Loss of methylthioadenosine phosphorylase immunoreactivity correlates with poor prognosis and elevated uptake of 11C-methionine in IDH-mutant astrocytoma.

PURPOSE: The proximate localization of MTAP, which encodes methylthioadenosine phosphorylase, and CDKN2A/B on Chromosome 9q21 has allowed the loss of MTAP expression as a surrogate for homozygous deletion of CDKN2A/B. This study aimed to determine whether MTAP status correlates with clinical outcomes and 11C-methionine uptake in astrocytomas with IDH mutations. METHODS: We conducted immunohistochemistry for MTAP in 30 patients with astrocytoma, IDH-mutant who underwent 11C-methionine positron emission tomography scans prior to surgical resection. The tumor-to-normal (T/N) ratio of 11C-methionine uptake was calculated using the mean standardized uptake value (SUV) for tumor and normal brain tissues. Cox regression analysis was used for multivariate survival analysis. RESULTS: Among IDH-mutant astrocytomas, 26.7% (8/30) exhibited the loss of cytoplasmic MTAP expression, whereas 73.3% (22/30) tumors retained MTAP expression. The median progression-free survival (PFS) was significantly shorter in patients with MTAP loss than those with MTAP retention (1.88 years vs. 6.80 years, p = 0.003). The median overall survival (OS) was also shorter in patients with MTAP loss than in MTAP-retaining counterparts (5.23 years vs. 10.69 years, p = 0.019). Multivariate analysis identified MTAP status (hazard ratio (HR), 0.081) and extent of resection (HR, 0.104) as independent prognostic factors for PFS. Astrocytomas lacking cytoplasmic MTAP expression showed a significantly higher median T/N ratio for 11C-methionine uptake than tumors retaining MTAP (2.12 vs. 1.65, p = 0.012). CONCLUSION: Our study revealed that the loss of MTAP expression correlates with poor prognosis and an elevated T/N ratio of 11C-methionine uptake in astrocytoma, IDH-mutant.

Decreased diffusivity along the perivascular space and cerebral hemodynamic disturbance in adult moyamoya disease.

Moyamoya disease (MMD) causes cerebral arterial stenosis and hemodynamic disturbance, the latter of which may disrupt glymphatic system activity, the waste clearance system. We evaluated 46 adult patients with MMD and 33 age- and sex-matched controls using diffusivity along the perivascular space (ALPS) measured with diffusion tensor imaging (ALPS index), which may partly reflect glymphatic system activity, and multishell diffusion MRI to generate freewater maps. Twenty-three patients were also evaluated via 15O-gas positron emission tomography (PET), and all patients underwent cognitive tests. Compared to controls, patients (38.4 (13.2) years old, 35 females) had lower ALPS indices in the left and right hemispheres (1.94 (0.27) vs. 1.65 (0.25) and 1.94 (0.22) vs. 1.65 (0.19), P < 0.001). While the right ALPS index showed no correlation, the left ALPS index was correlated with parenchymal freewater (ρ = -0.47, P < 0.001); perfusion measured with PET (cerebral blood flow, ρ = 0.70, P < 0.001; mean transit time, ρ = -0.60, P = 0.003; and oxygen extraction fraction, ρ = -0.52, P = 0.003); and cognitive tests (trail making test part B for executive function; ρ = -0.37, P = 0.01). Adult patients with MMD may exhibit decreased glymphatic system activity, which is correlated with the degree of hemodynamic disturbance, increased interstitial freewater, and cognitive dysfunction, but further investigation is needed.

Impact of [11C]methionine PET with Bayesian penalized likelihood reconstruction on glioma grades based on new WHO 2021 classification.

