Resolution of white matter hyperintensity after surgical revascularization in moyamoya disease - A report of three cases.

Background: Moyamoya disease often presents white matter hyperintensity (WMH) lesions on fluid-attenuated inversion recovery (FLAIR) images, which is generally accepted as irreversible. We, herein, describe three cases of moyamoya disease with WMH lesions that regressed or disappeared after surgical revascularization. Case Description: This report included two pediatric and one young adult case that developed transient ischemic attacks or ischemic stroke due to bilateral Moyamoya disease. Before surgery, five of their six hemispheres had WMH lesions in the subcortical and/or periventricular white matter on FLAIR images. The lesions included morphologically two different patterns: "Striated" and "patchy" morphology. In all of them, combined bypass surgery was successfully performed on both sides, and no cerebrovascular events occurred during follow-up periods. On follow-up magnetic resonance examinations, the "striated" WMH lesions completely disappeared within six months, while the "patchy" WMH lesions slowly regressed over 12 months. Conclusion: Based on radiological findings and the postoperative course of the WMH lesions, the "striated" WMH lesions may represent the inflammation or edema along the neuronal axons due to cerebral ischemia, while the "patchy" WMH lesions may represent vasogenic edema in the white matter through the blood-brain barrier breakdown. Earlier surgical revascularization may resolve these WMH lesions in Moyamoya disease.

Hemorrhage from metastatic brain epithelioid hemangioendothelioma: A case report.

In this report, we describe a very rare case of metastatic epithelioid hemangio-endothelioma (EHE) originating from other organs such as the lung and requiring craniotomy due to subsequent hemorrhage. A 50-year-old man was diagnosed with EHE in the bilateral lungs, the mediastinum, and the right adrenal gland 8 years earlier. One year earlier, he had developed spinal metastasis. Six months earlier, a screening brain MRI had revealed multiple brain metastases of tumor. He developed subcortical hemorrhage from the tumor in the right parietal lobe and successfully underwent removal of hematoma and tumor. Histopathological examinations revealed EHE. Metastatic EHE is very rare but may be at high risk of intracranial hemorrhage. It is quite important to consider the possibility of brain metastasis and subsequent bleeding when treating patients with EHE.

Intracerebral transplantation of MRI-trackable autologous bone marrow stromal cells for patients with subacute ischemic stroke.

BACKGROUND: Ischemic stroke is one of the leading causes of death and neurological disability worldwide, and stem cell therapy is highly expected to reverse the sequelae. This phase 1/2, first-in-human study evaluated the safety, feasibility, and monitoring of an intracerebral-transplanted magnetic resonance imaging (MRI)-trackable autologous bone marrow stromal cell (HUNS001-01) for patients with subacute ischemic stroke. METHODS: The study included adults with severe disability due to ischemic stroke. HUNS001-01 cultured with human platelet lysates and labeled with superparamagnetic iron oxide was stereotactically transplanted into the peri-infarct area 47-64 days after ischemic stroke onset (dose: 2 or 5 × 107 cells). Neurological and radiographic evaluations were performed throughout 1 year after cell transplantation. The trial was registered at UMIN Clinical Trial Registry (number UMIN000026130). FINDINGS: All seven patients who met the inclusion criteria successfully achieved cell expansion, underwent intracerebral transplantation, and completed 1 year of follow-up. No product-related adverse events were observed. The median National Institutes of Health Stroke Scale and modified Rankin scale scores before transplantation were 13 and 4, which showed improvements of 1-8 and 0-2, respectively. Cell tracking proved that the engrafted cells migrated toward the infarction border area 1-6 months after transplantation, and the quantitative susceptibility mapping revealed that cell signals at the migrated area constantly increased throughout the follow-up period up to 34% of that of the initial transplanted site. CONCLUSIONS: Intracerebral transplantation of HUNS001-01 was safe and well tolerated. Cell tracking shed light on the therapeutic mechanisms of intracerebral transplantation. FUNDING: This work was supported by the Japan Agency for Medical Research and Development (AMED; JP17bk0104045 and JP20bk0104011).

Clinical Significance of Carotid Endarterectomy and Carotid Artery Stenting in Older Patients Over 80.

