The effects of increased dose of exercise-based therapies to enhance motor recovery after stroke: a systematic review and meta-analysis.

BACKGROUND: Exercise-based therapy is known to enhance motor recovery after stroke but the most appropriate amount, i.e. the dose, of therapy is unknown. To determine the strength of current evidence for provision of a higher dose of the same types of exercise-based therapy to enhance motor recovery after stroke. METHODS: An electronic search of: MEDLINE, EMBASE, CINHAL, AMED, and CENTRAL was undertaken. Two independent reviewers selected studies using predetermined inclusion criteria: randomised or quasi randomised controlled trials with or without blinding of assessors; adults, 18+ years, with a clinical diagnosis of stroke; experimental and control group interventions identical except for dose; exercise-based interventions investigated; and outcome measures of motor impairment, movement control or functional activity. Two reviewers independently extracted outcome and follow-up data. Effect sizes and 95% confidence intervals were interpreted with reference to risk of bias in included studies. RESULTS: 9 papers reporting 7 studies were included. Only 3 of the 7 included studies had all design elements assessed as low risk of bias. Intensity of the control intervention ranged from a mean of 9 to 28 hours over a maximum of 20 weeks. Experimental groups received between 14 and 92 hours of therapy over a maximum of 20 weeks. The included studies were heterogeneous with respect to types of therapy, outcome measures and time-points for outcome and follow-up. Consequently, most effect sizes relate to one study only. Single study effect sizes suggest a trend for better recovery with increased dose at the end of therapy but this trend was less evident at follow-up Meta-analysis was possible at outcome for: hand-grip strength, -10.1 [-19.1,-1.2] (2 studies, 97 participants); Action Research Arm Test (ARAT), 0.1 [-5.7,6.0] (3 studies, 126 participants); and comfortable walking speed, 0.3 [0.1,0.5] (2 studies, 58 participants). At follow-up, between 12 and 26 weeks after start of therapy, meta-analysis findings were: Motricity Arm, 10.7 [1.7,19.8] (2 studies, 83 participants); ARAT, 2.2 [-6.0,10.4] (2 studies, 83 participants); Rivermead Mobility, 1.0 [-0.6, 2.5] (2 studies, 83 participants); and comfortable walking speed, 0.2 [0.0,0.4] (2 studies, 60 participants). CONCLUSIONS: Current evidence provides some, but limited, support for the hypothesis that a higher dose of the same type of exercised-based therapy enhances motor recovery after stroke. Prospective dose-finding studies are required.

Effects of conventional physical therapy and functional strength training on upper limb motor recovery after stroke: a randomized phase II study.

BACKGROUND: Functional training and muscle strength training may improve upper limb motor recovery after stroke. Combining these as functional strength training (FST) might enhance the benefit, but it is unclear whether this is better than conventional physical therapy (CPT). Comparing FST with CPT is not straightforward. OBJECTIVE: This study aimed at assessing the feasibility of conducting a phase III trial comparing CPT with FST for upper limb recovery. METHODS: Randomized, observer-blind, phase II trial. Subjects had upper limb weakness within 3 months of anterior circulation infarction. Subjects were randomized to CPT (no extra therapy), CPT + CPT, and CPT + FST. Intervention lasted 6 weeks. Primary outcome measure was the Action Research Arm Test (ARAT). Measurements were taken before treatment began, after 6 weeks of intervention, and 12 weeks thereafter. Attrition rate was calculated and differences between groups were interpreted using descriptive statistics. ARAT data were used to inform a power calculation. RESULTS: Thirty subjects were recruited (8% of people screened). Attrition rate was 6.7% at outcome and 40% at follow-up. At outcome the CPT + FST group showed the largest increase in ARAT score and this was above the clinically important level of 5.7 points. Median (interquartile range) increases were 11.5 (21.0) for CPT; 8.0 (13.3) for CPT + CPT; and 19.5 (22.0) for CPT + FST. The estimated sample size for an adequately powered subsequent phase III trial was 279 subjects at outcome. CONCLUSION: Further work toward a phase III clinical trial appears justifiable.

