Usefulness of Leksell GammaPlan for preoperative planning of brain tumor resection: delineation of the cranial nerves and fusion of the neuroimaging data, including diffusion tensor imaging.

Leksell GammaPlan (LGP) software was initially designed for Gamma Knife radiosurgery, but it can be successfully applied to planning of the open neurosurgical procedures as well. We present our initial experience of delineating the cranial nerves in the vicinity of skull base tumors, combined visualization of the implanted subdural electrodes and cortical anatomy to facilitate brain mapping, and fusion of structural magnetic resonance imaging and diffusion tensor imaging performed with the use of LGP before removal of intracranial neoplasms. Such preoperative information facilitated choosing the optimal approach and general surgical strategy, and corresponded well to the intraoperative findings. Therefore, LGP may be helpful for planning open neurosurgical procedures in cases of both extraaxial and intraaxial intracranial tumors.

Management of non-benign meningiomas with Gamma Knife radiosurgery.

OBJECTIVE: Results of Gamma Knife radiosurgery (GKS) were retrospectively evaluated in 16 patients with histologically confirmed atypical and anaplastic intracranial meningiomas. MATERIALS AND METHODS: There were nine men and seven women (mean age 61.0 years). Atypical meningiomas were diagnosed in nine cases and anaplastic meningiomas in seven. In nine patients there was malignant transformation of a tumor that had initially proved to be benign. In total, 21 radiosurgical procedures were performed. The mean tumor volume at the time of GKS was 7.1 cm3. The mean marginal and maximum irradiation doses were 18.8 and 37.0 Gy, respectively. The mean length of follow-up after treatment was 37.1 months. FINDINGS: Of 21 radiosurgical procedures, 6 (29 %) led to stabilization of tumor growth during the mean follow-up of 40.5 months. It was significantly associated with small lesion volume (P = 0.02), and greater marginal (P = 0.04) and maximum (P = 0.02) irradiation doses. Seven patients underwent eight surgical resections of a progressing tumor during the mean period of 26.1 months after irradiation. Five patients (31 %) died because of tumor progression within the average time period of 16.8 months after GKS. Overall, at the time of the last follow-up just two patients (13 %) had no evidence of tumor regrowth, and only three patients (19 %) maintained good activities of daily living during 12, 59, and 69 months, respectively, after radiosurgery. CONCLUSION: GKS has limited efficacy in cases of non-benign meningioma. Better tumor control rates can be attained for small neoplasms treated with greater marginal and maximum irradiation doses.

Cortically evoked responses of human pallidal neurons recorded during stereotactic neurosurgery.

Responses of neurons in the globus pallidus (GP) to cortical stimulation were recorded for the first time in humans. We performed microelectrode recordings of GP neurons in 10 Parkinson's disease (PD) patients and 1 cervical dystonia (CD) patient during surgeries to implant bilateral deep brain stimulation electrodes in the GP. To identify the motor territories in the external (GPe) and internal (GPi) segments of the GP, unitary responses evoked by stimulation of the primary motor cortex were observed by constructing peristimulus time histograms. Neurons in the motor territories of the GPe and GPi responded to cortical stimulation. Response patterns observed in the PD patients were combinations of an early excitation, an inhibition, and a late excitation. In addition, in the CD patient, a long-lasting inhibition was prominent, suggesting increased activity along the cortico-striato-GPe/GPi pathways. The firing rates of GPe and GPi neurons in the CD patient were lower than those in the PD patients. Many GPe and GPi neurons of the PD and CD patients showed burst or oscillatory burst activity. Effective cathodal contacts tended to be located close to the responding neurons. Such unitary responses induced by cortical stimulation may be of use to target motor territories of the GP for stereotactic functional neurosurgery. Future findings utilizing this method may give us new insights into understanding the pathophysiology of movement disorders.

[Unruptured aneurysm arising from fenestration of the horizontal (A1) segment in the anterior cerebral artery: a case report and review of the literature].

