Expression of drebrin E in migrating neuroblasts in adult rat brain: coincidence between drebrin E disappearance from cell body and cessation of migration.

Migrating neuroblasts in the adult brain form the rostral migratory stream (RMS) from the lateral ventricle to the olfactory bulb (OB) and then differentiate in the OB. In this study, we immunohistochemically analyzed drebrin expression in the RMS of the adult rat brain. Although drebrin is concentrated in dendritic spines of mature neurons, drebrin-immunopositive (DIP) cell bodies were observed in the RMS. The polysialated form of a neural cell adhesion molecule (PSA-NCAM) was detected in DIP cells. K(i)-67, a marker of proliferating cells, was also detected in a subset of DIP cells; however, neither glial fibrillary acidic protein, nestin nor vimentin was detected in DIP cells. These results indicate that DIP cells in the RMS are migrating neuroblasts. An image subtraction method, based on using anti-pan-drebrin and anti-drebrin A antibodies, demonstrated that DIP migrating neuroblasts are immunopositive for drebrin E but not for drebrin A (E+A-). Furthermore, olfactory bulbectomy increased the number of cells with drebrin E+A- signals in the RMS, indicating that these cells migrate along the RMS. Drebrin E+A- cells were also found in the subgranular layer of the dentate gyrus and in the piriform cortex. Thus, detection of drebrin E+A- signals is useful for identifying migrating neuroblasts in the adult brain. In the OB, drebrin E+A- signals were observed in the cell bodies of migrating neuroblasts in the core region; however, only fibrous and punctate drebrin E+A- signals were observed in postmigratory neuroblasts at the outer layers. These data demonstrate that the disappearance of drebrin E+A- signals from the cell body coincides with the cessation of neuronal migration. The disappearance of drebrin E from the cell body may be a molecular switch for the cessation of migration in newly generated neuroblasts.

Pituitary adenomas treated by microsurgery with or without Gamma Knife surgery: experience in 122 cases.

The clinical outcome of 122 patients with pituitary adenomas treated by microsurgery and/or Gamma Knife radiosurgery (GKRS) was analyzed to evaluate patient selection criteria and the role of GKRS. Sixty-six resections were performed in 59 patients. All tumors were macroadenomas, except for 5 ACTH-producing adenomas. Twenty-four of the 31 hypersecreting adenomas showed normal serum hormone values after treatment. Postoperative complications were rhinorrhea, cranial nerve palsies, and a small thalamic infarct. GKRS was performed on 18 of the operated patients because of residual tumors, mostly in the cavernous sinus. Thirty-five of the 63 patients treated by GKRS were followed for more than 2 years. All adenomas except 2 were stable or had decreased in size. Eleven of 17 functioning adenomas showed normal serum hormone values after treatment. It is concluded that tumors that compress the optic pathway should be removed and that residual tumors in the cavernous sinus are good indications for radiosurgery.

The role of intravascular embolization prior to radiosurgery of cerebral arteriovenous malformations. from the standpoint of hemorrhage and early obliteration after gamma knife radiosurgery.

The role of intravascular embolization prior to radiosurgery of cerebral arteriovenous malformations was evaluated based on the basis of the results of gamma knife radiosurgery in relation to hemorrhage and early obliteration after treatment. Nine of 213 patients experienced hemorrhage 4 to 42 months after radiosurgery. All AVMs in these patients had dilated feeding arteries, and the flow of the AVM was rapid and/or high. An intranidal aneurysm was seen in one patient. Drainage of all AVMs consisted of a single and/or deep draining veins, and venous obstruction was found in six. Sixty-three of 87 patients followed for more than four years after radiosurgery were examined angiographically, and total obliteration of AVM was observed in 52 of them (82.5%). Early obliteration was found in 19 of the 34 patients examined within 12 months. The obliteration rate was significantly higher in slow- and low-flow AVMs (73.9%) than in rapid- and/or high-flow AVMs (18.2%). It is concluded that the role of intravascular embolization prior to radiosurgery is not only decreasing the size of the AVM but decreasing the risk of hemorrhage and shortening the latency period by decreasing their flow rate and flow volume.

Stimulation of L-type Ca2+ channel in growth cones activates two independent signaling pathways.

