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Objective: Clazosentan (CLA) reduces cerebral vasospasm after aneurysmal subarachnoid hemorrhage (aSAH). However, adverse events including pulmonary edema were reported. We examined whether the strict management of fluid balance reduces the adverse events and improves patient outcomes. Methods: Patients with aSAH between 2020 and 2023 were included. They were divided into pre-CLA (before CLA approval) and post-CLA (after approval) groups. The patients in the post-CLA group were further divided into the post-CLA1 (before the change in fluid management) and post-CLA2 (after the change) groups. To achieve fluid balance of 0–500 ml/day according to the modified protocol, the infusion volume was restricted. Results: The daily fluid balance increased from the pre-CLA to the post-CLA1 periods (p = 0.01). The protocol changes decreased the pulmonary edema (post-CLA1 vs. post-CLA2, 44 vs. 22 %, p = 0.09) and discontinuation of CLA (44 vs. 9 %, p

Abstract Recent studies have indicated the involvement of neutrophil-mediated inflammatory responses in the process leading to intracranial aneurysm (IA) rupture. Receptors mediating neutrophil recruitment could thus be therapeutic targets of unruptured IAs. In this study, complement C5a receptor 1 (C5AR1) was picked up as a candidate that may cause neutrophil-dependent inflammation in IA lesions from comprehensive gene expression profile data acquired from rat and human samples. The induction of C5AR1 in IA lesions was confirmed by immunohistochemistry; the up-regulations of C5AR1/C5ar1 stemmed from infiltrated neutrophils, which physiologically express C5AR1/C5ar1, and adventitial fibroblasts that induce C5AR1/C5ar1 in human/rat IA lesions. In in vitro experiments using NIH/3T3, a mouse fibroblast-like cell line, induction of C5ar1 was demonstrated by starvation or pharmacological inhibition of mTOR signaling by Torin1. Immunohistochemistry and an experiment in a cell-free system using recombinant C5 protein and recombinant Plasmin indicated that the ligand of C5AR1, C5a, could be produced through the enzymatic digestion by Plasmin in IA lesions. In conclusion, we have identified a potential contribution of the C5a–C5AR1 axis to neutrophil infiltration as well as inflammatory responses in inflammatory cells and fibroblasts of IA lesions. This cascade may become a therapeutic target to prevent the rupture of IAs.

Background and purposeIntracranial aneurysm growth is a significant risk factor for rupture; however, a few aneurysms remain unruptured for long periods, even after growth. Here, we identified hemodynamic features associated with aneurysmal rupture after growth.Materials and methodsWe analyzed nine middle cerebral artery aneurysms that grew during the follow-up period using computational fluid dynamics analysis. Growth patterns of the middle cerebral artery aneurysms were divided into homothetic growth (Type 1), de novo bleb formation (Type 2), and bleb enlargement (Type 3). Hemodynamic parameters of the four ruptured aneurysms after growth were compared with those of the five unruptured aneurysms.ResultsAmong nine aneurysms (78%), seven were Type 1, one was Type 2, and one was Type 3. Three (43%) Type 1 aneurysms ruptured after growth. Maximum oscillatory shear index after aneurysmal growth was significantly higher in ruptured Type 1 cases than in unruptured Type 1 cases (ruptured vs. unruptured: 0.455 ± 0.007 vs. 0.319 ± 0.042, p = 0.003). In Type 1 cases, a newly emerged high-oscillatory shear index area was frequently associated with rupture, indicating a rupture point. Aneurysm growth was observed in the direction of the high-pressure difference area before enlargement. In Types 2 and 3 aneurysms, the maximum oscillatory shear index decreased slightly, however, the pressure difference values remain unchanged. In Type 3 aneruysm, the maximum OSI and PD values remained unchanged.ConclusionsThis study suggests that hemodynamic variations and growth pattern changes are crucial in rupture risk determination using computational fluid dynamics analysis. High-pressure difference areas may predict aneurysm enlargement direction. Additionally, high maximum oscillatory shear index values after enlargement in cases with homothetic growth patterns were potential rupture risk factors.

Background The utility of screening for the degree of common carotid artery (CCA) stenosis as a predictor of cardiovascular disease (CVD) in a general population remains unclear. Methods and Results We studied 4775 Japanese men and women whose CCA was measured using bilateral carotid ultrasonography at baseline (April 1994–August 2001). We calculated the degree of stenosis as a percentage of the stenotic area of the lumen in the cross‐section perpendicular to the long axis. The Cox proportional hazards model was used to calculate multivariable‐adjusted hazard ratios (HRs) with 95% CIs for incident CVD and its subtypes according to the degree of CCA stenosis. During the median 14.2 years of follow‐up, 385 incident CVD events (159 coronary heart disease and 226 stroke) were documented. The degree of CCA stenosis was associated with increased risks of incident CVD, coronary heart disease, and stroke, with multivariable‐adjusted HRs (95% CIs) for

BackgroundAnemia can occur due to an aspiration maneuver of blood with thrombi during mechanical thrombectomy (MT) for stroke. However, the association between postoperative anemia and stroke outcomes is unknown.MethodsIn a registry-based hospital cohort, consecutive patients with acute ischemic stroke who underwent MT were retrospectively recruited. Patients were divided into the following three groups according to their hemoglobin (Hb) concentrations within 24 h after MT; no anemia (Hb concentrations ≥13 g/dL for men and ≥ 12 g/dL for women), mild anemia (Hb concentrations of 11–13 g/dL and 10–12 g/dL, respectively), and moderate-to-severe anemia (Hb concentrations