OBJECTIVE: The uptake of [11C]methionine in positron emission tomography (PET) imaging overlapped in earlier images of tumors. Bayesian penalized likelihood (BPL) reconstruction increases the quantitative values of tumors compared with conventional ordered subset-expectation maximization (OSEM). The present study aimed to grade glioma malignancy based on the new WHO 2021 classification using [11C]methionine PET images reconstructed using BPL. METHODS: We categorized 32 gliomas in 28 patients as grades 2/3 (n = 15) and 4 (n = 17) based on the WHO 2021 classification. All [11C]methionine images were reconstructed using OSEM + time-of-flight (TOF) and BPL + TOF (ß = 200). Maximum standardized uptake value (SUVmax) and tumor-to-normal tissue ratio (T/Nmax) were measured at each lesion. RESULTS: The mean SUVmax was 4.65 and 4.93 in grade 2/3 and 6.38 and 7.11 in grade 4, and the mean T/Nmax was 7.08 and 7.22 in grade 2/3 and 9.30 and 10.19 in grade 4 for OSEM and BPL, respectively. The BPL significantly increased these values in grade 4 gliomas. The area under the receiver operator characteristic (ROC) curve (AUC) for SUVmax was the highest (0.792) using BPL. CONCLUSIONS: The BPL increased mean SUVmax and mean T/Nmax in lesions with higher contrast such as grade 4 glioma. The discrimination power between grades 2/3 and 4 in SUVmax was also increased using [11C]methionine PET images reconstructed with BPL.

Synergistic Interaction of Thyroid Autoantibodies and Ring Finger Protein 213 Variant in Moyamoya Disease.

Recently, thyroid autoantibodies were found to be associated with moyamoya disease (MMD). The ring finger protein 213 (RNF213) p.R4810K variant represents the most important susceptibility genotype of this disease, but its relationship with thyroid autoantibodies remains to be elucidated. Thus, in this study, we aimed to evaluate the clinical relevance of thyroid autoantibodies in each RNF213 genotype in patients with MMD. Included in this study were patients with MMD without a thyroid disease history and in euthyroid status; they were then classified into the mutated or nonmutated based on the RNF213 p.R4810K genotype and positive or negative based on thyroid autoantibody (thyroperoxidase and thyroglobulin) levels. Clinical data of each group were thereafter evaluated. Among the 209 patients, the mutated RNF213 p.R4810K variant and positive thyroid autoantibodies were detected in 155 and 41 patients, respectively. Positive thyroid autoantibodies were found to be more common in the nonmutated patients than in the mutated patients (31.5% vs. 15.5%; P = 0.011). In the mutated patients, as compared to autoantibody-negative patients, autoantibody-positive patients were determined to be more likely to have advanced disease with posterior cerebral artery involvement (54.2% vs. 29.0%; P = 0.017), white matter infarction (58.3% vs. 37.6%; P = 0.046), and a higher modified Rankin Scale at last visit (16.7% vs. 3.1%; P = 0.021). These results suggest that thyroid autoantibodies can act as an immunity inducer in patients with MMD lacking the susceptibility gene RNF213 p.R4810K variant. Moreover, the simultaneous presence of thyroid autoantibodies and the variant seems to aggravate the disease, which indicates synergy between thyroid autoantibodies and the variant.

Long-term prognosis of 452 moyamoya disease patients with and without revascularization under perfusion-based indications.

OBJECTIVES: To evaluate the long-term outcomes of patients treated under our perfusion-based strategy and assess whether conservative treatment without surgical treatment under our strategy is acceptable. MATERIALS AND METHODS: A total of 315 adult and 137 pediatric MMD patients (follow-up period ≥ 3 years from 2001 to 2020) were included. Follow-up events in each patient group (pediatric or adult, surgically treated or conservatively treated) were evaluated and compared to each other using a log-rank test. Risk factors for stroke and nonstroke events were also investigated using a multivariate Cox proportional hazard model. RESULTS: In adult-onset patients, the stroke event rates (person-year %) were not different between surgically treated patients and conservatively treated patients (2.00 % vs. 1.59 %, p = 0.558); however, conservative patients showed a higher stroke rate than surgically treated hemispheres (0.34 %; p = 0.025) and hemorrhagic stroke was the major type (18/26, 69.2 %). Hemorrhagic onset was associated with increased risk of stroke in adults (hazard ratio (95 % confidence interval) = 2.43 (1.10-5.36)). In pediatric-onset patients, no conservatively treated patients experienced stroke; however, nonstroke events occurred more frequently than in surgically treated hemispheres (4.86 % vs. 1.71 %, p = 0.020 for transient ischemic attack; and 7.91 % vs. 1.31 %, p < 0.001 for asymptomatic progression on magnetic resonance angiography). CONCLUSIONS: In adult patients, conservatively treated patients experienced stroke more frequently, especially hemorrhagic stroke. An additive strategy to prevent stroke in hemorrhagic-onset patients without hemodynamic disturbance seems to be needed. Pediatric patients with mild hemodynamic disturbance can be safely observed without initial surgical intervention, but close follow-up for disease progression is necessary.

