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Background: There is conflicting evidence as to whether intra-arterial thrombolysis (IAT) adds benefit in patients with acute stroke who undergo mechanical thrombectomy (MT)., Methods: We conducted a systematic review to identify studies that evaluate IAT in patients with acute stroke who undergo MT. Data were extracted from relevant studies found through a search of PubMed, Scopus, and Web of Science until February 2023. Statistical pooling with random effects meta-analysis was undertaken to evaluate odds of functional independence, mortality, and near-complete or complete angiographic recanalization with IAT compared to no IAT., Results: A total of 18 studies were included (3 matched, 14 unmatched, and 1 randomized). The odds ratio (OR) for functional independence (modified Rankin Scale: 0-2) at 90 days was 1.14 (95% confidence interval (CI): 0.95-1.37, p = 0.17, 16 studies involving 7572 patients) with IAT with moderate between-study heterogeneity (I 2  = 38.1%). The OR for functional independence with IAT was 1.28 (95% CI: 0.92-1.78, p = 0.15) in studies that were either matched or randomized and 1.24 (95% CI: 0.97-1.58, p = 0.08) in studies with the highest quality score. IAT was associated with higher odds of near-complete or complete angiographic recanalization (OR: 1.65, 95% CI: 1.03-2.65, p = 0.04) in studies that were either matched or of randomized comparisons., Conclusion: Although the odds of functional independence appeared to be higher with IAT and MT compared with MT alone, none of the results were statistically significant. A prominent effect of the design and quality of the studies was observed on the association between IAT and functional independence at 90 days., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Rationale and Hypothesis: Surgical removal of spontaneous intracerebral hemorrhage may reduce secondary destruction of brain tissue. However, large surgical trials of craniotomy have not demonstrated definitive improvement in clinical outcomes. Minimally invasive surgery may limit surgical tissue injury, and recent evidence supports testing these approaches in large clinical trials., Methods and Design: MISTIE III is an investigator-initiated multicenter, randomized, open-label phase 3 study investigating whether minimally invasive clot evacuation with thrombolysis improves functional outcomes at 365 days compared to conservative management. Patients with supratentorial intracerebral hemorrhage clot volume ≥ 30 mL, confirmed by imaging within 24 h ofknown symptom onset,and intact brainstem reflexes were screened with a stability computed tomography scan at least 6 h after diagnostic scan. Patients who met clinical and imaging criteria (no ongoing coagulopathy; no suspicion of aneurysm, arteriovenous malformation, or any other vascular anomaly; and stable hematoma size on consecutive scans) were randomized to either minimally invasive surgery plus thrombolysis or medical therapy. The sample size of 500 was based on findings of a phase 2 study., Study Outcomes: The primary outcome measure is dichotomized modified Rankin Scale 0-3 vs. 4-6 at 365 days adjusting for severity variables. Clinical secondary outcomes include dichotomized extended Glasgow Outcome Scale and all-cause mortality at 365 days; rate and extent of parenchymal blood clot removal; patient disposition at 365 days; efficacy at 180 days; type and intensity of ICU management; and quality of life measures. Safety was assessed at 30 days and throughout the study.

