Sex Differences in Intracranial Atherosclerosis in Patients With Hypertension With Acute Ischemic Stroke.

Background Studies suggest the presence of sex differences in hypertension prevalence and its associated outcomes in atherosclerosis and stroke. We hypothesized a higher intracranial atherosclerosis burden among men with hypertension and acute ischemic stroke compared with women. Methods and Results A multicenter retrospective study was performed from a prospective database identifying patients with hypertension presenting with intracranial atherosclerosis-related acute ischemic stroke and imaged with intracranial vessel wall magnetic resonance imaging. Proximal and distal plaques on vessel wall magnetic resonance imaging were scored. Negative binomial models assessed the associations between plaque-count and sex and the interaction between sex and treatment. Covariates were selected by a least absolute shrinkage and selection operator procedure. Sixty-one patients (n=42 men) were included. There were no significant differences in demographic or cardiovascular risk factors except for smoking history (P=0.002). Adjusted total and proximal plaque counts for men were 1.6 (95% CI, 1.2-2.1; P<0.01) and 1.4 (95% CI, 1.0-1.9; P=0.03) times as high as women, respectively. Female sex was more protective for proximal plaque if treated for hypertension. The risk ratio of men versus women was 1.5 (95% CI, 1.0-2.1) for treated patients. The risk ratio of men versus women was 0.7 (95% CI, 0.4-1.3) for untreated patients. The relative difference between these 2 risk ratios was 2.0 (95% CI, 1.1-3.9), which was statistically significant from the interaction test, P=0.04. Conclusions Men with hypertension with acute ischemic stroke have significantly higher total and proximal plaque burdens than women. Women with hypertension on anti-hypertensive medication showed a greater reduction in proximal plaque burden than men. Further confirmation with a longitudinal cohort study is needed and may help evaluate whether different treatment guidelines for managing hypertension by sex can help reduce intracranial atherosclerosis burden and ultimately acute ischemic stroke risk.

Encephaloduroarteriosynangiosis (EDAS) revascularization for symptomatic intracranial atherosclerotic steno-occlusive (ERSIAS) Phase-II objective performance criterion trial.

BACKGROUND: Intracranial atherosclerotic disease (ICAD) is one of the most challenging stroke etiologies, with frequent recurrences despite optimized medical management. Encephaloduroarteriosynangiosis (EDAS) is an indirect revascularization method that produces extra-cranial collaterals to intracranial vessels. We present the results of a phase-II trial of EDAS in intracranial atherosclerotic disease patients. AIMS: To evaluate the feasibility, safety, and preliminary efficacy of EDAS in intracranial atherosclerotic disease patients. METHODS: ERSIAS was a prospective objective-performance-criterion trial of EDAS plus intensive medical management (IMM) in intracranial atherosclerotic disease (ICAD) patients failing medical treatment. Primary endpoint was any stroke/death within 30-days post-surgery or stroke in the territory of the qualifying artery beyond 30 days. The primary analysis compared event rates through one year with an objective-performance-criterion based on a 10% reduction from the 20% rate in the intensive medical management arm of the stenting versus aggressive medical management for preventing recurrent stroke in intracranial stenosis trial (SAMMPRIS) in patients with poor collaterals. Event rates through two years were compared with propensity-score-matched (PSM) medically treated patients from SAMMPRIS and the carotid occlusion surgery study (COSS). RESULTS: During a median follow-up of 24.5 months, 5 (9.6%) of 52 patients had a primary endpoint event. The primary endpoint rate at one year met the threshold for nonfutility and advancement to phase III (<10%). In the sensitivity analysis, primary endpoint event rate at two years was lower than in PSM controls, 9.6% versus 21.2% (p < 0.07). Overall, 86% of EDAS-plus-intensive medical management patients were functionally independent at last follow-up and 89% demonstrated neovascularization. There were two (3.8%) surgical complications and no intracranial hemorrhages. CONCLUSION: ERSIAS phase II provides evidence of safety and strong signals of efficacy of EDAS-plus-intensive medical management, supporting advancement to a seamless phase-IIb/III trial. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov.NCT01819597.

Self-perceptions on cognitive versus motor disability among neurologists.

