Dimethyl fumarate treatment for unruptured intracranial aneurysms: a study protocol for a double-blind randomised controlled trial.

INTRODUCTION: Intracranial aneurysm (IA) is a common cerebrovascular disease. Considering the risks and benefits of surgery, a significant proportion of patients with unruptured IA (UIA) choose conservative observation. Previous studies suggest that inflammation of aneurysm wall is a high-risk factor of rupture. Dimethyl fumarate (DMF) acts as an anti-inflammatory agent by activating nuclear factor erythroid 2-related factor 2 (Nrf2) and other pathways. Animal experiments found DMF reduces the formation and rupture of IAs. In this study, DMF will be evaluated for its ability to reduce inflammation of the aneurysm wall in high-resolution vessel wall imaging. METHODS AND ANALYSIS: This is a multi-centre, randomised, controlled, double-blind clinical trial. Three hospitals will enrol a total of 60 patients who have UIA with enhanced wall. Participants will be assigned randomly in a 1:1 proportion, taking either 240 mg DMF or placebo orally every day for 6 months. As the main result, aneurysm wall enhancement will be measured by the signal intensity after 6 months of DMF treatment. Secondary endpoints include morphological changes of aneurysms and factors associated with inflammation. This study will provide prospective data on the reduction of UIA wall inflammation by DMF. ETHICS AND DISSEMINATION: This study has been approved by Medical Ethics Committee of the Beijing Tiantan Hospital, Capital Medical University (approval no: KY2022-064-02). We plan to disseminate our research findings through peer-reviewed journal publication and relevant academic conferences. TRIAL REGISTRATION NUMBER: NCT05959759.

Treatment of fusiform aneurysms with a pipeline embolization device: a multicenter cohort study.

BACKGROUND: Intracranial fusiform aneurysms are less common than saccular aneurysms, but are associated with higher mortality and morbidity. We conducted this study to determine the safety and efficacy of the pipeline embolization device (PED) to treat intracranial fusiform aneurysms. METHODS: This was a multicenter, retrospective, and observational study. Data for this study came from the PLUS study conducted from 2014 to 2019 across 14 centers in China. Univariate and multivariable logistic regression analyses were performed to evaluate predictors of the occlusion rate and complication. RESULTS: A total of 1171 consecutive patients with 1322 intracranial aneurysms participated in this study. Among the participants, 104 patients with 109 fusiform aneurysms were eligible for this analysis (mean age 49 years, 36.5% women, aneurysm mean size 14.7 mm, 55% in the posterior circulation, and 6% in the basilar artery). Mean follow-up time was 9.0 months (range 3-36 months). The last DSA angiographic follow-up was available for 85 patients, and 58 aneurysms (68.2%) were completely occluded. The overall complication rate and mortality were 17.3% and 2.8%, respectively. Multivariate analysis demonstrated that age (OR=1.007, p=0.037) and cerebral atherosclerosis (OR=1.441, p=0.002) were associated with incomplete occlusion of fusiform aneurysms after PED treatment. CONCLUSION: PEDs may be an effective treatment for intracranial fusiform aneurysms, with a favorable occlusion rate. However, because these treatments have a relatively high rate of complications, PED treatment for fusiform aneurysms should be carefully and strictly controlled. Our analysis showed that PEDs with adjunctive coiling did not significantly improve the occlusion rate of fusiform aneurysms.

Predictors of improvement for patients with CNS vasculitis stenoses: A high-resolution vessel wall MRI follow-up study.