Cerebral aneurysms arising from fenestration of the horizontal (A(1)) segment in the anterior cerebral artery (ACA) are very rare. In this paper, we report our case, discuss radiological features, and review previous cases. A 70-year-old male was referred to our hospital presenting with memory disturbance. His unruptured cerebral aneurysm in the A(1) segment was incidentally found by magnetic resonance angiography (MRA). Three dimensional computed tomographic angiography (3D-CTA) demonstrated this aneurysm arising from fenestration of the A(1) segment. Surgical neck clipping was performed via the pterional approach, while sacrificing one pair of the A(1) segment. The patient's post operative course was uneventful. Only 14 cases with an aneurysm arising from fenestration of the A(1) segment have been reported previously. In the present case, 3D-CTA was very useful for finding out where the aneurysm arose from, and we also had to be careful about perforating arteries from the A(1) segment during the surgery.

Nondominant parietotemporal cortical dysplasia manifesting as hypermotor seizures.

We describe the case of a 33-year-old man with nondominant right parietotemporal cortical dysplasia. Habitual seizures were violent, ballistic movements of the extremities with pelvic thrusting, resembling complex gestural automatisms or "hypermotor seizures." Scalp electroencephalography (EEG) and interictal [(123)I]iomazenil single-photon-emission computed tomography revealed an epileptogenic zone including a lesion observed on magnetic resonance imaging. Corticectomy of the inferior parietal lobule was performed via invasive EEG monitoring, but resulted in failed seizure control. The middle and posterior temporal cortices were additionally resected in the second surgery. The patient experienced contralateral hemianopsia postoperatively, but no hemispatial neglect. Hypermotor seizures have not been seen for 1.5years since surgery. This is the first description of a patient with a parietal lobe lesion experiencing hypermotor seizures. The middle and posterior temporal cortices were considered epileptogenic together with the inferior parietal lobule in the present case.

EphA4 promotes cell proliferation and migration through a novel EphA4-FGFR1 signaling pathway in the human glioma U251 cell line.

The Eph receptor tyrosine kinases and their ephrin ligands form a unique cell-cell contact-mediated bidirectional signaling mechanism for regulating cell localization and organization. High expression of Eph receptors in a wide variety of human tumors indicates some roles in tumor progression, which makes these proteins potential targets for anticancer therapy. For this purpose, we did gene expression profiling for 47 surgical specimens of brain tumors including 32 high-grade glioma using a microarray technique. The analysis, focused on the receptor tyrosine kinases, showed that EphA4 mRNA in the tumors was 4-fold higher than in normal brain tissue. To investigate the biological significance of EphA4 overexpression in these tumors, we analyzed EphA4-induced phenotypic changes and the signaling mechanisms using human glioma U251 cells. EphA4 promoted fibroblast growth factor 2-mediated cell proliferation and migration accompanied with enhancement of fibroblast growth factor 2-triggered mitogen-activated protein kinase and Akt phosphorylation. In addition, active forms of Rac1 and Cdc42 increased in the EphA4-overexpressing cells. Furthermore, we found that EphA4 formed a heteroreceptor complex with fibroblast growth factor receptor 1 (FGFR1) in the cells and that the EphA4-FGFR1 complex potentiated FGFR-mediated downstream signaling. Thus, our results indicate that EphA4 plays an important role in malignant phenotypes of glioblastoma by enhancing cell proliferation and migration through accelerating a canonical FGFR signaling pathway.

Antitumor activity of cetuximab against malignant glioma cells overexpressing EGFR deletion mutant variant III.

Anti-epidermal growth factor receptor (EGFR) monoclonal antibody, cetuximab, is a promising targeted drug for EGFR-expressing tumors. Glioblastomas frequently overexpress EGFR including not only the wild type but also a deletion mutant form called 'variant III (vIII)', which lacks exon 2-7, does not bind to ligands, and is constitutively activated. In this study, we investigated the antitumor activity of cetuximab against malignant glioma cells overexpressing EGFRvIII. For this purpose, we transfected human malignant glioma cell lines with the retroviral vector containing cDNA for EGFRvIII, and analyzed the mode of cetuximab-induced action on the EGFRvIII in the cells. Immunoprecipitation and immunofluorescence revealed binding of cetuximab to EGFRvIII. Notably, immunoblotting analyses showed that cetuximab treatment resulted in reduced expression levels of the EGFRvIII. However, cetuximab alone did not exhibit a growth-inhibitory effect against the EGFRvIII-expressing cells. On the other hand, an assay for antibody-dependent cell-mediated cytotoxicity (ADCC) demonstrated cetuximab-induced cytolysis in the presence of human peripheral blood mononuclear cells in a dose-dependent manner. These results suggest that deletion mutant EGFRvIII can be a target of cetuximab and that ADCC activity substantially contributes to the antitumor efficacy of cetuximab against the EGFRvIII-expressing glioma cells. Thus, cetuximab could be a promising therapy in malignant gliomas that express EGFRvIII.

