Changes in the clinical spectrum of pediatric moyamoya disease over 40 years.

OBJECTIVE: To investigate the chronological changes in the clinical presentation and long-term prognosis of pediatric-onset moyamoya disease in our institute over 40 years. METHODS: We evaluated 282 pediatric-onset (≤ 15 years old) moyamoya disease patients who visited our institute from 1981 to 2020 (divided into the former period, 1981-2000, and the latter period, 2001-2020). Differences in the clinical presentation and the long-term outcome were compared between the periods. Multivariate analysis was also performed to reveal the risk factors for poor long-term outcomes. RESULTS: Compared to the former period, the total number of patients, the onset age and both the number of patients with family history and relatively older patients without symptoms or with headache were greater in the latter period (p < 0.05). The number of patients with poor long-term outcomes was significantly lower in the latter period (24.9% vs. 6.7%, p < 0.01). Multivariate analysis revealed that stroke onset, late cerebrovascular events and postoperative complications were independent risk factors for poor long-term outcomes (odds ratio = 31.4, 40.8 and 5.4, respectively). CONCLUSIONS: Over the last 40 years, the number of pediatric moyamoya disease patients has increased, especially in relatively older patients with mild presentation and favorable long-term outcomes. In clinical studies, these chronological changes and the inclusion period of the participants need to be accounted for. Whether the increased diagnostic rate in the recent era has led to a decrease in late cerebrovascular events and favorable outcomes throughout life remains unknown and should be evaluated in the future.

Absence of the RNF213 p.R4810K variant may indicate a severe form of pediatric moyamoya disease in Japanese patients.

OBJECTIVE: The authors' objective was to investigate the influence of the RNF213 p.R4810K variant on the clinical presentation and outcomes of Japanese pediatric patients with moyamoya disease. METHODS: A total of 129 Japanese patients with pediatric-onset moyamoya disease (onset age ≤ 15 years) who visited the authors' department from 2012 to 2020 participated in this study. After RNF213 p.R4810K genotyping of each patient was performed, the relationship between genotype and clinical presentation or outcomes, including onset age, initial presentation, surgical outcomes, and subsequent cerebrovascular events, was evaluated. Patients without the p.R4810K variant were tested for RNF213 variants other than p.R4810K. The authors especially focused on the results of patients who presented with moyamoya disease at younger than 1 year of age (infantile onset). RESULTS: Compared with the patients with heterozygous variants, patients without the p.R4810K variant were younger at onset (7.1 ± 3.7 vs 4.4 ± 0.9 years), and all 4 patients with infantile onset lacked the p.R4810K variant. A greater proportion of patients without the p.R4810K variant presented with infarction than patients with the heterozygous variant (24.0% vs 7.6%) and a decreased proportion presented with transient ischemic attack (36.0% vs 71.7%). No significant correlation was observed between p.R4810K genotype and clinical outcomes, including surgical outcomes and subsequent cerebrovascular events; however, a decreased proportion of patients without the p.R4810K variant had good surgical outcomes compared with that of patients with the heterozygous variant (76.5% vs 92.2%). Among the 25 patients without the p.R4810K variant, 8 rare variants other than p.R4810K were identified. Three of 4 patients with infantile onset had RNF213 variants other than p.R4810K, which had a more severe functional effect on this gene than p.R4810K. CONCLUSIONS: Absence of the RNF213 p.R4810K variant may be a novel biomarker for identification of a severe form of pediatric moyamoya disease.

Clinical characteristics of the pregnancies and deliveries of patients with moyamoya disease: A single-center analysis over three decades.

