Dural arteriovenous fistulas are not observed to convert to a higher grade after partial embolization.

OBJECTIVE: Borden-Shucart type I dural arteriovenous fistulas (dAVFs) lack cortical venous drainage and occasionally necessitate intervention depending on patient symptoms. Conversion is the rare transformation of a low-grade dAVF to a higher grade. Factors associated with increased risk of dAVF conversion to a higher grade are poorly understood. The authors hypothesized that partial treatment of type I dAVFs is an independent risk factor for conversion. METHODS: The multicenter Consortium for Dural Arteriovenous Fistula Outcomes Research database was used to perform a retrospective analysis of all patients with type I dAVFs. RESULTS: Three hundred fifty-eight (33.2%) of 1077 patients had type I dAVFs. Of those 358 patients, 206 received endovascular treatment and 131 were not treated. Two (2.2%) of 91 patients receiving partial endovascular treatment for a low-grade dAVF experienced conversion to a higher grade, 2 (1.5%) of 131 who were not treated experienced conversion, and none (0%) of 115 patients who received complete endovascular treatment experienced dAVF conversion. The majority of converted dAVFs localized to the transverse-sigmoid sinus and all received embolization as part of their treatment. CONCLUSIONS: Partial treatment of type I dAVFs does not appear to be significantly associated with conversion to a higher grade.

Risk of Early Versus Later Rebleeding From Dural Arteriovenous Fistulas With Cortical Venous Drainage.

BACKGROUND: Cranial dural arteriovenous fistulas with cortical venous drainage are rare lesions that can present with hemorrhage. A high rate of rebleeding in the early period following hemorrhage has been reported, but published long-term rates are much lower. No study has examined how risk of rebleeding changes over time. Our objective was to quantify the relative incidence of rebleeding in the early and later periods following hemorrhage. METHODS: Patients with dural arteriovenous fistula and cortical venous drainage presenting with hemorrhage were identified from the multinational CONDOR (Consortium for Dural Fistula Outcomes Research) database. Natural history follow-up was defined as time from hemorrhage to first treatment, rebleed, or last follow-up. Rebleeding in the first 2 weeks and first year were compared using incidence rate ratio and difference. RESULTS: Of 1077 patients, 250 met the inclusion criteria and had 95 cumulative person-years natural history follow-up. The overall annualized rebleed rate was 7.3% (95% CI, 3.2-14.5). The incidence rate of rebleeding in the first 2 weeks was 0.0011 per person-day; an early rebleed risk of 1.6% in the first 14 days (95% CI, 0.3-5.1). For the remainder of the first year, the incidence rate was 0.00015 per person-day; a rebleed rate of 5.3% (CI, 1.7-12.4) over 1 year. The incidence rate ratio was 7.3 (95% CI, 1.4-37.7; P, 0.026). CONCLUSIONS: The risk of rebleeding of a dural arteriovenous fistula with cortical venous drainage presenting with hemorrhage is increased in the first 2 weeks justifying early treatment. However, the magnitude of this increase may be considerably lower than previously thought. Treatment within 5 days was associated with a low rate of rebleeding and appears an appropriate timeframe.

An imbalance between RAGE/MR/HMGB1 and ATP1α3 is associated with inflammatory changes in rat brain harboring cerebral aneurysms prone to rupture.

BACKGROUND AND PURPOSE: An aneurysmal subarachnoid hemorrhage is a devastating event. To establish an effective therapeutic strategy, its pathogenesis must be clarified, particularly the pathophysiology of brain harboring intracranial aneurysms (IAs). To elucidate the pathology in brain harboring IAs, we examined the significance of the receptor for advanced glycation end-products (RAGE)/mineralocorticoid receptor (MR) pathway and Na+/K+-ATPase (ATP1α3). METHODS: Ten-week-old female rats were subjected to oophorectomy as well as hypertension and hemodynamic changes to induce IAs, and were fed a high-salt diet. Brain damage in these rats was assessed by inflammatory changes in comparison to sham-operated rats fed a standard diet. RESULTS: Six weeks after IA induction (n = 30), irregular morphological changes, i.e., an enlarged vessel diameter and vascular wall, were observed in all of the left posterior cerebral arteries (Lt PCAs) prone to rupture. Approximately 20% of rats had ruptured IAs within 6 weeks. In brain harboring unruptured IAs at the PCA, the mRNA levels of RAGE and MR were higher, and that of ATP1α3 was lower than those in the sham-operated rats (p < 0.05, each). Immunohistochemically, elevated expression of RAGE and MR, and decreased expression of ATP1α3 were observed in the brain parenchyma adjacent to the Lt PCA, resulting in increased Iba-1 and S100B expression that reflected the inflammatory changes. There was no difference between the unruptured and ruptured aneurysm rat groups. Treatment with the MR antagonist esaxerenone abrogated these changes, and led to cerebral and vascular normalization and prolonged subarachnoid hemorrhage-free survival (p < 0.05). CONCLUSIONS: Regulation of the imbalance between the RAGE/MR pathway and ATP1α3 may help attenuate the damage in brain harboring IAs, and further studies are warranted to clarify the significance of the down-regulation of the MR/RAGE pathway and the up-regulation of ATP1α3 for attenuating the pathological changes in brain harboring IAs.

