Abstract
Spasticity is a disorder of excess muscle tone associated with CNS disease. We hypothesized that botulinum toxin, a neuromuscular blocking agent, would reduce tone in spastic muscles after stroke. This randomized, double-blind, placebo-controlled, multicenter clinical trial evaluated the safety and efficacy of botulinum toxin type A (BTXA) in the treatment of chronic upper limb spasticity after stroke. Thirty-nine patients received IM injections of a total dose of either 75, 150, or 300 units of BTXA or placebo into the biceps, flexor carpi radialis, and flexor carpi ulnaris muscles. At baseline, patients demonstrated a mean wrist flexor tone of 2.9 and elbow flexor tone of 2.6 on the Ashworth Scale (0 to 4). Treatment with the 300-unit BTXA dose resulted in a statistically and clinically significant mean decrease in wrist flexor tone of 1.2 (p = 0.028), 1.1 (p = 0.044), and 1.2 (p = 0.026) points and elbow flexor tone of 1.2 (p = 0.024), 1.2 (p = 0.028), and 1.1 (p = 0.199) at weeks 2, 4, and 6 postinjection. In the placebo group, tone reduction at the wrist was 0.3, 0.2, and 0.0 and at the elbow was 0.3,0.3, and 0.6 at weeks 2, 4, and 6 postinjection. BTXA groups reported significant improvement on the physician and patient Global Assessment of Response to Treatment at weeks 4 and 6 postinjection. There were no serious adverse effects. In this 3-month study, BTXA safely reduced upper extremity muscle tone in patients with chronic spasticity after stroke.
After stroke, patients may display a wide variety of signs that together constitute the upper motor neuron syndrome. The syndrome consists of negative signs, including weakness, lack of dexterity, and paresis, and positive signs, such as flexor spasms, increased tendon reflexes, and rigidity. 1 These positive features interfere with rehabilitation and the activities of daily living, can cause fractures or contractures, increase the frequency of pressure sores, and are often associated with pain. 2
Spasticity is classically defined as a “velocity-dependent increase of tonic stretch reflexes (muscle tone) with exaggerated tendon jerks.” 3 However, spasticity may be viewed as a broader syndrome not limited to velocity-dependent increase of tonic stretch reflexes but including focal muscle hypertonia with dystonic features. The etiology and pathophysiologic mechanisms of spasticity are varied, and currently available treatment modalities are of limited benefit. Little and Merritt 4 describe a stepped approach for the treatment of spasticity. Initially, therapists rely on range of motion and stretching exercises. Muscle heating or cooling, electrical stimulation, and splinting may also be used as early interventions. If these conservative treatments are inadequate, drug therapy, dynamic splinting, and serial casting may be used.
Current pharmacotherapies for treating spasticity include neural depressants (e.g., oral or intrathecal baclofen, benzodiazepines, clonidine, and tizanidine) and muscle relaxants (e.g., dantrolene). Such systemic treatments are only partially effective in reducing spasticity and also may result in generalized weakness and sedation. 5 The next level of intervention includes motor point or nerve blocks with phenol or alcohol injections. However, these neurolytic agents are painful, may produce irreversible scarring or sensory loss, and have a variable duration of action. 6 Administration of phenol can be difficult because it requires percutaneous injection into accessible nerves or surgical isolation of the nerve in less accessible targets. 7 If spasticity remains problematic despite these therapies, surgical intervention (e.g., rhizotomies, myelotomies, neural transection, tendon transplant or lengthening) can be used. 2 These surgical procedures have variable efficacy, significant morbidity, and are irreversible.
In the present study, we investigate the safety and efficacy of local treatment of spasticity with IM injection of botulinum toxin type A (BTXA), a potent neurotoxin that prevents the release of acetylcholine from the presynaptic axon at motor endplates. 8 BTXA can be used therapeutically to produce a reversible, partial, chemical denemation when injected directly into the muscle. It is approved for use in the United States for the treatment of strabismus, blepharospasm, and facial nerve disorders. 9 BTXA is also effective in the treatment of various dystonias of the neck, larynx, and limbs. 10
Several open-label studies have reported improvement in patients with severe spasticity after BTXA treatment. 11–16 In a double-blind, placebo-controlled study, Snow et al. 17 found BTXA to be effective in the treatment of lower extremity spasticity associated with MS. Grazko et al 18 reported a study using a placebo cross-over design, in which 12 patients with spasticity, including 3 resulting from stroke, uniformly had significant reduction of tone after botulinum toxin injections. The present controlled trial evaluated the effectiveness of BTXA in treating upper extremity spasticity in chronic stroke patients.
