[Intraventricular schwannoma: a case report]. / Schwannome intraventriculaire: à propos d'un cas.

Ventricular schwannomas are very uncommon. We report such a tumor in the right lateral ventricle of a 16-year-old young man. The various etiopathogenic hypotheses are discussed.

[Primitive malignant melanoma arising in a spinal nerve root. A case report]. / Tumeur mélanocytaire primitive maligne radiculaire. A propos d'un cas.

We report the fourth case of primitive malignant melanoma arising in a spinal nerve root. A 39-year-old woman complained of one-year low back pain radiating to the right thigh and knee, and loss of 7 kg. Clinical examination found moderate quadricipital amyotrophy and hypoesthesia of anterior side of the thigh. MRI study demonstrated an enlargement of right L3 root with scalloping of the L3/L4 foramen. The T1-weighted MRI images showed a tumor hyperintensity, the T2-weighted images showed tumor isointensity and mild contrast enhancement. Due to the scalloping of L3/L4 foramen with root enlargement and slow evolution (more than one year between the first symptom and surgery without clinical worsening), the initial preoperative diagnosis was L3 schwannoma. After laminoarthrectomy and dural opening, a firm black lesion, well encapsulated and involved in a dorsal spinal root, was totally removed. The tumor was composed of irregular melanocytoid cells with high proliferation index (20%). Immunohistochemistry showed melanin, HMB-45 and S100 positivity, but reticulin was negative (that eliminates malignant melanocytic schwannoma). An extensive clinical and paraclinical research of other melanotic localisation was negative. So, the final diagnosis was intradural primitive malignant melanoma. Radiotherapy was performed on the site of the tumor. Fatal pulmonary metastasis occurred 18 months after surgery. The most common tumor with root enlargement and bony scalloping is the benign schwannoma. Despite the above described radiological features, MRI characteristics (hyperintensity when images are T1-weighted) suggest a melanocytic tumor, a tumor with a high adipose component or an intratumoral bleeding. Specific MRI sequences can eliminate adipose tissue tumor, but diagnosis between melanin and methemoglobin is still difficult. According to the index of proliferation, a primitive central melanocytic lesion can be a meningeal melanocytoma (considered as benign) or a primitive malignant melanoma. These tumors show identical protein expressions in immunohistochemistry, and their prognosis is very variable (some long-term remissions are reported for malignant melanomas and fast disseminations are described for meningeal melanocytomas treated by sub-total surgery). The L3/L4 foramen scalloping is unusual for a malignant lesion with theoretic high-speed development. The other 3 patients (reported in the literature) survive more than 3 years. The histological features of malignant lesion with benign clinical features lead to interrogation upon the actual pathologic classification.

CADASIL: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a recently identified cause of stroke and vascular dementia. It is a condition of mid-adulthood due to mutations of Notch 3 gene on chromosome 19. Whereas the disease was first reported in European families, since 1993 CADASIL has been observed in American, African and Asiatic pedigrees, suggesting that today, the disease probably still remains largely underdiagnosed. The pathological data first dealt with the white matter and the basal ganglia showing the features observed in Binswanger's subcortical arteriopathic encephalopathy; over the past few years, CADASIL has become appreciated as a systemic vascular disease with specific features. Here we have reviewed the literature from 1977 to the present for pathologically and genetically verified cases accompanied by relatively complete clinical descriptions so as to give the pathological features associated with this condition a clearer definition. The review will focus mainly on pathological studies and the pathophysiological mechanisms most likely to be involved in CADASIL.

Pineal parenchymal tumors: a correlation of histological features with prognosis in 66 cases.

The WHO classification of CNS tumors divides pineal parenchymal tumors (PPT) into pineocytoma (PC), pineoblastoma (PB) and mixed pineocytoma-pineoblastoma or PPT with intermediate differentiation. The reported incidence of mixed/intermediate PPT varies and this may reflect the difficulty in classifying tumors of this type. In an attempt to overcome the problem of the classification of PPT with intermediate differentiation, we describe the relationship between histological features and patient survival in a large cooperative series of 66 PPT from 12 neurosurgical centres. All tumors were studied with both light microscopy and immunohistochemically using antibodies against glial markers or neural/neuroendocrine markers. Our series included 11 PC, 39 mixed/intermediate PPT and 16 PB. A number of mitoses greater than 6 and the presence of necrosis were associated with a poorer outcome, while positive immunostaining for neurofilaments was associated with a better survival. We propose a new prognostic grading of 4 grades, grade I for PC, grade II for PPT with fewer than 6 mitoses and positive immunolabelling for neurofilaments, grade III for PPT with either 6 or more than 6 mitoses or fewer than 6 mitoses but without immunostaining for neurofilaments and grade IV for PB.

