A phase II clinical trial with repeated intrathecal injections of autologous mesenchymal stem cells in patients with amyotrophic lateral sclerosis.

Background: Mesenchymal stem cells (MSC) were shown to induce beneficial effects in animal models of neurodegeneration and in pilot human trials in multiple sclerosis and amyotrophic lateral sclerosis (ALS). Aim: An open-label, clinical trial to evaluate the safety and efficacy of repeated intrathecal administrations of autologous-MSC in ALS-patients. Methods: The study included 20 subjects (age: 20-70) with definite diagnosis of ALS and Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALSFRS-R) score of >20. The patients were treated with 1-4 intrathecal injections of MSC, at intervals of 3-6 months. The primary endpoints were safety and tolerability. Efficacy measurements including ALSFRS-R score and forced vital capacity (FVC), were assessed as secondary endpoints. Results: No serious adverse events were observed during the whole period of the trial. One patient withdrew from the study before the first injection. The monthly rate of progression in ALSFRS-R was ameliorated by more than 25% in 15/19 patients between the 1st and 2nd injection (mean improvement of 107.1%); in 11/12 between the 2nd and 3rd injection and in 8/10 between the 3rd and 4th injection. Overall, during the whole period till the last transplantation 13 patients had a >25% improvement in the slope of progression of ALSFRS-R (mean improvement of 47.4%, p < 0.0038, Wilcoxon rank signed test). 7 out of 19 patients actually improved clinically (range of increase in ALSFRS-R: +1 to +4 degrees) after the first transplantation and 5 remained improved after the second cycle. The response rate correlated with the time-intervals between the injections. Conclusion: The results of our study show that repeated intrathecal injections of autologous MSC was safe in patients with ALS and provide indications of medium-term clinical benefits that were related to the intervals between the administrations of the cells. Larger studies are needed to confirm these observations.

Number of stentriever passes and outcome after thrombectomy in stroke.

BACKGROUND AND PURPOSES: Stroke secondary to emergent large vessel occlusions (ELVO) involving the anterior circulation can be treated with intravenous tissue plasminogen activator (IV-tPA) or thrombectomy. Data regarding the influence of the number of stentriever passes needed for vessel recanalization on outcome is lacking. PATIENTS AND METHODS: We prospectively accrued data on consecutive patients with ELVO that were treated with thrombectomy. Procedural details including the number of stentriever passes needed to achieve vessel recanalization and clot length were collected. Functional outcome was determined with the modified Rankin Scale (mRS) at 90 days post stroke with mRS ≤ 2 considered favorable outcome. Data on demographics, risk factors, stroke severity, survival, and occurrence of symptomatic intracranial hemorrhage (sICH) was also collected. RESULTS: On univariate analysis more than one pass needed to achieve recanalization impacted survival and functional outcome after 90 days as did age, stroke severity and collateral and reperfusion status. On multivariate logistic regression the number of passes needed to achieve revascularization (OR: 10.0, 95% CI: 2.28-43.94, P = 0.002), age (OR: 0.90, 95% CI: 0.84-0.96, P = 0.001) and collateral status (OR: 7.90, 95% CI: 1.87-33.35, P = 0.005) remained significant modifiers for favorable outcome. On logistic regression the only variable associated with the need to perform more than a single stentriever pass was time from symptom onset to target vessel recanalization (OR: 1.007, 95% CI: 1.002-1.012). CONCLUSIONS: The number of passes needed to achieve target vessel recanalization modifies outcome after thrombectomy and successful recanalization after a single pass is associated with favorable outcome.

Direct Thrombectomy versus Bridging for Patients with Emergent Large-Vessel Occlusions.

BACKGROUND AND AIMS: Patients with emergent large-vessel occlusion (ELVO) that present earlier than 4 h from onset are usually treated with bridging systemic thrombolysis followed by endovascular thrombectomy (EVT). Whether direct EVT (dEVT) could improve the chances of favorable outcome remains unknown. METHODS: Consecutively, prospectively enrolled patients with ELVO presenting within 4 h of onset were entered into a National Acute Stroke Registry of patients undergoing revascularization. Patients treated with bridging were compared to those treated with dEVT. Excellent outcome was defined as having a modified Rankin Scale score ≤1 at 90 days following stroke. RESULTS: Out of 392 patients that underwent thrombectomy, 270 (68%) presented within 4 h and were included. Of those, 159 (59%) underwent bridging and 111 (41%) underwent dEVT. Atrial fibrillation and congestive heart failure were more common in the dEVT group (43 vs. 30%, p = 0.04 and 20 vs. 8%, p = 0.009, respectively), but other risk factors, demographics, stroke severity and subtypes as well as baseline vessel patency state and time metrics did not differ. Excellent target vessel recanalization defined as TICI 3 (thrombolysis in cerebral infarction score) was more common in the dEVT group (75 vs. 61%, p = 0.03), but in-hospital mortality, discharge destinations, short- and long-term excellent outcome rates did not differ. On multivariate regression analysis, treatment modality did not significantly modify the chances of excellent outcome at discharge (OR 0.7; 95% CI 0.3-1.5) or at 3 months (OR 0.78 95% CI 0.4-1.4). CONCLUSIONS: The chances of attaining excellent functional outcomes are similar in ELVO patients undergoing dEVT or bridging.

Increased Risk for Unfavorable Outcome in Patients with Pre-Existing Disability Undergoing Endovascular Therapy.

INTRODUCTION: Most studies evaluating endovascular therapy (EVT) for stroke only included patients without pre-existing disabilities. However, in real life many patients have pre-existing disabilities, and whether they can benefit from EVT remains unknown. METHODS: Patients with emergent large vessel occlusions undergoing EVT were prospectively enrolled. Patients with no or mild pre-existing disabilities (modified Rankin Scale [mRS], 0-2) were compared with patients presenting with pre-existing moderate disability (mRS ≥ 3). Baseline demographics and risk factors, stroke severity (studied with the National Institutes of Health Stroke Scale [NIHSS]), imaging data including pretreatment Alberta Stroke Program Early Computerized Tomography Score (ASPECTS) and ASPECTS collateral scores, as well as procedure-related variables were accrued. Unfavorable outcome was defined as mRS ≥ 4 at day 90. RESULTS: Of 131 enrolled patients, 108 had a baseline mRS of 2 or lower, and 23 had a prestroke mRS score of 3 or higher. Patients with pre-existing mRS scores of 3 or higher were significantly older (80.3 ± 10 versus 66.9 ± 13.7; P = .001) and more often had previous strokes (39% versus 16%; P = .02). Patients with mRS scores of 3 or higher were more likely to have poor outcomes or death (odds ratio [OR], 4.4; 95% confidence interval [CI], 1.3-15.0). Of the 23 patients with pre-existing moderate disability, 8 (35%) maintained their previous degree of disability. On multivariate analysis, age (OR, .92; 95% CI, .88-.97; P = .001), admission NIHSS (OR, .92; 95% CI, .85-.99; P = .042) and pretreatment ASPECTS (OR, 6.4; 95% CI, 1.4-29.5; P = .017) remained significant modifiers of favorable outcome. DISCUSSION AND CONCLUSIONS: Patients with pre-existing moderate disabilities have higher chances of sustaining unfavorable outcomes despite EVT. Nevertheless, some patients maintain the same level of moderate disabilities, and therefore, patients with pre-existing moderate disabilities should not be excluded from EVT.