Risk stratification of delayed causative aneurysm detection and long-term outcome in angiographically negative spontaneous subarachnoid haemorrhage.

BACKGROUND: The risk factors of aetiology and poor outcome in angiographically negative subarachnoid haemorrhage (anSAH) were unclearly. METHODS: The authors performed a retrospective review of a prospectively maintained database for anSAH patients between 2014 and 2018. AnSAH was defined as SAH presents in CT with no underlying vascular abnormality on initial digital subtraction angiography (DSA) within 72 hours of admission. Baseline and follow-up information, including medical history, bleeding pattern (perimesencephalic angiogram-negative SAH (PAN-SAH) and non-PAN-negative SAH (NPAN-SAH)), modified Fisher Scale (mFS), Glasgow Coma Score (GCS), Hunt-Hess grade, repeated imaging and causative vascular lesions and follow-up modified Rankin Scale (mRS) were reviewed. Poor outcome was defined as mRS scored 3-6 at last clinical follow-up. RESULTS: Among 303 enrolled patients, 272 patients underwent at least once repeated imaging examination (median follow-up time, 3.0 months). Twenty-one (7.7%) aneurysms were detected. Multivariate logistic analysis showed that NPAN-SAH and mFS 3-4 were associated with a high rate of aneurysm detection in anSAH patients. Based on risk stratification, the aneurysm detection rate in the high-risk group (both NPAN-SAH and mFS 3-4) was as high as 20.370 per 100 person-years. Furthermore, of 251 non-aneurysm anSAH patients, after a total follow-up time of 1265.83 patient-years, poor outcome occurred in 18 (7.2%) patients. Multivariate Cox analysis found that NPAN-SAH and GCS 3-12 were associated with a high rate of poor outcome of anSAH. The cumulative 5-year incidence rate for poor outcome in the non-aneurysm anSAH patients in the high-risk group (both NPAN-SAH and GCS 3-12) was as high as 75.302 per 100 person-years. CONCLUSIONS: Even in anSAH confirmed by initial DSA, patients with NPAN-SAH and mFS 3-4 should be monitored for delayed causative aneurysm detection, meanwhile in non-aneurysm anSAH patients, NPAN-SAH and initial functional impairment are associated with poor prognosis.

Zabramski classification in predicting the occurrence of symptomatic intracerebral hemorrhage in sporadic cerebral cavernous malformations.

OBJECTIVE: The authors aimed to investigate the evolutionary characteristics of the Zabramski classification of cerebral cavernous malformations (CCMs) and the value of the Zabramski classification in predicting clinical outcome in patients with sporadic CCM. METHODS: This retrospective study consecutively included cases of sporadic CCM that had been untreated from January 2001 through December 2021. Baseline and follow-up patient information was recorded. The evolution of the Zabramski classification of a sporadic CCM was defined as the initial lesion type changing into another type for the first time on MRI follow-up. The primary outcome was the occurrence of a hemorrhage event, which was defined as a symptomatic event with radiological evidence of overt intracerebral hemorrhage. RESULTS: Among the 255 included cases, 55 (21.6%) were classified as type I CCM, 129 (50.6%) as type II CCM, and 71 (27.8%) as type III CCM, based on initial MRI. During a mean follow-up of 58.8 ± 33.6 months, 51 (20.0%) patients had lesion classification transformation, whereas 204 (80.0%) patients maintained their initial type. Among the 51 transformed lesions, 29 (56.9%) were type I, 11 (21.6%) were type II, and 11 (21.6%) were type III. Based on all follow-up imaging, of the initial 55 type I lesions, 26 (47.3%) remained type I and 27 (49.1%) regressed to type III because of hematoma absorption; 91.5% of type II and 84.5% of type III lesions maintained their initial type during MRI follow-up. The classification change rate of type I lesions was statistically significantly higher than those of type II and III lesions. After a total follow-up of 1157.7 patient-years, new clinical hemorrhage events occurred in 40 (15.7%) patients. The annual cumulative incidence rate for symptomatic hemorrhage in all patients was 3.4 (95% CI 2.5-4.7) per 100 person-years. Kaplan-Meier survival analysis showed that the annual cumulative incidence rate for symptomatic hemorrhage of type I CCM (15.3 per 100 patient-years) was significantly higher than those of type II (0.6 per 100 patient-years) and type III (2.3 per 100 patient-years). CONCLUSIONS: This study suggests that the Zabramski classification is helpful in estimating clinical outcome and can assist with surgical decision-making in patients with sporadic CCM.

Somatic GJA4 mutation in intracranial extra-axial cavernous hemangiomas.

