Prenatal Brain Damage Research Articles

A thiourea dihydropyridine as a highly selective and sensitive “turn-on” fluorescent chemosensor for mercury(II) ion in water and its application for cell imaging

The existence of extremely toxic mercury contaminants in the environment, even at very low concentrations, poses severe human health issues. Mercury exposure may lead to various diseases, such as prenatal brain damage, cognitive severe, motion disorders, and Minamata diseases. Hence, developing an effective and selective method to detect Hg2+ in the environment and biological samples is of great interest. Amongst various Hg2+ detection techniques, fluorescent chemosensors offer more convenient procedures, affordable cost, high selectivity, and the capability to perform cell imaging for Hg2+ detection. Herein, a novel "turn-on" fluorescent chemosensor, Thiourea-DHP derivative (TUD), highly selective to Hg2+, was successfully developed. TUD was synthesized by cyclotrimerization of β-amino acrylate, followed by the thioacylation of the resulting dihydropyridine (DHP) with dimethylamino thiocarbonyl chloride. The Hg2+ detection by TUD displayed an astonishing naked-eye blue fluorescence signal under blacklight, exhibiting an LOD of 69 nM or 14 ppb at pH 7.4 in the HEPES buffer. Hg2+-induced hydrolytic desulfurization of the low fluorescent TUD to produce the strongly fluorescent urea-DHP (UD) is proposed as a mechanism for this fluorescence enhancement. The formation of UD was confirmed by 1H NMR, 13C NMR, and HRMS. This detecting system of TUD provided excellent percentage recovery (>97 %) for the analysis of Hg2+ contaminants in real-environmental water samples. Besides, the TUD probe showed nontoxic properties in living cells towards RAW264.7 murine macrophage cell line even at high concentrations (100 µM). Our proposed TUD probe demonstrated superior sensitivity in pure aqueous media compared to current mercury-desulfurization fluorescent chemosensors. This sensing system proved effective for analysing Hg2+ contaminants in real-environmental water samples. Additionally, the nontoxic TUD probe successfully revealed the remarkable biocompatibility for Hg2+ detection in living cells.

Extremely Preterm Infants with a Near-total Absence of Cerebellum: Usefulness of Quantitative Magnetic Resonance in Predicting the Motor Outcome.

This study aims to evaluate in extremely premature infants the severity of brain structural injury causing total absence or near-total absence of cerebellar hemispheres by using MRI visual and volumetric scoring systems. It also aims to assess the role of the score systems in predicting motor outcome. We developed qualitative and quantitative MRI scoring systems to grade the overall brain damage severity in 16 infants with total absence or near-total absence of cerebellar hemispheres. The qualitative scoring system assessed the severity of macrostructural abnormalities of cerebellum, brainstem, supratentorial gray and white matters, ventricles while the quantitative scoring system weighted the loss of brain tissue volumes, and gross motor function classification system (GMFCS) was used to assess motor function at 1- and 5-year follow-ups.Positive correlations between both MRI scores and GMFCS scales were detected at follow-ups (p > 0.05), but only the volumetric score could identify those infants developing higher levels of motor impairment.Brain volumetric MRI offers an unbiassed assessment of prenatal brain damage. The quantitative scoring system, performed at term equivalent age, can be a helpful tool for predicting the long-term motor outcome in extremely preterm infants with a near-total absence of cerebellum.

FGL2 deficiency alleviates maternal inflammation-induced blood-brain barrier damage by blocking PI3K/NF-κB mediated endothelial oxidative stress.

