Chronological Change of the Clinical Features and Treatment Outcomes for Subarachnoid Hemorrhage in Japan: A Multicenter Retrospective Study.

Aneurysmal subarachnoid hemorrhage (SAH) treatment has progressed, and patients are rapidly aging in Japan. Consequently, dynamic changes must have emerged in the clinical practice of SAH. This study aimed to elucidate chronological changes of aneurysmal SAH and the prognostic factors in the previous quarter century in Japan. We conducted a retrospective survey regarding aneurysmal SAH in eight institutions in Japan. The study included 848, 863, and 781 patients in the first (1989-1993), second (1999-2003), and third (2009-2013) periods, respectively. The chronological changes of factors that influenced the poor outcomes and differences between the nonelderly (<75 years) and elderly patients were investigated. Mean age was significantly higher in patients in the third period (61.4 years) than in those in the other two periods (first, 57.8 years; second, 59.5 years). During these periods, the proportion of good outcomes did not change; however, the mortality rate significantly decreased from 19% in the first period to 11% and 9.2% in the second and third periods, respectively. The poor outcome was mainly caused by the significantly higher incidence of systemic complication and procedural complication in the first period and the significantly lower incidence of delayed ischemic neurological deficit in the third period. The elderly patients had significantly poorer clinical outcomes than the nonelderly ones. During the last 25 years, the age of patients with aneurysmal SAH has rapidly increased. The study results may contribute to the improvement of the treatment strategy of SAH in advanced countries with a rapidly aging population.

Stereotactic body radiotherapy for adenoid cystic carcinoma metastatic to the lung: a case report.

BACKGROUND: Adenoid cystic carcinoma (ACC) is a rare malignant tumor involving mostly the head and neck region, and frequently the salivary glands. The development of lung metastasis after treatment of the primary tumor is a common occurrence in ACC. Although lung metastases show a slow rate of growth, approximately 10% of patients die from distant metastases. The radioresistance of ACC limits the efficacy of conventional radiotherapy for lung metastases, and the optimal dose remains to be determined. Stereotactic body radiotherapy (SBRT) using CyberKnife can deliver a high dose to the lung tumor, while sparing the surrounding normal lung tissues, leading to favorable local control in non-squamous cell lung cancer and metastatic lung tumors. We report a case of lung metastases from ACC treated successfully with SBRT using CyberKnife. CASE PRESENTATION: A 76-year-old Japanese man with ACC who was treated with carbon ion radiotherapy for a primary oropharynx tumor presented with three metastatic lesions in the lung. The tumor masses were located in the right upper, right lower, and left lower lobes of the lungs. Surgical resection was not indicated because of the presence of multiple tumors. The patient underwent SBRT at 60 Gy in 10 sequential fractions for each tumor. The biologically effective dose based on an alpha/beta ratio of 2 Gy was 240 Gy per tumor. The percentage of the total lung volume irradiated with >20 Gy was 4.9%, 3.2%, and 2.6% for each tumor. The patient developed acute radiation pneumonitis during the initial therapy, which resolved at 6 months after the CyberKnife treatment. At 21 months after the first CyberKnife treatment, three tumors showed no signs of recurrence. No late toxicity was observed. CONCLUSIONS: SBRT using CyberKnife is an effective and feasible approach to the management of multiple lung metastases of ACC.

Comprehensive investigation of RNF213 nonsynonymous variants associated with intracranial artery stenosis.

Intracranial artery stenosis (ICAS) is the most common cause of ischemic stroke worldwide. RNF213 single nucleotide variant c.14429G > A (p.Arg4810Lys, rs112735431) was recently reported to be associated with ICAS in East Asians. However, the disease susceptibility of other RNF213 variants has not been clarified. This study comprehensively investigated ICAS-associated RNF213 variants in a pool of 168 Japanese ICAS patients and 1,194 control subjects. We found 138 nonsynonymous germline variants by target resequencing of all coding exons in RNF213. Association study between ICAS patients and control subjects revealed that only p.Arg4810Lys had significant association with ICAS (P = 1.5 × 10-28, odds ratio = 29.3, 95% confidence interval 15.31-56.2 [dominant model]). Fourteen of 138 variants were rare variants detected in ICAS patients not harboring p.Arg4810Lys variant. Two of these rare variants (p.Cys118Arg and p.Leu2356Phe) consistent with variants previously reported in moyamoya disease patients characterized by stenosis of intracranial artery and association with RNF213, and three rare variants (p.Ser193Gly, p.Val1817Leu, and p.Asp3329Tyr) were found neither in control subjects and Single Nucleotide Polymorphism Database. The present findings may improve our understanding of the genetic background of intracranial artery stenosis.