Mast Cell Promotes the Development of Intracranial Aneurysm Rupture.

BACKGROUND AND PURPOSE: Inflammation has emerged as a key component of the pathophysiology of intracranial aneurysms. Mast cells have been detected in human intracranial aneurysm tissues, and their presence was associated with intramural microhemorrhage and wall degeneration. We hypothesized that mast cells play a critical role in the development of aneurysmal rupture, and that mast cells can be used as a therapeutic target for the prevention of aneurysm rupture. METHODS: Intracranial aneurysms were induced in adult mice using a combination of induced systemic hypertension and a single injection of elastase into the cerebrospinal fluid. Aneurysm formation and rupture were assessed over 3 weeks. Roles of mast cells were assessed using a mast cell stabilizer (cromolyn), a mast cell activator (C48/80), and mice that are genetically lacking mature mast cells (KitW-sh/W-sh mice). RESULTS: Pharmacological stabilization of mast cells with cromolyn markedly decreased the rupture rate of aneurysms (80% versus 19%, n=10 versus n =16) without affecting the aneurysm formation. The activation of mast cells with C48/80 significantly increased the rupture rate of aneurysms (25% versus 100%, n=4 versus n=5) without affecting the overall rate of aneurysm formation. Furthermore, the genetic deficiency of mast cells significantly prevented aneurysm rupture (80% versus 25%, n=10 versus n=8, wild-type versus KitW-sh/W-sh mice). CONCLUSIONS: These results suggest that mast cells play a key role in promoting aneurysm rupture but not formation. Stabilizers of mast cells may have a potential therapeutic value in preventing intracranial aneurysm rupture in patients.

Treatment of Unruptured Cerebral Aneurysms with the Mineralocorticoid Receptor Blocker Eplerenone-Pilot Study.

BACKGROUND: Currently there are no pharmacological therapies for patients with unruptured cerebral aneurysms. Elsewhere we showed that the mineralocorticoid receptor antagonist eplerenone prevented the formation of cerebral aneurysms in our ovariectomized hypertensive aneurysm rat model. The current pilot study evaluated whether it can be used to prevent the growth and rupture of cerebral aneurysms in hypertensive patients. METHODS: Between August 2011 and May 2014, we enrolled 82 patients with 90 aneurysms in an open-label uncontrolled clinical trial. All provided prior informed consent for inclusion in this study, and all were treated with eplerenone (25-100 mg/d). The primary end points of our study were the rupture and enlargement of the cerebral aneurysms. RESULTS: Of the 82 patients, 80 (88 unruptured aneurysms) were followed for a mean of 21.3 months (153.4 aneurysm-years); 12 patients (15.0%) permanently discontinued taking the drug. One month after the start of eplerenone administration and throughout the follow-up period, eplerenone kept the blood pressure within the normal range. Most notably, no aneurysms smaller than 9 mm ruptured or enlarged. However, of 2 large thrombosed aneurysms, 1 enlarged and the other ruptured. The overall annual rupture rate was .65%; it was 13.16% for aneurysms larger than 10 mm; the overall annual rate for reaching the primary end points was 1.30%. CONCLUSION: Our observations suggest that eplerenone may help to prevent the growth and rupture of unruptured cerebral aneurysms smaller than 9 mm. To assess its potential long-term clinical benefits, large clinical trials are needed.

Optimal Timing of Diffusion-Weighted Imaging to Avoid False-Negative Findings in Patients With Transient Ischemic Attack.