Although growth cones respond to various modulators of neurite outgrowth, such as neurotrophins, neurotransmitters, and cell adhesion molecules, the signal-transducing mechanisms for these modulators in growth cones are unclear. Since recent studies have suggested that the signals of these modulators are mediated by Ca2+ influx through L-type voltage-sensitive Ca2+ channels (VSCCs) in the growth cone, we examined L-type VSCC-dependent signaling pathways, using isolated growth cones (IGCs) from developing rat forebrains. Binding assays revealed that L-type VSCC is enriched in growth cone membrane and gradually decreased in amount developmentally, while N-type VSCC has the opposite tendency. In intact IGCs, Bay K 8644 (BK, an L-type agonist) induced much more rapid elevation of [Ca2+]i than that in adult synaptosomes. Ca2+-dependent phosphorylation of GAP-43 and MARCKS protein by protein kinase C (PKC) was enhanced in the IGC by BK, resulting in the release of these proteins from the membrane, which is consistent with our recent report. In addition, the Ca2+-dependent degradation of brain spectrin (fodrin) by calpain was also enhanced by BK or GABA, consequently inducing the release of alpha-actinin from the membrane skeleton of the growth cones. The activities of PKC and calpain were not inhibited by inhibitors of the other, indicating that these reactions occur independently. Our results suggest that Ca2+ influx through L-type VSCCs activates two distinct signaling branches, probably in the different domains of the growth cone, i.e., Ca2+-dependent phosphorylation of GAP-43 and MARCKS protein, and Ca2+-dependent degradation of brain spectrin and the release of alpha-actinin by calpain.

Treatment of unruptured arteriovenous malformations in the brain.

Clinical features and treatment results of 33 patients with unruptured arteriovenous malformations (AVMs) were evaluated. Nine AVMs were located in the frontal lobe, 8 in the motor cortex, 5 in the parietal lobe, 6 in the temporal lobe, 2 in the occipital lobe and 3 in other parts of the brain. Nine patients were treated with microsurgery and 24 with radiosurgery. Total extirpation of the AVM was performed in all 9 microsurgery patients. One patient with an AVM in the motor cortex experienced upper extremity weakness postoperatively. Eleven of 24 patients treated with radiosurgery had follow-up imaging studies. Obliteration was obtained in 8 patients and decreased size in 3. Complications included 1 patient with a hemiparesis and 1 with an AVM rupture prior to obliteration. The remaining 13 patients did not experience any complications over a mean period of 21.2 months. Microsurgery appears to be the best treatment for unruptured AVMs in non-eloquent areas. Radiosurgery is a safe, effective treatment for unruptured AVMs in eloquent areas, although a bleeding risk remains during the latency period prior to obliteration.

Regeneration of hemisectioned spinal cords with and without supporting materials.

Nerve regeneration in hemisectioned spinal cords with and without supporting materials was examined in rats. Cell migration and newly formed capillaries surrounded by laminin-positive materials appeared at the lesioned site 7 days postoperatively. Reactive astrocytes increased at the lesioned site and extended into the spinal cord within 3 weeks. However, cell reactions decreased by 4 weeks and a cavity formed at the lesioned site in all animals. Regenerated axons were found only proximal to the lesioned site at 4 to 8 weeks. In the presence of supporting material (sciatic nerve containing proliferated Schwann cells or membrane filter), no cavity formed in the spinal cord and glial reactions were modest around the supporting material. Regenerated axons with growth cones were observed in the supporting material. However, no regenerated axons penetrated into the distal part of the spinal cord. Spinal cord axons can regenerate in the presence of supporting materials, but appropriate microenvironments, such as those found in the injured sciatic nerve, are required for spinal axons to traverse a lesion and penetrate into the spinal cord.

Basal interhemispheric supra- and/or infrachiasmal approaches via superomedial orbitotomy for hypothalamic lesions: preservation of hypothalamo-pituitary functions in combination treatment with radiosurgery.