Generation of dopamine neurons from embryonic stem cells in the presence of the neuralizing activity of bone marrow stromal cells derived from adult mice.

Stromal cell lines such as PA6 and MS5 have been employed for generating dopamine (DA) neurons from embryonic stem (ES) cells. The present study was designed to test whether bone marrow stromal cells (BMSC) derived from adult mice might be available as a feeder layer to produce DA cells efficiently from ES cells. When ES cells were grown on BMSC in the presence of fibroblast growth factor 8 (FGF8) and sonic hedgehog (SHH), about 40% of TuJ1-positive neurons expressed tyrosine hydroxylase (TH). Because these cells labeled with TH were negative for dopamine-beta-hydroxylasae (DBH), the marker for noradrenergic and adrenergic neurons, the TH-positive cells were most likely DA neurons. They indeed expressed midbrain DA neuron markers such as Nurr 1, Ptx-3, and c-ret and were capable of synthesizing and releasing DA in vitro. Furthermore, DA neurons differentiated from ES cells in this differentiation protocol survived transplantation in rats with 6-hydroxydopamine lesions and reversed the lesion-induced circling behavior. The data indicate that BMSC can facilitate an efficient induction of DA neurons from ES cells and that the generated DA neurons are biologically functional both in vitro and in vivo. Insofar as BMSC have recently been employed in autologous cell therapy for ischemic heart and arteriosclerotic limb diseases, the present study raises the possibility that autologous BMSC can be applied in future cell transplantation therapy in Parkinson's disease.

Frequent and variable abnormalities in p14 tumor suppressor gene in glioma cell lines.

Ten glioma cell lines were examined for abnormalities of exon 1beta of the p14 gene and then for abnormalities of the entire p14 gene with the use of previous findings of other exons. Abnormalities of exon 1beta and the entire p14 gene were detected in eight of ten cases: homozygous deletion of the entire gene in six cases, hemizygous deletion of exon 1beta with homozygous deletion of downstream exons in one case, and hemizygous deletion of the entire coding region with a missense mutation (A97V) at the C-terminal nucleolar localization domain in one case. The remaining two cases revealed no such abnormalities. p14 gene expression was observed in the latter two cases and one case with A97V mutation in the hemizygously deleted coding region, but not in the others, including one case with only exon 1beta. In the three cases with p14 gene expression, immunocytochemistry revealed p14 nucleolar staining, suggesting the retention of the functional activity of p14 protein and, in the case with the A97V mutation, an insufficient mutational effect as well. The present findings of the frequent and variable p14 gene abnormalities, including rare-type ones with or without sufficient mutational effect in glioma cell lines, might be of value for better understanding of the p14 gene and its related pathways in glioma carcinogenesis.

Late-onset tumefactive multiple sclerosis.

A patient with tumefactive multiple sclerosis (MS) initially presented at the age of 87 years; the revised diagnostic criteria from the International Panel on MS (2001) were fulfilled. Late-onset MS and tumefactive demyelinating lesions are discussed. This case suggests that MS can occur at any age. MS should be borne in mind for differential diagnosis if a brain tumor-like lesion with little mass effect and edema is found in an elderly patient.

Protection of dopamine neurons by bone marrow stromal cells.

