Philippe Evrard

Prevention by magnesium of excitotoxic neuronal death in the developing brain: an animal model for clinical intervention studies.

Excitotoxic disturbances during brain development were studied in the mouse using intracerebral injections of ibotenate, a glutamatergic agonist of the N‐methyl‐D‐aspartatc (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 PO 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‐oblilerable 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.

Outcome and prognosis of whiplash shaken infant syndrome; Late consequences after a symptom-free interval

Long‐term follow‐up five to 13 (mean seven years) of 13 cases of whiplash‐shaken‐infant syndrome (WSIS) demonstrated long sign‐free intervals. Full clinical appearance of neurological deficits takes four months tor the interruption of brain growth, six to 12 months for lesions of the central nervous system long pathways, up to two years for epilepsy, and three to six years for behavioural and neurospychological signs. In our series, WSIS ocurred at a mean postnatal age of 5.5 months and caused intracranial, retinal and preretinal haemorrhages, intracranial haematomas, oedema, contusional tears, and developmental disturbances interfering with the growth and differentiation of neural tissue and with synaptic stabilisation. These mechanisms account for the long sign‐free interval that makes its impossible to formulate a precise and final neurological prognosis before the age of school entrance. Only one of our patients seems to have remained normal even several years after the shaking.

The germinative zone produces the most cortical astrocytes after neuronal migration in the developing mammalian brain

The origin of astrocytes of the mouse neocortex during the fetal and early postnatal periods as determined by immunocytological, autoradiographic, electron microscopic and antimitotic methods is described. Most astrocytes destined for the white matter and the infragranular cortical layers are derived from the transformation of radial glial cells between P0 and P10 with an inside-out pattern. This cell metamorphosis is not directly preceded by mitosis and involves the activation of the radial glial lysosomal apparatus. In opposition to recent hypotheses, our findings suggest that most astrocytes destined for the supragranular cortical layers are produced in the germinative zone after the migration of the infragranular neurons and themselves migrate afterwards to the upper cortex between E16 and the first postnatal days. These astrocytes do not display an intermediate stage of the radial glial cell and do not participate in the pattern of appearance of the deeper astrocytes. This second step of astrocytogenesis is a condition for normal cytoarchitectonic development and the maintenance of the supragranular layers, since the deprivation of the astrocytic equipment of the supragranular layers by an antimitotic drug drastically reduces the number of supragranular neurons.

Cocaine-induced disturbances of corticogenesis in the developing murine brain

Exposure of fetuses to cocaine can induce behavioral disturbances and structural modifications of the CNS. Cocaine was injected into pregnant mice from the eighth day of gestation until term and the brains of their offspring were examined at the light and EM levels. Cocaine severely disturbs neocortical architecture, disrupting horizontal and vertical lamination, and inducing abnormal array of the axonal-dendritic bundles. Cocaine also alters several steps of gliogenesis. The severity of the malformations is variable, but evident in all exposed animals.

Transplacental Cocaine Exposure: A Mouse Model Demonstrating Neuroanatomic and Behavioral Abnormalities

Between 10% and 15% of infants born in urban America today have been exposed to cocaine in utero. Clinical studies have suggested that impairment of brain growth is the single best marker of significant prenatal cocaine exposure, and postnatal developmental compromise seen in a subset of affected children as a consequence of that exposure. We have developed an animal model, in mice, of prenatal cocaine exposure that has allowed us to dissociate the direct effects of cocaine in altering fetal development from the indirect effects associated with cocaine-induced malnutrition. We find that transplacental cocaine exposure independently impairs fetal brain and body growth and results in behavioral deficits and permanent alterations in neocortical cytoarchitecture in exposed offspring. (J Child Neurol 1994;9:234-241).

On an autosomal dominant form of retinal-cerebellar degeneration: an autopsy study of five patients in one family.

We describe a family with an autosomal dominant form of retinal-cerebellar atrophy. There is an extreme variability in age of onset and severity of the clinical symptoms: some patients remain nearly asymptomatic throughout their entire life; others develop severe retinal and cerebellar symptoms after the age of 35 years; others suffer from a severe disorder with onset in adolescence and death during the third decade of life; in others the onset is in early childhood with prevalence of cerebellar symptoms. There is neither dementia nor epilepsy in any of the patients. Four out of five autopsies showed a severe retinal atrophy, and all five autopsies were also characterized by (1) a cerebellar atrophy affecting the spinocerebellar and olivocerebellar tracts, the cerebellar cortex and the efferent cerebellar pathways, (2) an involvement of the pyramidal pathways and of the motor neurons of brain stem and spinal cord, and (3) an atrophy of the subthalamic nucleus and to a much lesser extent of the pallidum, with also some damage to the substantia nigra. The posterior columns are much less affected except in one patient. In this family, we have excluded linkage with the two loci for spinocerebellar ataxia, i.e., SCA1 on chromosome 6p and SCA2 on chromosome 12q as well as with the locus for Machado-Joseph disease (MJD) on chromosome 14q. A genome-wide search is currently being performed to detect the disease locus responsible.