Methods
Study subjects
Eligible subjects had to be at least 9 months poststroke and demonstrate an average elbow and wrist flexor tone of grade 2.5 or higher as measured by the Ashworth Scale 19 (0 = no increase in muscle tone, 4 = limb rigid in flexion or extension) with a minimum flexor score of 2 at both joints. Additionally, patients were required to have a stable clinical course for at least 2 months before study and to be willing to maintain ongoing spasticity treatments (medication, physical therapy, and so on) throughout the study. Patients with a fixed contracture, previous treatment with BTXA, neurolytic or surgical procedures in the study limb, or a neuromuscular disease were excluded.
Thirty-nine patients with upper limb spasticity post-stroke were enrolled in the study. Two patients were discontinued from the study before follow-up visits because of diagnoses of lymphoma and hypothyroidism, leaving 37 evaluable patients. For the 37 evaluable patients, the mean age (±SD) at the time of study entry was 59 ± 12 years (range 29 to 76). Twenty-one patients were women (57%) and 16 were men (43%). The mean time since stroke onset was 37 months (range 9 to 133). For the 35 patients whose records identified the type of stroke, 22 were thrombotic (63%), 5 were embolic (14961, and 8 were hemorrhagic (23%). There were no significant differences in baseline demographics between the treatment groups.
Study design
This study was a randomized, multi-center, graduated dose, double-blind, parallel-group comparison of BTXA with placebo in patients with chronic upper limb spasticity after stroke. The study sites for this multicenter trial were the Colorado Neurological Institute in Englewood, Colorado; Daniel Freeman Memorial Hospital in Los Angeles, California; and Mount Sinai Hospital in New York, New York. Patients were randomly assigned to receive a single treatment of either a low (75 units [U]), medium (150 U), or high (300 U) total dose of BTXA or placebo. To monitor the safety of progressively escalating doses of BTXA in this study population, the first four patients at each site received 75 U or placebo, the next four received 150 U or placebo, and the last four received 300 U or placebo. Study medication was prepared by a pharmacist or study nurse who had no role in evaluating or injecting patients. BTXA (BOTOX Purified Neurotoxin Complex, Allergan, Inc., Irvine, CA) was supplied as a vacuum dried powder and reconstituted with sterile normal (0.9%) saline without preservatives. The amount of diluent added to the vials determined the dosage. A total volume of 3 mL was injected into each patient.
BTXA injection technique
Study medication was injected into the biceps (four sites), flexor carpi radialis (one site), and flexor carpi ulnaris (one site) (table 1) using a 27-gauge Teflon-coated needle with EMG guidance. The combination EMG-injection needle (BOTOX® Injection Needle, Allergan, Inc.) allowed recording of muscle EMG activity via an audio and video signal and injection of study medication through the same needle.
Table 1 BTXA dosing regimen
Clinical assessments
Baseline safety measures (blood pressure, pulse rate, ECG, and blood and urine analysis) were recorded at the screening visit; baseline efficacy measures (Ashworth Scale, Functional Independence Measure [FIM], Rand 36-Item Health Survey 1.0, Fugl-Meyer Scale, caregiver dependency scale, function and pain assessment, motor task/function rating scale, grip strength, and arm and forearm circumference) were recorded at the injection visit. Follow-up visits were scheduled at 2, 4, 6, 10, and 16 weeks postinjection and included measurements of blood pressure, pulse rate, muscle tone (Ashworth Scale), caregiver dependency scale, function and pain assessment, motor task/function rating scale, grip strength, and the Global Assessment of Spasticity Scale (physician's and patient's independent evaluation of response to treatment, graded from 0 = unchanged, to +4 = complete abolishment of symptom or to −4 = severe worsening). Follow-up measurements of the FIM, Rand 36-Item Health Survey 1.0, and Fugl-Meyer Scale were conducted at weeks 2, 6, and 16. ECG recordings were taken 1 hour after injection and at weeks 2 and 16; additional blood and urine samples were collected at weeks 2, 6, and 16; arm and forearm circumference were measured at week 16.
statistical analysis
All variables were analyzed with nonparametric procedures. For all categorical variables, within-group change from baseline was analyzed at all follow-up visits using the Wilcoxon signed-rank test; among-group analyses at all scheduled visits were performed using the Kruskal-Wallis one-way ANOVA using ranks. All pairwise comparisons were analyzed at all scheduled visits using the Wilcoxon rank-sum test. The Fisher exact test was used to compare incidence distributions for dichotomous variables.
