Treatment of Spasticity with Bodnurn Toxin: A Double-Blind Study Barry J. Snow, MB ChB, FRACP, Joseph K. C. Tsui, MB, MRCP, FRCPC, Mohit H. Bhatt, MD, DM, Michael Varelas, FRCPC, Stanley A. Hashimoto, FRCPC, and Donald B. Calne, DM, FRCP, FRCPC ~~
~~
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We studied the effect of botulinum-A toxin on spasticity of the leg adductors in 9 patients who were either chairbound or bed-bound with chronic stable multiple sclerosis. We injected botulinum toxin (400 mouse units) or placebo into the adductor muscles in a randomized, crossover, double-blind design. Two physicians, who were unaware of the treatment order, used an objective rating scale and independently assessed the patients; interobserver correlation was excellent (r = 0.93-0.81). We found that botulinum toxin produced a significant reduction in spasticity ( p = 0.009) and a significant improvement in the ease of nursing care ($ = 0.009). There were no adverse effects during this shortterm trial. This is the first demonstration of the beneficial effect of botulinum toxin on focal spastic muscle contractions. Snow BJ, Tsui JKC, Bhatt MH, Varelas M, Hashimoto SA, Calne DB. Treatment of spasticity with botulinum toxin: a double-blind study. Ann Neurol 1990;28:512-5 15
Spasticity of the lower limbs, especially adductor spasm, is a major cause of disability in patients with chronic disorders of the pyramidal tract. Until now, no satisfactory treatment has been available. Medications seldom produce useful reductions in spasticity without side effects such as sedation and generalized weakness [1-31. Adductor spasticity can be particularly resistant to drug treatment [ 2 } . Surgical procedures, including section of nerve roots or the spinal cord and amputation of the femoral head, may be disfiguring, are not without risk, and spasticity can recur. Intrathecal infusion of baclofen by implanted pumps reduces spasticity, but this treatment requires close monitoring of the patient and the pump [4}.There is a need for an easily administered treatment that will control troublesome muscle spasm without producing generalized weakness or systemic effects, and injected botulinum-A toxin may meet these criteria { 5 } . Botulinum-A exotoxin is produced by the bacterium Clostvidium botulinum. When injected, in a purified form, it produces a dose-related weakness of skeletal muscle by impairing the release of acetylcholine at the neuromuscular junction [GI. Local injection of botulinum toxin selectively controls abnormal muscle activity in blepharospasm [7}, strabismus {8}, hemifacial spasm [9], spasmodic torticollis [lo], and spasmodic dysphonia 111). Injections are well tolerated, effective for about 3 months, and associated with
minimal side effects. To date, botulinum toxin has not been evaluated in spasticity. We designed a double-blind, placebo-controlled, crossover study to test the hypothesis that injection of botulinum toxin reduces spasticity of the leg adductors in multiple sclerosis.
From the Behberg Laboratory of Clinical Neuroscience, Division of Neurology, University of British Columbia, Vancouver, British Columbia, Canada.
Address correspondence to Dr Calne, Department of Medicine, University Hospital, 221 1 Wesbrook Mall, Vancouver, BC V6T 1W5, Canada.
Patients and Methods We performed a pilot study on 2 patients with multiple sclerosis and spastic contractions of the adductor muscles of the legs that made nursing difficult. Following injection of botulinurn toxin, both patients had marked reductions in adductor spasticity that lasted approximately 10 weeks. From this experience, we devised a rating scale and estimated an expected improvement on that scale of approximately 50% with a similar standard deviation. We calculated that a sample size of approximately 10 was needed to show a significant one-sided difference at p values of less than 0.05 with a power of 80%. The rating protocol is shown in the Table. We based the assessment of the degree of muscle tone on the Ashworth scale [123, modified to examine specifically the adductors. From the product of the scores for the degree of muscle tone and the spasm frequency, we derived a spasticity score. We designed the hygiene score to measure the degree to which spastic contraction made nursing care difficult. Ten patients (age 23-61 years, mean age 40.2 years; 1 man and 9 women) were recruited from two long-stay institutions. All had stable, chronic multiple sclerosis (duration of disease 9-35 years; mean duration 18.2 years), and all
Received Jan 22, 1990, and in revised form Apr 12. Accepted for publication Apr 13, 1990.
