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.

Moyamoya disease is characterized by severe stenosis at the ends of the bilateral internal carotid arteries and the development of collateral circulation. The disease is very diverse in terms of age at onset, onset patterns, radiological findings, and genetic phenotypes. The pattern of onset is mainly divided into ischemic and hemorrhagic onsets. Recently, the opportunity to identify asymptomatic moyamoya disease, which sometimes manifests as nonspecific symptoms such as headache and dizziness, through screening with magnetic resonance imaging has been increasing. Various recent reports have investigated the associations between the clinical features of different onset patterns of moyamoya disease and the corresponding imaging characteristics. In this article, we have reviewed the natural history, clinical features, and imaging features of each onset pattern of moyamoya disease.

Regardless of treatment, the clinical progression of neurofibromatosis type 2 (NF2), particularly in terms of hearing, swallowing, and gait, tend to worsen throughout the patients’ lives. We performed a retrospective analysis of functional outcomes in Japanese NF2 patients to predict their functional prognosis. We analyzed genotype–phenotype correlation based on genetic data from a cohort of 57 patients with a mean follow-up of 14.5 ± 6.0 years. Their functional outcomes, including hearing, swallowing, and ambulation, were reviewed. Performing a targeted deep sequencing, germline NF2 mutations were identified in 28 patients (49.1%), and mosaic NF2 was identified in 20 patients (20, 35.0%). The functional preservation period and outcome differed significantly depending on clinical/genetic factors. Among these factors, “Truncating”, “Mosaic”, and “Age of symptom onset ≥ 25” had the most significant effects on functional disability. By applying a combination of an NF2 mutation type/location, and age of symptom onset, we classified different degrees of functional preservation and progression, schwannoma growth rate and total interventions per year per patient. The prediction of detailed functional outcomes in NF2 patients can plan better strategies for life-long disease management and social integration.

NF2 alteration is the most commonly–found genetic abnormality in meningiomas and is known to initiate events for aggressive-type meningiomas. Whereas the prognosis of meningiomas differs depending on their epigenomic/transcriptomic profile, the effect of NF2 alteration on the prognosis of benign meningiomas is not fully elucidated. This study aimed to probe the importance of NF2 alteration in prognosis of WHO grade I meningiomas. A long-term retrospective follow-up (5.3 ± 4.5 years) study involving 281 consecutive WHO grade I meningioma patients was performed. We assessed tumour recurrence in correlation with extent of resection (EOR), histopathological findings, tumour location, and NF2 alteration. “NF2 meningioma” was defined as meningiomas with presence of NF2 mutation and/or 22q loss. Overall, NF2 meningioma per se was not a predictor of prognosis in the whole cohort; however, it was a predictor of recurrence in supratentorial meningiomas, together with EOR and Ki-67. In a striking contrast, NF2 meningioma showed a better prognosis than non-NF2 meningioma in infratentorial lesion. Supratentorial NF2 meningiomas had higher Ki-67 and forkhead box protein M1 expression than those of others, possibly explaining the worse prognosis in this subtype. The combination of NF2 alteration, high Ki-67 and supratentorial location defines subgroup with the worst prognosis among WHO grade I meningiomas. Clinical connotation of NF2 alteration in terms of prognosis of WHO grade I meningioma differs in an opposite way between supratentorial and infratentorial tumors. Integrated anatomical, histopathological, and genomic classifications will provide the best follow-up schedule and proactive measures.

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.

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BACKGROUND: Gross total resection, without causing neurological deficits, is challenging in skull base meningioma (SBM). Therefore, stereotactic radiosurgery (SRS) is an important approach for SBMs; however, it is difficult to predict the long-term prognosis. OBJECTIVE: To identify the predictive factors for tumor progression after SRS for World Health Organization (WHO) grade I SBMs, focusing on the Ki-67 labeling index (LI). METHODS: In this single-center retrospective study, factors affecting progression-free survival rates (PFSs) and neurological outcomes in patients undergoing SRS for postoperative SBMs were evaluated. Based on the Ki-67 LI, patients were classified into 3 groups: low (<4%), intermediate (4%-6%), and high LI (>6%). RESULTS: In the 112 patients enrolled, the cumulative 5- and 10-year PFSs were 93% and 83%, respectively. The PFSs were significantly higher in the low LI group (95% at 10 years) compared with the other groups (intermediate LI, 60% at 10 years, P = .007; high LI, 20% at 10 years, P = .001). Multivariable Cox proportional hazard analysis demonstrated that the Ki-67 LI was significantly associated with the PFSs (low vs intermediate LI; hazard ratio, 6.00; 95% CI, 1.41-25.54; P = .015; low vs high LI; hazard ratio, 31.90; 95% CI, 5.59-181.77; P = .001). CONCLUSION: Ki-67 LI may be a useful predictor of long-term prognosis in SRS for postoperative WHO grade I SBM. SRS provides excellent long- and mid-term PFSs in SBMs with Ki-67 LIs <4% or 4% to 6%, with a low risk of radiation-induced adverse events.