Abstract Subarachnoid hemorrhage being the rupture of intracranial aneurysm (IA) as a major cause has quite poor prognosis, despite the modern technical advances. Thereby, the mechanisms underlying the rupture of lesions should be clarified. Recently, we and others have clarified the formation of vasa vasorum in IA lesions presumably for inflammatory cells to infiltrate in lesions as the potential histopathological alternation leading to rupture. In the present study, we clarified the origin of vasa vasorum as arteries located at the brain surface using 3D-immunohistochemistry with tissue transparency. Using Hypoxyprobe, we then found the presence of hypoxic microenvironment mainly at the adventitia of intracranial arteries where IA is formed. In addition, the production of vascular endothelial growth factor (VEGF) from cultured macrophages in such a hypoxic condition was identified. Furthermore, we found the accumulation of VEGF both in rupture-prone IA lesions induced in a rat model and human unruptured IA lesions. Finally, the VEGF-dependent induction of neovessels from arteries on brain surface was confirmed. The findings from the present study have revealed the potential role of hypoxic microenvironment and hypoxia-induced VEGF production as a machinery triggering rupture of IAs via providing root for inflammatory cells in lesions to exacerbate inflammation.

Introduction We aimed to evaluate the efficacy and safety of mechanical thrombectomy (MT) for medium vessel occlusion (MeVO) with the disabling deficit. Methods The study period was from January 2011 to December 2022. Inclusion criteria were 1) within 24 hours of stroke onset, 2) prestroke mRS score ≤1, 3) NIHSS score ≥4 or disabling deficit (complete hemianopia (≥2 on NIHSS), severe aphasia (≥2 on NIHSS), visual sensory extinction (≥1 on NIHSS), significant weakness with NIHSS subscore of paralysis ≥2), 4) MeVO (MCA distal M2, M3, ACA A1, A2, A3, PCA P1, P2, and P3). Outcomes were compared between the MT and standard medical treatment (SMT) groups. Outcome was defined as the favorable outcome (mRS score 0‐2 at 90 days), death within 90 days, and symptomatic intracranial hemorrhage (SICH). Results Of all, 192 patients (72 women, median age 78 years, median NIHSS score 11 points) were enrolled, and 76.6% (n=147) had distal M2 occlusion. Compared to the SMT group (n=153), the MT group (n=39) had a significantly larger median Tmax>10 sec volume (median 25 mL vs. 5 mL, P 6‐sec volume (61 mL vs. 44 mL, P

Background We aimed to clarify which time‐to‐maximum of the tissue residue function (Tmax) mismatch ratio is useful in predicting anterior intracranial atherosclerotic stenosis (ICAS)–related large‐vessel occlusion (LVO) before endovascular therapy. Methods and Results Patients with ischemic stroke who underwent perfusion‐weighted imaging before endovascular therapy for anterior intracranial LVO were divided into those with ICAS‐related LVO and those with embolic LVO. Tmax ratios of >10 s/>8 s, >10 s/>6 s, >10 s/>4 s, >8 s/>6 s, >8 s/>4 s, and >6 s/>4 s were considered Tmax mismatch ratios. Binominal logistic regression was used to identify ICAS‐related LVO, and the adjusted odds ratio (aOR) and 95% CI for each Tmax mismatch ratio increase of 0.1 were calculated. A similar analysis was performed for ICAS‐related LVO with and without embolic sources, using embolic LVO as the reference. Of 213 patients (90 women [42.0%]; median age, 79 years), 39 (18.3%) had ICAS‐related LVO. The aOR (95% CI) per 0.1 increase in Tmax mismatch ratio in ICAS‐related LVO with embolic LVO as reference was lowest with Tmax mismatch ratio >10 s/>6 s (0.56 [0.43–0.73]). Multinomial logistic regression analysis also showed the lowest aOR (95% CI) per 0.1 increase in Tmax mismatch ratio with Tmax >10 s/>6 s (ICAS‐related LVO without embolic source: 0.60 [0.42–0.85]; ICAS‐related LVO with embolic source: 0.55 [0.38–0.79]). Conclusions A Tmax mismatch ratio of >10 s/>6 s was the optimal predictor of ICAS‐related LVO compared with other Tmax profiles, with or without an embolic source before endovascular therapy. Registration clinicaltrials.gov. Identifier NCT02251665.

The rate of recanalization after coil embolization for unruptured intracranial aneurysms (UIAs) is reported to occur around 11.3%-49%. This study aims to investigate the factors that influence the recanalization after coil embolization for UIAs in our institution. We retrospectively investigated 307 UIAs in 296 patients treated at our institution between April 2004 and December 2016. The stent-used cases were excluded. Cerebral angiography and 3D time-of-flight magnetic resonance angiography (TOF MRA) were used for evaluation of the postoperative occlusion status. Volume embolization ratio (VER), aneurysmal size, neck width, and aspect ratio (AR) were compared between the recanalized and non-recanalized groups. The mean follow-up period ranged from 6 to 172 months (mean: 79.0 ± 39.8 months). Recanalization was noted in 78 (25.4%) aneurysms, and 19 (6.2%) aneurysms required retreatment. There was no aneurysmal rupture during the follow-up period. Univariate analysis showed that the aneurysm size (p < 0.001), neck width (p < 0.001), AR (p = 0.003), and VER (p = 0.012) were associated with recanalization. Multivariate logistic regression analysis showed that the AR (p =0.004) and VER (p =0.015) were significant predictors of recanalization. To summarize, a higher AR and a lower VER could lead to recanalization after coil embolization of UIAs. Careful follow-up is required for coiled aneurysms with these features.

