A Preliminary Assessment of the Benefits of the Addition of Botulinum Toxin A to a Conventional Therapy Program on the Function of People With Longstanding Stroke

Article Outline

• Abstract
• Methods
  • Procedures
  • Functional Assessments
    • Primary
    • Secondary
  • Physiologic Assessments
    • Primary
    • Secondary
  • Study Medication
  • Therapy Intervention Procedures
  • Concomitant Spasticity-Related Medications
  • Statistical Methods
  • Power Calculation
• Results
  • Participants
  • Primary Functional Outcome
    • Motor Activity Log
    • Amount of use
    • Quality of movement
  • Primary Physiologic Outcome
    • Ashworth score
    • Ashworth wrist extension
    • Wrist flexion
    • Elbow extension
  • Secondary Physiologic Measures
    • Range of motion
    • Active wrist extension ROM
    • Active wrist flexion ROM
    • Active elbow extension ROM
    • Motor
  • Secondary Functional Outcome Measures
    • MOS-36
    • Klein-Bell activities of daily living
    • Other measures
• Discussion
  • Study Limitations
• Conclusion
• Acknowledgments
• References
• Copyright

Abstract 

Meythaler JM, Vogtle L, Brunner RC. A preliminary assessment of the benefits of the addition of botulinum toxin A to a conventional therapy program on the function of people with longstanding stroke.

Objective

To determine if botulinum toxin type A (BTX-A) combined with therapy can facilitate improved upper-extremity (UE) functional status versus therapy alone.

Design

Double-blind randomized crossover trial.

Setting

Tertiary care outpatient rehabilitation center.

Participants

Convenience sample of 21 men and women (ages 19–80y) with stroke more than 6 months after insult who had tone greater than 3 on the Ashworth Scale for 2 joints in the involved UE.

Intervention

Subjects were consecutively recruited and randomized to a double-blind crossover trial. Subjects received either BTX-A combined with a defined therapy program or placebo injection combined with a therapy program in two 12-week sessions.

Main Outcome Measures

The primary functional outcome measure was the Motor Activity Log (MAL). Subjects were also assessed on physiologic measures including tone (Ashworth Scale), range of motion, and motor strength.

Results

Improvements were noted in the functional status of the subjects in both arms of the study as measured by the MAL. All subjects had a significant change in functional status on MAL with therapy (P<.05). The use of BTX-A combined with therapy as compared with therapy only improved the functional status of the subjects on the MAL Quality of Movement subscale (P=.0180, t test) and showed a trend toward significance in the Amount of Use subscale (P=.0605, analysis of variance). Six weeks after treatment, the BTX-A combined with therapy decreased the Ashworth score statistically (P=.0271), but the therapy alone group decreased a similar amount at 6 weeks (P=.0117), indicating that most of the physiologic tone change could be attributed to therapy. After each 12-week period, tone had largely returned to baseline (P>.05).

Conclusion

A focused therapy program showed the most improvement in function in this defined stroke population. BTX-A combined with a focused traditional therapy program slightly enhanced the functional status of stroke subjects beyond that obtained with therapy alone 12 weeks after injection.

Key Words: Activities of daily living, Botulinum toxins, Humans, Intramuscular injections, Rehabilitation, Spasticity, Stroke, Therapy

List of Abbreviations: ANOVA, analysis of variance, AOU, amount of use, BTX-A, botulinum toxin type A, CNS, central nervous system, MAL, Motor Activity Log, MOS, Medical Outcomes Study, QOM, quality of movement, ROM, range of motion, UE, upper extremity

IT HAS BEEN WELL ESTABLISHED that a focused therapy program will improve the functional status of the person with a stroke even if they are more than 1 year beyond the event.¹, ², ³, ⁴ In poststroke populations, both the constraint-induced method and the focused neurodevelopmental techniques have been reported to be successful in improving functional status.¹, ², ³, ⁴ However, most of the studies performed by using these techniques have excluded subjects with moderate to severe spastic hypertonia of greater than 3 on the Ashworth score.⁴, ⁵

