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The term 'periventricular leukomalacia' (PVL) usually covers necrotic and/or gliotic lesions from perinatal origin occurring in the periventricular ring of telencephalic white matter. PVLs are found post-mortem in one third of brains from autopsies of premature infants; PVLs are diagnosed in 4 to 10% of infants born before 33 weeks of gestation and remaining alive more than 3 days after birth. PVL is very rare in at term infants. The proportion of PVLs from prenatal origin is estimated between one third and one half of cases. Recent progresses in neuroepidemiology, developmental neurobiology and imaging methods permit to revisit the pathophysiology of PVLs on a multifactorial basis. The final result of these multiple factors seem to be calcium influx due to glutamatergic overactivation triggered by cytokines, infection and inflammation, and deficit in neurotrophic factors. Periventricular topography can be explained by properties of intracerebral vascular wall at this stage of angiogenesis and by perfusion failure/hypoxia.

The term 'periventricular leukomalacia' (PVL) usually covers necrotic and/or gliotic lesions from perinatal origin occurring in the periventricular ring of telencephalic white matter. Carrying motor and neuropsychological consequences, PVLs could be the most severe danger for very premature brains. Positive rolandic sharp waves recorded on EEG and precocious abnormally echogenous periventricular images on ultrasound suggest prospective periventricular cysts. Cystic periventricular cavitations certify the diagnosis of PVL. More subtle lesions of PVL do not reach the cystic grade and their diagnosis is confirmed by MRI. Treatment of infections is already available and potentially a tool for prevention. When the overwhelming glutamatergic signal has been triggered, neuroprotective agents turning off the excitotoxic cascade, including calcium blockers, growth factors and others, are promising therapeutic tools.

Background: Stroke is a rare cause of neonatal seizures., Case Reports: During a 5-year period, eight full-term infants were admitted to hospital for seizures due to a stroke. Seizures began shortly after birth and were always one-sided. Early CT scans showed cerebral infarctions. Motor disabilities such as hemiparesis were found in three out of seven cases; language difficulties were observed in the same proportion; however all the children had not reached school age., Conclusion: Neonatal localized seizures may be symptomatic of a stroke and therefore justify a computerized tomography (CT) scan. Motor and cognitive sequelae require early management.

A 3-d-old neonate presented with fever, hepatosplenomegaly, coagulopathy, thrombopenia and anaemia. Secondary haemophagocytic lymphohistiocytosis was suspected, as persistent cytopenias were associated with hypofibrinogenaemia, haemophagocytosis in bone marrow and decreased NK cell. There was no positive family lymphohistiocytosis history or parental consanguinity. Bacterial investigation proved negative. The diagnosis of enterovirus maternofoetal infection was carried out. The infant's condition improved with symptomatic therapy from day 7. Follow up at 1 y was normal without relapse. This is the first report of a neonatal enteroviral infection that was responsible for excessive macrophage activation.

A hyaluronectin (HN)-like antigen was found in rat O-2A progenitors and oligodendrocytes, as well as in Schwann cells and in their culture medium. The HN-like antigen secreted in culture supernatants had a higher molecular mass than HN extracted from rat brain at acidic pH. In vitro the secreted HN-like antigen was spontaneously and slowly degraded into species whose Mr was close to that of HN found in acidic brain extract. In brain or nerve neutral pH extracts, both HN-like antigen and HN were present. The high Mr of the secreted antigen, the homology in amino acid sequences between HN and N-terminal domain of PG-M/versican, in addition to a positive hybridization between Schwann cell RNAs and a probe obtained with primers derived from HN sequences also found in versican suggested that HN is closely related to the large proteoglycan PG-M/versican. The presence in Schwann cell extract of a HN mRNA whose Mr was compatible with the size expected for HN showed that HN may be directly secreted by cells and not only the consequence of a proteolytic cleavage. The similarity of HN with PG-M (V3) suggested that HN found in vivo could be the result of an alternative splicing of a single gene. We conclude that HN as other members of the PG-M/versican family is a marker of oligodendrocytes and Schwann cells in culture.