Regression of periventricular anastomosis after indirect revascularization in pediatric patients with moyamoya disease.

OBJECTIVE: The aim of this study was to evaluate whether indirect revascularization in pediatric patients with moyamoya disease leads to periventricular anastomosis (PVA) regression, which is markedly developed in moyamoya vessels and is regarded as a risk factor for hemorrhage. METHODS: Pediatric patients with moyamoya disease treated with indirect revascularization from 2011 to 2021 were included in this study. Magnetic resonance angiography and arterial spin labeling images acquired before and 1 year after surgery were assessed to obtain a visual scale of postoperative collateral artery formation, moyamoya vessels, PVA, and quantitative values of cerebral blood flow (CBF). The relationship between background information (age, sex, RNF213 p.R4810K variant status, and preoperative CBF) and postoperative collateral artery formation, as well as postoperative CBF improvement and regression of moyamoya vessels and PVA, was evaluated. RESULTS: Of 89 hemispheres in 58 patients (34 females; mean [SD] patient age 8.0 [3.4] years), 74.2% showed good postoperative collateral artery formation and a significant increase in CBF (p < 0.001). Postoperative PVA showed significant regression (postoperative score 1.46 [1.06] vs 2.02 [1.69], p = 0.001), especially in those arising from choroidal arteries (postoperative score 0.28 [0.50] vs 0.72 [0.67], p < 0.001). Compared with hemispheres without good collateral artery formation, those with good collateral artery formation were more likely to show a higher increase in CBF (9.74 [12.44] ml/min/100 g vs -4.86 [9.68] ml/min/100 g, p < 0.001) and regression of PVA (54.5% [36/66] vs 30.4% [7/23], p = 0.015). Although not statistically significant, patients with postoperative PVA progression were younger than those with regression (6.75 [3.03] years vs 8.18 [3.17] years, p = 0.188), and patients with the RNF213 p.R4810K variant were more likely to show regression (28/57 [49.1%] hemispheres vs 5/13 [38.5%] hemispheres, p = 0.069). CONCLUSIONS: Indirect revascularization in pediatric patients with moyamoya disease resulted in good collateral extracranial artery formation and an increase in CBF and PVA regression, especially of vessels arising from choroidal arteries. With good postoperative collateral artery development, patients were more likely to show improved CBF and regression of moyamoya vessels, including PVA. Whether postoperative PVA changes reduce future hemorrhage risk requires further investigation.

T2-FLAIR mismatch sign correlates with 11C-methionine uptake in lower-grade diffuse gliomas.

PURPOSE: The T2-FLAIR mismatch sign is recognized as an imaging finding highly suggestive of IDH-mutant astrocytomas. This study was designed to determine whether the T2-FLAIR mismatch sign correlates with uptake of 11C-methionine in lower-grade gliomas. METHODS: We included 78 histopathologically verified lower-grade gliomas (grade 2: 31 cases, grade 3: 47 cases) in this study. 78 patients underwent 11C-methionine positron emission tomography (MET-PET) scans and magnetic resonance (MR) imaging scans prior to histological diagnosis. The tumor-to-normal ratio (T/N) of 11C-methionine uptake was calculated by dividing the maximum standardized uptake value (SUV) for the tumor by the mean SUV of the normal brain. MR imaging scans were evaluated for the presence of the T2-FLAIR mismatch sign by three independent reviewers. We compared molecular status, the T2-FLAIR mismatch sign and 11C-methionine uptake among patients with different lower-grade glioma molecular types. RESULTS: The 78 lower-grade gliomas were assigned to one of three molecular groups: Group A (IDH-mutant and 1p/19q non-codeleted, n = 22), Group O (IDH-mutant and 1p/19q codeleted, n = 20), and Group W (IDH wildtype, n = 36). T2-FLAIR mismatch was found in 16 cases (20.5%) that were comprised of 8 (36.4%), 0 (0%), 8 (22.2%) cases in the molecular group A, O and W, respectively. The median T/N ratio of MET-PET in tumors with T2-FLAIR mismatch was 1.50, which was significantly lower than that of tumors without T2-FLAIR mismatch (1.83, p < 0.001, Mann-Whitney U test). In the Groups A and W (excluding Group O), the median T/N ratio on MET-PET in groups A and W (but not group O) with T2-FLAIR mismatch was 1.50, which was significantly lower than that of tumors without T2-FLAIR mismatch (1.81, p = 0.002, Mann-Whitney U test). CONCLUSION: The T2-FLAIR mismatch sign correlated with lower 11C-methionine uptake in lower grade gliomas.