512 Copyright 0 1990 by the American Neurological Association
Rating Scales
Degree of Muscle Tone 0 No increase. 1 Increased tone, hips easily adducted to 4 5 degrees by one person. 2 Hips abducted to 45 degrees by one person with mild effort. 3 Hips abducted to 45 degrees by one person with major effort. 4 Two people required to abduct the hips to 45 degrees. Spasm Frequency Score 0 No spasms. 1 One or fewer spasms per day. 2 Between 1 and 5 spasms per day. 3 Five to less than 10 spasms per day. 4 Ten or more spasms per day, or continuous contraction. Hygiene Score 0 Independent with self-care. 1 One person is able to clean and catheterize with ease. 2 One person is able to clean and catheterize with effort. 3 One person is able to clean and catheterize only with major difficulty. 4 Two people required, but together they can clean and catheterize easily. 5 Two people clean and catheterize with difficulty.
were chair-bound or bed-bound (expanded disability status scale [13} 8.0-9.5). All had spastic contraction of adductor muscles that interfered with sitting, positioning in bed, cleaning, or urethral catheterization. Most patients had previously taken medication for the control of spasticity without success; none were on such medication during this trial. One patient had adductor tenotomy 10 years previously, but adductor spasm recurred. The injection of botulinum toxin was prepared by diluting freeze-dried toxin (supplied by Smith-Kettlewell Eye Research Institute, San Francisco, CA) with 0.9% saline to a concentration of 100 mouse units (MU)/ml. The solution was colorless and odorless, and indistinguishable from an equal quantity of isotonic saline used for the placebo injection. To minimize variation, and to ensure maximum effect from this dose of toxin, only the adductor muscles on one side were injected in each patient. On the basis of our previous experience with dystonic muscles, we chose 400 MU (160 ng) as a standard dose of botulinum toxin for each patient. The toxin was given in divided doses of 50 MU into adductor brevis (total 100 MU), adductor longus (total 100 MU), and adductor magnus (total 200 MU). The site of injection was guided by the standard locations used for elecuomyography [14). A randomized crossover design was used. The patients were examined and scored independently by two physicians “blind” to the nature of the injection (M.B. and M.V.). Choice of the first injection was made by consulting a table of random numbers. The injections were administered by B.S. who was also blinded. Follow-up assessment was performed at 2 and 6 weeks. After 3 months, the evaluation was
repeated and the crossover injection was administered. Further assessments were performed 2 and 6 weeks after the second injection. The nursing staff caring for the patients was asked to observe and record any side effects that could possibly have been due to the medication. Neither patients nor nurses were informed of the identity of the injection. Because the rating scales were noncontinuous, we used nonparametric statistical methods. To test the hypothesis that botulinum toxin reduces spasticity, we used one-sided tests of significance. The study was reviewed by the University of British Columbia Ethics Committee, and patients and relatives gave consent after a full explanation.
Results The injections were easily performed and were either painless or produced discomfort only while the needle was in the muscle. No side effects attributable to the toxin were noted at any stage of the study. Five weeks after the first injection, 1 patient (age 23 years) developed left-sided numbness and hemiparesis, and she was withdrawn from the trial. The code was broken and we found that saline had been administered. The results from the remaining 9 patients have been analyzed.
Validation of Scale The scores assigned by the blind observers were in close agreement. The correlation coefficient was 0.93 for the spasticity scores and 0.81 for the hygiene scores (Spearman’s rank correlation). The mean scores of the two observers were used for further analysis. Effect on Spasticity Following botulinum toxin, there was a significant reduction in the spasticity score at 6 weeks (mean 7.9 t 4.87 to 4.7 4.31, p = 0.007, Wilcoxon signed rank test). There was no significant difference following placebo (mean 6.8 5.26 to 7.1 t 4.77). Comparison of the differences before and 6 weeks after botulinum toxin with the differences before and 6 weeks after placebo showed a significant improvement with toxin (p = 0.009) (Fig 1).The major contribution to the reduction in the spasticity score was the decrease in the muscle tone (mean 2.6 i 0.98 to 1.4 0.98, p = 0.008), with a nonstatistically significant contribution from the decrease in spasm frequency (mean 2.9 & 1.08 to 2.7 k 1.35). There was no statistical evidence for a carry-over effect (p = 0.6) El51.
