Takeshi Funaki

Significance of the Hemorrhagic Site for Recurrent Bleeding: Prespecified Analysis in the Japan Adult Moyamoya Trial

Background and Purpose— The primary results of the Japan Adult Moyamoya Trial revealed the statistically marginal superiority of bypass surgery over medical treatment alone in preventing rebleeding in moyamoya disease. The purpose of this analysis is to test the prespecified subgroup hypothesis that the natural course and surgical effects vary depending on the hemorrhagic site at onset. Methods— The hemorrhagic site, classified as either anterior or posterior, was the only stratifying variable for randomization. Statistical analyses were focused on the assessment of effect modification according to the hemorrhagic site and were based on tests of interaction. Results— Of 42 surgically treated patients, 24 were classified as anterior hemorrhage and 18 as posterior hemorrhage; of 38 medically treated patients, 21 were classified as anterior and 17 as posterior. The hazard ratio of the primary end points (all adverse events) for the surgical group relative to the nonsurgical group was 0.07 (95% confidence interval, 0.01–0.55) for the posterior group, as compared with 1.62 (95% confidence interval, 0.39–6.79) for the anterior group (P=0.013 for interaction). Analysis within the nonsurgical group revealed that the incidence of the primary end point was significantly higher in the posterior group than in the anterior group (17.1% per year versus 3.0% per year; hazard ratio, 5.83; 95% confidence interval, 1.60–21.27). Conclusions— Careful interpretation of the results suggests that patients with posterior hemorrhage are at higher risk of rebleeding and accrue greater benefit from surgery, subject to verification in further studies. Clinical Trial Registration— URL: http://www.umin.ac.jp/ctr/index.htm. Unique identifier: C000000166.

Impact of posterior cerebral artery involvement on long-term clinical and social outcome of pediatric moyamoya disease

OBJECT In the study of pediatric moyamoya disease, information on long-term social outcomes and risk factors for unfavorable social outcomes remains insufficient. The authors analyzed the long-term results of surgical revascularization for pediatric patients with moyamoya disease to determine whether the involvement of a stenoocclusive lesion in the posterior cerebral artery (PCA), relatively common in pediatric moyamoya disease, represents an underlying predictor for unfavorable social outcomes. METHODS Prospectively collected data on 61 consecutive patients with moyamoya disease who had undergone combined bypass surgery were analyzed. Neuroradiological features and other baseline clinical factors were incorporated into univariate and multivariate analyses to determine any association with an unfavorable social outcome, defined as difficulty attending regular school or obtaining regular employment. RESULTS Posterior cerebral artery involvement detected by angiography on admission was noted in 22 (36.1%) of the 61 patients. Follow-up data were acquired in 56 patients (91.8%), and the mean follow-up period was 15.8 years. While transient ischemic attacks were eliminated in 52 (92.9%) of these 56 patients after surgery, and late-onset ischemic stroke was observed in only 1 patient during the follow-up period, 10 (17.9%) experienced an unfavorable social outcome. Although younger age at onset, longer duration between onset and surgery, infarction present on preoperative neuroradiological images, and PCA involvement had been identified as risk factors for an unfavorable social outcome in univariate analysis, only infarction present on preoperative images and PCA involvement remained statistically significant after multivariate adjustment. CONCLUSIONS Posterior cerebral artery involvement can be considered one of the underlying risk factors for unfavorable social outcome and should be studied further to improve social outcome in pediatric moyamoya disease.

Histologic characterization of mobile and nonmobile carotid plaques detected with ultrasound imaging.

