Jian-Wei Pan

Dissociation of vasospasm-related morbidity and outcomes in patients with aneurysmal subarachnoid hemorrhage treated with clazosentan: a meta-analysis of randomized controlled trials

OBJECT Clazosentan therapy after aneurysmal subarachnoid hemorrhage (SAH) has been found to be effective in reducing the incidence of vasospasm in randomized controlled trials. However, while vasospasm-related morbidity, including delayed ischemic neurological deficits (DINDs) and delayed cerebral infarctions, was consistently decreased, statistical significance was not demonstrated and outcomes were not affected by clazosentan treatment. The objective of this meta-analysis was to determine whether clazosentan treatment after aneurysmal SAH significantly reduced the incidence of DINDs and delayed cerebral infarctions and improved outcomes. METHODS All randomized controlled trials investigating the effect of clazosentan were retrieved via searches with sensitive and specific terms. Six variables were abstracted after the assessment of the methodological quality of the trials. Analyses were performed following the method guidelines of the Cochrane Back Review Group. RESULTS Four randomized, placebo-controlled trials met eligibility criteria, enrolling a total of 2181 patients. The meta-analysis demonstrated a significant decrease in the incidence of DINDs (relative risk [RR] 0.76 [95% CI 0.62-0.92]) and delayed cerebral infarction (RR 0.79 [95% CI 0.63-1.00]) in patients treated with clazosentan after aneurysmal SAH. However, this treatment regimen was not shown to outcomes including functional outcomes measured by Glasgow Outcome Scale-Extended (RR 1.12 [95% CI 0.96-1.30]) or mortality (RR 1.02 [95%CI 0.70-1.49]). Adverse events, including pulmonary complications, anemia, and hypotension, were all significantly increased in patients who received clazosentan therapy. CONCLUSIONS The results of the present meta-analysis show that treatment with clazosentan after aneurysmal SAH significantly reduced the incidence of the vasospasm-related DINDs and delayed cerebral infarctions, but did not improve poor neurological outcomes in patients with aneurysmal SAH. Further study is required to elucidate the dissociation between vasospasm-related morbidity and outcomes.

Ultra-Early Surgery for Poor-Grade Intracranial Aneurysmal Subarachnoid Hemorrhage: A Preliminary Study

Purpose To describe the therapeutic effect and possibility of the ultra-early surgery for poor-grade aneurysmal subarachnoid hemorrhage (Hunt-Hess grades IV - V). Materials and Methods Nine cases with intracranial aneurysms, demonstrated by computed tomographic angiography (CTA), were treated by ultra-early surgery under general anesthesia within 24 hours from subarachnoid hemorrhage (SAH), 5 cases were treated within 6 hours and 4 cases in 6 - 24 hours. Preoperative Hunt-Hess grade: 6 cases were IV and 3 cases were V. The clinical outcome was evaluated by Glasgow Outcome Scores (GOS). Results In operation, difficult dissection occurred in 5 cases (55.6%), and rupture of aneurysm occurred and temporary obstructions were performed in 4 cases (44.4%). After clipping of aneurysm, 2 cases underwent V-P shunt because of hydrocephalus, pulmonary infection occurred in 3 cases, hypothalamus reaction accompanied with upper gastrointestinal hemorrhage in 2 cases. The clinical outcome were favorable (GOS 4 - 5) in 4 cases (44.4%), dissatisfied (GOS 2 - 3) in 3 cases (33.3%), and dead (GOS 1) in 2 cases (22.2%) when patients departed from our hospital. Conclusion The ultra-early surgery can avoid early rebleeding of intracranial aneurysm, therefore, should be considered in the treatment of Hunt-Hess grade IV-V intracranial aneurysms. The appliance of CTA can make it possible to use of ultra-early surgery and improve the therapeutic effect.

