A role of iron as a target to prevent stroke-induced neurodegeneration has been recently revisited due to new evidence showing that ferroptosis inhibitors are protective in experimental ischemic stroke and might be therapeutic in other neurodegenerative brain pathologies. Ferroptosis is a new form of programmed cell death attributed to an overwhelming lipidic peroxidation due to excessive free iron and reactive oxygen species (ROS). This study aims to evaluate the safety and tolerability and to explore the therapeutic efficacy of the iron chelator and antioxidant deferoxamine mesylate (DFO) in ischemic stroke patients. Administration of placebo or a single DFO bolus followed by a 72 h continuous infusion of three escalating doses was initiated during the tPA infusion, and the impact on blood transferrin iron was determined. Primary endpoint was safety and tolerability, and secondary endpoint was good clinical outcome (clinicalTrials.gov NCT00777140). DFO was found safe as adverse effects were not different between placebo and DFO arms. DFO (40–60 mg/Kg/day) reduced the iron saturation of blood transferrin. A trend to efficacy was observed in patients with moderate-severe ischemic stroke (NIHSS > 7) treated with DFO 40–60 mg/Kg/day. A good outcome was observed at day 90 in 31% of placebo vs. 50–58% of the 40–60 mg/Kg/day DFO-treated patients.

Background: A significant proportion of stroke patients presenting with mild symptoms does not have a successful recovery, especially when a large vessel is occluded. IV thrombolysis is safe and may benefit patients presenting with mild symptoms. In this study, we tested whether endovascular therapy (ET) is superior to medical therapy in these patients. Methods: Observational, prospectively collected, multicenter study of 78 consecutive patients admitted from 2009 to 2012 within 6 h of stroke, with NIHSS ≤5 at presentation or during initial diagnostic work-up and large vessel occlusion. Data for patients undergoing ET and/or IV thrombolysis were taken from the SONIIA registry of reperfusion therapies in Catalonia, or from our local stroke registry if no reperfusion therapy was delivered. We compared risk factors, clinical course, collateral circulation, revascularization rates, hemorrhagic complications, infarct volume, and the functional outcome at 3 months of patients treated with ET and those not receiving ET. Ordinal regression was used to assess the independent effect of ET on functional outcome. Results: Baseline characteristics were similar for ET (n = 34) and medically (n = 44) treated patients, except for older age in the latter. The occlusions were located in the terminal internal carotid artery (1%), M1 segment of the middle cerebral artery (33%), M2 segment (30%), posterior circulation (31%), and 5% of the patients had tandem lesions, with no significant differences between groups. Most patients in both treatment groups had good collateral flow. The rate of successful revascularization (91.2 vs. 63.4%; p = 0.006) and the risk of symptomatic intracranial hemorrhage (11.8 vs. 0%; p = 0.033) were higher in the ET group. The NIHSS scores were similar at hospital arrival, after initial neuroimaging, and at 24 h in both treatment groups and there were no significant differences in the infarct volume in a follow-up MRI. At 3 months, 35.9% of the patients had some disability. The functional outcome was similar in both treatment groups in univariate analysis and also in models adjusted for age and initial NIHSS or for variables associated to functional outcome on univariate comparison. Conversely, IV thrombolysis was associated with significantly greater chances of full recovery after adjusting for baseline differences (OR 3.70, p = 0.015). Conclusions: One third of stroke patients with mild symptoms and large vessel occlusions do not have a successful recovery. ET is effective to recanalize the occluded vessel but increases the risk of serious bleeding significantly without improving the functional outcome, and is therefore not justified routinely in these patients.