In this report, we, the Research Committee on Moyamoya Disease (Spontaneous Occlusion of the circle of Willis), describe in detail the changes in the new “Diagnostic Criteria 2021” for moyamoya disease and its scientific basis to make it widely known to the world. The revised criteria cover all aspects of the disease, including a definition of the disease concept, diagnostic imaging, and the concept of quasi-moyamoya disease (moyamoya syndrome).

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

Introduction We aim to investigate the difference in mechanical thrombectomy (MT) outcome for cancer‐related stroke (CRS) with active and inactive cancer. Methods Of the consecutive acute ischemic stroke (AIS) patients admitted to our institute from 2010 to 2021, patients with cancer who received MT within 24 hours of onset and were enrolled.Outcomes including the favorable outcome (modified Rankin Scale score of 0 to 2) at3 months, 1‐year,and death within 3 months or 1‐yearwere assessed between patients with active and inactive cancer among patients with cancer. The rate offirst pass effect (FPE, extendedThrombolysis in Cerebral Infarction[eTICI] 2c/3 after first pass) and final eTICI 2c/3 achievement were also assessed. Active cancer was defined as a cancer that was diagnosed within 6 months; required chemotherapy or surgical treatment within 6 months; or was recurrent, metastatic, or inoperable. Results Of 59 patients (26 women; median age, 80 years; median NIH Stroke Scale score[NIHSS] 17), 19 (32.2%) patients had an active cancer. Patients with active cancer has less atrial fibrillation (47% vs. 78%,P< 0.01) and higher medianD‐dimer(4.60μg/mLvs. 2.00μg/mL,P< 0.01). There were no significant differences in the favorable outcome at 3 months (26% vs. 45%,P = 0.26) and at 1 year (26% vs. 45%,P = 0.26) between both groups, but death within 3 months (32% vs. 5%,P< 0.01) and within 1 year (42% vs. 8%,P< 0.01) were more frequent in patients with active cancer than those with inactive cancer. Conclusions Long‐term clinical outcomes of patients with active cancer were worse than those with inactive cancer.

Abstract The role of the bifurcation angle in progression of saccular intracranial aneurysms (sIAs) has been undetermined. We, therefore, assessed the association of bifurcation angles with aneurysm progression using a bifurcation-type aneurysm model in rats and anterior communicating artery aneurysms in a multicenter case–control study. Aneurysm progression was defined as growth by ≥ 1 mm or rupture during observation, and controls as progression-free for 30 days in rats and ≥ 36 months in humans. In the rat model, baseline bifurcation angles were significantly wider in progressive aneurysms than in stable ones. In the case–control study, 27 and 65 patients were enrolled in the progression and control groups. Inter-observer agreement for the presence or absence of the growth was excellent (κ coefficient, 0.82; 95% CI, 0.61–1.0). Multivariate logistic regression analysis showed that wider baseline bifurcation angles were significantly associated with subsequent progressions. The odds ratio for the progression of the second (145°–179°) or third (180°–274°) tertiles compared to the first tertile (46°–143°) were 5.5 (95% CI, 1.3–35). Besides, the bifurcation angle was positively correlated with the size of aneurysms (Spearman’s rho, 0.39; P = 0.00014). The present study suggests the usefulness of the bifurcation angle for predicting the progression of sIAs.

Background We investigated the impact of the ring finger protein 213 p.R4810K variant, a founder variant for moyamoya disease in East Asians, on endovascular therapy outcomes in patients with acute anterior‐circulation large‐vessel occlusion stroke in comparison with noncarriers. Methods Of the consecutive patients with ischemic stroke admitted to our institute from 2011 to 2021, patients who underwent endovascular therapy for acute occlusion of the intracranial internal carotid artery or M1 segment of the middle cerebral artery were included. Outcomes were instant reocclusion, final modified Thrombolysis in Cerebral Infarction reperfusion ≥2b, and early reocclusion. Instant reocclusion was defined as the occurrence of reocclusion during the procedure, and early reocclusion was defined as reocclusion detected on magnetic resonance angiography within 2 weeks after the confirmation of successful reperfusion. Results Of the 277 patients analyzed (128 women; median age, 76 years), 10 patients (3.6%) carried the ring finger protein 213 p.R4810K variant. Variant carriers were younger (P=0.01) and more frequently had intracranial atherosclerotic disease‐related large‐vessel occlusion as a cause of acute large‐vessel occlusion (P

