Clinical Rehabilitation 2010; 24: 501–513

Does low-dose botulinum toxin help the recovery of arm function when given early after stroke? A phase II randomized controlled pilot study to estimate effect size Elizabeth Cousins School of Health and Rehabilitation, Keele University and Institute for Science and Technology in Medicine, Anthony Ward North Staffordshire Rehabilitation Centre, Stoke on Trent, Christine Roffe Stroke Service, University Hospital of North Staffordshire, Institute for Life Course Studies, Keele University, Lesley Rimington School of Health and Rehabilitation, Keele University and Institute for Life Course Studies, Keele University and Anand Pandyan School of Health and Rehabilitation, Keele University and Institute for Science and Technology in Medicine, Keele University, Staffordshire, UK Received 20th January 2009; returned for revisions 14th March 2009; revised manuscript accepted 14th November 2009.

Objective: Spasticity after stroke may be associated with worse functional outcome. Our study aim is to establish whether a low dose of botulinum toxin, given early post stroke before clinically evident spasticity warrants treatment, will improve recovery of arm function. Design: A double-blind randomized placebo-controlled trial. Setting: An acute stroke unit. Subjects: Individuals recruited within three weeks of stroke onset with severe arm function deficits. Interventions: Injections of quarter and half standard dose botulinum toxin A to the upper limb, with a control of normal saline injections. Main measures: Arm function, active and passive movement, and spasticity at elbow and wrist were recorded at baseline, and at 4, 8, 12 and 20 weeks post intervention. A pre-planned subgroup analysis included only subjects with no arm function at baseline (Action Research Arm Test score ¼ 0). Results: Thirty subjects were recruited, and 21 completed all assessments. Arm function scores improved in all three groups between baseline and week 20. There was no benefit for active treatment over control in the whole group analysis. In the subgroup analysis the active groups improved when compared with the control group and effect sizes for improvement in this subgroup were 0.6 and 0.5 for the quarter dose and half dose groups respectively. Conclusions: Individuals with no arm function within three weeks of stroke may benefit functionally from botulinum toxin. Using the effect size of 0.5, further studies would need a minimum of 101 participants in each group to confirm this finding.

Background

Address for correspondence: Dr Anand Pandyan, School of Health and Rehabilitation, Keele University, Staffs, UK. e-mail: [email protected]

Spasticity is a phenomenon defined as ‘disordered sensori-motor control, resulting from an upper motor neuron lesion, presenting as intermittent or sustained involuntary activation of muscles’.1

ß The Author(s), 2010. Reprints and permissions: http://www.sagepub.co.uk/journalsPermissions.nav

10.1177/0269215509358945

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E Cousins et al.

About 20% of patients have clinical signs of spasticity (as measured with a clinical scale of stiffness) three months after the stroke, and 30–40% at one year.2,3 Recent data suggest that prevalence of spasticity can be as high as 80% six weeks post stroke for those without arm function when muscle activation levels are recorded.4 Spasticity poses challenges both to the individual experiencing the spasticity and to their rehabilitation team.5 It may contribute to loss of function as well as to the development of joint contractures and pain.6 Initial management involves physiotherapy, positioning and removal of aggravating factors.7 Pharmacological treatment, such as botulinum toxin, is indicated for the management of established focal spasticity causing functional problems or pain and unresponsive to conservative measures.8 Botulinum toxin temporarily blocks the exocytosis of acetylcholine at the neuromuscular junction, thus leading to a temporary reduction in muscle activity.9 Recovery at the neuromuscular junction occurs over a period of a few weeks, and by three months post injection with botulinum toxin, the neuromuscular junction functions as well as it did prior to injection.9 In routine clinical practice, botulinum toxin is normally given once the clinical signs of spasticity have become established; therefore it is usually given at least three months post stroke. By this time secondary complications such as pain and changes in muscle and tendon structure are likely to be established.10 If spasticity (i.e. increased muscle activation levels) could be reduced in individuals before secondary complications become established, there may be a subsequent beneficial effect on functional outcomes. While botulinum toxin is an established treatment for post-stroke spasticity, current evidence for improvement of arm function following treatment is weak, due to methodological issues including patient selection and choice of outcome measure.11–13 This study tests the hypothesis that botulinum toxin, given early after the stroke, before clinical evidence of severe spasticity is established, will help recovery of arm function by preventing secondary complications. Current recommendations for dosing of botulinum toxin are based on studies which used indirect rather than direct measures of spasticity and which were carried out on individuals at a later stage of recovery, when potential confounding factors of

secondary biomechanical changes could already have been present.14–16 In two of these studies excessive muscle weakening in the highest dose group was reported.14,16 There is likely to be a trade-off between shutting down excessive muscle activity and paralysing the muscle altogether. The use of standard doses of botulinum toxin may lead to weakening of the muscles injected. Since patients recruited to this study do not yet have evidence of clinically significant spasticity it was considered that a smaller dose of botulinum toxin would be sufficient to prevent clinically evident spasticity without reducing strength of the injected muscles. Patients with more severe strokes and greater functional deficits after the stroke are more likely to develop clinical signs of spasticity.17 It can therefore be hypothesized that patients with severe strokes and no significant recovery of arm function early after the stroke are more likely to benefit from early botulinum toxin treatment. In this study therefore an additional subgroup analysis was planned in patients with no functional recovery at baseline. The aim of the pilot study presented here is to establish the effect size of treatment with low dose (half standard dose and quarter standard dose) botulinum toxin given early, before there is evidence of clinically significant spasticity, on recovery of arm function in patients within three weeks of acute stroke.