OBJECTIVE: Extra-axial cavernous hemangiomas (ECHs) are sporadic and rare intracranial occupational lesions that usually occur within the cavernous sinus. The aetiology of ECHs remains unknown. METHODS: Whole-exome sequencing was performed on ECH lesions from 12 patients (discovery cohort) and droplet digital polymerase-chain-reaction (ddPCR) was used to confirm the identified mutation in 46 additional cases (validation cohort). Laser capture microdissection (LCM) was carried out to capture and characterise subgroups of tissue cells. Mechanistic and functional investigations were carried out in human umbilical vein endothelial cells and a newly established mouse model. RESULTS: We detected somatic GJA4 mutation (c.121G>T, p.G41C) in 5/12 patients with ECH in the discovery cohort and confirmed the finding in the validation cohort (16/46). LCM followed by ddPCR revealed that the mutation was enriched in lesional endothelium. In vitro experiments in endothelial cells demonstrated that the GJA4 mutation activated SGK-1 signalling that in turn upregulated key genes involved in cell hyperproliferation and the loss of arterial specification. Compared with wild-type littermates, mice overexpressing the GJA4 mutation developed ECH-like pathological morphological characteristics (dilated venous lumen and elevated vascular density) in the retinal superficial vascular plexus at the postnatal 3 weeks, which were reversed by an SGK1 inhibitor, EMD638683. CONCLUSIONS: We identified a somatic GJA4 mutation that presents in over one-third of ECH lesions and proposed that ECHs are vascular malformations due to GJA4-induced activation of the SGK1 signalling pathway in brain endothelial cells.

Simplex cerebral cavernous malformations with MAP3K3 mutation have distinct clinical characteristics.

Objectives: To investigate the clinical characteristics of cerebral cavernous malformations (CCMs) with MAP3K3 somatic mutation. Methods: We performed a retrospective review of our CCMs database between May 2017 and December 2019. The patients with simplex CCMs identified to harbor a MAP3K3 or CCM gene somatic mutation were included. Clinical characteristics were recorded. Univariate and multivariate logistic analyses were used to assess the risk factors associated with hemorrhage events of CCMs. To explore the underlying mechanism, we transfected MEKK3-I441M-overexpressing and CCM2-knockdown lentiviruses into human umbilical vein endothelial cells (HUVECs) and investigated thrombomodulin (TM) and tight junctions (TJs) protein expression by western blotting and immunofluorescence. Finally, immunohistochemistry was used to validate TM and TJs protein expression in surgical samples. Results: Fifty simplex CCMs patients were included, comprising 38 MAP3K3 mutations and 12 CCM gene mutations. Nine (23.7%) patients with MAP3K3 mutations and 11(91.7%) patients with CCM gene mutations exhibited overt hemorrhage, respectively. Multivariate logistic analyses revealed that MAP3K3 mutation was associated with a lower risk of hemorrhage events. In the vitro experiments, ZO-1 expression was not reduced in MEKK3-I441M-overexpressing HUVECs compared with wild type, whereas it was significantly decreased in CCM2-knockdown HUVECs compared with control. In the MEKK3-I441M-overexpressing HUVECs, TM expression was increased, and the NF-κB pathway was significantly activated. After treatment with an NF-κB signaling inhibitor, TM expression was further upregulated. Meanwhile, TM expression was increased, but the NF-κB pathway was not activated in CCM2-knockdown HUVECs. Accordingly, immunohistochemistry showed that ZO-1 expression in the MAP3K3-mutant samples was significantly higher than that in the CCM-mutant samples. TM expression in the MAP3K3-mutant lesions was significantly lower than that in the CCM-mutant samples. Conclusion: Simplex CCMs with MAP3K3 mutation occasionally present with overt hemorrhage, which is associated with the biological function of MAP3K3 mutation.

Grading scale based on arcuate fasciculus segmentation to predict postoperative language outcomes of brain arteriovenous malformations.

OBJECTIVE: The long-term postoperative language outcomes for brain arteriovenous malformations (bAVMs) have not been well characterised. With fibres scattered in the Broca's, Wernicke's and Geschwind's area, the arcuate fasciculus (AF) is considered as a crucial structure of language function. This study aimed to observe the language outcomes, determine the risk factors and construct a grading system for long-term postoperative language deficits (LDs) in patients with bAVMs involving the AF (AF-bAVMs). METHODS: We retrospectively reviewed 135 patients with AF-bAVMs. Based on the course of the AF and our clinical experience, three boundary lines were drawn to divide the AF into segments I, II, III and IV in spatial order from the frontal lobe to the temporal lobe. Surgery-related LD evaluations were performed 1 week (short term) and at the last follow-up (long term) after surgery. Finally, based on multivariable logistic regression analysis, a grading system was constructed to predict long-term postoperative LD. The predictive accuracy was assessed using the area under the receiver operating characteristic curve (AUC). RESULTS: Sixty-two (45.9%) patients experienced short-term postoperative LD. After a mean follow-up of 50.2±24.9 months, long-term LD was found in 14 (10.4%) patients. Nidus size (p=0.007), LD history (p=0.009) and segment II involvement (p=0.030) were independent risk factors for short-term LD. Furthermore, segment II involvement (p=0.002), anterior choroidal artery (AChA) feeding (p=0.001), patient age (p=0.023) and LD history (p=0.001) were independent risk factors for long-term LD. A grading system was developed by combining the risk factors for long-term LD; its predictive accuracy was 0.921. CONCLUSIONS: The involvement of the trunk of the AF between Broca's area and the inferior parietal lobule, a nidus supplied by the AChA, older patient age and history of LD were associated with long-term postoperative LD. The grading system combining these factors demonstrated favourable predictive accuracy for long-term language outcomes.

