Stroke remains a leading cause of adult disability. Some degree of spontaneous behavioral recovery is usually seen in the weeks after stroke onset. Variability in recovery is substantial across human ...patients. Some principles have emerged; for example, recovery occurs slowest in those destined to have less successful outcomes. Animal studies have extended these observations, providing insight into a broad range of underlying molecular and physiological events. Brain mapping studies in human patients have provided observations at the systems level that often parallel findings in animals. In general, the best outcomes are associated with the greatest return toward the normal state of brain functional organization. Reorganization of surviving central nervous system elements supports behavioral recovery, for example, through changes in interhemispheric lateralization, activity of association cortices linked to injured zones, and organization of cortical representational maps. A number of factors influence events supporting stroke recovery, such as demographics, behavioral experience, and perhaps genetics. Such measures gain importance when viewed as covariates in therapeutic trials of restorative agents that target stroke recovery. Ann Neurol 2008;63:272–287
Spontaneous behavioral recovery is usually limited after stroke, making stroke a leading source of disability. A number of therapies in development aim to improve patient outcomes not by acutely ...salvaging threatened tissue, but instead by promoting repair and restoration of function in the subacute or chronic phase after stroke. Examples include small molecules, growth factors, cell‐based therapies, electromagnetic stimulation, device‐based strategies, and task‐oriented and repetitive training‐based interventions. Stage of development across therapies varies widely, from preclinical to late‐phase clinical trials. The optimal methods to prescribe such therapies require further studies, for example, to best identify appropriate patients or to guide features of dosing. Likely, anatomic, functional, and behavioral measures of brain state, as well as measures of injury, will each be useful in this regard. Considerations for clinical trials of restorative therapies are provided, emphasizing both similarities and points of divergence with acute stroke clinical trial design. Ann Neurol 2008;63:549–560
Among the therapeutic strategies under study to improve long-term outcome after stroke are drugs targeting events that underlie recovery. Drugs that enhance recovery are separate from those that ...promote neuroprotection or reperfusion in patients with stroke. Recovery-based drugs have distinct therapeutic targets that are related to plasticity and growth following stroke, and in general, improvements in behavioral outcome are not accompanied by a reduction in infarct volume. Interventions targeting recovery have a time window measured in days or sometimes weeks-months, suggesting potential utility for a large percentage of patients with stroke. Currently, among drugs that enhance motor recovery after stroke in humans, the strongest evidence exists for serotonergic and dopaminergic agents. Restorative therapies generally target the brain directly, in contrast to approved stroke therapeutics that target arteries, clots, platelets, glucose, or cholesterol. Targeting the brain has wide-ranging implications, for example, in relation to drug delivery. In addition, because restorative drugs aim to change brain structure and function, their effects are influenced by concomitant behavioral experience, a finding that informs selection of entry criteria, outcome measures, and biomarkers in a clinical trial setting. These points underscore the importance of a neural systems approach in studying stroke recovery.
BACKGROUND AND PURPOSE—Stroke is a leading cause of long-term disability. Limited treatment options exist for patients with chronic stroke and substantial functional deficits. The current study ...examined safety and preliminary efficacy estimates of intravenous allogeneic mesenchymal stem cells in this population.
METHODS—Entry criteria included ischemic stroke >6 months prior and substantial impairment (National Institutes of Health Stroke Scale score ≥6) and disability. Enrollees received a single intravenous dose of allogeneic ischemia-tolerant mesenchymal stem cells. Phase 1 used a dose-escalation design (3 tiers, n=5 each). Phase 2 was an expanded safety cohort. The primary end point was safety over 1-year. Secondary end points examined behavioral change.
RESULTS—In phase 1 (n=15), each dose (0.5, 1.0, and 1.5 million cells/kg body weight) was found safe, so phase 2 subjects (n=21) received 1.5 million cells/kg. At baseline, subjects (n=36) averaged 4.2±4.6 years poststroke, age 61.1±10.8 years, National Institutes of Health Stroke Scale score 8 (6.5–10), and Barthel Index 65±29. Two were lost to follow-up, one was withdrawn and 2 died (unrelated to study treatment). Of 15 serious adverse events, none was possibly or probably related to study treatment. Two mild adverse events were possibly related to study treatment, a urinary tract infection and intravenous site irritation. Treatment was safe based on serial exams, electrocardiograms, laboratory tests, and computed tomography scans of chest/abdomen/pelvis. All behavioral end points showed significant gains over the 12-months of follow-up. For example, Barthel Index scores increased by 6.8±11.4 points (mean±SD) at 6-months (P=0.002) and by 10.8±15.5 points at 12-months (P<0.001) post-infusion; the proportion of patients achieving excellent functional outcome (Barthel score ≥95) increased from 11.4% at baseline to 27.3% at 6-months and to 35.5% at 12-months.