Galectins are differentially expressed in supratentorial pilocytic astrocytomas, astrocytomas, anaplastic astrocytomas and glioblastomas, and significantly modulate tumor astrocyte migration.

Galectins, a family of mammalian lectins with specificity to beta-galactosides, are involved in growth-regulatory mechanisms and cell adhesion. A relationship is assumed to exist between the levels of expression of galectins and the level of malignancy in human gliomas. A comparative study of this aspect in the same series of clinical samples is required to prove this hypothesis. Using computer-assisted microscopy, we quantitatively characterized by immunohistochemistry the levels of expression of galectins-1, -3 and -8 in 116 human astrocytic tumors of grades I to IV. Extent of transcription of galectins-1, -3, and -8 genes was investigated in 8 human glioblastoma cell lines by means of RT-PCR techniques. Three of these cell lines were grafted into the brains of nude mice in order to characterize in vivo the galectins-1, -3 and -8 expression in relation to the patterns of the tumor invasion of the brain. The role of galectin-1, -3 and -8 in tumor astrocyte migration was quantitatively determined in vitro by means of computer-assisted phase-contrast videomicroscopy. The data indicate that the levels of galectin-1 and galectin-3 expression significantly change during the progression of malignancy in human astrocytic tumors, while that of galectin-8 remains unchanged. These three galectins are involved in tumor astrocyte invasion of the brain parenchyma since their levels of expression are higher in the invasive parts of xenografted glioblastomas than in their less invasive parts. Galectin-3, galectin-1, and to a lesser extent galectin-8, markedly stimulate glioblastoma cell migration in vitro. Since bands for the transcripts of human galectins-2, -4 and -9 were apparently less frequent and intense in the 8 human glioblastoma cell lines, this system provides an excellent model to assign defined roles to individual galectins and delineate overlapping and distinct functional aspects.

Supratentorial pilocytic astrocytomas, astrocytomas, anaplastic astrocytomas and glioblastomas are characterized by a differential expression of S100 proteins.

The levels of expression of the S100A1, S100A2, S100A3, S100A4, S100A5, S100A6 and S100B proteins were immunohistochemically assayed and quantitatively determined in a series of 95 astrocytic tumors including 26 World Health Organization (WHO) grade I (pilocytic astrocytomas), 23 WHO grade II (astrocytomas), 25 WHO grade III (anaplastic astrocytomas) and 21 WHO grade IV (glioblastomas) cases. The level of the immunohistochemical expression of the S100 proteins was quantitatively determined in the solid tumor tissue (tumor mass). In addition twenty blood vessel walls and their corresponding perivascular tumor astrocytes were also immunohistochemically assayed for 10 cases chosen at random from each of the four histopathological groups. The data showed modifications in the level of S100A3 protein expression; these modifications clearly identified the pilocytic astrocytomas from WHO grade II-IV astrocytic tumors as a distinct biological group. Modifications in the level of S100A6 protein expression enabled a clear distinction to be made between low (WHO grade I and II) and high (WHO grade III and IV) grade astrocytic tumors. Very significant modifications occurred in the level of S100A1 protein expression (and, to a lesser extent, in their of the S100A4 and S100B proteins) in relation to the increasing levels of malignancy. While the S100A5 protein was significantly expressed in all the astrocytic tumors (but without any significant modifications in the levels of malignancy), the S100A2 protein was never expressed in these tumors. These data thus indicate that several S100 proteins play major biological roles in human astrocytic tumors.

Long-term thalamic stimulation in Parkinson's disease: postmortem anatomoclinical study.

Parkinsonian tremor may be suppressed by thalamic stimulation. For an equivalent clinical efficacy, its obvious advantage over micro-thalamotomy is its reversibility. This patient experienced postural tremor at the age of 44 years and akineto-rigid syndrome 8 years later. At the age of 60 years, intrathalamic stimulation was applied over a long-term period of 43 months until death and was efficient on tremor with low stimulation. This case is the first with anatomic verification. The extent of the lesion provoked by the electrode is very small. The location of the stimulation site was in the medio-inferior part of the intermedius complex at the entrance of cerebello-thalamic fibers. The stimulation of the cerebellar afferent axons could be the cause of the clinical effect. The stimulation site corresponds to the thalamic source of the precentral and accessory motor cortex, which correlates with changes observed in our PET study showing a regional cerebral blood flow decrease in cerebellar nuclei and also in precentral and accessory motor cortex. The places and mechanisms of the effects of stimulations and lesions could be different.