As the average life expectancy increases, neurosurgeons are likely to encounter patients aged 80 years and above with carotid stenosis; however, whether old age affects clinical post-treatment outcomes of carotid endarterectomy (CEA) or carotid artery stenting (CAS) remains inconclusive. Thus, this study aimed to evaluate the outcomes following CEA or CAS in patients aged 80 years and above. This study included older over 80 years (n = 34) and younger patients (<80 years; n = 222) who underwent CEA or CAS between 2012 and 2022. All of them were followed up for a mean of 55 months. All-cause mortality, the incidence of vascular events, ability to perform daily activities, and nursing home admission rates were assessed. During follow-up periods, 34 patients (13.3%) died due to coronary artery disease, malignancy, and pneumonia, and the incidence was significantly higher in the elderly group than in the younger group (P = 0.03; HR, 3.01; 95% CI, 1.53-5.56). The incidence of vascular events did not differ between the older group (29.5%) and the younger group (26.9%, P = 0.58); however, the incidence was significantly higher in patients with high-intensity plaques than in those without that (P = 0.008; HR, 2.83, 95%CI, 1.27-4.87). The decline in the ability to perform daily activities and increased nursing home admission rates were high in elderly patients (P < 0.01). Although the mortality rate was higher in the elderly group, subsequent vascular events were comparable to that in the younger group. The results suggest that CEA and CAS are safe and useful treatments for carotid stenosis in older patients, especially to prevent ipsilateral ischemic stroke.

Posterior cerebral artery involvement in unilateral moyamoya disease is exclusively ipsilateral and influenced by RNF213 mutation gene dose: The SUPRA Japan study: PCA involvement in unilateral moyamoya.

OBJECTIVES: The characteristics and clinical implications of posterior cerebral artery (PCA) involvement in unilateral moyamoya disease (U-MMD), such as laterality, frequency of the RNF213 p.R4810K mutation, and clinical outcomes, have not been well studied. POPULATION AND METHODS: We analyzed a cohort of 93 patients with U-MMD who participated in the SUPRA Japan study. Clinical characteristics and radiological examinations were collected from medical records. The presence of the p.R4810K mutation was determined using a TaqMan assay. The clinical outcome was assessed using the modified Rankin Scale (mRS). Univariate and multivariate logistic regression analyses were performed to assess the associations. RESULTS: Among the patients with U-MMD, PCA involvement was observed in 60.0 % (3/5) of patients with homozygous mutation, 11.3 % (7/62) of those with heterozygous mutation, and 3.8 % (1/26) of those with wild type, showing a significant linear trend (p < 0.001 for trend). PCA involvement was observed exclusively on the same side as the affected anterior circulation. Dyslipidemia and cerebral infarction at initial onset were independently associated with mRS ≥1. Hypertension was associated with mRS ≥1 and it was also linked to infarction at initial onset, suggesting a potential confounding effect. Although PCA involvement showed a trend for higher mRS, it was not statistically significant. CONCLUSIONS: Our findings indicate a gene dose effect of the p.R4810K mutation on PCA involvement, with the homozygous state showing the most significant effect. Both genetic and modifiable factors such as dyslipidemia may influence the progression of U-MMD.

Pituitary apoplexy in endocrinologically silent adenoma during somatostatin analog administration for pancreatic neuroendocrine tumor: A case report.

A dopamine agonist administered for prolactinoma treatment and pituitary stimulation tests are reported as risk factors for pituitary apoplexy. We report a case of an 82-year-old patient who suffered from pituitary apoplexy in an endocrinologically silent adenoma during lanreotide administration. The patient was diagnosed with a pancreatic neuroendocrine tumor with lymph node metastasis and treated with lanreotide for two years. An endoscopic endonasal transsphenoidal approach was used for tumor and hematoma removal. The specimen showed growth hormone and prolactin positivity and was diagnosed as pit1-lineage plurihormonal adenoma. The tumor also showed positivity for somatostatin receptor 2. Thus, lanreotide treatment is a risk factor for pituitary apoplexy even in silent adenoma.

Current status and future outlook of ultrasound treatment for prostate cancer.

