The national DBS brain tissue network pilot study: need for more tissue and more standardization.

Over 70,000 DBS devices have been implanted worldwide; however, there remains a paucity of well-characterized post-mortem DBS brains available to researchers. We propose that the overall understanding of DBS can be improved through the establishment of a Deep Brain Stimulation-Brain Tissue Network (DBS-BTN), which will further our understanding of DBS and brain function. The objectives of the tissue bank are twofold: (a) to provide a complete (clinical, imaging and pathological) database for DBS brain tissue samples, and (b) to make available DBS tissue samples to researchers, which will help our understanding of disease and underlying brain circuitry. Standard operating procedures for processing DBS brains were developed as part of the pilot project. Complete data files were created for individual patients and included demographic information, clinical information, imaging data, pathology, and DBS lead locations/settings. 19 DBS brains were collected from 11 geographically dispersed centers from across the U.S. The average age at the time of death was 69.3 years (51-92, with a standard deviation or SD of 10.13). The male:female ratio was almost 3:1. Average post-mortem interval from death to brain collection was 10.6 h (SD of 7.17). The DBS targets included: subthalamic nucleus, globus pallidus interna, and ventralis intermedius nucleus of the thalamus. In 16.7% of cases the clinical diagnosis failed to match the pathological diagnosis. We provide neuropathological findings from the cohort, and perilead responses to DBS. One of the most important observations made in this pilot study was the missing data, which was approximately 25% of all available data fields. Preliminary results demonstrated the feasibility and utility of creating a National DBS-BTN resource for the scientific community. We plan to improve our techniques to remedy omitted clinical/research data, and expand the Network to include a larger donor pool. We will enhance sample preparation to facilitate advanced molecular studies and progenitor cell retrieval.

Diffusion tensor microscopy indicates the cytoarchitectural basis for diffusion anisotropy in the human hippocampus.

BACKGROUND AND PURPOSE: Observing changes to water diffusivity and fractional anisotropy (FA) for particular hippocampal regions may improve the sensitivity and specificity of diffusion tensor MR imaging for hippocampal pathologies like Alzheimer disease and mesial temporal sclerosis. As a first step toward this goal, this study characterized the cytoarchitectural features underlying diffusion anisotropy in human hippocampus autopsy specimens at 60-microm in-plane resolution. MATERIALS AND METHODS: Eight-millimeter coronal segments of the hippocampal body were dissected from 5 autopsy specimens (mean = 55.6 +/- 6.2 years of age) with short postmortem intervals to fixation (21.2 +/- 5.7 hours) and no histologic evidence of neuropathology. Diffusion tensor microscopy data were collected from hippocampal specimens by using a 14.1T magnet with a protocol that included 21 unique diffusion gradient orientations (diffusion time = 17 ms, b = 1250 s/mm(2)). The resulting images were used to determine the mean diffusivity, FA, and principal fiber orientation for manually segmented hippocampal regions that included the stratum oriens, stratum radiatum, stratum pyramidale (CA1 and CA3), stratum lacunosum-molecular, hilus, molecular layer, granule cell layer, fimbria, and subiculum. RESULTS: Diffusion-weighted images had high signal-to-noise ratios (31.1 +/- 13.0) and delineated hippocampal anatomy well. Water diffusivity ranged from 1.21 +/- 0.22 x 10(-4) mm(2)/s in the fimbria to 3.48 +/- 0.72 x 10(-4) mm(2)/s in granule cells (analysis of variance, P<.001). Color fiber-orientation maps indicated the underlying microstructures responsible for diffusion anisotropy in the hippocampal lamina. CONCLUSION: Diffusion tensor microscopy provided novel microstructural information about the different lamina of the human hippocampus. These ex vivo data obtained at high-magnetic-field strengths can be used to study injury-specific diffusion changes to susceptible hippocampal regions and may lead to more specific MR imaging surrogate markers for Alzheimer disease or epilepsy.

Characterization of a primary central nervous system atypical teratoid/rhabdoid tumor and derivative cell line: immunophenotype and neoplastic properties.