In toto mouse embryos were cultivated at embryonic day 8.5 for 26 h with 105, 310 or 620 microM caffeine; 105-310 microM correspond to concentrations transferred by the placenta of heavy caffeine consumers. Failure of neural tube closure, excessive proliferation of neuroepithelial cells and premature evagination of telencephalic vesicles were present in 50% of treated embryos. When reaching the embryonic neural tube before neuronal migration, caffeine regionally modifies the schedule and/or rate of neural cell proliferation.

Serial flow cytometry analyses of peripheral blood mononuclear cells obtained from 8 patients infected with Listeria monocytogenes showed a higher percentage (P < 0.01) of gammadelta T cells (median, 11.7; range, 3.7 to 35.3) than did 16 age-matched uninfected controls (1.7, 0.4 to 13). Most in vivo-expanded gammadelta T cells expressed the Vgamma9 and Vdelta2 gene products and displayed a memory phenotype (CD45RO[high]), and patients' gammadelta T cells expressed significantly more (P < 0.01) activation marker HLA-DR than did controls (19.8% [median] and 0.9 to 87.6% [range] versus 2.3% and 0 to 4.7%, respectively). When peripheral blood mononuclear cells from normal donors were cultured in vitro with heat-killed Listeria cells, analysis of CD25 and HLA-DR expression on gammadelta and alphabeta T cells indicated that a high percentage of gammadelta T cells was activated early compared to alphabeta T cells. In addition, depletion of gammadelta T cells before culture abrogated the early lymphocyte proliferative response induced by the pathogen. Taken together, these results argue for the involvement of gammadelta T cells during L. monocytogenes infection in humans.

Excitotoxic damage may be a critical factor in the formation of brain lesions associated with cerebral palsy. When injected at birth, the glutamatergic analog ibotenate induces mouse brain lesions that strikingly mimic human microgyria. When ibotenate is injected at postnatal day 5, it produces transcortical necrosis and white matter cysts that mimic human perinatal hypoxic-like lesions. Vasoactive intestinal peptide (VIP) has potent growth-related actions and neuroprotective properties that influence mitosis and neuronal survival in culture. The goal of this study was to assess the protective role of VIP against excitotoxic lesions induced by ibotenate in developing mouse brain. VIP cotreatment reduced ibotenate-induced microgyric-like cortical lesions and white matter cysts by up to 77 and 85%, respectively. VIP protective effects were reproduced by a peptide derived from activity-dependent neurotrophic factor (ADNF), a trophic factor released by VIP-stimulated astrocytes, and by stearyl norleucine VIP, a specific VIP agonist that does not activate adenylate cyclase. Neither forskolin, an adenylate cyclase activator, nor pituitary adenylate cyclase-activating peptide, provided VIP-like protection. VIP and neurotrophic analogs, acting through a cAMP-independent mechanism and inducing ADNF release, could represent new avenues in the understanding and prevention of human cerebral palsy.

The study of genetic/epigenetic/environmental factors underlies all therapeutic and preventive approaches in fetal, perinatal and paediatric neurology, including rehabilitation. In this paper, we selected a few targets of environmental determinants of brain development leading to underlying priorities for protection of the developing brain. Preparation of the neural germinative epithelium has to be protected against noxious pharmacological agents. New tools have been developed to improve early neural teratology, including the whole-embryo culture method. The neopallial astrocytic precursors have a dual origin. Astrocytes of the white matter and deep neocortical layers derive from transformed radial glial cells, whereas astrocytes of the upper neocortical layers derive from astrocytic precursors that migrate from the late germinative zone after the end of neuronal migration. Among numerous factors able to interfere with these gliogenetic events are the control factors of the lysosomal and autophagic functions, interfering with radial glial cell transformation into astrocytes. All lesions interrupting the migratory corridors of late astroglial migration can produce cytoarchitectonic disturbances of the neocortical supragranular layers, with long-term consequences. The developing brain is weltering in a complex mixture including newly recognized excitotoxic substances, cytokines and growth factors. These substances are sometimes environmental friends like maternal vasointestinal peptide, which prevents brain intrauterine growth retardation. They are sometimes excellent endogenous friends like neurotrophic excitatory agents in physiological conditions. They become often dangerous killers triggered by environmental signals like hypoxias/ischaemias and toxins produced by intrauterine infections, launching the excitotoxic cascade. In this paper, we reviewed mainly environmental determinants interfering with neural cytogenesis and histogenesis during the embryonic, fetal and neonatal span of early life.