Transplantation of bone marrow stromal cells (BMSC) has recently been demonstrated to provide neuroprotection in animal models of brain injuries such as ischemia and trauma. The present study was undertaken to explore whether BMSC can promote the survival of dopamine (DA) neurons in neuronal insult models in vitro. We also examined whether BMSC can increase the survival rate of embryonic DA neurons grafted into the striatum of a rat model of Parkinson's disease (PD). Treatment with conditioned media derived from BMSC cultures was found to significantly prevent the death of DA neurons in in vitro cell injury models such as serum deprivation and exposure to the neurotoxin 6-OHDA. In a transplantation study, we also found that the survival of grafted DA cells was significantly enhanced by treating donor cells with the conditioned media at the steps of both cell dissociation and implantation. The results suggest that BMSC may secrete diffusible factors able to protect DA neurons against neuronal injuries. Indeed, BMSC expressed mRNA encoding brain-derived neurotrophic factor, fibroblast growth factor-2 and glial cell line-derived neurotrophic factor, all of which have previously been shown to exhibit potent neurotrophic effects on DA cells. Enzyme-linked immunosorbent assay revealed that the cells release these growth factors into culture media. The present data indicate that BMSC may be a potential donor source of cell-based regenerative therapy for PD where the progressive loss of the midbrain DA neurons takes place.

The usefulness and problem of intraoperative rapid diagnosis in surgical neuropathology.

Intraoperative rapid diagnosis has been a useful neurosurgery tool for maximal resection and minimal morbidity. However, only a few studies have been conducted regarding diagnostic accuracy and associated problems. The present study reviews our experience in treating patients and investigates the accuracy and problems associated with intraoperative rapid diagnosis in surgical neuropathology. There were 180 cases of intracranial lesions excluding pituitary lesions. The patients consisted of 89 males and 91 females, ranging from 5 months to 84 years, with a mean age of 46 years. Of the 180 cases, 152 cases received open surgery, 28 cases had stereotactic surgery including a biopsy and were histologically verified. The correlation between the intraoperative diagnosis and the final diagnosis overall was seen in 172 of 180 cases, proving a high diagnostic sensitivity of 95.6%. No correlation was seen in 8 cases (4.4%). The diagnostic inaccuracy was seen in the grading of gliomas and the diagnosis of undifferentiated malignant tumors such as undifferentiated metastatic carcinomas, primitive neuroectodermal tumors (PNETs), and sarcomas. It was also recognized in rare types of histology such as gliomatosis and xanthomatous lesions. These results suggested that the intraoperative rapid diagnosis was quite useful, but that we should also maintain a cautious attitude.

Sublabial transnasal approach combined with a partial resection of the nasal floor for midline skull base tumors.

A variety of surgical approaches have been used in the treatment of midline cranial base tumors. These approaches usually involve complicated techniques, particularly when they are employed for tumors involving the entire clivus. This paper describes the feasibility, efficacy, and safety of the sublabial transnasal approach combined with a partial resection of the nasal floor in the treatment of midline skull base lesions. We performed this approach in three patients with midline cranial base lesions, including invasive pituitary adenoma involving the whole clivus, fibrous dysplasia, and adenocystic carcinoma. The rostrocaudal extent of surgical exposure with this technique was the planum sphenoidale superiorly and the lowermost level of the clivus inferiorly. The lateral extent of the exposure was limited to the distance between the bilateral extradural internal carotid arteries. The average time taken to expose the entire length of the clivus was approximately 30 minutes. There were no serious complications related to the surgical procedure. None of the patients developed cosmetic abnormalities. Experience with these three patients indicates that the sublabial transnasal approach combined with a partial resection of the nasal floor is a safe, less invasive and effective approach in certain cases of midline skull base tumors.

Closed-lip schizencephaly around the central sulcus with intractable epilepsy treated by peri-lesional focus resection.