OBJECTIVES Although mobile plaques in the carotid arteries detected by duplex ultrasound imaging are considered to cause unstable neurologic symptoms such as crescendo transient ischemic attack or progressive stroke, the histology of mobile plaques has not been sufficiently documented. This study examined the histopathologic features of mobile plaques of the carotid artery and compared the histopathology between mobile and nonmobile plaques. METHODS Of 228 carotid plaques assessed by preoperative carotid ultrasound imaging, 21 (9.3%) were diagnosed as mobile symptomatic plaques. Of these, 18 were intact after excision by endarterectomy and enrolled for histologic examination. From the remaining 207 nonmobile plaque specimens, 17 nonmobile but symptomatic plaque specimens were extracted for histologic comparison. An investigator blinded to the ultrasound findings assessed both plaque specimens for fibrous cap thickness, fibrous cap rupture, fibrous cap area, necrotic core size, inflammatory cells, intraplaque hemorrhage, and mural thrombus. Clinical data, including progressive ischemic symptoms after admission, were also examined. RESULTS Progressive ischemic symptoms were more frequently seen in patients with mobile plaques than in those with nonmobile plaques (33.3% vs 0%, P = .02). The ratio of the cross-sectional area of the necrotic core to that of the entire plaque was significantly larger for mobile plaques than for nonmobile plaques (mean, 0.660 vs 0.417, P < .0001). Mural thrombus was more prevalent among mobile plaques (89%) than among nonmobile plaques (59%), but the difference was not significant (P = .06). The median minimum thickness of the fibrous cap was extremely small in both groups (80 μm in mobile plaques and 100 μm in nonmobile plaques, P = .33). CONCLUSIONS The histologic characteristics of mobile carotid plaques are different from those of nonmobile symptomatic plaques, especially in the area of the necrotic core. This histologic difference may partly explain the unstable neurologic presentations of patients with mobile carotid plaques.

Successful obliteration and shrinkage of giant partially thrombosed basilar artery aneurysms through a tailored flow reduction strategy with bypass surgery

OBJECT The authors evaluated the efficacy of a new flow reduction strategy for giant partially thrombosed upper basilar artery (BA) aneurysms, for which proximal parent artery occlusion is not always effective. METHODS Eight consecutive patients with severely symptomatic, partially thrombosed, giant upper BA aneurysms were treated with a tailored flow reduction strategy, or received conservative therapies. The flow reduction strategy comprised isolation of several branches from the upper BA at their origins with bypasses in addition to parent artery occlusion. RESULTS The median follow-up period of all 8 patients was 15.0 months (range 4-31 months). In 6 patients treated with flow reduction, the mean decrease in residual blood lumen was -10.7 mm (95% CI -19.7 to -1.7 mm; p = 0.029) and the mean decrease in diameter of the aneurysms was -11.5 mm (95% CI -25.1 to 2.1 mm; p = 0.082). Complete or virtually complete thrombosis was achieved in all but 1 aneurysm (83%) and shrinkage was observed in 4 (67%). In those in whom complete or virtually complete thrombosis was achieved, significant shrinkage of the aneurysm was observed (mean decrease in diameter -14.8 mm; 95% CI -28.8 to -0.8 mm; p = 0.043). Improvement or stabilization of symptoms occurred in 67% of the patients who received flow reduction treatment. Both patients who received conservative treatment had unfavorable outcomes. CONCLUSIONS The flow reduction strategy is effective at promoting complete thrombosis of the aneurysm. This strategy can also induce shrinkage of the aneurysm if successful thrombosis is achieved. Although the neurological outcome of the treatment appears favorable considering its intractable nature, further study of the treatment is necessary to confirm its clinical efficacy and safety.

Visualization of Periventricular Collaterals in Moyamoya Disease with Flow-sensitive Black-blood Magnetic Resonance Angiography: Preliminary Experience

Fragile abnormal collaterals in moyamoya disease, known as “moyamoya vessels,” have rarely been defined. While flow-sensitive black-blood magnetic resonance angiography (FSBB-MRA) is a promising technique for visualizing perforating arteries, as of this writing no other reports exist regarding its application to moyamoya disease. Six adults with moyamoya disease underwent FSBB-MRA. It depicted abnormal collaterals as extended lenticulostriate, thalamic perforating, or choroidal arteries, which were all connected to the medullary or insular artery in the periventricular area and supplied the cortex. This preliminary case series illustrates the potential for FSBB-MRA to reveal abnormal moyamoya vessels, which could be reasonably defined as periventricular collaterals.

