Junichi Murata

Two-year follow-up of chronic stimulation of the posterior subthalamic white matter for tremor-dominant Parkinson's disease.

OBJECTIVE:To determine the efficacy and safety of unilateral deep brain stimulation on the posterior subthalamic white matter, including the zona incerta (ZI) and the prelemniscal radiation (PRL), for tremor-dominant parkinsonian patients and to determine the exact location of electrodes that were most effective. METHODS:Eight parkinsonian patients with severe resting tremor underwent unilateral stimulation of the ZI/PRL by use of stereotactic guidance. Electrophysiological targeting was obtained by macrostimulation and by somatosensory evoked potentials recorded directly through a quadripolar deep brain stimulation lead. Postoperative computed tomographic scans and magnetic resonance images were performed to confirm anatomic location of the electrode. Parkinsonian motor disabilities were evaluated by use of the Unified Parkinson’s Disease Rating Scale in the medication-off state before surgery and every 6 months after electrode implantations. RESULTS:The mean location of the clinically effective contacts was in the posterior subthalamic white matter, including the ZI and the PRL (mean, 5.6 ± 1.2 mm posterior to the midcommissural point, 3.2 ± 1.1 mm inferior to the anterior commissure-posterior commissure line, and 10.5 ± 1.2 mm lateral to the midline). At 24 months after operation, ZI/PRL stimulation resulted in significant improvement in mean Unified Parkinson’s Disease Rating Scale motor score by 44.3%, contralateral tremor by 78.3%, contralateral rigidity by 92.7%, and contralateral akinesia by 65.7% above the “off-stimulation” scores. Handwriting, posture, and gait were also improved. There were no or only mild adverse events. CONCLUSION:Unilateral ZI/PRL stimulation is a reliable and long-term therapeutic modality and can be considered another surgical target for the treatment of tremor-dominant Parkinson’s disease.

Nitric oxide as a carcinogen: Analysis by yeast functional assay of inactivating p53 mutations induced by nitric oxide

We have used a yeast p53 functional assay to study induction of mutations in the p53 tumor suppressor gene by nitric oxide and cytosine methylation. The yeast assay identifies only biologically important p53 mutations. p53 cDNA was treated with the nitric oxide donor sydnonimine, PCR-amplified and transfected into yeast. Sydnonimine produced a significant, dose-dependent increase in C:G-->A:T transversions. Many important p53 mutational hotspots are postulated to arise by deamination of methylCpG in tumors. We therefore examined nitric oxide induction of mutations in p53 cDNA methylated by PCR-mediated substitution of 5-methylcytosine for cytosine or by treatment with the SssI CpG methylase. Both methylation procedures increased the baseline mutation rate, and nitric oxide treatment produced a further increase in mutation yield. Sequence analysis showed that methylation alone led to C:G-->T:A transitions, whereas nitric oxide treatment simply produced more C:G-->A:T transversions. Thus the most important factor in C:G-->T:A transition at CpG sites identified in this experimental system is cytosine methylation, consistent with spontaneous conversion of 5-methylcytosine to thymine by deamination.

Careful exclusion of non-neoplastic brain components is required for an appropriate evaluation of O6-methylguanine-DNA methyltransferase status in glioma: relationship between immunohistochemistry and methylation analysis.

Evaluation of O6-methylguanine-DNA methyltransferase (MGMT) expression is important for antiglioma therapy as many clinical trials have demonstrated that promoter hypermethylation and low level expression of MGMT are associated with an enhanced response to alkylating agents. However, here we report that the current strategies used to evaluate MGMT status in gliomas are unreliable. We observed discordance in the MGMT expression status when immunohistochemical evaluation and polymerase chain reaction-based methylation assessments were used: 73% of gliomas with methylated MGMT promoter had substantial numbers of MGMT-immunopositive tumor cells. Furthermore, when MGMT expression was tested in tumor homogenates using reverse transcription-polymerase chain reaction, 43% of tumors were found positive, in comparison to only 24%, when histologic samples were assayed immunohistochemically. To explain these inconsistencies we undertook a detailed immunohistochemical evaluation of tumor samples and found that some gliomas demonstrated remarkably high expression of MGMT in the entire tumor whereas others contained only a small immunopositive area. Additionally, we found that gliomas contained various types of non-neoplastic cells expressing MGMT, including lymphocytes, vascular endothelial cells, and macrophages/microglias, which contribute to overall MGMT expression detected in tumor homogenates, and thus result in overestimation of tumor MGMT expression. Therefore, to correctly establish MGMT expression in the tumor, which could be informative of glioma sensitivity to alkylating agents, exclusion of non-neoplastic brain components from analysis is required.