Abstract Background Removal of large hypervascular tumors in the lateral ventricle still poses a surgical challenge. These tumors are usually fed from choroidal arteries, and vascular control is typically performed late during the removal. We aimed to evaluate the clinical efficacy of our strategy for persistent preoperative obliteration of feeders from the choroidal arteries to manage large hypervascular tumors in the lateral ventricle. Methods We retrospectively analyzed six patients with hypervascular tumors in the lateral ventricle. We first attempted to obstruct feeders using endovascular treatment, and, if unavailable, performed initial microsurgical occlusion through the temporal horn for the staged tumor removal. Results In all patients, feeder obliteration was successfully performed; the anterior choroidal arteries were occluded by the endovascular treatment and microsurgical occlusion in one and five patients, respectively, while the lateral posterior choroidal arteries were occluded via endovascular treatment in four patients. No patients had permanent symptoms due to feeder obliteration, and tumor devascularization was achieved at the mean rate of 69.9%. During the tumor removal, the mean blood loss volume was 253 ml. No postoperative hemorrhage had occurred, and all patients scored ≤ 2 on the modified Rankin Scale at six months post-removal. Conclusions Although further studies are warranted, persistent feeder obliteration of choroidal arteries could be an effective treatment strategy against large hypervascular tumors in the lateral ventricle.

Abstract Background As subarachnoid hemorrhage due to rupture of an intracranial aneurysm (IA) has quite a poor outcome despite of an intensive medical care, development of a novel treatment targeting unruptured IAs based on the correct understanding of pathogenesis is mandatory for social health. Methods Using previously obtained gene expression profile data from surgically resected unruptured human IA lesions, we selected G-protein coupled receptor 120 (GPR120) as a gene whose expression is significantly higher in lesions than that in control arterial walls. To corroborate a contribution of GPR120 signaling to the pathophysiology, we used an animal model of IAs and examine the effect of a GPR120 agonist on the progression of the disease. IA lesion was induced in rats through an increase of hemodynamic stress achieved by a one-sided carotid ligation and induced hypervolemia. Eicosapentaenoic acid (EPA) was used as an agonist for GPR120 in this study and its effect on the size of IAs, the thinning of media, and infiltration of macrophages in lesions were examined. Result EPA administered significantly suppressed the size of IAs and the degenerative changes in the media in rats. EPA treatment also inhibited infiltration of macrophages, a hallmark of inflammatory responses in lesions. In in vitro experiments using RAW264.7 cells, pre-treatment of EPA partially suppressed lipopolysaccharide-induced activation of nuclear factor-kappa B and also the transcriptional induction of monocyte chemoattractant protein 1 (MCP-1), a major chemoattractant for macrophages to accumulate in lesions. As a selective agonist of GPR120, TUG-891, could reproduce the effect of EPA in RAW264.7 cells, EPA presumably acted on this receptor to suppress inflammatory responses. Consistently, EPA remarkably suppressed MCP-1 expression in lesions, suggesting the in vivo relevance of in vitro studies. Conclusions These results combined together suggest the potential of the medical therapy targeting GPR120 or using EPA to prevent the progression of IAs.

Background Extended thrombolysis in cerebral infarction (eTICI) 2c/3 reperfusion after mechanical thrombectomy (MT) is associated with better stroke outcomes than eTICI 2b. Whether additional MT attempt after achieving eTICI 2b (beyond 2b attempt) leads to better outcomes is unknown. Methods Consecutive patients with acute anterior circulation stroke who achieved eTICI 2b during MT were divided into 2 groups: those who further tried MT (beyond‐2b group) and those without (nonbeyond‐2b group). The patients who directly achieved eTICI 2c/3 without experiencing 2b (direct‐2c/3 group) were also studied. The outcomes included the reperfusion status, favorable outcome (3‐month modified Rankin scale score of 0–2), neurological improvement (a ≥10‐point decrease of the National Institutes of Health Stroke Scale score from baseline or the score of 0) at 24 hours and symptomatic intracranial hemorrhage. Results Of 308 patients, 50 were in the beyond‐2b group, 87 in the nonbeyond‐2b group, and the remaining 171 in the direct‐2c/3 group. Perfusion of middle cerebral artery branches supplying the primary motor cortex was worse in the beyond‐2b than the nonbeyond‐2b group at the time of eTICI 2b (P=0.007). Favorable outcome was similarly common (48% for each, P=0.40). Neurological improvement was more frequent (52% versus 37%; P=0.04) and symptomatic intracranial hemorrhage tended to be more common (6% versus 1%, P=0.11) in the beyond‐2b than the nonbeyond‐2b group. Eighteen patients (36%) in the beyond‐2b group finally achieved eTICI 2c/3; 10 of these (56%) and 14 of the remaining 32 (44%) had favorable outcome (P=0.83). The former rate was similar to that in the direct‐2c/3 group (58%; P=0.99). Conclusions Patients undergoing additional MT attempt after achieving eTICI 2b had numerically but not significantly more symptomatic intracranial hemorrhage and showed a similar level of functional outcome at 3 months than those who did not. When eTICI 2c/3 was finally achieved by additional attempts, functional outcome was similar with that of patients who directly achieved eTICI 2c/3 without experiencing 2b. Clinical Trial Registration Information URL: https://www.clinicaltrials.gov. Unique identifier: NCT02251665.

