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PubMed1985

Effect of neonatal periventricular haemorrhage on neurodevelopmental outcome.

All 56 infants born between 23 and 28 weeks' gestation admitted to this hospital in 1981 were examined for periventricular haemorrhage with cerebral ultrasonography. Haemorrhage was diagnosed in 34 (61%)-12 (22%) had germinal layer haemorrhage, 18 (32%) had intraventricular haemorrhage, and four (7%) had intracerebral haemorrhage. The two year outcome of survivors with and without periventricular haemorrhage was compared to determine the effect on neurodevelopment. Only three (16%) of 19 infants with normal scans or germinal layer haemorrhages had evidence of major disability but nine (75%) of 12 infants with intraventricular or intracerebral haemorrhage had major disability. The mental and psychomotor performance on the Bayley scales of infant development was also significantly worse in the latter group. All three survivors with intracerebral haemorrhage had major disability. The continuation of life support treatment for extremely preterm infants who are at very high risk of severe handicap is a matter of increasing concern in neonatal intensive care. Our results show that if extensive periventricular haemorrhage, in particular intracerebral haemorrhage, occurs in this gestational group, extreme pessimism is warranted.

Birth Weight↗

PubMed1989

Early diet in preterm babies and developmental status in infancy.

Few data from randomised prospective studies address whether early diet influences later neurodevelopment in man. As part of a larger multicentre trial, 502 low birthweight infants were assigned randomly, for a median of 30 days, to receive a preterm formula or unfortified donor breast milk as sole diets or as supplements to their mothers' expressed milk. Surviving infants were assessed at nine months after their expected date of delivery without knowledge of their feeding regimen. The mean developmental quotient was 0.25 standard deviations lower in those fed donor breast milk rather than preterm formula. In infants fed their mother's expressed milk, however, the disadvantage of receiving banked milk compared with preterm formula as a supplement, was greater when the supplement was over half the total intake, and approached five points, representing 0.5 standard deviations for developmental quotient. Infants fed donor breast milk were at particular disadvantage following fetal growth retardation, with developmental quotients 5.3 points lower. We suggest that the diet used for low birthweight babies over a brief, but perhaps critical, postnatal period has developmental consequences that persist into infancy; infants who are small for gestational age are especially vulnerable to suboptimal postnatal nutrition.

Child Development↗

PubMed2003

Brain haemorrhage in five infants with coagulopathy.

Most intracranial haemorrhages in infants after the neonatal period are secondary to non-accidental injury. Occasionally brain haemorrhages in non-mobile infants are due to an inherited coagulopathy. This may often be diagnosed with a coagulation screen on admission. Little is known about the neurological outcome of infants in the latter group. Five infants are described who presented with acute spontaneous brain haemorrhage secondary to an inherited coagulopathy (n = 3) and vitamin K deficiency in alpha(1) antitrypsin deficiency (n = 1) and Alagille's syndrome (n = 1). Despite the critical clinical presentation and the severe imaging findings, these five infants made a good neurological recovery. Infants presenting with spontaneous ICH due to a significant (inherited) coagulopathy are usually easy to differentiate from non-accidental shaking injury; their bleeding pattern within the brain seems different from non-accidental shaking injury and neurodevelopment outcome appears better.

Alagille Syndrome↗

PubMed1996

Cerebral metabolic rate for glucose during the first six months of life: an FDG positron emission tomography study.

AIM: To measure the local cerebral metabolic rate for glucose (LCMRGlc) in neonatal brains during maturation using positron emission tomography (PET) and 2-[18F]fluoro-2-deoxy-D-glucose (FDG). METHODS: Twenty infants were studied using PET during the neonatal period. The postconceptional age ranged from 32.7 to 60.3 weeks. All infants had normal neurodevelopment and were normoglycaemic. The development of the infants was carefully evaluated (follow up 12-36 months) clinically, and by using a method based on Gesell Amatruda's developmental diagnosis. LCMRGlc was quantitated using PET derived from FDG kinetics and calculated in the whole brain and for regional brain structures. RESULTS: LCMRGlc for various cortical brain regions and the basal ganglia was low at birth (from 4 to 16 mumol/100 g/minute). In infants 2 months of age and younger LCMRGlc was highest in the sensorimotor cortex, thalamus, and brain stem. By 5 months, LCMRGlc had increased in the frontal, parietal, temporal, occipital and cerebellar cortical regions. In general, the whole brain LCMRGlc correlated with postconceptional age (r = 0.90; P < 0.001). The change in the glucose metabolic pattern observed in the neonatal brain reflects the functional maturation of these brain regions. CONCLUSION: These findings show that LCMRGlc in infants increases with maturation. Accordingly, when LCMRGlc is measured during infancy, the postconceptional age has to be taken into account when interpretating the results.