Categorical variable analyses were performed on the Ashworth scale, global assessment of response to treatment, pulse rate and blood pressure, FIM, Rand 36-Item Health Survey 1.0, Fugl-Meyer Scale, caregiver dependency scale, function and pain assessment, motor tasW function rating scale, grip strength, and arm and forearm circumference. The frequency of adverse events and abnormal ECGs were analyzed as dichotomous variables.
Results
Change in muscle tone after injection
At baseline, patients demonstrated a mean Ashworth wrist flexor tone of 2.9 and elbow flexor tone of 2.6 (table 2). At follow-up, significant improvement (p <0.05) was observed in the BTXA-treated groups compared with placebo. Patients treated with the 300-U dose of BTXA had a mean decrease in wrist flexor tone of 1.2 points (p = 0.028) at week 2 postinjection, 1.1 (p = 0.044) at week 4, and 1.2 (p = 0.026) at week 6. The mean decrease in elbow flexor tone in the high-dose group was 1.2 (p = 0.024) at week 2, 1.2 (p = 0.028) at week 4, and 1.1 (p = 0.199) at week 6. Patients treated with the 75-U dose of BTXA had a mean decrease in wrist flexor tone of 0.7 (p = 0.030) points at week 6 postinjection. Patients in the 150-U group had a similar trend of decrease in muscle tone as those in the 75-U group; however, those changes did not reach statistical significance. By week 16, muscle tone returned to near baseline values in all BTXA-treated groups. No consistent significant changes in tone were seen in other noninjected muscle groups of the forearm, arm, or shoulder.
Table 2 Summary of baseline Ashworth scores and changes from baseline at follow-up visits
Global assessment of response
Patients in the 300-U BTXA group scored a 1.4-point improvement on the physician's global assessment of response to treatment (−4 to +4) at weeks 4 and 6 postinjection (table 3). This was significantly higher than the placebo group (0.0 at week 4, p = 0.01; 0.2 at week 6, p = 0.008). The 75-U BTXA group reported an improvement of 1.0 (p = 0.021), 1.1 (p = 0.0091, and 0.9 (p = 0.035) points at weeks 2, 4, and 6 postinjection. Changes on the physician global assessment in the 150-U BTXA group were not significantly different from placebo.
Table 3 Summary of global assessment of response to treatment*
Patients in the 300-U BTXA group had improvement on the subject's global assessment of 1.0 at week 4 and 1.6 point at week 6 postinjection. This was significantly higher than the placebo group (−0.2 at week 4, p = 0.044; 0.2 at week 6, p = 0.007). The 75-U group scored 1.6 (p = 0.004) and 1.0 (p = 0.035) point improvements on the subject global assessment scale at weeks 4 and 6 postinjection. Changes in the 150-U BTXA group did not reach statistical significance.
Safety measures and adverse events
There were no significant among- or between-group differences in blood pressure, pulse rate, arm and forearm circumference, blood chemistry, or urinalysis. No clinically significant changes in ECGs were reported in the BTXA groups.
There were three serious adverse events reported in the BTXA-treated groups (hypothyroidism, visceral lymphoma, and pain due to spasticity) that were not considered to be related to the study medication. Nonserious and reversible adverse events included transient global amnesia, finger twitch, rash, soreness and pain at the injection site, and bladder instability. There were no significant among- or between-group differences in the frequency of adverse events.
Additional measures
The average overall baseline score for grip strength was 5.6 kg. Patients treated with 75-U BTXA had an increase in grip strength of 2.9 kg at week 6 and 3.7 kg at week 16. This was significantly greater than the placebo group at weeks 6 (−0.1, p = 0.016) and 16 (−0.3, p = 0.009). There were no significant changes in grip strength in the 150-U and 300-U BTXA groups. No consistently significant differences between BTXA and placebo groups were detected on the FIM, Fugl-Meyer, caregiver dependency, function and pain assessment, motor/function task rating scale, or the Rand 36-Item Health Survey 1.0 (data not shown).
Discussion
The results of this study indicate that BTXA reduces upper limb spasticity in poststroke patients. There were no BTXA-related serious adverse events nor changes in safety measures, indicating that BTXA injections were well tolerated.