Methods This is a single-centre phase II randomized double-blind placebo-controlled pilot study with the primary aim of establishing the effect size for treatment with half standard dose of botulinum toxin and quarter standard dose when compared with placebo. Patients were recruited from the stroke unit of the University Hospital of North Staffordshire, a large teaching hospital. The protocol was approved by the North Staffordshire Local Research Ethics Committee (ref. 03/34). Because botulinum toxin was used outside its licensed indications in patients without clinical signs of spasticity, permission was also applied for and gained from the Department of Health Medicines Control Agency (Medicines

Low-dose botulinum toxin for the arm post stroke Exemption from Licenses Special Cases and Miscellaneous Provisions Order 1972 to use BOTOX ref. no: MF 8000/12447). Informed consent was sought from all competent participants. In subjects who were unable to give fully informed consent, assent from the next of kin was accepted. Potential participants were approached within three weeks of a first stroke affecting upper limb function. Adult subjects were eligible for inclusion if they were unable to score the maximum on the easiest test of the Grasp subsection of the Action Research Arm Test18 (i.e. if they were unable to, or experienced difficulty with lifting a 2 cm cube onto a shelf with their affected hand). Subjects were excluded from participation if they had any neurological or musculoskeletal condition that affected upper limb function prior to the stroke, if they had a brainstem stroke, if the stroke affected both hemispheres, or if they were unconscious or moribund. Participants who were unable to score in any section of the Action Research Arm Test were identified so they could then be included in the planned subgroup analysis of those without return of arm function. Following recruitment participants were randomized to one of three groups (telephone randomization) using a computer-generated randomization sequence to which the assessor was blinded. Figure 1 shows the number of patients screened for the study, the number recruited, drop-outs and the final number of participants analysed.

Intervention Botulinum toxin (BOTOX) was used as active treatment, and the same volume of normal saline was used as control. The standard doses and the muscles to inject were chosen by a rehabilitation consultant with extensive experience of botulinum toxin injection on the basis of published guidance7 and clinical experience. These were 100 IU for biceps brachii, 60 IU for brachialis, 50 IU for brachioradialis, 50 IU for flexor digitorum superficialis and 50 IU for flexor digitorum profundus. For this study the identified standard doses were halved or quartered dependent on the group the participant had been allocated to. Both assessor and participant were blinded as to which intervention was received.

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There was a wide range of patients who were eligible for this study, with consequent potential for significant intra-subject variations within the sample. The dose for each subject was calculated not using the weight of the participant (which may not be reflective of the muscle mass of the participants), but rather using an estimation of muscle mass. Anthropometric measures of mid upper arm circumference and triceps skinfold thickness were taken, which were then used with a formula to estimate upper arm muscle area (Appendix 1). These were then evaluated against published upper arm anthropometric norms for elderly white subjects which had been calculated using the same formula.19 In participants whose upper arm muscle area fell within the upper and lower 25th percentiles the botulinum toxin dose was increased or decreased by 25% respectively. Thus, an individual with normal muscle mass allocated to the half dose group would be given 50 U BOTOX, but this would be increased to 62.5 U for individuals with an upper arm muscle area in the upper 25th percentile, and reduced to 37.5 U if muscle mass was in the lower 25th percentile. Assessments Participants were assessed on recruitment to the trial, and again at 4, 8, 12 and 20 weeks post injection. The same assessor carried out all the assessments. The primary outcome measure was upper limb function, assessed using the Action Research Arm Test18 (scores for individual tasks on the Action Research Arm Test depend on whether the specific task is partially completed, or completed, and in this study a score of zero was given if the subject was unable to reach and grasp the object). Secondary outcome measures were spasticity, grip strength, range of movement (both active and passive) and isometric muscle strength at the elbow and the wrist. Spasticity was assessed using a neurophysiological measure of muscle activation levels during an externally imposed passive stretch of the joints at a slow velocity. Surface electromyography (sEMG) was used to monitor muscle activation levels during this imposed movement. The additional measures of range of movement and isometric muscle strength of elbow, wrist and grip were taken using an electrogoniometer

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E Cousins et al. 1287 patients admitted to an acute stroke unit screened

1227 patients excluded

60 approached

593 176 175 92 89 38

TIA / rapid recovery of UL function Too unwell for consideration Previous history of CVA Recruited to conflicting research trials Co-morbidities affecting upper limb function Transferred onto Acute Stroke Unit outside of recruitment window 30 Transferred out of area 22 Subarachnoid haemorrhage/space-occupying lesion 12 No next of kin available to approach for assent

30 participants recruited

30 refused to participate in trial

Group A Half dose 9 patients

Group B Quarter dose 10 patients

Group C Placebo 11 patients

Losses n = 0

Losses n=3 1 medical opinion 2 restroked after baseline assessment

Losses n =6 1 withdrew 2 RIP 2 required treatment with BTX and were unblinded and withdrawn from study 1 had subsequent subdural haemorrhage

Numbers completing study =9

Numbers completing study=7

Numbers completing study=5

2 individuals who had data post intervention included in analysis Numbers included in analysis=7

Figure 1

Flow diagram for study participants.

and a JAMAR dynamometer (Biometrics Ltd, Cwmfelinfach, Gwent, UK), respectively. A data acquisition system (DataLINK; Biometrics Ltd) was used to record the sEMG, electrogoniometer and JAMAR dynamometer data.