The impairment of blood-brain barrier (BBB) is one of the key contributors to maternal inflammation induced brain damage in offspring. Our previous studies showed Fibrinogen-like protein 2 (FGL2) deficiency alleviated maternal inflammation induced perinatal brain damage. However, its role in BBB remains undefined. Lipopolysaccharide (LPS) was intraperitoneally injected to dams at Embryonic day 17 to establish maternal inflammation model. FGL2 knockout mice and primary brain microvascular endothelial cells (BMECs) were used for the in-vivo and in-vitro experiments. BBB integrity was assessed by sodium fluorescein extravasation and tight junction (TJ) protein expression. Oxidative stress and the activation of PI3K/NF-κB pathway were evaluated to explore the mechanisms underlying. Upon maternal inflammation, BBB integrity was remarkedly reduced in neonatal mice. Meanwhile, FGL2 expression was consistently increased in BBB-impaired brain as well as in LPS-treated BMECs. Moreover, FGL2 deficiency attenuated the hyperpermeability of BBB, prevented the decline of TJ proteins, and reduced the cytokine expressions in LPS-exposed pups. Mechanistically, the indicators of oxidative stress, as well as the activation of PI3K/NF-κB pathway, were upregulated after LPS exposure in vivo and in vitro. FGL2 deletion decreased the generation of ROS and NO, reduced the endothelial iNOS and NOX2 expressions, and suppressed the PI3K/NF-κB pathway activation. Besides, inhibition of PI3K by LY294002 decreased the oxidative stress in LPS-treated wild-type BMECs. While, overexpression of PI3K by lentivirus reemerged the induction of NOX2 and iNOS as well as NF-κB activation in FGL2-deleted BMECs. Our findings indicate that FGL2 deficiency alleviates the maternal inflammation-induced BBB disruption by inhibiting PI3K/NF-κB mediated oxidative stress in BMECs. Targeting FGL2 may provide a new therapy for prenatal brain damage of offspring.

Fetal brain imaging following laser surgery in twin-to-twin surgery.

To describe the incidence and nature of prenatal brain damage following fetoscopic laser selective coagulation (FLSC) of placental vessels for twin-to-twin transfusion syndrome (TTTS). Retrospective observational study. Single center cohort. All consecutive cases referred for TTTS treated by FLSC between 2003 and 2015. After the FLSC, patients were followed weekly by ultrasound. Fetal magnetic resonance imaging (MRI) scans were systematically planned at 30-32 weeks of gestation. Brain damage diagnosed prenatally by ultrasound or MRI. In total, 1023 cases were reviewed. Brain damage was diagnosed prenatally in 22/1023 (2.1%) cases. Diagnosis was performed by ultrasound prior to MRI in 18 (82%) cases. All lesions were within the spectrum of ischaemic haemorrhagic lesions. Postoperative twin anaemia polycythaemia sequence and recurrence of TTTS were significantly associated with brain damage. The incidence of prenatal brain damage is low following FSLC, and is strongly associated with incomplete surgery. Following FSLC for TTTS, prenatal brain damage occurs in 2% of cases and is associated with incomplete surgery.

Efficacy of Human Adipose Tissue-Derived Stem Cells on Neonatal Bilirubin Encephalopathy in Rats.

Kernicterus is a neurological syndrome associated with indirect bilirubin accumulation and damages to the basal ganglia, cerebellum and brain stem nuclei particularly the cochlear nucleus. To mimic haemolysis in a rat model such that it was similar to what is observed in a preterm human, we injected phenylhydrazine in 7-day-old rats to induce haemolysis and then infused sulfisoxazole into the same rats at day 9 to block bilirubin binding sites in the albumin. We have investigated the effectiveness of human adiposity-derived stem cells as a therapeutic paradigm for perinatal neuronal repair in a kernicterus animal model. The level of total bilirubin, indirect bilirubin, brain bilirubin and brain iron was significantly increased in the modelling group. There was a significant decreased in all severity levels of the auditory brainstem response test in the two modelling group. Akinesia, bradykinesia and slip were significantly declined in the experience group. Apoptosis in basal ganglia and cerebellum were significantly decreased in the stem cell-treated group in comparison to the vehicle group. All severity levels of the auditory brainstem response tests were significantly decreased in 2-month-old rats. Transplantation results in the substantial alleviation of walking impairment, apoptosis and auditory dysfunction. This study provides important information for the development of therapeutic strategies using human adiposity-derived stem cells in prenatal brain damage to reduce potential sensori motor deficit.