Primary central nervous system (CNS) atypical teratoid/malignant rhabdoid tumors (ATT/RhT) occur during early childhood and are almost invariably fatal. Expression of multiple phenotypes in ATT/RhT suggests the presence of an undifferentiated progenitor with the potential to differentiate along multiple lines. These properties have made it difficult to characterize the etiology and histogenesis of these tumors and complicate efforts to develop targeted therapies. This paper characterizes the immunophenotype of a human CNS ATT/RhT and describes the properties of a derivative cell line (Atrt95) which retained morphological and immunochemical characteristics of the parent tumor including diverse differentiation. Most tumor cells were strongly immunoreactive for glial fibrillary acidic protein, vimentin and A2B5. Scattered, large tumor cells that showed a rhabdoid phenotype were immunoreactive for synaptophysin. The morphology of cultured Atrt95 cells was heterogeneous, but often fit into 1 of 3 classes that appeared to correspond to cell populations observed within the parent tumor including: 1) tightly-packed small-cell colonies, 2) large, well-spread highly motile cells and 3) arrays of elongated cells. In vitro assays demonstrated that growth of the entire culture was anchorage-dependent but not serum-dependent. Transplantation of Atrt95 cells into the rat spinal cord resulted in tumor growth and CNS invasion. Preliminary cytogenetics study revealed complex aneuploidy but no apparent monosomy or deletions of chromosome 22. The immunophenotype of this neoplasm and derivative cell line is consistent with a primitive glioneuronal lineage and its in vitro characteristics are that of an invasive malignancy similar to the naturally occurring tumor. This unique cell line (Atrt95) provides a valuable model to study the biology and genetics of the CNS ATT/RhT.

Expression of neurofilament proteins in the hypertrophic granule cells of Lhermitte-Duclos disease: an explanation for the mass effect and the myelination of parallel fibers in the disease state.

The expression of neurofilament (NF) proteins was examined in the surgical specimen from a 42-year-old woman with Lhermitte-Duclos disease. Hypertrophic granule cell neurons of the dysplastic tissues were reactive with monoclonal antibodies, including antibodies to each of the three human NF subunits. Furthermore, antibodies to dephosphorylation-dependent epitopes on NF proteins stained the cell bodies of hypertrophic granule cells, whereas antibodies to phosphorylation-dependent epitopes stained the enlarged and myelinated axons of the hypertrophic granule cells. Enzymatic dephosphorylation of this tissue abolished axonal staining with phosphorylation-dependent antibodies and uncovered determinants recognized by antibodies to the dephosphorylated state of NF proteins. The NF protein immunoreactivity of hypertrophic granule cells was indistinguishable from that of large, NF-rich neurons in control human cerebellum, suggesting that a normal pattern of expression and phosphorylation of NF proteins occurs in hypertrophic granule cells in Lhermitte-Duclos disease. An increased expression of NF proteins by cerebellar granule cells may account for many of the observed alterations of Lhermitte-Duclos disease, including the hypertrophy of the granule cells and enlargement of their axons, leading to the myelination of parallel fibers within the molecular layer of the cerebellum. Attention should now be directed at the underlying mechanisms which lead to the coordinated up-regulation of the three NF genes and whether or not additional gene products or cell types are altered in Lhermitte-Duclos disease.

Cerebellar dysplasias in humans: development and possible relationship to glial and primitive neuroectodermal tumors of the cerebellar vermis.

Cerebellar dysplasias are commonly found in the white matter and nodulus of the vermis in newborns and are particularly prominent in infants with trisomy 13-15 and trisomy 18 syndromes. Little is known of the developmental biology of these structures. We have studied the development of cerebellar dysplasias in human fetuses ranging from 15 to 32 weeks gestational age and from 11 days to 15 months postnatal. The expression of developmentally regulated neuronal and glial polypeptides was investigated by immunohistochemistry using a panel of extensively characterized monoclonal antibodies. Dysplasias were first observed at 15 weeks gestation as irregularly distributed, parenchymal or perivascular clusters of primitive cells in the inferior vermis. These cell clusters resembled primitive neuroepithelial cells or cells of the cerebellar external granule cell layer and they persisted into postnatal life. They retained the capacity to undergo cell division and were weakly reactive for the low affinity nerve growth factor receptor but were negative for all other neuronal or glial proteins at all gestational ages. At about 20 weeks gestation, cerebellar dysplasias become more complex with the appearance of ganglion cells which matured histologically and phenotypically in parallel with normal dentate neurons and Purkinje cells. These dysplasias often contained a prominent glial component which was identified by immunostaining for glial fibrillary acidic protein. Our findings suggest that midline cerebellar dysplasias are normal variants of development. Whether the mitotically active cells comprising these dysplasias are targets for neoplastic transformation into cerebellar primitive neuroectodermal tumors or other types of childhood tumors such as pilocytic astrocytomas or atypical teratoid/rhabdoid tumors remains speculative.