Background: Studies of interventions to prevent the many neurological complications of sickle cell disease must take into account multiple outcomes of variable severity, with limited sample size. The goals of the studies presented were to use investigator preferences across outcomes to determine an attitude-based weighting of relevant clinical outcomes and to establish a valid composite outcome for a clinical trial., Methods: In Study 1, investigators were surveyed about their practice regarding hydroxyurea therapy and opinions about outcomes for the "Hydroxyurea to Prevent the Central Nervous System Complications of Sickle Cell Disease Trial" (HU Prevent), and their minimally acceptable relative risk reduction for the two outcome components, motor and neurocognitive deficits. In Study 2, HU Prevent investigators provided overall weights for these two components. In Study 3, they provided more granular rankings, ratings, and maximum number acceptable to harm. A weighted composite outcome, the Stroke Consequences Risk Score, was constructed that incorporates the major neurologic complications of sickle cell disease. The Stroke Consequences Risk Score represents the 3-year risk of suffering the adverse consequences of stroke. In Study 4, the results of the Optimizing Primary Stroke Prevention in Sickle Cell Anemia (STOP2) and Silent Infarct Transfusion Trials were reanalyzed in light of the composite outcome., Results: In total, 22 to 27 investigators participated per study. In Study 1, across three samplings between 2009 and 2015, the average minimally acceptable relative risk reduction ranged from 0.36 to 0.50, at or below the target effect size of 0.50. In 2015, 21 (91%) reported that a placebo-controlled trial is reasonable; 23 (100%), that it is ethical; and 22 (96%), that they would change their practice, if the results of the trial were positive. In Studies 2 and 3, the weight elicited for a cognitive decline (of 10 IQ points) from the overall assessment was 0.67 (and for motor deficit, the complementary 0.33); from ranking, 0.6; from rating, 0.58; and from maximal number acceptable to harm, 0.5. Using data from two major clinical trials, Study 4 demonstrated the same conclusions as the original trials using the Stroke Consequences Risk Score, with smaller p-values for both reanalyses. An assessment of acceptability was performed as well., Conclusion: This set of studies provides the rationale, justification, and validation for the use of a weighted composite outcome and confirms the need for the phase III HU Prevent study. Surveys of investigators in multi-center studies can provide the basis of clinically meaningful outcomes that foster the translation of study results into practice while increasing the efficiency of a study.

Background Intraventricular hemorrhage is a significant cause of mortality and morbidity worldwide. Treating intraventricular hemorrhage with intraventricular fibrinolytic therapy via a catheter is becoming an increasingly utilized intervention. Aims This meta-analysis aimed to investigate the role of intraventricular fibrinolytic treatment in hypertensive intraventricular hemorrhage patients and evaluate the effect sizes for survival as well as level of function at differing time points. Summary of review PubMed, CNKI, VIP, and Wanfang were searched using the terms "IVH" and "IVH and ICH" for human studies with adult patients published between January 1950 and July 2016. Seventeen publications were selected. Data analysis showed lower rates of mortality in the treatment group at 30 days ( P < 0.001), 180 days ( P = 0.001), 365 days ( P = 0.40), and overall ( P < 0.001). Pooling modified Rankin Scale and Glasgow outcome scale data, the treatment group had more good functional outcomes at 30 days ( P = 0.38), 90 days ( P = 0.04), 180 days ( P = 0.31), 365 days ( P = 0.76), and overall ( P = 0.02). Good functional outcome was defined as modified Rankin Scale score of 0 to 3 or a Glasgow outcome scale score of 3 to 5. Conclusions Intraventricular fibrinolytic for treatment of hypertensive intraventricular hemorrhage reduces mortality and potentially leads to an increased number of good functional outcomes. Different functional outcome scales (modified Rankin Scale or Glasgow outcome scale) produce different effect sizes. Intraventricular fibrinolytic treatment may offer intraventricular hemorrhage patients a targeted therapy that produces meaningful mortality benefit and possible functional outcome benefits.

Background: In adults, intraventricular thrombolytic therapy with recombinant tissue plasminogen activator (rtPA) facilitates resolution of intraventricular haemorrhage (IVH), reduces intracranial pressure, decreases duration of cerebrospinal fluid diversion, and may ameliorate direct neural injury. We hypothesize that patients with small parenchymal haematoma volumes (<30 cc) and relatively large IVH causing acute obstructive hydrocephalus would have improved clinical outcomes when given injections of low-dose rtPA to accelerate lysis and evacuation of IVH compared with placebo., Methods: The Clot Lysis Evaluation of Accelerated Resolution of Intraventricular Hemorrhage III trial is an investigator-initiated, phase III, randomized, multicenter, double-blind, placebo-controlled study comparing the use of external ventricular drainage (EVD) combined with intraventricular injection of rtPA to EVD plus intraventricular injection of normal saline (placebo) for the treatment of IVH. Patients with known symptom onset within 24 h of the computed tomography scan confirmed IVH and third or fourth ventricle obstruction, with or without supratentorial intracerebral haemorrhage volume <30 cc, who require EVD are screened with a computed tomography scan at least six hours after EVD placement and, if necessary, at consecutive 12-h intervals until stabilization of any intracranial bleeding has been established. Patients who meet clinical and imaging criteria (no ongoing coagulopathy and no suspicion of aneurysm, arteriovenous malformation, or any other vascular anomaly) will be randomized to either intraventricular rtPA or placebo., Results: The primary outcome measure is dichotomized modified Rankin Scale 0-3 vs. 4-6 at 180 days. Clinical secondary outcomes include additional modified Rankin Scale dichotomizations at 180 days (0-4 vs. 5-6), ordinal modified Rankin Scale (0-6), mortality and safety events at 30 days, mortality at 180 days, functional status measures, type and intensity of intensive care unit management, rate and extent of ventricular blood clot removal, and quality of life measures., (© 2013 The Authors. International Journal of Stroke © 2013 World Stroke Organization.)