Informing dose-finding studies of repetitive transcranial magnetic stimulation to enhance motor function: a qualitative systematic review.

OBJECTIVE: Repetitive transcranial magnetic stimulation (rTMS) of the lesioned hemisphere might enhance motor recovery after stroke, but the appropriate dose (parameters of rTMS) remains uncertain. The present review collates evidence of the effect of rTMS on corticospinal pathway excitability and motor function in healthy adults and in people after stroke. METHODS: The authors searched MEDLINE and EMBASE (1996 to April 2007), their own collection of peer-reviewed articles, and the reference lists of included studies. They included healthy adults or people with stroke who received rTMS to the primary motor cortex to facilitate or inhibit contralateral corticospinal excitability or movement control. FINDINGS: Of the 625 references identified, 37 studies were included with 455 healthy adults (34 studies) and 69 people with stroke (3 studies). For healthy adults, the effects of rTMS on corticospinal pathway excitability varied within each frequency, for example, 1 Hz rTMS was found to facilitate, inhibit, and have no effect on amplitude of motor-evoked potentials (MEPs). After stroke there was a trend for recovery of MEPs (ie, presence of MEPs) after 10 daily sessions of 3 Hz rTMS (one study). Motor function in healthy adults might be adversely affected by 1 Hz rTMS (two studies), whereas combined frequency rTMS was found to have no effect (one study). INTERPRETATION: There is as yet insufficient published evidence to guide the dose of rTMS to the lesioned hemisphere after stroke to improve recovery of a paretic limb. Moreover, it is apparent that there is variability in response to rTMS in healthy adults. Dose-finding studies in groups of well-characterized stroke patients are needed.

Sensory loss in hospital-admitted people with stroke: characteristics, associated factors, and relationship with function.

OBJECTIVE: To characterize the nature of sensory impairments after stroke, identify associated factors, and assess the relationships between sensory impairment, disability, and recovery. METHODS: Prospective cross-sectional survey of 102 people with hemiparesis following their first stroke. Tactile and proprioceptive sensation in the affected arm and leg were measured using the Rivermead Assessment of Somatosensory Perception 2-4 weeks post-stroke. Demographics, stroke pathology, weakness, neglect, disability, and recovery were documented. RESULTS: Tactile impairment was more common than proprioceptive (P < .000), impairment of discrimination was more common than detection (P < .000), and tactile sensation was more severely impaired in the leg than the arm ( P < .000). No difference in proprioception between the arm and leg (P = .703) or between proximal and distal joints (P = .589, P = .705) was found. The degree of weakness and the degree of stroke severity were significantly associated with sensory impairment; demographics, stroke side and type, and neglect were not associated. All the sensory modalities were significantly related to independence, mobility, and recovery (r = 0.287 [P < .011] to r = 0.533 [P < .000]). CONCLUSION: Sensory impairments of all modalities are common after stroke, although tactile impairment is more frequent than proprioceptive loss, especially in the leg. They are associated with the degree of weakness and the degree of stroke severity but not demographics, stroke pathology, or neglect, and they are related to mobility, independence in activities of daily living, and recovery.

The relationship between balance, disability, and recovery after stroke: predictive validity of the Brunel Balance Assessment.