BACKGROUND AND AIMS: As moyamoya disease in pregnancy is clinically rare, it is poorly understood. We therefore analyzed our experiences of moyamoya disease pregnancies and deliveries over three decades. METHODS: The clinical data of 78 pregnancies and 77 deliveries among 62 moyamoya disease cases at Tokyo Medical and Dental University Hospital from 1991 to 2019 were retrospectively reviewed. RESULTS: There were six, 17 and 55 pregnancies in the first, second, and last decades, respectively. The mean patient age at delivery was 29.3 ± 5.0 years. The primary symptoms of moyamoya disease at diagnosis were ischemia in 50 cases (64.1%) and intracranial hemorrhage in eight cases (10.2%). Cesarean section was performed in 75 cases (96.2%). Fifteen pregnancies (19.2%) developed hypertensive disorders of pregnancy; of these, 13 (86.7%) developed hypertensive disorders of pregnancy after 34 weeks of gestation and 9 (60%) required emergency cesarean section because of a sudden increase in blood pressure. Four (5.1%) women experienced renal artery stenosis complications and three of them developed hypertension during pregnancy. Two (2.6%) experienced cerebral infarctions several days after delivery, both of whom had no subsequent aftereffects. No cases of hemorrhagic stroke were reported in the peripartum period. CONCLUSIONS: To date, this is the largest single-center analysis. It showed the number of moyamoya disease pregnancies has risen rapidly over the last decade. The hypertensive disorders of pregnancy and emergency cesarean section rates were high among moyamoya disease patients. Minor ischemic stroke was observed, but its prevalence was low. Therefore, pregnant women with moyamoya disease should be managed with the understanding that hypertensive disorders of pregnancy is a common complication.

Rare and Low-Frequency Variants in RNF213 Confer Susceptibility to Moyamoya Syndrome Associated with Hyperthyroidism.

BACKGROUND: Moyamoya syndrome (MMS), distinguished from definite moyamoya disease (MMD), is characterized by moyamoya vasculopathy thought to develop secondary to underlying conditions (e.g., hyperthyroidism). Recent studies have shown that a proportion of East Asian (EAS) patients with MMS possess the p.R4810K variant of RNF213 (rs112735431), the foremost susceptibility variant among EAS patients with MMD. We evaluated the association between hyperthyroidism-associated MMS (hMMS) and sequence variants in RNF213. METHODS: We performed next-generation sequencing of RNF213 in 15 patients with hMMS. Candidate coding variants for the association analysis were defined by allelic frequencies of <1%, based on the p.R4810K frequency in the Japanese population. The association with hMMS was tested using a collapsing method, and 260 unrelated EAS women from the 1000 Genomes Project served as population-based controls. RESULTS: All patients were female, reflecting female predominance in both moyamoya and hyperthyroid conditions. Five candidate missense variants in RNF213 were identified in 8 of 15 patients (53.3%): p.C118R, p.R4062Q, and p.R4810K as heterozygous; and p.A3468V and p.S3986N as compound heterozygous with p.R4810K. Among 260 EAS female controls, 36 (13.8%) had putatively functional variants. All identified variants were missense variants and were significantly overrepresented among patients compared with EAS controls (permuted P = 0.00010; odds ratio = 7.03; 95% confidence interval, 2.09-24.3). CONCLUSIONS: Rare and low-frequency missense variants in RNF213 confer susceptibility to both MMD and hMMS. This finding indicates that susceptibility variants in RNF213 may require additional clinical factors with an effect equivalent to hyperthyroidism in order to develop moyamoya vasculopathy.

Novel and recurrent RNF213 variants in Japanese pediatric patients with moyamoya disease.

Moyamoya disease is a progressive steno-occlusive condition of the main intracranial arteries that results in the compensatory formation of fragile moyamoya vessels at the base of the brain. RNF213 is the most significant susceptibility gene and is often found with the p.Arg4810Lys founder variant in East Asian patients. We identified three putatively deleterious variants of this gene from three pediatric patients: two were novel, and one was a recurrent missense variant previously reported in other pediatric patients.

Case of Familial Moyamoya Disease Presenting 10 Years After Initial Negative Magnetic Resonance Screening in Childhood.

BACKGROUND: Both genetic and environmental factors are considered to contribute to the onset of moyamoya disease, but the exact mechanism has not yet been clarified. Furthermore, the typical time course of progression to vessel occlusion has not been established, even in the genetically high-risk population. CASE DESCRIPTION: We present the case of a 21-year-old female with familial history of moyamoya disease. She underwent screening for moyamoya disease 10 years prior, but no abnormalities in magnetic resonance imaging or magnetic resonance angiography were found. She presented to our hospital for transient numbness of the left upper and lower extremities and dysarthria at the age of 21. She was diagnosed with moyamoya disease and underwent bilateral encephaloduroarteriosynangiosis. Gene analysis on the point mutation of RNF213, p.R4810K, was conducted for this patient, her younger sister with moyamoya disease, and their nonsymptomatic parents. A rare variant (p.R4810K) was positive in these sisters and their mother. CONCLUSION: We show a case of familial moyamoya disease diagnosed 10 years after the magnetic resonance imaging screening in childhood. We must carefully consider when, how, and for whom screening for moyamoya disease should be performed, taking into account familial history of the disease.