Background and Purpose: This randomized controlled trial tests the efficacy of bilateral arm training with rhythmic auditory cueing (BATRAC) versus dose-matched therapeutic exercises (DMTEs) on upper-extremity (UE) function in stroke survivors and uses functional magnetic resonance imaging (fMRI) to examine effects on cortical reorganization., Methods: A total of 111 adults with chronic UE paresis were randomized to 6 weeks (3×/week) of BATRAC or DMTE. Primary end points of UE assessments of Fugl-Meyer UE Test (FM) and modified Wolf Motor Function Test Time (WT) were performed 6 weeks prior to and at baseline, after training, and 4 months later. Pretraining and posttraining, fMRI for UE movement was evaluated in 17 BATRAC and 21 DMTE participants., Results: The improvements in UE function (BATRAC: FM Δ = 1.1 + 0.5, P = .03; WT Δ = -2.6 + 0.8, P < .00; DMTE: FM Δ = 1.9 + 0.4, P < .00; WT Δ = -1.6 + 0.7; P = .04) were comparable between groups and retained after 4 months. Satisfaction was higher after BATRAC than DMTE (P = .003). BATRAC led to significantly higher increase in activation in ipsilesional precentral, anterior cingulate and postcentral gyri, and supplementary motor area and contralesional superior frontal gyrus (P < .05). Activation change in the latter was correlated with improvement in the WMFT (P = .01)., Conclusions: BATRAC is not superior to DMTE, but both rehabilitation programs durably improve motor function for individuals with chronic UE hemiparesis and with varied deficit severity. Adaptations in brain activation are greater after BATRAC than DMTE, suggesting that given similar benefits to motor function, these therapies operate through different mechanisms.

Objective: Stroke survivors with motor deficits often have pyramidal tract atrophy caused by degeneration of corticospinal fibers. The authors hypothesized that the degree of atrophy correlates with severity of motor impairment in patients with chronic stroke and predicts the response to rehabilitation training., Methods: They performed a post hoc analysis of 42 hemiparetic patients (>6 months) who had been randomized to either 6 weeks of bilateral arm training with rhythmic auditory cueing (BATRAC) or dose-matched therapeutic exercise (DMTE). Arm function was measured using the Fugl-Meyer (FM) and modified Wolf Motor Function Test (WMFT). Structural MRI and diffusion tensor imaging (DTI) on the pontine level measured corticospinal tract (CST) atrophy by planimetric measurement of the mesencephalon (mesencephalic atrophy ratio) and fractional anisotropy (FA), respectively. Voxel-based lesion symptom mapping (VLSM) was used to determine the lesions associated with highest degrees of atrophy. The predictive value of CST atrophy for impairment and training response was analyzed., Results: CST atrophy predicted baseline motor arm function measured by the FM and WMFT. The authors found only a trend for the correlation with FA. No measure of atrophy predicted response to either BATRAC or DMTE. CST atrophy was higher with larger lesions and those that affected the CST. VLSM identified internal capsule lesions as being associated with highest CST atrophy., Conclusion: Larger lesions, internal capsule lesions, and those overlapping the pyramidal tract are associated with greater CST atrophy. CST atrophy explains in part the variability of baseline deficits but does not seem to predict the response to BATRAC or unilateral arm training on upper-extremity function.