[Geometrical growth models of the fetal forebrain, cerebellum, brainstem and change of the cranial base angles during fetal period]. / Modèles géométriques de croissance du cerveau, cervelet, tronc cérébral et modification des angles de la base du crâne au cours de la période fœtale.

INTRODUCTION: Brain growth plays likely an important role for the skull growth. In the fetus, there exists an heterochrony for the growth of supratentorial (forebrain) and infratentorial regions (brainstem and cerebellum). The aim of the study was thus to model geometrically the growth of these two regions and to compare it with the inflection of the base of skull. MATERIAL AND METHODS: Brain growth measurements were performed from midsagittal photographs of fetal brains obtained from an Anatomical Atlas over a period from 10 to 40 amenorrhea weeks (AW). After countouring and pointing anatomical and geometrical landmarks, we have developed a linear growth model based on principal component analysis (PCA). Besides, the variation of the sphenoidal and clivo-foraminal angles was studied from anatomical midsagittal slices of fetal heads sampled over a period from 16 to 39 AW. RESULTS: The PCA model brings to light the radial expansion of the forebrain growth (first component) associated with an inferior and posterior rotation of the occipital lobe. The growth of the infratentoriel region presents an inferior and posterior expansion associated with a second component corresponding to inferior and anterior expansions. From the 17 AW, appears an heterochrony between the supra- and infratentorial growths and an inversion of the ratio between the infra- and supratentorial dimensions after 30 AW. The sphenoidal and clivo-foraminal angles decrease slightly until 25 AW, and then increase quickly until the 39 AW. CONCLUSIONS: The growth of brain is accompanied by morphological change between the compartments supra- and infratentoriel but also on the level of the base of skull. The possible interactions will be discussed.

Abnormal Sylvian fissure on prenatal cerebral imaging: significance and correlation with neuropathological and postnatal data.

OBJECTIVE: To illustrate and determine the significance of abnormal Sylvian fissure development (or abnormal operculization) in cases in which prenatal cerebral imaging is suggestive of underlying cortical dysplasia. METHODS: This was a retrospective study of 15 fetuses at 24-34 weeks in which abnormal operculization was identified on prenatal cerebral imaging and for which follow-up data were available. The imaging findings were correlated to macro- and microscopic neuropathological data (n = 11) or to postnatal clinical and imaging findings (n = 4). RESULTS: On microscopic examination of fetuses from 11 terminated pregnancies, abnormal operculization was associated with cortical dysplasia in four cases and the cortex was normal in seven. Abnormal operculization was associated with cortical dysplasia in only one of the four liveborn infants. Cases of abnormal Sylvian fissure development with normal cortical architecture were classified, according to associated anomalies of the central nervous system, into one of five groups: those with neural tube defects, microcephaly or frontal hypoplasia, glutaric aciduria, other cerebral abnormalities, and extracerebral anomalies. CONCLUSION: Abnormal operculization on prenatal imaging does not systematically reflect underlying cortical dysplasia. It may be related to extracortical factors such as abnormal cerebral volume or other developmental anomalies of the central nervous system. An understanding of the significance of abnormal Sylvian fissure development could be useful in integrating its analysis into a more general one of the whole central nervous system.

[Neuropathological study of 134 fetuses in HIV infected mother]. / Etude neuropathologique de 134 foetus dans un contexte d'infection maternelle par le VIH.

A neuropathological study performed in 134 foetuses from HIV infected mothers, between 16 and 35 weeks of gestation, revealed two cases of hypoxic-ischemic brain damage, related to long labor and drug abuse. Immunostains against HIV proteins were negative in all cases. Nests of migrating cells in the cerebrum and cerebellar heterotopias were found in most cases and were considered to be common findings in fetal brain. Our study clearly showed the absence of cerebral HIV infection during early pregnancy and raises the question of the frequency of vertical transmission during HIV infection. However, the evaluation of cerebral changes in infants with HIV infection should take into consideration the features of the developing brain and the existence of other adverse factors that may interfere with its development during pregnancy.

Sexual differences in anthropometric measurements in French newborns.