BACKGROUND AND PURPOSE: We aimed to investigate the optimal timing of diffusion-weighted imaging (DWI) in patients with transient ischemic attack (TIA). METHODS: Seventy-three consecutive patients with TIA underwent DWI on admission (initial DWI) and at 24 hours after admission (second DWI). Patients were divided into 2 groups based on initial DWI findings in relation to the second examination: false negative (group 1) and other (group 2). The probability of initial false-negative findings was determined for each hour from TIA onset to initial DWI. Multivariate analysis was used to evaluate the independent risk factors associated with false-negative findings on initial DWI. RESULTS: Of the 73 patients examined (56 men; mean age, 68 years), 9 (12%) were categorized into group 1. The latency from TIA onset to initial DWI was 1.7±0.6 hours for group 1 (range, 1-2.8 hours) and 3.3±2.6 hours for group 2 (range, 35 minutes to 12 hours). The probability of false-negative findings on initial DWI decreased in a time-dependent manner (25%, 21%, and 7% for 1, 2, and 3 hours, respectively), and no false-negative findings were observed on initial DWI performed at >3 hours from symptom onset. Short latency (≤2 hours) from TIA onset to initial DWI was an independent risk factor related to false-negative findings (odds ratio, 13.11; 95% confidence interval, 1.07-161.38; P=0.045). CONCLUSIONS: If the duration between TIA symptom onset and initial DWI is <2 hours, a repeat examination should be performed to minimize the risk of false-positive findings.

Bazedoxifene, a selective estrogen receptor modulator, reduces cerebral aneurysm rupture in Ovariectomized rats.

BACKGROUND: Estrogen deficiency is thought to be responsible for the higher frequency of aneurysmal subarachnoid hemorrhage in post- than premenopausal women. Estrogen replacement therapy appears to reduce this risk but is associated with significant side effects. We tested our hypothesis that bazedoxifene, a clinically used selective estrogen receptor (ER) modulator with fewer estrogenic side effects, reduces cerebral aneurysm rupture in a new model of ovariectomized rats. METHODS: Ten-week-old female Sprague-Dawley rats were subjected to ovariectomy, hemodynamic changes, and hypertension to induce aneurysms (ovariectomized aneurysm rats) and treated with vehicle or with 0.3 or 1.0 mg/kg/day bazedoxifene. They were compared with sham-ovariectomized rats subjected to hypertension and hemodynamic changes (HT rats). The vasoprotective effects of bazedoxifene and the mechanisms underlying its efficacy were analyzed. RESULTS: During 12 weeks of observation, the incidence of aneurysm rupture was 52% in ovariectomized rats. With no effect on the blood pressure, treatment with 0.3 or 1.0 mg/kg/day bazedoxifene lowered this rate to 11 and 17%, almost the same as in HT rats (17%). In ovariectomized rats, the mRNA level of ERα, ERß, and the tissue inhibitor of metalloproteinase-2 was downregulated in the cerebral artery prone to rupture at 5 weeks after aneurysm induction; the mRNA level of interleukin-1ß and the matrix metalloproteinase-9 was upregulated. In HT rats, bazedoxifene restored the mRNA level of ERα and ERß and decreased the level of interleukin-1ß and matrix metalloproteinase-9. These findings suggest that bazedoxifene was protective against aneurysmal rupture by alleviating the vascular inflammation and degradation exacerbated by the decrease in ERα and ERß. CONCLUSIONS: Our observation that bazedoxifene decreased the incidence of aneurysmal rupture in ovariectomized rats warrants further studies to validate this response in humans.

Intra-arterial high signals on arterial spin labeling perfusion images predict the occluded internal carotid artery segment.

PURPOSE: Arterial spin labeling (ASL) involves perfusion imaging using the inverted magnetization of arterial water. If the arterial arrival times are longer than the post-labeling delay, labeled spins are visible on ASL images as bright, high intra-arterial signals (IASs); such signals were found within occluded vessels of patients with acute ischemic stroke. The identification of the occluded segment in the internal carotid artery (ICA) is crucial for endovascular treatment. We tested our hypothesis that high IASs on ASL images can predict the occluded segment. METHODS: Our study included 13 patients with acute ICA occlusion who had undergone angiographic and ASL studies within 48 h of onset. We retrospectively identified the high IAS on ASL images and angiograms and recorded the occluded segment and the number of high IAS-positive slices on ASL images. The ICA segments were classified as cervical (C1), petrous (C2), cavernous (C3), and supraclinoid (C4). RESULTS: Of seven patients with intracranial ICA occlusion, five demonstrated high IASs at C1-C2, suggesting that high IASs could identify stagnant flow proximal to the occluded segment. Among six patients with extracranial ICA occlusion, five presented with high IASs at C3-C4, suggesting that signals could identify the collateral flow via the ophthalmic artery. None had high IASs at C1-C2. The mean number of high IAS-positive slices was significantly higher in patients with intra- than extracranial ICA occlusion. CONCLUSION: High IASs on ASL images can identify slow stagnant and collateral flow through the ophthalmic artery in patients with acute ICA occlusion and help to predict the occlusion site.

