Difference in Clinical Phenotype, Mutation Position, and Structural Change of RNF213 Rare Variants Between Pediatric and Adult Japanese Patients with Moyamoya Disease.

It is unclear how rare RNF213 variants, other than the p.R4810K founder variant, affect the clinical phenotype or the function of RNF213 in moyamoya disease (MMD). This study included 151 Japanese patients with MMD. After performing targeted resequencing for all coding exons in RNF213, we investigated the clinical phenotype and statistically analyzed the genotype-phenotype correlation. We mapped RNF213 variants on a three-dimensional (3D) model of human RNF213 and analyzed the structural changes due to variants. The RNF213 p.R4810K homozygous variant, p.R4810K heterozygous variant, and wild type were detected in 10 (6.6%), 111 (73.5%), and 30 (19.9%) MMD patients, respectively. In addition, 15 rare variants were detected in 16 (10.6%) patients. In addition to the influence of the p.R4810K homozygous variant, the frequency of cerebral infarction at disease onset was higher in pediatric patients with other rare variants (3/6, 50.0%, P = 0.006) than in those with only the p.R4810K heterozygous variant or with no variants (2/51, 3.9%). Furthermore, on 3D modelling of RNF213, the majority of rare variants found in pediatric patients were located in the E3 module and associated with salt bridge loss, contrary to the results for adult patients. The clinical phenotype of rare RNF213 variants, mapped mutation position, and their predicted structural change differed between pediatric and adult patients with MMD. Rare RNF213 variants, in addition to the founder p.R4810K homozygous variant, can influence MMD clinical phenotypes or structural change which may contribute to the destabilization of RNF213.

Enterprise Treatment for Recurrent Basilar Tip Aneurysm after PulseRider-assisted Coil Embolization: A Case Report.

PulseRider (Cerenovus, Irvine, CA, USA) is a relatively novel device used for the treatment of wide-neck aneurysms with a coil-assisted effect. However, treatment options for recurrent aneurysms after PulseRider-assisted coil embolization remain controversial. Here we report a case of recurrent basilar tip aneurysm (BTA) treated with Enterprise 2 after PulseRider-assisted coil embolization. A woman in her 70s underwent coil embolization for a subarachnoid hemorrhage with ruptured BTA 16 years ago. Recurrence was detected at 6-year follow-up, and an additional coil embolization was performed. Nevertheless, gradual recurrence still occurred, and PulseRider-assisted coil embolization was performed without any complications 9 years after the second treatment. However, recurrence was detected once more at 6-month follow-up. Thus, stent-assisted coil embolization using Enterprise 2 (Cerenovus) through PulseRider was selected for angular remodeling. Enterprise 2 was deployed between the right P2 segment of the posterior cerebral artery (PCA) and basilar artery (BA) after an effective coil embolization, which achieved effective angular remodeling between the right PCA and BA. The patient's postoperative course was uneventful, and no recanalization was detected after half a year. Although PulseRider is effective for wide-neck aneurysm treatment, recurrence remains a possibility. Additional treatment using Enterprise 2 is safe and effective with the expectation of angular remodeling.

Bilateral symptomatic large cavernous carotid artery aneurysms treated by extracranial-intracranial bypass with parent artery occlusion.

Bilateral large cavernous sinus internal carotid aneurysms (CCAs) occur very rarely. While the choice of treatment method is important, the timing of contralateral side treatment is equally important. We herein report the case of a 72-year-old woman who presented with progressive bilateral visual impairment and was treated by two-stage. First, the left CCAs had been treated, and the aneurysm was thrombosed, but her left visual acuity did not recover; the right CCA was becoming larger 2 years later, and her right visual acuity began worsening. The right CCAs was treated by almost same method. Her right visual acuity improved compared with the second preoperative findings. Our case findings suggest the importance of considering the appropriate timing to avoid symptom aggravation in patients with bilateral CCAs.

Subclavian Artery-Carotid Artery Bypass for Subclavian Artery or Common Carotid Artery Severe Stenosis or Occlusion.