Participants were positioned in sitting or, if they were unable to tolerate a sitting position for the duration of the assessment session, half lying. Surface EMG electrodes were placed over the biceps, triceps, long wrist and finger flexors and

Low-dose botulinum toxin for the arm post stroke the long wrist and finger extensors. Where available, guidelines written by the Surface Electromyography for the Non-Invasive Assessment of Muscles group were adopted for the surface electromyography procedures.20 The reference electrode was placed over the olecranon of the affected arm. Two electrogoniometers were placed, one spanning the elbow joint, the other the wrist. The starting position for all elbow assessments was with the shoulder abducted and supported at 90 degrees, or as close as could be achieved without the patient complaining of pain. Holding a custom-built, hand-held force transducer (Biometrics Ltd) placed immediately proximal to the subject’s wrist, the elbow was initially moved from maximal flexion through to maximal extension at a slow velocity. During this movement muscle activity levels in the biceps during the slow stretch was measured. Active flexion at the elbow was assessed with the arm fully supported by the assessor, and the arm held in maximal extension. The participant was then asked to bend their arm as far as possible. For active elbow extension the participants were asked to straighten their arm from a position of maximum flexion. Isometric elbow muscle strength was recorded with the arm fully supported, and the elbow placed at 90 degrees. A hand-held force transducer was held against the wrist while the participant was asked to actively resist elbow flexion followed by elbow extension. Wrist assessment for spasticity followed previously published protocols.4 For isometric muscle strength measurements at the wrist the force transducer was placed in either the palm of the hand (for flexor strength) or across the dorsum of the hand (for extensor strength). Grip strength measurements took place in the same starting position as the wrist measurements. The JAMAR dynamometer was placed in the participant’s hand, and the assessor maintained this position of the JAMAR. Participants were instructed to attempt a maximal grip and to maintain that grip for a 10-second period. Data analysis Raw sEMG data were notch filtered (50 Hz) and then smoothed using root mean square methods (20 ms window width). For the analysis of spasticity the average integrated sEMG levels

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(referenced to angular displacement) were calculated during the slow passive stretches. This was done in Mathcad version 12.1 (Mathsoft Engineering and Education). Two analyses were carried out on the data: first, a whole-group analysis including all patients for whom there was completed data, and second, the previously defined subgroup analysis including only patients who had no arm function (defined as an Action Research Arm Test score of 0) at baseline. The time points used for the effect size calculation were the baseline and final assessment taken 20 weeks post intervention. A Kruskal–Wallis test was initially carried out on the baseline data to test for any differences between the groups in the whole group and subgroup analysis. The primary outcome measure was upper limb function assessed by the Action Research Arm Test. The score was treated as interval level data for the purposes of the analyses. The effect sizes were calculated using the mean difference of the changes recorded in upper extremity function from baseline to the final assessment 20 weeks post intervention. The difference between the means of the two groups was then divided by the pooled variance to establish the effect size. The analysis of spasticity measures included all the data collection points over the study period so that any trends of an increase or decrease in spasticity following the intervention could be observed. Missing data were handled in the following manner. Where data were available either side of a missing data point, the mean of the two data points on either side of the missing one was calculated, and used. Where a participant had data post intervention but had subsequently been lost to follow-up, the last data point available was used for the subsequent missed assessments.

Results One thousand two hundred and eighty-seven individuals admitted with stroke to the study hospital’s stroke unit were screened over a period of two years. From this, 30 participants were recruited to the study. The flow diagram in Figure 1 shows the recruitment data including reasons for exclusion

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from the study, and the subsequent randomization and progress of participants through the trial. The mean age of participants was 69 years (SD 11.8), and the male:female ratio was 13:17. Seventeen of the participants had a severe stroke (total anterior circulation syndrome), and 13 had less severe strokes (9 partial anterior circulation syndrome, 4 lacunar syndrome). Of the 30 participants, 10 (30%) had had a right hemiparesis. The mean time from stroke onset to baseline assessment was 23 (SD 9) days. Nine participants were lost to follow-up (Figure 1). Two developed clinical signs of spasticity of sufficient concern to their clinicians to warrant treatment with botulinum toxin. These two participants were therefore removed from the trial in order to unblind them, and allow for appropriate treatment. Both were in the placebo group. Reasons for the withdrawal of the other seven participants are documented in Figure 1. Of these seven, five were withdrawn from the study after the baseline assessment, and in the absence of any data post intervention, these participants were removed from the analysis. The remaining two participants did have valid data from after the intervention, and these were included in the analysis. The analysis was therefore carried out on 23 participants, nine of whom were in the half dose group, and seven each in the quarter dose and placebo group. No serious adverse events related to the administration of botulinum toxin were reported during this study. The high level of attrition observed during the follow-up period was due to events unrelated to the intervention. One participant complained of excessive pain during the injections, but otherwise the injections were well tolerated by the study participants. The subgroup analysis of patients who had no arm function at baseline (Action Research Arm Test ¼ 0) included 17 participants (8 randomized to the half dose group, 5 to the quarter dose group, and 4 to the placebo group). Baseline data for passive and active range of movement and isometric muscle strength at the wrist and elbow are contained within Table 1 for the whole-group analysis, and Table 2 for the subgroup analysis. In the whole-group analysis there were no significant differences between the three treatment groups (P-values ranged from 0.2 to 0.91, Kruskal–Wallis test). In the subgroup analysis of subjects without arm function at baseline