Efficacy and Feasibility of Salvage Re-Irradiation with CyberKnife for In-Field Neck Lymph Node Recurrence: A Retrospective Study.

Neck lymph node (LN) recurrence in the irradiated field represents an important aspect of treatment failure after primary radiotherapy owing to the lack of a standard treatment. The aim of this study is to investigate the efficacy and safety of CyberKnife treatment for neck LN recurrence after radiotherapy. Between 2008 and 2016, 55 neck LN recurrences after radiotherapy in 16 patients were treated with CyberKnife. The median follow-up period was 17 months (range, 2-53 months). The median previous radiotherapy dose was 68 Gy (range, 50-70 Gy). The median marginal dose as equivalent dose delivered in 2-Gy fractions (α/ß = 10) was 50 Gy (range, 40-58 Gy). The one-year local control (LC) and overall survival rates were 81% and 71%, respectively. The one-year LC was higher with a target volume ≤1.0 cm3 than that with a target volume >1.0 cm3 (p = 0.006). Fatal bleeding was observed in one patient who had large (91 cm3) and widespread tumor with invasion to the carotid artery before CyberKnife treatment. CyberKnife treatment for neck LN recurrence is safe and feasible in most cases. Indication for the treatment should be carefully considered for large and widespread tumors.

Reversible Cerebral Metabolism Changes Using Proton Magnetic Resonance Spectroscopy in a Patient with Intracranial Dural Arteriovenous Fistula: A Case Report.

BACKGROUND: Cerebral metabolism can be disrupted by venous congestion in patients with intracranial dural arteriovenous fistula (DAVF), which may lead to adverse neurological outcomes. However, there are no clear indicators to guide cerebral evaluation and treatment selection in cases of DAVF. We describe a patient with a DAVF whose proton magnetic resonance spectroscopy ((1)H-MRS) findings were associated with improvements in clinical status. CASE DESCRIPTION: An elderly woman with a history of myocardial infarction presented with progressive dementia, aphasia, and a severe headache. We detected a transverse-sigmoid sinus DAVF, as well as abnormal levels of lactate and N-acetylaspartic acid (NAA) in the (1)H-MRS, and successfully treated the patient using surgical sinus skeletonization. However, follow-up (1)H-MRS revealed inconsistent reversals in the levels of lactate and NAA. In addition, we calculated the NAA/creatinine ratios from before and after surgery, which revealed postoperative increases in the ratios for the left temporal, right parietal, and left parietal regions. These increases occurred concurrently with improvements in the patient's cognitive function. CONCLUSIONS: (1)H-MRS may be useful for pretreatment detection of increased lactate levels, decreased NAA levels, and/or decreased NAA/creatinine ratios. These findings may indicate poorer cerebral metabolism, and show a need for more aggressive treatment. Furthermore, (1)H-MRS may be useful for evaluating the effect of conservative treatment and for indicating conversion to a more aggressive treatment.

Internal carotid artery stenosis with persistent primitive hypoglossal artery treated with carotid artery stenting: A case report and literature review.

Persistent primitive hypoglossal artery (PPHA) is a persistent carotid-basilar anastomosis. It rarely remains at birth. It occasionally may be a risk for ischemia and embolic infarction to the posterior cerebral circulation, especially in patients with carotid stenosis proximal to the origin of persistent primitive arteries. We describe a case of a 60-year-old woman with asymptomatic internal carotid artery (ICA) stenosis and ipsilateral PPHA successfully treated by carotid artery stenting (CAS). A few cases of CAS for ICA stenosis with PPHA have been reported, but the strategy and methods in each case were different because of its unique anatomy and hemodynamics. It is essential to prevent distal embolisms and preserve blood flow at the territory of both the ICA and PPHA. The protection method should be selected carefully. We review the literature and discuss appropriate treatment strategies.

Genetic Analysis of RNF213 c.14576G>A Variant in Nonatherosclerotic Quasi-Moyamoya Disease.