BackgroundLeukocytes contribute to tissue damage after cerebral ischemia; however, the mechanisms underlying this process are still unclear. This study investigates the temporal and spatial relationship between vascular leukocyte recruitment and tissue damage and aims to uncover which step of the leukocyte recruitment cascade is involved in ischemic brain injury.MethodsMale wild-type, ICAM-1-deficient, anti-CD18 antibody treated, or selectin-deficient [fucusyltransferase (FucT IV/VII−/−)] mice were subjected to 60 min of middle cerebral artery occlusion (MCAo). The interaction between leukocytes and the cerebrovascular endothelium was quantified by in vivo fluorescence microscopy up to 15 h thereafter. Temporal dynamics of neuronal cell death and leukocyte migration were assessed at the same time points and in the same tissue volume by histology.ResultsIn wild-type mice, leukocytes started to firmly adhere to the wall of pial postcapillary venules two hours after reperfusion. Three hours later, neuronal loss started and 13 h later, leukocytes transmigrated into brain tissue. Loss of selectin function did not influence this process. Application of an anti-CD18 antibody or genetic deletion of ICAM-1, however, significantly reduced tight adhesion of leukocytes to the cerebrovascular endothelium (-60%; p < 0.01) and increased the number of viable neurons in the ischemic penumbra by 5-fold (p < 0.01); the number of intraparenchymal leukocytes was not affected.ConclusionsOur findings suggest that ischemia triggers only a transient adhesion of leukocytes to the venous endothelium and that inhibition of this process is sufficient to partly prevent ischemic tissue damage.

Background We retrospectively compared early‐ (

Introduction: The ring finger protein 213 gene (RNF213) has been identified as a susceptibility gene for moyamoya disease, and the p.R4810K polymorphism as a founder variant commonly found in East Asian patients. 1 A recent large case‐control study including over 46,958 Japanese subjects reported that the RNF213 p.R4810K variant was a strong risk factor for Japanese cerebral infarction: the variant was found in 5.2% of patients with non‐cardioembolic stroke and in 2.1% of healthy controls. 2 Mechanical thrombectomy (MT) is a standard treatment for acute ischemic stroke due to occlusion of the internal carotid artery and M1 segment of the middle cerebral artery, but in East Asians, about 15–25% of LVOs for which MT was performed were reportedly caused by intracranial atherosclerotic disease (ICAD). 3 RNF213 p.R4810K variant may be involved to some extent in ICAD‐related LVO of Asian patients undergoing MT. In this study, we aimed to investigate the impact of RNF213 p.R4810K variant on EVT for anterior circulation LVO stroke. Methods: Of the consecutive ischemic stroke patients from 2011 to 2021 seen in our institute, patients who underwent EVT for acute occlusion of the intracranial ICA or M1 segment of MCA and signed a consent form for RNF213 genotyping were included. Outcomes were instant re‐occlusion, final modified Thrombolysis in Cerebral Infarction (mTICI) ≥2b reperfusion, early re‐occlusion, and modified Rankin Scale (mRS) score 0–2 at 90 days. Instant re‐occlusion was defined as occurrence of re‐occlusion during the procedure, whereas early re‐occlusion as re‐occlusion detected on magnetic resonance angiography within 2 weeks after confirmation of successful reperfusion at the end of the procedure. 4 Results: Of the 277 patients (128 women [46.2%]; median age, 76 years) analyzed, 10 (3.6%) patients had the RNF213 p.R4810K variant. The variant carriers were younger (67 years vs. 76 years, P

Introduction: The usefulness of the blind exchange with mini-pinning (BEMP) technique has recently been reported for mechanical thrombectomy in patients with stroke owing to medium vessel occlusion (MeVO). The Tron stent retriever can be delivered and deployed through a 0.0165-inch microcatheter. This retriever has potential as an effective and safe treatment for acute ischemic stroke (AIS) due to occlusion of the M2 segment of the middle cerebral artery (MCA). Here, we report the outcomes of the BEMP technique using Tron stent retrievers for M2 occlusion thrombectomy.Methods: Consecutive patients with AIS owing to M2 occlusion who underwent the BEMP technique using 2 × 15-mm or 4 × 20-mm Tron stent retrievers were included. The technique involves deploying a Tron stent retriever through a 0.0165-inch microcatheter, followed by microcatheter removal and blind navigation of a 3MAX or 4MAX aspiration catheter over the bare Tron delivery wire until the aspiration catheter reaches the clot. A Tron stent retriever is inserted into the aspiration catheter like a cork and subsequently pulled as a unit. We assessed procedural outcomes [first-pass expanded thrombolysis in cerebral infarction (eTICI) score 2c/3 and 2b/2c/3], safety outcomes [symptomatic intracranial hemorrhage (sICH)], and clinical outcomes (good outcome rate defined as modified Rankin Scale score 0–2 at 90 days and mortality at 90 days).Results: Eighteen M2 vessels were treated in 15 patients (six female, median age: 80 years, and median National Institutes of Health Stroke Scale score: 18). The BEMP technique was performed successfully in all cases. Whether to use a 3MAX or 4MAX catheter was determined by considering one of the following target vessels: dominant, non-dominant, or co-dominant M2 (3MAX, n = 9; 4MAX, n = 9). The first-pass eTICI 2c/3 and 2b/2c/3 rates were 47 (7/15) and 60% (9/15), respectively; sICH was not observed. Seven patients (47%) achieved good outcomes, and one patient (7%) died within 90 days.Conclusions: The Tron stent retriever was safely and effectively used in the BEMP technique for acute MCA M2 occlusion and can be combined with a 0.0165-inch microcatheter, which may be useful for treating MeVO, in general.