Hyperhomocysteinemia induced by excessive methionine intake promotes rupture of cerebral aneurysms in ovariectomized rats.

BACKGROUND: Hyperhomocysteinemia (HHcy) is associated with inflammation and a rise in the expression of matrix metalloproteinase-9 (MMP-9) in the vascular wall. However, the role of HHcy in the growth and rupture of cerebral aneurysms remains unclear. METHODS: Thirteen-week-old female Sprague-Dawley rats were subject to bilateral ovariectomy and ligation of the right common carotid artery and fed an 8 % high-salt diet to induce cerebral aneurysms. Two weeks later, they underwent ligation of the bilateral posterior renal arteries. They were divided into two groups and methionine (MET) was or was not added to their drinking water. In another set of experiments, the role of folic acid (FA) against cerebral aneurysms was assessed. RESULTS: During a 12-week observation period, subarachnoid hemorrhage due to aneurysm rupture was observed at the anterior communicating artery (AcomA) or the posterior half of the circle of Willis. HHcy induced by excessive MET intake significantly increased the incidence of ruptured aneurysms at 6-8 weeks. At the AcomA of rats treated with MET, we observed the promotion of aneurysmal growth and infiltration by M1 macrophages. Furthermore, the mRNA level of MMP-9, the ratio of MMP-9 to the tissue inhibitor of metalloproteinase-2, and the level of interleukin-6 were higher in these rats. Treatment with FA abolished the effect of MET, suggesting that the inflammatory response and vascular degradation at the AcomA is attributable to HHcy due to excessive MET intake. CONCLUSIONS: We first demonstrate that in hypertensive ovariectomized rats, HHcy induced by excessive MET intake may be associated with the propensity of the aneurysm wall to rupture.

Two-layered susceptibility vessel sign on 3-tesla T2*-weighted imaging is a predictive biomarker of stroke subtype.

BACKGROUND AND PURPOSE: A susceptibility vessel sign (SVS) on 1.5-tesla (T)-T2*-weighted images may predict cardioembolism. It has also been detected in patients with large artery atherosclerosis. In patients with major vessel occlusion, the SVS was comprised 2 layers on 3T-T2*-weighted images. We assessed the efficacy of 2-layered SVS on 3T-T2*-weighted imaging scans for predicting cardioembolism. METHODS: Our study included 132 patients who had ischemic stroke within the preceding 24 hours and presented with internal carotid artery or middle cerebral artery occlusion because of cardioembolism or large artery atherosclerosis. We compared 2-layered SVS and SVS on 3T-T2*-weighted imaging scans for their sensitivity, specificity, and diagnostic odds ratio for predicting cardioembolism. RESULTS: We enrolled 132 patients (72 men; mean age, 74.5 years); of these, 63 (47.7%) were presented with cardioembolism. Although the sensitivity of SVS and 2-layered SVS for cardioembolism and large artery atherosclerosis was not statistically different (74.6% and 58.0%, respectively), the sensitivity of 2-layered SVS was significantly higher in patients with cardioembolism (42.9%) than those with large artery atherosclerosis (2.9%; P<0.001). The specificity and diagnostic odds ratio for 2-layered SVS for cardioembolism were 97.1% and 25.1; for SVS they were 42.0% and 2.1, respectively. CONCLUSION: The specificity of 2-layered SVS for cardioembolism was high. It may be useful for predicting cardioembolism and for the management of patients with acute ischemic stroke.

Protective Role of Peroxisome Proliferator-Activated Receptor-γ in the Development of Intracranial Aneurysm Rupture.

BACKGROUND AND PURPOSE: Inflammation is emerging as a key component of the pathophysiology of intracranial aneurysms. Peroxisome proliferator-activated receptor-γ (PPARγ) is a nuclear hormone receptor of which activation modulates various aspects of inflammation. METHODS: Using a mouse model of intracranial aneurysm, we examined the potential roles of PPARγ in the development of rupture of intracranial aneurysm. RESULTS: A PPARγ agonist, pioglitazone, significantly reduced the incidence of ruptured aneurysms and the rupture rate without affecting the total incidence aneurysm (unruptured aneurysms and ruptured aneurysms). PPARγ antagonist (GW9662) abolished the protective effect of pioglitazone. The protective effect of pioglitazone was absent in mice lacking macrophage PPARγ. Pioglitazone treatment reduced the mRNA levels of inflammatory cytokines (monocyte chemoattractant factor-1, interleukin-1, and interleukin-6) that are primarily produced by macrophages in the cerebral arteries. Pioglitazone treatment reduced the infiltration of M1 macrophage into the cerebral arteries and the macrophage M1/M2 ratio. Depletion of macrophages significantly reduced the rupture rate. CONCLUSIONS: Our data showed that the activation of macrophage PPARγ protects against the development of aneurysmal rupture. PPARγ in inflammatory cells may be a potential therapeutic target for the prevention of aneurysmal rupture.

