Prenatal abnormal features of the fourth ventricle in Joubert syndrome and related disorders.

Joubert syndrome and related disorders (JSRD) are characterized by absence or underdevelopment of the cerebellar vermis and a malformed brainstem. This family of disorders is a member of an emerging class of diseases called ciliopathies. We describe the abnormal features of the brain, particularly the fourth ventricle, in seven fetuses affected by JSRD. In three cases abnormality of the fourth ventricle was isolated and in four cases there were associated malformations. The molar tooth sign (MTS) was always present and visible on two-dimensional ultrasound and, when performed, on three-dimensional ultrasound and magnetic resonance imaging. The fourth ventricle was always abnormal, in both axial and sagittal views, presenting pathognomonic deformities. It is important to identify JSRD, preferably prenatally or at least postnatally, due to its high risk of recurrence of about 25%. A detailed prenatal assessment of the fourth ventricle in several views may help to achieve this goal.

Limits of the surgically induced model of myelomeningocele in the fetal sheep.

PURPOSE: The prevention of Chiari type II malformation (CM) is commonly used as a primary outcome for the evaluation of techniques of fetal myelomeningocele (MMC) surgery in the fetal lamb. The aim of our study was to investigate the frequency of the associated CM in the MMC fetal sheep model and to investigate the contribution of prenatal ultrasound evaluation of CM at the time of prenatal repair. METHODS: A MMC-like lesion was surgically created at 75 days of gestation in 21 fetuses performing a L1-L5 laminectomy followed by an excision of the exposed dura and a midline myelotomy. At a 90-day gestation, among the 19 alived fetuses, a conventional repair of the MMC-like lesion was performed in seven, four of whom underwent cerebral ultrasound (US) examination before the repair. Twelve fetuses remained untreated (control group). All fetuses underwent post-mortem examination (PM) at 138 days. RESULTS: At a 90-day gestation, CM was demonstrated by US examination in all four evaluated fetuses. At birth, CM was found in 3/6 control whether CM was absent in all alived fetuses in the prenatal repair group (n = 4). CONCLUSIONS: Creation of a MMC-like lesion with an additional myelotomy does not always lead to hindbrain herniation. Our study suggests that CM should be assessed by ultrasound examination at the time of the prenatal repair to demonstrate the effectiveness of new techniques for the prenatal repair of MMC.

Fetal tumors of the choroid plexus: is differential diagnosis between papilloma and carcinoma possible?

Fetal choroid plexus tumors are uncommon. The prognosis is widely variable and depends on the histological findings: papilloma or carcinoma. We report a case of prenatal diagnosis of choroid plexus mass detected by ultrasound at 33 weeks of gestation. Prenatal (T1, T2, T2* and diffusion weighted sequences) magnetic resonance imaging (MRI) was used to rule out a hematoma. Follow-up examination by ultrasound and MRI revealed a significant increase in the volume of the mass, suggesting a diagnosis of malignant tumor. A healthy neonate was delivered by Cesarean section at 38 weeks of gestation. Full surgical excision of the tumor was performed at 20 days after delivery and histological analysis revealed a papilloma.

Mycobacterium chelonae infection under adalimumab therapy for spondylarthritis.

Tumour necrosis factor (TNF)-alpha antagonists have been prescribed increasingly over the past few years to manage various inflammatory diseases. This widespread use was quickly followed by the heightened frequency of opportunistic mycobacterial infections including environmental non-tuberculous mycobacterial infections (ENTM). We describe a 66-year-old man taking adalimumab for spondyloarthropathy who developed an inflammatory infiltration in his right index finger. A non-necrotising granuloma with epitheloid and giant cells in the dermis and eosinophilic acid-fast bacilli, identified by using Ziehl-Neelsen staining suggested a mycobacterial infection. Cultures for mycobacteria grew positive on Loewenstein-Jensen medium and molecular identification confirmed M. chelonae infection. The outcome was favourable after five months of clarythromycin. In this context of more frequent ENTM infections, chronic non-specific cutaneous lesions of the extremities should evoke systematically cutaneous ENTM infections. Skin biopsy with histological examination and oriented microbiological cultures and molecular identification are mandatory to confirm the diagnosis.

