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).

Allogeneic Stem Cell Therapy for Acute Ischemic Stroke: The Phase 2/3 TREASURE Randomized Clinical Trial.

Importance: Cell therapy is a promising treatment approach for stroke and other diseases. However, it is unknown whether MultiStem (HLCM051), a bone marrow-derived, allogeneic, multipotent adult progenitor cell product, has the potential to treat ischemic stroke. Objective: To assess the efficacy and safety of MultiStem when administered within 18 to 36 hours of ischemic stroke onset. Design, Setting, and Participants: The Treatment Evaluation of Acute Stroke Using Regenerative Cells (TREASURE) multicenter, double-blind, parallel-group, placebo-controlled phase 2/3 randomized clinical trial was conducted at 44 academic and clinical centers in Japan between November 15, 2017, and March 29, 2022. Inclusion criteria were age 20 years or older, presence of acute ischemic stroke (National Institutes of Health Stroke Scale [NIHSS] score of 8-20 at baseline), confirmed acute infarction involving the cerebral cortex and measuring more than 2 cm on the major axis (determined with diffusion-weighted magnetic resonance imaging), and a modified Rankin Scale (mRS) score of 0 or 1 before stroke onset. Data analysis was performed between May 9 and August 15, 2022. Exposure: Patients were randomly assigned to either intravenous MultiStem in 1 single unit of 1.2 billion cells or intravenous placebo within 18 to 36 hours of ischemic stroke onset. Main Outcomes and Measures: The primary end points were safety and excellent outcome at day 90, measured as a composite of a modified Rankin Scale (mRS) score of 1 or less, a NIHSS score of 1 or less, and a Barthel index score of 95 or greater. The secondary end points were excellent outcome at day 365, mRS score distribution at days 90 and 365, and mRS score of 0 to 1 and 0 to 2 at day 90. Statistical analysis of efficacy was performed using the Cochran-Mantel-Haenszel test. Results: This study included 206 patients (104 received MultiStem and 102 received placebo). Their mean age was 76.5 (range, 35-95) years, and more than half of patients were men (112 [54.4%]). There were no between-group differences in primary and secondary end points. The proportion of excellent outcomes at day 90 did not differ significantly between the MultiStem and placebo groups (12 [11.5%] vs 10 [9.8%], P = .90; adjusted risk difference, 0.5% [95% CI, -7.3% to 8.3%]). The frequency of adverse events was similar between treatment groups. Conclusions and Relevance: In this randomized clinical trial, intravenous administration of allogeneic cell therapy within 18 to 36 hours of ischemic stroke onset was safe but did not improve short-term outcomes. Further research is needed to determine whether MultiStem therapy for ischemic stroke has a beneficial effect in patients who meet specific criteria, as indicated by the exploratory analyses in this study. Trial Registration: ClinicalTrials.gov Identifier: NCT02961504.

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.

A validation study for wide-range remote assessment of cognitive functions in the healthy older Japanese population: a pilot randomised crossover trial.

BACKGROUND: The assessment of a wide range of cognitive functions using video teleconference (VTC) systems cannot be applied in practice yet. We aimed to determine the feasibility and reliability of previously unvalidated remote cognitive function tests in Japan using common information and communication technology (ICT) devices, software, and VTC systems compared with face-to-face (FTF) assessment. METHODS: The sample consisted of 26 participants from senior citizens clubs and an employment service centre in Sapporo Japan, including 11 females and 15 males (age averaged 78.6 ± 6.8 years). Tests included the RCPM, Story recall, 10/36 spatial recall, selective reminding test, SDMT, PASAT, FAB, TMT-A, TMT-B, visual cancellation task, digit span, tapping span. The experimental design was a counterbalanced crossover randomised controlled trial. Intraclass correlations (ICCs), paired-samples t-tests, Cohen's Kappa (κ) coefficients, and Wilcoxon signed-rank test were calculated to compare the scores between VTC and FTF assessments. RESULTS: All ICCs were significant and ranged from 0.47 (RCPM time) to 0.92 (RCPM score and PASAT), with a mean ICC of 0.75. Digit span using Cohen's Kappa (κ) coefficient was significant, but the tapping span was not. Paired samples t-test showed statistically significant differences in SDMT, RCPM time, and cancellation time. CONCLUSIONS: The results suggest that remote video conference-based neuropsychological tests even using familiar devices and software may be able to assess a wide range of cognitive functions in the Japanese older population. As for the processing speed tasks, we need to create our own standards for the remote condition. For the tapping span, we should consider increasing the number of trials.