Chronic fetal hypoxia affects axonal maturation in guinea pigs during development: A longitudinal diffusion tensor imaging and T2 mapping study.

To investigate the impact of chronic hypoxia on neonatal brains, and follow developmental alterations and adaptations noninvasively in a guinea pig model. Chronic hypoxemia is the prime cause of fetal brain injury and long-term sequelae such as neurodevelopmental compromise, seizures, and cerebral palsy. Thirty guinea pigs underwent either normoxic and hypoxemic conditions during the critical stage of brain development (0.7 gestation) and studied prenatally (n = 16) or perinatally (n = 14). Fourteen newborns (7 hypoxia and 7 normoxia group) were scanned longitudinally to characterize physiological and morphological alterations, and axonal myelination and injury using in vivo diffusion tensor imaging (DTI), T2 mapping, and T2 -weighted magnetic resonance imaging (MRI). Sixteen fetuses (8 hypoxia and 8 normoxia) were studied ex vivo to assess hypoxia-induced neuronal injury/loss using Nissl staining and quantitative reverse transcriptase polymerase chain reaction methods. Developmental brains in the hypoxia group showed lower fractional anisotropy in the corpus callosum (-12%, P = 0.02) and lower T2 values in the hippocampus (-16%, P = 0.003) compared with the normoxia group with no differences in the cortex (P > 0.07), indicating vulnerability of the hippocampus and cerebral white matter during early development. Fetal guinea pig brains with chronic hypoxia demonstrated an over 10-fold increase in expression levels of hypoxia index genes such as erythropoietin and HIF-1α, and an over 40% reduction in neuronal density, confirming prenatal brain damage. In vivo MRI measurement, such as DTI and T2 mapping, provides quantitative parameters to characterize neurodevelopmental abnormalities and to monitor the impact of prenatal insult on the postnatal brain maturation of guinea pigs.

Mutations of the thyroid hormone transporter MCT8 cause prenatal brain damage and persistent hypomyelination.

Mutations in the MCT8 (SLC16A2) gene, encoding a specific thyroid hormone transporter, cause an X-linked disease with profound psychomotor retardation, neurological impairment, and abnormal serum thyroid hormone levels. The nature of the central nervous system damage is unknown. The objective of the study was to define the neuropathology of the syndrome by analyzing brain tissue sections from MCT8-deficient subjects. We analyzed brain sections from a 30th gestational week male fetus and an 11-year-old boy and as controls, brain tissue from a 30th and 28th gestational week male and female fetuses, respectively, and a 10-year-old girl and a 12-year-old boy. Staining with hematoxylin-eosin and immunostaining for myelin basic protein, 70-kDa neurofilament, parvalbumin, calbindin-D28k, and synaptophysin were performed. Thyroid hormone determinations and quantitative PCR for deiodinases were also performed. The MCT8-deficient fetus showed a delay in cortical and cerebellar development and myelination, loss of parvalbumin expression, abnormal calbindin-D28k content, impaired axonal maturation, and diminished biochemical differentiation of Purkinje cells. The 11-year-old boy showed altered cerebellar structure, deficient myelination, deficient synaptophysin and parvalbumin expression, and abnormal calbindin-D28k expression. The MCT8-deficient fetal cerebral cortex showed 50% reduction of thyroid hormones and increased type 2 deiodinase and decreased type 3 deiodinase mRNAs. The following conclusions were reached: 1) brain damage in MCT8 deficiency is diffuse, without evidence of focal lesions, and present from fetal stages despite apparent normality at birth; 2) deficient hypomyelination persists up to 11 years of age; and 3) the findings are compatible with the deficient action of thyroid hormones in the developing brain caused by impaired transport to the target neural cells.