Age Factors↗

PubMed2001

Improved survival and neurodevelopmental outcome after prolonged ventilation in preterm neonates who have received antenatal steroids and surfactant.

AIMS: To assess survival and neurodevelopmental outcome following prolonged ventilation beyond 27 or 49 days of postnatal life in neonates treated with antenatal steroids and surfactant. METHODS: The medical records of 84 babies born in 1994-1996 requiring ventilation after 27 postnatal days at Liverpool Women's Hospital were reviewed to determine the duration of mechanical ventilation, survival, and neurodevelopmental outcome at 3 years of age. RESULTS: Fifty six babies were mechanically ventilated after 27 postnatal days but for less than 50 days; 48 (86%) survived to 3 years. Twenty six (54%) of the survivors had normal neurodevelopment at 3 years and seven (15%) had only mild disability. Twenty eight babies were ventilated after 49 postnatal days; 14 survived to 3 years. Five of these survivors were neurodevelopmentally normal at 3 years and two had mild disability. CONCLUSIONS: Survival decreases with more prolonged ventilation. When antenatal steroids and postnatal surfactant are used, there appears to be improved survival and neurodevelopmental outcome in preterm babies who require prolonged ventilation.

Developmental Disabilities↗

PubMed2001

Neonatal bone marrow transplantation for severe combined immunodeficiency.

AIMS: To evaluate outcome following neonatal bone marrow transplantation (BMT) for severe combined immunodeficiency (SCID) when there is a family history of a previously affected sibling, and to compare results with those published for in utero BMT. METHODS: A retrospective review of cases referred and transplanted between 1987 and 1999, focusing on infectious and graft versus host disease (GvHD) complications after BMT, and T and B lymphocyte function. Thirteen patients received 18 stem cell transplants: four whole marrow, one cord blood, 10 parental T cell depleted (TCD) haplo-identical, and three TCD unrelated donor BMT. Nine were conditioned with busulphan and cyclophosphamide. RESULTS: All are alive and well (six months to 11.5 years after BMT). Six had grade I-II acute GvHD and two chronic GvHD (now resolved). Three had a top up BMT for poor T cell function, one had a third BMT for graft failure and chronic GvHD, and one had a third BMT for graft failure. Twelve have good in vitro proliferation to T cell mitogens, and all have normal serum IgA levels. Three receive intravenous immunoglobulin; for one of these, it is less than one year since BMT. Nine are above the 2nd centile, and 10 of 12 old enough to be assessed have normal neurodevelopment. CONCLUSION: These results are better than those published for in utero BMT for SCID. Early postnatal BMT should be the preferred option in neonatal SCID.

Acute Disease↗

PubMed2001

Polychlorinated biphenyls (PCBs) and neurological development in children: a systematic review.

BACKGROUND: Polychlorinated biphenyls (PCBs) are complex mixtures of persistent contaminants that are widespread in the environment. Newborns are exposed across the placenta and through breast feeding. Experimental animal studies have indicated that PCBs are neurotoxic. The neurological effects of these compounds on children are not clear. METHODS: A systematic review of literature on the relation between neurological development in children and exposure to polychlorinated biphenyls. RESULTS: Seven follow up studies evaluated the effect of prenatal exposure to PCBs. Two of these studies evaluated highly exposed children. In newborns, an increase of the abnormal reflexes was observed in all four studies evaluating it. During the first months of life, a decrease in motor skills was observed in four of the five studies that investigated psychomotor development; deficits in the acquisition of cognitive skills were observed only in one study assessing non-highly exposed populations. At 4 years of age, an effect on the cognitive areas was observed in four of the five studies that evaluated it. Postnatal exposure to PCBs through breast feeding was not clearly related to any effect on neurological development. CONCLUSIONS: These studies suggest a subtle adverse effect of prenatal PCBs exposure on child neurodevelopment. Differences in study design, inconsistency in some of the results, and the lack of adequate quantitative exposure data, do not allow the derivation of the degree of risk associated with neurodevelopmental effects at current levels of exposure.

Breast Feeding↗

PubMed1990

Tetraploidy in a liveborn infant.

