Mesenchymal Stromal Cell Implants for Chronic Motor Deficits After Traumatic Brain Injury: Post Hoc Analysis of a Randomized Trial.

BACKGROUND AND OBJECTIVES: Traumatic brain injury (TBI) is frequently characterized by chronic motor deficits. Therefore, this clinical trial assessed whether intracranial implantation of allogeneic modified mesenchymal stromal (SB623) cells can improve chronic motor deficits after TBI. METHODS: Post hoc analysis of the double-blind, randomized, prospective, surgical sham-controlled, phase 2, STEMTRA clinical trial (June 2016 and March 2019) with 48 weeks of follow-up was conducted. In this international, multicenter clinical trial, eligible participants had moderate-to-severe TBI, were ≥12 months postinjury, and had chronic motor deficits. Participants were randomized in a 1:1:1:1 ratio to stereotactic surgical intracranial implantation of SB623 cells (2.5 × 106, 5.0 × 106, 10 × 106) or surgical sham-controlled procedure. The prespecified primary efficacy end point was significantly greater change from baseline of the Fugl-Meyer Motor Scale (FMMS) score, a measure of motor status, for the SB623 pooled vs control arm at 24 weeks. RESULTS: A total of 211 participants were screened, 148 were excluded, and 63 underwent randomization, of which 61 (97%; mean age, 34 [SD, 12] years; 43 men [70.5%]) completed the trial. Single participants in the SB623 2.5 × 106 and 5.0 × 106 cell dose groups discontinued before surgery. Safety and efficacy (modified intent-to-treat) were assessed in participants who underwent surgery (N = 61; SB623 = 46, controls = 15). The primary efficacy end point (FMMS) was achieved (least squares mean [SE] SB623: +8.3 [1.4]; 95% CI 5.5-11.2 vs control: +2.3 [2.5]; 95% CI -2.7 to 7.3; p = 0.04), with faster improvement of the FMMS score in SB623-treated groups than in controls at 24 weeks and sustained improvement at 48 weeks. At 48 weeks, improvement of function and activities of daily living (ADL) was greater, but not significantly different in SB623-treated groups vs controls. The incidence of adverse events was equivalent in SB623-treated groups and controls. There were no deaths or withdrawals due to adverse events. DISCUSSION: Intraparenchymal implantation of SB623 cells was safe and significantly improved motor status at 24 weeks in participants with chronic motor deficits after TBI, with continued improvement of function and ADL at 48 weeks. Cell therapy can modify chronic neurologic deficits after TBI. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov Identifier: NCT02416492. Submitted to registry: April 15, 2015. First participant enrolled: July 6, 2016. Available at: classic.clinicaltrials.gov/ct2/show/NCT02416492. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that intracranial implantation of allogeneic stem (SB623) cells in adults with motor deficits from chronic TBI improves motor function at 24 weeks.

Chronic pain following stroke: Current treatment and perceived effect.

BACKGROUND: Chronic pain is common following stroke, however there is little known about the treatments for pain that are being accessed by stroke survivors, nor their perceived effectiveness. OBJECTIVES: The objectives were to: i) identify the number and type of treatments for pain currently used by stroke survivors with chronic pain; and ii) examine the self-perceived effectiveness of medication and non-medication treatments for pain. METHODS: Cross-sectional survey. Participants with stroke and self-reported chronic pain completed an online survey that measured demographics, stroke related factors, intensity of pain, treatments for pain, and perceived effect of medication and non-medication treatments for pain. RESULTS: Of 322 stroke survivors who completed the survey, the majority (90.1%) reported current use of pain treatment(s). Medications were accessed by 257 (79.8%), with the most common being anti-inflammatories (39.8%), anticonvulsants (29.5%) and antidepressants (24.8%). Paracetamol (12.1%) was the most common non-prescribed medication used. Polypharmacy was high, with 129 (40.1%) reporting taking 2 or more medications. Medication treatments were self-reported to be effective in 47.1% of those taking medication. Non-medication treatments were accessed by 208 (64.6%), with Physical Therapy/Physiotherapy being most common (48.1%), followed by Occupational Therapy (15.5%) and Psychology (11.8%). Use of multiple non-medication treatments was reported by 85 (26.4%). Non-medication treatments were reported to be effective by 52.4% of those receiving them. CONCLUSIONS: Survey findings indicate that stroke survivors with chronic pain demonstrate high utilization of pain treatments, despite the perception that treatment is often ineffective. This highlights the need to develop effective pain interventions for stroke survivors.

Two-year safety and clinical outcomes in chronic ischemic stroke patients after implantation of modified bone marrow-derived mesenchymal stem cells (SB623): a phase 1/2a study.