Distinct neurodevelopmental patterns of bcl-2 and bcl-x expression are altered in glioneuronal hamartias of the human temporal lobe.

Bcl-2 and bcl-xL are homologous proteins that inhibit cell death and are expressed in the nervous system. We tested the hypothesis that aberrant expression of such "death suppressor" molecules may promote the survival of abnormal cells in glioneuronal lesions associated with temporal lobe epilepsy. The normal pattern of bcl-2 and bcl-x expression was studied in postmortem human fetal and adult temporal lobes. Formalin-fixed, paraffin-embedded tissue sections were probed for bcl-2 and bcl-x in immunohistochemical studies using well-characterized primary antibodies that had been raised against epitopes that are not shared by these proteins. Strong staining for both proteins was observed in the ventricular zone and in migrating, postmitotic and postmigratory young neurons of the neocortex, hippocampus, and entorhinal cortex from 6 to 20 weeks gestational age (GA). However, bcl-2 immunoreactivity gradually decreased to weak or nondetectable levels between 20 and 39 weeks GA, while strong bcl-x staining of neurons persisted throughout fetal development and into adulthood. Twenty-eight temporal lobe resections from children and adults ranging in age from 1 to 45 years (mean=19 years) with intractable epilepsy were then screened for differences in the pattern of bcl-2 and bcl-x expression compared to normal controls. Bcl-2 (but not bcl-x) was strongly immunoreactive in small, immature-appearing cells that were components of microscopic glioneuronal aggregates (hamartias) and that have been shown previously to express an embryonic form of the neural cell adhesion molecule. These immature cells were immunonegative for standard markers of neuronal and glial lineage and were negative for Ki67, suggesting that they are post-mitotic. The persistent expression of bcl-2 and apparent downregulation of bcl-x in these cells represent deviations from the normal ontogeny of these molecules in the human nervous system. These data suggest that dysregulation of bcl-2 and related proteins may be involved in the pathogenesis of some temporal lobe malformative lesions.

Bcl-2 immunoreactive cells with immature neuronal phenotype exist in the nonepileptic adult human brain.

Bcl-2, a cell death suppressor protein, is expressed during brain development but is largely down-regulated in the adult central nervous system. We previously reported strong expression of bcl-2 in small, "oligodendrocyte-like" cells (OLC) found in glioneuronal hamartias. These hamartias are microscopic cell rests found in temporal lobe resections from patients with intractable epilepsy and are considered a form of cerebral microdysgenesis. However, a causative relationship between these rests and seizures is not clear. We now report the identification, lineage characterization, and postnatal ontogeny of hamartia-like cell rests in temporal lobes of nonepileptic humans. Postmortem temporal lobes from 28 patients without history of neurologic disease (mean age = 53 years; range = 20 to 83 years) were studied. Microscopic cellular aggregates containing immature-appearing, bcl-2-immunoreactive cells (BIC) (identical to OLC) were observed in 23 of 28 (82%) temporal lobes from nonepileptic individuals. BIC were strongly immunoreactive for neuronal-specific class III beta tubulin, neuronal nuclear antigen, and MAP-2, but were consistently negative for neurofilament proteins and Ki67. Such cells were localized to subventricular regions of the caudal amygdala and often extended into the adjacent subcortical white matter and periamygdaloid cortex. BIC became less abundant with advancing age. These findings suggest that hamartia-like rests containing immature postmitotic neurons are normally present in the human brain and that glioneuronal hamartias may not always represent a maldevelopmental lesion associated with epilepsy.