Dysplastic gangliocytoma (Lhermitte-Duclos disease) associated with Cowden disease: report of a case and review of the literature for the genetic relationship between the two diseases.

We report a case of dysplastic gangliocytoma of the cerebellum (Lhermitte-Duclos disease, LDD). The patient also had cutaneous and mucosal hamartomas, adenomatous goiter, bilateral breast tumors, and gastrointestinal polyposis, indicating the diagnosis of Cowden disease (CD), the familial hamartoma syndrome. This was a rare sporadic case without any family history of CD, though CD is considered to be an autosomal dominant hereditary disease. Based on a thorough review of the previously reported cases, it is reasonable to consider that CD is inherited in autosomal dominant fashion through a CD gene (PTEN) containing a germline mutation, and that the occurrence of LDD is predicated on an additional somatic hit on the remaining normal CD allele or another unknown gene.

Twenty‐four hour rhythm of melatonin in patients with a history of pineal and/or hypothalamo‐neurohypophyseal germinoma

Abstract: Melatonin deficiency after a pinealectomy has been investigated in animals; however, in humans, this status can be assessed solely by investigating patients with a tumor originating in the pineal gland. This study analyzes secretion of melatonin and pituitary hormones in 14 patients with germinoma originating in the pineal or the hypothalamic‐neurohypophyseal region. Thirteen patients had been successfully treated prior to this study. One patient was included in this study before the initiation of treatments. Plasma sampling was performed every 2 hr for 24 hr and melatonin concentrations were measured by radioimmunoassay. Melatonin secretion was nearly absent in the patients with pineal germinoma regardless of treatment option, even in the patient who had been untreated. In contrast, melatonin secretion and its circadian rhythms were not affected in patients with a hypothalamo‐neurohypophyseal germinoma. The circadian rhythms of growth hormone and adrenocorticotropic hormone were not dysregulated in patients with the melatonin deficiency. We conclude that germinoma cells originating the pineal gland impair the production of melatonin by pineocytes and consequently induce a permanent melatonin deficiency in those patients. Since melatonin exerts multiple physiological functions, once a clinical concept of “melatonin deficiency syndrome” is established, melatonin replacement therapy could be investigated in patients who have a pineal germinoma or who have undergone a neurosurgical pinealectomy.

Reoxygenation of glioblastoma multiforme treated with fractionated radiotherapy concomitant with temozolomide: changes defined by 18F-fluoromisonidazole positron emission tomography: two case reports.

Two glioblastoma multiforme patients underwent (18)F-FMISO (fluoromisonidazole) positron emission tomography study to access the tumor oxygenation status before and immediately after fractionated radiotherapy concomitant with temozolomide chemotherapy. In both cases, a prominent (18)F-FMISO tumor accumulation observed in the first study was notably decreased in the second study, which was supposed to be a reoxygenation of the tumor. As far as we investigated, this is the first report of the changes of oxygenation status in glioblastoma multiforme treated through radiation therapy with temozolomide.

Intracerebral Hemorrhage Caused by a Neoplastic Aneurysm from Small-Cell Lung Carcinoma

A neoplastic cerebral aneurysm from lung cancer is an extremely rare occurrence despite its high metastatic potential to the brain. We report a neoplastic cerebral aneurysm from small-cell lung carcinoma that caused an intracerebral hematoma. A 63-year-old man underwent an urgent craniotomy for a massive intracerebral hematoma. After evacuation of the hematoma, an anomalous artery was found on the wall and a biopsy was done. The histological examination revealed that the artery was filled with neoplastic cells, and a part of the vessel wall was distended, forming an aneurysm. The histological feature of the tumor cells was consistent with small-cell lung carcinoma, which was disclosed in the left hilus.