We report a 3 month old boy with tetraploidy, found in peripheral blood and skin fibroblast cultures, with severely delayed growth and neurodevelopment, and with a cleft lip; these findings have not been described before. This report brings to seven the total number of liveborn infants with a 92,XXYY karyotype.

Abnormalities, Multiple↗

PubMed1999

Volumetric magnetic resonance imaging study of the brain in subjects with sex chromosome aneuploidies.

OBJECTIVES: Cognitive impairment has been reported in people with sex chromosome aneuploides (SCAs) and it has been proposed that the presence of an extra sex chromosome may have an adverse effect on neurodevelopment. This study examines the hypothesis with structural MRI of the brain. METHODS: Thirty two subjects with SCA (XXX (n=12), XYY (n=10), and XXY (n=10)) from a birth cohort study were matched groupwise for age, parental social class, and height with normal controls (13 female, 26 male). Brain MRI, measurements of IQ, and a structured psychiatric interview were performed. RESULTS: The XXX females and XXY males had significantly smaller whole brain volumes than controls of the same phenotypic sex (p=0.003 and p</=0.05 respectively). The XXY group also had bilaterally enlarged lateral ventricles (p</=0.05). No significant differences were found between the XYY group and controls. IQ scores in all SCA groups were lower than in the control groups. CONCLUSIONS: The main result of reduced brain volumes in XXX and XXY subjects, but not in XYY subjects, indicates that the presence of a supernumerary X chromosome has a demonstrable effect on brain development.

Adolescent↗

PubMed2005

Docosahexaenoic acid, fatty acid-interacting proteins, and neuronal function: breastmilk and fish are good for you.

In contrast to other tissues, the nervous system is enriched in the polyunsaturated fatty acids (PUFAs): arachidonic acid (AA, 20:4 n-6) and docosahexaenoic acid (DHA, 22:6 n-3). Despite their abundance in the nervous system, AA and DHA cannot be synthesized de novo by mammals; they, or their precursors, must be ingested from dietary sources and transported to the brain. During late gestation and the early postnatal period, neurodevelopment is exceptionally rapid, and substantial amounts of PUFAs, especially DHA, are critical to ensure neurite outgrowth as well as proper brain and retina development. Here, we review the various functions of DHA in the nervous system, the proteins involved in its internalization and metabolism into phospholipids, and its relationship to several neurological disorders, including Alzheimer's disease and depression.

Animals↗

PubMed2003

Iron status and neural functioning.

Iron deficiency in early life is associated with delayed development as assessed by a number of clinical trials using similar global scales of development; this poor development during infancy persists in most cases after iron therapy has corrected iron status. If iron deficiency occurs in preschool and older children, the consequences appear reversible with treatment. The biologic understanding of this relationship between development, brain iron status, and functioning is sparse though animal studies repeatedly demonstrate alterations in dopamine metabolism and in the myelination process. Dietary iron deficiency can rapidly deplete brain iron concentrations and repletion is able to normalize them. Residual alterations in striatal dopamine metabolism and myelin production persist if neonatal animals are used. Future studies with more specific measures of neurodevelopment in iron-deficient human infants, and animal models, will allow investigators to more clearly define causal roles of brain iron in neural development and functioning.

Adolescent↗

PubMed2005

Prenatal exposure to interleukin-6 results in inflammatory neurodegeneration in hippocampus with NMDA/GABA(A) dysregulation and impaired spatial learning.

During pregnancy, infection or immune responses induce cytokine release, which might influence fetal neurodevelopment, leading to neurodegenerative disease in adulthood. Because the hippocampus is a key area for learning and memory, we evaluated 4- and 24-wk-old rats for the effects of early and late prenatal exposure to interleukin-6 (IL-6) on hippocampal morphology, expression of mRNA for IL-6, the gamma-aminobutyric acid receptor (GABA(Aalpha5)), the NR1 subunit of the N-methyl-D-aspartate receptor, and glial fibrillary acidic protein (GFAP), caspase-3 protein and mRNA levels, and learning abilities. Late exposure increased serum IL-6 and hippocampal expression of IL-6 mRNA at 4 and 24 wk. All adult rats showed neuronal loss in the hilus and astrogliosis; males had losses mainly in the CA2 and CA3 regions, and females in CA1. Expression of GABA(Aalpha5), NR1, and GFAP mRNA increased in late-exposed males and females at 4 and 24 wk. mRNA and protein levels of the apoptosis marker caspase-3 were increased in all late-exposed rats except males at 4 wk. Evaluation of hippocampus-dependent working memory in the Morris water maze at 20 wk of age showed increases in escape latency and time spent near the pool wall in all IL-6 adult rats, especially females. These findings suggest that fetal IL-6 exposure, especially in late pregnancy, leads to increased IL-6 levels in the circulation and hippocampus, abnormalities of hippocampal structural and morphology, and decreased learning during adulthood.