Sexual differences in anthropometric measurements have been studied in a sample of 17,787 preterm and full-term infants, born between 1980 and 1990 in the maternity of Clamart Hospital (Hauts-de-Seine, France). Body weight, body length, head and chest circumferences were found significantly larger in male newborns. Conversely, the subscapular and tricipital skinfold thicknesses had higher values in females. Such greater fatness in females could be related to the better outcome in neonates of this sex. The weight-for-height indices, however, did not show this female advantage: the body mass index (BMI) and the body weight/body length index were greater in male neonates, the ponderal index (PI) showed no sexual difference.

Lethal familial fetal akinesia sequence (FAS) with distinct neuropathological pattern: type III lissencephaly syndrome.

We report on a distinct pattern of primary central nervous system (CNS) degeneration affecting neuronal survival in the brain and spinal cord in 5 fetuses with fetal akinesia sequence (FAS). This neuropathological pattern is characteristic of a lethal entity that we propose calling type III lissencephaly syndrome. Parental consanguinity and the recurrence in sibs support a genetic cause. The mechanism of neuronal death is not yet understood; abnormal apoptosis and/or deficiency in neurotropic factors may be considered possible causes.

Abnormal cortical plate (polymicrogyria), heterotopias and brain damage in monozygous twins.

We report 5 cases of abnormal cortical plate (polymicrogyria or microgyric-like pattern) and heterotopias associated with hypoxic-ischemic brain injuries in monochorionic diamniotic twin fetuses of respectively 22, 26, 28, 31, 32 weeks gestation. These fetuses belonged to a series of 5 pairs of patients (10 cases) presenting with the characteristic features of the twin-to-twin transfusion syndrome. Three of them (2 donors and 1 recipient) were macerated and the brains were not available for study. Two (most likely recipient twins) survived. In the remaining 5 fetuses (3 donors and 2 recipients) with neuropathological study there were cortical plate abnormalities. In 2 cases, the cortex was dysmorphic and consisted of focal nodular distribution or vertical stripes of neurons. True polymicrogyria was focal in 2 cases and involved almost the entire surface of the hemispheres in another one. Heterotopias of immature cells were found in 4 cases, either in the white matter or in the cortex or in both sites. There was a focal laminar necrosis only in 2 cases. The morphological pattern of the anomalies depends on the time of occurrence of the insult and on its severity. These abnormalities, although similar to those already described in singleton fetuses, illustrate the variety of cortical dysmorphia which may be associated with fetal hypoxic-ischemic injuries and emphasize the particular vulnerability of the brain in monozygotic twins, whether it belongs to the donor or the recipient.

Periventricular leukomalacia: correlation between MR imaging and autopsy findings during the first 2 months of life.

PURPOSE: To correlate magnetic resonance (MR) imaging and pathologic findings in premature infants with periventricular leukomalacia (PVL). MATERIALS AND METHODS: Eight premature infants with PVL who died after 3-7 weeks of life were studied with in vivo T1-weighted MR imaging, and imaging patterns were compared with hypoxic-ischemic injuries at pathologic analysis. RESULTS: Cavities were seen as zones of absent or weak signal intensity. Translucent sparsely cellular zones appeared as areas of intermediate intensity, and cellular reactions were seen as limited linear or punctate zones of increased intensity, usually less intense than the cortex. MR imaging provided reliable depiction of these lesions, with adequate estimation of their volume and topography. However, the extent of periventricular cellular lesions was underestimated. In one case, blood seen as hyperintense or isointense zones masked portions of cystic lesions, and in three cases small thalamic lesions were overlooked. CONCLUSION: With the above limitations, T1-weighted MR imaging offers precise evaluation of PVL.

Focal cerebral anomalies and retinal dysplasia in a 23-24-week-old fetus.

A 23-24-week-old fetus was the product of a normal pregnancy terminated because of diaphragmatic hernia and hydrocephalus diagnosed by ultrasound. Karyotype on fetal blood was normal. At autopsy, hydrocephalus was associated with multiple large intrameningeal nodules and focal cerebral dysplasia resembling type II lissencephaly. In addition, many structures of the brainstem were dysmorphic and the retina showed multiple rosettes. Skeletal muscle was normal. The peculiar features described in this case pose problems for classification and genetic implications of the anomalies.