Recently, BTX-A has been used for the control of focal spastic hypertonia in CNS injury⁶, ⁷ and has been successful in reducing UE tone associated with spastic hypertonia as a result of a stroke.⁸, ⁹, ¹⁰, ¹¹ There has been considerable interest in the use of BTX-A to facilitate the functional status of subjects and to establish claims that BTX-A can affect the CNS plasticity.⁹, ¹⁰, ¹¹, ¹² However, as far as we know, there have been no well-designed randomized trials that show improved function particularly in the UE in which it is most frequently used in stroke subjects. In studies performed by using BTX-A in stroke subjects as the type of therapy used, the amount or dose of therapy and subject selection have generally been limited to physician judgment and have not been controlled in previous trials.⁷, ⁸, ⁹, ¹⁰, ¹¹, ¹² Furthermore, it has been questioned whether the improved function is maintained after the BTX-A wears off, Nor has it been established whether any change in clinical improvement is caused by therapy alone and whether BTX-A added any functional benefit after the paralytic effects had largely worn off.

The objective of this study was to evaluate whether persons who have suffered a stroke would obtain a functional improvement in their affected UE on the MAL with a well-designed task-oriented therapy program combined with BTX-A as compared with a therapy program alone.

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Methods 

The study population consisted of a convenience sample of adults between the ages of 19 and 80 years recruited consecutively from a university-based outpatient rehabilitation stroke clinic with spasticity/dystonia of a UE¹³ caused by a stroke more than 6 months in duration. Subjects had tone with grades of greater than 3 on the Ashworth Scale for elbow extension and wrist extension.¹³, ¹⁴, ¹⁵ The patients may also qualify for inclusion in the study on the Penn Spasm frequency scale with spasms of greater than or equal to 2 in the affected limb with or without a fixed deformity.¹⁵, ¹⁶ This is similar to criteria used in previous studies with BTX-A.⁸, ⁹, ¹⁰ Subjects were a convenience sample and were randomized to 1 of 2 initial treatments, either BTX-A with therapy or placebo injections with therapy, and then crossed over after 12 weeks. The consort information is contained in figure 1. An institutional review board approved the consent form and the clinical protocol. Once subjects were selected, they were given the informed consent form following institutional review board requirements.

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• Fig 1. 

  The CONSORT diagram.

Procedures 

All measures used in this study are well validated.

Functional Assessments 

The primary functional outcome measure was the MAL, a semistructured interview of the subject that assessed the functional use of the paretic arm and hand during activities of daily living. The MAL results in 2 measures that are reported, one for AOU and one for the quality of use.¹⁷, ¹⁸ The clinimetric properties of the MAL have been well established in stroke patients.¹⁸

Dressing, eating, functional mobility, elimination, communication and bathing/hygiene were assessed by using the Klein-Bell Activities of Daily Living Scale.¹⁹ The Barthel Index²⁰ was used as a more general assessment of activities of daily living. The MOS-36 Item Short-Form Health Status Survey²¹, ²² assessed health status; this tool has 8 subscales that evaluate specific dimensions of health status.

Physiologic Assessments 

The primary physiologic outcome measure was the 5-point Ashworth Scale¹⁴, ¹⁶ used to assess muscle tone in the UE for joint movements.

The secondary physiologic outcome measures were as follows: (1) deep tendon reflexes score measured on a 5-point scale at the biceps and triceps monthly,¹⁶, ²³ (2) goniometer measurements assessing passive and active range of motion in UE joints monthly (elbow and wrist), and (3) motor strength at specified joints monthly (elbow, wrist, fingers; motor testing was assessed on a 5-point scale in which 1 = trace, 2 = poor [unable to move against gravity], 3 = fair [can move against gravity but cannot actively resist an opposing force], 4 = good [can actively resist but is not normal], and 5 = normal), (4) motor grip strength using a calibrated handheld dynamometer and a calibrated lateral pinch dynamometer,²⁴ and (5) pain assessed by using the numeric rating scale (0–10 scale) on a monthly basis.²⁵, ²⁶

Study Medication 

The study medication was packed and shipped in desiccated form by Allergan directly to the investigator. It was stored at −18°C in a secure freezer meant for medications. BTX-A was supplied in vials of 100U each that required reconstitution with preservative-free saline.

A nurse with appropriate training made 1-mL syringes unlabeled of either BTX-A 100U/mL or a 1-mL placebo dose of preservative-free saline per a previously developed randomization table. This person was not involved in any evaluation of subjects.