Adrenocorticotropic Hormone↗

PubMed2006

[Developmental centered care. Evaluation of Spanish neonatal units].

INTRODUCTION: Developmental and family centered care (DC) is a framework that aims to enhance the neurodevelopment of the infant. Over the last few years Spanish neonatal units have been working toward introducing this type of care. OBJECTIVE: To evaluate DC in Spanish neonatal units by assessing certain features of the care provided to very low birth weight infants and their families. MATERIAL AND METHOD: Spanish hospitals attending infants under 1,500 g were identified. A cross sectional study was performed using a telephone questionnaire with 25 DC-related items. RESULTS: Of the 100 hospitals attending infants under 1,500 g, 83 hospitals from all the Autonomous Communities in Spain participated in the survey. Of these, 31 % had noise pollution controls, 72 % controlled light intensity, 75 % bound the infants, and 29 % used saccharose as an analgesic. Ten percent allowed unrestricted parental visits. Twenty-two percent used kangaroo care without restriction. Sixty-three percent of the units reported difficulties when introducing DC-related changes. CONCLUSIONS: Practically all neonatal units have some type of DC activity, although in certain areas, such as unrestricted parental visits, the rate of implementation is low.

Cross-Sectional Studies↗

PubMed2006

[Congenital hyperinsulinism. Review of 22 cases].

INTRODUCTION: Congenital hyperinsulinism (CHI) is the most common cause of recurrent episodes of hypoglycemia in early childhood and consists of a group of distinct genetic disorders causing dysregulation of insulin secretion. OBJECTIVE: To review the presentation, management and outcome of patients with CHI attended at our hospital. MATERIAL AND METHODS: A retrospective review of all patients diagnosed with CHI between 1982 and 2004 was performed. Data were collected on age, gender, clinical presentation, medical and surgical management, and complications. RESULTS: Twenty-two patients were identified. Notable features were early symptom onset in 80 %, pancreatectomy in 72 %, and neurological sequels in 28 % (abnormal neurodevelopment in 22 % and epilepsy in 13 %). CONCLUSIONS: The presentation, management and outcome in our patients were similar to those in other series, indicating the need for early diagnosis and treatment to avoid neurological sequels.

Congenital Hyperinsulinism↗

PubMed2006

Integrative genomics identifies distinct molecular classes of neuroblastoma and shows that multiple genes are targeted by regional alterations in DNA copy number.

Neuroblastoma is remarkable for its clinical heterogeneity and is characterized by genomic alterations that are strongly correlated with tumor behavior. The specific genes that influence neuroblastoma biology and are targeted by genomic alterations remain largely unknown. We quantified mRNA expression in a highly annotated series of 101 prospectively collected diagnostic neuroblastoma primary tumors using an oligonucleotide-based microarray. Genomic copy number status at the prognostically relevant loci 1p36, 2p24 (MYCN), 11q23, and 17q23 was determined by PCR and was aberrant in 26, 20, 40, and 38 cases, respectively. In addition, 72 diagnostic neuroblastoma primary tumors assayed in a different laboratory were used as an independent validation set. Unsupervised hierarchical clustering showed that gene expression was highly correlated with genomic alterations and clinical markers of tumor behavior. The vast majority of samples with MYCN amplification and 1p36 loss of heterozygosity (LOH) clustered together on a terminal node of the sample dendrogram, whereas the majority of samples with 11q deletion clustered separately and both of these were largely distinct from the copy number neutral group of tumors. Genes involved in neurodevelopment were broadly overrepresented in the more benign tumors, whereas genes involved in RNA processing and cellular proliferation were highly represented in the most malignant cases. By combining transcriptomic and genomic data, we showed that LOH at 1p and 11q was associated with significantly decreased expression of 122 (61%) and 88 (27%) of the genes mapping to 1p35-36 and all of 11q, respectively, suggesting that multiple genes may be targeted by LOH events. A total of 71 of the 1p35-36 genes were also differentially expressed in the independent validation data set, providing a prioritized list of candidate neuroblastoma suppressor genes. Taken together, these data are consistent with the hypotheses that the neuroblastoma transcriptome is a sensitive marker of underlying tumor biology and that chromosomal deletion events in this cancer likely target multiple genes through alteration in mRNA dosage. Lead positional candidates for neuroblastoma suppressor genes can be inferred from these data, but the potential multiplicity of transcripts involved has significant implications for ongoing gene discovery strategies.