OBJECTIVE: To examine the influence of balance disability on function and the recovery of function after stroke and consequently to assess the predictive validity of the Brunel Balance Assessment (BBA). METHODS: Cross-sectional study of 102 patients admitted consecutively to 6 National Health Service hospitals with weakness 2 to 4 weeks after their first anterior circulation stroke; 75 of whom completed follow-up assessment at 3 months. The BBA was assessed during admission and compared to the Barthel Index and Rivermead Mobility Index at 3 months. RESULTS: Balance disability was the strongest predictor of function (in terms of activities of daily living [ADLs] and mobility disability) in the acute stages. Weakness was also an independent predictor. Recovery of ADLs was independently predicted by balance disability, weakness, age, and premorbid disability, whereas recovery of mobility disability was predicted by balance and age alone. At 3 months, a minority of people with limited sitting balance (0%-22%) and standing balance (25%-50%) recovered independent functional mobility. Most people who could walk initially recovered independent functional mobility (66%-84%), but 16% suffered a decline in their mobility and 44% had enduring limitations in everyday mobility activities. CONCLUSION: Initial balance disability is a strong predictor of function and recovery after stroke. These results demonstrate the predictive validity of the BBA.

Transcranial magnetic stimulation and muscle contraction to enhance stroke recovery: a randomized proof-of-principle and feasibility investigation.

OBJECTIVE: To explore the efficacy of repetitive transcranial magnetic stimulation (rTMS) and voluntary muscle contraction (VMC) to improve corticospinal transmission, muscle function, and purposeful movement early after stroke. METHODS: Factorial 2 x 2 randomized single-blind trial. SUBJECTS: n = 27, mean age 75 years, mean 27 days after middle cerebral artery infarct (24 subjects completed outcome measures). PROCEDURE: after baseline measurement (day 1), subjects were randomized to 1 of 4 groups. Treatment was given for the next 8 working days, and outcome was measured on day 10. INTERVENTIONS: (a) Real-rTMS + RealVMC, (b) Real-rTMS + PlaceboVMC, (c) Placebo-rTMS + RealVMC, and (d) Placebo-rTMS + PlaceboVMC. Real-rTMS consisted of 200 1-Hz stimuli at 120% motor threshold in 5 blocks of 40 separated by 3 minutes delivered to the lesioned hemisphere. Placebo-rTMS used a dummy coil. In RealVMC, the paretic elbow was repeatedly flexed/extended for 5 minutes. In PlaceboVMC, subjects viewed pairs of drawings of upper limbs and reported their likeness. OUTCOMES: frequency of motor-evoked potentials in biceps and triceps, muscle function (torque about elbow), and purposeful movement (Action Research Arm Test). ANALYSIS: group mean changes (outcome - baseline) were compared. RESULTS: In the Real-rTMS + RealVMC group, motor-evoked potential frequency increased 14% for biceps and 20% for triceps, whereas in the Placebo-rTMS + PlaceboVMC group, it decreased 12% for biceps and 6% for triceps. For other groups, there were changes of intermediate values. No meaningful differences were found for secondary outcomes. CONCLUSIONS: A positive trend for motor-evoked potential frequency was found for Real-rTMS + RealVMC, whereas a negative trend for motor-evoked potential frequency was found for Placebo-rTMS + PlaceboVMC.

Balance disability after stroke.

BACKGROUND AND PURPOSE: Balance disability is common after stroke, but there is little detailed information about it. The aims of this study were to investigate the frequency of balance disability; to characterize different levels of disability; and to identify demographics, stroke pathology factors, and impairments associated with balance disability. SUBJECTS: The subjects studied were 75 people with a first-time anterior circulation stroke; 37 subjects were men, the mean age was 71.5 years (SD=12.2), and 46 subjects (61%) had left hemiplegia. METHODS: Prospective hospital-based cross-sectional surveys were carried out in 2 British National Health Service trusts. The subjects' stroke pathology, demographics, balance disability, function, and neurologic impairments were recorded in a single testing session 2 to 4 weeks after stroke. RESULTS: A total of 83% of the subjects (n=62) had a balance disability; of these, 17 (27%) could sit but not stand, 25 (40%) could stand but not step, and 20 (33%) could step and walk but still had limited balance. Subjects with the most severe balance disability had more severe strokes, impairments, and disabilities. Weakness and sensation were associated with balance disability. Subject demographics, stroke pathology, and visuospatial neglect were not associated with balance disability. DISCUSSION AND CONCLUSION: Subjects with the most severe balance disability had the most severe strokes, impairments, and disabilities. Subject demographics, stroke pathology, and visuospatial neglect were not associated with balance disability.

