Treatment With Botulinum Toxin Type B for Upper-Limb Spasticity

Transcription

1 103 Treatment With Botulinum Toxin Type B for Upper-Limb Spasticity Allison Brashear, MD, Anita L. McAfee, OTR, Elizabeth R. Kuhn, RN, Walter T. Ambrosius, PhD ABSTRACT. Brashear A, McAfee AL, Kuhn ER, Ambrosius WT. Treatment with botulinum toxin type B for upper-limb spasticity. Arch Phys Med Rehabil 2003;84: Objective: To determine if botulinum toxin type B (Myo- Bloc) decreases spasticity. Design: Investigator-initiated trial, open-label, single-treatment session. Setting: Single site. Participants: Ten patients with stable upper-limb spasticity and an Ashworth Scale score of 2 or higher at the elbow, wrist, and fingers. Interventions: Total dose of 10,000U of botulinum toxin type B injected into 5 major muscles. Main Outcome Measures: The Ashworth Scale, goniometry, and functional assessments were performed at injection and weeks 4, 8, and 12. The principal investigator (PI) global assessment of change (GAC) and the patient GAC were done at weeks 4, 8, and 12 postinjection. The safety of the procedure was measured by adverse events and vital signs. Results: Improvements in Ashworth Scale scores were observed at weeks 4, 8, and 12 postinjection. At week 4, the mean changes (in Ashworth score) were elbow, 1.0 (P.016); wrist, 1.7 (P.004); finger, 1.35 (P.02); at week 8: elbow,.83 (P.016); wrist, 1.00 (P.016); finger,.94 (P.08); and at week 12: elbow,.61 (P.07); wrist, 1.00 (P.016); and finger,.89 (P.10). The PI GAC improved at all visits. Nine of the 10 subjects reported dry mouth at week 4, with resolution by week 12. No changes were seen on the functional measures. Conclusions: Botulinum toxin type B may be useful in treatment of spasticity. Key Words: Botulinum toxins; Rehabilitation; Spasticity; Stroke by the American Congress of Rehabilitation Medicine and the American Academy of Physical Medicine and Rehabilitation BECAUSE BOTULINUM TOXIN type B is safe and effective in the treatment of overactive muscles associated with cervical dystonia, 1-4 it follows that botulinum toxin type B may From the Department of Neurology, Indiana University School of Medicine, Indianapolis, IN (Brashear, Kuhn); Rehabilitation Services, Clarian Health Partners, Indianapolis, IN (McAfee); and Department of Public Health Sciences, Section on Biostatistics, Wake Forest University School of Medicine, Winston-Salem, NC (Ambrosius). Supported by Elan Pharmaceuticals. Presented in part at the American Academy of Physical Medicine and Rehabilitation s annual assembly, November 2000, San Francisco, CA. No commercial party having a direct financial interest in the results of the research supporting this article has or will confer a benefit upon the authors or upon any organization with which the authors are associated. Reprint requests to Allison Brashear, MD, Dept of Neurology, Indiana University School of Medicine, 550 University Blvd, Rm 6620, Indianapolis, IN , abrashea@iupui.edu /03/ $35.00/0 doi: /apmr be beneficial in the treatment of other muscle tone disorders, such as spasticity that occurs after stroke or with cerebral palsy. At the molecular level in the presynaptic nerve terminal, 5 botulinum toxin type B inhibits synaptobrevin, and botulinum toxin type A inhibits synaptosomal-associated protein However, both drugs achieve a similar clinical effect by inducing a temporary, localized weakness in injected muscles. Studies of the use of botulinum toxin type A in treatment of spasticity 7-9 after stroke suggest that botulinum toxins may be beneficial. To determine the effect of botulinum toxin type B on spasticity, we performed an open-label study of patients with upper-limb spasticity from an upper motoneuron lesion to determine if 10,000U of botulinum toxin type B are safe and effective in the treatment of spasticity of the elbow, wrist, and fingers. Use of botulinum toxin type B to treat spasticity has never been studied. METHODS Participants Patients aged 18 to 80 years old were considered for enrollment in the study if they had stable spasticity from an upper motoneuron lesion resulting from stroke or traumatic brain injury (TBI) for at least 6 months. In addition, subjects had to have a score of 2 or higher on the Ashworth Scale 10 at the elbow, wrist, and finger flexors and could not have changed their oral spasticity medications within 30 days before enrollment. No changes in physical or occupational therapy regimens (including splinting) were permitted during the study. Potential subjects were excluded if they had a history of unstable medical illnesses, a planned or previous injection of phenol to the upper limb being studied, surgery on the limb during