We describe a patient with an unusual neonatal disseminated form of neurofibromatosis (NF1). Prenatal ultrasound studies, at 35 weeks of gestation, revealed ambiguous external genitalia, an increased biparietal diameter and a decreased growth of long bones. Postnatal examination displayed generalized neurofibromatosis, with perineal, thoracic and spinal cord invasion by tumors. Spinal cord compression was responsible for paraparesis. The child died of a pulmonary infection at five years of age. No previous report of such prenatal abnormalities has been described. Genetic counselling is difficult because of the variable expression of the illness.

In a prospective study of 417 premature neonates born before 33 weeks' gestational age, neonatal tracings were reviewed to evaluate the use of EEG in prognosis of neurological injuries. The population was divided into two groups: Group 1, infants who died before the age of 1, and Group 2, survivors in which two categories of motor development were considered. Category A, were abnormal, and Category B, were always normal. Positive rolandic sharp waves (PRSW), which reflect white matter injury, occurred equally in both groups, indicating a similar incidence of white matter damage in Groups 1 and 2. In Group 2, there was a significant correlation of PRSW with developmental motor sequelae (Category A). A frequency of PRSW above 2/min (suggesting more severe periventricular white matter injury) and seizures were significantly more prevalent in Group 1 than in Group 2 and in Category A of Group 2 than in Category B. Background abnormalities occurred equally in both subgroups of extremely premature infants (< or = 28 weeks' gestation) they were significantly more numerous in the subgroup of very premature infants (between 28 and 33 weeks' gestation) who died, than in the subgroup of very premature infants who survived. This study shows the potential utility of using neonatal EEG in association with transfontanellar ultrasonography in anticipating the neurological development of very (> 28 weeks' gestation) and extremely (< or = 28 weeks' gestation) premature newborns.

Prevalence of cerebral palsy enhanced dramatically during the last decades in some western countries. Pathophysiology of perinatal brain lesions has been revisited. Etiology seems multifactorial including perfusion failure/hypoxia, preconceptional factors, thyroid hormone and growth factors deficiencies, maternal infections with production of cytokines. Excitatory amino acids and excitotoxic cascade seem to be a common final pathway leading to neural cell death. Pharmacological tools destined to inhibit the excitotoxic cascade have been recently developed and are promising for neonatal "neuroprotection".

The influence of the excitotoxic cascade on the developing brain was investigated using ibotenate, a glutamatergic agonist of both N-methyl-D-aspartate (NMDA) ionotropic receptors and metabotropic receptors. Injected in the neopallium of the golden hamster at the time of production of neurons normally destined for layers IV, III, and II, ibotenate induces arrests of migrating neurons at different distances from the germinative zone within the radial migratory corridors. The resulting cytoarchitectonic patterns include periventricular nodular heterotopias, subcortical band heterotopias, and intracortical arrests of migrating neurons. The radial glial cells and the extracellular matrix are free of detectable damage that could suggest a defect in their guiding role. The migration disorders are prevented by coinjection of DL-2-amino-7-phosphoheptanoic acid, an NMDA ionotropic antagonist, but are not prevented by coinjection of L(+)-2-amino-3-phosphonopropionic acid, a metabotropic antagonist. This implies that an excess of ionic influx through the NMDA channels of neurons alters the metabolic pathways supporting neuronal migration. Ibotenate, a unique molecular trigger of the excitotoxic cascade, produces a wide spectrum of abnormal neuronal migration patterns recognized in mammals, including the neocortical deviations encountered in the human brain.