Neuronal Loss in the Bilateral Medial Frontal Lobe Revealed by 123I-iomazenil Single-photon Emission Computed Tomography in Patients with Moyamoya Disease: The First Report from Cognitive Dysfunction Survey of Japanese Patients with Moyamoya Disease (COSMO-Japan Study).

Cognitive impairment in adult patients with moyamoya disease (MMD) is sometimes overlooked and can occur in patients with no ischemic or hemorrhagic lesions. Better profiling and reliable diagnostic methods that characterize the group and associate the impairments and pathology of MMD are required in order to deliver appropriate treatments and support. The potential of 123I-iomazenil single-photon emission computed tomography (SPECT) for this issue has been reported in some studies, but the universality of this method remains unclear. A multicenter study of adult patients (aged 18-60 years) with MMD who experienced difficulties in social lives despite normal activities of daily living was implemented to delineate the common characteristics of this group of patients. In this study, iomazenil SPECT, besides patient characteristics, cognitive functions, and conventional imaging, was acquired to examine whether this method is suitable as a universal diagnostic tool. A total of 36 patients from 12 institutes in Japan were included in this study. Domain scores of world health organization quality of life 26 indicated low self-rating in physical health and psychological domains. The percentages of patients who had <85 in each index were 27.8%-33.3% in the WAIS-III and 16.7%-47.2% in the Wechsler Memory Scale-Revised. The group analysis of iomazenil SPECT demonstrated a decreased accumulation in the bilateral medial frontal areas in comparison with the normal control, whereas there were no specific characteristics on conventional imaging in the cohort. Iomazenil SPECT is a possible universal diagnostic method for the extraction of patients with cognitive impairment in MMD.

Cost-effectiveness of seven-days-per-week rehabilitation schedule for acute stroke patients.

BACKGROUND: Rehabilitation is an essential medical service for patients who have suffered acute stroke. Although the effectiveness of 7-days-per-week rehabilitation schedule has been studied in comparison with 5- or 6-days-per-week rehabilitation schedule, its cost-effectiveness has not been analyzed. In this research, to help formulate more cost-effective medical treatments for acute stroke patients, we analyzed the cost-effectiveness of 7-days-per-week rehabilitation for acute stroke from public health payer's perspective, and public healthcare and long-term care payer's perspective in Japan. METHODS: Cost-effectiveness of 7-days-per-week rehabilitation for acute stroke patients was analyzed based on the result from a previous study using a Japanese database examining the efficacy of 7-days-per-week rehabilitation. Cost utility analysis was conducted by comparing 7-days-per-week rehabilitation with 5- or 6-days-per-week rehabilitation, with its main outcome incremental cost-effectiveness ratio (ICER) calculated by dividing estimated incremental medical and long-term care costs by incremental quality-adjusted life years (QALY). The costs were estimated using the Japanese fee table and from published sources. The time horizon was 5 years, and Markov modeling was used for the analysis. RESULTS: The ICER was $6339/QALY from public health payer's perspective, lower than 5,000,000 Yen/QALY (approximately US$37,913), which was the willingness-to-pay used for the cost-effectiveness evaluation in Japan. The 7-day-per-week rehabilitation was dominant from public healthcare and long-term care payer's perspective. The result of sensitivity analysis confirmed the results. CONCLUSION: The results indicated that 7-days-per-week rehabilitation for acute stroke rehabilitation was likely to be cost-effective.

Dual Antiplatelet Therapy With Cilostazol for Secondary Prevention in Lacunar Stroke: Subanalysis of the CSPS.com Trial.