there were also no significant differences between the groups (P-values ranged from 0.09 to 0.6), except for the active range of elbow flexion, which was greater in the quarter dose than in the other two groups (P ¼ 0.03). Table 1 shows the changes in arm function, range of movement and isometric muscle strength between the baseline and the final 20-week assessment for the whole-group analysis. The mean for the groups at the week 0 and week 20 assessment points are presented, along with the mean difference within the groups and the mean difference between the groups. Confidence intervals have been calculated for the mean difference between the groups. Table 2 shows the equivalent data for the subgroup analysis. The difference within the groups shows that in the whole-group analysis arm function improved in all three groups over the course of the study. However, there was no apparent benefit to the treatment groups over the placebo group. In the subgroup of subjects with no arm function at baseline (n ¼ 17) there was no improvement in arm function over 20 weeks (mean Action Research Arm Test change ¼ 1, SD 1) in the control group, while subjects in the active treatment groups did improve (mean Action Research Arm test change ¼ 7 (SD 9) and 6 (SD 10) for quarter dose and half dose respectively). The change in the level of spasticity as assessed by sEMG activity during slow passive stretch from baseline to final follow-up is shown in Table 3. For each group, at each data collection point, the mean and standard deviation of the levels of flexor muscle activity during the imposed stretch into extension were calculated. Higher levels indicate a greater response from flexor muscles during the imposed stretch. An increase in the levels within a group at successive data collection points indicates an increase in abnormal muscle activity during this passive movement (i.e. an increase in spasticity). A decrease in the mean levels of flexor muscle activity therefore indicates a reduction in spasticity. Effect size In the whole-group analysis the mean changes in the Action Research Arm Test score from baseline to week 20 were an 11.0 point improvement in the half dose group, a 6.4 point improvement in the

0.4 (1.3)

(26.5) (6.6) (4.7) (10.7) (2.6)

(2.5) (9.6) (11.0) (1.7) (2.8)

34.3 28.0 22.5 18.6 20.1

41.9 51.7 27.0 18.0 (57.6) (39.5) (31.9) (31.1) (33.2)

(27.3) (34.3) (31.2) (23.0) 28.0 37.8 24.7 17.9 14.1

65.2 59.5 27.7 21.6 (21.3) (22.8) (22.0) (14.1) (10.8)

(35.1) (39.3) (30.4) (11.6)

11.4 (19.4) 7.3 (8.0)

Half dose

Quarter dose

39.6 39.0 23.2 15.2 12.3

69.7 61.2 19.6 11.0 (37.9) (33.2) (20.6) (13.2) (12.8)

(36.0) (44.8) (18.5) (18.9) 30.8 22.5 19.3 16.6 18.8

19.0 37.8 23.9 17.2 (50.1) (32.8) (29.5) (27.7) (30.8)

(37.5) (30.0) (30.0) (20.8) 26.6 29.6 18.5 17.3 13.0

21.5 18.0 21.5 19.3

(20.0) (21.6) (16.8) (14.4) (12.3)

(41.4) (42.0) (28.0) (11.0)

14.1 (21.8) 11.0 (18.2) 6.4 (7.5)

Placebo (n ¼ 7)

SD, standard deviation; CI, confidence interval; ARAT, Action Research Arm Test.

13.0 6.5 3.7 6.1 2.0

(35.1) (52.4) (16.1) (9.7)

1.3 (2.0)

(36.0) 25.4 (52.0) 32.4 (9.4) 8.9 (4.8) 1.0

0.9 (1.9)

Quarter dose (n ¼ 7)

Half dose (n ¼ 9)

Half dose (n ¼ 9)

Placebo (n ¼ 7)

Week 20–week 0 Mean (SD)

Week 20 Mean (SD)

Week 0 Mean (SD) Quarter dose (n ¼ 7)

Difference within groups

Groups

Active range of movement (degrees) Elbow flexion 22.9 (42.5) 43.7 Elbow extension 13.9 (28.2) 41.5 Wrist flexion 3.1 (5.4) 6.2 Wrist extension 0.8 (4.4) 2.3 Strength (Newtons) Grip 3.5 (8.3) 1.4 Elbow flexion 5.5 (12.6) 8.2 Elbow extension 3.2 (6.9) 6.2 Wrist flexion 2.0 (6.1) 0.6 Wrist extension 1.3 (3.8) 1.1