The primary efficacy measure in this study was measurement of muscle tone of the elbow and wrist flexors using the Ashworth Scale. A change of 1 point on the Ashworth Scale is considered to be clinically significant. 20 Patients in the high-dose BTXA group showed both a clinically and statistically significant reduction in wrist and elbow flexor tone. Patients in the low- and medium-dose groups showed trends similar to the high-dose group, but most of these changes were not clinically significant. The peak effect occurred 2 to 6 weeks postinjection followed by a return to baseline. There was no consistent spread of effect (due to diffusion of toxin or to a synergistic effect) to adjacent noninjected muscle groups as measured by reduction of muscle tone or change in strength.
The changes reported on the physician and patient Global Assessment of Response to Treatment scales correlate well with the results of the Ashworth Scale. Both the physician and patient assessment scores in the high- and low-dose groups showed significant improvement at weeks 4 and 6 postinjection, which overlaps with the timing of peak reduction of muscle tone. Notably, patients in the medium-dose group lacked significant improvement on the global assessment scales. The average decrease in muscle tone at weeks 4 and 6 is almost identical in the lowand medium-dose groups, yet the low-dose patients reported significant improvement and the medium-dose patients did not. These results may be in part due to the graduated dosing design, that is, the first four patients enrolled at each site were randomized to low-dose or placebo, the next four to medium-dose or placebo, and the final four to high-dose or placebo. Some undefined difference between the patients enrolled early in the study versus those enrolled later might explain why they differ in their assessment of similar reductions in tone. Additionally, the relatively small sample size in this study might have contributed to these results.
Additional functional and quality of life measures showed few changes at follow-up visits. The high functional level (as measured by broad functional and quality of life indices) at which most patients entered the study may account in part for the lack of measurable improvements. The study population was an average of 3 years poststroke. Judging from their baseline scores on the FIM (at baseline, the average composite score for measures of physical functioning on the FIM was 78.2 out of a possible 91 points) and caregiver dependency scale, these patients had adapted to their spasticity. Many of the patients in this study functioned fairly independently for activities involving the upper limb, leaving little room for improvement on these scales. Furthermore, because relatively few muscles were injected, and these were standardized for all patients, the treated sites may not have been the precise muscles requiring injection to optimize functional gains for individual patients. For example, several patients from this trial that were treated with BTXA in an open label follow-up phase experienced considerable functional gains after injection of additional spastic muscles (i.e., finger flexors). This points to the need for detailed evaluation and individualized treatment of each patient to maximize the benefits of BTXA therapy.
A reduction in spasticity should benefit the patient. For example, in cases in which development of contractures is a concern, a decrease in muscle tone will help preserve range of motion and may prevent contractures. In such patients, BTXA injection of muscles controlling flexion or extension of a joint may be an effective treatment strategy. However, if treatment goals involve more than prevention of contractures (e.g., improved hygiene, reduction in pain, or unmasking of underlying volitional movement), it is important to inject those muscles in which overactivity interferes with the specific functional goals.
One functional measure that did change in the study patients was grip strength. Patients receiving 75 U BTXA had an increased grip strength compared with placebo. Although the finger flexors were not injected, these results suggest that a relatively low dose of BTXA may reduce muscle tone sufficiently in one set of muscles to unmask function in a nearby set. Future studies may identify clinical and physiologic factors to assist in identifying which muscles to inject with BTXA to maximize functional improvement.
In summary, the results of this study demonstrate that BTXA treatment safety reduces muscle tone in patients with chronic upper limb spasticity after stroke. All dose levels produced decreases in muscle tone, with consistent clinically significant improvements in the Ashworth score reported in the 300-U dose group. Peak improvement occurred at 2 weeks postinjection and continued through 6 weeks; spasticity returned toward baseline by 10 weeks postinjection. The highest dosing regimen (300 U) showed the greatest efficacy and longest duration of action as compared with the medium (150-U) and low (75-U) dose groups. There were no serious BTXA-related adverse events. Future research should explore the long-term effects of BTXA treatment and evaluate the potential functional gains that may be acquired through earlier, individualized, and extended use of BTXA in the treatment of spasticity after stroke.
Acknowledgments
We thank Candida Iodice, Leslie Kane, Susan Terrell, and Jan Miller for their assistance in patient evaluation; Drs. Michael Hausman and Nahid Nainzedeh for referral of patients; Jessica Moise and Sam Chin for technical assistance; and Dr. Robert Young for his guidance.
Footnotes
-
Supported by a grant from Allergan, Inc, who supplied the botulinum toxin and placebo used in this study.
Presented in part at the 47th Annual Meeting of the American Academy of Neurology, Seattle, WA, May 1995.
Received August 7, 1995. Accepted in final form October 27, 1995.
- Copyright 1996 by the American Academy of Neurology
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