Exploring threats to generalisability in a large international rehabilitation trial (AVERT).

OBJECTIVE: The purpose of this paper is to examine potential threats to generalisability of the results of a multicentre randomised controlled trial using data from A Very Early Rehabilitation Trial (AVERT). DESIGN: AVERT is a prospective, parallel group, assessor-blinded randomised clinical trial. This paper presents data assessing the generalisability of AVERT. SETTING: Acute stroke units at 44 hospitals in 8 countries. PARTICIPANTS: The first 20,000 patients screened for AVERT, of whom 1158 were recruited and randomised. MODEL: We use the Proximal Similarity Model, which considers the person, place, and setting and practice, as a framework for considering generalisability. As well as comparing the recruited patients with the target population, we also performed an exploratory analysis of the demographic, clinical, site and process factors associated with recruitment. RESULTS: The demographics and stroke characteristics of the included patients in the trial were broadly similar to population-based norms, with the exception that AVERT had a greater proportion of men. The most common reason for non-recruitment was late arrival to hospital (ie, >24 h). Overall, being older and female reduced the odds of recruitment to the trial. More women than men were excluded for most of the reasons, including refusal. The odds of exclusion due to early deterioration were particularly high for those with severe stroke (OR=10.4, p<0.001, 95% CI 9.27 to 11.65). CONCLUSIONS: A model which explores person, place, and setting and practice factors can provide important information about the external validity of a trial, and could be applied to other clinical trials. TRIAL REGISTRATION NUMBER: Australian New Zealand Clinical Trials Registry (ACTRN12606000185561) and Clinicaltrials.gov (NCT01846247).

Exercise reduces infarct volume and facilitates neurobehavioral recovery: results from a systematic review and meta-analysis of exercise in experimental models of focal ischemia.

BACKGROUND: Regular exercise reduces the risk of a first-ever stroke and is associated with smaller infarcts. Although evidence has suggested that therapeutic exercise following stroke is beneficial, we do not yet know whether exercise reduces stroke severity and improves functional recovery. The mechanisms underlying any benefit remain unclear. OBJECTIVE: To conduct a systematic review and meta-analysis of studies testing exercise in animal models of ischemic stroke where outcomes were measured as infarct volume, neurobehavioral score, neurogenesis, or a combination of these. We also sought evidence of publication bias. METHODS: We searched 3 online databases for publications reporting the use of exercise in focal cerebral ischemia. We used DerSimonian and Laird normalized random-effects meta-analysis and meta-regression to determine the impact of study quality and design on the efficacy of exercise. RESULTS. Overall, exercise reduced infarct volume by 25.2% (95% confidence interval [CI] = 19.0%-31.3%; 65 experiments and 986 animals) and improved neurobehavioral score by 38.2% (95% CI = 29.1%-47.3%; 42 experiments; n = 771). For both outcomes, larger effects were seen when exercise preceded ischemia rather than came after it. For neurobehavioral scores, we found evidence of publication bias. Reported study quality was moderate (median score 5/10). Both model-specific (e.g., type of ischemia) and exercise-specific characteristics influenced reported outcome. CONCLUSION. Exercise, either before or after ischemia, reduced infarct volume and improved neurobehavioral score. However, overall estimates of efficacy were higher in studies at risk of bias, and for neurobehavioral outcomes, there was evidence of a substantial publication bias.

Stroke rehabilitation in China: a systematic review and meta-analysis.