Background and Purpose—: Higher rates of target vessel patency at 24 hours were noted in the thrombectomy group compared with control group in recent randomized trials. As a prespecified secondary end point, we aimed to assess 24-hour revascularization rates by treatment groups and occlusion site as they related to clinical outcome and 24-hour infarct volume in REVASCAT (Randomized Trial of Revascularization With Solitaire FR Device Versus Best Medical Therapy in the Treatment of Acute Stroke Due to Anterior Circulation Large Vessel Occlusion Presenting Within Eight Hours of Symptom Onset). Methods—: Independent core laboratory adjudicated vessel status according to modified arterial occlusive lesion classification at 24 hours on computed tomographic/magnetic resonance (94.2%/5.8%) angiography and 24-hour infarct volume on computed tomography were studied (95/103 patients in the thrombectomy group versus 94/103 in the control group, respectively). Complete revascularization was defined as modified arterial occlusive lesion grade 3. Its effect on clinical outcome was analyzed by ordinal logistic regression. Results—: Complete revascularization was achieved in 70.5% of the solitaire group and in 22.3% of the control group ( P <0.001). Significant differences in complete revascularization rates were found for terminus internal carotid artery, M1, and tandem occlusions (all P <0.001) but not for M2 occlusions. In the thrombectomy group, 2 out of 63 patients (3.1%) with modified Thrombolysis in Cerebral Infarction 2b/3 after thrombectomy showed arterial reocclusion (modified arterial occlusive lesion grade 0/1) at 24 hours. Complete revascularization was associated with improved outcome in both thrombectomy (adjusted odds ratio, 4.5; 95% confidence interval, 1.9–10.9) and control groups (adjusted odds ratio, 2.7; 95% confidence interval, 1.0–6.7). Revascularization (modified arterial occlusive lesion grade 2/3) was associated with smaller infarct volumes in either treatment arm. Conclusions—: Complete revascularization at 24 hours is a powerful predictor of favorable clinical outcome, whereas revascularization of any type results in reduced infarct volume in both thrombectomy and control groups. Clinical Trial Registration—: URL: http://www.clinicaltrials.gov . Unique identifier: NCT01692379.

Background: We studied the evolution over time of diffusion weighted imaging (DWI) lesion volume and the factors involved on early and late infarct growth (EIG and LIG) in stroke patients undergoing endovascular treatment (EVT) according to the final revascularization grade. Methods: This is a prospective cohort of patients with anterior large artery occlusion undergoing EVT arriving at 1 comprehensive stroke center. Magnetic resonance imaging was performed on arrival (pre-EVT), <2 hours after EVT (post-EVT), and on day 5. DWI lesions and perfusion maps were evaluated. Arterial revascularization was assessed according to the modified Thrombolysis in Cerebral Infarction (mTICI) grades. We recorded National Institutes of Health Stroke Scale at arrival and at day 7. EIG was defined as (DWI volume post-EVT–DWI volume pre-EVT), and LIG was defined as (DWI volume at 5d–DWI volume post-EVT). Factors involved in EIG and LIG were tested via multivariable lineal models. Results: We included 98 patients (mean age 70, median National Institutes of Health Stroke Scale score 17, final mTICI≥2b 86%). Median EIG and LIG were 48 and 63.3 mL in patients with final mTICI<2b, and 3.6 and 3.9 cc in patients with final mTICI≥2b. Both EIG and LIG were associated with higher National Institutes of Health Stroke Scale at day 7 ( ρ =0.667; P <0.01 and ρ =0.614; P <0.01, respectively). In patients with final mTICI≥2b, each 10% increase in the volume of DWI pre-EVT and each extra pass leaded to growths of 9% (95% CI, 7%–10%) and 14% (95% CI, 2%–28%) in the DWI volume post-EVT, respectively. Furthermore, each 10% increase in the volume of DWI post-EVT, each extra pass, and each 10 mL increase in TMax6s post-EVT were associated with growths of 8% (95% CI, 6%–9%), 9% (95% CI, 0%–19%), and 12% (95% CI, 5%–20%) in the volume of DWI post-EVT, respectively. Conclusions: Infarct grows during and after EVT, especially in nonrecanalizers but also to a lesser extent in recanalizers. In recanalizers, number of passes and DWI volume influence EIG, while number of passes, DWI, and hypoperfused volume after the procedure determine LIG.