After the baseline examination and meeting the entry criteria, subjects were injected with the study medication (BTX-A or placebo) in a double-blind treatment design. A single physician using electromyographic guidance injected all subjects. The study physicians and therapists assessed the subjects separately with regard to the involved muscles and the kinesiologic limitations on the limb movement. They then determined the initial dose of BTX-A, which muscles to inject, and the dose required for each injection site. The dose target range was 300U to 400U or an equivalent volume of placebo using exactly the same injection sites for each subject in both arms of the study.

Therapy Intervention Procedures 

After injection with either BTX-A or placebo, a schedule of occupational therapy appointments was established. Subjects attended twice weekly 1-hour sessions for each 12-week arm of the study (24 weeks total). Subjects did not begin treatment until 10 days from the injection so that the medication would have maximal effect. At the initial occupational therapy appointment, the subjects were asked to establish 4 to 6 functional goals that they would like to accomplish in this study. Examples included grasping and lifting objects to put in the washer or dryer, putting away groceries, dressing items, and so on. The subjects were then assessed as to their ability to perform these goals followed by a designed interventional therapy plan that prioritized goals.

Therapy intervention addressed impairments that interfered with each goal followed by active practice of the goals established by the subject. A focused neurodevelopmental therapy program described in the methods of van der Lee et al¹⁸ was used for all subjects.

After phase 1, week 12, all postassessments were completed, and subjects were crossed over to the other arm of the study without a further washout period. The subjects followed the same dose of therapy and therapy protocol as in the first arm of the study.

Contracture/deformity management was addressed in those subjects who were believed to have contractures affecting their functional status, an inability to passively extend the wrist beyond 15° of extension. This was addressed via off-the-shelf adjustable-static splints.^a These static splints were fitted to the treated wrist. They were to be worn for a 4-hours-on and 1-to-2-hours-off schedule while awake and during sleep. In phase 2, the splint-wearing schedule was again 4 hours on and 1 to 2 hours off with full-time night wear.

Concomitant Spasticity-Related Medications 

Concurrent use of muscle relaxants, antispastic agents, or drugs having muscle relaxant properties during the study were maintained at a constant dosage throughout the study. All medications were logged during every clinic visit on the case report form. Antihypertensive medications that may potentially affect spastic hypertonia including clonidine, calcium channel blockers, and alpha methyl-dopa were explicitly excluded, but all other antihypertensive medications were allowed during the study.

Statistical Methods 

The study design was a randomized, double-blind placebo-controlled, 2-way crossover trial. Subjects' treatment response for each treatment phase was calculated as a difference between phase measurements and baseline. There were no interim analyses on the data before the finish of the trial.

Carryover effects were tested by comparing the sums of the subjects' treatment responses of the first and second treatment phases for subjects in group 1, with the subjects in group 2 using the t test. If there was no evidence of differential carryover effects at the end of the first treatment phase, a fixed-effects crossover ANOVA was performed comparing the change from the first phase to the second phase between the 2 treatment sequences.

When the P value was <.1, the carryover effect was considered to be statistically significant at the end of the first treatment phase into the second treatment phase; the values recorded in the first treatment phase were compared between the 2 treatment sequences using the Student t test. Data were then analyzed between subjects for either the change from baseline (phase effect) as well as the amount of change (treatment response effect) by using the Student t test in a parallel analysis of both groups using only the first treatment phase of the study.

Power Calculation 

Calculations of the expected statistical power for detecting the efficacy of BTX-A on the MAL and the Ashworth scale were based on the assumption of type I error equal to .05 (2-tailed) in a crossover analysis. The study size of 20 subjects was expected to provide more than 85% power to detect an important difference (effect size ≥.70) in changes after 12 weeks of BTX-A treatment versus placebo on each of the primary outcome measures. The statistical power for assessing the change of treatment effect over time should easily exceed 90% if this change is moderate to large (effect size ≥.40).

Because subjects were hemiparetic with no abnormal neurologic function on 1 side, as determined by normal motor strength, sensation, deep tendon reflexes, and had no abnormal tone or spasms in those extremities, motor impairments (tone, reflexes, spasm frequency), data were analyzed only for the treated side. Significance was placed at P<.05.