[Venous infarction of the neonate]. / L'infarctus veineux hémorragique du nouveau-né

PURPOSE: To determine the imaging features of hemorrhagic infarction in neonates. PATIENTS AND METHODS: Retrospective study (1998-2008) of 19 children (17 premature and 2 term deliveries) with early lobar hyperechogenicity on transfontanel US (TFUS). Group I: 11 born infants with clinical as well as TFUS and MRI follow-up. Group II: 8 premature infants deceased within a week from multisystem pathology, with neuropathological study available in 3 cases. RESULTS: Group I (n=11): periventricular hyperechogenicity in a frontal (7), frontoparietal (2), parietooccipital (1) and temporoparietal (1) distribution with developing cavitary change (n=6). MRI showed a cortex sparing intraparenchymal hematoma. Group II (n=8): periventricular hyperechogenicity in a frontal (4), frontoparietal or parietal (3) and occipital (1) with developing cavitary change (3). Neuropathological examination showed characteristic lesions of venous hemorrhagic infarction. Clinical outcome was generally favorable for the surviving infants with contralateral motor deficit (n=5) non-correlated to the extent of the initial lesions. CONCLUSION: Venous hemorrhagic infarction mainly affetcs premature infants and typically involves the periventricular frontal white matter. Prognosis is generally favorable. It is thus important to differentiate this entity from asymmetrical cystic periventricular leukomalacia with much different prognosis.

Molecular heterogeneity in fetal forms of type II lissencephaly.

Type II lissencephaly (type II LIS) is a group of autosomal recessive congenital muscular dystrophies (CMD) associated with defects in alpha-DG O-glycosylation, which comprises Walker-Warburg syndrome, Fukuyama cerebral and muscular dystrophy, or muscle-eye-brain disease. The most severe forms of these diseases often have a fetal presentation and lead to a pregnancy termination. We report here the first molecular study on fetal type II LIS in a series of 47 fetuses from 41 unrelated families. Sequencing of the different genes known to be involved in alpha-DG O-glycosylation allowed the molecular diagnosis in 22 families: involvement of POMT1 was demonstrated in 32% of cases, whereas POMGNT1 and POMT2 were incriminated in 15% and in 7% of cases, respectively. We found 30 different mutations in these three genes, 25 were described herein for the first time, 15 in POMT1, and five in POMT2 and POMGNT1. Despite sequencing of FKRP, FCMD, and LARGE, no definitive molecular diagnosis could be made for the other half of our cases. Preliminary results concerning genotype-phenotype correlations show that the choice of the first gene sequenced should depend on the clinical severity of the type II LIS; POMT1 and POMT2 for severest clinical picture and POMGNT1 for milder disease. The other genes, FKRP, FCMD, and LARGE, seem not to be implicated in the fetal form of CMD.

Fetal aqueductal glioneuronal hamartoma: a clinicopathological and physiopathological study of three cases.

UNLABELLED: Fetal hydrocephalus due to aqueductal stenosis is classified into two main groups: congenital (X-linked, atresia, septa and forking) and acquired (post-infectious or post-hemorrhagic, gliosis and tumors). MATERIAL AND METHODS: We report three fetal cases presenting with severe hydrocephalus, two of which being apparently sporadic, and the third possibly inherited. On macroscopic examination, no associated malformations were identified, either craniofacial dysmorphy, or visceral abnormalities. Neuropathological study revealed massive hydrocephalus caused by narrowing of the Aqueduct of Sylvius. Histological examination evidenced a nodular, well-demarcated mass producing into the aqueductal lumen, and containing numerous immature proliferating glioneuronal cells. Immunohistochemical analyses did not suggest a developmental abnormality of the subcommissural organ but rather a hamartomatous malformative process. RESULTS: Hamartoma of the posterior fossa has been rarely reported. Post-natal cases have been described in the cerebello-pontine angle or in the quadrigeminal plate, and have always been diagnosed as pilocytic or low-grade astrocytomas. In our cases, the lesions could be related to so-called pencil glioma, sometimes associated with type 1 neurofibromatosis and, to our knowledge, have never been described prior to birth. The occurrence during fetal life and the progressive maturation of the nodules are more likely in favor of a hamartomatous process. CONCLUSION: Even though they could sporadically occur, an accurate genetic counseling should be required in order to ensure that there is no familial history of Recklinghausen disease, and to provide a more precise evaluation of recurrence risk.