Expression of neuronal and glial polypeptides during histogenesis of the human cerebellar cortex including observations on the dentate nucleus.

In order to gain a more complete understanding of the sequential pattern of gene expression during neurogenesis and gliogenesis in humans, we followed the expression of well-characterized, developmentally regulated polypeptides in the cerebellar cortex and dentate nucleus by immunohistochemistry using monoclonal antibodies of highly defined specificity. At 8-10 weeks gestational age (GA), progenitor cells and their immediate progeny in the rhombencephalic ventricular zone expressed vimentin and nestin and, to a lesser extent, microtubule-associated protein 5 (MAP5) and glial fibrillary acidic protein (GFAP), but not the low affinity nerve growth factor receptor (NGFR). In contrast, postmitotic, migrating immature neurons in the intermediate zone gave strong reactions for MAP2, tau, and a nonphosphorylated form of middle molecular weight neurofilament (NF) protein (NF-M) and weak reactivity for NGFR. At 15 weeks GA, proliferating cells of the superficial part of the cerebellar external granular layer stained only for NGFR, while more deeply situated cells of the external granular layer stained positively for NGFR, MAP2, MAP5, tau, and chromogranin A, which correlates with the early outgrowth of parallel fibers. All phosphoisoforms of NF-M as well as the low (NF-L) and high (NF-H) molecular weight NF proteins and alpha-internexin were expressed in the somatodendritic domain of Purkinje cells and dentate nucleus neurons from about 20 weeks GA with a gradual compartmentalization of highly phosphorylated forms of NF-M and NF-H into axons by the end of gestation. Alpha-internexin was also expressed strongly in axons of the deep white matter from 20 weeks GA to adulthood. MAP2, synaptophysin, and NGFR showed early, transient expression in the somatodendritic domain of Purkinje cells followed by the appearance of a 220 kDa nestin-like peptide that continued to be expressed in adult Purkinje cells. Notably, developing dentate nucleus neurons expressed many of these proteins in a similar temporal sequence. Early in the developing cerebellar cortex, the expression of NF protein and synaptophysin occurred in discrete patches or columns similar to those described for other antigens (i.e., zebrins). Finally, radial glia were positive for vimentin, GFAP, and nestin from 8 weeks GA to 8 months postnatal. This study describes the distinct molecular programs of lineage commitment in cerebellar progenitor cells and in differentiating neurons and astrocytes of the human cerebellum. The acquisition of a mature molecular neuronal phenotype correlates with the establishment of structural polarity in cerebellar neurons.

Divergent differentiation in pleomorphic xanthoastrocytoma. Evidence for a neuronal element and possible relationship to ganglion cell tumors.

We report the detection of cytoplasmic immunoreactivity for neuronal/neuroendocrine antigens in a subpopulation of tumor cells within seven pleomorphic xanthoastrocytomas (PXAs). The expression of glial and neuronal polypeptides was examined in routinely prepared surgical resections by immunohistochemistry using well-characterized antibodies that recognize glial fibrillary acidic protein (GFAP), synaptophysin (SYN), and neurofilament triplet polypeptides (NFPs) in microwave-enhanced single- and double-immunolabelling experiments. Each neoplasm contained cells that were immunoreactive for SYN and/or NFPs, GFAP, and occasionally for both GFAP and either NFP or SYN. We conclude that abortive neuronal/neuroendocrine differentiation may occur in PXAs, suggesting a relationship between PXA and other developmental neoplasms that reveal a more overt neuronal phenotype, such as ganglioglioma, dysembryoplastic neuroepithelial tumor, and desmoplastic ganglioglioma, and with tumors expressing ambiguous glial/neuronal lineage, such as the subependymal giant cell tumor of tuberous sclerosis. These findings suggest that aberrant expression and accumulation of neuronal intermediate filaments may account for the large, pleomorphic cell morphology observed in many of these tumors.

Desmoplastic primitive neuroectodermal tumor with divergent differentiation. Broadening the spectrum of desmoplastic infantile neuroepithelial tumors.