A 24-year-old man presented with closed-lip schizencephaly around the right central sulcus manifesting as an 11-year history of intractable epilepsy. Mild motor paresis in the left extremities and mental retardation were observed. Tonic posture with bilateral facial tonic contraction was asymmetrical, predominantly in the left extremities. Magnetic resonance imaging demonstrated closed-lip schizencephaly around the right central sulcus. The epileptogenic zone was determined in the supplementary motor area, and premotor and primary sensorimotor cortices using invasive recordings. As the thickened cortex was considered functional, corticectomy of the supplementary motor area and premotor area was performed, preserving the primary sensorimotor area. Histological examination revealed marked cortico-subcortical gliosis, particularly in the medial part of the resection. Asymmetrical tonic postural seizure disappeared completely after surgery. Medically intractable epilepsy with schizencephaly represents a considerable challenge in epilepsy surgery. Partial corticectomy adjacent to the thickened cortex was effective for seizure control in a patient with closed-lip schizencephaly around the central sulcus.

Transplantation of autologous sympathetic neurons as a potential strategy to restore metabolic functions of the damaged nigrostriatal dopamine nerve terminals in Parkinson's disease.

Grafting of catecholamine-producing cells can be a possible therapeutic strategy for attenuating motor symptoms in Parkinson's disease (PD). The potential of autologous sympathetic neurons has been investigated as a donor for cell therapy of PD. The clinical trials of autotransplantation of sympathetic ganglion cells in PD have revealed that the grafts increase the duration of L-DOPA (L-dihydroxy phenyl alanine)-induced beneficial effects, and that the graft-mediated effect is detectable during a follow-up period of at least 1 year postgrafting. In an in vitro analysis of the ability of human sympathetic neurons to release catecholamines, although DA was not detectable under basal conditions, DA levels were significantly increased upon exposure to exogenous L-DOPA. Furthermore, animal experiments with xenografting of human sympathetic ganglionic neurons in the DA-denervated striatum of rats demonstrated that a significant increase in striatal DA levels is noted after systemic L-DOPA treatment, and that the DA levels remain high for longer periods of time in the grafted rats than in control animals with sham surgery. The L-DOPA-induced rise of striatal DA levels was significantly attenuated when given reserpine pretreatment. This suggests that DA derived from exogenously administered L-DOPA is subjected to, at least in part, vesicular storage in grafted sympathetic neurons. Histological examinations indeed showed that the grafts express aromatic-L-amino acid decarboxylase and vesicular monoamine transporter-2, both of which are important molecules for the synthesis and the storage of DA, respectively. Taken together, grafted sympathetic neurons can provide a site for both the conversion of exogenous L-DOPA to DA and the storage of the synthesized DA in the DA-denervated striatum. This might be an explanation for a mechanism by which sympathetic neuron autografts can increase the duration of L-DOPA effects in PD patients. This review article summarizes the clinical effect of transplantation of autologous sympathetic neurons in PD and discusses the underlying mechanism for the effect based on experimental evidence previously obtained.

[Radiographic characteristics of fibrous dysplasia of the clivus: a case report and review of the literature].

Whereas fibrous dysplasia is a well-known, developmental skeletal disorder with a benign clinical course, fibrous dysplasia of the clivus is extremely rare and has seldom been reported. Differentiating this benign entity from more aggressive diseases involving the clivus is important for the proper management of lesions in this area. We here report a case of fibrous dysplasia of the clivus and discuss its radiographic features. The patient was 55-year-old male who had suffered from headache for months. Physical and neurological examinations found no abnormalities. The computed tomographic (CT) scan and magnetic resonance imaging (MRI) showed an abnormal mass lesion in the lower of the third clivus. On CT scan, the mass lesion exhibited a ground-glass appearance. The lesion was detected as hypointense and a mixture of hyperintense and isointense areas on T1-weighted and T2-weighted MRI, respectively. Heterogenous enhancement was noted after infusion of GD-DTPA. The patient underwent a transsphenoidal resection of the mass and the histopathologic diagnosis was fibrous dysplasia.

Two cases of ringlike enhancement on MRI mimicking malignant brain tumors.