BACKGROUND: The effectiveness of long-term dual antiplatelet therapy (DAPT) to prevent recurrent strokes in patients with lacunar stroke remains unclarified. Therefore, this study aimed to compare and to elucidate the safety and effectiveness of DAPT and single antiplatelet therapy (SAPT) in preventing recurrence in chronic lacunar stroke. METHODS: CSPS.com (Cilostazol Stroke Prevention Study for Antiplatelet Combination) was a prospective, multicenter, randomized controlled trial. In this prespecified subanalysis, 925 patients (mean age, 69.5 years; 69.4% men) with lacunar stroke were selected from 1884 patients with high-risk noncardioembolic stroke, enrolled in the CSPS.com trial after 8 to 180 days following stroke. Patients were randomly assigned to receive either SAPT or DAPT using cilostazol and were followed for 0.5 to 3.5 years. The primary efficacy outcome was the first recurrence of ischemic stroke. The safety outcomes were severe or life-threatening bleeding. RESULTS: The DAPT group receiving cilostazol and either aspirin or clopidogrel and SAPT group receiving aspirin or clopidogrel alone comprised 464 (50.2%) and 461 (49.8%) patients, respectively. Ischemic stroke occurred in 12 of 464 patients (1.84 per 100 patient-years) in the DAPT group and 31 of 461 patients (4.42 per 100 patient-years) in the SAPT group, during follow-up. After adjusting for multiple potential confounding factors, ischemic stroke risk was significantly lower in the DAPT group than in the SAPT group (hazard ratio, 0.43 [95% CI, 0.22-0.84]). The rate of severe or life-threatening hemorrhage did not differ significantly between the groups (2 patients [0.31 per 100 patient-years] versus 6 patients [0.86 per 100 patient-years] in the DAPT and SAPT groups, respectively; hazard ratio, 0.36 [95% CI, 0.07-1.81]). CONCLUSIONS: In patients with lacunar stroke, DAPT using cilostazol had significant benefits in reducing recurrent ischemic stroke incidence compared with SAPT without increasing the risk of severe or life-threatening bleeding. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT01995370. URL: https://www.umin.ac.jp/ctr; Unique identifier: UMIN000012180.

Impact of RNF213 c.14576G>A Variant on the Development of Direct and Indirect Revascularization in Pediatric Moyamoya Disease.

BACKGROUND: Superficial temporal artery (direct) and encephalomyosynangiosis (indirect) revascularization may develop after combined bypass surgery in pediatric patients with moyamoya disease (MMD). However, arterial development varies widely among patients, and the underlying mechanisms remain unknown. OBJECTIVES: We evaluated the relationship between the development of donor arteries after bypass surgery in pediatric patients with MMD and the MMD-susceptibility gene variant c.14576G>A of ring finger protein (RNF) 213. METHODS: The data of pediatric patients with MMD (age <16 years at the time of surgery) treated with combined bypass surgery between September 2013 and April 2019 were consecutively analyzed. Quantitative measurements of the superficial temporal artery (STA), deep temporal artery (DTA), and middle meningeal artery (MMA) diameters with magnetic resonance angiography (MRA) source imaging were performed preoperatively and at 6-12 months postoperatively. The postoperative caliber change ratios (CCRs) were calculated. The relationship between CCRs and RNF213 c.14576G>A status was examined. RESULTS: Forty-eight hemispheres from 28 pediatric patients with MMD were examined. Three hemispheres belonged to patients with the AA genotype; 33 to patients with the AG genotype (AA/AG group); and 12 to patients with the GG genotype (GG group; wild type). The CCRs for the DTA were significantly higher in patients with RNF213 variant (AA/AG group; 2.5 ± 0.1) than in the GG group (2.0 ± 0.2) (p = 0.03), whereas the CCRs for the STA were significantly higher in the GG (1.6 ± 0.1) than in the AA/AG group (1.3 ± 0.6) (p = 0.02). There was no significant difference in the CCRs for the MMA and basilar artery between the groups. Other factors, including sex, age, and MRA grading, were not associated with the development of specific bypass development. CONCLUSIONS: The extent of collateral development associated with direct or indirect bypass was found to differ between the genotypes of the RNF213 c.14576G>A associated with pediatric MMD. This genetic variant correlates with the development of the disease and affects revascularization after bypass surgery in pediatric patients with MMD.

Intravenous transplantation of amnion-derived mesenchymal stem cells promotes functional recovery and alleviates intestinal dysfunction after spinal cord injury.