Buyang Huanwu decoction increases angiopoietin-1 expression and promotes angiogenesis and functional outcome after focal cerebral ischemia *

Buyang Huanwu decoction (BYHWD), a traditional Chinese herbal prescription, has been widely used clinically to treat stroke in China for hundreds of years; however, the mechanisms of this drug for stroke treatment are still unclear. This study aims to observe the cerebral angiogenesis effects of BYHWD on chronic brain injury after focal cerebral ischemia in rats and to explore its possible mechanisms. The ischemia was induced by occlusion of the right middle cerebral artery for 90 min. BYHWD (12.5 and 25.0 g/(kg·d), equivalent to the dry weight of the raw materials) was orally administered twice a day beginning 2 h after surgery. BYHWD significantly attenuated the neurological dysfunction, infarct volume, and brain atrophy after ischemia. There was a significant increase in the microvessel density, as assessed by immunofluorescence CD31, and a significant increase in angiopoietin-1 (Ang-1) in the penumbra areas of the rats was shown by immunohistochemical staining and Western blotting. The results indicate that the neurorestorative effects of BYHWD are associated with angiogenesis and the enhancement of the expressions of Ang-1 on chronic brain injury after focal cerebral ischemia.

Plasma gelsolin levels and outcomes after aneurysmal subarachnoid hemorrhage

IntroductionLower gelsolin levels have been associated with the severity and poor outcome of critical illness. Nevertheless, their link with clinical outcomes of aneurysmal subarachnoid hemorrhage is unknown. Therefore, we aimed to investigate the relationship between plasma gelsolin levels and clinical outcomes in patients with aneurysmal subarachnoid hemorrhage.MethodsA total of 262 consecutive patients and 150 healthy subjects were included. Plasma gelsolin levels were measured by enzyme-linked immunosorbent assay. Mortality and poor long-term outcome (Glasgow Outcome Scale score of 1-3) at 6 months were recorded.ResultsPlasma gelsolin levels on admission were substantially lower in patients than in healthy controls (66.9 (26.4) mg/L vs. 126.4 (35.4) mg/L, P < 0.001), and negatively associated with World Federation of Neurological Surgeons score (r = -0.554, P < 0.001) and Fisher score (r = -0.538, P < 0.001), and identified as an independent predictor of poor functional outcome (odds ratio, 0.957; 95% confidence interval (CI), 0.933-0.983; P = 0.001) and death (odds ratio, 0.953; 95% CI, 0.917-0.990; P = 0.003) after 6 months. The areas under the ROC curve of gelsolin for functional outcome and mortality were similar to those of World Federation of Neurological Surgeons score and Fisher score (all P > 0.05). Gelsolin improved the predictive values of World Federation of Neurological Surgeons score and Fisher score for functional outcome (both P < 0.05), but not for mortality (both P > 0.05).ConclusionsGelsolin levels are a useful, complementary tool to predict functional outcome and mortality 6 months after aneurysmal subarachnoid hemorrhage.

Long noncoding RNA MEG3 mediated angiogenesis after cerebral infarction through regulating p53/NOX4 axis

OBJECTIVE This study aimed to explore the mechanism of lncRNA MEG3 on angiogenesis after cerebral infarction (CI). METHODS The rat brain microvascular endothelial cells (RBMVECs) isolated from rat was used to establish CI model, which were treated with oxygen-glucose deprivation/reoxygenation (OGD/R). The genes mRNA and protein expression levels in RBMVECs were determined by the quantitative real-time polymerase chain reaction (RT-qPCR) and western blot, respectively. The flow cytometry was used to measured cell apoptosis and intracellular reactive oxygen species (ROS) generation. The RBMVECs activities was detected by MTT method. The RNA-immunoprecipitation (RIP) assay was used to detect the interaction between MEG3 and p53, and the relationship between p53 and NOX4 was proved by chromatin co-immunoprecipitation (chip) assay. RESULTS The results showed that OGD or OGD/R increased MEG3 and NOX4 expression, and there was positive correlation between MEG3 and NOX4 expression in RBMVECs. Next, knockdown of MEG3 indicated that inhibition of MEG3 was conducive to protect RBMVECs against OGD/R-induced apoptosis, with decreased NOX4 and p53 expression, further enhanced pro-angiogenic factors (HIF-1α and VEGF) expression, and reduced intracellular ROS generation. And then the RIP and CHIP assay demonstrated that MEG3 could interacted with p53 and regulated its expression, and p53 exerted significant binding in the promoters for NOX4, suggesting that MEG3 regulated NOX4 expression via p53. At last, knockdown of NOX4 indicated that inhibition of NOX4 protected RBMVECs against OGD/R-induced apoptosis, with increased cell viability and pro-angiogenic factors expression, and reduced ROS generation. CONCLUSION LncRNA MEG3 was an important regulator in OGD/R induced-RBMVECs apoptosis and the mechanism of MEG3 on angiogenesis after CI was reduced ROS by p53/NOX4 axis.