Distribution of weakness in the upper and lower limbs post-stroke.

OBJECTIVE: To assess the distribution of weakness in the upper and lower limbs post-stroke and the factors associated with weakness. METHOD: The design was a prospective cross-sectional survey. A consecutive sample of 75 patients (37 (49%) men, mean age 71.5 (SD 12.2) years, 46 (61%) left hemiplegics) with a first-time anterior-circulation stroke, tested 2 - 4 weeks post-stroke, were recruited from two NHS trusts. MAIN OUTCOME MEASURES: Weakness (Motricity Index, MI). RESULTS: Mean MI score was 58.5 (SD 39.6) and 69.1 (SD 33.6) for the upper and lower limb (p < 0.001), but examination of individual data indicated 36 (48%) had no/ negligible difference (0 +/- 9 points) in MI score between the limbs. When there was a difference, the lower limb was more frequently the stronger. There was no significant difference between the proximal and distal joints in either limb (p < 0.217 and 0.410). Severity of weakness was not associated with the subjects' demographics or stroke pathology, but was associated with neglect and sensation. CONCLUSIONS: Although group analysis showed that the leg was significantly stronger than the arm, individual analysis showed that most participants had a similar degree of weakness in both limbs. When there was a difference, the lower limb was more frequently the stronger. Proximal joints were not more severely affected than distal joints. Patient demographics and stroke pathology factors were not associated with weakness, but stroke-related impairments were.

Late-onset seizures as a predictor of subsequent stroke.

UNLABELLED: BACKGROUND Cerebrovascular disease is thought to be a major cause of epilepsy in late life. We investigated the hypothesis that the onset of seizures after the age of 60 years in people with no history of overt stroke might be associated with an increased risk of subsequent stroke. METHODS: Data were obtained from the UK General Practice Research Database on 4709 individuals who had seizures beginning at or after the age of 60 years, and on 4709 randomly selected controls with no history of seizures, matched for age, sex, and general practice. Individuals with a history of cerebrovascular disease, other acquired brain injury, brain tumour, drug or alcohol misuse, or dementia were not eligible for inclusion. Computerised patients' records were searched for subsequent diagnoses of stroke. FINDINGS: Log-rank testing, adjusted for matching, showed a highly significant difference in stroke-free survival between the two groups (p<0.0001). With a Cox's model, we estimated that the relative hazard of stroke at any point for people with seizures compared with the control group was 2.89 (95% CI 2.45-3.41). INTERPRETATION: Our findings show that the onset of seizures in late life is associated with a striking increase in the risk of stroke. Further research is warranted to assess the benefit of specific interventions to prevent stroke in patients with seizures.

The potential for utilizing the "mirror neurone system" to enhance recovery of the severely affected upper limb early after stroke: a review and hypothesis.

Recovery of upper limb movement control after stroke might be enhanced by repetitive goal-directed functional activities. Providing such activity is challenging in the presence of severe paresis. A possible new approach is based on the discovery of mirror neurons in the monkey cortical area F5, which are active both in observing and executing a movement. Indirect evidence for a comparable human "mirror neurone system" is provided by functional imaging. The primary motor cortex, the premotor cortex, other brain areas, and muscles appropriate for the action being observed are probably activated in healthy volunteers observing another's movement. These findings raise the hypothesis that observation of another's movement might train the movement execution system of stroke patients who have severe paresis to bring them to the point at which they could actively participate in rehabilitation consisting of goal-directed activities. The point of providing an observation therapy would be to facilitate the voluntary production of movement; therefore, the condition of interest would be observation with intent to imitate. However, there is as yet insufficient evidence to enable the testing of this hypothesis in stroke patients. Studies in normal subjects are needed to determine which brain sites are activated in response to observation with intent to imitate. Studies in stroke subjects are needed to determine how activation is affected after damage to different brain areas. The information from such studies should aid identification of those stroke patients who might be most likely to benefit from observation to imitate and therefore guide phase I clinical studies.