Significant Association of the RNF213 p.R4810K Polymorphism with Quasi-Moyamoya Disease.

BACKGROUND Quasi-moyamoya disease is an angiographical moyamoya disease equivalent accompanied by known underlying diseases. Mysterin/RNF213 is a major susceptibility gene for moyamoya disease, of which the p.R4810K variant is a founder polymorphism. The genetics of quasi-moyamoya disease is poorly understood, therefore, this study investigated a potential association between the p.R4810K polymorphism and quasi-moyamoya disease. METHODS Genotyping of the p.R4810K variant was performed on 18 quasi-moyamoya disease cases and 91 controls, who visited Kyoto University Hospital or Kobe City Medical Center, Japan, between 2006 and 2015. RESULTS The p.R4810K variant was found in 12 of 18 quasi-moyamoya disease patients. The frequency of p.R4810K carriers was significantly higher in quasi-moyamoya disease cases than in controls (66.7% versus 2.2%, odds ratio 89.0, 95% confidence interval: 19.2-669.4). CONCLUSIONS Our data showed that the RNF213 p.R4810K polymorphism was significantly associated with quasi-moyamoya disease.

Differential gene expression in relation to the clinical characteristics of human brain arteriovenous malformations.

Arteriovenous malformations (AVMs) of the central nervous system are considered as congenital disorders. They are composed of abnormally developed dilated arteries and veins and are characterized microscopically by the absence of a capillary network. We previously reported DNA fragmentation and increased expression of apoptosis-related factors in AVM lesions. In this article, we used microarray analysis to examine differential gene expression in relation to clinical manifestations in 11 AVM samples from Japanese patients. We categorized the genes with altered expression into four groups: death-related, neuron-related, inflammation-related, and other. The death-related differentially expressed genes were MMP9, LIF, SOD2, BCL2A1, MMP12, and HSPA6. The neuron-related genes were NPY, S100A9, NeuroD2, S100Abeta, CAMK2A, SYNPR, CHRM2, and CAMKV. The inflammation-related genes were PTX3, IL8, IL6, CXCL10, GBP1, CHRM3, CXCL1, IL1R2, CCL18, and CCL13. In addition, we compared gene expression in those with or without clinical characteristics including deep drainer, embolization, and high-flow nidus. We identified a small number of genes. Using these microarray data we are able to generate and test new hypotheses to explore AVM pathophysiology. Microarray analysis is a useful technique to study clinical specimens from patients with brain vascular malformations.

Significant association of RNF213 p.R4810K, a moyamoya susceptibility variant, with coronary artery disease

Background The genetic architecture of coronary artery disease has not been fully elucidated, especially in Asian countries. Moyamoya disease is a progressive cerebrovascular disease that is reported to be complicated by coronary artery disease. Because most Japanese patients with moyamoya disease carry the p.R4810K variant of the ring finger 213 gene (RNF213), this may also be a risk factor for coronary artery disease; however, this possibility has never been tested. Methods and results We genotyped the RNF213 p.R4810K variant in 956 coronary artery disease patients and 716 controls and tested the association between p.R4810K and coronary artery disease. We also validated the association in an independent population of 311 coronary artery disease patients and 494 controls. In the replication study, the p.R4810K genotypes were imputed from genome-wide genotyping data based on the 1000 Genomes Project. We used multivariate logistic regression analyses to adjust for well-known risk factors such as dyslipidemia and smoking habits. In the primary study population, the frequency of the minor variant allele was significantly higher in patients with coronary artery disease than in controls (2.04% vs. 0.98%), with an odds ratio of 2.11 (p = 0.017). Under a dominant model, after adjustment for risk factors, the association remained significant, with an odds ratio of 2.90 (95% confidence interval: 1.37–6.61; p = 0.005). In the replication study, the association was significant after adjustment for age and sex (odds ratio = 4.99; 95% confidence interval: 1.16–21.53; p = 0.031), although it did not reach statistical significance when further adjusted for risk factors (odds ratio = 3.82; 95% confidence interval: 0.87–16.77; p = 0.076). Conclusions The RNF213 p.R4810K variant appears to be significantly associated with coronary artery disease in the Japanese population.