Chromosome Aberrations↗

PubMed1998

Patterns of vertebrate neurogenesis and the paths of vertebrate evolution.

Any substantial change in brain size requires a change in the number of neurons and their supporting elements in the brain, which in turn requires an alteration in either the rate, or the duration of neurogenesis. The schedule of neurogenesis is surprisingly stable in mammalian brains, and increases in the duration of neurogenesis have predictable outcomes: late-generated structures become disproportionately large. The olfactory bulb and associated limbic structures may deviate in some species from this general brain enlargement: in the rhesus monkey, reduction of limbic system size appears to be produced by an advance in the onset of terminal neurogenesis in limbic system structures. Not only neurogenesis but also many other features of neural maturation such as process extension and retraction, follow the same schedule with the same predictability. Although the underlying order of event onset remains the same for all of the mammals we have yet studied, changes in overall rate of neural maturation distinguish related subclasses, such as marsupial and placental mammals, and changes in duration of neurodevelopment distinguish species within subclasses. A substantial part of the regularity of event sequence in neurogenesis can be related directly to the two dimensions of the neuraxis in a recently proposed prosomeric segmentation of the forebrain [Rubenstein et al., Science, 266: 578, 1994]. Both the spatial and temporal organization of development have been highly conserved in mammalian brain evolution, showing strong constraint on the types of brain adaptations possible. The neural mechanisms for integrative behaviors may become localized to those locations that have enough plasticity in neuron number to support them.

Animals↗

PubMedDate not supplied

Fetal thyrotrophin: the best indicator of long term thyroid function after in utero exposure to iodine-131?

A woman treated with radioiodine for thyrotoxicosis was subsequently found to be 19 weeks pregnant at the time of treatment. Fetal thyroid hormone levels in utero were normal or mildly elevated but fetal thyrotrophin (TSH) levels were very high. The baby remained euthyroid after birth, but required treatment with thyroid hormone replacement to normalise the TSH level. Neurodevelopment was normal at age 36 months.

Adult↗

PubMed2002

Metamodulation of the biogenic amines: second-order modulation by steroid hormones and amine cocktails.

An evolutionarily conserved feature of neural systems is that they can be modified by neuromodulators. These modulatory chemical signals include the biogenic amines, octopamine (OA), serotonin (5-HT) and dopamine (DA). Such modulation effectively broadens the operational range in which specific neural circuits can function adaptively. This report discusses how these amines are themselves modulated; for example, by the steroid hormone 20-hydroxyecdysone (20-E) or by the addition of a second biogenic amine. Such second-order neuromodulation, termed metamodulation, is discussed in the context of two well-studied invertebrate systems: the tobacco hornworm moth Manduca sexta, a model of neurodevelopment and plasticity, and the medicinal leech Hirudo medicinalis, a long-favored preparation used to study neural circuits at the level of identified neurons. A portion of this article reviews our previous research of M. sexta that shows that the 'preadult' rise in 20-E is both necessary and sufficient for the increased levels of octopamine observed in the adult. Such elevated levels likely play an important role in the production and modulation of adult behaviors. The somatic growth of median octopaminergic neurons and the late expression of OA-immunoreactivity by novel lateral neurons are also demonstrated to be dependent on 20-E. New immunocytochemical results of stained dopaminergic neurons in the larval and adult moth brain are provided as well, and the potential influence of 20-E on the developmental expression of this neuromodulator is presented. Turning attention to the leech, data indicate that the actions of OA are dramatically altered when 5-HT is combined with OA in the bath surrounding the isolated nervous system. Although either OA or 5-HT alone induces fictive swimming behavior, a cocktail of these two amines strongly inhibits the generation of swimming. Subsequent removal of such a mixture induces nearly continuous swimming and constitutes the best swim-inducing stimulus encountered to date. To understand better how these nonadditive effects are achieved, new results are discussed that indicate that the leech brain is the target of metamodulation by the two amines. Both the arthropod and annelid systems presented here highlight the multiple levels of metamodulation that can exist in nervous systems, and the diverse ways that a modulator's actions can become altered over short or long time periods.

Animals↗