ARAT

Outcome

(37.8) (39.6) (20.02) (23.2) 26.6 (17.5) 32.5 (29.9) 19.5 (16.8) 9.1 (5.4) 10.3 (10.3)

44.3 28.8 10.7 12.0

12.8 (20.0)

Placebo

4 10 0 8 9

25 9 13 5

(39 (44 (27 (15 (18

(66 (28 (15 (18

to to to to to

to to to to

47) 24) 27) 30) 35)

15) 46) 42) 29)

2 (22 to 19)

(69 (58 (18 (14

to to to to

23) 37) 39) 28) 0 (22 to 22) 3 (33 to 28) 1 (21 to 19) 8 (5 to 21) 3 (11 to 16)

23 11 11 7

7 (24 to 11)

Half dose-placebo Quarter dose-placebo

Week 20–week 0 Mean (95% CI)

Difference between groups

Table 1 Mean of groups (standard deviation), mean difference within groups (standard deviation), and mean difference between groups (95% CI), whole-group analysis

Low-dose botulinum toxin for the arm post stroke 507

0 (0)

0 (0)

15.9 19.1 17.4 12.1 12.7

0 (0) 2.1 (4.1) 2.2 (2.7) 0 (0) 0.8 (1.7)

(17.8) (31.1) (30.0) (25.8) (26.3)

(25.0) (30.0) (29.6) (20.9) 31.7 40.1 22.7 20.1 16.2

67.5 60.4 28.9 22.0 (21.7) (20.8) (22.3) (16.6) (1.9)

(36.9) (40.2) (37.1) (14.1)

7 (8.5)

23.6 (21.4) 34.3 (46.2) 10.4 (13.3) 5.7 (4.0) 5.2 (5.5)

52.3 (39.3) 43.1 (47.1) 8.9 (10.2) 4.6 (4.6)

0.75 (1.0)

SD, standard deviation; CI, confidence interval; ARAT, Action Research Arm Test.

37.2 45.1 22.3 14.0

5.75 (9.8)

1.9 (2.2) 0.9 (1.8) 0 (0) 0 (0)

0 (0)

15.0 17.5 16.4 12.1 12.7

28.1 40.5 20.8 13.4

(18.2) (31.2) (30.1) (25.8) (26.3)

(27.4) (30.9) (30.4) (20.5)

5.75 (9.8)

29.7 36.3 16.0 20.1 16.2

35.7 34.2 23.1 18.8

(20.1) (19.1) (16.7) (16.6) (1.9)

(40.4) (38.9) (33.9) (13.4)

7 (8.5)

23.6 (21.4) 32.2 (42.1) 8.2 (10.6) 5.7 (4.0) 4.4 (3.9)

50.4 (37.4) 42.2 (46.0) 8.9 (10.2) 4.6 (4.6)

0.75 (1.0)

Quarter dose Placebo

Half dose (n ¼ 8)

Half dose Quarter dose Placebo (n ¼ 8) (n ¼ 5) (n ¼ 4)

Half dose

Week 20–week 0 Mean (SD)

Week 20 Mean (SD)

Week 0 Mean (SD) Quarter dose Placebo (n ¼ 5) (n ¼ 4)

Difference within groups

Groups

Active range of movement (degrees) Elbow flexion 9.1 (10.2) 31.8 (32.6) Elbow extension 4.6 (4.8) 26.2 (47.0) Wrist flexion 1.5 (2.8) 5.8 (10.3) Wrist extension 0.6 (1.7) 3.2 (5.6) Strength (Newtons) Grip 0.9 (2.4) 2.0 (2.8) Elbow flexion 1.6 (4.4) 3.8 (4.0) Elbow extension 1.0 (1.8) 6.7 (13.0) Wrist flexion 0 (0) 0 (0) Wrist extension 0 (0) 0 (0)

ARAT

Outcome

15 (77 to 47) 8 (75 to 59) 14 (29 to 56) 14 (3 to 31) 6.1 (27 to 39) 4 (45 to 53) 8 (15 to 31) 14 (6 to 35) 12 (3 to 27)

9 (35 to 18) 15 (62 to 33) 8 (27 to 44) 6 (23 to 36) 8 (22 to 38)

6 (4 to 16)

Quarter dose–placebo

22 (64 to 20) 2 (51 to 48) 12 (24 to 47) 9 (14 to 33)

5 (6 to 16)

Half dose–placebo

Week 20–week 0 Mean (95% CI)

Difference between groups

Table 2 Mean of groups (SD), mean difference within groups (SD), and mean difference between groups (95% CI) for subgroup analysis Action Research Arm Test week 0 ¼ 0

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Low-dose botulinum toxin for the arm post stroke Table 3

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Change in the EMG level of spasticity during slow passive stretch from baseline to week 20 EMG level (mV)

All participants Elbow Wrist Subgroup ARAT W0 ¼ 0 Elbow Wrist

Week 0

Week 4

Week 8

Week 12

Week 20

Half dose Quarter dose Placebo Half dose Quarter dose Placebo

16.4 13.6 15.3 10.1 10.3 26.4

(11.1) (13.1) (12.7) (5.8) (5.3) (25.6)