BACKGROUND: Quasi-moyamoya disease (MMD) and MMD (definite MMD) have similar cerebral angiographic features, but whether these related diseases have similar etiology or genetic background remains unclear. Recently, we have reported that the recently identified MMD susceptibility gene variant RNF213 c.14576G>A (rs112735431) was associated with atherosclerotic intracranial major artery stenosis/occlusion. The present study investigated the occurrence of RNF213 c.14576G>A in patients with nonatherosclerotic quasi-MMD. METHODS: This study was a 2-hospital-based case-control study conducted at the Department of Neurosurgery, The University of Tokyo Hospital and Kanto Neurosurgical Hospital. A total of 87 Japanese patients who agreed to participate in this study were enrolled among both new and revisiting outpatients from October 2011 to December 2013 as follows: 78 patients with definite MMD and 9 patients with nonatherosclerotic quasi-MMD. RESULTS: The 9 patients with nonatherosclerotic quasi-MMD included 3 patients with previous irradiation, 2 with hyperthyroidism, 1 with Turner syndrome, 1 with meningitis, 1 with Behçet disease, and 1 with idiopathic pachymeningitis. The 78 patients with definite MMD included 66 patients (84.6%) with the c.14576G>A variant (64 heterozygotes and 2 homozygous). In contrast, no patients with nonatherosclerotic quasi-MMD had the variant. CONCLUSIONS: Nonatherosclerotic quasi-MMD did not have RNF213 c.14576G>A variant. Moyamoya disease and related diseases might be classified by genetic analysis of the RNF213 c.14576G>A genotype. Further larger studies are required to confirm the present findings.

Genetic variant RNF213 c.14576G>A in various phenotypes of intracranial major artery stenosis/occlusion.

BACKGROUND AND PURPOSE: Recently, we reported a common genetic variant, ring finger protein 213 (RNF213) c.14576G>A variant, a susceptibility gene for moyamoya disease (MMD), among patients with intracranial major artery stenosis/occlusion (ICASO) in a selected Japanese population. The aim of this 2-center-based case-control study was to confirm our previous finding in a larger population. METHODS: Study participants were recruited from The University of Tokyo Hospital and Kanto Neurosurgical Hospital. The occurrence rate of c.14576G>A variant was investigated in 323 patients, 22 with definite MMD, 8 with unilateral MMD, 84 with ICASO in the absence of MMD (non-MMD ICASO), 34 with extracranial carotid atherosclerosis, 44 with cerebral aneurysm, 21 with intracerebral hemorrhage, and 110 control subjects. RESULTS: RNF213 c.14576G>A variant was found in 1.8% (2/110) of the normal control group and had significant associations with definite MMD (P<0.0001; odds ratio, 144.0; 95% confidence interval, 26.7-775.9), unilateral MMD (P=0.0001; odds ratio, 54.0; 95% confidence interval, 7.5-386.8), and non-MMD ICASO (P<0.0001; odds ratio, 16.8; 95% confidence interval, 3.81-74.5). There was no significant association with extracranial carotid atherosclerosis, cerebral aneurysm, or intracerebral hemorrhage. This result replicated our previous findings. CONCLUSIONS: A particular subset of patients with various phenotypes of ICASO has a common genetic variant, RNF213 c.14576G>A, indicating that RNF213 c.14576G>A variant is a high-risk allele for ICASO.

Effects of cilostazol on cerebral vasospasm after aneurysmal subarachnoid hemorrhage: a multicenter prospective, randomized, open-label blinded end point trial.