White Matter Injury and Autistic-Like Behavior Predominantly Affecting Male Rat Offspring Exposed to Group B Streptococcal Maternal Inflammation

The impact of the group B streptococcus (GBS)-induced maternal inflammation on offspring's brain has not yet been investigated despite GBS being one of the most frequent bacteria colonizing or infecting pregnant women. According to our hypothesis GBS-induced maternal immune activation plays a role in offspring perinatal brain damage and subsequent neurodisabilities such as autism. Using a new preclinical rat model of maternal inflammation triggered by inactivated GBS, we demonstrated placental, neuropathological and behavioral impacts on offspring. GBS-exposed placentas presented cystic lesions and polymorphonuclear infiltration located within the decidual/maternal side of the placenta, contrasting with macrophagic infiltration and necrotic areas located in the labyrinth/fetal compartment of the placenta after lipopolysaccharide-induced maternal inflammation. Brain damage featured lateral ventricles widening, predominately in the male, reduction of periventricular external capsules thickness, oligodendrocyte loss, and disorganization of frontoparietal subcortical tissue with no glial proliferation. Autistic hallmarks were found in offspring exposed to GBS, namely deficits in motor behavior, social and communicative impairments, i.e. profound defects in the integration and response to both acoustic and chemical signals that are predominant modes of communication in rats. Surprisingly, only male offspring were affected by these combined autistic-like traits. Our results show for the first time that materno-fetal inflammatory response to GBS plays a role in the induction of placental and cerebral insults, remarkably recapitulating cardinal features of human autism such as gender dichotomy and neurobehavioral traits. Unlike other models of prenatal inflammatory brain damage (induced by viral/toll-like receptor 3 (TLR3) or Gram-negative/TLR4), maternal inflammation resulting from GBS/TLR2 interactions induced a distinctive pattern of chorioamnionitis and cerebral injuries. These results also provide important evidence that beyond genetic influences, modifiable environmental factors play a role in both the occurrence of autism and its gender imbalance.

Prenatal Brain Damage in Preeclamptic Animal Model Induced by Gestational Nitric Oxide Synthase Inhibition

Cerebral palsy is a major neonatal handicap with unknown aetiology. There is evidence that prenatal brain injury is the leading cause of CP. Severe placental pathology accounts for a high percentage of cases. Several factors predispose to prenatal brain damage but when and how they act is unclear. The aim of this paper was to determine if hypoxia during pregnancy leads to damage in fetal brain and to evaluate the localization of this injury. An animal model of chronic hypoxia produced by chronic administration of a nitric oxide synthase inhibitor (L-NAME) was used to evaluate apoptotic activity in fetal brains and to localize the most sensitive areas. L-NAME reproduces a preeclamptic-like condition with increased blood pressure, proteinuria, growth restriction and intrauterine mortality. Apoptotic activity was increased in L-NAME brains and the most sensitive areas were the subventricular and pallidum zone. These results may explain the clinical features of CP. Further studies are needed.

Chronological changes of the amplitude‐integrated EEG in a neonate with molybdenum cofactor deficiency

Molybdenum cofactor (Moco) deficiency is a rare neurometabolic disorder, characterized by neurological impairment and refractive seizures, due to toxic accumulation of sulfite in the brain. Earlier it was suggested that in Moco-deficient humans maternal clearance of neurotoxic metabolites prevents prenatal brain damage. However, limited data are available about the time profile in which neurophysiologic deterioration occurs after birth. The amplitude-integrated electroencephalography (aEEG) is a bedside method in neonates to monitor cerebral recovery after hypoxic-ischemic insults, detect epileptic activity, and evaluate antiepileptic drug treatment. We describe a chronological series of changes in aEEG tracings in a neonate with Moco deficiency. He presented with myoclonic spasms and hypertonicity a few hours after birth, however, the aEEG pattern was still normal. Within 2 days, the aEEG rapidly changed into a burst suppression pattern with repetitive seizures. After antiepileptic treatment, the aEEG remained abnormal. In this patient, the normal aEEG pattern at birth may have been due to maternal clearance of sulfite in utero. After birth, accumulation of sulfite causes progressive brain damage, reflected by the progressive depression of the aEEG tracings. This is in agreement with the results from a Moco-deficient mouse model, suggesting that maternal sulfite clearance suppresses prenatal brain damage. To our knowledge, this is the first case report describing the chronological changes in the aEEG pattern in a Moco-deficient patient. Insight into the time profile in which neurologic deterioration in Moco-deficient humans occurs is essential, especially when potential treatment strategies are being evaluated.