*
+_
Effect on Hygiene and Putient Care There was a statistically significant improvement in the hygiene score 6 weeks after botulinum toxin (p = 0.009), and no significant difference following placebo (Fig 2). When the differences before and 6 weeks after botulinum toxin were compared with the differences before and 6 weeks after placebo, there was a significant improvement with toxin ( p = 0.02). Snow et al: Botulinum Toxin in Spasticity 513
and healed. Because this study was designed as an initial exploration of the effect of botulinum toxin on spastic muscle contraction, we chose to administer the toxin in a uniform dose injected in the same muscles in each patient. Even greater improvement may be expected when the muscles to be injected are selected according to the particular pattern of contractions in each patient. The mechanism of action of the toxin on spasticity was presumably related to the weakening of muscle contraction by blockade of the neuromuscular junctions of extrafusal fibers. It is also possible that the neuromuscular junctions of the intrafusal fibers of b muscle spindles were blocked 117. If so, this may have -10 L---i effectively dampened the stretch reflex that induces Before After Before After spastic muscle contraction. If this was a major mechaBotulinum Toxin Placebo nism, however, we expect that the spasm frequency score would have been reduced more than we obFig 1 Plot showing the change in the meun spusticity scoves 6 served in our patients. wee& after botulinum toxin and placebo in 9 patients. The The patients in this study were not troubled by pain spasticity score i.r the product of the scores f.r muscle tone and from their muscle spasms. We have treated, on an spasm frequency. open-label basis, 2 patients with severe pain related to adductor spasms. Both had marked reduction in pain and required less analgesia than previously. Botulinum toxin also produces significant pain relief in patients with spasmodic torticollis {lo]. None of our patients developed side effects attributable to botulinum toxin despite receiving much higher doses than those used in treating spasmodic torticollis. The toxin is quantified in terms of mouse units, where 1 MU is equivalent to 0.4 ng. The dose used for eye or eyelid muscles is approximately 5 to 50 MU IS-81, and doses up to 200 MU are used in the neck. A potential adverse effect in patients exposed to large doses of toxin is weakness in muscles remote from the site of injection. Dysphagia has been reported in paI tients treated with botulinum toxin for spasmodic torBefore After Before After ticollis [167. The mechanism by which botulinum toxin Botulinum Toxin Placebo produces dysphagia is not known but might involve local diffusion. Fig 2. Plot showing the change in the mean hygiene scores 6 The action of botulinum toxin persists for approxiweeks afer botulinum toxin and plucebo i n 9 patients. mately 3 months in most conditions [S, 9, 11, 173. To maintain the therapeutic effect of the toxin, repeated Discussion injections are necessary. Further work is required beWe have shown that botulinum-A toxin significantly fore establishing the long-term efficacy and safety of reduces leg adductor spasticity in multiple sclerosis. the higher doses of toxin used in spasticity of the lower This is the first demonstration of such an effect, and it limbs. opens up new possibilities for the application of botBotulinum toxin represents a new approach to the ulinum toxin in clinical practice. treatment of spasticity with important differences to The ease of patient care, as measured by the hygiene systemic drug treatment. Systemic drugs remain the score, improved signlficantly following treatment with best treatment for the patient with generalized spasticbotulinum toxin. The greatest clinical benefit occurred ity in whom overall reduction in muscle tone is rein patients with the highest initial scores. In 2 patients, quired. In contrast, botulinum toxin is potentially more beneficial for patients with isolated troublesome one nurse was able to perform care that required two nurses before treatment. In another patient, a chronic muscle contractions. Potential applications would be in perineal excoriation became accessible to treatment patients with adductor spasticity making care of the
L
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514 Annals of Neurology Vol 28 No 4 October 1990
perineum difficult, patients at risk for soft-tissue necrosis from pressure between the legs, and patients with flexion and adduction of the hip causing pressure necrosis over the head of the femur. A further application may be in patients who depend on spastic extension of the legs to facilitate weight bearing yet have debilitating contractions in other muscle groups. The generalized effect of systemic drugs can block the helpful spasticity, while botulinum toxin would treat the troublesome contractions without affecting the useful spasticity. In summary, botulinum-A toxin reduced spastic muscle contractions. The toxin was easily administered and was not associated with adverse effects. Within the strict protocol of this study, there was an improvement in the ease of nursing care following injection of the toxin. This improvement may be expected to be even greater as we gain more experience in the use of botulinum-A toxin for spasticity. This study was supported by the British Columbia Health Care Research Foundation, the New Zealand Neurological Foundation, and the Dystonia Medical Research Foundation. Dr Alan Scott of the Smith-Kettlewell Eye Institute, San Francisco, gave helpful advice and support for this study. Dr Michael Schulzer helped with statistical analysis. We thank the staff, and the patients and their relatives of Pearson Hospital and Buchanan Court for their cooperation.