Encephalo-Duro-Pericranio-Synangiosis for the Treatment of Moyamoya Disease with Posterior Cerebral Artery Lesions.

OBJECTIVE: We describe our experience performing encephalo-duro-pericranio synangiosis for the parieto-occipital region (EDPS-p) as a treatment for moyamoya disease (MMD) with hemodynamic disturbances caused by lesions of the posterior cerebral artery. METHODS: From 2004 to 2020, 60 hemispheres of 50 patients with MMD (38/50 females, age 1-55 years) underwent EDPS-p as a treatment for hemodynamic disturbances in the parieto-occipital region. A skin incision was made on the parieto-occipital area to avoid the major skin arteries, and the pedicle flap was created by attaching the pericranium to the dura mater under the craniotomy with multiple small incisions. The surgical outcome was assessed on the basis of the following points: perioperative complications, postoperative improvement of clinical symptoms, subsequent novel ischemic events, qualitative assessment of the development of collateral vessels by magnetic resonance arteriography, quantitative assessment of postoperative perfusion improvement based on the mean transit time, and cerebral blood volume on dynamic susceptibility contrast imaging. RESULTS: Perioperative infarction occurred in 7/60 hemispheres (11.7%). The transient ischemic symptoms observed preoperatively disappeared in 39/41 hemispheres (95.1%) during the follow-up period (12-187 months), and none of the patients experienced novel ischemic events. Collateral vessels supplied from the occipital arteries, middle meningeal arteries, and posterior auricular arteries developed postoperatively in 56/60 hemispheres (93.3%). Postoperative mean transit time and cerebral blood volume showed significant improvement in the occipital, parietal, and temporal areas (P < 0.001), as well as the frontal area (P = 0.01). CONCLUSIONS: EDPS-p seems to be an effective surgical treatment for patients with MMD who suffer hemodynamic disturbances caused by posterior cerebral artery lesions.

Increased Parenchymal Free Water May Be Decreased by Revascularization Surgery in Patients with Moyamoya Disease.

PURPOSE: Moyamoya disease (MMD) is a cerebrovascular disease associated with steno-occlusive changes in the arteries of the circle of Willis and with hemodynamic impairment. Previous studies have reported that parenchymal extracellular free water levels may be increased and the number of neurites may be decreased in patients with MMD. The aim of the present study was to investigate the postoperative changes in parenchymal free water and neurites and their relationship with cognitive improvement. METHODS: Multi-shell diffusion MRI (neurite orientation dispersion and density imaging and free water imaging using a bi-tensor model) was performed in 15 hemispheres of 13 adult patients with MMD (11 female, mean age 37.9 years) who had undergone revascularization surgery as well as age- and sex-matched normal controls. Parameter maps of free water and free-water-eliminated neurites were created, and the regional parameter values were compared among controls, patients before surgery, and patients after surgery. RESULTS: The anterior and middle cerebral artery territories of patients showed higher preoperative free water levels (P ≤ 0.007) and lower postoperative free water levels (P ≤ 0.001) than those of normal controls. The change in the dispersion of the white matter in the anterior cerebral artery territory correlated with cognitive improvement (r = -0.75; P = 0.004). CONCLUSION: Our study suggests that increased parenchymal free water levels decreased after surgery and that postoperative changes in neurite parameters are related to postoperative cognitive improvement in adult patients with MMD. Diffusion analytical methods separately calculating free water and neurites may be useful for unraveling the pathophysiology of chronic ischemia and the postoperative changes that occur after revascularization surgery in this disease population.

