Long-term outcomes of stereotactic radiosurgery for intracranial schwannoma in neurofibromatosis type 2: a genetic analysis perspective.

PURPOSE: Neurofibromatosis type 2 (NF2) is intractable because of multiple tumors involving the nervous system and is clinically diverse and genotype-dependent. Stereotactic radiosurgery (SRS) for NF2-associated schwannomas remains controversial. We aimed to investigate the association between radiosurgical outcomes and mutation types in NF2-associated schwannomas. METHODS: This single-institute retrospective study included consecutive NF2 patients with intracranial schwannomas treated with SRS. The patients' types of germline mutations ("Truncating," "Large deletion," "Splice site," "Missense," and "Mosaic") and Halliday's genetic severity scores were examined, and the associations with progression-free rate (PFR) and overall survival (OS) were analyzed. RESULTS: The study enrolled 14 patients with NF2 with 22 associated intracranial schwannomas (median follow-up, 102 months).　The PFRs in the entire cohort were 95% at 5 years and 90% at 10-20 years. The PFRs tended to be worse in patients with truncating mutation exons 2-13 than in those with other mutation types (91% at 5 years and 82% at 10-20 years vs. 100% at 10-20 years, P = 0.140). The OSs were 89% for patients aged 40 years and 74% for those aged 60 years in the entire cohort and significantly lower in genetic severity group 3 than in the other groups (100% vs. 50% for those aged 35 years; P = 0.016). CONCLUSION: SRS achieved excellent PFR for NF2-associated intracranial schwannomas in the mild (group 2A) and moderate (group 2B) groups. SRS necessitates careful consideration for the severe group (group 3), especially in cases with NF2 truncating mutation exons 2-13.

The importance of considering competing risks in recurrence analysis of intracranial meningioma.

BACKGROUND: The risk of recurrence is overestimated by the Kaplan-Meier method when competing events, such as death without recurrence, are present. Such overestimation can be avoided by using the Aalen-Johansen method, which is a direct extension of Kaplan-Meier that accounts for competing events. Meningiomas commonly occur in older individuals and have slow-growing properties, thereby warranting competing risk analysis. The extent to which competing events are considered in meningioma literature is unknown, and the consequences of using incorrect methodologies in meningioma recurrence risk analysis have not been investigated. METHODS: We surveyed articles indexed on PubMed since 2020 to assess the usage of competing risk analysis in recent meningioma literature. To compare recurrence risk estimates obtained through Kaplan-Meier and Aalen-Johansen methods, we applied our international database comprising ~ 8,000 patients with a primary meningioma collected from 42 institutions. RESULTS: Of 513 articles, 169 were eligible for full-text screening. There were 6,537 eligible cases from our PERNS database. The discrepancy between the results obtained by Kaplan-Meier and Aalen-Johansen was negligible among low-grade lesions and younger individuals. The discrepancy increased substantially in the patient groups associated with higher rates of competing events (older patients with high-grade lesions). CONCLUSION: The importance of considering competing events in recurrence risk analysis is poorly recognized as only 6% of the studies we surveyed employed Aalen-Johansen analyses. Consequently, most of the previous literature has overestimated the risk of recurrence. The overestimation was negligible for studies involving low-grade lesions in younger individuals; however, overestimation might have been substantial for studies on high-grade lesions.

Somatic GJA4 gain-of-function mutation in orbital cavernous venous malformations.

Orbital cavernous venous malformation (OCVM) is a sporadic vascular anomaly of uncertain etiology characterized by abnormally dilated vascular channels. Here, we identify a somatic missense mutation, c.121G > T (p.Gly41Cys) in GJA4, which encodes a transmembrane protein that is a component of gap junctions and hemichannels in the vascular system, in OCVM tissues from 25/26 (96.2%) individuals with OCVM. GJA4 expression was detected in OCVM tissue including endothelial cells and the stroma, through immunohistochemistry. Within OCVM tissue, the mutation allele frequency was higher in endothelial cell-enriched fractions obtained using magnetic-activated cell sorting. Whole-cell voltage clamp analysis in Xenopus oocytes revealed that GJA4 c.121G > T (p.Gly41Cys) is a gain-of-function mutation that leads to the formation of a hyperactive hemichannel. Overexpression of the mutant protein in human umbilical vein endothelial cells led to a loss of cellular integrity, which was rescued by carbenoxolone, a non-specific gap junction/hemichannel inhibitor. Our data suggest that GJA4 c.121G > T (p.Gly41Cys) is a potential driver gene mutation for OCVM. We propose that hyperactive hemichannel plays a role in the development of this vascular phenotype.