Although several approaches to the hypothalamus have been used, none is able to give full views of the hypothalamus. The risk of permanent morbidity for hypothalamo-pituitary functions is still high, especially in patients with craniopharyngioma. Basal interhemispheric supra-chiasmal or infra-chiasmal approaches via superomedial orbitotomy were developed for better visualization of the hypothalamus. Operative techniques and results, including combination treatment with radiosurgery, are reported. Twelve patients with tumors compressing the hypothalamus upward or extending into the III ventricle, or both, were operated on: 3 tumors were removed totally, 6 tumors subtotally and 3 tumors partially. Six patients received radiosurgery for residual tumor. Four patients with hypopituitarism preoperatively required oral corticosteroids and thyroid hormones postoperatively. The basal interhemispheric approach via superomedial orbitotomy is useful for better visualization of the hypothalamus and preservation of hypothalamo-pituitary functions.

Neurite formation induced in neuroblastoma cells and genetically altered non-neuronal cells.

Ultrastructural changes associated with neurite formation were examined in suitably cultured neuroblastoma cells (Neuro-2a) and drebrin (developmentally regulated brain protein) gene-transfected fibroblasts (L cells) in culture. Both neuroblastoma cells and fibroblasts initially were flattened and epitheloid, with many microspikes or microvilli diffusely distributed over their surfaces. Intracellular organelles were abundant and diffusely arranged. In the transformed state, both cell types were round to oval with long processes where microspikes were concentrated. A constant arrangement of surface and intracellular structures was apparent, though drebrin gene-transfected fibroblasts retained some of their original characteristics. Neurite formation programmed by genes may be initiated by environmental factors in neuroblastoma cells. Neurite-like processes in fibroblasts may be formed due to changes in microfilaments resulting from transfection of the drebrin (actin-binding protein) gene.

Gamma knife for glioma: selection factors and survival.

PURPOSE: To determine factors associated with survival differences in patients treated with radiosurgery for glioma. METHODS AND MATERIALS: We analyzed 189 patients treated with Gamma Knife radiosurgery for primary or recurrent glioma World Health Organization (WHO) Grades 1-4. CONCLUSION: The median minimum tumor dose was 16 Gy (8-30 Gy) and the median tumor volume was 5.9 cc (1.3-52 cc). Brachytherapy selection criteria were satisfied in 65% of patients. Median follow-up of all surviving patients was 65 weeks after radiosurgery. For primary glioblastoma patients, median survival from the date of pathologic diagnosis was 86 weeks if brachytherapy criteria were satisfied and 40 weeks if they were not (p = 0.01), indicating that selection factors strongly influence survival. Multivariate analysis showed that increased survival was associated with five variables: lower pathologic grade, younger age, increased Karnofsky performance status (KPS), smaller tumor volume, and unifocal tumor. Survival was not found to be significantly related to radiosurgical technical parameters (dose, number of isocenters, prescription isodose percent, inhomogeneity) or extent of preradiosurgery surgery. We developed a hazard ratio model that is independent of the technical details of radiosurgery and applied it to reported radiosurgery and brachytherapy series, demonstrating a significant correlation between survival and hazard ratio. CONCLUSIONS: Survival after radiosurgery for glioma is strongly related to five selection variables. Much of the variation in survival reported in previous series can be attributed to differences in distributions of these variables. These variables should be considered in selecting patients for radiosurgery and in the design of future studies.

A comparison of children with suprasellar germ cell tumors and craniopharyngiomas: final height, weight, endocrine, and visual sequelae after treatment.

BACKGROUND: Although treatment results of craniopharyngiomas and germ cell tumors in children have been reported extensively, the relationship between various posttreatment sequelae and the nature of the tumor is not well understood. METHODS: From 1968-94, 47 children with 23 suprasellar germ cell tumors and 24 craniopharyngiomas were treated at Gunma University Hospital, Japan. Forty survivors were assessed with regard to Karnofsky scores, visual scores, final height, final weight, and other endocrine sequelae as long-term functional prognostic indicators. RESULTS: Kaplan-Meier life-table estimates and Karnofsky scores were not significantly different between the two histologic groups. The visual function of survivors did not differ significantly at diagnosis. However, the final visual function following treatment in the germ cell tumor group was better than in the craniopharyngioma group (p < 0.05). Antidiuretic hormone secretion was significantly impaired at diagnosis in the germ cell tumor group (p < 0.0001). However, there was only a marginally significant difference in posttreatment persistent diabetes insipidus. Craniopharyngioma children were shorter and more obese at diagnosis (p < 0.02), and became much more obese than germinoma children with the same hormone therapy (p < 0.003), although the height difference became insignificant following growth hormone treatment. CONCLUSIONS: Children with craniopharyngiomas tended to have more visual disturbances, increased dwarfism and obesity, and less diabetes insipidus than patients with germ cell tumors despite adequate therapy. The method of quantifying visual function may in itself be useful.