Background: Although multiple studies and meta-analyses have consistently suggested that regular physical activity (PhA) is associated with a decreased stroke risk and recurrence, there is limited data on the possible preconditioning effect of prestroke PhA on stroke severity and prognosis. We aimed to study the association of prestroke PhA with different outcome variables in patients with acute ischemic stroke due to an anterior large vessel occlusion. Methods: The Prestroke Physical Activity and Functional Recovery in Patients with Ischemic Stroke and Arterial Occlusion trial is an observational and longitudinal study that included consecutive patients with acute ischemic stroke admitted to a single tertiary stroke center. Main inclusion criteria were: anterior circulation ischemic stroke within 12 h from symptom onset; presence of a confirmed anterior large vessel occlusion, and functional independence previous to stroke. Prestroke PhA was evaluated with the International Physical Activity Questionnaire and categorized into mild, moderate and high levels by means of metabolic equivalent (MET) minutes per week thresholds. The primary outcome measure was good functional outcome at 3 months (modified Rankin scale ≤2). Secondary outcomes were severity of stroke at admission, complete early recanalization, early dramatic neurological improvement and final infarct volume. Results: During the study period, 159 patients fulfilled the above criteria. The mean age was 68 years, 62% were men and the baseline NIHSS score was 17. Patients with high levels of prestroke PhA were younger, had more frequently distal occlusions and had lower levels of blood glucose and fibrinogen at admission. After multivariate analysis, a high level of prestroke PhA was associated with a good functional outcome at 3 months. Regarding secondary outcome variables and after adjustment for relevant factors, a high level of prestroke PhA was independently associated with milder stroke severity at admission, early dramatic improvement, early arterial recanalization after intravenous thrombolysis and lower final infarct volume. The beneficial association of prestroke PhA with stroke outcomes was already present with a cutoff point of 1,000 MET min/week, a level of PhA easily achieved by walking 1 h/day during 5 days or by doing a vigorous aerobic activity 1 h/day twice a week. Conclusions: Prestroke PhA is independently associated with favorable stroke outcomes after a large vessel occlusion. Future research on the underlying mechanisms is needed to understand this neuroprotective effect of PhA.

Background: Hemorrhagic transformation (HT) is a complication that occurs spontaneously or after thrombolysis in acute ischemic stroke (AIS) and can increase morbidity and mortality. The association of biomarkers with the risk of HT has been variably reported. We conducted a systematic review of the literature and meta-analysis and sought to compare blood biomarkers associated with HT and its subtypes by evaluating its predictability and correlation with outcome in AIS. Methods: The study protocol was registered in the PROSPERO database (CRD42020201334) and adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Among 2,230 articles identified from Cochrane Library, PubMed, and Web of Science databases, 30 quality-appraised articles were found eligible. Meta-analysis was conducted for matrix metalloproteinase-9 (MMP-9), cellular fibronectin (c-Fn), ferritin, S100 calcium-binding protein B (S100B), and neutrophil-lymphocyte ratio (NLR). We also reviewed biomarkers for correlation with the functional outcome at 90 days from stroke onset (poor outcome modified Rankin scale >2). Results: The pooled diagnostic odds ratio (DOR_pooled) was the highest for baseline c-Fn levels (299.253 [95% CI, 20.508–4,366.709]), followed by MMP-9 (DOR_pooled, 29.571 [95% CI 17.750–49.267]) and ferritin (DOR_pooled, 24.032 [95% CI 2.557–225.871]). However, wide confidence intervals for ferritin and c-Fn suggested lesser reliability of the markers. Patients with MMP-9 levels ≥140 ng/mL were 29.5 times at higher risk of developing symptomatic HT after AIS (area under the curve = 0.881). S100B (DOR_pooled, 6.286 [95% CI, 1.861–21.230]) and NLR (DOR_pooled, 5.036 [95% CI, 2.898–8.749]) had lower diagnostic accuracies. Among the markers not included for meta-analysis, caveolin-1, thrombin-activated fibrinolysis inhibitor, plasminogen activator inhibitor-1, and soluble ST2 were highly sensitive. Elevated levels of MMP-9, ferritin, and NLR were found to be associated with poor functional outcomes and mortality. Conclusion: Of the 5 biomarkers, there was enough evidence that MMP-9 has higher diagnostic accuracy for predicting the risk of HT before thrombolysis. MMP-9, ferritin, and NLR also predicted poor short-term outcomes.