Review of past and present research on experimental models of moyamoya disease

Moyamoya disease (MMD) is characterized by a progressive steno-occlusive disease affecting the terminal portions of the cerebral internal carotid artery (ICA) and by formation of an abnormal vascular network at the base of the brain. Several pathogeneses, including inflammation, immune complex, upregulation of angiogenic factors, and abnormality of endothelial progenitor cells (EPCs) have been hypothesized. However, the mechanisms of MMD are largely unknown, and in vivo and in vitro models of MMD have not yet been established. Previously, inflammation- and immune-complex-related animal models have been reported but failed to reproduce severe stenotic lesions in the terminal portion of ICA. Thereafter, several clinical studies revealed that angiogenic activity of circulating EPCs was defective in MMD patients. These results suggested that the function and quantity of EPCs could be useful as a cellular model of MMD. Very recently, RING finger protein 213 (RNF213) was identified as an MMD susceptibility gene, a discovery that led to the efforts to generate gene mutation-based animal models. Although RNF213 knockout animal models have not yet successfully represented the phenotype of MMD, they have provided new insights into the role of RNF213 in remodeling after vascular injury and postischemic angiogenesis. Furthermore, the use of induced pluripotent stem cells (iPSCs) and an appropriate differentiation protocol have made it possible to obtain abundant quantities of MMD-specific vascular cells. In summary, studies have shown that endothelial cells derived from MMD-iPSCs have impaired angiogenic activity, which is a finding consistent with the results of EPC studies. Further studies are needed to create true MMD-specific experimental models to promote understanding of MMC pathogenesis and aid drug development

Spinal rosette-forming glioneuronal tumor A case report

Rationale: Rosette-forming glioneuronal tumor (RGNT) is a rare tumor which has been first reported as the fourth ventricle tumor by Komori et al and is classified as a distinct clinicopathological entity by the WHO Classification of Tumors of the Central Nervous System as in 2007. Although RGNTs were reported to occur in both supratentorial and inflatentorial sites, only 4 case reports of spinal RGNT have been demonstrated. Patientconcerns: A 37-year-old female presenting with slowly progressing right-sided clumsiness. Cervical magnetic resonance imaging revealed a spinal intramedullary tumor between the C2 and C5 levels. Diagnoses: Pathological analysis showed unique biphasic cellular architecture consisting of perivascular pseudorosettes dominantly with few neurocytic rosettes and diffuse astrocytoma component. The tumor cells composed of perivascular pseudorosettes showed positivity for both synaptophysin and glial markers such as GFAP and Olig2. Therefore, the diagnosis of RGNT was made. Interventions: Gross total resection of the tumor was achieved. No adjuvant chemotherapy nor radiotherapy was conducted after operation. Outcomes: At 2 years after the operation, no recurrence was observed. Lessons: Although RGNT arising from the spinal cord is extremely rare, we need to consider the tumor as a differential diagnosis for intramedullary spinal cord tumors

Investigation of the Neuropathic Pain Caused by Syringomyelia Associated with Chiari I Malformation

Study Design: Retrospective cohort study. Purpose: To investigate the correlation between the syrinx morphology and neuropathic pain caused by syringomyelia associated with Chiari I malformation. Overview of Literature: Neuropathic pain caused by syringomyelia is refractory and markedly impairs the patient. Methods: We examined 24 patients with neuropathic pain caused by syringomyelia associated with Chiari I malformation. We statistically analyzed the illness duration and age at surgery between patients with and without neuropathic pain. Additionally, we classified the morphology of the syringes into deviated (D), enlarged (E), central (C), and bulkhead (B) types using T2-weighted axial imaging. Moreover, we investigated the correlation between syrinx morphology and neuropathic pain. A Mann-Whitney U-test was performed to compare between the presence or absence of neuropathic pain and the presence or absence of type D syringes. Results: The median age at surgery was 27.5 years, and the median illness duration was 24 months. Among the 24 patients, 11 had preoperative neuropathic pain, one of which was free of neuropathic pain during the final follow-up period. Among patients with neuropathic pain, the syringes' preoperative morphology was type D in nine patients and types E and C in one patient each. No patient exhibited type B morphology. Among patients without neuropathic pain, the preoperative morphology of the syringes was type D in three patients, type E in seven patients, and types C and B in two patients each. For types D and E, a correlation between neuropathic pain and syrinx morphology was observed. Moreover, type D was associated with significant neuropathic pain in both preoperative and postoperative states. Conclusions: This study showed a correlation between the morphological features of the syringes and the occurrence of neuropathic pain in patients with syringomyelia associated with Chiari I malformation

Estimation of the number of feeding arteries of spinal arteriovenous malformations by using three-dimensional digital subtraction angiography