Methylmercury and the Developing Brain

We reported that prenatal exposure to methylmercury causes cognitive impairment in an estimated 316,588 children born in the United States each year, costing this nation $8.7 billion annually in lost productivity (Trasande et al. 2005). Each year, this exposure also causes an estimated 1,566 cases of mental retardation (Trasande et al. 2006). The principal (70%) source of the mercury that enters the bodies of American children is combustion of coal in electricity-generating plants. In their reanalysis of our data, Griffiths et al. (2007) made a series of incorrect judgments and poorly considered assumptions, each of which diminishes the import of our findings. We note the following errors in their analysis: First, Griffiths et al. (2007) incorrectly used a linear model to relate cognitive function to prenatal methylmercury exposure, despite the National Research Council’s (NRC) clear finding that a logarithmic model provides a better statistical fit. The NRC, in their examination of the Faroe Islands cohort study, the study on which they place greatest reliance, stated that “[b]ecause these calculations necessitate extrapolating to estimate the mean response at zero exposure level,” logarithmic models “lead to lower estimates of the Benchmark Dose (BMD) than linear or K-power models” (NRC 2000, p. 294). Recent analyses of early childhood lead exposure further corroborate the validity of logarithmic models in representing subclinical dose–response relationships of neuro-developmental injury (Canfield et al. 2003). Second, Griffiths et al. (2007) unwisely based their analysis on potentially biased data from the Seychelles cohort study. By contrast, our model (Trasande et al. 2005), like that of the NRC, is based primarily on Faroes data. We chose not to use Seychelles data because of concern that the tests of neurobehavioral function used there were not well validated for a non-American population and therefore may not have been sensitive to detect cognitive impairment (Landrigan and Goldman 2003). Another major potential source of bias in the Seychelles study, not acknowledged by Griffiths et al. (2007), is that it fails to consider the potentially beneficial nutrients found in the fish-based diet of the Seychelles. These nutrients, omega-3 fatty acids in particular, may partially offset the toxicity of methylmercury. Indeed, if maternal fish intake is taken into account in the Seychelles cohort, as recently was done, the estimate of methylmercury toxicity increases (Budtz-Jorgensen et al. 2007). Griffiths et al. (2007) cited previous meta-analyses of the Faroes, Seychelles, and New Zealand studies by Ryan (2005) in applying IQ decrements of 0.13–0.18 points/ppm hair mercury, but these are likely underestimates, and further invalidate the analysis of Griffiths et al. Third, in attributing mercury deposition to sources of emission, Griffiths et al. (2007) relied inexplicably and without justification on a mathematical model that posits that only 16% of deposits are attributable to American sources. They ignored empiric data from the U.S. Environmental Protection Agency (EPA)-sponsored Steubenville study, which found that 80–90% of mercury emissions deposit within 30–50 miles of the source (U.S. EPA 2007); and from the Electric Power Research Institute, which estimated that 30% of mercury deposits are attributable to American sources (Seigneur et al. 2004). Fourth, Griffiths et al. (2007) incorrectly assumed that reductions in mercury emissions from power plants do not result in any reduced levels of fish contamination until after 15 years. This is not correct. Reductions in power-plant emissions in 2008 will, in fact, begin immediately to minimize methylmercury body burden among children born to women in 2008, and the degree of reduction will increase further in subsequent years, perhaps through 2038, thus reducing the number of children damaged, the severity of the prenatal brain damage in these children, and the resulting economic burden. Finally, Griffiths et al. (2007) incorrectly based their estimate of the economic value of a child’s social productivity on the 1992 Current Population Survey rather than on the currently available 2005 data set. This miscalculation substantially underestimates the economic impact of methylmercury on the developing brain. Viscusi and Aldy (2004) estimated that this value is currently on the order of $4–9 million/child, a value far greater than that used by Griffiths et al., and greater even than our estimate.