Spinal cord injury (SCI) is often accompanied by gastrointestinal dysfunction due to the disconnection of the spinal autonomic nervous system. Gastrointestinal dysfunction reportedly upregulates intestinal permeability, leading to bacterial translocation of the gut microbiome to the systemic circulation, which further activates systemic inflammation, exacerbating neuronal damage. Mesenchymal stem cells (MSC) reportedly ameliorate SCI. Here, we aimed to investigate their effect on the associated gastrointestinal dysfunction. Human amnion-derived MSC (AMSCs) were intravenously transplanted one day after a rat model of midthoracic SCI. Biodistribution of transplanted cells, behavioral assessment, and histological evaluations of the spinal cord and intestine were conducted to elucidate the therapeutic effect of AMSCs. Bacterial translocation of the gut microbiome was examined by in situ hybridization and bacterial culture of the liver. Systemic inflammations were examined by blood cytokines, infiltrating immune cells in the spinal cord, and the size of the peripheral immune tissue. AMSCs released various neurotrophic factors and were mainly distributed in the liver and lung after transplantation. AMSC-transplanted animals showed smaller spinal damage and better neurological recovery with preserved neuronal tract. AMSCs transplantation ameliorated intestinal dysfunction both morphologically and functionally, which prevented translocation of the gut microbiome to the systemic circulation. Systemic inflammations were decreased in animals receiving AMSCs in the chronic phase. Intravenous AMSC administration during the acute phase of SCI rescues both spinal damage and intestinal dysfunction. Reducing bacterial translocation may contribute to decreasing systemic inflammation.

Cystic Intracranial Recurrence of Olfactory Neuroblastoma without Accumulation on Fluorine-18-fluorodeoxyglucose Positron Emission Tomography.

A 66-year-old man underwent multimodal treatment for olfactory neuroblastoma (ONB). When he was 72 years old, a cystic intracranial lesion without accumulation on fluorine-18-fluorodeoxyglucose positron emission tomography was detected. Surgical resection was performed when the patient was 73 years old. The pathological examination revealed recurrence of ONB, and the patient underwent focal irradiation. At age 81, he presented with a second recurrence in the right occipital lobe with radiological and pathological findings similar to the prior recurrence. This case suggests that pathological confirmation should be considered in cases with atypical radiological findings following the treatment of ONB.

Analysis of induced pluripotent stem cell clones derived from a patient with mosaic neurofibromatosis type 2.

The diagnosis of mosaicism is challenging in patients with neurofibromatosis type 2 (NF2) subset due to low variant allele frequency. In this study, we generated induced pluripotent stem cells (iPSCs) were generated from a patient clinically diagnosed with NF2 based on multiple schwannomas, including bilateral vestibular schwannomas and meningiomas. Genetic analysis of the patient's mononuclear cells (MNCs) from peripheral blood failed to detect NF2 alteration but successfully found p.Q65X (c.193C>T) mutation in all separate tumors with three intracranial meningiomas and one intraorbital schwannoma, and confirming mosaicism diagnosis in NF2 alteration using deep sequencing. Five different clones with patient-derived iPSCs were established from MNCs in peripheral blood, which showed sufficient expression of pluripotent markers. Genetic analysis showed that one of five generated iPSC lines from MNCs had the same p.Q65X mutation as that found in NF2. There was no significant difference in the expression of genes related to NF2 between iPSC clones with the wild-type and mutant NF2. In this case, clonal expansion of mononuclear bone marrow-derived stem cells recapitulated mosaicism's genetic alteration in NF2. Patient-derived iPSCs from mosaic NF2 would contribute to further functional research of NF2 alteration.

Impact of RNF213 founder polymorphism (p.R4810K) on the postoperative development of indirect pial synangiosis after direct/indirect combined revascularization surgery for adult Moyamoya disease.