Improvement of Plasma Biomarkers after Switching Stroke Patients from Other Angiotensin II Type I Receptor Blockers to Olmesartan.

BACKGROUND: Managing hypertension is crucial for preventing stroke recurrence. Some stroke patients experience resistant hypertension. In our experimental stroke model, olmesartan increased the expression of angiotensin (Ang) II converting enzyme-2. We hypothesized that switching to olmesartan affects biomarkers and the blood pressure (BP) in stroke patients whose BP is insufficiently controlled by standard doses of Ang II type I receptor blockers (ARBs) other than olmesartan. METHODS: We recruited 25 patients to study our hypothesis. All had a history of stroke or silent cerebral infarction. We switched them to olmesartan (10-40 mg per day) for 12 weeks and determined their plasma level of Ang-(1-7), peroxiredoxin, oxidized low-density lipoprotein (oxLDL)/ß-2-glycoprotein I (ß2GPI) complex, adiponectin, high mobility group box 1 (HMGB1), and tumor necrosis factor-α (TNFα) and recorded their BP before and after olmesartan treatment. RESULTS: After switching the patients to olmesartan, their plasma level of Ang-(1-7) as a vasoprotective indicator and adiponectin regulating metabolic syndrome was increased, and peroxiredoxin and the oxLDL/ß2GPI complex indicating its antioxidative stress and its proatherogenicity were lower than their baseline. This suggests that olmesartan may be more effective than other ARBs to improve these conditions. Neither HMGB1 nor TNFα reflecting an inflammatory response was affected, suggesting that the anti-inflammatory effects of olmesartan are similar to those of other ARBs. The recommended BP (<140/90) was obtained in 10 of the 25 patients after switching to olmesartan. No adverse events occurred. CONCLUSIONS: Switching from other ARBs to olmesartan may be a promising therapeutic option in patients with resistant hypertension.

Roles of hypertension in the rupture of intracranial aneurysms.

BACKGROUND AND PURPOSE: Systemic hypertension has long been considered a risk factor of aneurysmal rupture. However, a causal link between systemic hypertension and the development of aneurysmal rupture has not been established. In this study, using a mouse model of intracranial aneurysm rupture, we examined the roles of systemic hypertension in the development of aneurysmal rupture. METHODS: Aneurysms were induced by a combination of deoxycorticosterone acetate (DOCA)-salt and a single injection of elastase into the cerebrospinal fluid in mice. Antihypertensive treatment was started 6 days after aneurysm induction. Aneurysmal rupture was detected by neurological symptoms and confirmed by the presence of intracranial aneurysm with subarachnoid hemorrhage. Hydralazine (direct vasodilator) or discontinuation of DOCA-salt treatment was used to assess the roles of systemic hypertension. Captopril (angiotensin-converting enzyme inhibitor) or losartan (angiotensin II type 1 receptor antagonist) was used to assess the roles of the local renin-angiotensin system in the vascular wall. RESULTS: Normalization of blood pressure by hydralazine significantly reduced the incidence of ruptured aneurysms and the rupture rate. There was a dose-dependent relationship between reduction of blood pressure and prevention of aneurysmal rupture. Captopril and losartan were able to reduce rupture rate without affecting systemic hypertension induced by DOCA-salt treatment. CONCLUSIONS: Normalization of blood pressure after aneurysm formation prevented aneurysmal rupture in mice. In addition, we found that the inhibition of the local renin-angiotensin system independent from the reduction of blood pressure can prevent aneurysmal rupture.

Intra-arterial signal on arterial spin labeling perfusion MRI to identify the presence of acute middle cerebral artery occlusion.