Infarction Patterns and Recurrent Adverse Cerebrovascular Events in Moyamoya Disease.

For moyamoya disease (MMD) patients who suffered an acute ischemic attack, the infarction patterns on DWI and its association with recurrent adverse cerebrovascular events (ACEs) after bypass surgery remain unknown. 327 patients who suffered an acute ischemic attack and received following revascularization surgery were retrospectively reviewed and were divided into three patterns according to the lesion number and distribution on DWI that obtained within 7 days of onset: no acute infarction (NAI), single acute infarction (SAI), and multiple acute infarctions (MAIs). We used Cox proportional hazard models to estimate hazard ratios (HR) for associations of infarction patterns and the risk of recurrent ACEs and strokes. Over a median follow-up of 41 months (IQR 26-60), there were 61 ACEs and 27 strokes. Compared to the NAI cohort, patients with SAI (HR, 2.92; 95% CI, 1.41-6.05; p = 0.004) and MAIs (HR, 4.44; 95% CI, 2.10-9.41; p < 0.001) were associated with higher risk of ACEs recurrences. In analysis adjusted for age and surgery modalities, the corresponding HR was 2.90 (95% CI: 1.41-5.98) for SAI and 4.10 (95% CI: 1.95-8.63) for MAIs, and this effect remained persistent on further adjustment for several potential confounders. Similar but less precise association was found in separate analysis that only takes into account stroke recurrences. Thus, different infarction patterns on DWI imply different risks of recurrent ACEs, and more attention should be paid to prevent ACEs in MMD patients with MAIs.

China Stroke Statistics: an update on the 2019 report from the National Center for Healthcare Quality Management in Neurological Diseases, China National Clinical Research Center for Neurological Diseases, the Chinese Stroke Association, National Center for Chronic and Non-communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention and Institute for Global Neuroscience and Stroke Collaborations.

China faces the greatest challenge from stroke in the world. According to results from the Global Burden of Disease Study 2019, there were 3.94 million new stroke cases, 28.76 million prevalent cases and 2.19 million deaths due to stroke in China in 2019. Furthermore, stroke is also the leading cause of disability-adjusted life-year (DALY) in China, the number of DALYs reached 45.9 million in 2019. Several recent large-scale epidemiological surveys have updated the data on pre-existing conditions contributed to stroke. The age-adjusted prevalence of overweight among Chinese adults aged 18-69 years was 34.4%, and the prevalence of obesity was 16.8% in 2018. 50.9% of Chinese adults ≥18 years of age without history of hypertension had prehypertension in 2018. The weighted prevalence of hypertension in adults was 27.5% in 2018. The weighted prevalence of total diabetes and pre-diabetes diagnosed by the American Diabetes Association criteria were 12.8% and 35.2%, respectively, among Chinese adults ≥18 years of age in 2017. The weighted atrial fibrillation prevalence was 1.8% among Chinese adults ≥45 years of age and equates to being present in an estimated 7.9 million people in China. Data from 1672 tertiary public hospitals in the Hospital Quality Monitoring System (HQMS) showed that 3 411 168 stroke cases were admitted during 2019. Of those, 2 818 875 (82.6%) were ischaemic strokes (ISs), 485 474 (14.2%) were intracerebral haemorrhages (ICHs), 106 819 (3.1%) were subarachnoid haemorrhages (SAHs). The average age was 66 years old, and 59.6% were male. A total of 1379 (<0.1%), 2604 (0.5%), 1250 (1.2%) paediatric strokes (age <18 years) were identified among IS, ICH and SAH, respectively. Over one-third (1 231 519 (36.1%)) of the stroke cases were covered by urban resident basic medical insurance, followed by urban employee basic medical insurance (891 103 (26.1%)) and new rural cooperative medical schema (543 108 (15.9%)). The leading risk factor was hypertension (57.3% for IS, 69.9% for ICH and 44.1% for SAH), and the leading comorbidity was pneumonia or pulmonary infection (10.4% for IS, 34.6% for ICH and 29.7% for SAH). In-hospital death/discharge against medical advice rate was 8.5%, ranging from 6.0% for IS to 20.6% for SAH. The median and IQR of length of stay was 9.0 (6.0-13.0) days, ranging from 10.0 (7.0-13.0) in IS to 14.0 (8.0-22.0) in ICH. Similar data from 2847 secondary public hospitals or private hospitals in the HQMS were also reported. Data from HQMS showed that higher proportions of interprovincial admission to other provinces were seen in Inner Mongolia, Anhui, Tibet and Beijing. Higher proportions of interprovincial admission from other provinces were seen in Beijng, Tianjin, Shanghai and Ningxia. Data from 323 601 strokes from 1337 hospitals in the Chinese Stroke Center Alliance during 2019 demonstrated that the composite scores of guideline-recommended key performance indicators for patients with IS, ICH and SAH were 0.78±0.20, 0.69±0.27 and 0.60±0.31, respectively.