PURPOSE: To investigate the predictors of the improvement for patients with isolated intracranial vasculitis stenoses using high-resolution vessel wall magnetic resonance imaging (HR VW-MRI). METHODS: We retrospectively reviewed data from consecutive patients with confirmed intracranial vasculitis under the same conventional conservative treatment based on a prospectively established HR VW-MRI database between December 2016 and December 2020. According to the changes between the degree of stenosis at baseline compared to follow-up MR angiography, the patients were divided into an improvement group and a non-improvement group. A multivariate analysis was performed to identify the predictive factors associated with the improvement of stenoses secondary to intracranial vasculitis. RESULTS: Overall, 41 patients (mean age 32.0 ± 10.1 years, 16 females) with isolated intracranial vasculitis stenoses were included (41.5 % [17/41] in the improvement group, and 58.5 % [24/41] were in the non-improvement group). The degree of wall enhancement on follow-up imaging was significantly reduced compared with that on the baseline imaging in the improvement group (P = 0.004). The multivariate analysis showed that the degree of enhancement (OR, 0.219, 95 % CI, 0.054 to 0.881; P = 0.033) at baseline was an independent predictive factor associated with the improvement in the intracranial vasculitis stenoses. CONCLUSIONS: In patients with isolated intracranial vasculitis stenoses, the less enhancement the vessel wall was, the more likely the degree of stenosis would be reduced by conventional conservative therapy.

In-Stent Stenosis After Pipeline Embolization Device in Intracranial Aneurysms: Incidence, Predictors, and Clinical Outcomes.

BACKGROUND: In-stent stenosis (ISS) is a delayed complication that can occur after pipeline embolization device use when treating intracranial aneurysms (IAs). OBJECTIVE: To assess the incidence, predictors, and outcomes of ISS. METHODS: This was a retrospective, multicenter, observational study. All patient data were collected from a PLUS registry study. We collected data from patients with IA who completed digital subtraction angiography at follow-up and divided patients into "non-ISS," "mild ISS," or "severe ISS" groups. Multivariate logistic regression analysis was conducted to determine predictors of ISS. RESULTS: A total of 1171 consecutive patients with 1322 IAs participated in this study. Angiographic follow-up was available for 662 patients with 728 IAs, and the mean follow-up time was 9 months. ISS was detected in 73 cases (10.03%), including 61 mild ISS cases and 12 severe ISS cases. Univariate and multivariable analysis demonstrated that current smoking history (mild ISS: OR 2.15, 95% CI 1.122-4.118, P = .021; severe ISS: OR 5.858, 95% CI 1.186-28.93, P = .030) and cerebral atherosclerosis (mild ISS: OR 5.694, 95% CI 3.193-10.15, P = .001; severe ISS: OR 6.103, 95% CI 1.384-26.91, P = .017) were independent predictors of ISS. Compared with the other groups, the severe ISS group had higher rate of ischemic stroke (33.3%). CONCLUSION: ISS occurs in approximately 10.03% of cases at a mean follow-up of 9 months. Statistically, current smoking history and cerebral atherosclerosis are the main predictors of ISS. Severe ISS may be associated with higher risk of neurological ischemic events in patients with IA after pipeline embolization device implantation.

Atorvastatin for unruptured intracranial vertebrobasilar dissecting aneurysm (ATREAT-VBD): protocol for a randomised, double-blind, blank-controlled trial.

INTRODUCTION: Vertebrobasilar dissecting aneurysms (VBDAs) are associated with serious complications and a poor prognosis. It is believed that inflammation of the aneurysm wall may be the main cause of rupture or deterioration. Atorvastatin has been shown to inhibit inflammation and may be a suitable drug candidate. Here, we report a clinical research study protocol to investigate whether atorvastatin inhibits inflammation of the aneurysm wall, as measured by signal index enhancement. METHODS AND ANALYSIS: We have designed a single-centre, randomised, double-blind, blank-controlled clinical trial. 40 patients with non-ruptured VBDAs with enhancement aneurysm walls will be enrolled in Beijing Tiantan Hospital. Eligible patients will be randomly divided into two treatment groups, at a ratio of 1:1, to receive atorvastatin 20 mg orally for 6 months or no treatment. The primary assessment outcome will be the change in aneurysm wall enhancement, as measured by the signal index during the 6-month treatment period. The secondary assessment outcomes will be the aneurysm morphology (intramural haematoma, dissection valve and false lumen) and changes in the concentrations of inflammatory factors, including C reactive protein, tumour necrosis factor-α, interleukin (IL)-1ß and IL-6. ETHICS AND DISSEMINATION: The protocol has been approved by the medical ethics committee of the Beijing Tiantan Hospital at which the work will be conducted (Approval No. KY 2019-024-02). Written informed consent will be obtained from all participants. Findings from the study will be submitted for publication in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: NCT04943783.