BACKGROUND: The susceptibility vessel sign on gradient echo-type-T2*-weighted imaging is a well-known marker of arterial occlusion. Stagnant flow in front of the middle cerebral artery (MCA) occlusion sites may contribute to the intra-arterial, high-intensity signal on arterial spin labeling magnetic resonance imaging (MRI), making it another potential marker of MCA occlusion. We compared the intra-arterial, high-intensity signal and susceptibility vessel sign in patients with symptomatic MCA occlusion and patients without major vessel occlusion. METHODS: We identified transient ischemic attack or ischemic stroke patients with (1) 3-T MRI performed within 24 h after clinical onset including arterial spin labeling, T2*-weighted imaging, and magnetic resonance angiography (MRA) and (2) either having MCA occlusion (n = 34 patients) or without major vessel occlusion (n = 24 patients). The intra-arterial, high-intensity signal was defined as an enlarged circular or linear bright hyperintensity within the artery. The susceptibility vessel sign was defined as an enlarged spot of hypointensity within the MCA, in which the diameter of the hypointense signal within the vessel exceeded the contralateral vessel diameter. The presence or absence of the intra-arterial, high-intensity signal and susceptibility vessel sign were assessed, along with their inter-rater agreement and consistency with the presence of MCA occlusion on MRA. RESULTS: The intra-arterial, high-intensity signal was detectable in 30 patients (52%), and susceptibility vessel sign was observed in 17 patients (29%). The sensitivity of the intra-arterial high-intensity signal was significantly higher than that of the susceptibility vessel sign (88% vs. 50%; p < 0.05). The accuracy of the intra-arterial high-intensity signal was also higher than that of the susceptibility vessel sign (93% vs. 71%; p < 0.05). The intra-arterial high-intensity signal was situated in the proximal regions of the susceptibility vessel sign on T2*WI within the MCA. Neither the intra-arterial high-intensity signal nor the susceptibility vessel sign was observed in patients without major vessel occlusion. Inter-rater agreement was good for intra-arterial high-intensity signal detection (κ = 0.73) and moderate for susceptibility vessel sign detection (κ = 0.47). The presence or absence of the intra-arterial high-intensity signal was highly consistent with that of MCA occlusion on MRA (κ = 0.74). CONCLUSIONS: The intra-arterial high-intensity signal on arterial spin labeling appears to be useful to identify the presence of acute MCA occlusion and may be associated with stagnant flow in front of occlusion sites. The intra-arterial high-intensity signal may also be used to identify the occlusion site.

Nonconvulsive status epilepticus in patients with acute subarachnoid hemorrhage is associated with negative arterial spin labeling on peri-ictal magnetic resonance images.

Purpose: Non-convulsive status epilepticus (NCSE) is characterized by repetitive or continuous seizures without convulsions. Arterial spin labeling (ASL) is useful for assessing hyperperfusion due to neurovascular unit coupling in patients with NCSE; subarachnoid hemorrhage (SAH) impairs the neurovascular unit. We hypothesized that the sensitivity of ASL in detecting NCSE is low in patients with SAH during the acute phase. Methods: Based on ASL findings obtained within 48 h after the clinical suspicion of focal-onset NCSE, we divided 34 patients into ASL-negative (no hyperperfusion; n = 10) and ASL-positive (confirmed hyperperfusion; n = 24) groups. We further divided the two groups according to the NCSE etiology: patients who were diagnosed with NCSE within 14 days after SAH onset (acute SAH, n = 11) and patients with NCSE due to factors other acute SAH (n = 23) and compared their characteristics. Results: In 10 of the 34 patients (29.4 %) the ASL findings were normal. The rate of acute SAH was significantly higher in ASL-negative- (n = 8, 80.0 %) than ASL-positive patients (n = 3, 12.5 %). The rate of patients in aphasic status was significantly lower in ASL-negative patients (n = 1, 10 %) than in ASL-positive patients (n = 12, 50.0 %). Conclusion: Normal ASL findings alone should not be used to exclude a diagnosis of NCSE particularly in patients in the acute phase of SAH with deterioration or no improvement in consciousness.

The VEBAS score: a practical scoring system for intracranial dural arteriovenous fistula obliteration.