the study, or a previous injection of any form of botulinum toxin anywhere in the body. All participants signed a consent from approved by the Indiana University School of Medicine Institutional Review Board. Study Design Because spasticity has not been previously treated with botulinum toxin type B, we designed this open-label, singlesite, study of the effect of 1 dose of botulinum toxin type B (MyoBloc) in the upper limb. The study lasted 12 weeks, and patients received 1 injection of botulinum toxin type B. The study was sponsored by Elan Pharmaceuticals, but the company did not participate in the study design, the collection, analysis, or interpretation of the data or the writing of this report. The study was performed under an investigational new drug approval to the principal investigator (PI; AB) from the US Food and Drug Administration. Efficacy measures. The primary prospectively defined efficacy measure was the Ashworth score at week 4. The Ashworth Scale is a 5-point scale (range, 0 4) that measures the degree of spasticity in a muscle (half points are allowed). The scale is rated as follows: 0 equals no increase in muscle tone; 1.0 equals slight increase in muscle tone, manifested by a catch

2 104 BOTULINUM TOXIN TYPE B IN UPPER-LIMB SPASTICITY, Brashear Table 1: GAC Scale and Results GAC Scale markedly moderately mildly slightly worse unchanged slightly better mildly moderately markedly Worse Better Week 4 Week 8 Week 12 PI GAC (P.004) (P.016) (P.031) Patient GAC (P.008) (P.031) (P.07) Therapist GAC (P.004) (P.031) (P.25) NOTE. Values are mean standard deviation (SD). P values were calculated by using the Wilcoxon signed-rank test. The GAC was assessed by the patient, PI, and therapist at each visit after injection by using the scale shown above. and release, or by minimal resistance at the end of the range of motion (ROM) when the affected part is moved in flexion or extension; 2.0 equals more marked increase in muscle tone through most of the ROM, but the affected limb is easily moved; 3.0 equals considerable increase in muscle tone, passive movement is difficult; and 4.0 equals affected part is rigid in flexion or extension. The PI rated each patient at each visit and did not review the previous ratings. The secondary outcome measurements were the principal investigator global assessment of change (PI GAC), the patient global assessment of change (patient GAC), and the global assessment by the occupational therapist (therapist GAC). These were on a 4 (much worse) to 4 (completely resolved) scale, with zero being unchanged. See table 1 for the scale. The tertiary outcome measurements were goniometry measurements performed by the occupational therapist, overall pain assessment by the patient, the Nine Hole Peg Test 11 (NHPT), and the Jebsen Hand Function Test 12 (JHFT). The NHPT is a simple, timed test of fine motor coordination that scores subjects on the amount of time it takes them to place and remove all 9 pegs. The JHFT evaluates a patient s functional capabilities in commonly used activities in a standardized fashion. We selected subscales of the JHFT to provide a broad sampling on hand function. The subscales included timed assessments of writing, turning over 3 5-in cards, picking up small common objects, simulated feeding, stacking checkers, picking up large objects, and picking up heavy objects. Safety measurements. Safety was assessed through reports of any adverse events, and changes in vital signs as noted through physical examinations at each visit. Treatment and study activities. Ten patients (5 men, 5 women) were recruited from local therapists, neurologists, and stroke support groups. Each subject made 4 visits to the treatment site on treatment day (baseline) and at weeks 4, 8, and 12. The subjects eligibility to participate in the study was determined on the first visit, when their medical and neurologic histories were taken and they underwent physical and neurologic examinations in which their weight, height, pulse, and blood pressure were recorded. Muscle tone was assessed with the Ashworth Scale and women had urine pregnancy tests, if applicable. Goniometry measurements were taken, and the NHPT and JHFT were given. After eligibility was confirmed, patients signed informed consent forms and were given the treatment injection. During follow-up visits at weeks 4, 8, and 12, muscle tone was assessed with the Ashworth Scale, goniometry measurements were taken; pain was measured; and the JHFT, NHPT, PI GAC, patient GAC, and therapist GAC were administered. The PI performed the injections and the Ashworth Scale at each visit, and the occupational therapist (ALM) performed all of the other tests. Safety