Exome Sequencing Identified CCER2 as a Novel Candidate Gene for Moyamoya Disease.

The etiology of Moyamoya disease (MMD) is still largely unclear, despite identification of RNF213 as the most significant susceptibility gene in East Asian patients. Following up our previous study confirming genetic heterogeneity in Japanese patients with MMD, we extensively surveyed novel candidate genes for a new perspective on the etiology of this disease. Two characteristic pedigrees without susceptibility variants in RNF213 were selected for whole-exome sequencing; 1 harbored 3 affected members, and the other included discordant monozygotic twins. In the former pedigree, 12 rare mutations in 12 genes were co-segregated with MMD. One of the most deleterious amino acid changes among these was p.T76_G80delinsPS in CCER2, which was also mutated in the latter pedigree (p.E242K), although the unaffected twin sister shared the same mutation reflecting reduced penetrance. These CCER2 mutations were predicted to promote aggregation or oligomerization of their protein product, using in silico functional analysis. Subsequent CCER2 re-sequencing in an additional 135 MMD probands identified 1 recurrent and an additional 2 in-frame insertion-deletion mutations, recurrent p.T76_G80delinsPS, p.H218_H220del, and p.E299del. Although CCER2 molecular function is not well characterized, it is a secretory protein expressed in the brain; therefore, it constitutes a potential biomarker of MMD.

First autopsy analysis of a neovascularized arterial network induced by indirect bypass surgery for moyamoya disease: case report.

The object of this study was to analyze the pathology of collateral vessels newly induced by indirect bypass surgery for moyamoya disease (MMD). An autopsy analysis was conducted on a 39-year-old woman with MMD who had died of a brainstem infarction. The patient had undergone bilateral indirect bypass surgeries 22 years earlier. Sufficient revascularization via bilateral external carotid arterial systems was confirmed by cerebral angiography before her death. Macroscopic observation of the operative areas revealed countless meandering vessels on the internal surface of the dura mater connected with small vessels on the brain surface and in the subpial brain tissue. Notably, microscopic analysis of these vessels revealed the characteristic 3-layer structure of an arterial wall. This autopsy analysis was the first to confirm that indirect bypass surgery had induced the formation of a new arterial network (arteriogenesis) and that this network had been maintained for more than 20 years to compensate for the chronic cerebral ischemia caused by the MMD.

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.

Practical clinical use of dynamic susceptibility contrast magnetic resonance imaging for the surgical treatment of moyamoya disease.

BACKGROUND: Precise evaluation of hemodynamic stress is important for the treatment of moyamoya disease (MMD). OBJECTIVE: To explore whether dynamic susceptibility contrast magnetic resonance imaging could predict the effects and risk of indirect bypass surgery on MMD. METHODS: Clinical data of patients with MMD who were evaluated preoperatively and postoperatively with dynamic susceptibility contrast magnetic resonance imaging and digital subtraction angiography were evaluated retrospectively. Indirect bypass surgery was performed on 115 hemispheres of 69 patients (mean age, 15 years; range, 3-54 years). We examined the correlations of ischemic events and revascularization with the mean transit time (MTT) delay to cerebellum. RESULTS: The hemispheres that caused the ischemic events (responsible hemisphere) had a significantly longer preoperative MTT delay than the nonresponsible hemispheres (2.66 ± 1.34 vs 1.57 ± 1.09 seconds). The postoperative MTT delay fell significantly in the patients whose symptoms disappeared (preoperative, 2.61 ± 1.35 seconds; postoperative, 1.35 ± 0.96 seconds). Perioperative infarction occurred in 4 hemispheres (3.5%), and the MTT delay was significantly longer in those hemispheres than in the others (3.97 ± 1.20 vs 2.38 ± 1.34 seconds). The MTT delay was significantly longer in patients with higher angiographic stages. Indirect bypass surgery ameliorated the MTT delay to the same degree in adults and children. Digital subtraction angiography revealed that the induced revascularization was far superior in areas with longer MTT delays. CONCLUSION: Dynamic susceptibility contrast magnetic resonance imaging proved to be a useful clinical imaging method for patients with MMD. It may be helpful for selecting candidates for MMD intervention and for predicting the effects and risks of surgery. ABBREVIATIONS: DSC-MRI, dynamic susceptibility contrast magnetic resonance imagingMMD, moyamoya diseaseMTT, mean transit timeROI, region of interest.