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Results 

Participants 

A convenience sample of 21 subjects was enrolled out of the 23 subjects who were screened. Of the participants, only 18 subjects completed the 24-week trial and were included in the efficacy analyses of the data. One subject was not started on the study after being enrolled because it was discovered that this subject's age would be greater than 80 years before the end of the study, and 2 others did not finish the study because of transportation problems. The average age of the participants was 53.33±14.8y (range, 21–79y of age). There were 15 men and 6 women. Of the sample, 8 were white and 11 were black. After randomization, 11 were randomized to receive BTX-A injections followed by placebo injections (group 1), whereas 10 received placebo injections followed by BTX-A injections (group 2). Three subjects had no active wrist extension at the beginning of the trial, and 2 did not recover any active wrist extension by the end of the double-blind randomized trial. Only 1 subject required fitting with adjustable splints to reduce wrist flexion contractures.

Eight of the 11 group 1 subjects finished the 24 weeks of the study. This group received BTX-A combined with therapy and, if necessary, splinting in the first 12 weeks (phase 1) and then received a placebo injection with continued therapy and a splinting program for the second 12 weeks (phase 2).

All 10 of the group 2 subjects finished the 24 weeks of the study. This group received placebo with therapy and, if necessary, splinting for the first 12 weeks (phase 1) and then received BTX-A with therapy and splinting for the second 12 weeks of the study (phase 2).

There were no statistically significant differences between the age of group 1 (55.64±14.4) and group 2 subjects (51.9±15.8) (P=.6833, paired Student t test). There also was not a statistical difference between groups 1 and 2 for sex (P=.6351, Fisher exact test) and race (P=.6594, Fisher exact test).

There was a statistical difference in the Beck Depression Inventory between group 1 and group 2 (P=.0154, t test), but it was not considered to be clinically relevant becauses subjects did not meet the clinically relevant levels of depression to be excluded from the study on the test. Hence, no subjects screened were excluded from the study.

Despite the latitude of the physician to choose which muscle groups to inject, all subjects received injections to the wrist flexors including the flexor carpi radialis and flexor carpi ulnaris in an effort to reduce the tone and improve the range of motion for wrist extension, and all but 3 subjects received injections to the elbow flexors.

Primary Functional Outcome 

The MAL was the primary functional outcome measure in the study (table 1). This outcome measure specifically is a subject-based report focused on hand use for functional activities. This functional measure did show improvement throughout the study and in both arms of the study for each group (Fig 2, Fig 3).

Table 1. Changes in the MAL for Both the AOU and the Quality of Use Scores, for Group 1 (BTX-A – Placebo) and Group 2 (Placebo – BTX-A) for Both Crossover Phases of the Trial

NOTE. Values are mean ± SD unless otherwise noted.

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• Fig 2. 

  The mean MAL with standard deviation bars or AOU presented individually for both group 1 BTX-A/drug followed by placebo and group 2 placebo followed by BTX-A at baseline and the end of each 12-week arm.

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• Fig 3. 

  The mean MAL with standard deviation bars for QOM presented individually for both group 1 BTX-A/drug followed by placebo and group 2 placebo followed by BTX-A at baseline and the end of each 12-week arm.

The MAL for AOU of the treated UE improved consistently throughout the study. In group 1, those who received BTX-A first improved .36±.36 points with BTX-A and therapy combined and then maintained this with a .31±.31 functional change from baseline in phase 2 (see table 1). In group 2, in which the placebo injection was received first, the MAL improved .45±.48 points as it went from .73±.81 to 1.21±1.05. However, there was a larger change to 1.01±.92 points from baseline in the second 12 weeks with BTX-A (see table 1).

In a crossover analysis for the randomized trial, there was a clear advantage of BTX-A combined with therapy over the placebo-controlled therapy (P=.0605, ANOVA). However, there was a borderline but not statistically significant crossover effect in the study (P=.0978, t test). A parallel group analysis for the phase 1 data showed a treatment response that approached statistical significance favoring a positive effect for group 1 as compared with group 2 (P=.1489), but this is much less powered than a crossover analysis (see fig 2). It is clear that the therapy had a profound effect on the AOU and that BTX-A had a clinically marginal effect on further improving the AOU 12 weeks after injection (see fig 2).