Machine Learning-Enabled Determination of Diffuseness of Brain Arteriovenous Malformations from Magnetic Resonance Angiography.

The diffuseness of brain arteriovenous malformations (bAVMs) is a significant factor in surgical outcome evaluation and hemorrhagic risk prediction. However, there are still predicaments in identifying diffuseness, such as the judging variety resulting from different experience and difficulties in quantification. The purpose of this study was to develop a machine learning (ML) model to automatically identify the diffuseness of bAVM niduses using three-dimensional (3D) time-of-flight magnetic resonance angiography (TOF-MRA) images. A total of 635 patients with bAVMs who underwent TOF-MRA imaging were enrolled. Three experienced neuroradiologists delineated the bAVM lesions and identified the diffuseness on TOF-MRA images, which were considered the ground-truth reference. The U-Net-based segmentation model was trained to segment lesion areas. Eight mainstream ML models were trained through the radiomic features of segmented lesions to identify diffuseness, based on which an integrated model was built and yielded the best performance. In the test set, the Dice score, F2 score, precision, and recall for the segmentation model were 0.80 [0.72-0.84], 0.80 [0.71-0.86], 0.84 [0.77-0.93], and 0.82 [0.69-0.89], respectively. For the diffuseness identification model, the ensemble-based model was applied with an area under the Receiver-operating characteristic curves (AUC) of 0.93 (95% CI 0.87-0.99) in the training set. The AUC, accuracy, precision, recall, and F1 score for the diffuseness identification model were 0.95, 0.90, 0.81, 0.84, and 0.83, respectively, in the test set. The ML models showed good performance in automatically detecting bAVM lesions and identifying diffuseness. The method may help to judge the diffuseness of bAVMs objectively, quantificationally, and efficiently.

Quantitative angiographic haemodynamic evaluation of bypasses for complex aneurysms: a preliminary study.

OBJECTIVE: Open microsurgery, often with bypass techniques, is indispensable for complex aneurysms. To date, it remains unknown whether arterial anatomy or quantitative blood flow measurements can predict insufficient flow-related stroke (IRS). The present study aimed to evaluate the risk factors for IRS in patients treated with open microsurgery with bypass procedures for complex internal carotid artery aneurysms. METHODS: Patients with complex aneurysms undergoing bypass surgery were retrospectively reviewed. The recipient/donor flow index (RDFI) was preoperatively evaluated using colour-coding angiography. RDFI was defined as the ratio of the cerebral blood volume of the recipient and donor arteries. The sizes of the recipient and donor arteries were measured. The recipient/donor diameter index (RDDI) was then calculated. IRS was defined as the presence of new postoperative neurological deficits and infarction on postoperative CT scans. We assessed the association between RDFI and other variables and the IRS. RESULTS: Twenty patients (38±12 years) were analysed. IRS was observed in 12 patients (60%). Patients with postoperative IRS had a higher RDFI than those without postoperative IRS (p<0.001). RDDI was not significantly different between patients with and without IRS (p=0.905). Patients with RDFI >2.3 were more likely to develop IRS (p<0.001). CONCLUSION: Quantitative digital subtraction angiography enables preoperative evaluation of cerebral blood volume. RDFI >2.3, rather than RDDI, was significantly associated with postoperative IRS. This preoperative evaluation allows appropriate decisions regarding the treatment strategy for preventing postoperative IRS.

Effects and safety of aspirin use in patients after cerebrovascular bypass procedures.