Purpose Spinal angiography is the gold standard for evaluation or diagnosis of spinal arteriovenous malformations (AVMs). However, some feeding arteries might be overlooked when multiple feeders exist. This study aimed to retrospectively review cases of spinal intra-dural AVMs, which were identified by three-dimensional digital subtraction angiography (3D-DSA), and attempted to estimate the number of feeding arteries.Methods We retrospectively reviewed patients with spinal intra-dural AVMs who underwent 3D-DSA at Hokkaido University Hospital from January 2005 to December 2016. We selected 9 patients in whom we could obtain data of multi-planar reconstruction of 3D-DSA. We measured the computed tomography (CT) values of feeding arteries and draining veins. The CT values represented the averages of maximum CT values of 5 continuous axial slices. The ratio of the CT value of feeders to that of drainers (F/D ratio) was calculated. The correlation between the F/D ratio and the number of feeders was examined with Pearson's correlation coefficient.Results The average number of feeders was 2.3 (1-4), and the number of feeders was significantly positively correlated with the F/D ratio (r=0.855, P=.003).Conclusions We conclude that the number of feeding arteries of spinal intra-dural AVMs can be estimated by using the F/D ratio obtained from 3D-DSA

Circulating miRNome profiling in Moyamoya disease-discordant monozygotic twins and endothelial microRNA expression analysis using iPS cell line

Abstract Background Moyamoya disease (MMD) is characterized by progressive stenosis of intracranial arteries in the circle of Willis with unknown etiology even after the identification of a Moyamoya susceptible gene, RNF213. Recently, differences in epigenetic regulations have been investigated by a case-control study in MMD. Here, we employed a disease discordant monozygotic twin-based study design to unmask potential confounders. Methods Circulating genome-wide microRNA (miRNome) profiling was performed in MMD-discordant monozygotic twins, non-twin-MMD patients, and non-MMD healthy volunteers by microarray followed by qPCRvalidation, using blood samples. Differential plasma-microRNAs were further quantified in endothelial cells differentiated from iPS cell lines (iPSECs) derived from another independent non-twin cohort. Lastly, their target gene expression in the iPSECs was analyzed. Results Microarray detected 309 plasma-microRNAs in MMD-discordant monozygotic twins that were also detected in the non-twin cohort. Principal component analysis of the plasma-microRNA expression level demonstrated distinct 2 groups separated by MMD and healthy control in the twin- and non-twin cohorts. Of these, differential upregulations of hsa-miR-6722-3p/− 328-3p were validated in the plasma of MMD (absolute log2 expression fold change (logFC) > 0.26 for the twin cohort; absolute logFC > 0.26, p < 0.05, and q < 0.15 for the non-twin cohort). In MMD derived iPSECs, hsa-miR-6722-3p/− 328-3p showed a trend of up-regulation with a 3.0- or higher expression fold change. Bioinformatics analysis revealed that 41 target genes of miR-6722-3p/− 328-3p were significantly down-regulated in MMD derived iPSECs and were involved in STAT3, IGF-1-, and PTEN-signaling, suggesting a potential microRNA-gene expression interaction between circulating plasma and endothelial cells. Conclusions Our MMD-discordant monozygotic twin-based study confirmed a novel circulating microRNA signature in MMD as a potential diagnostic biomarker minimally confounded by genetic heterogeneity. The novel circulating microRNA signature can contribute for the future functional microRNA analysis to find new diagnostic and therapeutic target of MMD

Constant current stimulation may improve apraxia of eyelid opening induced by deep brain stimulation

Background: Apraxia of eyelid opening (AEO) is a common side effect of subthalamic nucleus deep brain stimulation (STN-DBS) and difficult to treat. We report the case of a patient with Parkinson's disease (PD) whose DBS-induced AEO was alleviated after adjustment from constant-voltage (CV) to constant-current (CC) stimulation. Case description: A female patient with PD underwent bilateral STN-DBS surgery 12 years after onset. Three months after the start of stimulation, she developed bilateral AEO though her motor symptoms improved. Her AEO severity deteriorated in line with an increase in stimulation-voltage. Three years after surgery, we replaced the implantable pulse generators (IPGs) because of low voltage. We changed the stimulation programs from CV stimulation to CC stimulation as only CC stimulation was available on the new IPG model. Her AEO was significantly improved after the stimulation programs were changed from CV to CC stimulation, even though the stimulation intensity did not change markedly. Her motor symptoms did not change. We evaluated the association between AEO severity and stimulation contact point and found that stimulation at the lowest contact on the left side strongly induced AEO. Conclusion: Shifting from CV stimulation to CC stimulation may improve DBS-induced AEO. The exact mechanism underlying this improvement is unknown and further studies are needed to confirm the efficacy of CC stimulation for AEO