The biochemical pathway of neurofibrillary degeneration in aging and Alzheimer's disease.

OBJECTIVE: To determine the spatiotemporal mapping of neurofibrillary degeneration (NFD) in normal aging and the different stages of AD. BACKGROUND: The pathophysiologic significance of AD lesions, namely amyloid plaques and neurofibrillary tangles, is still unclear, especially their interrelationship and their link with cognitive impairment. METHODS: The study included 130 patients of various ages and different cognitive statuses, from nondemented control subjects (n = 60, prospective study) to patients with severe definite AD. Paired helical filaments (PHF)-tau and Abeta were used as biochemical and histologic markers of NFD and amyloid plaques, respectively. RESULTS: NFD with PHF-tau was systematically present in variable amounts in the hippocampal region of nondemented patients age >75 years. When NFD was found in other brain areas, it was always along a stereotyped, sequential, hierarchical pathway. The progression was categorized into 10 stages according to the brain regions affected: transentorhinal cortex (S1), entorhinal (S2), hippocampus (S3), anterior temporal cortex (S4), inferior temporal cortex (S5), medium temporal cortex (S6), polymodal association areas (prefrontal, parietal inferior, temporal superior) (S7), unimodal areas (S8), primary motor (S9a) or sensory (S9b, S9c) areas, and all neocortical areas (S10). Up to stage 6, the disease could be asymptomatic. In all cases studied here, stage 7 individuals with two polymodal association areas affected by tau pathologic states were cognitively impaired. CONCLUSIONS: The relationship between NFD and Alzheimer-type dementia, and the criteria for a biochemical diagnosis of AD, are documented, and an association between AD and the extent of NFD in defined brain areas is shown.

Severe brain and limb defects with possible autosomal recessive inheritance: a series of six cases and review of the literature.

Six fetuses with normal chromosomes were found to have severe craniofacial, limb, and visceral malformations during the second trimester of pregnancy. Two of these fetuses were monozygotic twins while a third one had a healthy dizygotic twin brother. A case with familial recurrence was also observed. Autopsy and skeletal radiographs suggested several diagnoses such as neural tube defect with limb defects or XK aprosencephaly. The development of these severe conditions in monozygotic twins and familial recurrence emphasize the difficulties of genetic counseling in such situations. These cases may suggest autosomal recessive inheritance.

Quantitation of Alzheimer's amyloid peptide and identification of related amyloid proteins by dot-blot immunoassay.

In Alzheimer's disease, the main component of amyloid deposits is a 39-43 amino acid peptide referred to as amyloid peptide or A beta. A crucial issue in the study of this disorder is to define the sequence of events that lead to amyloid deposition. In the present study, a new approach was developed that allows to specifically solubilize A beta peptide trapped within amyloid deposits and to quantify its amount by dot-blot immunoassay. The present method also permits to isolate components tightly bound to A beta and that are likely to catalyze its aggregation. Biochemical A beta quantitation was performed in 4 Brodmann areas from 17 elderly individuals exhibiting different degrees of amyloidosis. In parallel, classical neuropathology was done by histochemical and immunohistochemical methods. A beta amounts (pmol) were correlated to the number of amyloid deposits determined by neuropathology showing high statistical significance. Moreover, amyloid-binding proteins including apolipoprotein E and heparan sulfate proteoglycans were also found associated to A beta in the amyloid preparation. The present biochemical procedure is a new and reliable method to quantify amyloid deposition in brain. Furthermore, it allows to detect amyloid-associated components such as apolipoprotein E, that may be involved in the pathological process of amyloidogenesis.