The MAL for QOM showed a more significant effect. It improved from .31±.37 to .49±.31 during the first 12 weeks in group 1 and further improved with therapy and splinting alone to .61±.49. In group 2, there was a marked improvement with therapy and splinting alone as the MAL-QOM improved from .83±.88 to 1.67±1.28 during phase 1 of the trial and further improved with BTX-A to 1.81±1.39 in phase 2 (see table 1).

There was a statistically significant carryover effect throughout both of the arms of the study (P=.0240, t test). Consequently, evaluation of the data in a parallel design for phase 1 of the study indicated there was a statistically significant effect favoring BTX-A with therapy as compared with placebo and therapy (P=.0180, t test) (see fig 3). Here again, the QOM was improved statistically the most by the therapy with BTX-A slightly enhancing the effect of therapy 12 weeks after injection (see fig 3).

Primary Physiologic Outcome 

Subjects were evaluated at baseline and after 12 weeks of treatment, presumably after most of the paralytic effects of BTX-A had worn off.

The primary physiologic outcome measure was the Ashworth score. Six weeks after injection with BTX-A, the Ashworth scores average for wrist extension and elbow extension decreased from 2.35±1.06 at baseline to 1.67±.83 (P=.0271, Wilcoxon signed-rank test). However, the scores also decreased from 2.35±1.06 and were at 1.67±.99 (P=.0117, Wilcoxon signed-rank test) after 6 weeks when treated with therapy alone, indicating that therapy affected the tone perhaps to an equal extent in the UE. After 12 weeks, the tone rebounded on both arms of the study and was 1.88±.73 on BTX-A with therapy and 2.06±1.04 on therapy alone, which was not a statistically significant change (P=.2862, Wilcoxon signed-rank test).

Throughout each arm of the study, the Ashworth scores trended toward improvement after 12 weeks whether the subjects were treated with therapy alone (placebo arm) or therapy with BTX-A. Consequently, we present detailed analyses of the Ashworth scores for wrist extension and flexion and elbow extension to evaluate the carryover effects on tone at 12 weeks for both arms of the studies for both groups to analyze the effects more completely.

The 8 subjects in group 1 decreased their tone .75±1.58 points for wrist extension over the first 12 weeks. This tone reduction was maintained over the second 12 weeks on the placebo arm because it only slightly rebounded to .50±1.69 points (table 2).

Table 2. Changes in the Ashworth Scale for Individual Joint Movements for Group 1 (BTX-A – Placebo) and Group 2 (Placebo – BTX-A) for Both Crossover Phases of the Trial

NOTE. Values are mean ± SD unless otherwise noted.

Of the 10 subjects in group 2 who received placebo with therapy, the Ashworth score for wrist extension decreased .20±.79 points. The tone decreased more with BTX-A combined with therapy, dropping by 0.5±.53 points (see table 2).

There was no statistically significant effect of BTX-A within subject analyses for the crossover study. On crossover analyses, there was a trend toward a more significant improvement on the Ashworth Scale for wrist extension with the use of BTX-A combined with therapy (P=.1539, ANOVA). The clinical effect of BTX-A with therapy on the spastic hypertonia of wrist extension was not significantly different than with therapy alone 12 weeks after each injection.

Because the wrist flexors were injected with BTX-A in all subjects, it is important to evaluate whether the Ashworth score for wrist flexion was affected in a synergistic manner by the injections. The 8 subjects in group 1 decreased their tone .50±1.20 points for wrist flexion over the first 12 weeks. This tone reduction further improved with placebo and therapy over the next 12 weeks; it decreased a further 1.00±1.41 points (see table 2).

Of the 10 subjects in group 2 who received placebo with therapy, the Ashworth score for wrist flexion did not change and remained at 1.5±1.27 at the start of the study and was 1.5±1.27 after the first 12 weeks. The tone decreased slightly when BTX-A combined with therapy was administered during the second 12 weeks, dropping to 1.4±.97 for a mean change of only 0.1 points (see table 2).

These decreases were not statistically significant for a treatment effect with the BTX-A at 12 weeks postinjection in the crossover study for wrist flexion tone (P=.1471, ANOVA).