Peripheral nerve regeneration in a silicone tube: effect of collagen sponge prosthesis, laminin, and pyrimidine compound administration.

Regeneration of transected peripheral nerve with a 10-mm gap encased in a silicone tube was evaluated in the presence of collagen sponge with or without laminin, or with systemic administration of a pyrimidine compound, MS-818. The sciatic nerve of 20 adult rats was transected and the proximal and distal nerve stumps were fixed in a silicone tube. The lumen of the silicone tube was empty, or filled with a collagen sponge alone or with a laminin-soaked collagen sponge. Also, a pyrimidine compound was injected intraperitoneally after implantation of the empty silicone tube. Three weeks later, the contents of the silicone tubes were processed for histological examination of regenerated nerve fibers. Other animals were observed 6, 12, and 18 months after surgery to examine the long-term effects of the collagen sponge on nerve regeneration. All animals had regenerated tissue within the tube 3 weeks after nerve transection. The diameter of the tissue decreased toward the distal stump in the empty tube, but was the same throughout the full length in the collagen sponge-containing tube. Immunohistochemical studies revealed that the nerve fibers extended beyond the midline of the regenerated tissue in animals treated with a laminin-containing collagen sponge or receiving a pyrimidine compound. Long-term observation showed the regenerated nerve was thick as the proximal stump and many neurofilament- and peripheral myelin-positive fibers were observed around the collagen sponge. Collagen sponge assists the progress of regenerated tissues in silicone tubes, and laminin-containing prostheses and administration of a pyrimidine compound enhance peripheral nerve regeneration.

Intracranial hypoglossal neurinoma without preoperative hypoglossal nerve paresis--case report.

A 46-year-old female presented with an intracranial hypoglossal neurinoma manifesting only as spasticity in the lower extremities without hypoglossal nerve paresis. Magnetic resonance imaging greatly aided in the early detection of the tumor with this atypical presentation. Unilateral suboccipital craniotomy with resection of the occipital condyle allowed us to approach the tumor in front of the medulla from an inferolateral direction and to remove it successfully. We emphasize the need to pack dead space with fatty tissue to prevent cerebrospinal fluid leakage.

Pathobiology of cerebral gliomas in children and the role of radiosurgery.

Twenty-five gliomas of the cerebral hemisphere in children were examined. Most hemispheric gliomas in children have relatively clear margins and less infiltrative potential. Radiosurgery has a role in the treatment of these tumors in addition to reducing the risk of radiation injuries developing later. Fifteen patients were alive 1-27 years (mean 8.4) following treatment and 10 patients died. Histologic examination demonstrated 10 differentiated gliomas, 10 poorly differentiated gliomas and 5 other gliomas. Most tumors had relatively clear margins on computed tomography and/or magnetic resonance images, and peritumoral edema was slight. In 9 autopsy cases, tumor dissemination and/or metastasis were seen in 7. However, tumor infiltration was not extensive, and clear tumor margins were found in some cases. Thus, cerebral gliomas in children have relatively clear margins and low infiltrative potential. Radiosurgery has a role in the treatment of these tumors.

K252a, a potent inhibitor of protein kinases, inhibits the migration of cerebellar granule cells in vitro.

In order to elucidate the cellular mechanisms of migrating neurons, we developed an assay system in vitro, using an aggregation culture of developing granule cells from the rat cerebellum. This assay system allowed us to eliminate the effects of various factors other than neurons and to examine the direct effects of individual molecules on neuronal migration. In this assay system, we examined the effects of several protein kinase inhibitors on cerebellar granule cell migration, and revealed that K252a, an inhibitor of protein kinases and of the actions of neurotrophins, inhibited the migration. Within 5 min after the addition of K252a to the culture medium, most of the migrating spindle-shaped cells changed into non-migrating large and polygonal cells, which had many microspikes. Staining with rhodamine-phalloidin revealed the appearance of actin bundles that resembled stress fibers within these large cells. On the other hand, extension of neurites was not severely inhibited by the addition of K252a. These results suggest that the migration is regulated by a different mechanism from that of neurite growth.