Specific tau variants in the brains of patients with myotonic dystrophy.

The mutation causing myotonic dystrophy (DM) is an unstable CTG trinucleotide repeat in a gene encoding for a protein with putative serine-threonine kinase activity. Several studies have reported the appearance of abnormally frequent neurofibrillary tangles (NFTs) in the cortex of patients with DM. Using immunologic probes against normal and pathologic hyperphosphorylated tau proteins, the basic components of NFTs, we performed a biochemical and immunohistochemical study of the brains of two DM cases. We compared the tau profiles with those found in Alzheimer's disease (AD) using mono- and two-dimensional immunoblotting. Patients were aged 53 and 61 years at death. In both cases, we observed few perikaryal and axonal inclusions in the hippocampus as well as the entorhinal and inferior temporal cortices. As in AD brain homogenates, pathologic tau proteins, named tau 55, 64, and 69, were exclusively immunodetected in the DM cases in the hippocampus, the entorhinal cortex, and in most of the temporal areas. Amounts of pathologic tau proteins were higher in the more severely affected case, but lower than in AD brain homogenates. Pathologic tau proteins were less acidic in DM than in AD. We found a very low amount of the tau 69 isoform in DM extracts, and in most of the cortical areas, tau 55 was overexpressed compared with AD homogenates. A link between the increase of kinase activity and the presence of pathologic tau proteins is discussed.

Creutzfeldt-Jakob disease: neurophysiologic visual impairments.

OBJECTIVE: The predictive value of electrophysiologic visual testing in Creutzfeldt-Jakob disease (CJD) was investigated, and the retinal pathologic findings in three cases are reported. BACKGROUND: The fatal prognosis of CJD, its transmissibility, and the lack of treatment make early diagnosis essential in averting human-to-human transmission. Electroretinogram and visual evoked potentials have been studied in few cases of CJD. METHODS: A visual electrophysiologic examination was performed in 41 consecutive patients referred with suspected CJD. The disease had been diagnosed in 24 patients (CJD group; 15 were confirmed neuropathologically and 9 by clinicolaboratory methods in accordance with diagnostic criteria). The remaining 17 patients were diagnosed with other neurologic disorders, and served as a control group. RESULTS: Flash electroretinogram revealed a significant decrease in the amplitude of the B1 wave (<60 microV) and the B/A ratio (<2) in the CJD group compared with those in the control group. Flash visual evoked potentials revealed no significant difference in latency, but amplitude was increased (>10 microV) in the CJD group, especially in patients with myoclonus. CONCLUSIONS: The visual electrophysiologic abnormalities provide an interesting noninvasive diagnostic tool in idiopathic CJD. The B1-wave decrease is closely correlated with the outer plexiform layer abnormalities observed on neuropathologic examination.

Lipomatous differentiation in ependymomas: a report of three cases and comparison with similar changes reported in other central nervous system neoplasms of neuroectodermal origin.

Three cases of surgically removed ependymomas with lipomatous transformation of tumor cells are reported. Patients' ages were 13, 16, and 48 years at the time of operation. One patient's tumor was located in the third ventricle; the other two occupied paraventricular hemispheric white matter. Histologically all three cases fulfilled the criteria of ependymomas. In case 1, electron microscopy also confirmed this diagnosis, and preoperative radiologic studies (scans) suggested large amounts of lipids to be present in the tumor. Histologically, in all three cases many tumor cells contained fat droplets coalescing into a single large droplet, resulting in an appearance indistinguishable from adipocytes by conventional stains, but maintaining immunohistological positivity for glial fibrillary acidic protein and neuron-specific enolase in the cytoplasmic rims of the affected cells, attesting to their glial nature as opposed to being true adipocytes in a mixed glial/mesenchymal hamartoma. The alterations were also different from the "xanthomatous" changes seen in some gliomas. Lipomatous transformation of neuroectodermal tumor cells has been previously observed in neurocytomas, medulloblastomas, cerebellar and spinal cord astrocytomas, and primitive neuroectodermal tumors. Our three cases represent the first reported ependymomas with such changes. In medulloblastomas of adults, lipomatous changes have been found to signal relatively benign biologic behavior. So far, all three of our patients are doing well, but only more extended follow-up will show whether such benign behavior applies to lipomatous ependymomas as well.

Short stature, abnormal face, joint laxity, dislocation, hernias, delayed bone age, and severe psychomotor retardation in two brothers: previously undescribed MCA/MR syndrome.