Genetics of brain arteriovenous malformations and cerebral cavernous malformations.

Cerebrovascular malformations comprise abnormal development of cerebral vasculature. They can result in hemorrhagic stroke due to rupture of lesions as well as seizures and neurological defects. The most common forms of cerebrovascular malformations are brain arteriovenous malformations (bAVMs) and cerebral cavernous malformations (CCMs). They occur in both sporadic and inherited forms. Rapidly evolving molecular genetic methodologies have helped to identify causative or associated genes involved in genesis of bAVMs and CCMs. In this review, we highlight the current knowledge regarding the genetic basis of these malformations.

Hypertensive disorders of pregnancy in moyamoya disease: A single institution experience.

OBJECTIVE: The characteristics of pregnancy and delivery in patients with moyamoya disease (MMD) remain unclear. We retrospectively investigated perinatal outcomes in patients with MMD to evaluate the risks associated to this condition. MATERIALS AND METHODS: Clinical data of women with MMD who delivered at the University of Tokyo Hospital between 2000 and 2021 were collected. Maternal characteristics including genetic data, obstetric complications, method of delivery and anesthesia, neonatal outcomes, neurological events during pregnancy, delivery, and postpartum course, were reviewed. RESULTS: Thirteen pregnancies with MMD were identified. The median maternal age was 30 years. The initial clinical symptoms were identified as transient ischemic attack, infarction, and headache. Eight patients had a history of bypass surgery. The median gestational age at delivery was 37 weeks. DNA samples were collected from five patients, responsible for six pregnancies. Of these six cases, five had the RNF213 c.14429G > A (p.Arg4810Lys) heterozygous variant. Of the 13 pregnancies, seven had hypertensive disorder of pregnancy (HDP). Additionally, three of five pregnancy cases with RNF213 p.Arg4810Lys heterozygous variant presented with HDP. Nine patients underwent cesarean section, and four delivered vaginally with epidural anesthesia. One case of ischemic stroke was confirmed during the postpartum period. Regarding newborns, neither Apgar scores lower than 7 nor neonatal intensive care unit admissions were reported. CONCLUSIONS: This study suggests that the frequency of HDP is higher in patients with MMD compared to those with normal pregnancies. Strict blood pressure control should be performed in patients with MMD during pregnancy and postpartum period.

Reliability and sensitivity to altered hemodynamics measured with resting-state fMRI metrics: Comparison with 123I-IMP SPECT.

Blood oxygenation level-dependent (BOLD) contrast is sensitive to local hemodynamic changes and thus is applicable to imaging perfusion or vascular reactivity. However, knowledge about its measurement characteristics compared to reference standard perfusion imaging is limited. This study longitudinally evaluated perfusion in patients with steno-occlusive disease using resting-state functional MRI (rsfMRI) acquired before and within nine days of anterior circulation revascularization in patients with large cerebral artery steno-occlusive diseases. The reliability and sensitivity to longitudinal changes of rsfMRI temporal correlation (Rc) and time delay (TDc) relative to the cerebellar signal were examined voxel-wise in comparison with single-photon emission CT (SPECT) cerebral blood flow (CBF) using the within-subject standard deviation (Sw) and intraclass correlation coefficients (ICCs). For statistical comparisons, the standard deviation (SD) of longitudinal changes within the cerebellum, the number of voxels with significant changes in the left middle cerebral artery territory ipsilateral to surgery, and their average changes relative to the cerebellar SD were evaluated. The test-retest reliability of the fMRI metrics was also similarly evaluated using the human connectome project (HCP) healthy young adult dataset. The test-retest time interval was 31 ± 18 days. Test-retest reliability was significantly higher for SPECT (cerebellar SD: -2.59 ± 0.20) than for fMRI metrics (cerebellar SD: Rc, -2.34 ± 0.24, p = 0.04; TDc, -2.19 ± 0.21, p = 0.003). Sensitivity to postoperative changes, which was evaluated as the number of voxels, was significantly higher for fMRI TDc (8.78 ± 0.72) than for Rc (7.42 ± 1.48, p = 0.03) or SPECT CBF (6.88 ± 0.67, p < 0.001). The ratio between the average Rc, TDc, and SPECT CBF changes within the left MCA target region and cerebellar SD was also significantly higher for fMRI TDc (1.21 ± 0.79) than Rc (0.48 ± 0.94, p = 0.006) or SPECT CBF (0.23 ± 0.57, p = 0.001). The measurement variability of time delay was also larger than that of temporal correlation in HCP data within the cerebellum (t = -8.7, p < 0.001) or in the whole-brain (t = -27.4, p < 0.001) gray matter. These data suggest that fMRI time delay is more sensitive to the hemodynamic changes than SPECT CBF, although the reliability is lower. The implication for fMRI connectivity studies is that temporal correlation can be significantly decreased due to altered hemodynamics, even in cases with normal CBF.