Hypothalamic hamartoma: anatomic, immunohistochemical and ultrastructural features.

Four patients with hypothalamic hamartoma were examined by CT and/or MR imaging, immunohistochemistry and electron microscopy. The hamartomas arose from the hypothalamus and extended inferiorly. LH-RH neurons were detected in three cases by immunohistochemistry. Electron microscopy revealed large myelinated axons, axon terminals containing dense-core vesicles and axon terminals with clear vesicles forming asymmetrical synapses. The development of hypothalamic hamartoma and its functional manifestations (precocious puberty and laugh attacks) are discussed in reference to the migration of LH-RH neurons from the olfactory placode.

Grafts of genetically modified fibroblasts expressing neural cell adhesion molecule L1 into transected spinal cord of adult rats.

L1, a neural cell adhesion molecule, is known to promote neurite elongation via a homophilic interaction in vitro. In the present study, fibroblast L cells that were genetically modified to express the L1 molecule were grafted to a lesion of rat spinal cord immediately after hemisection. Grafts drastically promoted regeneration of the axons in the injured spinal cord 2 weeks after grafting. A number of regenerating axons penetrated the glial scar along the host-graft interface, and elongated into the graft. These results suggest that grafts of genetically modified cells expressing L1 can provide an environment suitable for regeneration of the axons in the injured spinal cord.

Classification of arteriovenous malformations for radiosurgery. Neuroimaging, histopathology and radiobiologic effects.

Arteriovenous malformations (AVMs) were classified based on morphologic and hemodynamic factors. They were categorized as Moya type, shunt type or mixed type on the basis of hemodynamic factors, and as homogeneous or heterogeneous types on the basis of morphology. Histopathologic and radiobiologic characteristics were evaluated with respect to these AVM types. Classification depending on the type as well as the size of an AVM is important for modern treatment modalities, especially radiosurgery.

Gamma Knife thalamotomy for the treatment of functional disorders.

Gamma Knife thalamotomy was performed with a 4-mm collimator in 2 cases with thalamic pain following a stroke and in 1 case of Parkinson's disease with tremor. In both cases with pain the maximum dose of 130 Gy was focused at the mediocaudal region of the previous thalamic lesion. In the case with tremor in Parkinson's disease, the maximum dose was 150 Gy. Longer follow-up is now proceeding, but the short-term results are encouraging. Based on data obtained from selective thalamotomy with depth microrecording, Gamma Knife thalamotomy could be a safe and effective technique for the treatment of these functional disorders.

Fractionated Gamma Knife radiosurgery for malignant gliomas: neurobiological effects and FDG-PET studies.

Experimental single-dose neural irradiation was performed in rats and monkeys. Acute and 'early' late damage was observed following single high-dose treatments. By contrast, following a single low-dose treatment, neither 'early' nor 'delayed' late damage was noted. Based on these experiments, a clinical trial of fractionated Gamma Knife surgery for malignant gliomas was begun, and patients were followed by FDG-PET studies. An acute response of the tumor was obtained without damage to the surrounding brain. Fractionated Gamma Knife surgery is a potential alternative treatment for malignant gliomas.

Gamma Knife radiosurgery for the treatment of brainstem tumors.

Ten patients with brainstem tumors (BST) underwent Gamma Knife radiosurgery. In 5 cases, there were definitive histological diagnoses; ependymoma (n = 3) and CNS lymphoma (n = 2). The others were diagnosed as ependymoma (n = 1), CNS lymphoma (n = 2) and glioma (n = 2) on clinical grounds. Of 4 cases with ependymoma, the tumor showed a marked response in 3 cases. Of 4 cases with CNS lymphoma, all responded rapidly and the clinical symptoms improved markedly. However, in the 2 cases with glioma, the tumor remained unchanged or continued to grow. Gamma Knife radiosurgery was effective in local growth control of BST without adverse effects. An alternative treatment design will be required in glioma cases.