Direct superficial temporal artery (STA) to middle cerebral artery (MCA) anastomosis combined with indirect pial synangiosis provides favorable surgical collaterals for Moyamoya disease (MMD), especially in adults; however, factors leading to the development of each direct and indirect collateral are not well documented.We aimed to investigate the association between RNF213 founder polymorphism (p.R4810K) and each direct and indirect collateral development. By qualitative and quantitative evaluations of direct and indirect surgical collaterals using time-of-flight MR angiography, postoperative development of each type of bypass was evaluated independently into two categories. Multivariate logistic regression analysis was performed to study the contributing factors for the development of each surgical collateral. Excellent development of postoperative direct and indirect bypass was observed in 65 hemispheres (70%) by qualitative evaluation, which was confirmed by quantitative evaluation. Multivariate logistic regression analysis of excellent indirect bypass development revealed a significant positive correlation with the p.R4810K (odds ratio, OR4.0; 95%-confidence interval, CI 1.2-16), advanced MR angiographic stage (OR9.5; 95%CI 1.7-73), and preoperative middle meningeal artery caliber (OR6.8; 95%CI 1.8-35), but a significant negative correlation was found with the excellent direct bypass development (OR0.17; 95%CI 0.03-0.75). No significant correlation was observed between excellent direct bypass development and the p.R4810K (OR0.95; 95%CI 0.37-2.4).In conclusion, excellent development of indirect collaterals after STA-MCA anastomosis combined with indirect pial synangiosis occurs more frequently in adult MMD with the RNF213 founder polymorphism, suggesting a role of the p.R4810K variant for marked in-growth of indirect collaterals and the utility of preoperative genetic analysis.

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.

Induction of large cerebral aneurysms by intraperitoneal administration of ß-aminopropionitrile fumarate in male rats.

BACKGROUND: It is necessary and useful to obtain an experimental model which steadily and rapidly induces aneurysms for investigation of the pathogenesis of cerebral aneurysm. We attempted to examine whether intraperitoneal administration of ß-aminopropionitrile fumarate (BAPN-F) with additional treatments of induced hypertension and hemodynamic stress could steadily and rapidly induce aneurysms in male rats. METHODS: Seven-week-old male Sprague-Dawley rats pretreated with ligation of left common carotid and bilateral posterior renal arteries were administrated BAPN-F intraperitoneally. Induction rate and size of aneurysms was investigated with varying dose and duration of BAPN-F administration (low dose; 400 mg/kg/week for 4 or 8 weeks and high dose; 2800 mg/kg/week for 8 or 12 weeks). RESULTS: Induction rate in the high-dose groups was significantly higher (P<0.01) than that in the low-dose groups. Making comparisons between 8 and 12 weeks of the high-dose groups, while there was no difference in induction rate (8 weeks; 85.2% vs. 12 weeks; 76.9%), aneurysmal size was larger in 12 weeks (8 weeks; 127.5 µm, vs. 12 weeks; 181.7 µm in terms of median) but lethal intrathoracic hemorrhage was increased in 12 weeks (8 weeks; 7.4% vs. 12 weeks; 30.8%). Induction rate of large aneurysm was 22.2% and 30.8% in 8 and 12 weeks of the high-dose groups, respectively. CONCLUSIONS: High-dose BAPN-F administration can cause high-frequency aneurysmal induction. Although there was the difference in size and mortality rate based on administration duration, intraperitoneal administration of 2800 mg/kg/week BAPN-F for 8 weeks would be suitable for aneurysmal induction.

The Japan Neurosurgical Database: Statistics Update 2018 and 2019.

Each year, the Japan Neurosurgical Society (JNS) reports up-to-date statistics from the Japan Neurosurgical Database regarding case volume, patient demographics, and in-hospital outcomes of the overall cohort and neurosurgical subgroup according to the major classifications of main diagnosis. We hereby report patient demographics, in-hospital mortality, length of hospital stay, purpose of admission, number of medical management, direct surgery, endovascular treatment, and radiosurgery of the patients based on the major classifications and/or main diagnosis registered in 2018 and 2019 in the overall cohort (523283 and 571143 patients, respectively) and neurosurgical subgroup (177184 and 191595 patients, respectively). The patient demographics, disease severity, proportion of purpose of admission (e.g., operation, 33.9-33.5%) and emergent admission (68.4-67.8%), and in-hospital mortality (e.g., cerebrovascular diseases, 6.3-6.5%; brain tumor, 3.1-3%; and neurotrauma, 4.3%) in the overall cohort were comparable between 2018 and 2019. In total, 207783 and 225217 neurosurgical procedures were performed in the neurosurgical subgroup in 2018 and 2019, respectively, of which endovascular treatment comprised 19.1% and 20.3%, respectively. Neurosurgical management of chronic subdural hematoma (19.4-18.9%) and cerebral aneurysm (15.4-14.8%) was most common. Notably, the proportion of management of ischemic stroke/transient ischemic attack, including recombinant tissue plasminogen activator infusion and endovascular acute reperfusion therapy, increased from 7.5% in 2018 to 8.8% in 2019. The JNS statistical update represents a critical resource for the lay public, policy makers, media professionals, neurosurgeons, healthcare administrators, researchers, health advocates, and others seeking the best available data on neurosurgical practice.