Various surgical treatments are available for occlusive subclavian and common carotid artery diseases. Nevertheless, to date, when cerebral endovascular treatment is utilized, revascularization via direct surgery may be required. This study reported five symptomatic cases of revascularization for CCA and SCA occlusive and stenotic lesions that were expected to be challenging to treat with endovascular treatment. We performed subclavian artery-common carotid artery or internal carotid artery bypass using artificial blood vessels or saphenous vein grafts in five patients with subclavian steal syndrome, symptomatic common carotid artery occlusion, and severe proximal common carotid artery stenosis. In this study, good bypass patency was achieved in all five cases. Although there were no intraoperative complications, one patient had a postoperative lymphatic leak. Moreover, there was no recurrence of stroke during postoperative follow-up for an average of 2 years. Conclusively, subclavian artery-common carotid artery bypass can be an effective surgical treatment for common carotid artery occlusion, proximal common carotid artery stenosis, and subclavian artery occlusion.

A Case of Cavernous Malformation of the Midbrain Removed via an Interhemispheric Transcallosal Subchoroidal Approach.

Cavernous malformations of the midbrain have a higher rate of hemorrhage and a poorer prognosis than vascular malformations of other brain areas. Surgical resection of these lesions is often necessary to avoid neurological deficits in affected patients. Herein, the literature surrounding cavernous malformations was examined, and the case of a 48-year-old man with left hemiparesis and diplopia caused by incomplete right oculomotor nerve palsy, who was diagnosed with a hemorrhage from a midbrain cavernous malformation, was discussed. The lesion expanded gradually on magnetic resonance imaging and was symptomatic; radical removal of the lesion before the onset of irreversible symptoms due to recurring bleeding was therefore considered to be beneficial for the patient. Surgical removal of the entire cavernous malformations of the midbrain was performed using an interhemispheric transcallosal subchoroidal approach, with excellent postoperative results and complete recovery from the oculomotor nerve palsy and left hemiparesis. This case shows that this approach is the most appropriate for surgical resections of lesions in the upper midbrain.

Kissing Aneurysms of the Posterior Inferior Cerebellar Artery Treated by Anchor Coil Technique and Stenting from the Contralateral Side: A Case Report.

Kissing aneurysms refer to the condition in which two cerebral aneurysms with separate necks are in contact with each other. At present, there is scarce information on kissing aneurysms occurring near the vertebral artery (VA)-posterior inferior cerebellar artery (PICA). We report the first case of VA-PICA and nonbranched PICA kissing aneurysms, which were successfully treated with contralateral stenting after the anchor coil technique using two microcatheters. A 64-year-old woman was diagnosed with a left VA-PICA aneurysm (5.5 mm) and an adjacent small PICA aneurysm (2.5 mm) with the aneurysmal walls in close contact. For stenting, microcatheters were navigated to the PICA from the contralateral side, and framing coils for the anchor were placed into each aneurysm from the ipsilateral side. Next, a Neuroform Atlas stent was deployed from the PICA to the distal side of the VA, and coiling was completed using the jailing technique. The patient had a good postoperative course, and a left vertebral angiogram revealed complete occlusion of both aneurysms after 6 months. Adequate surgical planning and application of an appropriate stent-assisted coil embolization technique contributed to the success of the procedure in this rare case.

Clinical Significance of Cytotoxic Lesions of the Corpus Callosum in Subarachnoid Hemorrhage Patients: A Retrospective Analysis.

INTRODUCTION: Cytotoxic lesions of the corpus callosum are secondary lesions induced by significant increases in cytokine levels in the brain and are associated with subarachnoid hemorrhage (SAH). However, their clinical significance in SAH patients remains unclear. METHODS: We retrospectively analyzed SAH patients who were treated in our hospital and evaluated between-group differences in the backgrounds, clinical findings, and outcomes between SAH patients who developed cytotoxic lesions of the corpus callosum and those who did not. We further compared patients who achieved good outcomes with those who had poor outcomes. Multivariate logistic regression analysis was used to identify risk factors for poor clinical outcomes. RESULTS: We analyzed 159 SAH patients; 17 patients (10.7%) had cytotoxic lesions of the corpus callosum. Patients with cytotoxic lesions of the corpus callosum were more likely to be in a severe condition (World Federation of Neurosurgical Societies grading IV-V: odds ratio [OR], 4.53; 95% confidence interval [95% CI]: 1.60-12.84; p = 0.0042) and have an intraventricular (OR, 5.98; 95% CI: 1.32-27.13; p = 0.0054) or an intraparenchymal hematoma (OR, 3.62; 95% CI: 1.25-10.45; p = 0.023). Patients with cytotoxic lesions of the corpus callosum had a greater propensity of a poor outcome 3 months after onset (modified Rankin Scale score 0-2: OR, 0.22; 95% CI: 0.07-0.66; p = 0.0043). Multivariate analysis confirmed that cytotoxic lesions of the corpus callosum increased the risk of a poor outcome (OR, 4.39; 95% CI: 1.06-18.1; p = 0.037). DISCUSSION/CONCLUSIONS: The development of cytotoxic lesions of the corpus callosum may be related to the extent of hematomas in SAH patients. Although they are usually reversible lesions, the development of cytotoxic lesions of the corpus callosum may be a predictor of poor outcomes in SAH patients.