Presence of abnormally phosphorylated Tau proteins in the entorhinal cortex of aged non-demented subjects.

An immunoblot study was performed in several cortical samples from non-demented aged controls and compared with those from Alzheimer patients, using antibodies against Tau 55, 64 and 69, which are specific and reliable markers of the neurofibrillary degeneration of the Alzheimer type. The immunodetection of Tau 55, 64 and 69 was positive in all cortical areas from Alzheimer patients, in the entorhinal cortex from each control aged more than 65 but not in cortical samples from younger controls. We demonstrate that the entorhinal cortex is the most vulnerable neuronal population in aging and that the biochemical dysfunctions observed in this area are typically of the 'Alzheimer-type'.

Glial reaction in the hippocampal formation is highly correlated with aging in human brain.

Glial fibrillary acidic protein (GFAP), a biochemical marker of astrocytes and glial reaction, was quantified by immunoblotting in different brain areas from 33 non-demented patients with a Mini Mental State Examination score above 26 and aged from 12 to 98 years. An increase of GFAP with age was first found in the hippocampus and then in the entorhinal cortex. In both regions, GFAP amounts were correlated with age (r = 0.768). In the isocortex, the increase of GFAP as a function of age was also significant (r = 0.672), but less than for the hippocampal region. GFAP levels increased dramatically after the age of 65 years, and more especially in the hippocampal formation. This glial reaction was observed in aged controls that do not show cognitive impairment and the neuropathological hallmarks of Alzheimer's disease.

Cortical mapping of Alzheimer pathology in brains of aged non-demented subjects.

1. The presence of Alzheimer-type neurofibrillary pathology and amyloid deposits within the brains of 27 aged non-demented subjects was investigated by immunoblotting and immunohistochemistry using antibodies directed against pathological Tau proteins 55, 64 and 69 and beta A4 respectively. 2. The abnormal Tau triplet, a biochemical marker of neurofibrillary degeneration was quantified by western blot and densitometric analysis in several cortical areas including the entorhinal cortex (EC), hippocampus and Brodmann areas (BA) 38, 20, 22, 35, 9, 44 and 39. 3. The abnormal Tau triplet was detected in the EC and the hippocampus of most of the controls aged over 70 years. In few control cases abnormal Tau proteins were also detected in the isocortex, in BA38 alone or also in BA20. Some cases and especially those with Tau pathology in the temporal lobe contained numerous senile plaques (SP) in the neocortex. 4. The authors conclude that control cases with Tau pathology in the temporal lobe and numerous SP in the neocortex were likely to be subclinical stages of AD whereas others with Tau pathology exclusively detected in the EC and hippocampus and without or few SP in the neocortex were related to normal aging.

Effects of 1.32-micron Nd-YAG laser on brain thermal and histological experimental data.

Considering that the 1.32-microns Nd-YAG laser should have physicothermal properties close to those of the CO2 laser, a series of experiments were conducted on rat cortex (N = 51). Three laser wavelengths were compared: CO2 laser (10.6 microns), 1.06-microns Nd-YAG, and 1.32-microns Nd-YAG lasers. For each shot, temperature measurements were recorded with an infrared thermographic videocamera. The digitized signals were figured as thermal profiles and temperature developments. Ninety-five shots were correctly studied and analyzed: CO2, N = 29; 1.06-microns Nd-YAG, N = 20; 1.32-microns Nd-YAG, N = 46. The histological lesions produced by these three lasers were compared on animals killed 24 hours (N = 20), 8 days (N = 20), and 30 days (N = 5) after the laser impacts. For equivalent densities of energy, the depth of cortical necrosis was comparable for the CO2 laser (200-250 microns) and the 1.32-microns Nd-YAG laser (210-260 microns) whatever the date of death; the 1.06-microns Nd-YAG laser shots were responsible for much more important damage (400-550 microns). Because of its important absorption in water and nervous tissue, the authors consider the 1.32-microns Nd-YAG laser most suitable for neurosurgery, particularly because it is conducted through optic fibers, and therefore is easy to handle during neurosurgical procedures.