assessments, including vitals signs, concomitant medications, and adverse events were recorded at each visit. Study drug and injection technique. The drug was provided in 3.5-mL vials containing either 5000 or 10,000U of botulinum toxin type B. Each 1.0mL contained 5000U of toxin. The medication was provided in liquid form, was stored in a refrigerator, and was not further diluted. A nerve stimulator was used for each muscle, and each patient received a total of 2.0mL of the drug, injected with a 37-gauge Teflon -coated needle into the muscles listed in table 2. Analysis Overview of methods and types of analyses. All data were entered into an Excel spreadsheet, a and the SAS software program b was used. Average measurements and average changes were reported. For many variables, we calculated the standard deviation (SD). We used the Friedman test by using time as a 4-level grouping variable for Ashworth score and vital signs to test for an overall time effect. 13 For the GAC, we used a 3-level grouping variable to examine for changing perceptions of change. The Wilcoxon signed-rank test was used to compare distributions to zero and to compare change scores. 13 We used this nonparametric test because the distributions were often far from normal. No adjustment for multiple testing was made. For the timed NHPT, we used the average of 3 measurements at each visit. RESULTS Patient Demographics Ten subjects enrolled in the study, and none left it early. One patient missed a visit at week 8. The mean age SD of the subjects was years. The etiology of spasticity was stroke in 9 subjects and TBI in 1 subject. Efficacy Results Primary outcome measure. There was no overall evidence of a time effect for Ashworth score at the elbow (P.40, Table 2: Study Drug Units Used Per Muscle Muscles Injected Dose of Botulinum Toxin Type B (U) Biceps 3750 Flexor carpi ulnaris 2500 Flexor carpi radialis 2500 Flexor digitorum sublimis 625 Flexor digitorum profundus 625 Total limb dose 10,000

3 BOTULINUM TOXIN TYPE B IN UPPER-LIMB SPASTICITY, Brashear 105 Ashworth Scale Table 3: Physician s Ashworth Score Results at Week 4 at Week 8 at Week 12 Elbow (P.016) (P.016) (P.07) Wrist (P.004) (P.016) (P.016) Finger (P.02) (P.08) (P.10) Thumb (not injected) (P.69) (P 1.00) (P.25) NOTE. Values are mean SD. The Ashworth Scale was measured at each visit and the changes calculated from baseline. P values were calculated using the Wilcoxon signed-rank test. Friedman) or at the thumb (P.77, Friedman). There was a highly significant effect at the wrist (P.0029, Friedman) and a significant effect at the finger (P.0154, Friedman). The prospectively defined primary efficacy outcome variable for this study was the Ashworth score at week 4. The results are listed in table 3 and figure 1. By using the Ashworth Scale, we showed a statistical change from baseline at the elbow at weeks 4 and 8; at the wrist at weeks 4, 8 and 12; and at the fingers for week 4 only. We did not inject the thumb muscles, and, as anticipated, they did not any show changes in the Ashworth score. Secondary outcome measures. There was no evidence that the perceived GAC varied over time for assessments done by the PI (P.15, Friedman) or the patient (P.63, Friedman), but there was a significant change in assessments done by the therapist (P.0108, Friedman). The secondary outcome measurements were the PI GAC, the patient GAC, and the therapist GAC. At all visits, the PI GAC showed improvement. The therapist and patient GACs did not show improvement in week 12 as shown in table 1. Tertiary Outcome Measures Jebsen Hand Function Test. At baseline, none of the subjects were able to perform all of the subscales of the JHFT. No statistical analysis was done for this test, because only a few subjects could perform any part of it. Tasks requiring smaller movements, such as moving small common objects, could be done by only 2 additional patients 4 weeks after treatment. Goniometry measurements. The results of the goniometry measurement showed no statistical change in most of the active and passive measures of elbow, wrist, and finger flexion and extension. The measurement that showed the greatest gain was the increase of an average of 33.2 of passive wrist extension Fig 1. Mean change in Ashworth score from baseline at weeks 4, 8, and 12. *P<.05 (Wilcoxon signed-rank test); **P<.01 (Wilcoxon signed-rank test). at week 4 (P.027), with a gradual decrease in this benefit at weeks 8 (P.38) and 12 (P.15). In addition, metacarpal phalangeal passive extension improved by 15 throughout all 12 weeks, but was not statistically significant. More study of the goniometry changes in a larger patient population is needed to