The present study was performed to investigate two cases with ringlike enhanced lesions mimicking malignant tumors on magnetic resonance imaging (MRI) and to determine the utility of thallium-201 single-photon emission tomography (201Tl-SPECT) and diffusion-weighted MR imaging (DWI) for differential diagnosis between neoplastic and nonneoplastic lesions. One patient was a 50-year-old man who presented with a right caudate lesion. The 201Tl-SPECT study revealed no uptake in the lesion. Stereotactic biopsy was performed, and pathological findings indicated cerebral infarction. The other patient was a 58-year-old woman who presented with a right frontal lesion with edema. DWI showed a hypointense signal, and the apparent diffusion coefficient (ADC) revealed a hyperintense signal in the lesion. Stereotactic biopsy with endoscopy was performed, and the pathological findings suggested a demyelinating disease. Combined 201Tl-SPECT and DWI studies may be useful for differential diagnosis between neoplastic and nonneoplastic lesions. However, stereotactic biopsy should be performed for the final pathological diagnosis.

Histological effects of intraputaminal infusion of glial cell line-derived neurotrophic factor in Parkinson disease model macaque monkeys.

Glial cell line-derived neurotrophic factor (GDNF) is a potent neuroprotection and regeneration molecule for dopamine neurons in the substantia nigra. A recent clinical study showed that intraputaminal infusions of GDNF restored the striatal dopaminergic function, resulting in improvement in patients with Parkinson disease. To investigate the efficacy and the safety of this treatment, the histological changes associated with intraputaminal GDNF infusions were investigated in non-human primate models of Parkinson disease. Two types of Parkinson disease model were constructed: unilateral infusion of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridin (MPTP) into the internal carotid artery to induce hemiparkinsonism and intermittent systemic injection to induce Parkinson disease. GDNF (50 microg) was infused into the putamen on the day of the first MPTP treatment and 4 weeks later. The monkey brains were examined by immunohistochemistry 2-4 weeks after the second GDNF infusion. Losses of the nigral dopamine neurons were mild (30-50% loss) on the side of GDNF infusion, and moderate (approximately 70% loss) on the side of vehicle infusion in the Parkinson disease model. The dopamine fibers were thick and dense in the striatum around the GDNF infusion sites. Both GDNF- and vehicle-treated monkeys of the hemiparkinsonian model showed severe decrease of dopamine neurons to 10% of the intact side. Although reactive astrocytes proliferated around the GDNF infusion sites, the densities of striatal neurons involving GABAergic and cholinergic neurons were not affected. Intraputaminal infusions of GDNF have beneficial effects in parkinsonian monkeys, but dose control is required according to the severity of the disease. The specificity for dopamine neurons is quite high and there are no serious histological changes.

Neurocytoma manifesting as intraventricular hemorrhage--case report.

A 43-year-old man presented with a neurocytoma manifesting as severe headache and disturbance of consciousness. Computed tomography revealed intraventricular hemorrhage, and a small mass lesion with calcification on the wall of the left lateral ventricle. The lesion appeared as mixed intensity regions on both T(1)- and T(2)-weighted magnetic resonance imaging, and heterogeneous enhancement with gadolinium-diethylenetriaminepenta-acetic acid. Angiography showed the pooling sign near the calcification in the late venous phase. Neurologically, amnestic syndrome was demonstrated in the subacute phase. Gross total removal of the lesion was performed through a transcallosal approach. His transient memory disturbance resolved. The histological diagnosis was neurocytoma. Intraventricular hemorrhage is rare as the initial presentation of neurocytoma. Surgery should avoid fornix injury and the risk of permanent memory disturbance.

Successful recanalization by in-stent percutaneous transluminal angioplasty with distal protection for acute carotid stent thrombosis.

A 71-year-old male presented with severe left cervical internal carotid artery stenosis manifesting as repeated transient ischemic attacks consisting of right hemiparesis and motor aphasia. Carotid artery stenting (CAS) under distal protection was performed to prevent further ischemic events. This procedure was uneventful. However, the patient exhibited progressive right hemiparesis and motor aphasia 3 days after CAS. Emergent angiography revealed carotid artery occlusion due to in-stent thrombosis. In-stent percutaneous transluminal angioplasty (PTA) was performed under distal protection. The carotid artery was recanalized with small residual thrombus. The neurological deficits almost completely disappeared after PTA. Follow-up angiography 9 months after stenting showed restenosis but no in-stent thrombosis. Carotid thrombosis after CAS can be resolved by in-stent PTA under distal protection and subsequent treatment with antithrombotic agents.