Syndromal hypothalamic hamartoblastoma with holoprosencephaly sequence, microphthalmia, pulmonary malformations, radial hypoplasia and müllerian regression: further delineation of a new syndrome?

A 24-week-old fetus is described here with holoprosencephaly sequence (arhinencephaly and agenesis of the corpus callosum) associated with brain and meningeal dysplasia, microphthalmia with an ectopic pigmentary layer, hypothalamic hamartoblastoma, preaxial asymmetric limb reduction, lung hypoplasia, gastric hypoplasia, Müllerian regression, intestinal malrotation, asplenia, and normal chromosomes. The differential diagnosis includes the Cerebroacrovisceral-Early lethality (CAVE) phenotype, and the Pallister-Hall syndrome, but the anomalies best fit the severe form of microgastria-limb reduction syndrome. Together with a previous case reported by Meinecke, the pattern of anomalies appears to represent a combination of defects, related to but distinct from the microgastria-limb reduction syndrome.

[Familial subcortical dementia with arteriopathic leukoencephalopathy. A clinico-pathological case]. / Démence sous-corticale familiale avec leucoencéphalopathie artériopathique. Observation clinico-pathologique.

A 54-year-old man died after a subcortical dementia that had developed over 7 years with focal neurological signs and a stepwise course. Clinical and radiological features were similar to those of Binswanger's disease but there was no vascular risk factor, especially no hypertension. Three similar cases had occurred in the family affecting the patient's mother, her brother and sister, suggesting an autosomal dominant hereditary disease. Postmortem examination disclosed an arteriopathic leukoencephalopathy. The white matter was mainly affected in the periventricular areas of the frontal and parietal lobes with myelin loss and pallor, sparing the U fibers. The vascular changes involved the small vessels and were not arteriosclerotic. There was severe thickening of the internal lamina and degradation products of the elastic fibers. There was no amyloid. This vascular leukoencephalopathy was different from Binswanger's disease and amyloid angiopathy. We think that the vascular lesions could correspond to a genetically transmitted specific degenerative pathology of the small arteries of the brain.

[Neuropathologic study of 50 cases of senile dementia]. / Etude neuropathologique de 50 cas de démence sénile.

Fifty brains from patients prospectively studied in a geriatric hospital (Charles Richet Study) were examined pathologically. The patients were senile (mean age: 85) and demented and had been clinically diagnosed as senile dementia of Alzheimer type (SDAT), vascular or multi-infarct dementia (VD), mixed dementia (MD). The whole brain was studied after formalin fixation and coronal sections. The senile changes were quantified in 6 neocortical areas, hippocampus and amygdala and subcortical structures after staining by thioflavine--S and Bodian's method. The other vascular and degenerative lesions were semiquantitatively studied. Three groups of patients were identified after microscopic examination: 1. SDAT (n = 27), 2. VD (n = 6), 3. MD (n = 15), 2 patients had no significant pathological correlate for dementia. Comparison of thioflavine S and Bodian's method in 30 cases showed the former to be more sensitive for the identification of senile plaques. In SDAT, 13/27 brains lacked neurofibrillary tangles in the neocortex. Amyloid angiopathy was observed in 78% of the brains but lacked in 5/6 cases affected by pure VD. Significant lesions of the substantia nigra were observed in 13 cases with typical features of Parkinson's disease in 2 cases. The locus coeruleus was affected mainly in SDAT cases (20/27) and in some cases of VD or MD (6/21). The raphe nuclei showed neuronal loss in 18% of the cases, mostly SDAT. In this series of cases, neocortical neurofibrillary tangles could be lacking in SDAT. Amyloid angiopathy was almost always present in SDAT and MD. Subcortical structures involved in cholinergic, noradrenergic and serotoninergic innervation of the cortex were more severely impaired in SDAT and MD than in VD. Mixed dementia was frequent in these very old demented patients. Clinical and pathological criteria are needed to identify this group of patients.