OBJECT: Superficial temporal artery to middle cerebral artery (STA-MCA) bypass is the most effective treatment for Moyamoya disease (MMD). In this study, we aimed to assess whether aspirin improves STA-MCA bypass patency and is safe in patients with MMD. METHODS: We performed a retrospective medical record review of patients with ischaemic-onset MMD who had undergone STA-MCA bypass at two hospitals between January 2011 and August 2018, to clarify the effects and safety of aspirin following STA-MCA bypass. The neurological status at the last follow-up (FU) was compared between patients with FU bypass patency and occlusion. Results Among 217 identified patients (238 hemispheres), the mean age was 41.4±10.2 years, and 51.8% were male; the indications for STA-MCA bypass were stroke (48.2%), followed by a transient ischaemic attack (44.0%). Immediate bypass patency was confirmed in all cases. During the FU period (1.5±1.5 y), 15 cases were occluded at FU imaging, resulting in an overall cumulative patency rate of 94%. The patency rates were 93% and 94% in the short-term FU group (n=131, mean FU time 0.5±0.2 years) and long-term FU group (n=107, mean FU time 4.1±3.5 years), respectively. The STA-MCA bypass patency rate in the aspirin group was higher than that in the non-aspirin group (98.7% vs 89.7%; HR 1.57; 95% CI 1.106 to 2.235; p=0.012). No significant difference in the FU haemorrhagic events was observed between the aspirin and non-aspirin groups. CONCLUSIONS: Among adult patients with ischaemic-onset MMD undergoing STA-MCA bypass procedures, aspirin might increase the bypass patency rate, without increasing the bleeding risk. FU bypass patency may be associated with a better outcome. Additional studies, especially carefully designed prospective studies, are needed to address the role of aspirin after bypass procedures.

Classification of brain arteriovenous malformations located in motor-related areas based on location and anterior choroidal artery feeding.

OBJECTIVE: Surgical management of arteriovenous malformations (AVMs) involving motor cortex or fibre tracts (M-AVMs) is challenging. This study aimed to construct a classification system based on nidus locations and anterior choroidal artery (AChA) feeding to pre-surgically evaluate motor-related and seizure-related outcomes in patients undergoing resection of M-AVMs. METHODS AND MATERIALS: A total of 125 patients who underwent microsurgical resection of M-AVMs were retrospectively reviewed. Four subtypes were identified based on nidus location: (I) nidus involving the premotor area and/or supplementary motor areas; (II) nidus involving the precentral gyrus; (III) nidus involving the corticospinal tract (CST) and superior to the posterior limb of the internal capsule; (IV) nidus involving the CST at or inferior to the level of posterior limb of the internal capsule. In addition, we divided type IV into type IVa and type IVb according to the AChA feeding. Surgical-related motor deficit (MD) evaluations were performed 1 week (short-term) and 6 months (long-term) after surgery. RESULTS: The type I patients exhibited the highest incidence (62.0%) of pre-surgical epilepsy among the four subtypes. Multivariate analysis showed that motor-related area subtypes (p=0.004) and diffuse nidus (p=0.014) were significantly associated with long-term MDs. Long-term MDs were significantly less frequent in type I than in the other types. Type IV patients acquired the highest proportion (four patients, 25.0%) of long-term poor outcomes (mRS >2). Type IVb patients showed a significantly higher incidence of post-surgical MDs than type IVa patients (p=0.041). The MDs of type III or IV patients required more recovery time. Of the 62 patients who had pre-surgical seizures, 90.3% (56/62) controlled their seizures well and reached Engel class I after surgery. CONCLUSIONS: Combining the consideration of location and AChA feeding, the classification for M-AVMs is a useful approach for predicting post-surgical motor function and decision-making.

Safety of Aspirin Use in Patients With Stroke and Small Unruptured Aneurysms.

OBJECTIVE: We initiated a multicenter, prospective cohort study to test the hypothesis that aspirin is safe for patients with ischemic cerebrovascular disease (ICVD) harboring unruptured intracranial aneurysms (UIAs) <7 mm. METHODS: This prospective, multicenter cohort study consecutively enrolled 1,866 eligible patients with ICVD harboring UIAs <7 mm in diameter from 4 hospitals between January 2016 and August 2019. Baseline and follow-up patient information, including the use of aspirin, was recorded. The primary endpoint was aneurysm rupture. RESULTS: After a total of 4,411.4 person-years, 643 (37.2%) patients continuously received aspirin treatment. Of all included patients, rupture occurred in 12 (0.7%). The incidence rate for rupture (IRR) was 0.27 (95% confidence interval [CI] 0.15-0.48) per 100 person-years. The IRRs were 0.39 (95% CI 0.21-0.72) and 0.06 (95% CI 0.010-0.45) per 100 person-years for the nonaspirin and aspirin groups, respectively. In the multivariate analysis, uncontrolled hypertension and UIAs 5 to <7 mm were associated with a high rate of aneurysm rupture, whereas aspirin use was associated with a low rate of aneurysm rupture. Compared with other groups, the high-risk group (UIAs 5 to <7 mm with concurrent uncontrolled hypertension) without aspirin had higher IRRs. CONCLUSION: Aspirin is a safe treatment for patients with concurrent small UIAs and ICVD. Patients who are not taking aspirin in the high-risk group warrant intensive surveillance. CLINICALTRIALSGOV IDENTIFIER: NCT02846259. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that for patients harboring UIAs <7 mm with ICVD, aspirin does not increase the risk of aneurysm rupture.