The distribution of apolipoprotein E alleles in Scottish perinatal deaths

Background: The apolipoprotein E (ApoE) polymorphism has been well studied in the adult human population, in part because the e4 allele is a known risk factor for Alzheimer’s disease. Little...

Simultaneous glutamate and GABA A receptor agonist administration increases calbindin levels and prevents hippocampal damage induced by either agent alone in a model of perinatal brain injury

Perinatal brain injury is associated with the release of amino acids, principally glutamate and GABA, resulting in massive increases in intracellular calcium and eventual cell death. We have previously demonstrated that independent administration of kainic acid (KA), an AMPA/kainate receptor agonist, or muscimol, a GABA A receptor agonist, to newborn rats results in hippocampal damage [Hilton, G.D., Ndubuizu, A., and McCarthy, M.M., 2004. Neuroprotective effects of estradiol in newborn female rat hippocampus. Dev. Brain Res. 150, 191–198; Hilton, G. D., Nunez, J.L. and McCarthy, M.M., 2003. Sex differences in response to kainic acid and estradiol in the hippocampus of newborn rats. Neuroscience. 116, 383–391; Nunez, J.L. and McCarthy, M.M., 2003. Estradiol exacerbates hippocampal damage in a model of preterm infant brain injury. Endocrinology. 144, 2350–2359; Nunez, J.L., Alt, J.J. and McCarthy, M.M., 2003. A new model for prenatal brain damage. I. GABA(A) receptor activation induces cell death in developing rat hippocampus. Exp. Neurol. 181, 258–269]. We now report that KA or muscimol alone administered to immature hippocampal neurons in culture induces significant cell death as evidenced by TUNEL assay. Surprisingly, simultaneous administration of equimolar quantities of these two agonists blocks the effect of either one alone. Moreover, treatment of newborn pups results in less damage compared to either muscimol or KA alone. We further observed that immunoreactivity for the calcium-binding protein, calbindin D 28K, is increased in the brains of pups simultaneously administered KA and muscimol as compared to either alone.

195 Prenatal Inflammation, Brain Damage and Two-Year Neurologic Outcome in Very Preterm Infants

Background: Intrauterine inflammation has been associated with preterm birth and with fetal inflammatory response affecting various organs including immature brain. Prenatal etiology has been defined in a majority of term infants with later neurologic sequela but only in a minority of very preterm infants. Risk factors of cerebral white matter damage (WMD) may differ between term and preterm infants.Objective: To examine whether prenatal inflammation serves as a risk factor of WMD and poor neurologic and neurocognitive outcome in infants born before 32 weeks of gestation with birth weight under 1000 g.Design/Methods: A regional cohort of 61 infants born between 1998 and 2002 were enrolled in a prospective follow-up study. Medical records during hospitalization were observed. Placental pathology was examined. Sera from umbilical cord blood were analyzed for proinflammatory cytokines (IL-1 alpha, IL-1 beeta, IL-6, IL-8, TNF-alpha). Serial brain ultrasound examinations and magnetic resonance imaging were performed. Neurologic and neurocognitive outcome were assessed at two years of corrected age. The study was approved by the ethics committee of Oulu University Hospital.Results: Histologic chorioamnionitis (HCA) and high IL-6 predicted spontaneous preterm labor with high accuracy. High IL-6 and IL-8 associated with HCA. Intraventricular hemorrhage grade 2 to 3 was predicted by HCA (OR 8.1, 95%CI 1.6 - 42.5). Neither HCA or the cytokines directly associated with WMD, poor neurologic, or poor neurocognitive outcome. However, HCA and concomitant placental perfusion defect increased the risk of poor neurologic outcome (OR 15.2, 95%CI 1.3 - 181) and together with WMD additively predicted poor outcome. Several clinical factors describing cardiopulmonary instability after birth associated with WMD and with poor neurologic outcome.Conclusions: HCA and fetal cytokine response are not risk factors of WMD in very preterm extremely low birth weight infants. Present results support the theory of a complexity of pathogenetic mechanisms leading to poor neurologic outcome.