We report an unusual large, multicystic, posterior fossa neuroepithelial neoplasm involving the cerebellum, brain-stem, and quadrigeminal cistern of a 9-month-old girl. The neoplasm consisted of variably sized, sharply demarcated nests of small cells with a high nuclear-cytoplasmic ratio and moderately basophilic nuclei, embedded in a desmoplastic, immature-appearing, mesenchymal stroma. The nests contained mitoses but none were seen in the stroma. Glial fibrillary acidic protein (GFAP), neurofilament protein, synaptophysin, and cytokeratin (AE-1) were expressed in the nests. Mesenchymal cells were negative for neural markers but positive for vimentin and desmin. The neoplasm was interpreted as a mixed mesenchymal and primitive neuroectodermal tumor (PNET) with histologic features reminiscent of a recently described intraabdominal desmoplastic small cell tumor. The tumor responded poorly to chemotherapy and a second operation was performed 1 year later. The second specimen bore no resemblance to the original and consisted of epithelial-like nests and clusters of neoplastic cells frequently interrupted by sinusoidal vessels. Tumor cells had medium-sized vesicular nuclei with small nucleoli, and a granular cytoplasm. Occasional less cellular islands of neuropil-like tissue contained larger cells having eccentric, vesicular nuclei with prominent nucleoli and abundant pink cytoplasm. Mitoses were not conspicuous. Many cells expressed synaptophysin, neurofilament protein, and GFAP. Neurofilament protein was strongly positive in the larger, neuron-like cells and synaptophysin stained the neuropil-like areas strongly but was less prominent in the neuronal perikarya. Unexpectedly, the neuropil-like areas expressed epithelial membrane antigen, whereas the neuronal cells were negative for chromogranin A. The peculiar histologic picture, combination of phenotypic markers, and remarkable biologic behavior of this unusual tumor defies classification according to existing nomenclature and exemplifies the broad range of phenotypes expressed by primitive neuro-epithelial neoplasms.

Composite pleomorphic xanthoastrocytoma and ganglioglioma: report of four cases and review of the literature.

Composite pleomorphic xanthoastrocytoma (PXA)-ganglioglioma (GG) is a rare recently described entity. Only three examples have been documented, one of which showed evidence of malignant transformation. We report an additional four cases and update the literature. With the exception of an 82-year-old man, all patients have been under 30 years of age. The temporal lobe was involved in three cases and cerebellum in another three. Radiologic features were those common to PXA and GG. Histologically, all were "collision tumors" composed of abutting, although spatially distinct, PXA and GG components. In two cases, the second element was only recognized at reexcision or recurrence. Histologic anaplasia, always in the PXA component, was evident as brisk mitotic activity and/or necrosis in five cases. Of the seven patients, one died of disease 17 years after the onset of seizures and after multiple recurrences, the last of which largely resembled glioblastoma. We conclude that the composite PXA-GG is a rare neoplasm that shares many features of its individual components. In addition to its temporal lobe predilection, the cerebellum is frequently affected. As when it occurs in isolation, the PXA component of composite PXA-GG possesses the potential for malignant transformation.

Aggressive uterine sarcoma with rhabdoid features: diagnosis by peritoneal fluid cytology and absence of INI1 gene mutation.

We report a primary uterine sarcoma with classic histologic, immunohistochemical, and ultrastructural features of a malignant extrarenal rhabdoid tumor (MERT). It arose in a 71-year-old woman who presented with postmenopausal bleeding, ascites, and a right pelvic mass. Malignant cells with rhabdoid morphology were identified by cytologic examination of the peritoneal fluid. Exploratory laparotomy revealed a 10-cm right adnexal mass and disseminated peritoneal tumor. Pathologic study showed diffuse expansion of the endometrial stroma by rhabdoid-like cells with transmural infiltration of the myometrium and extensive involvement of uterine serosa and right ovary by tumor. Neoplastic cells were immunoreactive for vimentin, cytokeratin, and epithelial membrane antigen, and cytoplasmic whorls of intermediate filaments were observed by electron microscopy. Fluorescence in situ hybridization (FISH) studies with chromosome 22-specific probes showed no loss of the INI1 gene, and no coding sequence mutation was identified.

