Safety and efficacy of co-careldopa as an add-on therapy to occupational and physical therapy in patients after stroke (DARS): a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Dopamine is a key modulator of striatal function and learning and might improve motor recovery after stroke. Previous small trials of dopamine agonists after stroke provide equivocal evidence of effectiveness on improving motor recovery. We aimed to assess the safety and efficacy of co-careldopa plus routine occupational and physical therapy during early rehabilitation after stroke. METHODS: This double-blind, multicentre, randomised controlled trial of co-careldopa versus placebo in addition to routine NHS occupational and physical therapy was done at 51 UK NHS acute inpatient stroke rehabilitation services. We recruited patients with new or recurrent clinically diagnosed ischaemic or haemorrhagic (excluding subarachnoid haemorrhage) stroke 5-42 days before randomisation, who were unable to walk 10 m or more, had a score of less than 7 points on the Rivermead Mobility Index, were expected to need rehabilitation, and were able to access rehabilitation after discharge from hospital. Participants were assigned (1:1) using stratified random blocks to receive 6 weeks of oral co-careldopa or matched placebo in addition to routine NHS physiotherapy and occupational therapy. The initial two doses of co-careldopa were 62·5 mg (50 mg of levodopa and 12·5 mg of carbidopa) and the remaining doses were 125 mg (100 mg of levodopa and 25 mg of carbidopa). Participants were required to take a single oral tablet 45-60 min before physiotherapy or occupational therapy session. The primary outcome was ability to walk independently, defined as a Rivermead Mobility Index score of 7 or more, at 8 weeks. Primary and safety analyses were done in the intention-to-treat population. The trial is registered on the ISRCTN registry, number ISRCTN99643613. FINDINGS: Between May 30, 2011, and March 28, 2014, of 1574 patients found eligible, 593 (mean age 68·5 years) were randomly assigned to either the co-careldopa group (n=308) or to the placebo group (n=285), on an average 18 days after stroke onset. Primary outcome data were available for all 593 patients. We found no evidence that the ability to walk independently improved with co-careldopa (125 [41%] of 308 patients) compared with placebo (127 [45%] of 285 patients; odds ratio 0·78 [95% CI 0·53-1·15]) at 8 weeks. Mortality at 12 months did not differ between the two groups (22 [7%] vs 17 [6%]). Serious adverse events were largely similar between groups. Vomiting during therapy sessions, after taking the study drug, was the most frequent adverse event and was more frequent in the co-careldopa group than the placebo group (19 [6·2%] vs 9 [3·2%]). INTERPRETATION: Co-careldopa in addition to routine occupational and physical therapy does not seem to improve walking after stroke. Further research might identify subgroups of patients with stroke who could benefit from dopaminergic therapy at different doses or times after stroke with more intensive motor therapy. FUNDING: Medical Research Council.

The DARS (Dopamine Augmented Rehabilitation in Stroke) trial: protocol for a randomised controlled trial of Co-careldopa treatment in addition to routine NHS occupational and physical therapy after stroke.

BACKGROUND: Stroke has a huge impact, leaving more than a third of affected people with lasting disability and rehabilitation remains a cornerstone treatment in the National Health Service (NHS). Recovery of mobility and arm function post-stroke occurs through re-learning to use the affected body parts and/or learning to compensate with the lesser affected side. Promising evidence suggests that the addition of Co-careldopa to physical therapy and occupational therapy may improve the recovery of arm and leg movement and lead to improved function. METHODS/DESIGN: Dopamine Augmented Rehabilitation in Stroke (DARS) is a multi-centre double-blind, randomised, placebo, controlled clinical trial of Co-careldopa in addition to routine NHS occupational therapy and physical therapy as part of early stroke rehabilitation. Participants will be randomised on a 1:1 basis to either Co-careldopa or placebo. The primary objective of the trial is to determine whether the addition of six weeks of Co-careldopa treatment to rehabilitation therapy can improve the proportion of patients who can walk independently eight weeks post-randomisation. DISCUSSION: The DARS trial will provide evidence as to whether Co-careldopa, in addition to routine NHS occupational and physical therapy, leads to a greater recovery of motor function, a reduction in carer dependency and advance rehabilitation treatments for people with stroke. TRIAL REGISTRATION: ISRCTN99643613 assigned on 4 December 2009.

Effort test performance in clinical acute brain injury, community brain injury, and epilepsy populations.

Effort tests have become commonplace within medico-legal and forensic contexts and their use is rising within clinical settings. It is recognized that some patients may fail effort tests due to cognitive impairment and not because of poor effort. However, investigation of the base rate of failure among clinical populations other than dementia is limited. Forty-seven clinical participants were recruited and comprised three subgroups: acute brain injury (N = 11), community brain injury (N = 20), and intractable epilepsy (N = 16). Base rates of failure on the Word Memory Test (WMT; Green, 2003 ) and six other less well-validated measures were investigated. A significant minority of patients failed effort tests according to standard cutoff scores, particularly patients with severe traumatic brain injury and marked frontal-executive features. The WMT was able to identify failures associated with significant cognitive impairment through the application of profile analysis and/or lowered cutoff levels. Implications for clinical assessment, effort test interpretation, and future research are discussed.

Working with a brain injury: personal experiences of returning to work following a mild or moderate brain injury.