Background and purposeEstablishment of drug therapy to prevent rupture of unruptured intracranial aneurysms (IAs) is needed. Previous human and animal studies have gradually clarified candidate drugs for preventive treatment of IA rupture. However, because most of these candidates belong to classes of drugs frequently co-administered to prevent cardiovascular diseases, epidemiological studies evaluating these drugs simultaneously should be performed. Furthermore, because drugs included in the same class may have different effects in terms of disease prevention, drug-by-drug assessments are important for planning intervention trials.Materials and methodsWe performed a cross-sectional study enrolling patients diagnosed with IAs between July 2011 and June 2019 at our institution. Patients were divided into ruptured or unruptured groups. The drugs investigated were selected according to evidence suggested by either human or animal studies. Univariate and multivariate logistic regression analyses were performed to assess the association of drug treatment with rupture status. We also performed drug-by-drug assessments of the association, including dose-response relationships, with rupture status.ResultsIn total, 310 patients with ruptured and 887 patients with unruptured IAs were included. Multivariate analysis revealed an inverse association of statins (odds ratio (OR), 0.54; 95% confidence interval (CI) 0.38-0.77), calcium channel blockers (OR, 0.41; 95% CI 0.30-0.58), and angiotensin II receptor blockers (ARBs) (OR, 0.67; 95% CI 0.48-0.93) with ruptured IAs. Moreover, inverse dose-response relationships with rupture status were observed for pitavastatin and rosuvastatin among statins, benidipine, cilnidipine, and amlodipine among calcium channel blockers, and valsartan, azilsartan, candesartan, and olmesartan among ARBs. Only non-aspirin non-steroidal anti-inflammatory drugs were positively associated with ruptured IAs (OR, 3.24; 95% CI 1.71-6.13).ConclusionsThe present analysis suggests that several types of statins, calcium channel blockers, and ARBs are candidate drugs for preventive treatment of unruptured IAs.

Background and objectiveIt has long been believed that the bony carotid canal has no plasticity and that a small canal represents a hypoplastic internal carotid artery. We aimed to show whether the carotid canal can narrow according to morphological changes in the internal carotid artery.Materials and methodsThe carotid canal diameter was longitudinally measured in seven individuals who underwent carotid artery ligation. As moyamoya disease is known to be associated with negative remodeling of the internal carotid artery, the carotid canal diameter was measured in 106 patients with moyamoya disease, and an association with the outer diameter of the internal carotid artery or a correlation with the disease stage was investigated. The carotid canal was measured by computed tomography (106 patients), and the outer diameter of the artery was measured by high-resolution magnetic resonance imaging (63 patients). The carotid canal area was calculated by the product of the maximum axial diameter and its perpendicular diameter.ResultsAll seven patients who underwent carotid artery ligation showed narrowing of the carotid canal, and the carotid canal area decreased by 12.2%-28.9% during a mean follow-up period of 4.2 years. In patients with moyamoya disease, the carotid canal area showed a linear correlation with the outer area of the internal carotid artery (r = 0.657, p < 0.001), and a negative correlation with the disease stage (ρ = -0.283, p < 0.001).ConclusionThe bony carotid canal has plasticity, and its area reflects the outer area of the internal carotid artery, therefore, it can be used to assess the remodeling of the carotid artery. A narrow carotid canal may not necessarily indicate hypoplastic internal carotid artery.

A 51-year-old man with type 2 diabetes mellitus was admitted with a 2-month history of repeated episodes of transient aphasia and right hemiparesis after food intake. His blood pressure (BP) fell when the neurological deficits developed. The fall in BP after each meal was confirmed by 24-h ambulatory blood pressure monitoring (ABPM), which established the diagnosis of postprandial hypotension (PPH). Diffusion-weighted magnetic resonance imaging of the brain showed multiple high-intensity lesions at the borderzone between the anterior and middle cerebral artery (MCA) territories in the left hemisphere. Digital subtraction angiography showed tapered occlusion at the origin of the left internal carotid artery (ICA). Despite sufficient antiplatelet therapy and medication for PPH, the transient symptoms remained. Positron emission tomography scanning using H215O showed decreased cerebral blood flow with increased oxygen extraction fraction in the left MCA territory. As the symptomatic left ICA occlusion was intractable, an extracranial-intracranial (EC-IC) bypass surgery was conducted without any perioperative complications. Although PPH remained, cerebrovascular ischemic events including repeated transient ischemic attack disappeared for 2 months after surgery. The coincidence of stroke with ABPM-proved transient hypotension suggested that the brain infarcts were caused by hemodynamic changes related to PPH co-existent with the chronic left ICA occlusion. ABPM is useful in evaluating hemodynamic infarcts associated with BP fluctuation, and should be considered for patients with chronic ICA occlusion. In addition, EC-IC bypass may be a treatment option for symptomatic chronic ICA occlusion due to PPH.

