Cerebellar hypoplasia with heterotopic purkinje cells in the molecular layer and preservation of the granule layers associated with severe encephalopathy. A new entity?

We present the case of an infant girl, born to first cousins, with a clinical phenotype consisting of microcephaly, hypotonia, strabismus and severe psychomotor retardation. Magnetic resonance imaging (MRI) showed global cerebellar atrophy involving the vermis and both hemispheres. The patient's serum transferrin levels were consistently unremarkable. Cerebellar biopsy, performed at 13 months of age, revealed heterotopic Purkinje cells in the molecular layer, but preservation of the external and internal granular layers. To our knowledge, this histological pattern of cerebellar cortical disorganization has not been described previously. The consanguinity of the parents suggests an autosomal recessive inheritance.

Lethal X-linked microcephaly with dysmorphic features, bilateral optic pathway aplasia and normal eyes.

We describe a family, consisting of two brothers and a maternal uncle who died of an apparently identical condition, within a few days of birth, suggestive of an X-linked mode of inheritance. The propositus (the older sibling) was investigated in detail and showed the following clinical features: microcephaly, facial dysmorphism, malformations of hands and feet, and cryptorchidism. Examination of the brain revealed arhinencephaly, a primitive gyral pattern, arrested cortical maturation, absence of corticofugal tracts and corpus callosum, agenesis of the optic pathway with preserved eyes and oculomotor system, absent auditory pathway, agenesis of the pars compacta of the substantia nigra and severe hypoplasia of the cerebellum and its connections. This family belongs to the group of X-linked microcephalies and has some features in common with the Juberg-Marsidi syndrome. The fact that the CNS abnormalities were incompatible with life and the facial dysmorphic features were quite different makes it unlikely that the affected individuals in this family had Juberg-Marsidi syndrome. However, this does not exclude the possibility that more restricted anterior induction defects may occur in some X-linked microcephalies such as Juberg-Marsidi syndrome resulting in prolonged survival.

alpha-Lipoic acid decreases oxidative stress even in diabetic patients with poor glycemic control and albuminuria.

In the present cross-sectional study, the influence of alpha-lipoic acid on markers of oxidative stress, assessed by measurement of plasma lipid hydroperoxides (ROOHs), and on the balance between oxidative stress and antioxidant defence, determined by the ratio ROOH/(alpha-tocopherol/cholesterol), was examined in 107 patients with diabetes mellitus. Patients receiving alpha-lipoic acid (600 mg/day for > 3 months) had significant lower ROOHs and a lower ROOH/(alpha-tocopherol/cholesterol) ratio than those without alpha-lipoic acid treatment [ROOH: 4.76 +/- 2.49 vs. 7.16 +/- 3.22 mumol/l; p < .0001] and [ROOH/(alpha-tocopherol/cholesterol): 1.37 +/- 0.72 vs. 2.16 +/- 1.17; p < 0.0001]. In addition, the influence of glycemic control and albuminuria on ROOHs and on the ratio of ROOH/(alpha-tocopherol/cholesterol) was examined in the presence and absence of alpha-lipoic acid treatment. Patients were subdivided into three groups based on (1) their HbA1 levels (< 7.5, 7.5-9.5, and > 9.5%) and (2) their urinary albumin concentrations (< 20, 20-200, and > 200 mg/l). Neither poor glycemic control, nor the presence of micro- or macroalbuminuria prevented the antioxidant effect of alpha-lipoic acid. Using stepwise multiple regression analysis, alpha-lipoic acid was found to be the only factor significantly predicting low ROOHs and a low ratio of ROOH/(alpha-tocopherol/cholesterol). These data provide evidence that treatment with alpha-lipoic acid improves significantly the imbalance between increased oxidative stress and depleted antioxidant defence even in patients with poor glycemic control and albuminuria.

The mysterious prion diseases--a historical perspective.

The spongiform encephalopathies are a group of diseases sharing a common pathology and affecting both humans and animals. The human diseases include both sporadic and familiar disorders. Creutzefeld-Jakob disease and kuru are sporadic, familial Creutzfeld-Jakob, fatal familial insomnia and the Gerstmann-Sträussler-Scheinker syndrome are genetic and inherited as autosomal dominants. The hallmark of these diseases is the presence of abnormal forms of a membrane protein called prion, particularly abundant in the brain. Transmission of these diseases has been documented from humans to humans, from humans to animals and, more controversially, from animals to humans. Many questions in the aetiology and pathogenesis remain unanswered.