OBJECTIVE: The aim of this study was to evaluate the safety and clinical outcomes associated with stereotactic surgical implantation of modified bone marrow-derived mesenchymal stem cells (SB623) in patients with stable chronic ischemic stroke. METHODS: This was a 2-year, open-label, single-arm, phase 1/2a study; the selected patients had chronic motor deficits between 6 and 60 months after nonhemorrhagic stroke. SB623 cells were administered to the target sites surrounding the subcortical stroke region using MRI stereotactic image guidance. RESULTS: A total of 18 patients were treated with SB623 cells. All experienced at least 1 treatment-emergent adverse event (TEAE). No patients withdrew due to adverse events, and there were no dose-limiting toxicities or deaths. The most frequent TEAE was headache related to the surgical procedure (88.9%). Seven patients experienced 9 serious adverse events, which resolved without sequelae. In 16 patients who completed 24 months of treatment, statistically significant improvements from baseline (mean) at 24 months were reported for the European Stroke Scale (ESS) score, 5.7 (95% CI 1.4-10.1, p < 0.05); National Institutes of Health Stroke Scale (NIHSS) score, -2.1 (95% CI -3.3 to -1.0, p < 0.01), Fugl-Meyer (F-M) total score, 19.4 (95% CI 9.9-29.0, p < 0.01); and F-M motor scale score, 10.4 (95% CI 4.0-16.7, p < 0.01). Measures of efficacy reached plateau by 12 months with no decline thereafter. There were no statistically significant changes in the modified Rankin Scale score. The size of transient lesions detected by T2-weighted FLAIR imaging in the ipsilateral cortex at weeks 1-2 postimplantation significantly correlated with improvement in ESS (0.619, p < 0.05) and NIHSS (-0.735, p < 0.01) scores at 24 months. CONCLUSIONS: In this completed 2-year phase 1/2a study, implantation of SB623 cells in patients with stable chronic stroke was safe and was accompanied by improvements in clinical outcomes.Clinical trial registration no.: NCT01287936 (clinicaltrials.gov).

Clinical Outcomes of Transplanted Modified Bone Marrow-Derived Mesenchymal Stem Cells in Stroke: A Phase 1/2a Study.

BACKGROUND AND PURPOSE: Preclinical data suggest that cell-based therapies have the potential to improve stroke outcomes. METHODS: Eighteen patients with stable, chronic stroke were enrolled in a 2-year, open-label, single-arm study to evaluate the safety and clinical outcomes of surgical transplantation of modified bone marrow-derived mesenchymal stem cells (SB623). RESULTS: All patients in the safety population (N=18) experienced at least 1 treatment-emergent adverse event. Six patients experienced 6 serious treatment-emergent adverse events; 2 were probably or definitely related to surgical procedure; none were related to cell treatment. All serious treatment-emergent adverse events resolved without sequelae. There were no dose-limiting toxicities or deaths. Sixteen patients completed 12 months of follow-up at the time of this analysis. Significant improvement from baseline (mean) was reported for: (1) European Stroke Scale: mean increase 6.88 (95% confidence interval, 3.5-10.3; P<0.001), (2) National Institutes of Health Stroke Scale: mean decrease 2.00 (95% confidence interval, -2.7 to -1.3; P<0.001), (3) Fugl-Meyer total score: mean increase 19.20 (95% confidence interval, 11.4-27.0; P<0.001), and (4) Fugl-Meyer motor function total score: mean increase 11.40 (95% confidence interval, 4.6-18.2; P<0.001). No changes were observed in modified Rankin Scale. The area of magnetic resonance T2 fluid-attenuated inversion recovery signal change in the ipsilateral cortex 1 week after implantation significantly correlated with clinical improvement at 12 months (P<0.001 for European Stroke Scale). CONCLUSIONS: In this interim report, SB623 cells were safe and associated with improvement in clinical outcome end points at 12 months. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01287936.

Lesion location, stability, and pretreatment management: factors affecting outcomes of endovascular treatment for vertebrobasilar atherosclerosis.

BACKGROUND AND PURPOSE: The proper role of endovascular treatment of cervicocerebral atherosclerosis is unclear. Posterior circulation disease has not been investigated as extensively as disease in the anterior circulation. In this study, we characterized the rates of technical success, transient ischemic attack, stroke, and death or disability, for both acute and elective endovascular treatment of atherosclerosis in the vertebrobasilar system. METHODS: We identified patients with atherosclerosis of the vertebrobasilar circulation who underwent endovascular intervention at our hospital through retrospective medical record review, and evaluated the association between lesion and treatment features and subsequent stroke, death, or disability at 30 days and 1 year. RESULTS: We identified 136 lesions in 122 patients, including 13 interventions for acute strokes. Technical success was achieved in 123 of 136 cases (90.4%). Elective procedures had higher rates of technical success (6.5% vs 15.4%, p=0.21) and better clinical outcomes. In multivariate analysis, intracranial lesions were associated with more disability (modified Rankin Scale score >2) at 30 days (OR 7.1, p=0.01) and 1 year (OR 10, p=0.03). Patients with non-hypoperfusion related symptoms had fewer strokes at follow-up at 1 year when treated after an asymptomatic interval of >10 days compared with those treated within 10 days of the presenting symptoms (OR 0.2, p=0.03). Statin treatment prior to intervention was associated with favorable outcomes across several examined endpoints. Preoperative antiplatelet treatment was associated with lower rates of disability at 30 days and 1 year (OR 0.1, p<0.01 and OR 0.07, p=0.01, respectively), and preoperative anticoagulation treatment was associated with higher rates of death at 30 days, particularly when prescribed for reasons other than atrial fibrillation (OR 6.4, p=0.01). CONCLUSIONS: Endovascular treatment of symptomatic vertebrobasilar atherosclerosis can be performed safely and with good outcomes. Technical results were better for those with extracranial disease while clinical outcomes were more favorable in those patients with non-progressive symptoms in the subacute period and those receiving statin therapy.