We describe two brothers with severe psychomotor retardation, short stature, microbrachycephaly, flat occiput, ptosis, low set and prominent ears, "beaked" nose, joint hyperlaxity and dislocation, hernias, delayed bone age, and abnormalities on skin biopsy. Their parents are first cousins. To the best of our knowledge, this syndrome has not been reported before.

New autosomal recessive cerebellar ataxia disorder in a large inbred Lebanese family.

A large inbred Lebanese pedigree with congenital spastic ataxia, microcephaly, optic atrophy, short stature, speech defect, abnormal osmiophilic pattern of skin vessels, cerebellar atrophy, and severe mental retardation transmitted as an autosomal recessive trait has been studied. None of the children had any evidence of a metabolic disease, and the analysis of respiratory chain complex abnormalities was unremarkable. Only one child had a history of perinatal difficulties. Differential diagnosis and the possibility that this disorder is a hitherto unreported one are discussed.

Lactoferrin is synthesized by activated microglia in the human substantia nigra and its synthesis by the human microglial CHME cell line is upregulated by tumor necrosis factor alpha or 1-methyl-4-phenylpyridinium treatment.

The presence of the iron-binding protein lactoferrin (Lf) in some specific areas of the central nervous system and particularly in the normal human substantia nigra, where it is found in dopaminergic (DA) neurons and some glial cells, led us to investigate Lf synthesis in this area. Lf mRNA were identified using in situ hybridization and found in small ameboid cells. These cells were identified using immunocytochemistry as activated microglia since they exhibited macrophage markers such as the CD68 and the CR1 antigens. Double immunofluorescent labeling confirmed that the two Lf immunostained cell populations were activated microglia and DA neurons. Since activated microglia contained both Lf and its messenger, these cells are the Lf producing cells. The presence of Lf in DA neurons in which no Lf messengers were visible, might be due to an endocytosis mechanism, DA neurons probably internalizing Lf produced in microglial cells located in their neighborhood. In neuropathological disorders, such as Alzheimer's and Parkinson's diseases, inflammatory process and oxidative stress are events that contribute to neuronal death. Since Lf concentration increases during these pathologies, we studied the level of Lf expression under these different stresses and showed, using RT-PCR, that the immortalized human embryonic microglial CHME cell line produced Lf transcripts under tumor necrosis factor alpha or 1-methyl-4-phenylpyridinium treatment whereas untreated cells did not. These data confirm that Lf is produced only when microglia are activated.

Ultrastructural study of the choroid plexus of spontaneously hypertensive rats.

We previously gave an account of an increased ion transport activity in choroid plexus from spontaneously hypertensive rats. We have since examined this organ in scanning and transmission electronic microscopy. In the choroid plexus from young spontaneously hypertensive rats, the epithelial cells showed the following: a partial loss of the brush border and infoldings of basolateral membranes, an increased number of Golgi apparatus, vesicles, and mitochondria, and an activated nucleus. In adult hypertensive rats, the mitochondria had increased in number and tended to fill the cytoplasma while the nuclei had returned to a resting level. These ultrastructural changes furthermore suggest an increased secretory activity in the choroid plexus in spontaneously hypertensive rats.

The effect of cicletanine on cerebrovascular injury in stroke-prone spontaneously hypertensive rats.

The stroke-prone spontaneously hypertensive rat (SHR-SP) is one of the most suitable models for stroke study. The present trial work was undertaken so as to obtain further information concerning the action of a new furopyridine, cicletanine. Forty-six males--SHR-SP/Iffa Credo rats--aged 7 weeks, were divided into three groups. Group 1 was a control group, groups 2 and 3 were orally treated with cicletanine at 30 and 100 mg/kg. Their drinking water contained 1% NaCl. Systolic blood pressure, body weight, and survival were recorded. After 6 weeks, all the rats were sacrificed. Samples of heart, brain, and kidney were fixed for light and ultrastructural examination. We found that cicletanine treatment (30 and 100 mg/kg) had significantly inhibited the incidence of hypertensive cerebral damages as characterized by cerebral infarction and vascular alterations with fibrinoid necrosis. Compared with the control group, the rats treated with the cicletanine had a significantly increased survival rate (P less than .001); the cicletanine also had an important protective effect on tissue. Cicletanine administration prevented the development of hypertensive cerebral vascular damage, probably through direct action on the vascular walls.

Skin biopsy value and leukoaraiosis.