Calbindin-D28k in subsets of medulloblastomas and in the human medulloblastoma cell line D283 Med.

OBJECTIVE: To evaluate the antigenic expression of calbindin-D28k in surgically resected cerebellar medulloblastomas and the human medulloblastoma cell line D283 Med in relation to glial neoplasms, the human glioblastoma (U-251 MG) and rat glioma (C-6) cell lines, and other primary and metastatic brain tumors. DESIGN: Immunohistochemical staining was performed using an antiserum and a monoclonal antibody against calbindin-D28k on (1) formalin-fixed, paraffin-embedded human, predominantly posterior fossa, brain tumor specimens (49 medulloblastomas, 59 glial and mesenchymal primary central nervous system tumors, 1 posterior fossa rhabdoid tumor, and 34 metastatic tumors); (2) formalin-70% alcohol-, or Bouin's-fixed tumor cell lines (D283 Med, U-251 MG, and C-6) maintained in a three-dimensional gelatin foam (Gelfoam matrix) system, with or without treatment with dibutyryl cyclic adenosine monophosphate; and (3) formalin-fixed, paraffin-embedded C-6 glioma cells transplanted intracerebrally to rats. RESULTS: Calbindin-D28k immunohistochemical staining was detected in 20 of 49 cerebellar medulloblastomas and in cells of the human medulloblastoma cell line D283 Med grown in gelatin Gelfoam matrices, with or without treatment with dibutyryl cyclic adenosine monophosphate. In surgical resection specimens, calbindin-D28k reactivity was evident in populations of poorly differentiated cells of classic (non-nodular) medulloblastomas (16/20) and in mature Purkinje neuronlike phenotypes in medulloblastomas with ganglion cells (4/6) but was absent in desmoplastic medulloblastomas, including in areas of neoplastic neuritogenesis ("pale islands") (0/23). Calbindin-D28k staining was also present in D283 Med explants for up to 29 days in vitro. Reactivity was more widespread in dibutyryl cyclic adenosine monophosphate-treated cultures, coinciding with neuronal morphologic alterations of cultured cells. Focal calbindin-D28k stainig was present in neural-like cells of an embryonal cerebellar tumor with divergent mesenchymal, epithelial, and neuroectodermal/neuroendocrine differentiation suggestive of a malignant rhabdoid tumor. No calbindin-D28k staining was obtained in primary glial and mesenchymal (intra- and extra-axial) brain tumors (0/59), in explants of human glioblastoma cell line U-251 MG, or in the rat glioma line C-6 maintained in Gelfoam matrices or transplanted intracerebrally. Among 34 epithelial and mesenchymal tumors metastatic to the posterior fossa, only subpopulations of cells in two small-cell (neuroendocrine) carcinomas originating in the lung were calbindin positive. CONCLUSION: Calbindin-D28k expression in classic medulloblastomas, medulloblastomas with ganglion cells, and in the human medulloblastoma cell line D283 Med (which was derived from a metastatic classic medulloblastoma) suggests a phenotypic kinship between subsets of this tumor and neuronal progeny of the ventricular neuroepithelium, thus conferring additional support for its neuroblastic nature.

A cytomorphological scheme of differentiating neuronal phenotypes in cerebellar medulloblastomas based on immunolocalization of class III beta-tubulin isotype (beta III) and proliferating cell nuclear antigen (PCNA)/cyclin.