Radical prostatectomy and radiation therapy are the standard treatment options for localized prostate cancer (PC). However, radical prostatectomy may cause the deterioration of urinary and sexual function, and radiation-induced hemorrhagic cystitis and severe rectal bleeding are risk factors for fatal conditions in patients after radiation therapy. With the recent development of magnetic resonance imaging (MRI) for the localization of clinically significant PC (csPC) and treatment modalities, "focal therapy", which cures csPC while preserving anatomical structures related to urinary and sexual functions, has become a minimally invasive treatment for localized PC. Based on the clinical results of transrectal high-intensity focused ultrasound (HIFU) for localized PC in the whole gland and focal therapy, HIFU is considered an attractive treatment option for focal therapy. Recently, the short-term clinical results of transurethral high-intensity directional ultrasound (HIDU) have been reported. With the resolution of some issues, HIDU may be commonly used for PC treatment similar to HIFU. Because HIFU and HIDU have limitations regarding the treatment of patients with large prostate calcifications and large prostate volumes, the proper use of these modalities will enable the treatment of any target area in the prostate. To establish a standard treatment strategy for localized PC, pair-matched and historically controlled studies are required to verify the oncological and functional outcomes of ultrasound treatment for patients with localized PC.

Effects of superficial temporal artery to middle cerebral artery (STA-MCA) anastomosis on the cerebrospinal fluid gas tensions and pH in hemodynamically compromised patients.

PURPOSE: This study was aimed to directly measure cerebrospinal fluid (CSF) gas tensions and pH before and after STA-MCA anastomosis for occlusive carotid artery diseases to investigate its direct effects on the ischemic brain. METHODS: This study included 9 patients who underwent STA-MCA anastomosis on the basis of CBF studies. About 1 mL of CSF was collected before and after bypass procedures, and CSF pH, CSF PO2, and CSF PCO2 were measured with a blood gas analyzer. As the controls, the CSF was collected from 6 patients during surgery for unruptured cerebral aneurysm. CSF PO2 and CSF PCO2 were expressed as the ratio to PaO2 and PaCO2, respectively. RESULTS: Before bypass procedure, CSF PO2/PaO2 was 0.88 ± 0.16, being lower than the controls (1.10 ± 0.09; P = 0.005). CSF PCO2/PaCO2 was 0.93 ± 0.13, being higher than the controls (0.84 ± 0.06; P = 0.039). Ipsilateral-to-contralateral CBF ratio had a positive correlation with CSF PO2/PaO2 (P = 0.0028) but a negative correlation with the CSF PCO2/PaCO2 (P = 0.0045). STA-MCA anastomosis increased CSF pH from 7.402 ± 0.133 to 7.504 ± 0.126 (P = 0.0011) and CSF PO2/PaO2 from 0.88 ± 0.16 to 1.05 ± 0.26 (P = 0.018) but decreased CSF PCO2/PaCO2 from 0.93 ± 0.13 to 0.70 ± 0.17 (P = 0.0006). CONCLUSION: The severity of cerebral ischemia before surgery is intensely reflected in the gas tensions and pH of the CSF. STA-MCA anastomosis carries dramatic effects on CSF gas tensions and pH in hemodynamically compromised patients. CSF would be a valuable surrogate biomarker to monitor the severity of cerebral ischemia.

Coil embolization for post-bypass aneurysm of middle meningeal artery for moyamoya disease - preservation of transdural anastomosis.

Background: Middle meningeal artery (MMA) pseudoaneurysm following revascularization surgery for moyamoya disease (MMD) is rare. Case Description: Here, a 29-year-old man presented with an MMA pseudoaneurysm after he underwent revascularization surgery (superficial temporal artery-to-middle cerebral artery bypass and encephalo-duro-myoarterio-pericranial synangiosis) for hemorrhagic MMD. At 3 months post-surgery, digital subtraction angiography showed a pseudoaneurysm in the right MMA. Transdural anastomosis to the parietal and occipital lobes was opacified at the distal MMA of the pseudoaneurysm. Intra-aneurysmal coil embolization was performed for preservation of transdural anastomosis. The postoperative course was uneventful. At 1 month post-embolization, angiography revealed an entirely occluded pseudoaneurysm. Conclusion: An increase in blood flow in the MMA due to bypass surgery may accelerate aneurysm development by increasing the hemodynamic stress. This case suggested that intra-aneurysmal embolization may be a potential treatment.

Endoscopic third ventriculostomy for patients with Blake's pouch cyst with adult-onset hydrocephalus: Importance of improved cerebrospinal fluid flow in the prepontine cistern - A case report.