Ibotenate, a glutamatergic agonist, was used to study the spectrum of excitoxic disturbances at different ages of cerebral development. Cultures of whole mouse embryo were submitted to ibotenate at E8 for 20 h: during the phase of early premigratory differentiation: ibotenate did not induce any detectable histological lesion. During migration of supragranular neurons, newborn hamsters intracerebrally injected at PO with ibotenate display neuronal migration disorders graded from nodular heterotopias to extensive laminar heterotopias mimicking some aspects of lissencephalic and double-cortex syndromes. After completion of neuronal layer V, PO mice injected with ibotenate exhibit laminar neuronal depopulation of layer V-VIa mimicking human microgyria. At P5 in mouse, after completion of neuronal migration of the cortical plate, ibotenate induces neuronal loss in all cortical layers and the formation of porencephalic cysts. This study emphasizes the dramatic role played by glutamate in brain development, in the occurrence of neuronal migration disorders in the cortex, and in grey and white matter damage.

Background: Fetal growth standards of preterm infants are different from one study to another, especially for extremely preterm babies., Population and Methods: Between 1976 and 1990, a cross-sectional study of the resulting intrauterine growth of premature newborns from Haute-Normandie (France) was conducted by collecting data of the compulsory health certificate set up in the first week after birth. In spite of exclusions, curves for obstetrical terms ranging from 28 to 36 weeks of gestational age were settled. Equivalents of 8,042 birth weights, 7,792 statures, 8,041 head circumferences and 6,737 ponderal index were used., Results: Comparing our results with those published in the literature, we observed short differences for mean or middle values: from less than 170 to more than 180 g for weight, from less than 1 to more than 2.6 cm for stature and from less than 1 to more than 1.9 cm for head circumference., Conclusion: The selected normal lower threshold for each parameter and the varieties of fetal growth inadequacy are under discussion.

Excitotoxic disturbances during brain development were studied in the mouse using intracerebral injections of ibotenate, a glutamatergic agonist of the N-methyl-D-aspartate (NMDA) complex receptor, to analyse the protective effect of a systemic bolus of MgSO4, a non-competitive antagonist of the NMDA ionophore-complex receptor. MgSO4 did not prevent microgyia, induced by ibotenate when injected at P0 immediately after the post-migratory settlement of layer V, but did prevent ulegyrias, porencephalic cysts, and other cortical and cortical-subcortical hypoxic-like lesions arising after completion of the neocortical cyto-architectonic development at P5. Protection was optimal in 80 per cent of mice at 600mg/kg, with no mortality due to MgSO4; thereafter mortality increased with dosage. The protective effect appears after the developmental acquisition of two properties of the excitotoxic cascade, namely the coupling of the massive calcium influx with NMDA-receptor overstimulation and the predominance of magnesium-obliterable calcium channels. This animal model supports the clinical intervention studies with magnesium in hypoxias/perfusion failures and has implications for their design. If maturation of the excitotoxic cascade follows the same sequence in humans, protection is probably low before 26 weeks of gestational age.

Ibotenate, a glutamatergic agonist, was injected in developing mouse neopallium. When injected at the time of completion of supragranular neuronal migration (P0) ibotenate induces complete neuronal depopulation of layers V-VI and an abnormal sulcation of the overlying supragranular layers. Injected after completion of migration (P5-P10) ibotenate produces severe neuronal loss in layers II, III, IV, V, and VI. After exposure to ibotenate between P0 and P5, surviving neurons have the ability to resume their migration, inducing an abnormal neocortical pattern. Periventricular white matter lesions are observed after ibotenate injection at P2-P10, with a peak of occurrence at P5. Both gray and white matter damage are prevented by DL-2-amino-7-phosphonoheptanoic acid, an N-methyl-D-aspartate receptor antagonist, but not by L (+)-2-amino-3-phosphonopropionic acid, a metabotropic glutamate receptor antagonist. The microtubule-associated type 2 protein, a dendritic marker, is absent in all ibotenate lesions, which reflects the developmental impairment of the dendritic phase. These staged lesions of the gray and white matter disclose a developmental sequence of excitotoxin-affected events starting with the selective and layered sensitivity of postmigratory neocortical neurons and continuing in the white matter with the astroglial maturation and the axonal growth. They faithfully mimic microgyrias, focal cortico-subcortical dysplasias, porencephalic cysts, and white matter damage observed in human perinatal hypoxic/ischemic lesions. This mouse model provides tools for investigating excitotoxic influences on neural development at the various stages and for identifying protective substances against excitotoxicity from hypoxic and from nonhypoxic origins.