Prognostic Significance of Hyponatremia in Acute Stroke: A Systematic Review and Meta-Analysis.

OBJECTIVE: Hyponatremia is a common electrolyte disorder in patients with stroke, which leads to various fatal complications. We performed a systematic review and meta-analysis to investigate the outcomes of acute stroke patients with hyponatremia. METHODS: We searched MEDLINE, EMBASE, and the Cochrane Library databases for relevant literature in English published up to March 2020. Two review authors independently screened and selected the studies by assessing the eligibility and validity based on the inclusion criteria. Mortality at 90 days was set as the primary end point, and in-hospital mortality and length of hospital stay were set as the secondary end points. We conducted the data synthesis and analyzed the outcomes by calculating the odds ratio (OR) and mean difference. RESULTS: Of 835 studies, 15 studies met the inclusion criteria (n = 10,745). The prevalence rate of stroke patients with hyponatremia was 7.0-59.2%. They had significantly higher 90-day mortality (OR, 1.73; 95% confidence interval (CI), 1.24-2.42) and longer length of hospital stay (mean difference, 10.68 days; 95% CI, 7.14-14.22) than patients without hyponatremia. Patients with hyponatremia had a higher tendency of in-hospital mortality than those without hyponatremia (OR, 1.61; 95% CI, 0.97-2.69). CONCLUSIONS: The development of hyponatremia in the clinical course of stroke is associated with higher short-term mortality and a longer hospital stay. Although the causal relationship is unclear, hyponatremia could be a significant predictor of poor outcomes after stroke.

[A Case of Intraosseous Meningioma Suspected of Osteosarcoma Based on Preoperative Image Examinations].

Intraosseous meningioma(IM)is one of the less frequent tumors of the skull, which often cannot be distinguished from other common skull tumors based on preoperative radiological findings. Herein, we describe a case of IM suspected to be an osteosarcoma based on preoperative image examinations. A 72-year-old woman experienced an impact to her left parietal area, and a subcutaneous tumor appeared in the same area. It had enlarged gradually over seven months, although she exhibited no obvious symptoms. On preoperative diagnostic imaging, the tumor was mainly found in the skull, extending from the subcutaneous area to the intradural space, and was primarily suspected to be an osteosarcoma. After surgery, the pathological diagnosis was atypical meningioma, and there has been no recurrence for 1 year after the surgery. It is necessary for IM to be considered as a differential diagnosis for skull tumors exhibiting characteristics of osteosarcoma.

Novel RASA1 mutations in Japanese pedigrees with capillary malformation-arteriovenous malformation.

Capillary malformation-arteriovenous malformation (CM-AVM, MIM#608354) is a rare autosomal dominant disorder characterized by multiple cutaneous capillary malformations co-occurring with fast-flow vascular anomalies, such as arteriovenous malformation or fistula. Despite the identification of RASA1 as the first causative gene in Western patients with CM-AVM, there have been no literature reports of Japanese patients with this gene mutation. We herein report two Japanese pedigrees harboring multiple affected members with CM-AVM. Whole-exome sequencing in the two probands identified novel heterozygous mutations in RASA1, which were co-segregated with the disease in each family and were not reported in large-scale sequencing databases. One was a frameshift mutation and the other a splice-site mutation causing aberrant splicing, confirmed by a minigene assay. There were no other genes commonly disrupted among these probands. RASA1 was a major causative gene even in Japanese patients with CM-AVM, although obvious locus heterogeneity was known for this disease.

Genotype-Phenotype Correlation in Long-Term Cohort of Japanese Patients with Moyamoya Disease.