All but 3 subjects received injections to some elbow flexor muscle groups to reduce the tone with passive wrist extension. Of the 3 subjects who did not have the biceps injected, all had injections to the wrist extensors and the pronator teres, which may impact on elbow extension. One subject was prescribed elbow splinting and did not comply with the prescribed wearing time.

The 8 subjects in group 1 decreased their tone .63±.52 points for elbow extension over the first 12 weeks. This tone reduction was maintained over the next 12 weeks with therapy and splinting; it decreased a further .75±1.04 points (see table 2).

Of the 10 subjects in group 2 who received placebo with therapy, the Ashworth score for elbow extension did not change with therapy and remained at 2.4±.84 at the start of the study and was 2.4±.47 after the first 12 weeks. The tone decreased when BTX-A combined with therapy and splinting was administered during the second 12 weeks; the tone dropped to 2.0±.47 for a decrease of .40±.84 points (see table 2).

There was no statistically significant effect of BTX-A within subject analyses for the crossover study. There was no statistically significant change in the tone for elbow extension with BTX-A (P=.4575, ANOVA).

Secondary Physiologic Measures 

In general, active ROM did improve during the study in both arms of the study but not to a statistically significant level. This could be because of a ceiling effect because both subject groups were not overly restricted in their active ROM in the study. All but 3 of the subjects had some active wrist extension of 15° or greater, despite their tone, upon entry to the study. Because all subjects except 3 received injections to elbow flexors and all subjects had injections to wrist flexors to reduce the tone for wrist and elbow extension, we report the details of the active ROM for wrist extension, wrist flexion, and elbow extension. Active ROM is reported here because it is more physiologically relevant to functional status. It should be pointed out that passive ROM did not statistically change throughout the study either (table 3).

Table 3. The Changes in the Active Range of Motion in Degrees for Group 1 (BTX-A – Placebo) and Group 2 (Placebo – BTX-A) for Both Crossover Phases of the Trial

NOTE. Values are mean ± SD unless otherwise noted.

The full active ROM for wrist extension improved 2.9°±22.5° in those 8 subjects in group 1 who received the BTX-A first. Phase 2 of treatment group 1 continued to improve to 7.6°±21.5° in the ROM (see table 3).

In the 10 subjects in group 2 who received placebo combined with therapy in phase 1 ROM improved 22.6°±35.9°, going from 133.0°±29.8° to 155.2°±17.7°. In phase 2, group 2 further improved their wrist extension with the BTX-A to 137.9°±36.2° (see table 3).

Active wrist extension showed no significant improvement throughout the study (P=.2232, ANOVA). However, because the subjects as a group had greater than 130° of active ROM at the beginning of the study, there likely is a statistical ceiling effect on any further gains.

The full active ROM for wrist flexion improved 8.7°±28.6° in those 8 subjects in group 1 who received the BTX-A first. However, in phase 2 of treatment when group 1 received placebo combined with therapy and splinting, subjects lost −3.9°±36.8° in ROM (see table 3).

In the 10 subjects in group 2 who received placebo combined with therapy, they had a reduction in their ROM wrist flexion of −9.7°±31.3° in phase 1 going from 128.0°±29.8° to 121.5°±21.0°. With BTX-A in phase 2, group 2 regained most of their active wrist flexion to 127.2°±29.9° (see table 3).

Active wrist flexion trended toward improvement throughout the study with BTX-A and therapy, whereas there were decreases in the active ROM with placebo combined with therapy and splinting (P=.2426, ANOVA). However, it is unlikely any of these changes were clinically significant because most of the subjects in this study had relatively preserved physiologic active wrist flexion passively.

Active elbow extension improved in group 1 by 22.6°±56.2° in the first 12 weeks of the study. However, they only slightly improved 2.8° with therapy because the mean improvement from baseline was 25.4°±59.9° during the second 12 weeks (see table 3).

In group 2, the ROM for elbow extension did not change at all with placebo because it was 152.8°±29.9° at the start of the study and 152.2°±23.9° after the first 12 weeks. It improved in the second 12 weeks to 159.2°±28.4° with BTX-A in the second 12 weeks for a change from baseline of 14.1°±21.5° (see table 3). There was no change in active elbow extension ROM with therapy and some slight improvement when BTX-A was administered, but the change was minimal and not statistically significant (P=.3119, ANOVA).