BACKGROUND: Tools predicting intracranial dural arteriovenous fistulas (dAVFs) treatment outcomes remain scarce. This study aimed to use a multicenter database comprising more than 1000 dAVFs to develop a practical scoring system that predicts treatment outcomes. METHODS: Patients with angiographically confirmed dAVFs who underwent treatment within the Consortium for Dural Arteriovenous Fistula Outcomes Research-participating institutions were retrospectively reviewed. A subset comprising 80% of patients was randomly selected as training dataset, and the remaining 20% was used for validation. Univariable predictors of complete dAVF obliteration were entered into a stepwise multivariable regression model. The components of the proposed score (VEBAS) were weighted based on their ORs. Model performance was assessed using receiver operating curves (ROC) and areas under the ROC. RESULTS: A total of 880 dAVF patients were included. Venous stenosis (presence vs absence), elderly age (<75 vs ≥75 years), Borden classification (I vs II-III), arterial feeders (single vs multiple), and past cranial surgery (presence vs absence) were independent predictors of obliteration and used to derive the VEBAS score. A significant increase in the likelihood of complete obliteration (OR=1.37 (1.27-1.48)) with each additional point in the overall patient score (range 0-12) was demonstrated. Within the validation dataset, the predicted probability of complete dAVF obliteration increased from 0% with a 0-3 score to 72-89% for patients scoring ≥8. CONCLUSION: The VEBAS score is a practical grading system that can guide patient counseling when considering dAVF intervention by predicting the likelihood of treatment success, with higher scores portending a greater likelihood of complete obliteration.

Activation of the NLRP3/IL-1ß/MMP-9 pathway and intracranial aneurysm rupture associated with the depletion of ERα and Sirt1 in oophorectomized rats.

OBJECTIVE: Subarachnoid hemorrhage (SAH) due to intracranial aneurysm (IA) rupture is often a devastating event. Since the incidence of SAH increases especially in menopause, it is crucial to clarify the detailed pathogenesis of these events. The activation of vascular nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasomes has been studied in ischemic stroke and cardiovascular disease. However, the role of NLRP3 in IA rupture still needs to be explained. The authors sought to test their hypothesis that, under estrogen-deficient conditions, activation of NLRP3 inflammasomes via downregulation of the estrogen receptor (ER) facilitates IA rupture. METHODS: Ten-week-old female Sprague Dawley rats with and without oophorectomy were subjected to hemodynamic changes and hypertension (OVX+/HT and OVX-/HT, respectively) and fed a high-salt diet. Separately, using human brain endothelial cells (HBECs) and human brain smooth muscle cells (HBSMCs), the authors tested the effect of NLRP3 under estrogen-free conditions and in the presence of estradiol or of ER agonists. RESULTS: In OVX+/HT rats, the frequency of IA rupture was significantly higher than in OVX-/HT rats (p = 0.03). In the left posterior cerebral artery prone to rupture in OVX+/HT rats, the levels of the mRNAs encoding ERα and Sirt1, but not of that encoding ERß, were decreased, and the levels of the mRNAs encoding NLRP3, interleukin-1ß (IL-1ß), and matrix metalloproteinase 9 (MMP-9) were elevated. Immunohistochemical analysis demonstrated that the expression profiles of these proteins correlated with their mRNA levels. Treatment with an ER modulator, bazedoxifene, normalized the expression profiles of these proteins and improved SAH-free survival. In HBECs and HBSMCs under estrogen-free conditions, the depletion of ERα and Sirt1 and the accumulation of NLRP3 were counteracted by exposure to estradiol or to an ERα agonist but not to an ERß agonist. CONCLUSIONS: To the authors' knowledge, this work represents the first demonstration that, in an aneurysm model under estrogen-deficient conditions, the depletion of ERα and Sirt1 may contribute to activation of the NLRP3/IL-1ß/MMP-9 pathway, facilitating the rupture of IAs in the estrogen-deficient rat IA rupture model.

Natural history, angiographic presentation and outcomes of anterior cranial fossa dural arteriovenous fistulas.

BACKGROUND: Anterior cranial fossa dural arteriovenous fistulas (ACF-dAVFs) are aggressive vascular lesions. The pattern of venous drainage is the most important determinant of symptoms. Due to the absence of a venous sinus in the anterior cranial fossa, most ACF-dAVFs have some degree of drainage through small cortical veins. We describe the natural history, angiographic presentation and outcomes of the largest cohort of ACF-dAVFs. METHODS: The CONDOR consortium includes data from 12 international centers. Patients included in the study were diagnosed with an arteriovenous fistula between 1990-2017. ACF-dAVFs were selected from a cohort of 1077 arteriovenous fistulas. The presentation, angioarchitecture and treatment outcomes of ACF-dAVF were extracted and analyzed. RESULTS: 60 ACF-dAVFs were included in the analysis. Most ACF-dAVFs were symptomatic (38/60, 63%). The most common symptomatic presentation was intracranial hemorrhage (22/38, 57%). Most ACF-dAVFs drained through cortical veins (85%, 51/60), which in most instances drained into the superior sagittal sinus (63%, 32/51). The presence of cortical venous drainage predicted symptomatic presentation (OR 9.4, CI 1.98 to 69.1, p=0.01). Microsurgery was the most effective modality of treatment. 56% (19/34) of symptomatic patients who were treated had complete resolution of symptoms. Improvement of symptoms was not observed in untreated symptomatic ACF-dAVFs. CONCLUSION: Most ACF-dAVFs have a symptomatic presentation. Drainage through cortical veins is a key angiographic feature of ACF-dAVFs that accounts for their malignant course. Microsurgery is the most effective treatment. Due to the high risk of bleeding, closure of ACF-dAVFs is indicated regardless of presentation.