Amiel-Tison Neurological Assessment at term age: clinical application, correlation with other methods, and outcome at 12 to 15 months

The aims of this study were: (1) to perform the Amiel-Tison Neurological Assessment (ATNA) in a group of infants with different risk factors for brain damage; (2) to analyze the results of the examinations in light of the risk factors and presumed aetiology; (3) to compare results of examinations with results of cranial ultrasound, electroencephalography (EEG), and cerebral function monitoring (CFM); and (4) to evaluate neurological outcome at 12 to 15 months of age using the Amiel-Tison and Gosselin method, and developmental outcome using the Bayley Scales of Infant Development. Participants were 52 term, newborn infants (31 males, 21 females) with risk factors for brain damage. Mean birthweight was 3288g (SD 661g) and mean gestational age was 39.4wks (SD 1.2wks); range 38 to 41.3wks. Mean age at admission to a neonatal special care unit was 75h, (SD 13.7h). The group with a dynamic (evolving) clinical profile differed significantly from the group with a static (stable) profile in terms of aetiology, while the group with signs of prenatal brain damage differed from the group without these signs regarding aetiology and the level of severity of neurological signs. Sensitivity of the ATNA to detect infants with abnormal ultrasound was 0.97, with EEG 0.89, and with CFM 0.88. At follow-up at 12 to 15 months 47 children were examined: neurological examination was normal in 25 and five children had a minor, five a moderate, and 12 a severe neurological deficit. Agreement of the ATNA with neurological and developmental assessment at follow-up was very good. Our findings suggest that the ATNA is also of value in assessing aetiology and timing of brain lesions.

The value of autopsy in determining the cause of failure to respond to resuscitation at birth

Autopsy is invaluable in identifying the causes of severe depression and very low Apgar score after birth and in assessing contributory conditions. Brain scans are increasingly used in the care of neonates who fail to respond to resuscitation at birth but their interpretation depends on the information gained from sound neuropathological studies. Asphyxia, both acute intrapartum asphyxia and chronic asphyxia, is an important cause of low Apgar scores. The gestational age and the nature of the asphyxial insult both have a profound influence on the ultimate pattern of injury. Asphyxia in the preterm brain tends to damage preferentially the white matter but some white matter damage is also seen in many infants who have an hypoxia-ischaemic insult at term though the predominant site of injury is to the central grey matter. The nature of the cellular damage and reactive change seen at autopsy is described. There is an association between low Apgar scores and intrauterine exposure to infection and maternal pyrexia. Detailed autopsy examination should include the search for infection. The placenta, cord and membranes should be examined in view of the mounting evidence of the association between intrauterine infection of the placenta and fetal membranes and prenatal brain damage. Additionally, the presence of placental thrombosis and infarction should be sought in relation to focal and global injury in the full term infant. Acquired prepartum lesions rarely cause the infant to present with a low Apgar score. The exception to this is severe damage to the brainstem and basal ganglia. Traumatic injury to the brain is now much less common than in previous decades. Subdural haemorrhage occurs more frequently than intraventricular or subarachnoid haemorrhage. Instrumental and assisted deliveries are associated with an increased incidence of subdural haemorrhage though these rarely cause significant long term damage. Careful autopsy, particularly of the neck and paravertebral tissues, spinal cord, brainstem and nerve roots is important where trauma is suspected. Tearing of nerve roots or fibre bundles in the spinal cord is readily demonstrated under the microscope using immunocytochemistry to β-amyloid precursor protein. Disorders of the spinal cord, peripheral nerve and muscle as well as some metabolic diseases may cause a baby to be both floppy and weak. Metabolic disease, including peroxisomal disorders, non-ketotic hyperglycinaemia, lipid and glycogen storage disorders and mitochondrial diseases may cause profound hypotonia and respiratory failure at birth or shortly afterwards.

Sex differences and hormonal effects in a model of preterm infant brain injury.

Premature infants are at an exceptionally high risk for brain injury, with damage resulting in permanent behavioral deficits. A contributing factor to the severity of brain injury is gender, with males more sensitive to insult than females. The role of gender and early hormonal environment in addressed in our novel model of prenatal brain damage.