The mean grip strength, as measured by the handheld dynamometer, did not have a significant change in either direction during the study (table 4). BTX-A in groups 1 and 2 showed dichotomous changes and did not correlate at all with whether they received therapy or BTX-A (P=0.5761, ANOVA). Hence, the functional improvements were likely caused by improved motor control rather than an increase in motor strength.

Table 4. The Changes in the Grip Strength Using a Handheld Dynamometer for Group 1 (BTX-A – Placebo) and Group 2 (Placebo – BTX-A) for Both Crossover Phases of the Trial

NOTE. Values are mean ± SD unless otherwise noted.

Secondary Functional Outcome Measures 

Although the physical component summary of the MOS-36 did not show a statistical change during the study, the mental component summary had a trend toward a positive improvement (table 5). The subjects perceived an improvement in their general health (P=.04, ANOVA) subscore of the MOS-36. However, the data suggest that this appears entirely attributable to the use of the therapy because improvement was similar during their participation in both arms, suggesting that the subjects noted the improvements in their functional skills (see table 5).

Table 5. The Changes in Satisfaction With Life (MOS–36) Subscores for General Health and Mental Health During The Study for Group 1 (BTX-A – Placebo) and Group 2 (Placebo – BTX-A) for Both Crossover Phases of the Trial

NOTE. Values are mean ± SD unless otherwise noted.

The Emotional Health subscore of the MOS-36 showed improvement throughout the study (P=.0355, ANOVA). As can be noted in table 5, the emotional health score improved during the placebo phase as well.

The Klein-Bell total scores did not statistically change because it measures many functional activities that may require more than just improved physiologic function of the hand (table 6). However, the eating subscale scores of the Klein Bell, which are sensitive to UE functional movement, did show a trend toward improvement (P=.1045, ANOVA). The 30-item MAL includes 4 eating items so it is likely that changes in eating behaviors should be consistently reflected in both scales.

Table 6. The Changes in the Klein-Bell Subscores for Eating During the Trial for Group 1 (BTX-A – Placebo) and Group 2 (Placebo – BTX-A) for Both Crossover Phases of the P Trial

NOTE. Values are mean ± SD unless otherwise noted.

The Barthel scale (0–100 scale) had a trend toward improvement favoring therapy (P=0.10, ANOVA) (table 7). This was not unexpected because therapy may improve many areas of function that were not dependent on the areas injected with BTX-A. However, the change was not clinically relevant because it was only a 0.25-point gain from the baseline. There were no statistically significant changes in the deep tendon reflexes or the pain scores throughout the study. All patients met the personal functional goals that they set at the beginning of the study.

Table 7. The Subgroups for the MOS-36, Barthel, and Klein Bell Functional Subgroups

Test	P⁎
MOS-36
Physical component summary	.92
Mental component summary	.14
Physical function	.26
Role–physical	.97
Bodily pain	.16
General health	.04†
Vitality	.69
Social functioning	.59
Role–emotional	.04†
Mental health	.99
Barthel
Activities of daily living	.10
Klein Bell
Total	.48
Dressing	.93
Elimination	.28
Mobility	.50
Bathing	.24
Eating	.10
Communication	1.00

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Discussion 

In this project, we assessed whether the treatment with BTX-A would be an enhancement to a focused therapy program in stroke subjects more than 6 months out from their stroke. In this study, the use of BTX-A combined with therapy corresponded with a slight additional improvement to the functional status in the subjects when compared with the functional changes obtained by therapy alone. Therapy alone had an unexpectedly large effect when using the MAL, which has been one of the most important subject-based functional outcome measures in stroke therapy interventional trials of the UE.³, ⁴, ⁵, ¹⁸ The effects on the MAL are significant because this study indicates that therapy alone may be able to obtain lasting functional improvement. Considering that therapy by itself did improve the functional status to such an unexpectedly large extent, this is a remarkably robust finding. The subject population was similar to those recruited in other focused therapy trials with the exception of their having a higher level of wrist or elbow extensor tone.³, ⁴, ⁵ This is an important finding because van der Lee,⁴ Taub,⁵ and colleagues have largely excluded subjects with significant spastic hypertonia from their studies when attempting to improve the UE functional status of stroke subjects by using focused therapy techniques.⁴, ⁵ If not for their excessive tone, all but 3 of our subjects had active wrist extension of 15° and would have met the admission criteria of van der Lee⁴ and Taub⁵ for a focused stroke rehabilitation therapy program. In these previous studies, the MAL was also used as the primary outcome measure.⁴, ⁵, ¹⁸