OBJECTIVE: The modified Rankin Scale is a functional outcome measure that disproportionately represents motor deficits. We hypothesize that among physicians who most commonly use the modified Rankin Scale to counsel patients on neurological treatment options, personal perception of acceptable or optimal outcome may be discordant with those described in clinical trials. METHODS: A three-question anonymous voluntary survey was emailed to academic and community practicing neurologists and board-eligible or board-certified neurology fellows inquiring about their personal perception of a better quality of life between two choices featuring clinical scenarios that would qualify as modified Rankin Scale 2 and 4 disability outcome scores. RESULTS: Sixty-nine percent of participants were 30-45 years old, 24% were 45-60 years old, and 7% were over 60 years old. Most responders were general neurologists (31.3%). The remaining responders represented multiple subspecialties including neurocritical care, vascular neurology, neurohospitalist medicine, neuromuscular neurology, neurophysiology, child neurology, neuro-oncology, headache, neuroimmunology, movement disorders, and palliative care medicine. Forty-four of 45 neurologists (97.7%) stated they would choose needing a wheelchair if still able to function at their cognitive baseline at work (p < 0.000001). One responder preferred to get around without assistance, despite new cognitive symptoms that would preclude them from working as a physician. CONCLUSIONS: The modified Rankin Scale may not adequately represent preferred outcomes among neurology specialists, particularly with respect to cognitive symptoms. Future studies are needed to characterize long-term cognitive outcomes in patients with acute stroke-related conditions.

Differential expression of circulating exosomal microRNAs in refractory intracranial atherosclerosis associated with antiangiogenesis.

Intracranial atherosclerotic disease (ICAD) is a common cause of stroke with high rates of ischemic recurrence. We aimed to investigate the role of circulating exosomal microRNAs (e-miRNAs) in recurrent ischemic events in ICAD. Consecutive patients with severe ICAD undergoing intensive medical management (IMM) were prospectively enrolled. Those with recurrent ischemic events despite IMM during 6-month follow up were algorithmically matched to IMM responders. Baseline blood e-miRNA expression levels of the matched patients were measured using next generation sequencing. A total of 122 e-miRNAs were isolated from blood samples of 10 non-responders and 11 responders. Thirteen e-miRNAs predicted IMM failure with 90% sensitivity and 100% specificity. Ingenuity pathway analysis (IPA) determined 10 of the 13 e-miRNAs were significantly associated with angiogenesis-related biological functions (p < 0.025) and angiogenic factors that have been associated with recurrent ischemic events in ICAD. These e-miRNAs included miR-122-5p, miR-192-5p, miR-27b-3p, miR-16-5p, miR-486-5p, miR-30c-5p, miR-10b-5p, miR-10a-5p, miR-101-3p, and miR-24-3p. As predicted by IPA, the specific expression profiles of these 10 e-miRNAs in non-responders had a net result of inhibition of the angiogenesis-related functions and up expression of the antiangiogenic factors. This study revealed distinct expression profiles of circulating e-miRNAs in refractory ICAD, suggesting an antiangiogenic mechanism underlying IMM failure.

Differential Expression of Vascular Endothelial Growth Factor-A165 Isoforms Between Intracranial Atherosclerosis and Moyamoya Disease.

BACKGROUND: Vascular endothelial growth factor-A165 (VEGF-A165) has been identified as a combination of 2 alternative splice variants: proangiogenic VEGF-A165a and antiangiogenic VEGF-A165b. Intracranial atherosclerotic disease (ICAD) and moyamoya disease (MMD) are 2 main types of intracranial arterial steno-occlusive disorders with distinct capacities for collateral formation. Recent studies indicate that VEGF-A165 regulates collateral growth in ischemia. Therefore, we investigated if there is a distinctive composition of VEGF-A165 isoforms in ICAD and MMD. METHODS: Sixty-six ICAD patients, 6 MMD patients, and 5 controls were enrolled in this prospective study. ICAD and MMD patients received intensive medical management upon enrollment. Surgery was offered to 9 ICAD patients who had recurrent ischemic events, 6 MMD patients, and 5 surgical controls without ICAD. VEGF-A165a and VEGF-A165b plasma levels were measured at baseline, within 1 week after patients having surgery, and at 1, 3, and 6 months after treatment. RESULTS: A significantly higher baseline VEGF-A165a/b ratio was observed in MMD compared to ICAD (P = .016). The VEGF-A165a/b ratio increased significantly and rapidly after surgical treatment in ICAD (P = .026) more so than in MMD and surgical controls. In patients with ICAD receiving intensive medical management, there was also an elevation of the VEGF-A165a/b ratio, but at a slower rate, reaching the peak at 3 months after initiation of treatment (baseline versus 3 months VEGF-A165a/b ratio, P = .028). CONCLUSIONS: Our study shows an increased VEGF-A165a/b ratio in MMD compared to ICAD, and suggests that both intensive medical management and surgical revascularization elevate the VEGF-A165a/b ratio in ICAD patients.