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.

Effect of Temporal Sampling Rate on Estimates of the Perfusion Parameters for Patients with Moyamoya Disease Assessed with Simultaneous Multislice Dynamic Susceptibility Contrast-enhanced MR Imaging.

PURPOSE: The effect of temporal sampling rate (TSR) on perfusion parameters has not been fully investigated in Moyamoya disease (MMD); therefore, this study evaluated the influence of different TSRs on perfusion parameters quantitatively and qualitatively by applying simultaneous multi-slice (SMS) dynamic susceptibility contrast-enhanced MR imaging (DSC-MRI). METHODS: DSC-MRI datasets were acquired from 28 patients with MMD with a TSR of 0.5 s. Cerebral blood flow (CBF), cerebral blood volume (CBV), mean transit time (MTT), time to peak (TTP), and time to maximum tissue residue function (Tmax) were calculated for eight TSRs ranging from 0.5 to 4.0 s in 0.5-s increments that were subsampled from a TSR of 0.5 s datasets. Perfusion measurements and volume for chronic ischemic (Tmax ≥ 2 s) and non-ischemic (Tmax < 2 s) areas for each TSR were compared to measurements with a TSR of 0.5 s, as was visual perfusion map analysis. RESULTS: CBF, CBV, and Tmax values tended to be underestimated, whereas MTT and TTP values were less influenced, with a longer TSR. Although Tmax values were overestimated in the TSR of 1.0 s in non-ischemic areas, differences in perfusion measurements between the TSRs of 0.5 and 1.0 s were generally minimal. The volumes of the chronic ischemic areas with a TSR ≥ 3.0 s were significantly underestimated. In CBF and CBV maps, no significant deterioration was noted in image quality up to 3.0 and 2.5 s, respectively. The image quality of MTT, TTP, and Tmax maps for the TSR of 1.0 s was similar to that for the TSR of 0.5 s but was significantly deteriorated for the TSRs of ≥ 1.5 s. CONCLUSION: In the assessment of MMD by SMS DSC-MRI, application of TSRs of ≥ 1.5 s may lead to deterioration of the perfusion measurements; however, that was less influenced in TSRs of ≤ 1.0 s.

Differences in cerebral blood flow measurement using arterial spin labeling MRI between patients with moyamoya disease and patients with arteriosclerotic cerebrovascular disease.

BACKGROUND: It is unclear whether the accuracy of arterial spin labeling (ASL) magnetic resonance imaging (MRI) is the same between moyamoya disease (MMD), which is known to have markedly elevated cerebral blood volume (CBV), and atherosclerotic intracranial arterial stenosis (AS), which has relatively less elevated CBV. PURPOSE: To investigate how the differences in hemodynamics affect measurement of ASL-cerebral blood flow (CBF) using ASL for patients with MMD and AS. MATERIAL AND METHODS: Fourteen MMD and ten AS patients were evaluated with ASL-MRI, magnetic resonance angiography (MRA), and 15O-gas positron emission computed tomography (PET). The regional CBF values of ASL using two post-labeling delays (PLDs; 1525 ms and 2525 ms) were compared with the PET-derived CBF, CBV, and mean transit time (MTT). Corresponding anterior circulation results were evaluated by flow territory map-based analysis. RESULTS: The correlation between the ASL-CBF values (2525 ms) and PET-CBF declined in the MMD group (r = 0.28; P < 0.01), while the AS group showed good correlation (r = 0.77; P < 0.01). In the MMD group, the ASL-CBF values (2525 ms) overestimated the PET-CBF values as the regional CBV values increased (r = 0.35; P < 0.01). When the regions of interest were divided into two subgroups according to the degree of arterial stenosis by MRA, the correlation coefficient between the ASL-CBF (2525 ms) and PET-CBF values improved (mild stenosis: r = 0.36; P = 0.06; severe stenosis: r = 0.51; P < 0.01). CONCLUSION: The accuracy of CBF measurements using ASL-MRI differed between patients with MMD and AS. The prominent increase of CBV and the degree of arterial stenosis may have affected the accuracy of ASL-CBF in patients with MMD.