Arterial Transit Time-Based Multidelay Combination Strategy Improves Arterial Spin Labeling Cerebral Blood Flow Measurement Accuracy in Severe Steno-Occlusive Diseases.

BACKGROUND: Although perfusion imaging plays a key role in the management of steno-occlusive diseases, the clinical usefulness of arterial spin labeling (ASL) is limited by technical issues. PURPOSE: To examine the effect of arterial transit time (ATT) prolongation on cerebral blood flow (CBF) measurement accuracy and identify the best CBF measurement protocol for steno-occlusive diseases. STUDY TYPE: Prospective. POPULATION: Moyamoya (n = 10) and atherosclerotic diseases (n = 8). FIELD STRENGTH/SEQUENCE: A 3.0T/3DT1 -weighted and ASL. ASSESSMENT: Hadamard-encoded multidelay ASL scans with/without vessel suppression (VS) and single-delay ASL scans with long-label duration (LD) and long postlabeling delay (PLD), referred to as long-label long-delay (LLLD), were acquired. CBF measurement accuracy and its ATT dependency, measured as the correlation between the relative CBF measurement difference (ASL-single-photon emission computed tomography [SPECT]) and ATT, were compared among 1) Combo (incorporating multidelay and LLLD data based on ATT), 2) standard (LD/PLD = 1333/2333 msec), and 3) LLLD (LD/PLD = 4000/4000 msec) protocols, using whole-brain voxel-wise correlation with reference standard SPECT CBF. The effect of VS on CBF measurement accuracy was also assessed. STATISTICAL TESTS: Pearson's correlation coefficient, repeated-measures analysis of variance, t-test. P< 0.05 was considered significant. RESULTS: Pearson's correlation coefficients between ASL and SPECT CBF measurements were as follows: Combo = 0.55 ± 0.09; standard = 0.52 ± 0.12; LLLD = 0.41 ± 0.10. CBF measurement was least accurate in LLLD and most accurate in Combo. VS significantly improved overall CBF measurement accuracy in the standard protocol and in moyamoya patients for the Combo. ATT dependency analysis revealed that, compared with Combo, the standard and LLLD protocols showed significantly lower and negative and significantly higher and positive correlations, respectively (standard = -0.12 ± 0.04, Combo = -0.04 ± 0.03, LLLD = 0.17 ± 0.03). DATA CONCLUSION: By using ATT-corrected CBF derived from LD/PLD = 1333/2333 msec as a base and by compensating underestimation in delayed regions using multidelay scans, the ATT-based Combo strategy improves CBF measurement accuracy compared with single-delay protocols in severe steno-occlusive diseases. EVIDENCE LEVEL: 1 TECHNICAL EFFICACY: Stage 2.

Reliability and Sensitivity to Longitudinal CBF Changes in Steno-Occlusive Diseases: ASL Versus 123 I-IMP-SPECT.