Oligodendrocyte precursor cells that develop into myelin-forming cells of the central nervous system (CNS) were cultured from newborn rat brain to study how they proliferate and differentiate in normal conditioning medium, and their cell development was characterized by scanning electron microscopy (SEM) observation and immunocytochemical studies. We have identified A2B5-negative pre-O2A progenitor cells (so-called "type-1" oligodendrocytes) in the secondary cultures on the astrocyte feeder layer. These cells are very small (diameter: 3.5 microns), round, and glossy, and develop into the process-bearing O2A progenitor cells (called "type-2" oligodendrocytes), which also express myelin basic protein (MBP) both in the cell body and in their cell processes. Finally, they develop into mature oligodendrocytes (called "type-3" oligodendrocytes). After MBP expression is elicited in these cells and MBP accumulates in the cell process in the area in contact with the axon, these cells are capable of forming the myelin sheath. Therefore, we examined the mechanism of myelin-sheath formation of "type-3" oligodendrocytes using video time-lapse movies, and demonstrated that these cells initially sent out processes to search for axons several times before the onset of myelination. Then thick filopodia extended towards the axon, and at the same time, the axonal part of neuron moved forward. Finally the ruffling lamellipodial parts wrapped up the axon similarly to a transverse wave with the secured thick filopodial process on the axon acting as scaffolding. These results suggest that our experimental systems are useful in studying normal oligodendrocyte development and their cellular biochemistry, as well as investigating the mechanism of myelin formation by oligodendrocytes.

Hyaluronan (HA) is a polymerized nonsulfated extracellular matrix glycosaminoglycan that may be involved in brain development. We have tested the expression of HA and the HA-binding protein hyaluronectin (HN) in glial cell cultures from newborn rat brain. HA was secreted into the culture medium by type 1 astrocytes in the first stages of the primary cultures. The secretion was high during cell proliferation, reached a maximum when they were confluent, and then decreased. HA was not secreted at a detectable level by total O-2A lineage cell-enriched cultures. HA labeled small O-2A progenitor cells (GFA-, A2B5+, HA+), small O-2A progenitorlike (GFA-, A2B5-, HA+) cells, and type 2 astrocytes (GFA+, A2B5+, HA+), but not mature oligodendrocytes (Galc+, HA-). In contrast to HA, hyaluronectin labeled oligodendrocyte membranes (i.e., more mature cells) from day 8. A2B5+ GFA- cells were found to be either HA+ or HN+ at days 7-9, suggesting intermediary stages. The addition of HA to primary cultures and to O-2A progenitor-enriched cultures decreased significantly the increase in the number of O-2A progenitors, of mature (Galc+) oligodendrocytes proportionally to the decrease of the O-2A progenitor number, and of BrdU+ cells, suggesting that HA acts (directly or indirectly) on O-2A cell proliferation. This effect, which was seen for concentrations as low as 0.1 micrograms/ml, was HA specific and was not observed with other glycosaminoglycans. When primary cultures were performed in the presence of hyaluronidase-digested or HA-depleted (by passage on a HN column) fetal calf serum, the total number of O-2A lineage cells was dramatically increased (100%, p < 10(-4)) in comparison with control cultures in standard fetal calf serum. Platelet-derived growth factor increased the total number of O-2A lineage cells and of (Galc+) oligodendrocytes. This effect was opposed by HA dose dependently. The effect of HA was significantly inhibited by HN (30%, p < 10(-4)). HN had, however, no effect when it was added to culture in the presence of hyaluronidase in fetal calf serum, suggesting its effect was only due to its binding to HA. During cell maturation, HA disappears as HN appears. This and the fact that HA and PDGF have opposite effects suggest an effect of these factors, or of their balance, on myelination.