Chinese Stroke Association guidelines for clinical management of cerebrovascular disorders: executive summary and 2019 update of clinical management of intracerebral haemorrhage.

AIM: This evidence-based guideline aims to present current and comprehensive recommendations for the diagnosis and management of spontaneous intracerebral haemorrhage (ICH). METHODS: A formal literature search was conducted on MEDLINE (1 January 1990 to 30 June 2019). Data were synthesised using evidence tables. The members of the working group met by teleconference to update and formulate data-based recommendations. The recommendations are graded according to levels of evidence grading algorithm of the Chinese Stroke Association. The guideline draft has been reviewed by Chinese Stroke Association Stroke Council Guideline Writing Committee. RESULTS: Evidence-based guideline is proposed for the management of patients with ICH. The focus of the guideline is divided into the diagnosis and aetiology of ICH, management of ICH in emergency department, surgical treatment for removal of hematoma, management of complications and prevention of secondary ICH. CONCLUSIONS: This guideline provides a framework for ICH management. Early active and reasonable treatment may improve the clinical outcome of patients.

Aspirin and Growth of Small Unruptured Intracranial Aneurysm: Results of a Prospective Cohort Study.

BACKGROUND AND PURPOSE: The role of aspirin in unruptured intracranial aneurysm (UIA) growth remains largely unknown. We aim to identify whether aspirin is associated with a lower rate of UIA growth in patients with UIA <7 mm. METHODS: This prospective cohort study consecutively enrolled patients with UIAs <7 mm with ischemic cerebrovascular disease between January 2016 and December 2019. Baseline and follow-up patient information, including the use of aspirin and blood pressure level, were recorded. Patients were considered aspirin users if they took aspirin, including standard- and low-dose aspirin, ≥3× per week. The primary end point was aneurysm growth in any direction or an indisputable change in aneurysm shape. RESULTS: Among the 315 enrolled patients, 272 patients (86.3%) underwent imaging examinations during follow-up (mean follow-up time, 19.6±12.7 months). A total of 113 patients were continuously treated with aspirin. UIA growth occurred in 31 (11.4%) patients. In the multivariate Cox analysis, specific aneurysm locations (anterior communicating artery, posterior communicating artery, or middle cerebral artery; hazard ratio, 2.89 [95% CI, 1.22-6.88]; P=0.016) and a UIA size of 5 to <7 mm (hazard ratio, 7.61 [95% CI, 3.02-19.22]; P<0.001) were associated with a high risk of UIA growth, whereas aspirin and well-controlled blood pressure were associated with a low risk of UIA growth (hazard ratio, 0.29 [95% CI, 0.11-0.77]; P=0.013 and hazard ratio, 0.25 [95% CI, 0.10-0.66]; P=0.005, respectively). The cumulative annual growth rates were as high as 40.0 and 53.3 per 100 person-years in the high-risk patients (>1 risk factor) with and without aspirin, respectively. CONCLUSIONS: Aspirin therapy and well-controlled blood pressure are associated with a low risk of UIA growth; the incidence of UIA growth in high-risk patients in the first year is high, warranting intensive surveillance in this patient group. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02846259.

China Stroke Statistics 2019: A Report From the National Center for Healthcare Quality Management in Neurological Diseases, China National Clinical Research Center for Neurological Diseases, the Chinese Stroke Association, National Center for Chronic and Non-communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention and Institute for Global Neuroscience and Stroke Collaborations.