OBJECT: Cerebral vasospasm following aneurysmal subarachnoid hemorrhage (SAH) is a major cause of subsequent morbidity and mortality. Cilostazol, a selective inhibitor of phosphodiesterase 3, may attenuate cerebral vasospasm because of its antiplatelet and vasodilatory effects. A multicenter prospective randomized trial was conducted to investigate the effect of cilostazol on cerebral vasospasm. METHODS: Patients admitted with SAH caused by a ruptured anterior circulation aneurysm who were in Hunt and Kosnik Grades I to IV and were treated by clipping within 72 hours of SAH onset were enrolled at 7 neurosurgical sites in Japan. These patients were assigned to one of 2 groups: the usual therapy group (control group) or the add-on 100 mg cilostazol twice daily group (cilostazol group). The group assignments were done by a computer-generated randomization sequence. The primary study end point was the onset of symptomatic vasospasm. Secondary end points were the onset of angiographic vasospasm and new cerebral infarctions related to cerebral vasospasm, clinical outcome as assessed by the modified Rankin scale, and length of hospitalization. All end points were assessed for the intention-to-treat population. RESULTS: Between November 2009 and December 2010, 114 patients with SAH were treated by clipping within 72 hours from the onset of SAH and were screened. Five patients were excluded because no consent was given. Thus, 109 patients were randomly assigned to the cilostazol group (n = 54) or the control group (n = 55). Symptomatic vasospasm occurred in 13% (n = 7) of the cilostazol group and in 40% (n = 22) of the control group (p = 0.0021, Fisher exact test). The incidence of angiographic vasospasm was significantly lower in the cilostazol group than in the control group (50% vs 77%; p = 0.0055, Fisher exact test). Multiple logistic analyses demonstrated that nonuse of cilostazol is an independent factor for symptomatic and angiographic vasospasm. The incidence of new cerebral infarctions was also significantly lower in the cilostazol group than in the control group (11% vs 29%; p = 0.0304, Fisher exact test). Clinical outcomes at 1, 3, and 6 months after SAH in the cilostazol group were better than those in the control group, although a significant difference was not shown. There was also no significant difference in the length of hospitalization between the groups. No severe adverse event occurred during the study period. CONCLUSIONS: Oral administration of cilostazol is effective in preventing cerebral vasospasm with a low risk of severe adverse events. Clinical trial registration no. UMIN000004347, University Hospital Medical Information Network Clinical Trials Registry.

Detection of compression vessels in trigeminal neuralgia by surface-rendering three-dimensional reconstruction of 1.5- and 3.0-T magnetic resonance imaging.

OBJECTIVE: Surface-rendered three-dimensional (3D) 1.5-T magnetic resonance (MR) imaging is useful for presurgical simulation of microvascular decompression. This study compared the sensitivity and specificity of 1.5- and 3.0-T surface-rendered 3D MR imaging for preoperative identification of the compression vessels of trigeminal neuralgia. METHODS: One hundred consecutive patients underwent microvascular decompression for trigeminal neuralgia. Forty and 60 patients were evaluated by 1.5- and 3.0-T MR imaging, respectively. Three-dimensional MR images were constructed on the basis of MR imaging, angiography, and venography data and evaluated to determine the compression vessel before surgery. MR imaging findings were compared with the microsurgical findings to compare the sensitivity and specificity of 1.5- and 3.0-T MR imaging. RESULTS: The agreement between MR imaging and surgical findings depended on the compression vessels. For superior cerebellar artery, 1.5- and 3.0-T MR imaging had 84.4% and 82.7% sensitivity and 100% and 100% specificity, respectively. For anterior inferior cerebellar artery, 1.5- and 3.0-T MR imaging had 33.3% and 50% sensitivity and 92.9% and 95% specificity, respectively. For the petrosal vein, 1.5- and 3.0-T MR imaging had 75% and 64.3% sensitivity and 79.2% and 78.1% specificity, respectively. Complete pain relief was obtained in 36 of 40 and 55 of 60 patients undergoing 1.5- and 3.0-T MR imaging, respectively. CONCLUSIONS: The present study showed that both 1.5- and 3.0-T MR imaging provided high sensitivity and specificity for preoperative assessment of the compression vessels of trigeminal neuralgia. Preoperative 3D imaging provided very high quality presurgical simulation, resulting in excellent clinical outcomes.

Genetic alterations in primary glioblastomas in Japan.

Current knowledge of genetic alterations in glioblastomas is based largely on genetic analyses of tumors from mainly caucasian patients in the United States and Europe. In the present study, screening for several key genetic alterations was performed on 77 primary (de novo) glioblastomas in Japanese patients. SSCP followed by DNA sequencing revealed TP53 mutations in 16 of 73 (22%) glioblastomas and PTEN mutations in 13 of 63 (21%) cases analyzed. Polymerase chain reaction (PCR) showed EGFR amplification in 25 of 77 (32%) cases and p16 homozygous deletion in 32 of 77 (42%) cases. Quantitative microsatellite analysis revealed LOH 10q in 41 of 59 (69%) glioblastomas. The frequencies of these genetic alterations were similar to those reported for primary glioblastomas at the population level in Switzerland. As previously observed for glioblastomas in Europe, there was a positive association between EGFR amplification and p16 deletion (p=0.009), whereas there was an inverse association between TP53 mutations and p16 deletion (p=0.049) in glioblastomas in Japan. Multivariate analyses showed that radiotherapy was significantly predictive for longer survival of glioblastoma patients (p=0.002). SSCP followed by DNA sequencing of the kinase domain (exons 18-21) of the EGFR gene revealed mutations in 2 ou of 69 (3%) glioblastomas in Japan and in 4 of 81 (5%) glioblastomas in Switzerland. The allele frequencies of polymorphisms at codon 787 CAG/CAA (Gln/Gln) in glioblastomas in Japan were G/G (82.4%), G/A (10.8%), A/A (6.8%), corresponding to G 0.878 versus A 0.122, significantly different from those in glioblastomas in Switzerland: G/G (27.2%), G/A (28.4%), A/A (44.4%), corresponding to G 0.414 versus A 0.586 (p < 0.0001). These results suggest that primary glioblastomas in Japan show genetic alterations similar to those in Switzerland, suggesting a similar molecular basis in caucasians and Asians, despite different genetic backgrounds, including different status of a polymorphism in the EGFR gene.