Clinical and Radiological Outcomes After Treatment of Unruptured Paraophthalmic Internal Carotid Artery Aneurysms: a Comparative and Pooled Analysis of Single-Center Experiences

OBJECTIVE Unruptured paraophthalmic aneurysms present unique challenges, and the ideal management remains unknown. METHODS We performed a pooled analysis of single-center experiences to compare the risks and effectiveness involving patients with unruptured paraophthalmic aneurysms treated with clipping, coiling alone, stent-assisted coiling, and flow-diversion. The MEDLINE database was searched and thirty-three series (including our institutional experience) were included. RESULTS Clipping caused more intracranial hemorrhage (ICH) and neurologic complications (NCs) than coiling alone (ICH: odds ratio [OR] = 3.058, P = 0.013; NC: OR = 5.809, P < 0.001), stent-assisted coiling (ICH: P = 0.018; NC: OR = 7.367, P < 0.001), and flow-diversion (ICH: P = 0.006; NC: OR = 16.954, P < 0.001). Clipping also caused more unfavorable visual outcomes than both coiling alone (OR = 3.037, P = 0.001) and stent-assisted coiling (OR = 6.055, P = 0.005). Clipping resulted in a lower reoperation rate than coiling alone in large/giant aneurysm group, which approached statistical significance (OR = 0.133, P = 0.057). Clipping, stent-assisted coiling, and flow-diversion all showed higher occlusion rates compared with coiling alone (OR [clipping vs. coiling alone] = 2.852, P ≤ 0.001; OR [coiling alone vs. stent-assisted coiling] = 0.302, P = 0.003; OR [coiling alone vs. flow-diversion] = 0.400, P = 0.013). Flow-diversion showed comparative complication rate, clinical outcomes, and angiographic result compared with stent-assisted coiling. No significant differences were found among all 4 treatment modalities on mortality and poor outcome. CONCLUSIONS Endovascular therapies have benefits over surgical clipping in terms of fewer intracranial hemorrhage complications, fewer NCs, and lower unfavorable visual outcome rate. Flow diversion showed comparative safety and effectiveness to stent-assisted coiling, and they both achieved better radiologic results than coiling alone. Further validation by randomized cohort studies is still needed to provide robust evidence.

Patients with Supratentorial Aneurysmal Subarachnoid Hemorrhage During the Intermediate Period: Waiting or Actively Treating

Perhaps the most difficult practical decision for neurosurgeons these days is whether to secure aneurysms during the intermediate period (4–10 days) after aneurysmal subarachnoid hemorrhage (SAH). We retrospectively reviewed a series of 115 patients with a Hunt-Hess grade I-III upon admission who were admitted 4–10 days after initial supratentorial aneurysmal SAH. Patients who underwent active treatment in the intermediate period were assigned to the intermediate group (n = 49) while those who accepted delayed obliteration of a ruptured aneurysm (11–30 days) were assigned to the late group (n = 66). The demographic characteristics, size and site of aneurysms, and clinical conditions were well balanced in the two groups. There was no difference in outcome between the two groups according to the Glasgow Outcome Scale (GOS) at discharge or a six-month follow-up. Rebleeding before aneurysms obliteration was the leading factor resulting in poor outcome. In conclusion, for patients with supratentorial aneurysmal SAH who were in good clinical condition upon admission, active treatment during the intermediate period offered a good chance of a favorable outcome. An even larger number of patients from randomized clinical trials might be necessary to draw more reliable conclusions.

Morphology Parameters for Mirror Posterior Communicating Artery Aneurysm Rupture Risk Assessment