This immunohistochemical study compares the localization of the neuronal class III beta-tubulin isotype (beta III) to that of the proliferating cell nuclear antigen (PCNA)/cyclin in 46 cerebellar neuroblastic tumors (medulloblastomas). Both class III beta-tubulin (beta III) and PCNA/cyclin reactivities were present in all tumors, but the topographic distribution and cytomorphologic features of stained cells varied considerably between classic and desmoplastic medulloblastomas. Four neoplastic phenotypes, representing gradations of neuronal differentiation, were identified: [Allegranza 1991] apolar, blast-like PCNA/cyclin(+) cells devoid of beta III reactivity (Nb1); [Bravo et al. 1987] apolar, often binucleated and/or fusiform, PCNA/cyclin (+) cells with pronounced beta III staining in their protoperikarya and their growth cones (Nb2); [Burger et al. 1987] beta III-immunoreactive immature polar neurons with varying degrees of neuritic development, reading to significant neuritogenesis in the "pale islands" of desmoplastic medulloblastomas (Nb3). The majority of Nb3 phenotypes were PCNA/cyclin (-), although subpopulations of such polar tumor cells exhibiting PCNA staining were also identified; and [Burger et al. 1991] beta III-immunoreactive, PCNA/cyclin (-) mature ganglion-like cells (Nb4). A high PCNA/cyclin labeling index (> 80%) was obtained in 20 poorly differentiated classic medulloblastomas while, significant intratumoral staining heterogeneity was observed in 23 cases of desmoplastic medulloblastomas and 3 cases of "medulloblastomas with ganglion cells": A high labeling index (LI)(> 80%) in the reticulin-impregnated poorly differentiated areas of tumor contrasted with sharp decline of PCNA staining and a very low LI (< 10%) in areas of overt neoplastic neuritogenesis ("pale islands") displaying strong beta III reactivity. Neoplastic ganglion cells were beta III (+)/PCNA (-). Our findings indicate that the majority of differentiating neuronal phenotypes undergoing cytomorphological changes of neuritic development (Nb3), and all neoplastic ganglion cells (Nb4 phenotypes) are PCNA (-), in contrast to actively proliferating, poorly differentiated, tumor cells that are PCNA (+). Although PCNA staining corresponded in part, to beta III (-) blast-like elements (Nb1), a co-expressive pattern of staining for beta III and PCNA/cyclin also was observed in subpopulations of poorly differentiated tumor cells (Nb2), indicating that transformed neuroblasts are capable of expressing differentiation-associated neuronal cytoskeletal proteins while still remaining in the proliferative compartment of the cell cycle. Our observations suggest that only neuritogenesis and acquisition of ganglionic phenotype are significant maturational events in medulloblastomas (indicating entry into the quiescent phase of the cell cycle) and provide further support for the neuronal lineage and differentiation potential of these cerebellar embryonal tumors.

The stromal Schwann cell during maturation of peripheral neuroblastomas. Immunohistochemical observations with antibodies to the neuronal class III beta-tubulin isotype (beta III) and S-100 protein.

This immunohistochemical study compares the localization of the neuronal class III beta-tubulin isotype (beta III; analogous to the beta' 1-/beta 2-tubulin isoform) to the Schwann cell-associated S-100 protein focusing on topographic relationships of Schwann-like cells to differentiating neuronal phenotypes during stromal development in human peripheral neuroblastomas. The earliest appearance of Schwann cells in poorly differentiated (classical) neuroblastomas is heralded by S-100 protein-immunoreactive cells in close association with tumor blood vessels. In subsequent stages of maturation, i.e. maturing neuroblastoma (ganglioneuroblastoma and gangliocytoma), S-100 protein-positive cells are mostly confined to the connective tissue septa dividing tumor into lobules, and are not freely interspersed with beta III-immunoreactive neoplastic neurons. Significant ensheathment of individual axon-like processes by Schwann cells occurs only in mature ganglioneuromas. beta III is localized in a full spectrum of neoplastic neuronal phenotypes, ranging from poorly-differentiated apolar neuroblasts (often signaling ensuing neuritogenesis) to mature ganglion cells, but not in Schwann cells, or other cell types of the stroma. Our observations suggest that Schwann cells in peripheral neuroblastomas are stroma-derived cells and not an expression of divergent neoplastic differentiation.

Differential localization of class III, beta-tubulin isotype and calbindin-D28k defines distinct neuronal types in the developing human cerebellar cortex.