Mortality after treatment of intracranial aneurysms with the Pipeline Embolization Device.

BACKGROUND: The Pipeline Embolization Device (PED) is reported to be a safe treatment tool for aneurysms. However, mortality occurs in a few cases, and this has not been clearly studied. We conducted a multicenter study to retrospectively evaluate the causes of, and risk factors for, mortality in patients with intracranial aneurysms treated with the PED. METHODS: We retrospectively reviewed the prospectively maintained databases of patients with intracranial aneurysms treated by PED placement at 14 academic institutions from 2014 to 2019. Patients' data, including clinical and radiographic information, were analyzed with an emphasis on mortality-related complications. RESULTS: A total of 1171 consecutive patients underwent 1319 PED procedures to treat 1322 intracranial aneurysms. The mortality rate was 1.5% (17/1171), and in 1.3% of the patients (15/1171), deaths were caused by delayed aneurysmal rupture, distal intraparenchymal hemorrhage, and neurological compression symptoms associated with PED procedures. Multivariate analysis showed that previous treatment (OR, 12.657; 95% CI, 3.189 to 50.227; P<0.0001), aneurysm size ≥10 mm (OR, 4.704; 95% CI, 1.297 to 17.068; P=0.019), aneurysm location (basilar artery) (OR, 10.734; 95% CI, 2.730 to 42.207; P=0.001), and current subarachnoid hemorrhage (OR, 4.505; 95% CI, 0.991 to 20.474; P=0.051) were associated with neurological complications resulting in mortality. CONCLUSIONS: Delayed aneurysm rupture, distal intraparenchymal hemorrhage, and neurological compression were the main causes of mortality in patients with intracranial aneurysms treated with the PED. Large basilar aneurysms are associated with an increased risk of postoperative death and require increased attention and caution.

Postoperative occlusion degree after flow-diverter placement with adjunctive coiling: analysis of complications.

BACKGROUND: Although coiling with a flow diverter may provide immediate dome protection, no studies have evaluated the effect on complications of postoperative occlusion degree immediately postoperatively. The purpose of this study was to determine whether postoperative occlusion degree immediately after flow-diverter placement with adjunctive coiling was associated with complications. METHODS: All patients' data were collected from the post-market multi-center cohort study of embolization of intracranial aneurysms with a pipeline embolization device (PED) in China (PLUS) registry. We divided patients into those treated with a PED alone (PED-only (PO) group), those treated with a PED with coils and incomplete occlusion (PED + coils + incomplete occlusion (PCIO) group), and those treated with a PED with coils and complete occlusion (PED + coils + complete occlusion (PCCO) group). RESULTS: We evaluated 1171 consecutive patients with 1322 aneurysms treated with a PED: 685 aneurysms were treated with PO, 444 with PCIO, and 193 with PCCO. The PCCO group had a higher rate of aneurysm occlusion at the last follow-up than the PCIO and PO groups (P<0.0001). Multivariate analysis of the predictors of ischemic stroke and modified Rankin Scale score (mRS) deterioration showed that PCCO was an independent predictor of ischemic stroke (HR, 2.03; 95% CI, 1.12 to 3.67; P=0.019) and mRS deterioration (HR, 2.59; 95% CI, 1.57 to 4.26; P<0.0001). CONCLUSIONS: Although postoperative complete occlusion with a PED and adjunctive coiling can increase the rate of aneurysm occlusion, this approach may also increase the risk of ischemic stroke and lead to poor postoperative functional outcomes.

Exome sequencing of 112 trios identifies recessive genetic variants in brain arteriovenous malformations.