Successful coil embolization of a ruptured basilar artery aneurysm in a child with leukemia: a case report.

Ruptured intracranial aneurysms are rare in the pediatric population compared to adults. This has incited considerable discussion on how to treat children with this condition. Here, we report a child with a ruptured saccular basilar artery aneurysm that was successfully treated with coil embolization. A 12-year-old boy with acute lymphoblastic leukemia and accompanying abdominal candidiasis after chemotherapy suddenly complained of a severe headache and suffered consciousness disturbance moments later. Computed tomography scans and cerebral angiography demonstrated acute hydrocephalus and subarachnoid hemorrhage caused by saccular basilar artery aneurysm rupture. External ventricular drainage was performed immediately. Because the patient was in severe condition and did not show remarkable signs of central nervous system infection in cerebrospinal fluid studies, we applied endovascular treatment for the ruptured saccular basilar artery aneurysm, which was successfully occluded with coils. The patient recovered without new neurological deficits after ventriculoperitoneal shunting. Recent reports indicate that both endovascular and microsurgical techniques can be used to effectively treat ruptured cerebral aneurysms in pediatric patients. A minimally invasive endovascular treatment was effective in the present case, but long-term follow-up will be necessary to confirm the efficiency of endovascular treatment for children with ruptured saccular basilar artery aneurysms.

Clinical features of familial juvenile cases of moyamoya disease: analysis of patients treated in a single institute over a 28-year period.

OBJECT: The authors compared the clinical features between familial and sporadic cases of moyamoya disease (MMD) by retrospectively analyzing data on patients with MMD registered in the database of Tokyo Medical and Dental University over a period of 28 years. METHODS: In total, 383 patients with hospital records at Tokyo Medical and Dental University from 1980 to 2007 were registered into the database. The data on all of these patients were retrospectively reviewed to clarify the occurrence of familial cases. Clinical features of child or adolescent patients (< 20 years of age) with MMD were compared between familial and sporadic cases in a subgroup of patients who were registered after 1995, initially diagnosed using MR angiography, and assessed using an intelligence scale. RESULTS: Familial occurrence was observed in 59 patients (15.4%) in 40 pedigrees. The clinical features of juvenile patients were analyzed in 124 patients, 22 (17.7%) of whom had familial histories. In comparison with the sporadic cases, patients with familial histories were significantly younger at onset (4.7 vs 6.6 years old), had significantly more cortical infarction (59.1% vs 25.5%), and had significantly more stenoocclusive lesions in the posterior cerebral artery (45.4% vs 24.5%). The rate of patients with intellectual disturbance (intelligence quotient < 75) was significantly larger in the familial cases (47.4%) than in the sporadic cases (17.8%). CONCLUSIONS: This survey of the clinical features of familial MMD suggests that patients with familial MMD had a more serious clinical course in childhood than the sporadic MMD cases.

Long-term follow-up of surgically treated juvenile patients with Moyamoya disease.