Dual Antiplatelet Therapy Using Cilostazol in Patients With Stroke and Intracranial Arterial Stenosis.

Background Long-term benefit of dual antiplatelet therapy (DAPT) over single antiplatelet therapy (SAPT) for the prevention of recurrent stroke has not been established in patients with intracranial arterial stenosis. We compared the efficacy and safety of DAPT with cilostazol and clopidogrel or aspirin to those of SAPT with clopidogrel or aspirin in patients with intracranial arterial stenosis, who were recruited to the Cilostazol Stroke Prevention Study for Antiplatelet Combination trial, a randomized controlled trial in high-risk Japanese patients with ischemic stroke. Methods and Results We compared the vascular and hemorrhagic events between DAPT and SAPT in patients with ischemic stroke and symptomatic or asymptomatic intracranial arterial stenosis of at least 50% in a major intracranial artery. Patients were placed in two groups: 275 were assigned to receive DAPT and 272 patients SAPT. The risks of ischemic stroke (hazard ratio [HR], 0.47; 95% CI, 0.23-0.95); and composite of stroke, myocardial infarction, and vascular death (HR, 0.48; 95% CI, 0.26-0.91) were lower in DAPT than SAPT, whereas the risk of severe or life-threatening bleeding (HR, 0.72; 95% CI, 0.12-4.30) did not differ between the 2 treatment groups. Conclusions DAPT using cilostazol was superior to SAPT with clopidogrel or aspirin for the prevention of recurrent stroke and vascular events without increasing bleeding risk among patients with intracranial arterial stenosis after stroke. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01995370.

Correlation of active contact location with weight gain after subthalamic nucleus deep brain stimulation: a case series.

BACKGROUND: Weight gain (WG) is a frequently reported side effect of subthalamic deep brain stimulation; however, the underlying mechanisms remain unclear. The active contact locations influence the clinical outcomes of subthalamic deep brain stimulation, but it is unclear whether WG is directly associated with the active contact locations. We aimed to determine whether WG is associated with the subthalamic deep brain stimulation active contact locations. METHODS: We enrolled 14 patients with Parkinson's disease who underwent bilateral subthalamic deep brain stimulation between 2013 and 2019. Bodyweight and body mass index were measured before and one year following the surgery. The Lead-DBS Matlab toolbox was used to determine the active contact locations based on magnetic resonance imaging and computed tomography. We also created sweet spot maps for WG using voxel-wise statistics, based on volume of tissue activation and the WG of each patient. Fluorodeoxyglucose-positron emission tomography data were also acquired before and one year following surgery, and statistical parametric mapping was used to evaluate changes in brain metabolism. We examined which brain regions' metabolism fluctuation significantly correlated with increased body mass index scores and positron emission tomography data. RESULTS: One year after surgery, the body mass index increase was 2.03 kg/m2. The sweet spots for WG were bilateral, mainly located dorsally outside of the subthalamic nucleus (STN). Furthermore, WG was correlated with increased metabolism in the left limbic and associative regions, including the middle temporal gyrus, inferior frontal gyrus, and orbital gyrus. CONCLUSIONS: Although the mechanisms underlying WG following subthalamic deep brain stimulation are possibly multifactorial, our findings suggest that dorsal stimulation outside of STN may lead to WG. The metabolic changes in limbic and associative cortical regions after STN-DBS may also be one of the mechanisms underlying WG. Further studies are warranted to confirm whether dorsal stimulation outside of STN changes the activities of these cortical regions.

Efficacy of Carotid Artery Stenting Performed under General Anesthesia with Somatosensory Evoked Potential Monitoring.