BACKGROUND: Brain arteriovenous malformation (BAVM) is a main cause of cerebral hemorrhage and hemorrhagic stroke in adolescents. Morphologically, a BAVM is an abnormal connection between cerebrovascular arteries and veins. The genetic etiology of BAVMs has not been fully elucidated. In this study, we aim to investigate potential recessive genetic variants in BAVMs by interrogation of rare compound heterozygous variants. METHODS: We performed whole exome sequencing (WES) on 112 BAVM trios and analyzed the data for rare and deleterious compound heterozygous mutations associated with the disease. RESULTS: We identified 16 genes with compound heterozygous variants that were recurrent in more than one trio. Two genes (LRP2, MUC5B) were recurrently mutated in three trios. LRP2 has been previously associated with BAVM pathogenesis. Fourteen genes (MYLK, HSPG2, PEAK1, PIEZO1, PRUNE2, DNAH14, DNAH5, FCGBP, HERC2, HMCN1, MYH1, NHSL1, PLEC, RP1L1) were recurrently mutated in two trios, and five of these genes (MYLK, HSPG2, PEAK1, PIEZO1, PRUNE2) have been reported to play a role in angiogenesis or vascular diseases. Additionally, abnormal expression of the MYLK protein is related to spinal arteriovenous malformations. CONCLUSION: Our study indicates that rare recessive compound heterozygous variants may underlie cases of BAVM. These findings improve our understanding of BAVM pathology and indicate genes for functional validation.

Pipeline Embolization device for intracranial aneurysms in a large Chinese cohort: factors related to aneurysm occlusion.

BACKGROUND AND PURPOSE: The Pipeline Embolization Device (PED, Covidien/Medtronic) is widely used to treat intracranial aneurysms. This PED in China post-market multi-center registry study (PLUS) investigated safety and effectiveness of the PED for intracranial aneurysms in the Chinese population. METHODS: This was a panoramic, consecutive, real-world cohort registry study. Patients treated with PED with or without coils between November 2014 and October 2019 at 14 centers in China were included, and those treated by parent vessel occlusion or other stents were excluded. Study outcomes included angiographic evaluation of aneurysm occlusion, complications, in-stent stenosis, and predictors of aneurysm occlusion. A central committee reviewed all imaging and endpoint events. RESULTS: In total, 1171 patients with 1322 intracranial aneurysms were included. The total occlusion rate was 81.4% (787/967) at mean follow-up of 8.96 ± 7.50 months, with 77.1% (380/493) occlusion in the PED alone and 85.9% (407/474) in the PED plus coiling group. On multi-variate analysis, female sex, hyperlipidemia, vertebral aneurysms, PED plus coiling, and blood flow detained to venous phase were significant predictors of aneurysm occlusion. In posterior circulation cohort, there was no variable associated with aneurysm occlusion. In-stent stenosis predictors included current smoking and cerebral sclerosis/stenosis. CONCLUSION: In the largest series on PED of multi-center date of China, data suggest that treatment with the flow-diverting PED in intracranial aneurysms was efficacious. The treatment of PED combined coiling and blood flow detained to venous phase after PED implant were associated with aneurysmal occlusion. The occlusion rate of vertebral aneurysms was higher than other location aneurysms. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03831672.

The Siesta Habit is Associated with a Decreased Risk of Rupture of Intracranial Aneurysms.