Voxel Based Analysis of Surgical Revascularization for Moyamoya Disease: Pre- and Postoperative SPECT Studies.

Moyamoya disease (MMD) is a chronic, progressive, cerebrovascular occlusive disease that causes abnormal enlargement of collateral pathways (moyamoya vessels) in the region of the basal ganglia and thalamus. Cerebral revascularization procedures remain the preferred treatment for patients with MMD, improving the compromised cerebral blood flow (CBF). However, voxel based analysis (VBA) of revascularization surgery for MMD based on data from pre- and postoperative data has not been established. The latest algorithm called as Diffeomorphic Anatomical Registration Through Exponentiated Lie Algebra (DARTEL) has been introduced for VBA as the function of statistical parametric mapping (SPM8), and improved registration has been achieved by SPM8 with DARTEL. In this study, VBA was conducted to evaluate pre- and postoperative single photon emission computed tomography (SPECT) images for MMD by SPM8 with DARTEL algorithm, and the results were compared with those from SPM8 without DARTEL (a conventional method). Thirty-two patients with MMD who underwent superficial temporal artery-middle cerebral artery (STA-MCA) bypass surgery as the first surgery were included and all patients underwent pre- and postoperative 3D T1-weighted imaging and SPECT. Pre- and postoperative SPECT images were registered to 3D T1-weighted images, then VBA was conducted. Postoperative SPECT showed more statistically increased CBF areas in the bypassed side cerebral hemisphere by using SPM8 with DARTEL (58,989 voxels; P<0.001), and increased ratio of CBF after operation was less than 15%. Meanwhile, postoperative SPECT showed less CBF increased areas by SPM8 without DARTEL. In conclusion, VBA was conducted for patients with MMD, and SPM8 with DARTEL revealed that postoperative SPECT showed statistically significant CBF increases over a relatively large area and with at most 15% increase ratio.

Angiographic features of hemorrhagic moyamoya disease with high recurrence risk: a supplementary analysis of the Japan Adult Moyamoya Trial

OBJECTIVE In this paper, the authors set out to identify the angiographic features of moyamoya disease with posterior hemorrhage, which is a strong predictor of rebleeding. METHODS This cross-sectional study used the data set of the Japan Adult Moyamoya Trial (clinical trial registration no.: C000000166 [ www.umin.ac.jp/ctr/index.htm ]). The panel designed the ancillary measurement of angiography at onset, classifying the collateral vessels into 3 subtypes: lenticulostriate anastomosis, thalamic anastomosis, and choroidal anastomosis. The association between each collateral and the hemorrhage site (anterior vs posterior) was assessed in the hemorrhagic hemisphere by using multivariate adjustment for potential confounders, including age, sex, and involvement of the posterior cerebral artery (PCA). The association was confirmed through topographical analysis of bleeding points. RESULTS Among the 80 participants, 75 hemorrhagic hemispheres of 75 patients were analyzed. Lenticulostriate anastomosis was detected in 21 (28.0%) hemorrhagic hemispheres, thalamic anastomosis in 22 (29.3%), and choroidal anastomosis in 35 (46.7%). Choroidal anastomosis was a factor associated with posterior hemorrhage (OR 2.77 [95% CI 1.08-7.10], p = 0.034) and remained statistically significant after the multivariate adjustment (OR 2.66 [95% CI 1.00-7.07], p = 0.049). PCA involvement was also associated with posterior hemorrhage in both univariate and multivariate analyses. Topographical analysis revealed good correspondence between bleeding points associated with positive choroidal anastomosis and the anatomical distribution of the choroidal arteries, including the thalamus and the wall of the atrium. CONCLUSIONS Choroidal anastomosis and PCA involvement are characteristic of posterior hemorrhage in moyamoya disease. Choroidal anastomosis might be considered a potential source of posterior hemorrhage at high risk of rebleeding.