BACKGROUND: Noninvasive cerebral blood flow (CBF) monitoring using arterial spin labeling (ASL) magnetic resonance imaging is useful for managing large cerebral artery steno-occlusive diseases. However, knowledge about its measurement characteristics in comparison with reference standard perfusion imaging is limited. PURPOSE: To evaluate perfusion in a longitudinal manner in patients with steno-occlusive disease using ASL and compare with single-photon emission computed tomography (SPECT). STUDY TYPE: Prospective. POPULATION: Moyamoya (n = 10, eight females) and atherosclerotic diseases (n = 2, two males). FIELD STRENGTH/SEQUENCE: 3.0 T; gradient-echo three-dimensional T1 -weighted and spin-echo ASL. ASSESSMENT: Multi-delay ASL and [123 I]-iodoamphetamine SPECT CBF measurements were performed both before and within 9 days of anterior-circulation revascularization. Reliability and sensitivity to whole-brain voxel-wise CBF changes (ΔCBF) and their postlabeling delay (PLD) dependency with varied PLDs (in milliseconds) of 1000, 2333, and 3666 were examined. STATISTICAL TESTS: Reliability and sensitivity to ΔCBF were examined using within-subject standard deviation (Sw) and intraclass correlation coefficients (ICCs). For statistical comparisons, standard deviation of longitudinal ΔCBF within the hemisphere contralateral to surgery, and the ratio between it and average ΔCBF within the ipsilateral regions of interest were subjected to paired t tests, respectively. P < 0.05 was considered statistically significant. RESULTS: ASL test-retest time interval was 31 ± 18 days. Test-retest reliability was significantly lower for SPECT (0.16 ± 0.02) than ASL (0.13 ± 0.04). Sensitivity to postoperative changes was significantly higher for ASL (2.71 ± 2.79) than SPECT (0.27 ± 0.62). Test-retest reliability was significantly higher for a PLD of 2333 (0.13 ± 0.04) than 3666 (0.19 ± 0.05), and sensitivity to ΔCBF was significantly higher for PLDs of 1000 (2.53 ± 2.50) and 2333 than 3666 (0.79 ± 1.88). ICC maps also showed higher reliability for ASL than SPECT. DATA CONCLUSION: Higher test-retest reliability led to better ASL sensitivity than SPECT for postoperative ΔCBF. ASL test-retest reliability and sensitivity to ΔCBF were higher with a PLD of 2333. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY: Stage 2.

Targeted deep sequencing of DNA from multiple tissue types improves the diagnostic rate and reveals a highly diverse phenotype of mosaic neurofibromatosis type 2.

BACKGROUND: Although 60% of patients with de novo neurofibromatosis type 2 (NF2) are presumed to have mosaic NF2, the actual diagnostic rate of this condition remains low at around 20% because of the existing difficulties in detecting NF2 variants with low variant allele frequency (VAF). Here, we examined the correlation between the genotype and phenotype of mosaic NF2 after improving the diagnostic rate of mosaic NF2. METHODS: We performed targeted deep sequencing of 36 genes including NF2 using DNA samples from multiple tissues (blood, buccal mucosa, hair follicle and tumour) of 53 patients with de novo NF2 and elucidated their genotype-phenotype correlation. RESULTS: Twenty-four patients (45.2%) had the NF2 germline variant, and 20 patients with NF2 (37.7%) had mosaic NF2. The mosaic NF2 phenotype was significantly different from that in patients with NF2 germline variant in terms of distribution of NF2-related disease, tumour growth rate and hearing outcome. The behaviour of schwannoma correlated to the extent of VAF with NF2 variant in normal tissues unlike meningioma. CONCLUSION: We have improved the diagnostic rate of mosaic NF2 compared with that of previous studies by targeted deep sequencing of DNA from multiple tissues. Many atypical patients with NF2 diagnosed with 'unilateral vestibular schwannoma' or 'multiple meningiomas' presumably have mosaic NF2. Finally, we suggest that the highly diverse phenotype of NF2 could result not only from the type and location of NF2 variant but also the extent of VAF in the NF2 variant within normal tissue DNA.

The optimal management of ruptured basilar artery dissecting aneurysms: a case series and scoping review.