BACKGROUND: Previous studies have examined an association between the siesta habit and hypertension, as well as coronary heart disease. However, the relationship between a siesta and the risk of rupture of an intracranial aneurysm (IA) has not yet been established. We aimed to investigate the effects of a siesta on the risk of rupture of IAs. METHODS: We prospectively enrolled consecutive patients diagnosed with IAs at our hospital between January 2016 and December 2016. Univariate and multivariate logistic regression analysis were performed to identify independent risk factors associated with IA rupture. RESULTS: We studied 581 consecutive patients with 514 unruptured and 120 ruptured aneurysms. Univariate analysis demonstrated that hypertension, hyperlipidemia, diabetes mellitus, cigarette smoking, location, size, as well as shape and aspect ratio were associated with the risk of rupture of IAs. Multivariate analysis identified hypertension [odds ratio (OR) 1.68, 95% confidence interval (CI) 1.03-2.73], hyperlipidemia (OR 0.25, 95% CI 0.08-0.72), current cigarette smoking ≥20 cigarettes/day (d) (OR 3.48, 95% CI 1.63-7.47), siesta (siesta time <1 h, OR 0.49, 95% CI 0.24-0.98 and siesta time ≥1 h, OR 0.32, 95% CI 0.19-0.57), location of largest aneurysm on the anterior communicating and internal carotid-posterior communicating artery (PCOM) (anterior communicating artery OR 16.27, 95% CI 7.40-35.79 and PCOM OR 11.21, 95% CI 5.15-24.43), and size of aneurysm ≥7 mm (OR 2.19, 95% CI 1.21-3.97) as independent strong risk factors associated with risk of aneurysm rupture. CONCLUSION: In the present study, we found that a habitual siesta is a new predictive factor to assess the risk of rupture of an IA. We found the siesta habit may reduce the risk of aneurysm rupture. We also found that hypertension, hyperlipidemia, cigarette smoking, location, and size of aneurysm were associated with the risk of rupture of IAs.

Bifurcation Location Is Significantly Associated with Rupture of Small Intracranial Aneurysms (<5 mm).

BACKGROUND AND OBJECTIVE: Patients with small (<5 mm) unruptured intracranial aneurysms (UIAs) are at risk of subarachnoid hemorrhage, but risk assessment of these patients remains controversial in daily clinical practice. We aimed to identify the risk factors of aneurysmal rupture in these patients. METHODS: We retrospectively analyzed consecutive patients with small UIAs who were admitted to our center between February 2009 and December 2014. The enrolled patients were divided into ruptured and unruptured groups. The risk factors for aneurysmal rupture were determined using multivariate logistic regression analysis. RESULTS: A total of 548 patients with 618 small intracranial aneurysms (267 ruptured and 351 unruptured) were included. Univariate analysis showed that rupture of small aneurysms was related to sex, age, smoking, hypertension, aspect ratio, size ratio, irregular shape, aneurysm width, height, and neck diameter, and location at bifurcation or posterior circulation. Multivariate logistic regression showed that rupture was associated with bifurcation location (odds ratio [OR], 5.409; 95% confidence interval [CI], 3.656-8.001; P < 0.001), size ratio (OR, 3.092; 95% CI, 2.002-4.774; P < 0.001), location (OR, 2.624; 95% CI, 1.428-4.824; P = 0.002), hypertension (OR, 1.698; 95% CI, 1.1140-2.527; P = 0.009), and age at diagnosis of UIA (OR, 1.826; 95% CI, 1.225-2.723; P = 0.003). CONCLUSIONS: This study showed that 70.4% of small ruptured intracranial aneurysms (<5 mm) were located at parent artery bifurcations and that bifurcation location was a significant independent factor for the risk of rupture of small UIAs (<5 mm). Prophylactic treatment should be recommended for small UIAs in this location.

Assessment of Risk of Aneurysmal Rupture in Patients with Normotensives, Controlled Hypertension, and Uncontrolled Hypertension.

