated with environmental enrichment. The EE protocol started 24h after HI, in which pup rats with their dams were stimulated in a maintained EE (PND 8-22). Subsequently, animals were submitted to daily EE (1h/day, PND 23-60). The expression of some proteins involved in BBB structure (ß-catenin, occludin, connexin-43, aquaporin-4, glut-1 and GFAP) were quantified by western blotting in the hippocampi of rats in three periods, at PND 8, 22 and 60. The BBB permeability and integrity was assessed by Evans blue staining and the immunohistochemistry for GFAP in the CA1 region of the hippocampus were also performed. The results showed an HI-induced decreased occludin expression at PND 22 and low levels of occludin, ß-catenin and GFAP at PND 60 in the hippocampus of the hypoxic-ischemic rats. Interestingly, in young and adult rats, EE reversed these effects. Evans blue extravasation into the brain parenchyma confirmed the BBB dysfunction brought on by HI. No differences were observed at PND 8, probably due to the immaturity of the BBB at this age. The present study makes an important contribution to understanding the mechanism of the hypoxic-ischemic brain damage and also to presents, for the first time, the recovery of BBB dysfunction as a possible pathway for the protective effect of EE.