OBJECTIVE: Most brain injuries occur in people of working age. Individuals with mild or moderate injuries may have unrecognized problems affecting return to work. Previous studies have focused on factors that predict return to work after brain injury. There is limited information about the experiences of individuals returning to work. DESIGN: Individual interviews explored the work-related expectations and experiences of workers who had sustained mild to moderate brain injury. A sampling frame ensured a spread of participants by age, injury severity and work type. METHODS: Thirty-three interviews were conducted 4-6 months post-injury. Most participants had returned to work. Interviews were transcribed verbatim for thematic analysis. RESULTS: Key emerging issues for participants were the invisibility of their injury, continuing symptoms affecting their ability to do their job and lack of advice and guidance on returning to work. Return to work support systems were considered to be poorly coordinated and managed. CONCLUSION: It is important that healthcare professionals anticipate the vocational rehabilitation needs of patients who have sustained mild to moderate brain injury. These patients may require additional coordinated interventions and specific person-centred information to ensure a successful and, most importantly, a sustained return to work.

Associated reactions after stroke: a randomized controlled trial of the effect of botulinum toxin type A.

OBJECTIVE: To measure the impact of botulinum toxin A on associated reactions in patients following stroke. DESIGN: Randomized placebo-controlled trial. PATIENTS: Forty patients with spasticity in their paretic arm (median time since stroke: 2.7 years) were randomized to botulinum toxin A (Dysport; 1000 mouse units (MU) divided between elbow, wrist and finger flexors) or placebo. METHODS: Associated reactions were measured using hand dynamometry. The effort used was measured using maximum voluntary grip in the unaffected arm. Measurements were recorded at 2 pre-treatment and 3 post-intervention times. Activities that patients felt caused associated reactions and activities that were affected by associated reactions were recorded. RESULTS: Peak associated reactions force was reduced at week 6 with botulinum toxin A compared with placebo (mean group difference 19.0 N; 95% confidence interval (CI): 7.2, 30.9; p < 0.01) and week 2 (p = 0.005), with the effect wearing off by week 12 (p = 0.09). Thirty-one patients noted associated reactions on a regular basis and 24 said that these movements interfered with daily activities. Ten of 12 patients receiving botulinum toxin A and 2 of 12 receiving placebo reported reduction in interference with daily activities (p = 0.02). CONCLUSION: Botulinum toxin A reduces associated reactions and may be a useful adjunct to other rehabilitation interventions. The impact of associated reactions on daily activities may also be reduced.

Diagnosing late onset rheumatoid arthritis, polymyalgia rheumatica, and temporal arteritis in patients presenting with polymyalgic symptoms. A prospective longterm evaluation.

OBJECTIVE: . To examine for demographic and clinical differences between late onset rheumatoid arthritis (LORA), polymyalgia rheumatica (PMR), and temporal arteritis (TA) patients presenting with polymyalgic symptoms (PMS) and to identify baseline clinical and laboratory features that would lead to a more accurate final diagnosis. METHODS: Three hundred forty-nine consecutive patients with new onset of symptoms suggestive of LORA, PMR, or TA presenting at or above age 60 years were enrolled in a prospective study. RESULTS: During followup, 9 patients diagnosed initially as PMR developed LORA (giving a final total of 145), 5 patients initially diagnosed as LORA changed diagnosis to PMR (final total 147), and 29 patients had PMS that predated TA symptoms (final total 57). The delay in diagnosis ranged from 1 to 30 months. DRB1*04 was associated with development of both LORA and TA. CONCLUSION: In about 10% of patients the correct diagnosis of LORA, PMR, and TA in those presenting with PMS may be delayed due to similarities in initial clinical presentation. Longterm followup is essential to establish correct diagnosis. Laboratory tests tend to be unhelpful, although a positive rheumatoid factor or persistently raised plasma viscosity despite steroids might indicate RA, and the presence of HLA-DRB1*04 may indicate underlying RA or TA.

Measuring movement irregularity in the upper motor neurone syndrome using normalised average rectified jerk.

Movement irregularity is a feature of the upper motor neurone (UMN) syndrome which is difficult to measure. Average rectified jerk (ARJ) has been proposed as a measure of this movement irregularity, but ARJ depends upon the duration of movement. Since movements may be slower in UMN patients, duration dependence compromises ARJ as a measure of irregularity. A normalisation technique is proposed that generates a measure of movement irregularity which is independent of movement duration: normalised average rectified jerk (NARJ). This paper presents a validation of NARJ in the UMN syndrome. Nine control subjects, nine left hemiparetic stroke patients and nine right hemiparetic stroke patients were studied. Test movements comprised elbow extension/flexion in the horizontal plane; these were recorded with an electro-goniometer and accelerometer. The effectiveness of the normalisation technique has been demonstrated using trajectories of various durations; some of these were artificially generated from participants' trajectories, in order to preserve the movement profile. The variability of NARJ and ARJ have been compared in a sample of control subjects. NARJ has been criterion validated by correlation with expert subjective rating of irregularity in a heterogeneous set of trajectories. Construct validity has been tested by discrimination between movements of control subjects, left hemiparetic stroke patients and right hemiparetic stroke patients. When comparing trajectories of identical profile but two-fold difference in movement duration, NARJ differed only 2.6% whereas ARJ differed 706%. NARJ was less reproducible in healthy participants than ARJ: median non-parametric coefficients of variation for repeated movements were 55% and 41%, respectively. Spearman rank correlation coefficient for NARJ and expert rating was 0.92 (p<0.01). NARJ measurements on right hemiparetic patients differ significantly from those made on the control group (p<0.02); corresponding ARJ measurements do not attain statistical significance. NARJ is a valid measure of movement irregularity in the UMN syndrome.