Surface rendered three-dimensional MR imaging for the evaluation of trigeminal neuralgia and hemifacial spasm.

Surface rendered three-dimensional (SR3D) magnetic resonance (MR) imaging was used to visualize the cerebellopontine angle nerves, blood vessels and brain stem and compared with the operative view in patients undergoing microvascular decompression. Thirty-one patients with 32 affected nerves manifesting as trigeminal neuralgia (TN, 16 cases), hemifacial spasm (HFS, 14 cases) and glossopharyngeal neuralgia (2 cases) underwent microvascular decompression at the Kanto Neurosurgical Hospital between February 2001 and July 2002. Preoperative MR imaging and MR angiography were performed in all patients. The SR3D MR image and the operative view correlated in 30 of the 31 patients. A very thin artery was not detected in one patient with TN. SR3D MR imaging can clearly demonstrate the three-dimensional relationship between the nerves and the offending vessel, so is very effective for the preoperative planning of microvascular decompression in cases of TN and HFS.

Current usage of three-dimensional computed tomography angiography for the diagnosis and treatment of ruptured cerebral aneurysms.

Our previous study suggested that 3D-CT angiography could replace digital subtraction (DS) angiography in most cases of ruptured cerebral aneurysms, especially in the anterior circulation. This study reviewed our further experience. One hundred and fifty patients with ruptured cerebral aneurysms were treated between November 1998 and March 2002. Only 3D-CT angiography was used for the preoperative work-up study in patients with anterior circulation aneurysms, unless the attending neurosurgeons agreed that DS angiography was required. Both 3D-CT angiography and DS angiography were performed in patients with posterior circulation aneurysms, except for recent cases that were possibly treated with 3D-CT angiography alone. One hundred sixteen (84%) of 138 patients with ruptured anterior circulation aneurysms underwent surgical treatment, but additional DS angiography was required in 22 cases (16%). Only two recent patients were treated surgically with 3D-CT angiography alone in 12 patients with posterior circulation aneurysms. Most patients with ruptured anterior circulation aneurysms could be treated successfully after 3D-CT angiography alone. However, additional DS angiography is still necessary in atypical cases. 3D-CT angiography may be limited to complementary use in patients with ruptured posterior circulation aneurysms.

Late recurrence of subarachnoid hemorrhage due to regrowth of aneurysm after neck clipping surgery.

Late recurrence of subarachnoid hemorrhage (SAH) due to regrowth of aneurysm after neck clipping surgery occurred in four patients. Two patients underwent surgical treatment, and two patients received endovascular treatment. Endovascular treatment was successful in one case, but emergent surgery was necessary for the other case because of possible pseudoaneurysm formation. Postoperative course of all patients was excellent. Late recurrence of SAH can occur even after complete clipping, and further treatment should be considered.

Treatment of ruptured anterior circulation aneurysm based on computerized tomography angiography: surgical results and indications for additional digital subtraction angiography.

The purpose of this study is to determine whether or to what extent computerized tomography angiography (CTA) can replace digital subtraction angiography (DSA) for ruptured anterior circulation cerebral aneurysms. We reviewed our patients in two different periods and evaluated in what cases we should perform additional DSA. In the first period, both CTA and DSA were routinely performed except on patients that were suitable for emergent surgery with CTA only. In the second period, only CTA was performed routinely as a preoperative workup and if further information was necessary, additional DSA was performed. A total of 106 (52 in the first period and 54 in the second period) patients were included. Characteristics of the patients and outcome at three months were similar in the two periods. In the second period, ten patients underwent additional DSA. Our results suggest that most of cases with ruptured anterior circulation aneurysms can be successfully treated on the basis of CTA alone.