BACKGROUND: Homozygosity of this p.R4810K founder variant of RNF213moyamoya disease (MMD) susceptibility gene is known to influence the severity of the clinical disease phenotype at disease onset. However, the association between this genotype and long-term clinical manifestations has remained unclear. OBJECTIVES: The principal goal of this study was to investigate whether and how the p.R4810K variant of RNF213influences the long-term phenotype in Japanese patients with MMD. METHOD: This retrospective cohort study included 94 Japanese patients with MMD who underwent direct or combined bypass for revascularization with the p.R4810K genotype determined in our hospital. The following phenotypic parameters were analyzed at disease onset and over a long-term period: age and initial presentation at onset, recurrent stroke after initial revascularization, and final modified Rankin Scale. RESULTS: The p.R4810K genotype was significantly associated with the phenotype at onset, especially in younger patients. Over a median follow-up period of 100 months, recurrent stroke occurred in 6 out of 94 patients: none out of 5 patients with the homozygous variant, 5 out of 64 with the heterozygous variant, and 1 out of 25 in the wild-type group. There were no significant differences among the genotypes. In particular, recurrent cerebral hemorrhage occurred in 5 patients, all possessing the heterozygous variant. The log-rank test showed no difference between the genotypes in the stroke-free survival rate. Furthermore, the p.R4810K genotype was not associated with a poor functional condition. CONCLUSIONS: The p.R4810K founder variant of RNF213 affects the phenotype at disease onset. However, the optimal revascularization may be effective, regardless of the genotype, even for the homozygous variant, which has been thought to be the most pathogenic. This genotype may not strongly influence the long-term clinical manifestations or poor prognosis in MMD.

Langerhans Cell Histiocytosis of the Skull in a Burr Hole Site Covered with Hydroxyapatite Material.

BACKGROUND: Langerhans cell histiocytosis (LCH) is a rare dendritic histiocytic disorder that affects the bones, especially the skull. Langerhans cell histiocytosis (LCH) developing in a burr hole site for chronic subdural hematoma is extremely rare. CASE DESCRIPTION: A 53-year-old man underwent a burr hole irrigation for chronic subdural hematoma, and the burr hole was covered with a burr hole button made of hydroxyapatite. Seven months after the first surgery, the connective tissue rapidly proliferated around the burr hole button, and the pathologic diagnosis was LCH. LCH recurred at 13 and 19 months after the first operation, with curettage performed each time. At 3 months after the final operation, no recurrence was identified on magnetic resonance imaging. CONCLUSIONS: If there is rapid proliferation of connective tissue at an operative site where artificial material has been used, LCH should be considered.

Ruptured Vertebral Artery Dissecting Aneurysm as a Risk Factor for Ocular Symptoms Accompanied with Subarachnoid Hemorrhage.

OBJECTIVE: Although ruptured vertebral artery dissecting aneurysms (VADAs) are often associated with ocular symptoms, such as abducent nerve palsy and Terson syndrome (TS), their frequency and risk factors in comparison with those associated with ruptured aneurysms in other locations have not been reported. METHODS: Three hundred forty-three patients with nontraumatic subarachnoid hemorrhage were treated in our hospital from April 2002 to May 2016, among which 35 (10.2%) had VADA as the origin of hemorrhage. They were analyzed retrospectively for risk factors of ocular symptoms. RESULTS: Of the 343 patients, 26 had eye movement disturbance (7.6%) and 22 had TS (6.4%). Both eye movement disturbance (14 patients; 40.0%; P < 0.0001) and TS (10 patients; 28.6%; P < 0.0001) occurred more frequently in the VADA than the non-VADA group. Abducent nerve palsy accounted for all eye movement disturbances associated with ruptured VADA, although it occurred in 6 of 12 affected patients with ruptured aneurysms in other locations. Of these patients, 4 improved within 3 months (28.6%) and 8 did so within 1 year (66.7%). Multivariate logistic regression analysis indicated that ruptured VADA is a risk factor for both eye movement disturbance and TS (P < 0.0001 and P = 0.0033; 95% confidence interval of odds ratio: 3.41-29.5 and 1.72-14.33, respectively). CONCLUSIONS: Eye movement disturbance and TS occurs more frequently in patients with ruptured VADA than with aneurysms in other locations. Early evaluation by an ophthalmologist is recommended in these patients.

[Supratentorial Meningeal Melanoma with Nevus of Ota:A Case Report].