Newborn rat brain astrocytes (type 1 astrocytes, O-2A progenitor cells, and O-2A progenitor-derived cells, i.e. oligodendrocytes and type 2 astrocytes) were cultivated to investigate the effect of addition of caffeine to the culture medium on glial cell development and secretion of hyaluronan (hyaluronic acid, HA). HA is a glycosaminoglycan, secreted by type 1 astrocytes especially, which is a major component of the extracellular matrix of immature brain involved in morphogenesis and differentiation. Caffeine was added to the culture medium of primary glial cell cultures at concentrations of 102 microM (20 mg/L) or 255 microM (50 mg/L), considered therapeutic and toxic levels, respectively, in human newborns. HA was measured in the culture medium by immunoenzyme assay using sheep brain hyaluronectin, a glycoprotein that exhibits a strong affinity for HA, as probe. In primary glial cell cultures, 102 microM (20 mg/L) caffeine had no visible effect on cell number or on HA secretion. At 255 microM (50 mg/L), there was a significant reduction of cell number (i.e. type 1 astrocytes, O-2A progenitor cells, and progenitor-derived cells) and a significant increase of HA secretion per cell. These results suggest that caffeine at a high concentration in brain could have a prejudicial effect on the number of proliferating glial cells (astrocytes and oligodendrocytes) and on the composition of the extracellular matrix, which could affect myelination onset.

In the case of the central nervous system or hepatic involvement, the prognosis of neonatal herpes simplex infection remains poor, despite antiviral drugs, presumably effective if given early. We report the case of a neonate with herpes simplex hepatitis, where the course of the illness was unusual with chronic, ultimately fatal, cholestasis. The treatment was not effective, because its administration was delayed, because of high infant C reactive protein level and the absence of clinical maternal genital infection, and because it was interrupted due to misleading information: clinical improvement, negative viral tests and raised herpes IgG antibody titer.

In a prospective study of 301 premature newborn infants, neonatal tracings were done to evaluate the use of the electroencephalogram (EEG) and positive rolandic sharp waves (PRSW) in the diagnosis and prognosis of periventricular leucomalacia. Each infant had ultrasonographic studies and standardised neurological examinations at 1 year of age or later. Two hundred and eighty infants were followed up at 1 year. This study demonstrated that the absence of PRSW was correlated with a favourable motor development (98.2%) and confirmed the great value of PRSW in the diagnosis and the prognosis of periventricular leucomalacia. PRSW were sensitive (98%) and specific (84%) markers of developmental motor disability and were a sensitive (96%) marker of severe spastic diplegia. A frequency above 2/minute was a specific (92%) sign of severe spastic diplegia. Social and language developmental abnormalities were not correlated with the neonatal EEG.

Six infants with life-threatening fainting fits are reported; five had bronchopulmonary dysplasia and one Pierre Robin anomaly. Clinically unsuspected episodes of hypoxaemia, related to an underlying respiratory pathology, appear to be the origin of these fits.

During a 6 years period, 25 newborns admitted to a neonatal intensive care unit died suddenly in the first year of life. The risk of sudden death in this specific population is 5% and reaches 7.4% in the low birth weight population (less than or equal to 2,500 g). In 12 infants, the sudden death was partially explained; in 7 infants, the sudden death remained unexplained on the basis of clinical and necropsic findings; in 6 infants, the clinical data did not justify the sudden death but necropsies were not performed. A comparison with matched living control infants showed that there was a significant increase of minor malformations of the branchial arch system and that in the sudden infant death group, threatening premature labour was more frequent during the mothers' pregnancies.

A prospective study concerning 66 prematures born after 32 weeks of gestation showed a 33% incidence of positive rolandic sharp waves (PRSW) on EEGs. The results showed a good sensitivity (Se = 95%) and specificity (Sp = 93%) of PRSW for the diagnosis of periventricular ischemia with motor sequelae. A PRSW frequency higher than one per minute and its persistence on 2 successive EEGs constitutes an indication of severity of the lesions. This study emphasizes the necessity of several EEG recordings in prematures.

Four cases of periventricular ischemia without hemorrhage in premature infants are described in which positive rolandic sharp waves (PRSW) were predominant in the electroencephalogram (EEG). These findings suggest the relationship of PRSW to periventricular ischemia rather than to intraventricular hemorrhage, per se, as has been considered by most investigations in the past. These PRSW can provide an early indication of periventricular leukomalacia.