Background Decreased extracellular matrix formation and few vascular smooth muscle cells (VSMCs) in cerebral vascular walls are the main characteristics of intracranial aneurysm (IA) pathogenesis. Recently, osteoprotegerin was reported to activate collagen biosynthesis and VSMC proliferation via the TGF‐β1 (transforming growth factor‐β1) signaling. This study aimed to investigate whether osteoprotegerin can prevent IA progression in rats through enhanced collagen expression and VSMC proliferation. Methods and Results IAs were surgically induced in 7‐week‐old male Sprague–Dawley rats; at 1‐week post‐operation, recombinant mouse osteoprotegerin or vehicle control was continuously infused for 4 weeks into the lateral ventricle using an osmotic pump. In the osteoprotegerin‐treatment group, the aneurysmal size was significantly smaller (37.5 μm versus 60.0 μm; P

Background Oligodendrocyte precursor cells (OPCs) regulate neuronal, glial, and vascular systems in diverse ways and display phenotypic heterogeneity beyond their established role as a reservoir for mature oligodendrocytes. However, the detailed phenotypic changes of OPCs after cerebral ischemia remain largely unknown. Here, we aimed to investigate the roles of reactive OPCs in the ischemic brain. Methods and Results The behavior of OPCs was evaluated in a mouse model of ischemic stroke produced by transient middle cerebral artery occlusion in vivo. For in vitro experiments, the phenotypic change of OPCs after oxygen glucose derivation was examined using a primary rat OPC culture. Furthermore, the therapeutic potential of hypoxic OPCs was evaluated in a mouse model of middle cerebral artery occlusion in vivo. Perivascular OPCs in the cerebral cortex were increased alongside poststroke angiogenesis in a mouse model of middle cerebral artery occlusion. In vitro RNA‐seq analysis revealed that primary cultured OPCs increased the gene expression of numerous pro‐angiogenic factors after oxygen glucose derivation. Hypoxic OPCs secreted a greater amount of pro‐angiogenic factors, such as vascular endothelial growth factor and angiopoietin‐1, compared with normoxic OPCs. Hypoxic OPC‐derived conditioned media increased the viability and tube formation of endothelial cells. In vivo studies also demonstrated that 5 consecutive daily treatments with hypoxic OPC‐conditioned media, beginning 2 days after middle cerebral artery occlusion, facilitated poststroke angiogenesis, alleviated infarct volume, and improved functional disabilities. Conclusions Following cerebral ischemia, the phenotype of OPCs in the cerebral cortex shifts from the parenchymal subtype to the perivascular subtype, which can promote angiogenesis. The optimal use of hypoxic OPCs secretome would provide a novel therapeutic option for stroke.

Background We aimed to improve the assessment quality of plaque vulnerability with combined use of magnetic resonance imaging and contrast‐enhanced ultrasound (CEUS). Methods and Results We prospectively enrolled 71 patients with internal carotid artery stenosis who underwent carotid endarterectomy and performed preoperative CEUS and magnetic resonance plaque imaging. We distinguished high–signal‐intensity plaques (HIPs) and non‐HIPs based on magnetization‐prepared rapid acquisition with gradient echo images. We graded them according to the CEUS contrast effect and compared the CEUS images with the carotid endarterectomy specimens. Among the 70 plaques, except 1 carotid endarterectomy tissue sample failure, 59 were classified as HIPs (43 symptomatic) and 11 were classified as non‐HIPs (5 symptomatic). Although the magnetization‐prepared rapid acquisition with gradient echo findings alone had no significant correlation with symptoms (P=0.07), concomitant use of magnetization‐prepared rapid acquisition with gradient echo and CEUS findings did show a significant correlation (P

BackgroundChronic inflammation plays a key role in the pathogenesis of intracranial aneurysms (IAs). DPP‐4 (dipeptidyl peptidase‐4) inhibitors have anti‐inflammatory effects, including suppressing macrophage infiltration, in various inflammatory models. We examined whether a DPP‐4 inhibitor, anagliptin, could suppress the growth of IAs in a rodent aneurysm model. Methods and ResultsIAs were surgically induced in 7‐week‐old male Sprague Dawley rats, followed by oral administration of 300 mg/kg anagliptin. We measured the morphologic parameters of aneurysms over time and their local inflammatory responses. To investigate the molecular mechanisms, we used lipopolysaccharide‐treated RAW264.7 macrophages. In the anagliptin‐treated group, aneurysms were significantly smaller 2 to 4 weeks after IA induction. Anagliptin inhibited the accumulation of macrophages in IAs, reduced the expression of MCP‐1 (monocyte chemotactic protein 1), and suppressed the phosphorylation of p65. In lipopolysaccharide‐stimulated RAW264.7 cells, anagliptin treatment significantly reduced the production of tumor necrosis factor α, MCP‐1, and IL‐6 (interleukin 6) independent of GLP‐1 (glucagon‐like peptide 1), the key mediator in the antidiabetic effects of DPP‐4 inhibitors. Notably, anagliptin activated ERK5 (extracellular signal–regulated kinase 5), which mediates the anti‐inflammatory effects of statins, in RAW264.7 macrophages. Preadministration with an ERK5 inhibitor blocked the inhibitory effect of anagliptin on MCP‐1 and IL‐6 expression. Accordingly, the ERK5 inhibitor also counteracted the suppression of p65 phosphorylation in vitro. ConclusionsA DPP‐4 inhibitor, anagliptin, prevents the growth of IAs via its anti‐inflammatory effects on macrophages.