[Indirect Revascularization Surgery for Chronic Ischemia in Moyamoya Disease].

Indirect revascularization is a surgical procedure to reduce cerebral ischemia, using subcutaneous tissues or dura mater supplied by extracranial arteries as grafts. The perfusion pressure gradient between the cortex and the graft, if present, induces arteriogenesis and develops extracranial-intracranial anastomoses to supply blood flow to the cerebral cortex underneath the graft. Therefore, it is essential to perform the craniotomy over the site of the cerebral ischemia to induce functional anastomoses. The details of the indirect revascularization procedure vary among institutes in terms of the grafts used(skin arteries, such as the superficial temporal artery; temporal muscle, galea, or pericranium), dura mater incisions(removal and replacement with the grafts, linear incision, or multiple small incisions), and the location and size of the craniotomy. Indirect revascularization is especially effective in patients with moyamoya disease because the pathophysiology of the disease itself is related to intracranial to extracranial carotid system conversion. Generally, indirect revascularization was considered ineffective in patients with atherosclerotic steno-occlusive cerebrovascular disease; however, recent clinical trials suggested that it may also be effective in these patients. If a future clinical trial demonstrates a positive outcome, indirect revascularization may become a possible treatment for atherosclerotic patients.

Correlation of Intraoperative 5-ALA-Induced Fluorescence Intensity and Preoperative 11C-Methionine PET Uptake in Glioma Surgery.

BACKGROUND: 5-Aminolevulinic acid (5-ALA) is widely employed to assist fluorescence-guided surgery for malignant brain tumors. Positron emission tomography with 11C-methionine (MET-PET) represents the activity of brain tumors with precise boundaries but is not readily available. We hypothesized that quantitative 5-ALA-induced fluorescence intensity might correlate with MET-PET uptake in gliomas. METHODS: Adult patients with supratentorial astrocytic gliomas who underwent preoperative MET-PET and surgical tumor resection using 5-ALA were enrolled in this prospective study. The regional tumor uptake of MET-PET was expressed as the ratio of standardized uptake volume max to that of the normal contralateral frontal lobe. A spectrometric fluorescence detection system measured tumor specimens' ex vivo fluorescence intensity at 635 nm. Ki-67 index and IDH mutation status were assessed by histopathological analysis. Use of an antiepileptic drug (AED) and contrast enhancement pattern on MRI were also investigated. RESULTS: Thirty-two patients, mostly with Glioblastoma IDH wild type (46.9%) and anaplastic astrocytoma IDH mutant (21.9%), were analyzed. When the fluorescence intensity was ranked into four groups, the strongest fluorescence group exhibited the highest mean MET-PET uptake and Ki-67 index values. When rearranged into fluorescence Visible or Non-visible groups, the Visible group had significantly higher MET-PET uptake and Ki-67 index compared to the Non-visible group. Contrast enhancement on MRI and IDH wild type tumors were more frequent among the Visible group. AED use did not correlate with 5-ALA-induced fluorescence intensity. CONCLUSIONS: In astrocytic glioma surgery, visible 5-ALA-induced fluorescence correlated with high MET-PET uptake, along with a high Ki-67 index.

Spatial coefficient of variation of arterial spin labeling MRI for detecting hemodynamic disturbances measured with 15O-gas PET in patients with moyamoya disease.