Effect of CD4+ cell count and viral suppression on risk of ischemic stroke in HIV infection.

OBJECTIVES: Evidence from the current era of combination antiretroviral therapy supports an association between HIV and cerebrovascular disease. In addition to traditional vascular risk factors, HIV-specific factors including immunodeficiency and viral replication may also predict stroke risk. The aim of this study was to determine the relationship between CD4(+) cell count, viral suppression and validated ischemic stroke outcomes. DESIGN: A single-centre, case-control study. METHODS: We identified ischemic stroke cases in HIV-infected adults from an HIV clinic using International Classification of Diseases codes for cerebrovascular disease followed by validation of each case. Controls from the same HIV clinic were selected by incidence density sampling. Demographic and clinical data, including the most recent CD4(+) cell count and plasma HIV RNA concentration, were abstracted from hospital and HIV clinic electronic medical records. Matched conditional logistic regression models were used to evaluate the association between CD4(+) cell count, viral suppression and ischemic stroke. RESULTS: In an adjusted model, viral suppression decreased the odds of ischemic stroke by a factor of 0.16 [95% confidence interval (95% CI) 0.05-0.50, P = 0.002]. This association, although attenuated [odds ratio (OR) 0.31, 95% CI 0.09-1.06, P = 0.062], remained after restricting the analysis to ischemic strokes due to true atherosclerotic mechanisms (i.e. excluding infection and malignancy-related strokes). CONCLUSION: Achieving viral suppression may reduce ischemic stroke risk, including risk of atherosclerotic strokes, in HIV-infected individuals.

Rate and predictors of serious neurologic causes of dizziness in the emergency department.

OBJECTIVE: To describe the rate and predictors of central nervous system (CNS) disease in emergency department (ED) patients with dizziness in the modern era of neuroimaging. PATIENTS AND METHODS: We retrospectively reviewed the medical records of all adults presenting between January 1, 2007, and December 31, 2009, to an academic ED for a primary triage complaint of dizziness, vertigo, or imbalance. The final diagnosis for the cause of dizziness was independently assigned by 2 neurologists, with a third neurologist resolving any disagreements. The primary outcome was a composite of ischemic stroke, intracranial hemorrhage, transient ischemic attack, seizure, brain tumor, demyelinating disease, and CNS infection. Univariate and multivariate logistic regression were used to assess the association between clinical variables and serious CNS causes of dizziness. RESULTS: Of 907 patients experiencing dizziness (mean age, 59 years; 58% women [n=529]), 49 (5%) had a serious neurologic diagnosis, including 37 cerebrovascular events. Dizziness was often caused by benign conditions, such as peripheral vertigo (294 patients [32%]) or orthostatic hypotension (121 patients [13%]). Age 60 years or older (odds ratio [OR], 5.7; 95% confidence interval [CI], 2.5-11.2), a chief complaint of imbalance (OR, 5.9; 95% CI, 2.3-15.2), and any focal examination abnormality (OR, 5.9; 95% CI, 3.1-11.2) were independently associated with serious neurologic diagnoses, whereas isolated dizziness symptoms were inversely associated (OR, 0.2; 95% CI, 0.0-0.7). CONCLUSION: Dizziness in the ED is generally benign, although a substantial fraction of patients harbor serious neurologic disease. Clinical suspicion should be heightened for patients with advanced age, imbalance, or focal deficits.

Expression of the BMP antagonist Dan during murine forebrain development.

Dan (Differential screening-selected gene aberrative in neuroblastoma, also known as N03) is a member of a class of glycoproteins shown to be secreted inhibitors of the transforming growth factor-beta (TGF-beta) and bone morphogenic protein pathways. We examined Dan expression during murine forebrain development from embryonic day 10.5 to postnatal day 14 and found that Dan was expressed in highly specific spatiotemporal patterns. In early telencephalic development, Dan is highly expressed in the fibroblasts covering the cortex. From E12.5-E14.5, Dan is also weakly expressed in a region of neuroepithelium at the medial margin of the telencephalon called the cortical hem. From E17.5 on, Dan is expressed strongly in CA3 pyramidal neurons of the hippocampus as well as in the developing thalamus and amygdala. To determine if Dan expression is correlated with the expression of any of its known ligand targets, we examined the expression of GDF-5, -6 and -7 in the forebrain and found that GDF-5 is expressed in Cajal-Retzius cells in Layer I of cortex, immediately adjacent to the expression of Dan in the meninges.