OBJECT: Surgical revascularization is considered an effective treatment for juvenile patients with moyamoya disease (MMD). Yet the long-term outcome in surgically treated patients still needs to be clarified. More than 30 years have passed since the authors' department started intensively treating pediatric patients with MMD using indirect anastomosis techniques. In this study the authors surveyed the current status of these patients. METHODS: Activities of daily living (ADLs) were surveyed and present clinical status was assessed based on the modified Rankin scale (mRS). Cerebrovascular events subsequent to surgical treatment were also recorded. RESULTS: Since 1979, 208 patients younger than 19 years of age with MMD were surgically treated and followed up for > 3 years. Data were available on 172 patients (83%), who had been followed up for a mean of 14.3 years (range 3-32 years). Activity of daily living outcomes were as follows: 138 patients (80.2%) had mRS scores of 0-2, 29 (16.9%) a score of 3, 1 (0.6%) a score of 4, 1 (0.6%) a score of 5, and 3 (1.7%) a score of 6. Cerebrovascular events occurred 8 or more years after surgery in 6 patients (3.4%), that is, 6 hemorrhages and 3 infarctions. The cumulative risk of late-onset stroke at 10, 20, and 30 years after surgical intervention was 0.8%, 6.3%, and 10.0%, respectively. CONCLUSIONS: This long-term survey demonstrated that most surgically treated pediatric patients with MMD maintain good ADL outcomes. However, a significant number of new cerebrovascular events occurred more than 10 years after the initial surgery. Additional follow-up will help to identify which events may occur during the adult years of patients treated as children.

[Subarachnoid hemorrhage due to a ruptured intracranial vertebral artery aneurysm associated with cerebrovascular fibromuscular dysplasia: case report].

Fibromuscular dysplasia (FMD) is comprised of a group of nonatherosclerotic and noninflammatory arterial diseases. Cerebrovascular FMD occurs more frequently in women, and the mean age at which it is diagnosed is 50 years. The most common angiographic pattern of cerebrovascular FMD is the "string-of-beads" deformity at the extracranial internal carotid artery. We report the case of a 52-year-old woman who presented with a sudden severe headache and went into a deep coma. She had been complaining of headaches for 2 weeks, but no specific imaging findings were obtained. A computed tomography scan obtained on admission showed a diffuse subarachnoid hemorrhage (SAH) from the cerebellomedullary cistern to the basal cistern with evidence of clot in the fourth and third ventricles. We performed digital subtraction angiography and made the diagnosis of cerebrovascular FMD. Right carotid angiography and left vertebral angiography showed the classic "string-of-beads" pattern with multiple constrictions of the lumen. Left carotid angiography showed a long segment of tubular stenosis. Right vertebral angiography also revealed the "string-of-beads" pattern and a ruptured aneurysm at the intracranial segment, which presented as a diverticulum-like outpouching. The patient was treated with conservative measures but passed away on the 23rd day of hospitalization. An autopsy was not performed. To our knowledge, during the last three decades, there are only four previous reports which showed intracerebral ruptured aneurysms of the vertebral artery or its branch in adults with cerebrovascular FMD. We demonstrate and discuss the radiologic findings here.

[Clinical and serial angiographic study in patients with subarachnoid hemorrhage of unknown etiology with special reference to the clot distribution of perimesencephalic nonaneurysmal subarachnoid hemorrhage].

We investigated 22 cases with subarachnoid hemorrhage (SAH) of unknown etiology by the initial digital subtraction angiography (DSA). The computed tomography (CT) scans were obtained within 24 hours from onset. Patients were divided into two groups according to SAH distribution in CT on admission; perimesencephalic SAH (PMSAH) and non-PMSAH. The category of patients belonging to the PMSAH group was subdivided into typical or extended pattern of PMSAH. Typical PMSAH pattern of CT is defined as that having the center of clot immediately anterior to the upper brainstem with no definite extension into the anterior interhemispheric fissure (IFH) or sylvian fissure. Extended PMSAH pattern includes the extension of SAH into the anterior IHF or sylvian fissure with the center of the clot similarly located anterior to the upper brainstem. The number of patients with typical PMSAH, extended PMSAH or non-PMSAH was 2, 6, or 14, respectively. Follow-up DSA was obtained in 20 Spatients. The 2nd DSA revealed the lesions as bleeding sources in 3 patients with non-PMSAH. Eight patients further underwent the 3rd DSA, which identified bleeding sources in 3 patients with non-PMSAH. No bleeding sources were detected by serial DSA in PMSAH patients. Patients with extended PMSAH may be managed like those with typical PMSAH. The 3rd DSA is required if the 2nd DSA fails to identify the bleeding source in non-PMSAH. The 2nd DSA may be necessary in PMSAH patients because of the possible identification of bleeding sources. Optimal diagnostic protocol to confirm the bleeding sources should be established in SAH patients of unknown etiology.