Dural Arteriovenous Fistulas With Cognitive Impairment: Angiographic Characteristics and Treatment Outcomes.

BACKGROUND AND OBJECTIVES: Anecdotal cases of rapidly progressing dementia in patients with dural arteriovenous fistulas (dAVFs) have been reported in small series. However, large series have not characterized these dAVFs. We conducted an analysis of the largest cohort of dAVFs presenting with cognitive impairment (dAVFs-CI), aiming to provide a detailed characterization of this subset of dAVFs. METHODS: Patients with dAVFs-CI were analyzed from the CONDOR Consortium, a multicenter repository comprising 1077 dAVFs. A propensity score matching analysis was conducted to compare dAVFs-CI with Borden type II and type III dAVFs without cognitive impairment (controls). Logistic regression was used to identify angiographic characteristics specific to dAVFs-CI. Furthermore, post-treatment outcomes were analyzed. RESULTS: A total of 60 patients with dAVFs-CI and 60 control dAVFs were included. Outflow obstruction leading to venous hypertension was observed in all dAVFs-CI. Sinus stenosis was significantly associated with dAVFs-CI (OR 2.85, 95% CI: 1.16-7.55, P = .027). dAVFs-CI were more likely to have a higher number of arterial feeders (OR 1.56, 95% CI 1.22-2.05, P < .001) and draining veins (OR 2.05, 95% CI 1.05-4.46, P = .004). Venous ectasia increased the risk of dAVFs-CI (OR 2.38, 95% CI 1.13-5.11, P = .024). A trend toward achieving asymptomatic status at follow-up was observed in patients with successful closure of dAVFs (OR 2.86, 95% CI 0.85-9.56, P = .09). CONCLUSION: Venous hypertension is a key angiographic feature of dAVFs-CI. Moreover, these fistulas present at a mean age of 58 years-old, and exhibit a complex angioarchitecture characterized by an increased number of arteriovenous connections and stenosed sinuses. The presence of venous ectasia further exacerbates the impaired drainage and contributes to the development of dAVFs-CI. Notably, in certain cases, closure of the dAVF has the potential to reverse symptoms.

Activation of signal transducer and activator of transcription-3 by a peroxisome proliferator-activated receptor gamma agonist contributes to neuroprotection in the peri-infarct region after ischemia in oophorectomized rats.

BACKGROUND AND PURPOSE: The role of the phosphorylated signal transducer and activator of transcription-3 (p-STAT3) after cerebral ischemia by the peroxisome proliferator-activated receptor γ (PPARγ) agonist pioglitazone (PGZ) remains controversial. Whether the increase in p-STAT3 by estrogen is mediated by the estrogen receptor α is also obscure. We examined the role of p-STAT3, PPARγ, and estrogen receptor α against ischemic brain damage after PGZ treatment. METHODS: Female Wistar rats subjected or not subjected to bilateral oophorectomy were injected with 1.0 or 2.5 mg/kg PGZ 2 days, 1 day, and 1 hour before 90-minute middle cerebral artery occlusion-reperfusion and compared with vehicle-control rats. RESULTS: The cortical infarct size was larger in ovariectomized than in nonovarietomized rats; it was reduced by PGZ treatment. Inversely with the reduction of the infarct size, PPARγ, and p-STAT3 but not estrogen receptor α in the peri-infarct area were increased in PGZ-treated compared with vehicle-control rats. The increase in PPARγ and p-STAT3 was associated with the transactivation of antiapoptotic and survival genes and the reduction of caspase-3 in this area. Inhibitors of PPARγ or STAT3 abolished the PGZ-induced neuroprotection and the increase in p-STAT3. More importantly, p-STAT3 increased by PGZ was bound to PPARγ and the complex translocated to the nucleus to dock to the response element through p-STAT3. CONCLUSIONS: Our findings suggest that the activation in the peri-infarct region of p-STAT3 and PPARγ by PGZ is essential for neuroprotection after ischemia and that PGZ may be of benefit even in postmenopausal stroke patients.