Neuron migration within the radial glial fiber system of the developing murine cerebrum an electron microscopic autoradiographic analysis

The present analysis provides direct evidence in the mouse that in the course of course of neocortical histogenesis, contact between migrating neurons and the surfaces of radial glial fibers is both invariant and relatively selective. The analysis characterizes in detail the migratory behavior of the individual migrating cell with respect to the overall radial glial fiber system as this system varies systematically in its structure with ascent through the strata of the cerebral wall. A quantitative study of the relationships between the radial glial fibers confidently identified by their glycogen content and the migrating neurons marked autoradiographically by injection of [3H]thymidine was also performed at the ultrastructural level on tangential sections at different pallial levels in E16 and E17 embryos. The overall set of observations lend support to the hypothesis that radial glial fibers act specifically as guides to neuronal migration and illustrate the nature of the cell-to-cell interaction which serves this cellular process critical to neocortical histogenesis.

Dynamic structure of the radial glial fiber system of the developing murine cerebral wall. An immunocytochemical analysis

Dramatic changes occur in the radial glial fiber system of the murine forebrain in the course of neocortical histogenesis. Initially, prior to substratification of cortical and subcortical anlagen between E13 and E14, the system is uniformly radial in alignment. It appears to achieve maximum density and to be highly uniform in structure throughout its radial span, both in terms of apparent fiber density and the pattern of arrangement of fibers in fascicles. Subsequent to E14, concurrently with rapid growth of the cerebral wall and with the differentiation of the cortical substrata and intermediate zone, the subcortical segment of the system becomes laterally arced while the transcortical span of the system remains radially aligned. Although the spacing between fascicles changes little, there is an apparent general drop in fiber density associated with a progressive reduction in the number of fibers per fascicle. The changes in relative positioning of the fibers and the apparent decline in fiber density are most dramatic within the developing cortical plate and subplate and may be of specific significance for the migration and radial assembly of the neurons in the supragranular neocortical layers.

Symptomatology of Late Onset Krabbe's Leukodystrophy: The European Experience

The authors present a study of 50 patients with late onset Krabbes leukodystrophy (LOKL), including 27 from a pooled European Series collected in 1987, and 23 published between 1906 and 1987. In Europe, the disease appears to be relatively frequent in Sicily and exceedingly rare in Sweden. Most cases started before the age of 5 years. The initial signs consisted mainly of progressive motor impairment, although, characteristically, visual failure was the initial manifestation in 25% of patients. Low nerve conduction velocities and a high protein content in the CSF were only present in 50%. There was no age-linked symptomatic predominance. The pace and length of the disease was very variable, but in one-third of the children before the age of 3 the course was remarkably rapid. There was no difference in the residual activity of galactosylceramide galactosidase in LOKL compared to the early infantile form.

Topographical and cytological evolution of the glial phase during prenatal development of the human brain: histochemical and electron microscopic study.

An ultrastructural analysis of prenatal gliogenesis and neuronal-glial relationships in the developing fetal brain was carried out using reduced osmium and periodic acid-thiocarbohydrazide-silver proteinate to stain selectively the glycogen content of the glial population. Gliophilic neuronal migration was confirmed in the human fetus, with radial glial fibers (RGF) acting as obligatory corridors for neuronal migration in the prospective neocortex and underlying intermediate zone (IZ). With this method, the entire glial phase was differentiated from neuronal elements; this permitted a description of the evolutionary distribution pattern of RGF: in the cortical plate, glial fascicles fully dissociate by 18 weeks gestation, whereas in the IZ, they remain grouped in fascicles until their transformation into astrocytes. The most conspicuous and constant developmental feature observed in the maturing glial cytoplasm between 21 and 30 weeks gestation was a radical enhancement in the abundance and activity of the lysosomal apparatus and autophagic vacuoles observed in the RGF, a cytological basis for the transformation of radial glial cells into astrocytes. These data have implications for the understanding of the ontogenesis of the neocortical vertical modules in the human brain and for the phylogenetic analysis of the vertical cortical units in terms of comparative mammalian anatomy.