Congenital hypothalamic hamartoma syndrome: nosological discussion and minimum diagnostic criteria of a possibly familial form.

We report on congenital hypothalamic hamartomas, discovered at autopsy in 3 unrelated fetuses. In the first 2 patients, the tumor was associated with skeletal dysplasia only. In the third patient, it was part of a non-random congenital malformation association, suggestive of Meckel syndrome. In one family, a previous boy died soon after birth with similar craniofacial and skeletal abnormalities. As far as we know, the association between isolated skeletal dysplasia and congenital hypothalamic hamartomas has not yet been documented in the literature. Nevertheless, a spectrum of skeletal abnormalities has been described in association with congenital hypothalamic "hamartoblastoma" and a constellation of variable visceral malformations under the eponym of "Pallister-Hall syndrome" (PHS). A detailed analysis of the PHS reported cases shows that only skeletal dysplasia and oro-facial abnormalities are present constantly. They show similarities with those found in our first 2 cases. These findings prompt us to consider skeletal dysplasia and oro-facial abnormalities as common denominator and minimum criteria required to define a nosologically distinct, possibly familial entity, which we suggest calling "congenital hypothalamic hamartoma syndrome" (CHHS).

Growth velocity of some fetal parameters. I. Brain weight and brain dimensions.

In this study, fetal growth velocities of the brain weight (whole brain and infratentorial part) and of the right and left fronto-occipital diameters were established from 420 normal fetuses and neonates. The age of the subjects ranged from 10 to 41 gestational weeks. Growth rates were computed by time intervals, and velocity curves were plotted with their 95% confidence intervals. The whole brain displays an accelerating pattern of growth until 35 weeks; thereafter, the growth rate breaks down. The growth velocity of the infratentorial part of the brain increases throughout fetal life, without a fall at 35 weeks. Moreover, it grows faster than the whole brain after 24 weeks. The lengths of the hemispheres present a steady decreasing pattern of growth velocity throughout pregnancy.

Growth velocity of some fetal parameters. II. Body weight, body length and head circumference.

In this study, fetal growth velocities of the body weight, crown-heel length, crown-rump length and head circumference were established from 478 normal fetuses and neonates, aged 8-41 gestational weeks. The growth rates were computed by time intervals, and the velocity curves were plotted with their 95% confidence intervals. The body weight displayed an accelerating pattern of growth until 34-35 weeks and a breakdown of the growth rate afterwards, as we already observed for the brain weight in another study published in Biology of the Neonate. Decreasing patterns of growth velocity throughout pregnancy were observed for the crown-heel and the crown-rump lengths, with a marked fall at 35 weeks. The growth velocity curve of the head circumference is also decreasing, but in a more irregular way. A curious revival of growth velocity was observed in most parameters at about 38 weeks. These changes in the growth rhythm were similar to those found previously with ultrasound data.

Intrauterine brain damage in nonimmune hydrops fetalis.

Nonimmune hydrops fetalis has been described in a large number of pathological conditions, but brain aspect has been poorly explored. We report the neuropathological findings in a series of 38 fetuses and neonates with anasarca of various origin. Fourteen fetal cerebral ultrasonograms were available; 8 presented some abnormalities. On brain examination, 23 cases showed hypoxic-ischemic lesions. The white matter was the main site of damage that consisted in classical leucomalacia or other features such as: astrocytic glial reaction, microcalcifications and microthromboses either as isolated finding or in association. Anoxic neuronal damage was much less frequent. Anemia, hypoprotidemia and cardiac failure with hypotension, which often occur in hydrops fetalis, may account for brain perfusion failure and hypoxic-ischemic changes.

Growth velocity of the biparietal diameter, abdominal transverse diameter and femur length in the fetal period.

In this study, fetal growth rates of the biparietal diameter (BPD), abdominal transverse diameter (ATD) and femur length were established from 4333 ultrasound examinations. The age of the fetuses ranged from 7 to 40 gestational weeks. The growth rates were computed by periods of 3 weeks, and the velocity curves were plotted with their 95% confidence interval. Results displayed multiphasic patterns of growth velocity for these variables, with a common peak of velocity at about 16 weeks. Between 16 and 28 weeks, growth velocity of femur length decreased, while the ATD and the BPD grew at the same constant rate. From 28 to 37 weeks, only the ATD maintained a high rate of growth. After 37 weeks, all growth rates decreased abruptly. In all cases, no sex differences in growth velocity were found.