This study is a clear departure from previous studies on the use of BTX-A because there was an attempt to dose and quantify therapy according to what is most frequently used in the clinical setting and at 12 weeks after the injection with BTX-A, a point in time when the neurolytic blockade is expected to have largely worn off.⁶ The therapy methodology was similar to other therapy studies involving stroke subjects because it used the same primary functional outcome measures as the MAL.³, ⁴, ⁵ There was a positive trend in the eating subscale scores on the Klein-Bell Activities of Daily Living Scale involved with eating, which is consistent with changes noted in the MAL.

Most of this subject population typically had a more profound dystonia than spasticity. The reduction in tone 12 weeks after injection appears to be caused by therapy alone in this patient population. Even after 6 weeks postinjection, for each group in the first arm of the study, there was no statistical effect of BTX-A on the tone. This study clearly shows that therapy can affect tone and must be controlled in any study of spastic hypertonia by defining the type and dose of therapy.

There was no improvement in active ROM in this study. This was not surprising because this patient population appears to have had a functional ROM as compared with other studies.⁸ Also, the timing of our outcome measures (12 weeks after injection) and the different and more stringent functional admission criteria for our study resulted in a clearly different study population.⁸ Our subjects had minimal restrictions of their passive and active ROM at the initiation of the study. Hence, the functional improvements are the result of neural plasticity of the CNS because of therapy and that therapy may be facilitated by a reduction in tone using BTX-A.

Despite the fact that BTX-A is a neurolytic agent, there were no statistically significant changes in motor strength in the UEs. This is not unexpected because the paralytic effects of the BTX-A on motor function had largely worn off. Hence, the functional improvements were likely caused by improved motor control rather than an increase in motor strength. A more likely reason is that most of the improvement in functional status could be caused by the decreased spread of motor activity caused by spastic hypertonia during active motion. Once this excessive tone on active motor movement was reduced and subjects underwent therapy, they were able to benefit functionally from the therapy by facilitating neural plasticity.¹, ², ³, ⁴, ⁵, ¹⁸

Improvements to subsections involving emotional and general health on the MOS-36 are likely a result of the therapy and the interaction with the therapist. Because therapy has not been controlled in previous studies involving the use of BTX-A,⁷, ⁸, ⁹, ¹⁰, ¹¹, ²⁷ this study indicates that the dose of therapy is an important confounding variable. However, attributing changes in quality of life to the personal relationship to a therapist alone is a bit simplistic in light of some of the functional improvements personally noted by the subjects themselves during the study. An observable improvement by the subjects in their functional skills is a life-positive change that can affect health and emotional well-being.

Study Limitations 

The limitations of this study are the small groups and the need to analyze the data in a parallel design because of the unexpected and dramatic effects of the therapy. This study could serve as the basis of a power analysis for a larger parallel-design trial. Clearly, 90 patients in a 3-arm parallel trial would be sufficient. The trial should incorporate a several month follow-up period after therapy has been discontinued in both groups to evaluate if these functional changes are maintained without further intervention. This subject population was focused on improving functional status on the MAL. The study did not include those subjects in whom there may be an indication for BTX-A to reduce painful contractures and/or improve hygiene.⁶

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Conclusion 

In this study, therapy alone showed the most significant improvements in the functional outcome in stroke subjects as measured by the MAL. In this carefully selected population, BTX-A appears to somewhat enhance the functional gains obtained from therapy in stroke subjects even after the paralytic effects had largely worn off. Although most clinicians routinely prescribe therapy for their stroke subjects, this study indicates that one should clinically measure the effect of the treatment at 12 weeks before deciding to continue treatment. Clearly, the type and amount of therapy must be controlled for in any study evaluating functional changes in future studies evaluating functional outcome using BTX-A in the poststroke population.

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Acknowledgments 

We thank Scott Millis, PhD, for his statistical advice in the study and Ethica Clinical Research Inc, Montreal, Quebec, CA, for the independent statistical analyses of the data.

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