Background: Blake's pouch cyst (BPC) is a posterior fossa cystic malformation that commonly occurs in children with rare adult onset. Herein, we report a case of adult onsets BPC. Case Description: A 61-year-old man presented with gait and cognitive disturbance. Preoperative magnetic resonance imaging (MRI) revealed scarring in the prepontine cistern, and cine phase-contrast MRI revealed no pulsation. Endoscopic third ventriculostomy (ETV) was performed with opening the scarring in the prepontine cistern. Postoperative cine phase-contrast MRI revealed that cerebrospinal fluid (CSF) flow in the prepontine cistern improved, resolving the patient's symptoms. Conclusion: We report a case of adult-onset BPC. The mechanism by which is becomes symptomatic is still unclear. We opened the scar in prepontine cistern in addition to ETV with good results. In this report, we discussed the importance of the improvement in CSF dynamics in the prepontine cistern.

National trends in the outcomes of subarachnoid haemorrhage and the prognostic influence of stroke centre capability in Japan: retrospective cohort study.

OBJECTIVES: To examine the national, 6-year trends in in-hospital clinical outcomes of patients with subarachnoid haemorrhage (SAH) who underwent clipping or coiling and the prognostic influence of temporal trends in the Comprehensive Stroke Center (CSC) capabilities on patient outcomes in Japan. DESIGN: Retrospective study. SETTING: Six hundred and thirty-one primary care institutions in Japan. PARTICIPANTS: Forty-five thousand and eleven patients with SAH who were urgently hospitalised, identified using the J-ASPECT Diagnosis Procedure Combination database. PRIMARY AND SECONDARY OUTCOME MEASURES: Annual number of patients with SAH who remained untreated, or who received clipping or coiling, in-hospital mortality and poor functional outcomes (modified Rankin Scale: 3-6) at discharge. Each CSC was assessed using a validated scoring system (CSC score: 1-25 points). RESULTS: In the overall cohort, in-hospital mortality decreased (year for trend, OR (95% CI): 0.97 (0.96 to 0.99)), while the proportion of poor functional outcomes remained unchanged (1.00 (0.98 to 1.02)). The proportion of patients who underwent clipping gradually decreased from 46.6% to 38.5%, while that of those who received coiling and those left untreated gradually increased from 16.9% to 22.6% and 35.4% to 38%, respectively. In-hospital mortality of coiled (0.94 (0.89 to 0.98)) and untreated (0.93 (0.90 to 0.96)) patients decreased, whereas that of clipped patients remained stable. CSC score improvement was associated with increased use of coiling (per 1-point increase, 1.14 (1.08 to 1.20)) but not with short-term patient outcomes regardless of treatment modality. CONCLUSIONS: The 6-year trends indicated lower in-hospital mortality for patients with SAH (attributable to better outcomes), increased use of coiling and multidisciplinary care for untreated patients. Further increasing CSC capabilities may improve overall outcomes, mainly by increasing the use of coiling. Additional studies are necessary to determine the effect of confounders such as aneurysm complexity on outcomes of clipped patients in the modern endovascular era.

Late-onset, first-ever involuntary movement after successful surgical revascularization for pediatric moyamoya disease - Report of two cases.

Background: A small number of children with Moyamoya disease develop involuntary movements as an initial presentation at the onset, which usually resolves after effective surgical revascularization. However, involuntary movements that did not occur at the onset first occur after surgery in very rare cases. In this report, we describe two pediatric cases that developed involuntary movements during the stable postoperative period after successful surgical revascularization. Case Description: A 10-year-old boy developed an ischemic stroke and successfully underwent combined bypass surgery. However, he developed chorea six months later. Another 8-year-old boy developed a transient ischemic attack and successfully underwent combined bypass surgery. However, he developed chorea three years later. In both cases, temporary use of haloperidol was quite effective in resolving the symptoms, and involuntary movements did not recur without any medication during follow-up periods of up to 10 years. Conclusion: Postoperative first-ever involuntary movement is very rare in pediatric moyamoya disease, and the underlying mechanisms are still unclear, but a temporary, reversible imbalance of excitatory and inhibitory circuits in the basal ganglia may trigger the occurrence of these rare symptoms. Careful follow-up would be mandatory.

Risk Factors for Severe Erectile Dysfunction after Focal Therapy with High-Intensity Focused Ultrasound for Prostate Cancer.