Recent studies have shown that posterior communicating artery (PComA) aneurysms are more likely to rupture. However, surgical intervention for PComA aneurysms may be associated with increased treatment-related morbidity rate. Therefore, it is meaningful to investigate the factors related to PComA aneurysm rupture. The purpose of this study was to identify morphological parameters that significantly correlate with PComA aneurysm rupture. We divided 14 pairs of mirror posterior communicating artery aneurysms (PComA-MANs) into ruptured and unruptured groups. Computed tomography angiography (CTA) imaging was evaluated with three-dimensional (3D) Slicer to generate models of the aneurysms and surrounding vasculature. Nine morphological parameters [size, height, width, neck width, aspect ratio (AR), bottleneck factor (BNF), height/width ratio (H/W), size ratio (SR), and bleb formation] were examined in the two groups for significance with respect to rupture. By contrast, statistically significant differences were found in ruptured and unruptured group for size, AR, BNF, SR, and bleb formation (P < 0.05). Parameters that had no significant differences between the two groups were height (P = 0.103), width (P = 0.078), neck width (P = 0.808), and H/W (P = 0.417). We conclude that MANs may be a useful model for the morphological analysis of intracranial aneurysm rupture. Larger size, higher AR, BNF, SR, and bleb formation may be related to rupture of PComA aneurysms. Larger sample studies minimizing the interference from patient-related factors and aneurysm type were expected for acquiring more accurate assessment of the relationship between these parameters and PComA aneurysm rupture.

Buyang Huanwu Decoction attenuates H2O2-induced apoptosis by inhibiting reactive oxygen species-mediated mitochondrial dysfunction pathway in human umbilical vein endothelial cells.

BackgroundApoptosis of endothelial cells caused by reactive oxygen species plays an important role in ischemia/reperfusion injury after cerebral infarction. Buyang Huanwu Decoction (BYHWD) has been used to treat stroke and stroke-induced disability, however, the mechanism for this treatment remains unknown. In this study, we investigated whether BYHWD can protect human umbilical vein endothelial cells (HUVECs) from H2O2-induced apoptosis and explored the underlying mechanisms.MethodsTo investigate the effect of BYHWD on the apoptosis of HUVECs, we established a H2O2-induced oxidative stress model and detected apoptosis by Hoechst 33342 and propidium iodide staining. JC-1 and DCFH-DA assays,western blotting and electron microscopy were used to examine the mechanism of BYHWD on apoptosis.ResultsPretreatment with BYHWD significantly inhibited H2O2-induced apoptosis and protein caspase-3 expression in a concentration-dependent manner. In addition, BYHWD reduced reactive oxygen species production and promoted endogenous antioxidant defenses. Furthermore, loss of mitochondrial membrane potential and structural disruption of mitochondria were both rescued by BYHWD.ConclusionsBYHWD protects HUVECs from H2O2-induced apoptosis by inhibiting oxidative stress damage and mitochondrial dysfunction. These findings indicate that BYHWD is a promising treatment for cerebral ischemia diseases.

Stent, balloon-assisted coiling and double microcatheter for treating wide-neck aneurysms in anterior cerebral circulation

Abstract Objective: To investigate the clinical application of adjuvant coiling techniques in treating anterior-circulation wide-necked aneurysms. Methods: Over 4·5 years, 93 anterior-circulation wide-neck aneurysms in 81 patients were treated with different endovascular techniques: balloon-assisted, stent-assisted, and double-microcatheter coiling. Demographic, clinical, and angiographic data were reviewed retrospectively. Results: Of the 93 aneurysms, 45 were treated using stent, 28 using balloon, and 20 using double microcatheter. The proportion of ruptured aneurysms was significantly lower in the stent group (53·3%) than in the balloon (71·4%) or the double-microcatheter group (75%). Stent embolization was used for 61·1% of aneurysms located in the internal carotid artery, whereas aneurysms in the anterior communicating and middle cerebral arteries were mainly treated with balloon remodeling (42·9%) and double microcatheter (52·4%). The majority of aneurysms with neck ≧ 7 mm (87·5%) and all aneurysms with a dome/neck ratio < 1·0 (100%) were treated by stent-assisted coiling. For aneurysms with neck < 4 mm, the mean dome/neck ratio was 0·93 in the stent group, 1·08 in the balloon group, and 1·16 in the double-microcatheter group. Total occlusion was achieved in 21 cases (46·7%), with the rates for stent being significantly lower than for balloon (78·6%) or double microcatheter (75·0%). Clinical outcome was favorable in 73 cases (Glasgow Outcome Scale (GOS) 4–5) and fair in 4 (GOS 3), while 2 were severely disabled (GOS 2) and 2 others died (GOS 1). Conclusion: Double microcatheter was better for distal aneurysms with dome/neck ratio of 1·1–1·2, while stent was better for proximal aneurysms with an extremely wide neck (≧ 7 mm) and for loudspeaker-shaped aneurysms (dome/neck ratio < 1·0) with poor vessel condition. For emergency cases, both balloon remodeling and double microcatheter are better choices than stent.