A novel model for prenatal brain damage: Ii. long-term deficits in hippocampal cell number and hippocampal-dependent behavior following neonatal GABA A receptor activation

Premature infants are at especially high risk for asphyxia, seizures, and other conditions that cause hypoxia–ischemia. These events result in abnormal brain pathology and behavioral deficits that persist throughout adolescence and into adulthood. Current rodent models of human infant hypoxic–ischemic brain damage have focused on exogenous glutamate receptor agonist exposure in the postnatal day 7 rat. While this model is considered analogous to the newborn human, no adequate models for preterm infant brain damage have been developed. Recent work from our lab has proposed a potential model for preterm infant brain damage in which neonatal rats are treated with exogenous muscimol, the selective γ-aminobutyric acid A (GABA A) receptor agonist, on postnatal days 0 and 1. In the companion paper to this one (Exp. Neurol., in press), we report fewer neurons in the hippocampal formation on postnatal day 7 (6 days after treatment), but the persistence of these anatomical deficits, and potential resultant behavioral dysfunctions, were not investigated. In the current experiment, we documented that muscimol exposure on postnatal days 0 and 1 leads to fewer neurons in the male and female rat hippocampus (CA1, CA2/3, and dentate gyrus) on postnatal day 21. Also, neonatal muscimol exposed males and females displayed deficits on hippocampal-dependent learning tasks such as a preweanling version of the Morris water maze task and the open field task. We conclude that exposure to exogenous GABA A receptor activation over the first 2 days of postnatal life, a model for preterm infant hypoxic injury, produces anatomical and behavioral deficits observed into adolescence.

A new model for prenatal brain damage: I. GABA A receptor activation induces cell death in developing rat hippocampus

Premature infants are at exceptionally high risk for hypoxic–ischemic insults and other traumatic events that result in permanent brain damage. However, no current models adequately mimic these events. An emerging concept is that the major excitatory drive in immature neurons is derived from depolarizing responses following activation of the γ-aminobutyric acid (GABA) A receptor, resulting in the opening of voltage-sensitive calcium channels. While calcium-mediated signal transduction is trophic in developing neurons, excessive calcium entry is a major mediator of excitotoxicity. We report that exogenous activation of GABA A receptors by muscimol in newborn rats increases cell death in the hippocampus. The effects are region specific, persistent, and greater in males. Muscimol-induced damage is prevented by pretreatment with diltiazem, an L-type voltage-sensitive calcium channel blocker. Results using hippocampal cultures parallel those observed in vivo, indicating that the effects are mediated directly in the hippocampus. Existing models of pediatric hypoxic–ischemic brain damage focus on the effects of glutamate in the postnatal day 7 rat, because it is considered analogous to the newborn human. This makes the newborn rat analogous to the late gestational human. Ischemia in newborn rats induces GABA release and we propose that treatment with muscimol mimics the cell death cascade induced by hypoxia–ischemia in premature human infants.

Treatment and outcome of Taiwanese patients with 6-pyruvoyltetrahydropterin synthase gene mutations.

Ten cases of tetrahydrobiopterin (BH4) deficiency were identified in 1,337,490 newborns screened in a Chinese population in Taiwan. The high incidence of BH4 deficiency in the Taiwanese population may be explained by a founder effect, since all of the patients revealed 6-pyruvoyltetrahydropterin synthase gene mutations, and grouping N52S and P87S mutations together constituted 88.9% of the disease alleles. BH4 supplementation with restriction of high-protein foods gave control of plasma phenylalanine within normal range, and levodopa itself prevented seizure. However, the average intelligence quotient (IQ) score of these patients was only 76 +/- 14 (56-98). Statistically, the age of starting medication, including 5-hydroxytryptophan (5-HTP), was inversely correlated to IQ scores of these patients. We suggest the combination of BH4, levodopa and 5-HTP as the standard protocol to commence the treatment of BH4 deficiency as early as possible, although prenatal brain damage could have existed.