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.

Long-Term Clinical and Immunological Effects of Repeated Mesenchymal Stem Cell Injections in Patients With Progressive Forms of Multiple Sclerosis.

Background: Mesenchymal stem cells (MSC) were shown to possess immunomodulatory and neurotrophic effects. Our previous trials, have shown that intrathecal (IT) and intravenous (IV) administration of MSCs were safe and provided indications of beneficial clinical effects. Methods: This is an open prospective study to evaluate the safety and the long-term clinical and immunological effects of multiple injections of autologous MSCs in 24 patients with active-progressive MS. At inclusion, the mean age of the patients was 47.0 ± 9.22, and the mean EDSS score was 6.75 ± 0.68 (range: 5.5-7.5). Patients were initially treated with 1 ×106 MSCS/kg of body weight (IT + IV) and subsequently with up to additional eight courses of MSCs, at intervals of 6-12 months. The duration of the trial was 4 years. Results: No serious, treatment-related adverse events were observed during the follow-up period. Twenty-two of the 24 patients were either stable or improved at the last follow-up visit. Ten patients had a lower than baseline EDSS at the last follow-up (nine were among those who received >2 treatments and one in the subgroup of ≤ 2 treatments, p = 0.04). The mean EDSS score reduced from 6.75 ± 0.68 at baseline to 6.42 ± 0.84 at the last visit, during a median follow-up period of 27.8 months (p = 0.028). Immunological follow-up showed a transient upregulation of CD4+CD25+FoxP3+ cells and downregulation of the proliferative ability of lymphocytes. Conclusions: Repeated MSC treatments in patients with progressive MS were shown safe at the short/intermediate term and induced clinical benefits (especially in patients treated with >2 injections) that lasted for up to 4 years, paralleled by short-term immunomodulatory effects. Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT04823000.

Beneficial effects of autologous mesenchymal stem cell transplantation in active progressive multiple sclerosis.

In this study (trial registration: NCT02166021), we aimed to evaluate the optimal way of administration, the safety and the clinical efficacy of mesenchymal stem cell (MSC) transplantation in patients with active and progressive multiple sclerosis. Forty-eight patients (28 males and 20 females) with progressive multiple sclerosis (Expanded Disability Status Scale: 3.0-6.5, mean : 5.6 ± 0.8, mean age: 47.5 ± 12.3) and evidence of either clinical worsening or activity during the previous year, were enrolled (between 2015 and 2018). Patients were randomized into three groups and treated intrathecally (IT) or intravenously (IV) with autologous MSCs (1 × 106/kg) or sham injections. After 6 months, half of the patients from the MSC-IT and MSC-IV groups were retreated with MSCs, and the other half with sham injections. Patients initially assigned to sham treatment were divided into two subgroups and treated with either MSC-IT or MSC-IV. The study duration was 14 months. No serious treatment-related safety issues were detected. Significantly fewer patients experienced treatment failure in the MSC-IT and MSC-IV groups compared with those in the sham-treated group (6.7%, 9.7%, and 41.9%, respectively, P = 0.0003 and P = 0.0008). During the 1-year follow-up, 58.6% and 40.6% of patients treated with MSC-IT and MSC-IV, respectively, exhibited no evidence of disease activity compared with 9.7% in the sham-treated group (P < 0.0001 and P < 0.0048, respectively). MSC-IT transplantation induced additional benefits on the relapse rate, on the monthly changes of the T2 lesion load on MRI, and on the timed 25-foot walking test, 9-hole peg test, optical coherence tomography, functional MRI and cognitive tests. Treatment with MSCs was well-tolerated in progressive multiple sclerosis and induced short-term beneficial effects regarding the primary end points, especially in the patients with active disease. The intrathecal administration was more efficacious than the intravenous in several parameters of the disease. A phase III trial is warranted to confirm these findings.

Impact of previous stroke on outcome after thrombectomy in patients with large vessel occlusion.

BACKGROUND: Many patients with large vessel occlusion (LVO) who are otherwise candidates for endovascular treatment (EVT) have had previous strokes. We aimed to examine the effect of previous stroke on outcome after EVT. METHODS: Consecutive patients with LVO were prospectively entered into a National Acute Stroke registry of patients undergoing EVT. Patients treated with EVT were divided into those with and without previous strokes. The rates of favorable reperfusion status, mortality, and excellent outcome at 90 days post-stroke as well as symptomatic intracranial hemorrhage (sICH) were evaluated. RESULTS: A total of 390 underwent EVT and 35 had previous strokes. Patients with previous strokes were significantly older; more frequently had a history of prior myocardial infarction and more often had pre-existing functional disability. Favorable target vessel recanalization was less frequently achieved in patients with previous strokes (60% vs. 82%; p = 0.005) and ordinal regression analysis for functional outcome revealed higher frequency of deterioration at three months in patients with previous strokes. Nevertheless, 9% of these patients maintained their previous disability state and sICH rates did not differ between the groups. Mortality rates at one year post stroke were significantly higher in patients with previous strokes (37% vs. 16%; p = 0.005). CONCLUSIONS: Previous strokes are associated with higher likelihoods of mortality and unfavorable outcome in patients with LVO undergoing EVT. However, because some of these patients maintain their previous disability state, the presence of previous stroke should not be used as an exclusion criterion from EVT.

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.