We present a rare case of supratentorial meningeal melanoma associated with ipsilateral nevus of Ota, and a review of the literature. The patient was a 32-year-old man with a right-sided nevus of Ota, presenting with unconsciousness. His CT and MRI scans revealed an extra axial tumor with dural tail signs; no lesion was detected on systemic examination. Intraoperatively, the tumor demonstrated black hyperpigmentation and was histologically diagnosed as malignant melanoma. Following surgery, he received radiotherapy and chemotherapy. For over a year and a half, the patient has shown no recurrence of the lesion.

The Availability of a Tin-Alloyed Omnidirectional Retractor-Supporting Ring for Ventriculoperitoneal Shunt Laparotomy.

OBJECTIVE: We report the availability of a newly developed, malleable, tin-alloyed omnidirectional retractor-supporting (OD) ring for steady and safe ventriculoperitoneal (VP) shunt laparotomy. METHODS: The OD ring is principally circular in shape, 15 cm in diameter, and is sufficiently malleable to be fitted to the abdominal wall. There are 22 outward protrusions 12 mm in length that are welded to the outside of the ring at regular intervals. The OD ring with twisted rubber bands attached around the protrusions is placed on the abdominal wall surrounding the skin incision. Then the edge is omnidirectionally retracted with blunt minihooks attached to the rubber bands. In our hospital from January 2016 to February 2017, 15 consecutive patients underwent a VP shunt procedure using the OD ring. RESULTS: In a VP shunt procedure, our malleable, tin-alloyed OD ring could be smoothly placed on various types of abdominal walls. Moreover, our OD ring system provided a wider and shallower operative field allowing omnidirectional retraction during small laparotomy. Additionally, the OD ring system did not interfere with our surgical manipulations. CONCLUSIONS: Our newly developed retraction system with a malleable, tin-alloyed OD ring and minihooks may allow safe and steady small laparotomy for VP shunt.

Effectiveness of the Combined Use of Distal Filter Protection Device and Mo.Ma Ultra: Technical Note.

BACKGROUND: Although Mo.Ma Ultra is an embolic protection device for interrupting the anterograde blood flow to the internal carotid artery, incomplete blood stagnation is often observed. We report the effectiveness of the combined use of a distal filter protection device and Mo.Ma Ultra (Medtronic, Minneapolis, MN). MATERIALS AND METHODS: Our case series comprises 10 consecutive patients (11 carotid arteries) who underwent carotid artery stenting (CAS) using Mo.Ma Ultra and FilterWire EZ (Boston Scientific, Natick, MA). RESULTS: The superior thyroid artery originated from the proximal side of the bifurcation of the common carotid artery, except for 1 artery. Although complete blood stagnation was observed in 6 arteries, filter debris was detected in 3 of these 6 arteries. Positive postoperative findings on diffusion-weighted magnetic resonance imaging were observed in 3 cases (3 arteries). Only 1 patient had transient neurological deficits. CONCLUSION: The combined use of a distal filter protection device and Mo.Ma Ultra could provide a more reliable embolic protection in CAS.

Systematic Validation of RNF213 Coding Variants in Japanese Patients With Moyamoya Disease.

BACKGROUND: A founder variant of RNF213, p.R4810K (c.14429G>A, rs112735431), was recently identified as a major genetic risk factor for moyamoya disease (MMD) in Japan. Although the association of p.R4810K was reported to be highly significant and reproducible, the disease susceptibility of other RNF213 variants remains largely unknown. In the present study, we systematically evaluated the coding variants detected in Japanese patients and controls for associations with MMD. METHODS AND RESULTS: To detect variants of RNF213, all coding exons were sequenced in 27 Japanese MMD patients without p.R4810K. We also validated all previously reported variants in our case-control samples and tested for associations in combination with previous Japanese study cohorts, including the 1000 Genomes Project data set, as population-based controls. Forty-six missense variants other than p.R4810K were identified among 370 combined patients and 279 combined controls in Japan. Sixteen of 46 variants were polymorphisms with minor allele frequency >1%, and, after conditioning on the p.R4810K genotype, were not associated with MMD. We conducted a variable threshold test using Combined Annotation-Dependent Depletion on the remaining 30 rare variants (minor allele frequency <1%), and the results showed that the frequency of potentially functional variants was significantly higher in patients than in controls (permutation, minimum P=0.045). CONCLUSIONS: Not only p.4810K but also other functional missense variants of RNF213 conferred susceptibility to MMD. Our analysis also revealed that ≈20% of Japanese MMD patients did not harbor susceptibility variants of RNF213, indicating the presence of other susceptibility genes for MMD.