The treatment of Alzheimer's disease: success short of cure.

Metaphor has an important role in the discussion of scientific discovery because it enables researchers to talk about things of which their understanding is incomplete. Alzheimer's disease (AD) can be seen as a journey down a path, which becomes steadily less pleasant and ends in a wholly undesirable destination. To further the metaphor, treatments can be seen as attempts to help the patient return to the starting point, to slow the journey, or to stop at some point on the path. However, treatment may be successful but may not return the patient to their starting point or slow disease progression. We argue that treatments that steer the patient down a different path, to a destination preferable to that at the end of the AD path, can also be seen as successful. This metaphor has practical implications for clinical trials. It highlights the importance of individualised outcome measures that incorporate patients' preferences and should encourage us to develop better means of enabling the recovery of self. To understand how there can be treatment success short of cure, without knowing at the outset what form that success may take, will require systematic observation and careful description of patients' experiences.

Neurological rehabilitation: a science struggling to come of age.

Over the last few decades, there have been considerable improvements in the outcome of stroke patients both as regards mortality and disability. At least some of these improvements can be attributed to better organization of services and improved rehabilitation. Many patients, however, remain severely disabled and we will need to develop new strategies in which the focus will be on reversing impairments rather than simply helping patients to adapt to unaltered impairments. For this to happen, neurological rehabilitation research will have to develop therapies that have a clearly defined rationale and are rooted in neurosciences, are clinically described, are addressed to a well-characterized target population and are evaluated using appropriate outcome measures. Few studies at present meet all these criteria. The recent revolution in our understanding of the nervous system as being soft-wired, of the potential for recovery through reorganization and of the central role of afferent information associated with normal activity is ground for optimism and indicates the direction in which future therapies should be sought. The paper considers some approaches to providing appropriate afferent information, including inputs such as that from electrotherapy, novel approaches to assisted activity and constraint-induced therapy. We are on the verge of a revolution in neurological rehabilitation. If we exploit the new understanding of the nervous system arising from basic neurosciences in developing and evaluating therapies we should be able to build on the achievements of the last few decades so that fewer of our patients have to carry the burden of severe disability.

Dose-response study of mobilisation and tactile stimulation therapy for the upper extremity early after stroke: a phase I trial.

BACKGROUND: Physical therapy doses may need to be higher than provided in current clinical practice, especially for patients with severe paresis. The authors aimed to find the most effective and feasible dose of Mobilisation and Tactile Stimulation (MTS), which includes joint and soft-tissue mobilization and passive or active-assisted movement to enhance voluntary muscle contraction. METHODS: This 2-center, randomized, controlled, observer-blinded feasibility trial compared conventional rehabilitation but no extra therapy (group 1) with conventional therapy plus 1 of 3 daily doses of MTS, up to 30 (group 2), 60 (group 3), or 120 (group 4) minutes for 14 days. The 76 participants had substantial paresis (Motricity Index [MI] < 61) a mean of 30 days (standard deviation [SD] = 20 days) after anterior circulation stroke. MTS was delivered using a standardized schedule of techniques (eg, sensory input, active-assisted movement). The primary outcome was the Motricity Index (MI) and secondary outcome was the Action Research Arm Test (ARAT) tested on day 16. Adverse events were monitored daily. RESULTS: No difference was found in the change in control group MI compared with each of the 3 intervention groups (P = .593) or in the ARAT. Mean actual daily treatment time for all MTS groups was less than expected. The attrition rate was 1.3%. No adverse events related to overuse occurred. CONCLUSION: The authors were not able to deliver a maximum dose of 120 minutes of daily therapy each day. The mean daily dose of MTS feasible for subsequent evaluation is between 37 and 66 minutes.