Differential growth between the fetal brain and its infratentorial part.

From 298 normal fetuses, we established normative curves of the development of the brain in relation to gestational age and to body weight. Means and standard deviations were calculated. There exist good curvilinear relationships, expressed by polynomial models, between brain weight--body weight and brain weight--gestational age with a wider scatter in large fetuses. These results confirm literature data. Subsequently, fresh and fixed brain weights were analysed. In addition, the development of the infratentorial part of the brain was studied with the same methods and showed close relationship with age and total brain weight. The ratios: infratentorial weight/total brain weight, brain stem/total brain weight and cerebellum/total brain weight were expressed as percentages. After 20 weeks, the cerebellar growth rate was higher than that of the brain stem.

Fetal hydrocephalus. Clinical significance of associated anomalies and genetic counseling: a pathological approach.

We report on a consecutive series of 94 cases of fetal hydrocephalus. Pathological and neuropathological findings have been thoroughly analysed in order to define more precisely the clinical significance of associated anomalies and their implications in genetic counseling. In 90.5% of cases, hydrocephalus was associated with other central nervous system (84%) or extra neural (56%) anomalies. True aqueductal stenosis occurred only twice in our series. In only 9 fetuses, hydrocephalus was an isolated finding, secondary to haemorrhage or infection. Since fetal hydrocephalus is an etiologically heterogeneous disorder, its recurrence varies greatly. Without a final diagnosis, based on well documented pathological data and cytogenetic studies, accurate genetic counseling and prenatal diagnosis in subsequent pregnancies would be impossible.

Cerebral midline developmental anomalies: spectrum and associated features.

Cerebral midline anomalies are defects of anatomical relationships between the two hemispheres. They include holoprosencephalies, septal and commissural agenesis. Agenesis of the olfactory tract (arhinencephalies) are often included in the spectrum of holoprosencephalies and the facial phenotype is thought to be affected and characteristic in the midline development abnormalities. This work concerns a review of the literature and personal experience in two units of Fetopathology in Paris. This study confirms the relationships between various cerebral malformations and their frequent association. However, arhinencephaly and moreover agenesis of corpus callosum should be considered as heterogeneous entities, often totally distinct and independent from the malformative process of the holoprosencephaly. In addition, if major facial anomalies such as cyclopia are almost pathognomonic for holoprosencephaly, minor malformations such as lateral facial clefts of cleft palates result from a great variety of malformative processes.

Brain damage in monozygous twins.

A series of 15 monochorionic twins with a great variety of cerebral lesions is reported. Seven cases illustrate the classical situation: the recipient twin was affected and his co-twin, the donor was macerated. In 5 cases, the lesions were described in the donor twin as well and once, as early as 22 weeks. The lesions were usually hypoxic-ischemic, in 2 they were hemorrhagic. In 1 case there was a malformation. Fetal US were performed in 11 cases and the diagnosis of either IUGR, death of a fetus and/or brain lesions in the survivor could be made in 10 cases and once as early as 21 weeks. In fetuses born alive, transfontanellar US or CT scan have confirmed the diagnosis made on fetal US. The pathogenesis of the lesions is not fully understood. Lesions in the recipient twin may result from emboli or thromboplastic material originating from the macerated co-twin. We suggest that blood pressure instability or episodes of severe hypotension might as well lead to brain and/or visceral lesions in the recipient twin. In the donor, the lesions result from hypotension and/or anemia. With improvement and generalization of imaging techniques, the vitality of the fetuses as well as biometric parameters and anatomical structures will be better controlled. However, in case of a fetal death, occurrence of lesions in the survivor is unpredictable and no uniform policy has been proposed yet. Studies with Doppler and continuous monitoring of funicular circulation should improve our knowledge on feto-fetal transfusion and permit to detect hemodynamic fluctuation or impairment.