OBJECTIVES: During carotid artery stenting (CAS), hemodynamics may be affected by the carotid sinus reflex in some cases. Although general anesthesia has been reported to stabilize intraoperative hemodynamics, the patient's neurological condition must be assessed indirectly. Therefore, we investigated the changes in intraoperative hemodynamics and perioperative complications of CAS under general anesthesia and evaluated the efficacy of somatosensory evoked potential (SEP) monitoring in detecting a reduction in perfusion during CAS. MATERIALS AND METHODS: From April 2011 to August 2016,57 consecutive patients who underwent CAS under general anesthesia were evaluated. The follow-up period ranged from 3 to 8 years. During CAS, anesthesiologists monitored and managed the hemodynamics. SEP monitoring was performed during the CAS procedure in all patients. RESULTS: Intraoperative hypotension (systolic blood pressure ≤ 100 mmHg) was evident in 16 patients (28.1%), and 13 patients (22.8%) experienced intraoperative bradycardia; however, all of these cases were promptly managed under general anesthesia. None of the patients showed systolic blood pressure < 50 mmHg from baseline. Regarding perioperative complications, none of the patients exhibited myocardial infarction or postoperative hyperperfusion symptoms, and there was no mortality. Among 21 patients (36.8%) with a decrease in the intraoperative SEP, 3 (5.3%) exhibited transient ischemic symptoms and 1 (1.8%) had postoperative infarction. CONCLUSIONS: CAS under general anesthesia is a safe and effective management option in terms of intraoperative hemodynamic stability. In addition, our findings indicate that SEP monitoring could be helpful in evaluating transient postoperative cerebral ischemia or cerebral infarction after CAS.

Dual Antiplatelet Therapy Using Cilostazol With Aspirin or Clopidogrel: Subanalysis of the CSPS.com Trial.

Background and Purpose: Although dual antiplatelet therapy (DAPT) with aspirin and clopidogrel reduces the recurrence of ischemic stroke while significantly increasing the bleeding events compared with monotherapy, the CSPS.com trial (Cilostazol Stroke Prevention Study combination) showed that DAPT using cilostazol was more effective without the bleeding risk. In the CSPS.com trial, aspirin or clopidogrel was used as the underlying antiplatelet drug. The effectiveness and safety of each combination were examined and clarified. Methods: In the CSPS.com trial, a multicenter, open-label, randomized controlled study, patients with high-risk, noncardioembolic ischemic stroke 8 to 180 days after onset treated with aspirin or clopidogrel alone at the discretion of the physician in charge were recruited. Patients were randomly assigned to receive either monotherapy or DAPT using cilostazol and followed for 0.5 to 3.5 years. The primary efficacy outcome was first recurrence of ischemic stroke. The safety outcome was severe or life-threatening bleeding. The analysis was based on the underlying antiplatelet agents. Results: A total of 763 patients taking aspirin and 1116 taking clopidogrel were included in the intention-to-treat analysis. Although the clopidogrel group had more risk factors than the aspirin group, the primary efficacy outcome and safety outcome did not differ significantly between the 2 groups. In the aspirin group, the primary efficacy outcome and safety outcome did not differ significantly between the DAPT group and the aspirin-monotherapy group. In the clopidogrel group, the primary end point occurred at a rate of 2.31 per 100 patient-years in the DAPT group and 5.19 per 100 patient-years in the clopidogrel-monotherapy group (hazard ratio, 0.447 [95% CI, 0.258­0.774]). Safety outcome did not differ significantly between groups (0.51 per 100 patient-years versus 0.71 per 100 patient-years, respectively; hazard ratio, 0.730 [95% CI, 0.206­2.588]). Conclusions: The combination of cilostazol and clopidogrel significantly reduced the recurrence of ischemic stroke without increasing the bleeding risk in noncardioembolic, high-risk patients. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01995370. URL: https://www.umin.ac.jp/ctr/; Unique identifier: UMIN000012180.

Chronic deep brain stimulation reduces cortical ß-γ phase amplitude-coupling in patients with Parkinson's disease.

We compared ß-γ phase amplitude coupling (PAC) before and one year after chronic deep brain stimulation (DBS) in patients with Parkinson's disease using EEG and observed significant post-operative reduction of PAC values. Our findings suggest that the reduction in PAC due to DBS can be observed after chronic stimulation, which is not a transient phenomenon just after the start of DBS.