The natural history of ruptured basilar artery dissecting aneurysms (BADAs) remains unclear compared to that of ruptured vertebral artery dissecting aneurysms (VADAs). In this study, we investigated the natural history and optimal management of ruptured BADAs. We identified 17 patients with ruptured BADA among 4586 patients with aneurysmal subarachnoid hemorrhage (SAH) treated in seven participating hospitals. A scoping literature review was undertaken to investigate prognostic factors. Six patients among the profiled patients (35.3%) died, all with poor SAH grades (World Federation of Neurological Societies Grade IV and V). Rebleeding after admission was observed in three patients (17.6%) with poor SAH grades. Aggressive treatment and conservative management were initiated in seven and ten patients, respectively. Patients with good SAH grades had significantly higher favorable treatment outcomes than those with poor grades (83.3% vs. 9.1%, P = 0.005). Moreover, based on a scoping review of 158 cases with ruptured BADA, including the patients from our series, approximately 90% of patients with good SAH grades had favorable outcomes. A good SAH grade and no rebleeding after admission were favorable prognostic factors (P < 0.0001 and P = 0.002, respectively). The rebleeding rates were 20.2%, 13.3%, and 6.3% for dilated, pearl and string, and stenotic lesions, respectively. We concluded that the natural history of isolated ruptured BADAs may be better than that of VADAs. Although definitive treatment, if possible, is undoubtedly important, conservative management with careful radiological follow-up for morphological changes might be a viable option for patients in good clinical condition and with non-dilated lesions.

[Molecular Biological Background of Neurofibromatosis Type 2].

Neurofibromatosis type 2(NF2)is a hereditary tumor syndrome characterized by bilateral acoustic nerve tumors, multiple schwannomas, and multiple meningiomas. About half of the patients develop familial onset through an autosomal dominant mode of inheritance. The causative gene of NF2 is the NF2 gene, and those who have a germline mutation of the said gene invariably develop the disease. On the other hand, about half of NF2 patients are sporadic cases. It is thought that the somatic mosaic of the NF2 gene is involved in most of the sporadic cases, in which germline mutation of NF2 is not detected. It is becoming clear that the clinical features, such as the life and functional prognoses of NF2 patients, differ depending on the genotype of the causative gene.

[Solitary fibrous tumor/hemangiopericytoma].

Solitary fibrous tumor(SFT)/hemangiopericytoma(HPC)is a rare mesenchymal tumor with propensity for recurrence and metastasis. Although SFT and HPC were initially considered to be distinct entities, the identification of NAB2-STAT6 fusion as a definitive molecular alteration in both tumors has led to their integration into one disease entity, for both meningeal and non-meningeal lesions. This fusion leads to a nuclear relocation of the STAT6 protein and is detectable with immunohistochemistry. STAT6 immunohistochemistry has been shown to have excellent sensitivity and specificity for histological diagnosis. Although these discoveries have improved the diagnosis of SFT/HPC, the association of the NAB2-STAT6 fusion status with phenotype and prognosis remains unclear, and accurate prognostic factors have not been established. This comprehensive review provides current knowledge on the clinical, histological, and molecular characteristics of SFT/HPC.

[Molecular Pathogenesis of Cerebral Cavernous Malformations].

Cerebral cavernous malformations(CCMs)are vascular anomalies characterized by clusters of dilated capillaries and veins. They frequently cause epileptic seizures, hemorrhagic strokes, and focal neurological deficits. At present, CCMs can be treated only by surgical resection. However, the identification of germline and somatic mutations and the associated signaling pathways have improved our understanding of the underlying mechanisms; this has further led to testing of targeted molecular therapies for the disease. This review summarizes the current knowledge on the molecular pathogenesis of CCMs.

[Genetic Factors of Intracranial Artery Stenosis and Potential for Personalized Medicine].

It has been verified that the missense variant c.14429G>A(p.Arg4810Lys, rs112735431)of RNF213(Ringer finger protein 213)is significantly associated with intracranial artery stenosis(ICAS). The clinical features of ICAS with RNF213 p.Arg4810Lys are also becoming clear. In addition, RNF213 p.Arg4810Lys has been found to be associated with coronary artery stenosis/renal artery stenosis and pulmonary hypertension, and has been attracting attention as a variant that causes systemic vascular disease. Functional analysis of RNF213 is also progressing, but the mechanism involved in disease onset has not yet been clarified, and further analysis is expected for the realization of personalized medicine for ICAS.

Association Between the Onset Pattern of Adult Moyamoya Disease and Risk Factors for Stroke.