Disseminated microsporidiosis especially infecting the brain, heart, and kidneys. Report of a newly recognized pansporoblastic species in two symptomatic AIDS patients.

Microsporidia have emerged as important opportunistic AIDS pathogens of the alimentary, respiratory, and urinary tracts. Although nonhuman mammalian microsporidia infections typically include encephalitis, CNS microsporidiosis has not been reported in patients with AIDS. A 33-year-old white male and an 8-year-old black girl presented with seizures and declining mental status. Central nervous system (CNS) imaging studies revealed small peripherally and diffusely enhancing lesions present for at least 2 and 4 months before death, respectively. Both patients expired despite empirical anti-toxoplasma therapy. Their brains contained innumerable soft gray matter lesions that consisted of central areas of necrosis, filled with free spores and spore-laden macrophages, surrounded by microsporidia-infected astrocytes. The complete autopsy of the child also revealed necrotizing and sclerosing cardiac and renal microsporidiosis and infection of the pancreas, thyroid, parathyroids, liver, spleen, lymph nodes, and bone marrow. Infected cells included astrocytes, cardiac myocytes, epithelium, endothelium, vascular smooth muscle cells, hepatocytes, adipocytes, Schwann cells, and macrophages. Light and electron microscopic studies revealed pansporoblastic development within thick-walled sporophorous vacuoles of parasite origin. Although most similar to Pleistophora sp and Thelohania sp, this microsporidian is different from any known species. Microsporidiosis should be considered as the possible cause of a wide range of diseases in AIDS patients, including CNS, cardiac, and renal.

Studies of childhood brain tumors using immunohistochemistry and microwave technology: methodological considerations.

The immunohistochemical detection of antigens in archival tissue sections has been hampered by the poor reactivity of certain polypeptides in conventional formalin-fixed, paraffin-embedded material. For example, the poor reactivity of neurofilament proteins (NFPs) in surgical and autopsy specimens has been a major drawback of previous large, retrospective, clinicopathologic studies of pediatric primitive neuroectodermal tumors (PNETs), also known as medulloblastomas. We report our experience with a method of antigen retrieval which greatly enhanced the immunohistochemical detection of neuronal and glial intermediate filament proteins, retinal S-antigen (RSA), and the proliferating cell nuclear antigen (PCNA) in archival, paraffin-embedded, formalin or Bouin's-fixed, pediatric brain tumors, particularly PNETs. The technique involves adding a single brief step to an established avidin-biotin complex (ABC) immunohistochemical protocol (Vectastain Elite Kit). This step involves boiling tissue sections in distilled water for 5 min in a microwave oven. The specificity of staining was consistent with known cell and tissue specificities of the well-characterized monoclonal antibodies used and there was minimal background. Synaptophysin (SYN) staining was unaffected by heating and immunoreactivity of the low affinity nerve growth factor (p75NGFR) and the neural cell adhesion molecule (NCAM) were lost. The enhanced detection of neuronal and glial antigens in routinely prepared, formalin-fixed, archival material should facilitate large retrospective clinicopathologic studies designed to assess the prognostic implications of differentiation in PNETs and to better understand the biology of these tumors.

Mitogenic effect of myelinated vs unmyelinated garfish nerve extracts.

Mitogenic activities in crude extracts of unmyelinated olfactory nerves and myelinated trigeminal nerves of the garfish Lepisosteus osseus were compared. Extracts of each nerve type were added in a range of protein concentrations to serum-starved, subconfluent cultures of BALB/c 3T3 cells. At low protein concentrations (50-250 micrograms/ml) myelinated nerve extracts produced more [3H]thymidine incorporation in the cultured cells than unmyelinated nerve extracts, while at higher concentrations (500-1000 micrograms/ml), the latter caused as much DNA synthesis as the myelinated nerve extracts, surpassing them at the highest concentrations tested. The results suggest that both axonal and myelin components contribute to the growth-promoting activity in nerve tissue.

Isolated extranodal intracranial sinus histiocytosis in a 5-year-old boy. Case report.