The present study aimed to analyze the effect of predisposing clinical factors for severe erectile dysfunction (ED) in patients treated with focal therapy using high-intensity focused ultrasound (HIFU) for localized prostate cancer (PC). Patients without severe ED (International Index of Erectile Function-5 [IIEF-5] score ≥ 8) before focal HIFU therapy were included. A total of 92 of the 240 patients met the inclusion criteria and were included. The rate of severe ED (IIEF-5 ≤ 7) was 36% 12 months after treatment. Multivariable logistic regression analysis showed that the pre-procedural lower IIEF-5 score (odds ratio [OR] 0.812, p = 0.005), the pre-procedural lower score of the sexual domain of the Expanded Prostate Cancer Index Composite (OR 0.960, p = 0.038), and the treatment of the edge of the peripheral zone (PZ) in proximity to the neurovascular bundle (NVB) [treated vs. untreated, OR 8.048, p = 0.028] were significant risk factors for severe ED at 12 months after treatment. In conclusion, pre-procedural lower erectile function and treatment of the part in proximity to the NVB were significant risk factors for severe ED after focal therapy.

Differentiation of Fibroblasts Into Myofibroblasts in the Arachnoid Membrane of Moyamoya Disease.

BACKGROUND: Moyamoya disease (MMD) is a very specific disorder in terms of spontaneous development of extracranial-to-intracranial collateral circulation through the dura mater, but the underlying mechanisms are unclear. This study aimed to investigate the role of the arachnoid membrane in this unique angiogenesis in MMD. METHODS: A piece of arachnoid membrane and 1- to 2-mL cerebrospinal fluid were simultaneously harvested during surgery from 26 patients with MMD. The specimens were also collected during surgery as the controls from 6 patients with atherosclerotic carotid artery diseases. The arachnoid membrane was subjected to immunohistochemistry and the cerebrospinal fluid was used to measure the concentration of cytokines using ELISA. RESULTS: The number of cells positive for PDGFR (platelet-derived growth factor receptor) α was significantly higher in MMD than in the controls (5.4±3.1 versus 2.3±2.1 cells/field; P=0.02). The results were same in PDGFRß-positive cells (10.1±4.6 versus 4.8±2.8; P=0.01) and α-SMA (alpha-smooth muscle actin)-positive cells (8.8±3.1 versus 2.0±2.5; P<0.01). On multicolor immunofluorescence, 80.5±15.6% of cells positive for PDGFRα in MMD also expressed α-SMA, being significantly higher than 14.6±7.2% in the controls (P<0.01). The density of collagen in the arachnoid membrane was significantly higher in MMD than in the controls (60.3±15.0% versus 40.1±15.3%; P<0.01). In MMD, advanced disease stage was significantly associated with a larger number of α-SMA-positive cells in the arachnoid membrane (P=0.04). On ELISA, the cerebrospinal fluid concentrations of bFGF (basic fibroblast growth factor), HGF (hepatocyte growth factor), and TGF (transforming growth factor)-ß1 were significantly higher in MMD than in the controls. CONCLUSIONS: Based on these findings, MMD may elevate the concentrations of angiogenic factors in the cerebrospinal fluid and then promote the proliferation of fibroblasts in the arachnoid membrane and their differentiation into myofibroblasts, which may, in turn, enhance the production of collagen essential for spontaneous collateral formation across the arachnoid membrane.

[Bypass Surgery for Moyamoya Disease, Part 1: Special Considerations and Techniques].

In this review article, the author describes the eligible patients, concept, surgical technique, and long-term outcome of the superficial temporal artery to middle cerebral artery(STA-MCA)anastomosis and the ultimate indirect bypass, called encephalo-duro-myo-arterio-pericranial synangiosis(EDMAPS)for adult moyamoya disease, in addition to the novel diagnostic criteria. The procedure dramatically improves or normalizes the cerebral blood flow immediately after surgery and thus contributes to preventing ischemic complications during and after surgery. However, the arterial wall of these patients is extremely thin and fragile; therefore, the surgeons should be trained extensively and have absolute confidence in their ability to perform this procedure. The surgeons should be aware that STA-MCA anastomosis frequently induces the hyper-perfusion phenomenon in adult patients with moyamoya due to prolonged cerebral ischemia. The extent of craniotomy determines the amount of surgical collaterals after indirect surgery; thus, a wide craniotomy including most of the frontal area, especially the medial frontal area, is critical to improve the postoperative prognosis. This procedure can markedly diminish the dangerous periventricular collateral channels and provides excellent long-term outcomes for up to 20 years after surgery. Long-term follow-ups longer than 20 years are important to monitor the patients with this unique and peculiar disease.

Sebaceous adenoma occurring within an intracranial dermoid cyst.