determine if these changes are significant. Nine Hold Peg Test. The 3 postinjection attempts to place all 9 pegs into holes and then place them back on the table were timed and averaged over the 3 tests. There were changes in the NHPT. Pain assessment. Pain was assessed with a 4-point scale of 0 equals no pain, 1 equals mild pain, 2 equals moderate pain, 3 equals severe pain, and 4 equals intractable pain. In patients, pain was not a large concern, nor were we able to show any change with treatment. Safety Results Vitals signs. There was no overall evidence of a time change in diastolic blood pressure (P.80, Friedman), but there was evidence that systolic blood pressure (SBP; P.0295, Friedman) and pulse (P.0295, Friedman) changed over time. There were unanticipated changes in the vital signs at week 4. These were not deemed clinically significant, and no patients reported symptoms that might be related to lowered blood pressure or pulse at that visit. These findings were noted only after the statistical analysis. The changes in vitals signs at each visit, compared with baseline visit, are listed in table 4. Drug-related adverse events. Three events were thought to be related to the study drug. The first and most common was dry mouth, which was reported by 9 of the 10 subjects. Onset ranged between 1 day to 25 days postinjection. The average onset, per patient report, was at 10 days. The duration was from 29 to 63 days, with the average being 49 days. The severity at the week 4 follow-up visit was considered moderate by the patients. Subjects reported increasing fluid intake, using hard candy, and feeling as though they had cotton mouth. None reported changing their diets or choking. By week 8, dry mouth had decreased to a mild level in all 9 subjects. Most subjects reported it as being only slightly annoying. At week 12, dry mouth had resolved completely in all 9 subjects. The event itself was not life threatening and required no diet change or medical treatment. The other 2 possible drug-related adverse events were affected biceps pain and affected arm heaviness. Biceps pain was reported by 1 subject 1 day after injection and lasted for 42 days. The area showed no signs of infection, bruising, injury, or trauma to the site. Pain was defined as mild, and a nonsteroidal pain medication was prescribed. Affected arm heaviness was reported by another subject at 21 days postinjection and disappeared in 14 days. No treatment was required. This patient also reported increased sensations in her arm during this period and a decrease in the usual numbness. To this participant, it was an unexpected and positive experience, and she was dis-

4 106 BOTULINUM TOXIN TYPE B IN UPPER-LIMB SPASTICITY, Brashear Table 4: Changes in Vital Signs at Each Visit Vital Signs Change at Week 4 Change a Week 8 Change at Week 12 Systolic BP (P.063) (P.10) (P.94) Diastolic BP (P.66) (P.88) (P.89) Pulse (P.08) (P.66) (P.64) NOTE. Values are mean SD. Pulse and blood pressure were taken at each visit and changes calculated from baseline measurements. P values were calculated by using the Wilcoxon signed-rank test. Abbreviation: BP, blood pressure. appointed when the arm returned to baseline. The arm heaviness was possibly related to the study drug; however, the other new sensation reports of the subject cannot be explained. DISCUSSION The results of this study show that botulinum toxin type B has potential benefits in treating poststroke spasticity, as evidenced by the decrease in Ashworth score at the elbow, wrist, and fingers. In addition, there were overall improvements noted by the PI, patient, and the occupational therapist at nearly all visits. This was a preliminary study and its results must be confirmed in a double-blind, placebo-controlled trial. This study showed an effect of a total limb dose of 10,000U of botulinum toxin type B. This effect was across 3 joints, and its effect was maintained at the wrist throughout the 12-week study. The total body dose used in this study was the same as the total body dose in the large multicenter, placebo-controlled trials of botulinum toxin type B in the treatment of cervical dystonia. 1,2 Because there are no published data on injection of botulinum toxin type B in the limb, the total dose of 10,000U was distributed in all 10 patients to the 5 most commonly involved muscles, based on the size of the muscle. In addition, the PI relied on clinical experience with botulinum toxin type A injections to determine which muscles were more active in producing elbow, wrist, and finger flexion. 5 Muscle tone was evaluated with the Ashworth Scale, which, although simple, is an accepted measure for evaluating muscle tone in clinical trials. 