This immunohistochemical study compares the localization of the neuronal class III beta-tubulin isotype (beta III) to that of calbindin-D28k in 40 human fetal and postnatal cerebella ranging from 12 weeks gestation to adulthood. In the external granule layer of the developing cerebellar cortex, beta III staining was present in the premigratory (postmitotic) zone of horizontal neurons but was absent in "epithelioid" cells of the subpial proliferative mitotic zone. In the molecular layer, intense beta III staining was associated with parallel fibers, stellate/basket neurons and migrating fusiform granule neurons. beta III staining was also present in internal granule neurons. In contrast, beta III was not detectable in fetal and neonatal Purkinje neurons and Golgi II neurons, but was evident in these neurons from juvenile and adult cerebella. Calbindin-D28k staining was present in Purkinje neurons also delineating their somatic spines ("pseudopodia"), lateralizing and apical dendrites (including dendritic spines), subpopulations of small to intermediate-sized Golgi II neurons in the internal granule layer ("synarmotic cells" of Landau), large to medium-sized subcortical Golgi II neurons and neurons of cerebellar roof nuclei, at various gestational stages and postnatally. It was absent in the external granule layer, parallel fibers, stellate/basket and internal granule neurons. Variable degrees of beta III and calbindin-D28k staining were detected in subpopulations of immature neuroepithelial cells of the ventricular matrix at the roof of the fourth ventricle. Glial (including Bergmann glia) and mesenchymal cells were not stained for either antigenic determinants. The differential expression of calbindin-D28k and beta III defines distinct populations of neurons in the developing human cerebellar cortex and supports the ontogenetic concept of Ramon y Cajal.

Symmetrical neurofibroma with Schwann cell predominance and focal formation of microneurinomas.

A case of symmetrical neurofibroma with onion bulbs in various stages of development and progression to microneurinomas is presented. Immunohistochemistry with differentiation and growth factor markers as well as electron microscopy showed a Schwann cell origin of the concentrically arranged cells. The onion bulbs differed from those of hypertrophic neuropathy by their more compact structure. A partial expression of cellular proliferation markers in the onion bulbs was consistent with a multifocal proliferative activity, confirming the neoplastic nature of the lesion.

Vascular permeability changes in tumours of the peripheral nervous system.

Vascular permeability changes were examined in 34 tumours of the peripheral nervous system by immunohistochemical demonstration of serum proteins as endogenous tracers. The blood-tumour barrier was impaired in the reticular (Antoni type B) portions of neurinomas (Schwannomas) and in cutaneous neurofibromas but was similar to the normal blood-nerve barrier in fibrillary (Antoni type A) neurinomas, in most neurofibromas, in ganglioneuromas and in anaplastic tumours. These differences in permeability are discussed in relation to aspects of pathological tumour vascularization, the histogenesis of microcystic changes, and systemic therapeutic approaches.

Gliofibroma: immunohistochemical analysis.

A case of gliofibroma occurring in an adult patient as a large circumscribed supratentorial tumor is reported. The bimorphic pattern was substantiated and further analyzed by immunohistochemistry. Some evidence in favor of collagen production by mesenchymal and/or inflammatory cells leading to a progressive fibrous replacement of the glial cells in this particular tumor type is presented.

Basic fibroblast growth factor and somatomedin C in human medulloepithelioma.

Two published cases of medulloepithelioma, a rare malignant pediatric brain tumor composed of a mixture of primitive neuroepithelium and its differentiated neuronal and glial descendants, were examined by immunohistochemical staining for the presence of growth factors. From a panel of antibodies, those identifying basic fibroblast growth factor and insulin-like growth factor I, formerly known as somatomedin C, were strongly immunoreactive within the neuroepithelial cell population of the tumors. Immunoblots of purified recombinant basic fibroblast growth factor and insulin-like growth factor I showed antibody specificity without cross-reactivity. In controls, immunostaining of tissue sections was abolished by preabsorption of primary antibodies with the appropriate growth factor polypeptide antigen. Preabsorption with inappropriate growth factor did not reduce the intensity or alter the distribution of staining. The congruent histologic patterns of immunoreactivities suggest that more than one type of growth factor may be produced by the neuroepithelial component of medulloepithelioma. These growth factors may stimulate proliferation and differentiation of tumor cells by autocrine molecular mechanisms.

The brain in the 18q-syndrome.

The authors describe the cerebral neuropathological findings of a 25 1/2-year-old male with 18q-syndrome. An abnormal gyral pattern, atrophy of the olfactory and optic nerves and small neocerebellar hemispheres with hemispheral lobular sclerosis were noted. Microscopically there were pial glioneuronal heterotopias; misplacement of neurons in the molecular layer of the cortex, as well as in deep white matter; not readily identifiable Betz cells; gliosis of olfactory and optic tracts and elsewhere; and loss of Purkinje cells. Further detailed studies of other cases are needed to determine whether these abnormalities are characteristic of the 18q-syndrome.

Aqueductal atresia as a feature of arhinencephalic syndromes.