BACKGROUND AND PURPOSE: Few previous studies have comprehensively explored the relationship between the onset pattern of adult moyamoya disease and risk factors for stroke. We performed a retrospective analysis focusing on risk factors for stroke and related findings on magnetic resonance imaging/angiography with respect to the pattern of disease onset. We also examined whether risk factors for stroke were associated with an increased risk for symptomization in asymptomatic patients. METHODS: A total of 178 adult patients with moyamoya disease (asymptomatic, n=84; ischemic, n=71; hemorrhagic, n=23) at the University of Tokyo Hospital from 2000 to 2018 were included in this study. Data pertaining to patient background and magnetic resonance imaging findings were analyzed retrospectively. In the asymptomatic group, the effects of stroke-associated risk factors on symptom onset were analyzed. RESULTS: Comparisons among the 3 groups revealed no significant difference in the frequency of risk factors for stroke. The proportion of patients with magnetic resonance imaging/angiography findings indicating anterior choroidal artery anastomosis or microbleeds was significantly higher in the hemorrhagic group than in the asymptomatic or ischemic group. Among asymptomatic patients, the hazard ratios for symptomization with hypertension and dyslipidemia were 6.69 ([95% CI, 1.23-36.4] P=0.028) and 8.14 ([95% CI, 1.46-45.2] P=0.017), respectively. CONCLUSIONS: The development of anterior choroidal artery anastomosis and microbleeds on magnetic resonance imaging/angiography was significantly associated with hemorrhagic onset. Hypertension and dyslipidemia may increase the risk of cerebrovascular events in asymptomatic patients, and thus, early intervention to these factors may be important.

Risk Factors and Outcomes of Cerebral Stroke in End-Stage Renal Disease Patients Receiving Hemodialysis.

OBJECTIVE: Dialysis patients have a higher incidence of stroke, and outcomes are often poor. Diabetic nephropathy (DN) is a stroke risk-factor, but the importance is unclear in dialysis patients. This study investigated the stroke features and risk factors in hemodialysis (HD) patients. METHODS: All end-stage renal disease patients undergoing HD at Teraoka Memorial Hospital dialysis center were identified, with 195 recruited. Baseline clinical characteristics were collected, and the clinical outcomes and related factors of stroke in HD patients were retrospectively analyzed. The incidence rate of stroke and mortality were calculated using Kaplan-Meier survival analysis. Factors potentially related to stroke were analyzed by the log-rank test and Cox proportional hazards model for univariate and multivariate analysis. RESULTS: In total, 21.0% (41 of 195) patients developed stroke. The incidence rates of stroke per 1000 patient-years were 53.6, 65.2, and 34.0 in all HD patients, DN patients, and non-DN patients, respectively. The cumulative incidence rates of stroke in all HD patients, DN patients, and non-DN patients per 5 years, and per 10 years were 22.6%, 43.5%; 28.8%, 59.6%; and 17.6%, 31.1%, respectively. The incidence rate of stroke in the DN patients was significantly higher than in the non-DN patients (P = .013). DN was the significant risk factor for stroke by multivariate analysis (hazard ratio 2.63, 95% confidence interval 1.08-7.85; P = .032). CONCLUSIONS: This study revealed the trends of stroke in HD patients at a single institution in Japan. DN was shown to be a significant risk factor for stroke in HD patients.

Genetic Analysis of Ring Finger Protein 213 (RNF213) c.14576G>A in Intracranial Atherosclerosis of the Anterior and Posterior Circulations.