Sinus histiocytosis with massive lymphadenopathy was first described in 1969 by Rosai and Dorfman. The typical clinical characteristics of this disease include painless cervical lymphadenopathy, fever, and weight loss. The condition can present with an extranodal mass in about 25% of patients, and isolated masses without lymph node involvement occur rarely. The authors describe a 5-year-old boy with cavernous sinus syndrome due to an isolated extranodal form of sinus histiocytosis with massive lymphadenopathy in the temporal fossa. Several cases of this disease involving the central nervous system are reviewed. The histopathological and magnetic resonance imaging characteristics are discussed.

Central nervous system medulloepithelioma: a series of eight cases including two arising in the pons.

Medulloepithelioma is an uncommon childhood tumor of the central nervous system (CNS) whose histopathological appearance has been confused with medulloblastoma and other childhood primitive neuroectodermal tumors (PNETs), but which has a vastly different clinical course. The authors have reviewed the clinical features and treatment responses of eight children with these rare tumors, the largest series to date. In this series, the medulloepitheliomas were equally distributed between supratentorial and infratentorial primary sites. Four patients underwent gross- or near-total resections, one patient's tumor was partially resected, and one patient had biopsy only. Biopsy and ablative surgery were not attempted in two children with pontine tumors. Treatment included both radiation and chemotherapy (four patients), radiation alone (one patient), chemotherapy alone (one patient), and no post-operative treatment (two patients). Six patients died with a mean survival of 10 months and two are disease free with neurological impairment. Both long-term survivors underwent gross-total resections of their tumors. Postmortem examination revealed diffuse CNS tumor dissemination in four patients. Medulloepithelioma, often confused with less aggressive PNETs, can mimic intrinsic brainstem glioma, responds poorly to treatment, and is prone to CNS dissemination at the time of tumor progression.

The antagonism of bombesin in the CNS by substance P analogues.

The ability of substance P analogues to inhibit the action of bombesin in the CNS was investigated using receptor binding and biological assays. The putative substance P antagonists inhibited binding to central receptors for both substance P and bombesin-like peptides. Spantide, which was the most potent analogue tested, reversed the bombesin induced hypothermia and grooming. Therefore the putative substance P antagonists may also antagonize the actions of bombesin in the CNS.

Rapidly progressive dementia: a clinicopathologic correlation.

We evaluated a 66-year-old man with a rapidly progressive, akinetic-rigid dementia syndrome. Despite extensive testing, which included magnetic resonance imaging (MRI), we were unable to make the correct antemortem diagnosis. Autopsy demonstrated spontaneous progressive multifocal leukoencephalopathy. This report illustrates that even in the absence of characteristic MRI findings, this uncommon cause of dementia should be considered in the differential diagnosis of rapidly progressive, akinetic-rigid syndromes with dementia.

Cerebellar and brainstem development: an overview in relation to Joubert syndrome.

An overview of cerebellar and brainstem development is provided as a foundation for suggesting hypotheses about developmental defects in Joubert syndrome. Although neuropathologic studies of Joubert syndrome are rare, and the spectrum of brain pathology is not yet known, consistent findings include agenesis of the cerebellar vermis and hypoplasia or fragmentation of several brainstem nuclei (including dentate nuclei, inferior olives, and basis pontis), nuclei and tracts of cranial nerve V, solitary nuclei and tracts, and nuclei gracilis and cuneatus. Two aspects of cerebellar development might be important in the pathogenesis of Joubert syndrome: First, cerebellar development is regulated by a critical region of the embryo called the "midbrain-hindbrain organizer," and both mesencephalic and metencephalic elements take part in normal cerebellar development. While the metencephalon gives rise to the cerebellar hemispheres, the vermis is derived almost exclusively from the mesencephalon. This suggests that Joubert syndrome could involve an abnormality in formation of the pontomesencephalic junction (rhombomere 1). Second, the histogenesis of cranial nerve nuclei and brainstem structures derived from the embryonic rhombic lip (such as the inferior olives, neurons of the basis pontis, and arcuate nuclei) involves the formation, migration, and reorganization of nuclei and tracts during a critical period of development (6 to 8 weeks' gestation). Because these structures are abnormal in Joubert syndrome, an understanding of factors that regulate the proper formation and migration of cells that give rise to them could provide important clues about the pathogenesis of this disorder.