BACKGROUND: Stroke rehabilitation is regarded as an essential component of organized care, therefore withholding treatment is considered unethical in Western trials. Poststroke rehabilitation is not standard in China, and trials with no treatment controls have been possible. We believed aggregation of these data represented a unique opportunity to examine the 'effect size' of this intervention. AIM: The aim of this study was to systematically review randomized controlled trials that compare rehabilitation to standard care after stroke in China. METHODS: We searched 24 databases including Wanfangdata (China), MEDLINE, EMBASE, CENTRAL, Cochrane Stroke Group Register, and Cochrane Central Register of Controlled trials. The primary outcome of interest was activities of daily living (Barthel Index), and the secondary outcome was disability (Fugl-Meyer Score). Random-effect meta-analysis was performed. RESULTS: Thirty-seven randomized controlled trials consisting of 5916 patients met inclusion criteria. Mean age reported in each study range from 47.2 to 72.5 years, 52.6% were male and 23.8% had a haemorrhagic stroke. Rehabilitation interventions varied between studies, but all included additional exercise therapy. Control patients had no formal rehabilitation. Patients who received rehabilitation showed marked improvements in Barthel Index (standardized mean difference: 1.04, 95% confidence interval: 0.88-1.21, P < 0.001, I(2) = 85.9%) and Fugl-Meyer Score (standardized mean difference: 1.10, 95% confidence interval: 0.82-1.38, P < 0.001, I(2) = 94.3%) compared with controls. However, reporting quality was low, and time to start of rehabilitation was often unclear. CONCLUSION: These data provide some evidence that rehabilitation poststroke is more effective than no rehabilitation, improving activities of daily living and reducing disability. Although results are limited by low reporting quality and study heterogeneity, conducting research in countries in which rehabilitation is not standard care provides an opportunity to advance our understanding and should be encouraged.

Exploring the efficacy of constraint in animal models of stroke: meta-analysis and systematic review of the current evidence.

BACKGROUND: Constraint-induced movement therapy (CIMT) is used to counteract learned nonuse observed following stroke in humans and has been shown to improve function. Variations of CIMT used in animal models of stroke have the potential to inform and improve our understanding of this intervention. OBJECTIVE: To conduct a systematic review of studies investigating constraint in experimental stroke. The authors aimed to assess the quality and establish the efficacy of constraint on neurobehavior, cognitive function, infarct size, and stress and mortality and to determine the optimal dose or time to administration. METHODS: Systematic review with meta-analysis was used. Data were analyzed using DerSimonian and Laird weighted-mean-difference random effects meta-analysis. RESULTS: The quality scores of the 8 articles (15 studies) included were moderate (median 5/10; interquartile range, 4.8-6.0). There was a trend for animals with constraint to have worse neurobehavioral scores (-10% worse; 95% confidence interval [CI] = -20 to 0; P = .06). Infarct volumes were not significantly different between groups (-3% larger with constraint; 95% CI = -15 to 9; P = .63). Cognitive function was significantly better after constraint, although this estimate was based on only 28 animals from 2 studies. Insufficient data prevented analysis of the effect of constraint on stress and mortality. CONCLUSIONS: This meta-analysis showed no benefit of constraint on neurobehavioral scores, which is at odds with some human studies. Animal models may help us efficiently explore the biological basis of rehabilitation interventions; however, review of the data in this study raise uncertainty about its effectiveness in humans.

Post-lesion transcommissural olivocerebellar reinnervation improves motor function following unilateral pedunculotomy in the neonatal rat.

In the adult mammalian central nervous system, reinnervation and recovery from trauma are limited. During development, however, post-lesion plasticity may generate alternate paths providing models to investigate reinnervation and repair. Sometimes, these paths are maladaptive, although the relationship between dysfunction and anatomical abnormality remains unknown. After unilateral transection of the neonatal rat olivocerebellar path (pedunculotomy), axons from the remaining inferior olive reinnervate Purkinje cells in the denervated hemicerebellum with appropriate topography and synaptic function. However, whether this new pathway confers beneficial behavioural effects remains unknown. We studied the behavioural sequelae in rats with and without transcommissural reinnervation using righting and vestibular-drop reflexes, simple locomotion (bridge), complex locomotion (wire) and motor coordination (rotarod) tests. In animals pedunculotomised on day 3 (Px3), which develop olivocerebellar reinnervation, dynamic postural adjustments and complex motor skills develop normally, whereas simple gait is broad-based and slightly delayed. In contrast, Px11 animals, which do not develop reinnervation, have delayed maturation of postural reflexes, gait and complex locomotor skills. In addition, when compared to control animals, their performance in locomotory tasks was slower and the complex task impaired. On the rotarod, control and Px3 animals learned to coordinate their gait and walked for longer at 10 and 20 rpm than Px11 animals. These results show that transcommissural olivocerebellar reinnervation is associated with almost normal motor development and the ability to synchronise gait at slow and moderate speeds, i.e. this reinnervation confers significant behavioural function and is therefore truly compensatory.