[Familial parkinsonian syndrome with athymhormia and hypoventilation]. / Syndrome parkinsonien familial avec athymhormie et hypoventilation.

Five cases of parkinsonism with athymhormia observed in a single family are reported. Death caused by central respiratory disorders occurred after 6 to 8 years of progressive course. In 2 cases with autopsy, there was a severe neuronal loss predominant in the substantia nigra. Other brain stem nuclei (locus coeruleus, dorsal motor nucleus of the vagus nerve, nucleus of the tractus solitarius) were involved, as well as the striatum, pallidum and frontal cortex. No Lewy body was seen. In the surviving patient, positron emission tomography demonstrated, 4 years after the onset, a bilateral frontal hypometabolism. This disease is a rare variety of familial parkinsonism of dominant inheritance, already reported in 2 Canadian families by Perry et al. (1975) and Purdy et al. (1978) and in a family of West Virginia by Roy et al. (1988). The respiratory disorders can be explained by the involvement of the dorsal medullary nuclei. The peculiar neuropsychological disorder and motor slowing are best accounted for by the functional impairment of both motor and limbic striato-pallido-thalamo-frontal loops.

[X-ray computed tomography of lumbosacral roots and primary hypertrophic neuritis (Dejerine-Sottas disease)]. / Scanner X des racines lombo-sacrées et névrite hypertrophique primitive (maladie de Dejerine-Sottas).

CT without contrast of lumbosacral nerve roots was performed in 13 patients with peroneal atrophy and 28 control subjects. Two series of 5 mm serial sections parallel to the plane of the disk were examined at the L4-L5 and L5-S1 levels, and the transverse diameter of the S1 nerve roots measured at the lower part of the lateral recess. Results showed frank bilateral, grossly symmetrical hypertrophy of lumbosacral roots in 8 of the 13 patients. This hypertrophy involved all roots examined (L4, L5, S1), except in one case where only S1 roots were involved. Hypertrophy was often more marked on the distal part of the roots and on spinal nerves, contrasting with the sometimes normal or only slightly altered appearance of the nerve roots emerging from the dural sac. In these 8 cases, the diameter of the S1 nerve roots was 8 to 18 mm, in contrast to a mean of 3.5 +/- 1 mm in the 28 controls. CT scan images were normal in the remaining 5 patients. The presence of a CT image of nerve hypertrophy was in all cases associated with a marked fall in nerve conduction rate (median nerve motor conduction rate less than 25 msec-1), and a decrease in number of myelinated fibers with numerous onion bulbs. In contrast, the absence of CT nerve hypertrophy could not predict the results of electrophysiological and histological examinations.

[Diagnosis of fetal akinesia except for oligoamnios]. / Diagnostic des akinésies foetales en dehors de l'oligoamnios.

The term Fetal Akinesia Sequence (FAS) covers a large spectrum of developmental abnormalities resulting from a lack of intra-uterine fetal movements, which share heterogeneous etiologies. Environmental, "extrinsic" causes are easily ruled out. Various neuromuscular disorders, involving the motor unit at any level, constitute the main part of "intrinsic" fetal pathology. We propose a detailed schedule of prospective investigation of FAS, in order to standardize and gather the most pertinent information and to compare a wide panel of accurate data between fetopathological centers. The objective is to improve the understanding of various pathogenetic processes involved in the emergence of FAS, in order to propose better information and genetic counselling to parents, and potentially, to consider a prenatal prevention.