BACKGROUND: The prevalence of hypertension in patients with intracranial aneurysms has been an increased concern, but it is not well understood if uncontrolled hypertension has impact on aneurysmal rupture. The aim of this study was to determine whether the risk of aneurysmal rupture is higher in uncontrolled hypertensive cohorts than in controlled hypertensive cohorts and normotensive cohorts. METHODS: We retrospectively analyzed the records and angiographies of 456 patients with aneurysms who were treated at our center between June 2013 and June 2014. Three groups of patients were included in the study following the ESH-ESC (European Society of Hypertension-European Society of Cardiology) 2013 guidelines: normotensive group (n = 229), controlled hypertension group (n = 127), and uncontrolled hypertension group (n = 100). Paired comparisons of these 3 groups were analyzed with the Nemenyi test. Multivariate logistic regression analysis was used to exclude the impact of possible confounding factors. RESULTS: The results of the univariate analysis showed that hypertension, smoking, and size of the aneurysms were significantly associated with intracranial aneurysmal rupture (P < .05). The multivariate logistic regression analysis containing clinical and aneurysmal characteristics showed that uncontrolled hypertension, smoking, and aneurysm size were statistically significant predictors of intracranial aneurysmal rupture (P < .05). The paired comparisons of 3 groups showed that the risk of rupture of intracranial aneurysms in the uncontrolled hypertension group was significantly greater than that in the normotensive group (P < .05) and in the controlled hypertension group (P < .05). CONCLUSIONS: Uncontrolled hypertension is associated with increased risk of rupture of intracranial aneurysms. Given that aneurysmal rupture is a potentially fatal-but preventable-complication, these findings are of clinical relevance.

Impact of hypertension and smoking on the rupture of intracranial aneurysms and their joint effect.

BACKGROUND: In general population, the prevalence of intracranial aneurysm reaches as high as three percent. The goal of the study was to analyze retrospectively the independent risk factors for the rupture of intracranial aneurysms and their joint effect. METHODS: The records and angiographies of continuous 519 intracranial aneurysm patients treated at our center between February 2013 and July 2014 were retrospectively analyzed. Ruptured group and unruptured group were included in the study according to their clinical and imaging information. Univariate analysis and multivariate logistic regression analysis was used to identified independent risk factors for the rupture of intracranial aneurysms. We assessed the joint effect of independent risk factors for the rupture of intracranial aneurysms with an additional logistic regression analysis. RESULTS: The results of multivariate analysis show that hypertension (odds ratio [OR], 1.51; 95% confidence interval [CI], 1.05-2.18) and smoking (odds ratio [OR], 1.57; 95% confidence interval [CI], 1.06-2.33) were independent risk factors for rupture of intracranial aneurysms. The joint risk of hypertension and smoking was higher (OR, 2.28; 95% CI, 1.29-4.02) than the risks of hypertension (OR, 1.74; 95% CI, 1.11-2.72) and smoking (OR, 1.86; 95% CI, 1.05-3.29) independently. CONCLUSIONS: Hypertension and smoking increase of the rupture risk of intracranial aneurysms. And the joint risk of hypertension and smoking was higher than the risks of hypertension and smoking independently.

[Pathophysiological roles of matrix metalloproteinases and nitric oxide synthase in cerebral aneurysm].

OBJECTIVE: To explore the expressions of matrix metalloproteinases-2 (MMP-2), matrix metalloproteinases-9 (MMP-9) and inducible nitric oxide synthase (iNOS) in cerebral aneurysms, compare them with normal brain vessels tissue so as to gain a better understanding of the pathogenesis of cerebral aneurysms. METHODS: Twelve samples of cerebral aneurysms were obtained during operations and 10 cortical arteries as controls during surgery for temporal lobe epilepsy from 2009 to 2012 at Inner Mongolia People's Hospital and Beijing Tiantan Hospital. The activities of MMP-2, MMP-9 and iNOS in specimens were detected with spectrophotometry and substrate gel zymography. RESULTS: The MMP-2 and MMP-9 levels in cerebral aneurysm group were (199 598 ± 125 288) gray scale area × mg⁻¹ × L⁻¹ and (719 253 ± 376 519) gray scale area × mg⁻¹ × L⁻¹. Both in cerebral aneurysm group were significantly higher than that in control group (P < 0.05) . The TNOS and iNOS levels in cerebral aneurysm group were (23.6 ± 6.6) and (11.4 ± 2.6) U/mgprot. The difference of TNOS level was not significant between aneurysm and control groups (P > 0.05) while the levels of iNOS and iNOS/TNOS in cerebral aneurysm group were significantly higher than that in control group (P < 0.05). CONCLUSION: MMP-2, MMP-9 and iNOS are closely correlated with cerebral aneurysm.