CONCLUSIONS—Intravenous transfusion of allogeneic ischemia-tolerant mesenchymal stem cell in patients with chronic stroke and substantial functional deficits was safe and suggested behavioral gains. These data support proceeding to a randomized, placebo-controlled study of this therapy in this population.
CLINICAL TRIAL REGISTRATION—URLhttps://www.clinicaltrials.gov. Unique identifierNCT01297413.
The first Stroke Recovery and Rehabilitation Roundtable established a game changing set of new standards for stroke recovery research. Common language and definitions were required to develop an ...agreed framework spanning the four working groups: translation of basic science, biomarkers of stroke recovery, measurement in clinical trials and intervention development and reporting. This paper outlines the working definitions established by our group and an agreed vision for accelerating progress in stroke recovery research.
With increasing rates of survival throughout the past several years, stroke remains one of the leading causes of adult disability. Following the onset of stroke, spontaneous mechanisms of recovery at ...the cellular, molecular, and systems levels ensue. The degree of spontaneous recovery is generally incomplete and variable among individuals. Typically, the best recovery outcomes entail the restitution of function in injured but surviving neural matter. An assortment of restorative therapies exists or is under development with the goal of potentiating restitution of function in damaged areas or in nearby ipsilesional regions by fostering neuroplastic changes, which often rely on mechanisms similar to those observed during spontaneous recovery. Advancements in stroke rehabilitation depend on the elucidation of both spontaneous and therapeutic-driven mechanisms of recovery. Further, the implementation of neural biomarkers in research and clinical settings will enable a multimodal approach to probing brain state and predicting the extent of post-stroke functional recovery. This review will discuss spontaneous and therapeutic-induced mechanisms driving post-stroke functional recovery while underscoring several potential restorative therapies and biomarkers.
Stroke remains a major cause of human disability worldwide. In parallel with advances in acute stroke interventions, new therapies are under development that target restorative processes. Such ...therapies have a treatment time window measured in days, weeks, or longer and so have the advantage that they may be accessible by a majority of patients. Several categories of restorative therapy have been studied and are reviewed herein, including drugs, growth factors, monoclonal antibodies, activity-related therapies including telerehabilitation, and a host of devices such as those related to brain stimulation or robotics. Many patients with stroke do not receive acute stroke therapies or receive them and do not derive benefit, often surviving for years thereafter. Therapies based on neural repair hold the promise of providing additional treatment options to a majority of patients with stroke.
OBJECTIVES:To evaluate the quality of preclinical evidence for mesenchymal stromal cell (MSC) treatment of ischemic stroke, determine effect size of MSC therapy, and identify clinical measures that ...correlate with differences in MSC effects.
METHODS:A literature search identified studies of MSCs in animal models of cerebral ischemia. For each, a Quality Score was derived, and effect size of MSCs was determined for the most common behavioral and histologic endpoints.
RESULTS:Of 46 studies, 44 reported that MSCs significantly improved outcome. The median Quality Score was 5.5 (of 10). The median effect size was 1.78 for modified Neurological Severity Score, 1.73 for the adhesive removal test, 1.02 for the rotarod test, and 0.93 for infarct volume reduction. Quality Score correlated significantly and positively with effect size for the modified Neurological Severity Score. Effect sizes varied significantly with clinical measures such as administration route (intracerebral > intra-arterial > IV, although effect size for IV was nonetheless very large at 1.55) and species receiving MSCs (primate > rat > mouse). Because many MSC mechanisms are restorative, analyses were repeated examining only the 36 preclinical studies administering MSCs ≥24 hours poststroke; results were overall very similar.
CONCLUSIONS:In preclinical studies, MSCs have consistently improved multiple outcome measures, with very large effect sizes. Results were robust across species studied, administration route, species of MSC origin, timing, degree of immunogenicity, and dose, and in the presence of comorbidities. In contrast to meta-analyses of preclinical data for other stroke therapies, higher-quality MSC preclinical studies were associated with larger behavioral gains. These findings support the utility of further studies to translate MSCs in the treatment of ischemic stroke in humans.
...the mRS is a single score that reflects the combined functioning of many different neural systems. ...a score of 3 (moderate disability) could arise from visual, executive, language, or motor ...deficits. ...hypothesis testing in early phase translational recovery trials benefits from aligning endpoints with entry criteria. ...it is unclear whether S44819-mediated increases in cortical excitability do not improve stroke outcomes, or if S44819 simply does not increase cortical excitability in humans after a stroke.
The first Stroke Recovery and Rehabilitation Roundtable established a game changing set of new standards for stroke recovery research. Common language and definitions were required to develop an ...agreed framework spanning the four working groups: translation of basic science, biomarkers of stroke recovery, measurement in clinical trials and intervention development and reporting. This paper outlines the working definitions established by our group and an agreed vision for accelerating progress in stroke recovery research.
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