14 With the Ashworth Scale, we found a statistical change from baseline at week 4 for all 3 joints. Fewer benefits were seen over time, with only the wrist showing significant changes from baseline to study s end. It has been difficult to assess the possible functional benefits of injecting spastic limbs with botulinum toxin. 5,15 In this small study, we attempted to show objective improvement in function by using the JHFT. This test was difficult for many patients to perform at baseline. Some patients could do these tasks after injections, but they were too few in number to warrant comment. Additional measures of function unique to patients with focal spasticity after stroke need to be developed. The goniometry measurements did not show statistically significant changes after treatment with botulinum toxin type B. Although none of the changes demonstrated statistical significance in the goniometry measures, the Ashworth scores suggest that the drug does decrease muscle tone. Because we injected the elbow, wrist, and finger flexors, one would anticipate increased ROM in flexion as well as extension. Presumably, extension would be improved because the flexors are less active. In our study, we saw increased wrist extension as well as wrist flexion. There was also improvement at the metacarpophalangeal joints, presumably because of less involvement of finger flexors. Whether this trend for improved ROM is significant, and whether it correlates with functional improvement, remains to be determined. The reports of dry mouth in 9 subjects were unexpected. In the 3 large multicenter, placebo-controlled studies of botulinum toxin type B in cervical dystonia, 24% to 44% of subjects reported dry mouth. 1-3 In the study of botulinum toxin type B in subjects who continued to respond to botulinum toxin type A, dry mouth was reported more frequently in those treated with 10,000U than 5000U. In those studies, the dry mouth was thought to be related to the closeness of the neck injections to the muscles of the pharynx, the submandibular, and parotid glands. In this study, the most proximal muscle injected was the biceps. The presence of dry mouth in this study suggests that there may be a distant effect of the toxin on the autonomic neurons, or some other effect on the parotid or submandibular glands. The decrease in SBP in these 10 patients was unanticipated and was noted only after the statistical analysis was concluded. Although these poststroke patients had obvious cerebrovascular risk factors, only 1 patient changed blood pressure medication during the study. This medication was discontinued by the patient s primary care physician. The mean change in SBP was only 8mmHg. No patient reported symptoms of dizziness or syncope. It may be that this finding is best explained by the patients anxiety at the injection visit that was not present at the follow-up visit. This is particularly possible because no significant blood pressure or pulse changes were seen in the 2 large pivotal trials of botulinum toxin type B in cervical dystonia. 1,2 Regardless of cause, future studies of botulinum toxin type B in this patient population should include additional safety visits. The only true way to evaluate this adverse event is through a double-blind, placebo-controlled trial of botulinum toxin type B in focal poststroke spasticity. CONCLUSION This small, pilot, open-label study is the first to report the use of botulinum toxin type B in the treatment of poststroke spasticity. Despite the wide availability of the drug, all previous published studies with type B have been only with cervical dystonia. Our study shows that a relatively low dose of botulinum toxin type B is effective in decreasing the amount of tone in the upper limb, but questions remain including the mechanism of dry mouth, changes in SBP, and duration of effect. Given the decrease in the Ashworth score, coupled with the previously mentioned concerns, we recommend not starting with a dose higher than 10,000U in these patients. Also, additional studies are needed to assess improvement in activities of daily living with this treatment. The sensitivity of current functional scales to show change in this population with treatment of botulinum toxin also needs to be addressed. The results of this study suggest that further study in a double-blind, placebo-controlled clinical trial in the use of botulinum toxin type B in focal upper-limb spasticity is warranted. References 1. Brashear A, Lew MF, Dykstra DD, et al. Safety and efficacy of NeuroBloc (botulinum toxin type B) in type A-responsive cervical dystonia. Neurology 1999;53:

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