Among intracranial cystic lesions, dermoid cysts and epidermoid cysts are relatively common benign tumors. In a small number of these tumors, it is known that squamous cell carcinomas arise in the lining epithelium of the cysts. Among tumors derived from the appendage, only one case of hidradenoma within a dermoid cyst and no cases of sebaceous tumor have been reported previously. In the present case, a protruding lesion was present in the cystic wall, and it was composed of two cell types: sebaceous cells (sebocytes) and basaloid/germinated cells, being characteristic of this tumor. It is essential to distinguish it from other sebaceous lesions such as hyperplasia, sebaceoma, sebaceous carcinoma, and basal cell carcinoma with sebaceous differentiation derived from the epidermis. The critical distinguishing points in making a differential diagnosis among these lesions are the ratio of the two cell types and the presence or absence of other components such as hair sacs, invasion or cellular atypia. Immunohistochemical examination revealed that the tumor cells were positive for the epithelial markers, such as cytokeratin (CK)14, p63, p40, high-molecular CK, and adipophilin; these findings are peculiar to sebaceous adenoma. Although there have been several similar case reports of sebaceous tumors associated with dermmoid cysts in the ovaries, most of the intracranial lesions were squamous cell carcinomas that developed within the cysts, and there has been no precedent showing an association with a sebaceous tumor. The present report describes the first case of sebaceous adenoma that occurred in an intracranial dermoid cyst.

Thin calcification (< 2 mm) can highly predict intraplaque hemorrhage in carotid plaque: the clinical significance of calcification types.

PURPOSE: Calcification pathogenesis and the relationship between calcification and plaque composition remain unclear. This study explored the calcification characteristics of vulnerable plaques, especially focusing on calcification thickness, using computed tomography angiography and magnetic resonance plaque imaging. METHODS: Demographic, computed tomography angiography, and magnetic resonance plaque imaging data were acquired from 178 patients with 229 lesions diagnosed with carotid stenosis. The calcification types were categorized by calcification thickness. We evaluated their features, including the anatomical location and the plaque composition compared with MR plaque imaging, and clarify the clinical characteristics. Furthermore, an immunohistochemical subgroup analysis was performed on 84 lesions treated with carotid endarterectomy. RESULTS: The result of the ROC analysis suggested the threshold between symptomatic and asymptomatic calcification was 2.04 mm (AUC;0.841, 95%CI; 0.771-0.894). Calcification with ≥ 2 mm thickness was classified as thick calcification and < 2 mm thickness as thin calcification. Multivariate analysis suggested the prevalence of symptomatic patients in the thin calcification group was significantly higher than others (P = 0.01; odds ratio, 4.1; 95% confidence interval 2.8-7.2). Plaques with thin calcification were associated with plaque with intraplaque hemorrhage (P < 0.01). The interobserver reliability (κ) of calcification type was 0.962 (95% confidence interval, 0.941-0.988). Immunohistochemical analysis demonstrated that the numbers of CD68-positive cells and CD31-positive microvessels in shoulder lesions were significantly higher in the thin calcification group than in the non-thin group (both P < 0.01). CONCLUSIONS: Thin calcification was associated with plaques with intraplaque hemorrhage and had different clinical implications than thick calcification.

Genetic and nongenetic factors for contralateral progression of unilateral moyamoya disease: the first report from the SUPRA Japan Study Group.

OBJECTIVE: Although many studies have analyzed risk factors for contralateral progression in unilateral moyamoya disease, they have not been fully elucidated. The aim of this study was to examine whether genetic factors as well as nongenetic factors are involved in the contralateral progression. METHODS: The authors performed a multicenter cohort study in which 93 cases with unilateral moyamoya disease were retrospectively reviewed. The demographic features, RNF213 R4810K mutation, lifestyle factors such as smoking and drinking, past medical history, and angiographic findings were analyzed. A Cox proportional hazards model was used to find risk factors for contralateral progression. RESULTS: Contralateral progression was observed in 24.7% of cases during a mean follow-up period of 72.2 months. Clinical characteristics were not significantly different between 67 patients with the R4810K mutation and those without it. Cox regression analysis showed that the R4810K mutation (hazard ratio [HR] 4.64, p = 0.044), childhood onset (HR 7.21, p < 0.001), male sex (HR 2.85, p = 0.023), and daily alcohol drinking (HR 4.25, p = 0.034) were independent risk factors for contralateral progression. CONCLUSIONS: These results indicate that both genetic and nongenetic factors are associated with contralateral progression of unilateral moyamoya disease. The findings would serve to help us better understand the pathophysiology of moyamoya disease and to manage patients more appropriately.