PURPOSE: The aim of this study was to investigate whether the spatial coefficient of variation of arterial spin labeling (ASL-CoV) acquired in clinical settings can be used to estimate the hemodynamic disturbances measured with 15O-gas positron emission tomography (PET), especially an increased oxygen extraction fraction (OEF), in patients with moyamoya disease. METHODS: We evaluated 68 adult patients with moyamoya disease who underwent ASL (postlabeling delay (PLD) = 1525 ms and 2525 ms) and PET. Regional values were measured using the middle cerebral artery territorial atlas divided into proximal, middle, and distal regions based on the arterial transit time, and correlations of ASL-CoV with cerebral blood flow, cerebral blood volume, mean transit time, and OEF, as well as the relationship between increased OEF and ASL-CoV, were evaluated. RESULTS: Regardless of the choice of region and PLD, ASL-CoV was significantly correlated with PET-measured parameters, including OEF (|ρ|= 0.30-0.80, P < 0.001). Regions with an increased OEF showed a significantly higher ASL-CoV than regions with a nonincreased OEF (P ≤ 0.03) regardless of the choice of region and PLD. The accuracy of identification of an increased OEF was highest when using a PLD of 1525 ms and the middle region (area under the curve = 0.750; using a cutoff value of 31.27, sensitivity = 97.4%, specificity = 41.7%, negative predictive value = 92.6%, and positive predictive value = 67.9%). CONCLUSION: ASL-CoV may help identify patients with increased OEF.

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.

Imaging Pattern and the Mechanisms of Postoperative Infarction After Indirect Revascularization in Patients with Moyamoya Disease.

OBJECTIVE: To develop preventive strategies against postoperative infarction after indirect revascularization surgery in patients with moyamoya disease (MMD), we evaluated clinical information, with a specific focus on the imaging pattern of postoperative infarction. METHODS: We retrospectively evaluated 421 surgical procedures performed in 354 (262 pediatric and 159 adult) patients with MMD from April 1991 to March 2021 at our institute. In addition to clinical information, raw images of postoperative infarction were collected and categorized into subtypes by the location of the infarction. RESULTS: Symptomatic and asymptomatic postoperative infarction occurred in 47 and 12 patients (11.1% and 2.6%), respectively, and more than half (51.7%) of these cases of postoperative infarction occurred immediately or the day after the surgery. Cortical infarction around the craniotomy site was the most frequent pattern observed (50/59, 84.8%), and some of these cases seemed to occur under local compression from epidural or subdural hematomas (15/50, 30.0%). Ipsilateral white matter infarctions located in the watershed area (9/59, 15.3%) and contralateral infarctions (3/59, 5.1%) were also observed. Four patients (1.0%) showed sudden occlusions of ipsilateral or contralateral large intracranial arteries immediately after surgery. Postoperative infarction caused permanent neurologic deficits in 7 patients (1.7%), and all included the cortex outside the craniotomy site. CONCLUSIONS: Local cortical irritation, hemodynamic fluctuation, and thromboembolic events were suggested as possible mechanisms of postoperative infarction after indirect revascularization in patients with MMD. Minimizing cortical irritation, maintaining adequate cerebral blood flow, and perioperative antiplatelet agents might decrease the incidence of postoperative infarction.

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.

Effects of sevoflurane anesthesia on intraoperative high-frequency oscillations in patients with temporal lobe epilepsy.

PURPOSE: This is a cross-sectional study without an unexposed group. We elucidated the effects of sevoflurane anesthesia on high-frequency oscillations (HFOs) to examine the usefulness of assessing intraoperative HFOs. METHODS: We recorded electrocorticography in seven patients with medication-resistant temporal lobe epilepsy (TLE) caused by unilateral hippocampal sclerosis who were seizure-free after temporal lobectomy. We analyzed the number of intraoperative spikes and HFOs on spikes in the epileptogenic parahippocampal gyrus and nonepileptogenic superior temporal gyrus with sevoflurane concentrations of 1.5%, 2.0%, 2.5%, and 3.0%. RESULTS: The number of spikes and HFOs in the epileptogenic area significantly increased with an increase in the sevoflurane concentration. In the nonepileptogenic area, spikes and HFOs did not significantly increase with increases in the sevoflurane concentration. However, 2.5% sevoflurane markedly induced spikes and ripples but no fast ripples (FRs) in one patient, and 3.0% sevoflurane induced marked increases in both ripples and FRs in two patients. CONCLUSIONS: The proconvulsant effect of sevoflurane on intraoperative HFOs in patients with TLE depends on the concentration. While HFOs induced by higher sevoflurane concentrations may be a useful biomarker for epileptogenic areas, careful interpretation is also needed because a higher sevoflurane concentration can also induce false-positive HFOs in nonepileptogenic areas.