BACKGROUND: Intracranial atherosclerosis of the anterior circulation (anterior ICAS) and intracranial atherosclerosis of the posterior circulation (posterior ICAS) are thought to involve different pathogeneses and risk factors. Recently, we identified a genetic variant that has a significant association with ICAS. The variant was ring finger protein 213 (RNF213) c.14576G>A (rs112735431), which was originally identified as a susceptibility genetic variant for moyamoya disease (MMD). The present study investigated the association of RNF213 c.14576G>A with anterior and posterior ICAS. MATERIALS AND METHODS: A total of 221 study participants (43 with anterior ICAS, 61 with posterior ICAS, 12 with extracranial carotid atherosclerosis [ECAS], 5 with MMD, and 100 control subjects) were recruited from April 2015 to October 2015. A genetic analysis of RNF213 c.14576G>A and an association study with these cerebrovascular diseases were performed. RESULTS: RNF213 c.14576G>A was present in 10 of 43 patients in the anterior ICAS group and 4 of 5 patients in the MMD group, but was not present in the patients in the posterior ICAS and ECAS groups. c.14576G>A was found in 2 of 100 patients in the control group. RNF213 c.14576G>A showed a significant association with anterior ICAS (allele count: P = 3.9 × 10-5, odds ratio [OR] = 13.0, 95% confidence interval [CI] = 2.8-60.8; prevalence of carriers of c.14576G>A: P = 2.6 × 10-5, OR = 14.8, 95% CI = 3.1-71.3). However, RNF213 c.14576G>A showed no association with posterior ICAS. RNF213 c.14576G>A also had a significant association with MMD and had no association with ECAS. CONCLUSIONS: The genetic variant RNF213 c.14576G>A is significantly associated with anterior ICAS but not with posterior ICAS. The present findings may indicate factors involved in the pathogenesis of ICAS-related stroke.

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.

Subarachnoid hemorrhage secondary to a ruptured middle cerebral aneurysm in a patient with osteogenesis imperfecta: a case report.

BACKGROUND: Osteogenesis imperfecta (OI) is a heterogeneous group of inherited disorders that occur owing to the abnormalities in type 1 collagen, and is characterized by increased bone fragility and other extraskeletal manifestations. We report the case of a patient who was diagnosed with OI following subarachnoid hemorrhage (SAH) secondary to a ruptured saccular intracranial aneurysm (IA). CASE PRESENTATION: A 37-year-old woman was referred to our hospital because of sudden headache and vomiting. She was diagnosed with SAH (World Federation of Neurosurgical Society grade 2) owing to an aneurysm of the middle cerebral artery. She then underwent surgical clipping of the aneurysm successfully. She had blue sclerae, a history of several fractures of the extremities, and a family history of bone fragility and blue sclerae in her son. According to these findings, she was diagnosed with OI type 1. We performed genetic analysis for a single nucleotide G/C polymorphism (SNP) of exon 28 of the gene encoding for alpha-2 polypeptide of collagen 1, which is a potential risk factor for IA. However, this SNP was not detected in this patient or in five normal control subjects. Other genetic analyses did not reveal any mutations of the COL1A1 or COL1A2 gene. The cerebrovascular system is less frequently involved in OI. OI is associated with increased vascular weakness owing to collagen deficiency in and around the blood vessels. SAH secondary to a ruptured IA with OI has been reported in only six cases. CONCLUSION: The patient followed a good clinical course after surgery. It remains controversial whether IAs are caused by OI or IAs are coincidentally complicated with OI.

A comparative study of risk factors and the occurrence rate of coronary atherosclerosis in extra- and intracranial atherosclerotic lesions.

BACKGROUND: The risk factors and epidemiology of extracranial and intracranial atherosclerotic lesions may be different. We evaluated the importance of perioperative management of coronary atherosclerotic lesions in carotid endarterectomy (CEA) or carotid artery stenting (CAS) for extracranial cervical carotid artery stenosis and superior temporal artery (STA)-middle cerebral artery (MCA) bypass for intracranial severe MCA stenosis/occlusion. METHODS: The medical records of patients who underwent cerebrovascular surgery at Aizu Chuo Hospital between January 2000 and September 2010 were retrospectively analyzed. Preoperative cardiovascular screening was performed for all patients to prevent perioperative ischemic heart disease-related complications. The number of patients requiring preoperative treatment of the coronary artery was compared. RESULTS: A total of 320 patients underwent surgery for cervical carotid stenosis (IC group; 259 patients with CEA and 61 patients with CAS), and 92 patients underwent STA-MCA bypass for MCA stenosis/occlusion (MC group). Treatment for coronary lesions was required in 35 of 320 patients (10.9%) in the IC group and 14 of 92 patients (15.2%) in the MC group. Surgery was safely performed in both groups without any ischemic heart disease-related complications during the perioperative period. CONCLUSIONS: This study shows the importance of perioperative management of coronary atherosclerotic lesions for STA-MCA bypass, similar to that for CEA/CAS.