13.8 (12.8) 7.5 (3.4) 28.8 (19.5) 8.4 (4.9) 10.8 (6.5) 31.6 (29.8)

13.8 (13.7) 18.2 (22.4) 24.2 (16.6) 9.8 (2.4) 12.9 (8.0) 46.6 (48.9)

16.6 21.9 21.8 11.8 22.1 25.2

(16.5) (24.0) (20.5) (10.6) (15.4) (20.5)

20.2 27.2 22.5 14.6 24.4 29.6

Half dose Quarter dose Placebo Half dose Quarter dose placebo

15.6 (11.5) 11.9 (14.0) 17.5 (16.0) 8.7 (4.0) 9.1 (5.9) 32.8 (28.1)

14.2 (13.7) 6.1 (2.6) 31.8 (17.3) 8.6 (5.3) 8.5 (5.1) 38.3 (36.5)

14.0 (14.6) 18.64 (25.0) 26.5 (17.7) 9.4 (2.1) 11.9 (8.5) 68.5 (53.7)

15.8 20.9 23.0 11.7 20.5 29.0

(17.4) (29.3) (20.0) (11.3) (17.2) (23.0)

21.4 (20.8) 19.2 (24.5) 23.15 (19.9) 15.3 (13.5) 21.6 (28.3) 34.5 (20.1)

(19.7) (25.3) (21.0) (12.8) (24.5) (17.8)

All values are mean (SD). SD, standard deviation; ARAT, Action Research Arm Test.

quarter dose group, and a 12.9 point improvement in the placebo group. The effect sizes were 0.1 (95% confidence intervals (CI) 1.7 to 1.0) for the half dose group, and 0.4 (95% CI 0.7 to 0.5) for the quarter dose group, in favour of the placebo group (Appendix 2). In the subgroup of participants with no arm function at baseline there was some improvement in mean Action Research Arm Test scores in the two actively treated groups (a difference from baseline of 5.75 for the half dose and 7.0 for the quarter dose group), but no improvement in the placebo group (Action Research Arm Test score difference of 0.75). As the variance for the placebo group was very low in this subgroup, instead of using the pooled variance of the two groups, the variance of the half dose (or quarter dose group) alone was used. The impact of this would be to underestimate any effect size gained. The effect size for the half dose was calculated as 0.5 (95% CI 0.7 to 1.7), and for the quarter dose 0.6 (95% CI 1.0 to 2.3). These effect sizes are in favour of the treatment groups.

Discussion In the whole-group analysis arm function improved in all three study groups with no apparent benefit to

the treatment groups over the placebo group. In the subgroup analysis both treatment groups made clinically meaningful functional gains,21 while the control group made no improvement. The confidence intervals for the results are quite broad, indicating a wide variation in recovery within the study participants. This could indicate that some individuals did not respond to the intervention with improved functional outcomes, while other participants made excellent functional progress following the intervention. Overall the results of this study indicate that while early botulinum toxin treatment may not be beneficial for individuals who have some recovery of active arm function within a month post stroke, individuals who have had no recovery of arm function may benefit from early injection with low-dose botulinum toxin. These findings would need confirmation through a further study. Using the effect size obtained for the quarter dose, this study would need 52 participants in each group, with a power of 90% at a significance level of 0.05. Assuming an attrition level of 25% such as occurred in this pilot, 65 participants would need to be recruited to each group in a quarter dose study. The equivalent numbers for a half dose study would be 81 participants completing the assessments, which would require recruitment of 101 individuals.

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Mean EMG levels during slow stretch (mV)

Clinically evident spasticity does not usually become a problem within the first month after a stroke,2 but the data from this study suggest that sEMG evidence of spasticity is present even at this early stage (Table 3). This finding is in agreement with a recent study that evaluated the early development of spasticity in a severely impaired population.4 In both the whole-group and the subgroup analyses, sEMG activity levels increased at both the elbow and wrist between the baseline and week 4 in the placebo group indicating the development of spasticity. This is in contrast to the two treatment groups where sEMG activity reduced or remained stable. An example of the change in sEMG activity with time is shown in Figure 2. Spasticity developed later in the active treatment groups, between 8 and 12 weeks after the administration of botulinum toxin. The timing of the development of spasticity in the actively treated groups may be related to dosing, with an earlier increase in sEMG activity in the quarter dose group than in the half dose group. It is likely that the larger dose had a longer lasting effect, compatible with the three-month period of effectiveness normally attributed to botulinum toxin.9 Any effects of the botulinum toxin in the quarter dose group would appear to have worn off within two months of injection. Spasticity levels in the placebo group decreased in the week 12 and 20 assessments. Overall, spasticity levels across all three groups became similar at the final 20-week assessment.