China faces the greatest challenge from stroke in the world. The death rate for cerebrovascular diseases in China was 149.49 per 100 000, accounting for 1.57 million deaths in 2018. It ranked third among the leading causes of death behind malignant tumours and heart disease. The age-standardised prevalence and incidence of stroke in 2013 were 1114.8 per 100 000 population and 246.8 per 100 000 person-years, respectively. According to the Global Burden of Disease Study 2017, the years of life lost (YLLs) per 100 000 population for stroke increased by 14.6%; YLLs due to stroke rose from third highest among all causes in 1990 to the highest in 2017. The absolute numbers and rates per 100 000 population for all-age disability-adjusted life years (DALYs) for stroke increased substantially between 1990 and 2017, and stroke was the leading cause of all-age DALYs in 2017. The main contributors to cerebrovascular diseases include behavioural risk factors (smoking and alcohol use) and pre-existing conditions (hypertension, diabetes mellitus, dyslipidaemia and atrial fibrillation (AF)). The most prevalent risk factors among stroke survivors were hypertension (63.0%-84.2%) and smoking (31.7%-47.6%). The least prevalent was AF (2.7%-7.4%). The prevalences for major risk factors for stroke are high and most have increased over time. Based on the latest national epidemiological data, 26.6% of adults aged ≥15 years (307.6 million adults) smoked tobacco products. For those aged ≥18 years, age-adjusted prevalence of hypertension was 25.2%; adjusted prevalence of hypercholesterolaemia was 5.8%; and the standardised prevalence of diabetes was 10.9%. For those aged ≥40 years, the standardised prevalence of AF was 2.31%. Data from the Hospital Quality Monitoring System showed that 3 010 204 inpatients with stroke were admitted to 1853 tertiary care hospitals during 2018. Of those, 2 466 785 (81.9%) were ischaemic strokes (ISs); 447 609 (14.9%) were intracerebral haemorrhages (ICHs); and 95 810 (3.2%) were subarachnoid haemorrhages (SAHs). The average age of patients admitted was 66 years old, and nearly 60% were male. A total of 1555 (0.1%), 2774 (0.6%) and 1347 (1.4%) paediatric strokes (age <18 years) were identified among IS, ICH and SAH, respectively. Over one-third (1 063 892 (35.3%)) of the patients were covered by urban resident basic medical insurance, followed by urban employee basic medical insurance (699 513 (23.2%)) and new rural cooperative medical schema (489 361 (16.3%)). The leading risk factor was hypertension (67.4% for IS, 77.2% for ICH and 49.1% for SAH), and the leading comorbidity was pneumonia or pulmonary infection (10.1% for IS, 31.4% for ICH and 25.2% for SAH). In-hospital death/discharge against medical advice rate was 8.3% for stroke inpatients, ranging from 5.8% for IS to 19.5% for ICH. The median and IQR of length of stay was 10.0 (7.0-14.0) days, ranging from 10.0 (7.0-13.0) in IS to 14.0 (8.0-22.0) in SAH. Data from the Chinese Stroke Center Alliance demonstrated that the composite scores of guideline-recommended key performance indicators for patients with IS, ICH and SAH were 0.77±0.21, 0.72±0.28 and 0.59±0.32, respectively.

Digital subtraction angiographic characteristics of progression of moyamoya disease 6 months prior to surgical revascularisation.

Background: Evidence on the natural angiographic course of moyamoya disease (MMD) is lacking. It takes about 6 months for waiting for revascularisation surgery. The issue of when to perform subtraction angiography (DSA) for follow-up remains unclear. We investigated the natural course of MMD by DSA and attempted to determine the best interval to perform the follow-up DSA. Methods: This is a single-centre cohort study of Chinese MMD inpatients treated from 1 January 2015 to 31 August 2019. Their angiographic findings were evaluated on Suzuki stage and collateral circulation between two follow-ups of the same hemisphere. Results: A total of 110 patients who met the criteria were enrolled in this study. After a median 6 months follow-up, five patients (4.5%) had progression, four females and one male. Time interval of progression ranged from 4 to 137 months with a mean of 61.4 months. Of five patients with progression, four had unilateral lesion (two ipsilateral and two contralateral) and one had bilateral lesions. Collateral circulation was changed in three of five patients. Conclusions: The angiographic evidence of progression in MMD was rare in the short-term follow-up, and most patients with progression had initial unilateral involvement. DSA re-examination may be not needed in patients with bilateral MMD, but needed in unilateral MMD.

N6-methyladenosine methyltransferase METTL3 affects the phenotype of cerebral arteriovenous malformation via modulating Notch signaling pathway.

BACKGROUND: Cerebral arteriovenous malformation (AVM) is a serious life-threatening congenital cerebrovascular disease. Specific anatomical features, such as nidus size, location, and venous drainage, have been validated to affect treatment outcomes. Until recently, molecular biomarkers and corresponding molecular mechanism related to anatomical features and treatment outcomes remain unknown. METHODS: RNA N6-methyladenosine (m6A) Methyltransferase METTL3 was identified as a differentially expressed gene in groups with different lesion sizes by analyzing the transcriptome sequencing (RNA-seq) data. Tube formation and wound healing assays were performed to investigate the effect of METTL3 on angiogenesis. In addition, Methylated RNA Immunoprecipitation Sequencing technology (MeRIP-seq) was performed to screen downstream targets of METTL3 in endothelial cells and to fully clarify the specific underlying molecular mechanisms affecting the phenotype of cerebral AVM. RESULTS: In the current study, we found that the expression level of METTL3 was reduced in the larger pathological tissues of cerebral AVMs. Moreover, knockdown of METTL3 significantly affected angiogenesis of the human endothelial cells. Mechanistically, down-regulation of METTL3 reduced the level of heterodimeric Notch E3 ubiquitin ligase formed by DTX1 and DTX3L, thereby continuously activating the Notch signaling pathway. Ultimately, the up-regulated downstream genes of Notch signaling pathway dramatically affected the angiogenesis of endothelial cells. In addition, we demonstrated that blocking Notch pathway with DAPT could restore the phenotype of METTL3 deficient endothelial cells. CONCLUSIONS: Our findings revealed the mechanism by which m6A modification regulated the angiogenesis and might provide potential biomarkers to predict the outcome of treatment, as well as provide suitable pharmacological targets for preventing the formation and progression of cerebral AVM.