Abstract.: Intracranial aneurysm (IA) and aortic dissection are both complications of hypertension and characterized by degeneration of the media. Given the involvement of prostaglandin F2α and its receptor, FP, in extracellular matrix remodeling in a mouse model of pulmonary fibrosis, here we induced hypertension and IA in rats by salt loading and hemi-lateral ligation of renal and carotid arteries and examined effects of a selective FP antagonist, AS604872, on these vascular events. AS604872 significantly accelerated degeneration of the media in both cerebral artery and aorta as evidenced by thinning of the media and disruption of the elastic lamina and promoted IA and aortic dissection. Notably, AS604872 induced expression of pro-inflammatory genes such as E-selectin in lesions and significantly enhanced macrophage infiltration. Suppression of surface expression of E-selectin with cimetidine prevented macrophage infiltration and aortic dissection. Thus, AS604872 exacerbates vascular inflammation in hypertensive rats and facilitates IA and aortic dissection. These results demonstrate that both IA and aortic dissection are caused by chronic inflammation of the arterial wall, which is worsened by AS604872, cautioning that other FP antagonists may share such deleterious actions in vascular homeostasis and suggesting that AS604872 can be used to make models of these vascular diseases with extensive degeneration. [Supplementary materials: available only at http://dx.doi.org/10.1254/jphs.14148FP] Keywords:: prostaglandin F2α receptor (FP), AS604872, intracranial aneurysm, aortic dissection, chronic inflammation

BACKGROUND: The effectiveness of comprehensive stroke center (CSC) capabilities on stroke mortality remains uncertain. We performed a nationwide study to examine whether CSC capabilities influenced in-hospital mortality of patients with ischemic and hemorrhagic stroke. METHODS AND RESULTS: Of the 1,369 certified training institutions in Japan, 749 hospitals responded to a questionnaire survey regarding CSC capabilities that queried the availability of personnel, diagnostic techniques, specific expertise, infrastructure, and educational components recommended for CSCs. Among the institutions that responded, data on patients hospitalized for stroke between April 1, 2010 and March 31, 2011 were obtained from the Japanese Diagnosis Procedure Combination database. In-hospital mortality was analyzed using hierarchical logistic regression analysis adjusted for age, sex, level of consciousness on admission, comorbidities, and the number of fulfilled CSC items in each component and in total. Data from 265 institutions and 53,170 emergency-hospitalized patients were analyzed. Mortality rates were 7.8% for patients with ischemic stroke, 16.8% for patients with intracerebral hemorrhage (ICH), and 28.1% for patients with subarachnoid hemorrhage (SAH). Mortality adjusted for age, sex, and level of consciousness was significantly correlated with personnel, infrastructural, educational, and total CSC scores in patients with ischemic stroke. Mortality was significantly correlated with diagnostic, educational, and total CSC scores in patients with ICH and with specific expertise, infrastructural, educational, and total CSC scores in patients with SAH. CONCLUSIONS: CSC capabilities were associated with reduced in-hospital mortality rates, and relevant aspects of care were found to be dependent on stroke type.

Objective: Flow diverters (FDs), first introduced in Japan in 2015, were initially limited to wide-necked large cerebral aneurysms, which pose a high treatment risk. However, based on the results of the PREMIER study, the indications have expanded since 2020, and the number of treatment cases is increasing in Japan. At our hospital, FD placement with adjunctive coil embolization has been actively performed for medium-sized cerebral aneurysms, as indicated in the PREMIER study; herein, we report the outcomes of this treatment. Methods: Of the 25 patients with 28 aneurysms who underwent FD placement at our institution between April 2022 and June 2023, 15 with 17 wide-necked unruptured cerebral aneurysms with a maximum diameter of <12 mm in the internal carotid artery (ICA) or vertebral artery (VA) were included. Postoperative complications were investigated in each case, and the aneurysm occlusion status was assessed using ultrashort echo time (UTE)-MRA at 3 months postoperatively and angiography at 6 months postoperatively. Fifteen patients who underwent coiling or stent-assisted coiling (SAC) for the same criteria during the same period were compared. Baseline characteristics and treatment results were compared between FD and coiling/SAC cases. Results: Four males and 11 females with a mean age of 61.7 ± 12.8 years were included, and the median follow-up period was 9 months (6-18 months). There were 14 aneurysms of the ICA and 3 of the VA, and the mean maximum aneurysm diameter was 7.9 ± 1.7 mm. All patients were treated using the Pipeline Flex with Shield Technology (Medtronic, Minneapolis, MN, USA), and 14 aneurysms (82.4%) were treated with adjunctive coil embolization. There were no symptomatic strokes in the perioperative period; only one patient receiving corticosteroid therapy for thyroid eye disease had asymptomatic ICA occlusion at 3 months. Fifteen aneurysms (88.2%) were not visible on UTE-MRA at 3 months postoperatively, and angiography at 6 months showed complete occlusion in 16 (94.1%) aneurysms. The coiling/SAC group had a smaller neck size and higher volume embolization ratio than the FD group; however, complete occlusion was higher in the FD group. Conclusion: FD placement with adjunctive coil embolization for medium-sized cerebral aneurysms is expected to result in good occlusion rates in the early postoperative period. [ABSTRACT FROM AUTHOR]

Flow diverter (FD) devices are new-generation stents placed in the parent artery at the aneurysmal neck to obstruct intraaneurysmal blood flow, thus favoring intra-aneurysmal thrombosis. In Japan, about eight years have passed since health insurance approval was granted for FD devices, and FD placement to treat aneurysms has become widespread. Treatment indications have also been expanded with the introduction of novel devices. At present, three types of FD (Pipeline, FRED, and Surpass Streamline) are available in Japan. This report represents a compilation of available FD technologies and describes the current consensus on this treatment. [ABSTRACT FROM AUTHOR]