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EMG levels during slow stretch of the elbow - whole group analysis

30 25 20 15 10

Half dose Quarter dose

5

Placebo

0 Week 0

Figure 2

The results from both the whole group and the subgroup analysis indicate that botulinum toxin did prevent worsening of spasticity immediately post injection, but that once the effect of the drug has worn off, muscle activity levels increased. The fall in muscle activity levels in the placebo group after 4–8 weeks is also of interest. This may be due to plasticity within the central nervous system with consequent reduction in abnormal muscle activity levels. In the actively treated groups an increase in spasticity levels occurred between 8–12 weeks post intervention, later than the increase observed in the placebo group and maintained to the end of follow-up. It is unknown whether these groups too would have followed a similar trend to that observed in the placebo group of increased activity levels not being sustained in the long term. All the participants who were included in the subgroup analysis had very limited active movement capabilities at baseline (Table 2), with the exception of the quarter dose group who had good active movement capabilities at the elbow. It is therefore likely that the significant difference observed at baseline in active elbow flexion occurred as a result of this difference. During the course of the study, all groups regained active movement and some isometric muscle strength, except that this recovery was reduced at the wrist in the placebo group in comparison with the treatment groups. Two earlier studies, which also used

Week 4

Week 8

Week 12

Week 20

Line chart showing EMG levels in the biceps during slow stretch of the elbow – whole-group analysis.

Low-dose botulinum toxin for the arm post stroke lower doses of botulinum toxin,22,23 found unexpected increases in elbow or grip strength post injection. This finding of force generation not necessarily being impaired following administration of a low dose of botulinum toxin fits well with the results presented here. The Action Research Arm Test is a measure of arm function, divided into four sections, three of which require distal recovery as well as proximal. The improvements in the Action Research Arm Test observed in the treatment groups could be indicative of the improved levels of distal function in these two groups, or of lack of sufficient distal recovery in the placebo group. Although the cause of this return of distal movement in the intervention groups alone cannot be established, it is noted that the spasticity levels in the wrist for both treatment groups in this subgroup analysis were lower at baseline than those of the placebo group. These levels remained lower than those in the placebo group throughout the follow-up of this study (Table 3). It may be that by altering the time-course of spasticity development, functional outcome may have been influenced. While this could stem directly from botulinum toxin, an altered time-course may have allowed for an improved effectiveness of therapy during the acute rehabilitation period. One limitation of this study is the low numbers of participants completing the follow-up. Participants were recruited within the first month of stroke onset, and many had had severe neurological deficits. The commonest reasons for withdrawal from the study were medical complications such as extension of the stroke or pneumonia. These complications are common in patients with severe strokes, and as such the high attrition levels reflect the severity of the original stroke rather than an effect of the intervention. There were low numbers of eligible participants for the study, and a high percentage (50%) of those who were eligible declined to participate. In this study, the most common reasons for exclusion were a mild stroke (either subsequently classified as a transient ischaemic attack or with rapid resolution of upper limb symptoms), history of a previous stroke or being too unwell in the acute period post stroke to be considered for inclusion. A proportion of potential participants had to be excluded as they had already been recruited to alternative acute

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stroke research projects. It has been observed that recruitment to rehabilitation trials post stroke is difficult24 so these low eligibility rates are not necessarily unusual. The high number of eligible participants who declined to take part is of interest. Ethically, potential participants do not have to give a reason for refusal to enter a trial, therefore exact information on the underlying reasons behind these refusals is not available. Anecdotally many potential participants did acknowledge to the recruiter that they would rather see how things progressed before committing to a trial of this nature. This may reflect that recruitment in this trial occurred prior to spasticity being clinically evident in the majority of the participants. Spasticity is not necessarily a complication of stroke that potential recruits could appreciate despite descriptions. Recruitment to the study depended upon individuals appreciating a hypothetical description of a problem they had never come across before, or had witnessed. It is therefore probably not surprising that several potential recruits did not feel that there was a need to prevent spasticity and thus consent to participation in the trial. The aim of this study was to establish an effect size for the use of botulinum toxin early after stroke in promoting recovery of upper limb function, therefore an intention-to-treat approach was not considered appropriate. The effect size calculation was, however, carried out on all participants who had data which could be included. The two participants who had to be removed from the study for unblinding and subsequent treatment with botulinum toxin had both been allocated to the placebo group. Neither of these participants had any functional abilities at the baseline assessment. Given the extent of their clinical problems with spasticity, it is unlikely that either would have made functional progress without treatment. The withdrawal of these two unblinded participants in the effect size calculation is justified. The follow-up for this study was 20 weeks, and thus the effects of botulinum toxin on the neuromuscular junction should have ceased by the time of the final measures, although potentially not the preceding measure, taken at 12 weeks post injection. A longer follow-up might have yielded further information on the trends observed in the spasticity data and how this develops over time. Assessments of spasticity were done using sEMG to monitor muscle activation levels. This serial

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nature of the measurements meant that there were possibilities of confounding factors due to electrode position and the velocity of movement in the limb. While accepting that this is a limiting factor, efforts were made to control for this as much as possible. Electrode position was standardized for each participant, and analysis of velocity data for the slow movement showed acceptable consistency. The spasticity measurements could have been controlled further through the use of apparatus that could control the velocity and position of the perturbation.25 The use of such apparatus would, however, have limited recruitment to participants who could tolerate the apparatus. The adoption of the manual techniques used in this study allowed for the inclusion of participants with severe levels of disability who otherwise may not have been able to tolerate more inflexible assessment procedures. As early functional deficits are known to be associated with subsequent development of spasticity,17 it was considered preferable to adopt the more flexible assessment tools that would allow for inclusion of severely impaired individuals. As with many other similar studies, the confounding effects associated with non-specific rehabilitation therapy cannot be ruled out. There is always the possibility that patients who had responded to treatment with botulinum toxin may have received a different form of therapy to those who did not. Therefore, the functional recovery may have been secondary to this additional therapy. However, as this was a double-blind trial a systematic difference in treatment is unlikely. Clinical messages  Individuals who have had no recovery of arm function within a month post stroke may benefit from early injection with low dose botulinum toxin.  Spasticity is present in individuals with loss of arm function post stroke, within a month of stroke onset.