Wilms' tumour 1-associating protein inhibits endothelial cell angiogenesis by m6A-dependent epigenetic silencing of desmoplakin in brain arteriovenous malformation.

Brain arteriovenous malformations (AVMs) are congenital vascular abnormality in which arteries and veins connect directly without an intervening capillary bed. So far, the pathogenesis of brain AVMs remains unclear. Here, we found that Wilms' tumour 1-associating protein (WTAP), which has been identified as a key subunit of the m6A methyltransferase complex, was down-regulated in brain AVM lesions. Furthermore, the lack of WTAP could inhibit endothelial cell angiogenesis in vitro. In order to screen for downstream targets of WTAP, we performed RNA transcriptome sequencing (RNA-seq) and Methylated RNA Immunoprecipitation Sequencing technology (MeRIP-seq) using WTAP-deficient and control endothelial cells. Finally, we determined that WTAP regulated Desmoplakin (DSP) expression through m6A modification, thereby affecting angiogenesis of endothelial cells. In addition, an increase in Wilms' tumour 1 (WT1) activity caused by WTAP deficiency resulted in substantial degradation of ß-catenin, which might also inhibit angiogenesis of endothelial cells. Collectively, our findings revealed the critical function of WTAP in angiogenesis and laid a solid foundation for the elucidation of the pathogenesis of brain AVMs.

Natural Course of Moyamoya Disease in Patients With Prior Hemorrhagic Stroke.

Background and Purpose- Evidence on the natural history of hemorrhagic moyamoya disease is still insufficient. We investigated the incidence of recurrent intracranial bleeding, mortality, and risk factors for rebleeding in patients with moyamoya disease. Methods- A total of 128 conservatively managed patients with hemorrhagic presentation and complete follow-up data were included. Recurrent hemorrhages during long-term follow-up were documented. Annual and cumulative incidence rate of bleeding was generated via Kaplan-Meier survival analysis, and risk factors were analyzed using logistic regression analysis. Results- The median follow-up time was 10.1 (1-27) years. During a total of 1300.7 patient-years, 47 (36.7%) patients experienced 59 occurrences of recurrent hemorrhages, rendering an average annual incidence of 4.5%. Among them, 9 patients (19.1%) died from rebleeding and 12 patients sustained severe disability (modified Rankin Scale score of ≥3). The cumulative risk of rebleeding was 7.8% at 5 years, 22.6% at 10 years, and 35.9% at 15 years. Only 4 (3.1%) patients experienced ischemic stroke, yielding an average annual incidence of 0.3%. Multivariate analysis showed that smoking (odds ratio, 4.85; P=0.04) was an independent risk factor of rebleeding. Rebleeding (hazard ratio, 11.04; P=0.02) and hypertension (hazard ratio, 4.16; P=0.04) were associated with increased mortality. Age, type of initial bleeding, digital subtraction angiography staging, family history, and coexisting cerebral aneurysms were not associated with increased risk of rebleeding. Conclusions- Rebleeding events were common and the main cause of death in patients with hemorrhagic moyamoya disease. The risk of rebleeding steadily increased during long-term follow-up. Smoking was a risk factor for rebleeding, and hypertension was associated with increased mortality.

Lower serum retinoic acid level for prediction of higher risk of mortality in ischemic stroke.

OBJECTIVE: To explore the association between serum retinoic acid (RA) level in patients with acute ischemic stroke (AIS) and mortality risk in the 6 months after admission. METHODS: From January 2015 through December 2016, patients admitted to 3 stroke centers in China for first-ever AIS were screened. The primary endpoint was all-cause mortality or cardiovascular disease (CVD) mortality in the 6 months after admission. The significance of serum RA level, NIH Stroke Scale score, and established risk factors in predicting mortality were determined. The integrated discrimination improvement (IDI) and net reclassification improvement (NRI) statistics were applied in statistical analysis. RESULTS: Of the 1,530 patients enrolled, 325 died within 6 months of admission, with an all-cause mortality of 21.2% and CVD-related mortality of 13.1%. In multivariable analysis, RA levels were expressed as quartiles with the clinical variables. The results of the second to fourth quartiles (Q2-Q4) were compared with the first quartile (Q1); RA levels showed prognostic significance, with decreased all-cause and CVD mortality of 55% and 63%, respectively. After RA was added to the existing risk factors, all-cause mortality could be better reclassified, in association with only the NRI statistic (p = 0.005); CVD mortality could be better reclassified with significance, in association with both the IDI and NRI statistics (p < 0.01). CONCLUSIONS: Low circulating levels of RA were associated with increased risk of all-cause and CVD mortality in a cohort of patients with first-incidence AIS, indicating that RA level could be a predictor independent of established conventional risk factors.