Intraoperative Dual Monitoring During Carotid Endarterectomy Using Motor Evoked Potentials and Near-Infrared Spectroscopy

BACKGROUND Carotid endarterectomy (CEA) is a useful procedure to prevent subsequent ischemic stroke in patients with severe stenosis of internal carotid artery. However, lowering of morbidity is still essential to keep its clinical significance. This study aimed to evaluate the validity of dual monitoring using transcranial motor evoked potential (MEP) and near-infrared spectroscopy (NIRS) during CEA. METHODS Transcranial MEP and NIRS monitoring were conducted in 20 consecutive CEAs. MEP was recorded in the contralateral extremities. Regional cerebral saturation of oxygen (rSO(2)) was continuously measured in the ipsilateral forehead. The changes of MEP amplitudes and rSO(2) during cross-clamping of carotid artery were compared in each case. RESULTS The amplitudes of MEP significantly decreased when rSO(2) reduced to more than 20% during carotid clamping. There was a significant correlation between the changes of MEP amplitude and rSO(2) during carotid clamping in a quadratic manner (P < .001, r = 0.821). However, NIRS could not detect critical cerebral ischemia in 1 patient with cerebral infarction in the ipsilateral frontal lobe. On the other hand, MEP could not identify it in 1 patient with severe motor deficit. No perioperative complication occurred. CONCLUSIONS These findings strongly suggest that both MEP and NIRS can detect critical cerebral ischemia during CEA in most patients. Dual MEP and NIRS monitoring may further increase the sensitivity to identify it, being valuable to prevent perioperative complications due to cerebral ischemia during CEA.

A possible mechanism of isolated oculomotor nerve palsy by apoplexy of pituitary adenoma without cavernous sinus invasion: a report of two cases.

Isolated oculomotor nerve palsy occasionally occurs in patients with cavernous sinus invasion with or without pituitary apoplexy. We describe two cases of pituitary apoplexy without cavernous sinus invasion presenting with isolated oculomotor palsy. In both cases, computed tomography (CT) showed erosion of the right posterior clinoid process. Magnetic resonance imaging (MRI) depicted pituitary adenoma with apoplexy protruding latero-posteriorly to the right cavernous sinus. The medio-posterior wall of the cavernous sinus was markedly displaced latero-posteriorly by the tumor, and there was no evidence of cavernous sinus invasion. Oculomotor palsy may be caused first by unilateral erosion of the posterior clinoid process, resulting in latero-posterior protrusion of the adenoma. Hemorrhage may result in sudden kinking of the oculomotor nerve at the entrance of the oculomotor trigone.

Indolent dorsal midbrain tumor: new findings based on positron emission tomography.

OBJECT Intrinsic tumors arising in the dorsal midbrain cause obstructive hydrocephalus and have an indolent clinical course. Positron emission tomography (PET) with fluorine-18-labeled fluorodeoxyglucose (FDG) and l- [methyl-(11)C]methionine (MET) was used to evaluate the biological behaviors of dorsal midbrain tumors. METHODS The authors report on 4 patients (3 males and 1 female) with dorsal midbrain tumors who presented with obstructive hydrocephalus. A diagnosis was made with MR imaging in each patient. To manage the hydrocephalus, endoscopic third ventriculostomy was performed in all cases. The patients did not undergo any other surgical procedures except endoscopic biopsy procedure, chemotherapy, or radiation therapy. The patients in 3 cases underwent FDG- and MET-PET within 6 months of CSF-diverting procedures, and the patient in 1 case underwent PET 10 years after the procedure. RESULTS After the CSF-diverting procedure, clinical symptoms resolved or improved in all patients. Gliosis or glial proliferation was diagnosed in 1 patient, and possible low-grade glioma in 2 patients. Although all tumors appeared hyperintense on T2-weighted MR images, their appearance on T1-weighted images was variable (iso- and/or hypointense), and partial lesion enhancement was observed on images from 2 patients. On the other hand, the PET features of these lesions were almost identical, and the scans did not show a high uptake of FDG and MET compared with the cortical uptake in a normal brain. The mean tumor tissue/normal tissue ratio of FDG uptake was 0.65, and that of MET was 0.99. CONCLUSIONS Positron emission tomography findings suggested that the indolent dorsal midbrain lesion had nontumorous characteristics, thus supporting a good prognosis. Positron emission tomography studies may be more informative and predictive of the biological behavior of dorsal midbrain tumors than a biopsy procedure.