In the field of leukoaraiosis, the identification of CADASIL and its link to Notch 3 mutation has shed light on the pathogenesis of white matter (WM) abnormalities related to small-vessel disease. Since 1993, its systemic vascular involvement allows skin biopsy diagnosis and research on tissues before postmortem examination. We received 160 skin biopsies from patients presenting subcortical dementia, recurrent strokes, behavioral disturbances or migraines, and suspected CADASIL. Almost all the patients lacked the well-known vascular risk factors. The ultrastructural study was systematically carried out looking at the vessel walls and the other components found in skin. In a third, we found endothelial changes, destruction of vascular smooth muscle cells (VSMCs), and characteristic granular osmiophilic material (GOM). In these cases, the genetic analysis confirmed the Notch 3 mutation. Curiously, the skin biopsies from the other two thirds presented marked alterations within the vessel walls. Such changes included destruction of VSMCs, lack of GOM, and replacement of these cells by an extracellular matrix. Frequently, we noticed endothelial pathological changes as well as other tissue impairments. By now, we are able to describe eight different groups of lesions according to either the prevalence of a lesion or the association of different lesions. The skin biopsy ultrastructural study seems to be highly informative given that we can observe vessel lesions and association of impairments in various tissues that might, in part, explain the brain vessel involvement and then the leukoaraiosis and probably some clinical symptoms. Moreover, these vessel lesions often belonged to young people (30-50 years old), and many of them seemed to run in families. These new data associated with early onset of clinical symptoms and leukoaraiosis would be extremely valuable in clarifying the wide field of leucoencephalopathy and might provide genetic research with new issues.

Notch3 mutations in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a mendelian condition causing stroke and vascular dementia.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited condition whose key features include recurrent subcortical ischemic events, migraine attacks and vascular dementia in association with diffuse white-matter abnormalities seen on neuroimaging. Pathologic examination shows multiple small deep cerebral infarcts, a leukoencephalopathy and a nonatherosclerotic nonamyloid angiopathy involving mainly the media of small cerebral arteries. To progress in understanding the pathophysiological mechanisms of this condition, we undertook the identification of the mutated gene. We mapped the CADASIL gene on chromosome 19p13.1. More than 120 families have been referred to our lab. Genetic linkage analysis of 33 of these families allowed us to reduce the size of the genetic interval to less than 1 cM and to demonstrate the genetic homogeneity of this condition. In the absence of any candidate gene, we undertook positional cloning of this gene. We identified, within the CADASIL critical region, the human Notch3 gene, whose sequence analysis revealed deleterious mutations in CADASIL families co-segregating with the affected phenotype. These data establish that this gene causes CADASIL. Identification of the CADASIL gene will provide a valuable diagnostic tool for clinicians and could be used to estimate the prevalence of this underdiagnosed condition. It should help in the understanding of pathophysiological mechanisms of CADASIL and vascular dementia.

Paradoxical phosphorylation of the serine 199 on tau proteins from young individuals.

The microtubule-associated tau proteins are abnormally aggregated in many tauopathies. Phosphorylation modulates the functions of tau. The serine 199 residue of tau is abnormally phosphorylated at early and late stages of Alzheimer's disease. The presence of the phosphorylated Ser199 was investigated in autopsy-derived and biopsy-derived brain tissue samples from non-demented individuals. A paradoxical expression was found in the hippocampus of the youngest ones, in granule cells of the dentate gyrus and in pyramidal cells of the Ammon's horn, which are particularly prone to neurodegeneration in several tauopathies. The rate of positive cells decreased with age. These data emphasize the importance of the phosphorylation of the Ser199 residue of tau in ageing and susceptibility to neurodegeneration.

Differential diagnosis of a vascular leukoencephalopathy within a CADASIL family: use of skin biopsy electron microscopy study and direct genotypic screening.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a condition caused by mutations of Notch3 gene on chromosome 19. Ultrastructural analysis of skin vessels discloses typical granular osmiophilic material (GOM) within the vascular smooth muscle basal lamina. We describe a CADASIL family in which two members suffering from a vascular leukoencephalopathy were shown to be CADASIL phenocopies: clinical and magnetic resonance imaging (MRI) findings in these two patients were similar to those observed in their affected relatives. However, the skin biopsy performed on one of them did not reveal any GOM in the vascular smooth muscle cells, and the Notch3 mutation present in this family was shown to be absent in these two individuals. We emphasize the role of a direct DNA test for gene mutation to make a differential diagnosis between CADASIL and other forms of vascular leukoencephalopathy.

Ectopic prolactinoma within the sphenoid sinus.

A case of an ectopic prolactin-producing tumor located within the sphenoid sinus is reported. It was discovered in a girl who experienced secondary amenorrhea without galactorrhea. We discuss the different diagnoses proposed before immunocytochemical staining results were available. This case presented unusual radiological, surgical, and histopathological aspects.