Two cases are presented of aqueductal atresia associated with arhinencephalic syndromes. The first case was one of semilobar holoprosencephaly with occipital encephalocele, the second one of lobar holoprosencephaly (callosal agenesis with interhemispheric cyst). Only the second case was associated with obstructive hydrocephalus. The absence of hydrocephalus in the first case may be ascribed either to the greater distensibility of the encephalocele, or to the displacement of the choroid plexuses from the intracranial portion of the common ventricle into the hernial sac.

Focal neuronal gigantism and cerebral cortical thickening after therapeutic irradiation of the central nervous system.

An exceptional type of cortical dysplasia is described in the brain of a 32-year-old woman who had received radiation therapy for a large pituitary adenoma 6 years before death. Markedly thickened gyri of the left inferior frontal, insular, and temporal cortex were found grossly. Microscopically, these gyri showed laminar disorganization and many unusually large and abnormally shaped ganglion cells. These neurons were heavily impregnated with silver preparations; were strongly reactive for neuron-specific enolase, synaptophysin, and neuronal cytoskeletal proteins (68- and 200-kd subunits of neurofilament protein, microtubule-associated protein 2, and tau); and ultrastructurally contained numerous perikaryal neurofilaments. Collectively, these findings suggest that the abnormally large, misshapen neurons contained excessive accumulations of cytoskeletal intermediate filaments. The present case and a similar one described in 1964 are the only two documented instances of neuronal gigantism apparently related to therapeutic irradiation of the brain.

Absence of septum pellucidum and polymicrogyria: a forme fruste of the porencephalic syndrome.

Two cases are presented of absence of the septum pellucidum associated with bilateral polymicrogyria. In one case a circumscribed, completely enclosed cavity was present in the white matter of one cerebral hemisphere, different in structure from typical prenatal porencephaly. It is suggested that these cases represent a "forme fruste" of the syndrome of absent septum, bilateral porencephaly, polymicrogyria and heterotopia and may be ascribed to a similar, if less severe, encephaloclastic process of debatable etiology, operating around the midterm of pregnancy.

Aqueductal obstruction in sarcoidosis.

A 50-year-old woman presented with a severe obstructive hydrocephalus, only temporarily relieved by shunts. The diagnosis of sarcoidosis was suspected but never proven. Autopsy revealed multisystem sarcoidosis as well as widespread involvement of the CNS. The cause of hydrocephalus was established as occlusion of the aqueduct by subependymal granulomas and massive gliosis obliterating the lumen.

Hemimegalencephaly, hemifacial hypertrophy and intracranial lipoma: a variant of neurofibromatosis.

A case is presented of a 30-year-old, mentally retarded and epileptic patient, with a progressive hemifacial hypertrophy since birth. Repeated biopsies revealed the neurofibromatous nature of her facial lesion. Autopsy also revealed an ipsilateral hemimegalencephaly, as well as meningeal lipomas and osteomas. This combination of lesions represents an unusual variant within the spectrum of neurofibromatosis.

Epidermal growth factor receptor in meningiomas is expressed predominantly on endothelial cells.

The immunohistochemistry of the epidermal growth factor receptor (EGFR) was studied with monoclonal antibodies in 12 meningiomas of various histologic subtypes, nine benign and three malignant. Strong immunoreactivity of EGFR epitopes was found in the endothelia of the tumor vasculature in six cases. A much weaker reaction was detected within tumor cells in six cases, in one of which it was diffuse and five focal. No correlation was established between the presence of EGFR epitopes and the histologic type or biologic behavior of the meningiomas. The results suggest that the EGFR may participate in tumor angiogenesis, but its role in the growth of neoplastic meningioma cells remains elusive.

Ectopic midline spinal ganglion in diastematomyelia: a study of its connections.

The connections of an ectopic midline spinal ganglion associated with an asymptomatic sacral diastematomyelia were studied. The ganglion was intercalated in the ventral root of one hemicord and sent its efferents to the dorsal root of the other hemicord. The afferents joined the anterior root to form a midline intradural spinal nerve in the cauda equina. Islands of ectopic glia were present in both roots and the spinal nerve. Both the midline position of the ganglion and the glial heterotopias can be tentatively explained by the failure of incorporation of the dorsal cell wedge ("Zwischenstrang") into the divided neural tube.