Acknowledgements The authors would like to thank Dr Prabath Fernando, Dr Sandip Dutta and Dr Annelies

Vreeburg, who administered all the injections for the study, and the participants, who made this study possible. The study received support from the North Staffordshire Medical Institute and an unrestricted educational grant from Allergan Ltd.

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Low-dose botulinum toxin for the arm post stroke 10 Pandyan AD, Cameron M, Powell J, Stott DJ, Granat MH. Contractures in the post-stroke wrist: a pilot study of its time course of development and its association with upper limb recovery. Clin Rehabil 2003; 17: 88–95. 11 Sheaan GL. Botulinum treatment of spasticity: why is it so difficult to show a functional benefit? Curr Opin Neurol 2001; 14: 771–76. 12 Pandyan AD, Price CIM, Barnes MP, Johnson GR. A biomechanical investigation into the validity of the Modified Ashworth Scale as a measure of elbow spasticity. Clin Rehabil 2003; 17: 290–94. 13 Pandyan AD, Johnson GR, Price CIM, Curless RH, Barnes MP. A review of the properties and limitations of the Ashworth and Modified Ashworth Scales as measures. Clin Rehabil 1999; 13: 373–83. 14 Bakheit AMO, Thilmann AF, Ward AB et al. A randomized, double-blind, placebo-controlled, dose-ranging study to compare the efficacy and safety of three doses of botulinum toxin type A (Dysport) with placebo in upper limb spasticity after stroke. Stroke 2000; 31: 2402–406. 15 Childers MK, Brashear A, Jozefczyk P et al. Dose-dependent response to intramuscular botulinum toxin type A for upper-limb spasticity in patients after a stroke. Arch Phys Med Rehabil 2004; 85: 1063–69. 16 Suputtitada A, Suwanwela NC. The lowest effective dose of botulinum A toxin in adult patients with upper limb spasticity. Disabil Rehabil 2005; 27: 176–84. 17 Leathley MJ, Gregson JM, Moore AP, Smith TL, Sharma AK, Watkins CL. Predicting spasticity after stroke in those surviving to 12 months. Clin Rehabil 2004; 18: 438–43. 18 Lyle RC. A performance test for assessment of upper limb function in physical rehabilitation treatment and research. Int J Rehabil Res 1981; 4: 483–92. 19 Falciglia G, O’Connor J, Gedling E. Upper arm anthropometric norms in elderly white subjects. J Am Diet Assoc 1988; 88: 569–74. 20 Hermens HJ, Freriks B, Merletti R et al. SENIAM:European recommendations for surface electromyography. Roessingh, Roessingh Research and Development, 1999. 21 Van der Lee JH, Wagenaar RC, Lankhorst GJ, Vogelaar TW, Deville´ WL, Bouter LM. Forced use of the upper extremity in chronic stroke patients: results from a single-blind randomized clinical trial. Stroke 1999; 30: 2369–75.

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22 Pandyan AD, Vuadens P, van Wijck FMJ, Stark S, Johnson GR, Barnes MP. Are we underestimating the clinical efficacy of botulinum toxin (type A)? Quantifying changes in spasticity, strength and upper limb function after injections of Botox to the elbow flexors in a unilateral stroke population. Clin Rehabil 2002; 16: 654–60. 23 Simpson DM, Alexander DN, O’Brien CF et al. Botulinum toxin type A in the treatment of upper extremity spasticity: a randomized, double-blind, placebo-controlled trial. Neurology 1996; 46: 1306–10. 24 Blanton S, Morris DM, Prettyman MG et al. Lessons learned in participant recruitment and retention: the EXCITE trial. Phys Ther 2006; 86: 1520–33. 25 Burridge JH, Wood DE, Hermens HJ et al. Theoretical and methodological considerations in the measurement of spasticity. Disabil Rehabil 2005; 27: 69–80.

Appendix 1 – Estimation of upper arm muscle area Estimation of the upper arm muscle area was achieved using the following.19 Two measurements were taken: triceps skinfold and arm circumference at the mid-point of the upper arm. Arm muscle circumference was calculated as: arm circumference  ð  triceps skinfoldÞ Arm muscle area was then calculated as ¼ arm muscle circumference=4 All measurements were taken in cm.

Appendix 2 – Formula for the calculation of the confidence intervals for effect size ffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi s  Ne þ Nc d2 CI : ¼ þ Ne  Nc 2  ðNe þ Nc Þ where CI is 95% confidence interval, Ne is sample size of experimental group and Nc is sample size of control group.