References 1. Young RR, Delwade PJ. Drug therapy: spasticity (first of two parts). N Engl J Med 1981;304:28-33 2. Young RR, Delwade PJ. Drug therapy: spasticity (second of two parts). N Engl J Med 1981;3096-99
3. h c e GP. Pharmacotherapy of spasticity: some theoretical and practical considerations. Can J Neurol Sci 1987;14(suppl):510512 4. Penn RD, Savoy SM, Corcos D, et al. Intrathecal baclofen for severe spinal spasticity. N Engl J Med 1989;320:1517-1521 5 . Scott AB, Rosenbaum AL, Collins CC. Pharmacologic weakening of extraocular muscles. Invest Ophthalmol 1973;12:924927 6. Kao I, Drachman DB, Price DL. Botulinum toxin: mechanism of presynaptic blockade. Science 1976;193:1256-1258 7. Scott AB, Kennedy RA, Stubbs HA. Botulinum toxin injection as a treatment for blepharospasm. Arch Ophthalmol 1985; 103:347-350 8. Scott AB. Botulinum toxin injection of eye muscles to correct strabismus. Trans Am Ophthalmol SOC1981;79:734-770 9. Mauriello JA Jr. Blepharospasm, Meige syndrome, and hemifacial spasm: treatment with botulinum toxin. Neurology 1985; 35:1499-1500 10. Tsui JK, Eisen A, Stoessel J, et al. Double-blind study of botulinum toxin in spasmodic torticollis. Lancet 1986;2:245257 11. Ludlow CL, Naunton RF, Sedory SE, et al. Effects of botulinum toxin on specch in adduccor spasmodic dystonia. Neurology 1988;38:1220-1225 12. Ashworth B. Preliminary trial of carisoprodol in multiple sclerosis. Practitioner 1964;192:540-542 13. Kurtzke JF. Rating neurologic improvement in multiple sclerosis: an expanded disability rating scale (EDSS). Neurology 1983;33:1444-1452 14. Delagi EF, Perotto A, Iazzetti J, Morrison D. Anatomic guide for the electromyographer. Springfield: Charles C Thomas, 1980
15. Armitage P, Berry G. Statistical methods in medical research. Oxford: Blackwell Scientific, 1987:222-226 16. Stell R, Thompson PD, Marsden CD. Botulinum toxin in spasmodic torticollis. J Neurol Neurosurg Psychiatry 1988;51:92092 3 17. Tsui JK, Fross RD, Calne S, Calne DB. Local treatment of spasmodic torticollis with botulinum toxin. Can J Neurol Sci 1987;141533-535
Snow et al: Botulinum Toxin in Spasticity
515
~~
~
~
~~
We studied the effect of botulinum-A toxin on spasticity of the leg adductors in 9 patients who were either chairbound or bed-bound with chronic stable multiple sclerosis. We injected botulinum toxin (400 mouse units) or placebo into the adductor muscles in a randomized, crossover, double-blind design. Two physicians, who were unaware of the treatment order, used an objective rating scale and independently assessed the patients; interobserver correlation was excellent (r = 0.93-0.81). We found that botulinum toxin produced a significant reduction in spasticity ( p = 0.009) and a significant improvement in the ease of nursing care ($ = 0.009). There were no adverse effects during this shortterm trial. This is the first demonstration of the beneficial effect of botulinum toxin on focal spastic muscle contractions. Snow BJ, Tsui JKC, Bhatt MH, Varelas M, Hashimoto SA, Calne DB. Treatment of spasticity with botulinum toxin: a double-blind study. Ann Neurol 1990;28:512-5 15
Spasticity of the lower limbs, especially adductor spasm, is a major cause of disability in patients with chronic disorders of the pyramidal tract. Until now, no satisfactory treatment has been available. Medications seldom produce useful reductions in spasticity without side effects such as sedation and generalized weakness [1-31. Adductor spasticity can be particularly resistant to drug treatment [ 2 } . Surgical procedures, including section of nerve roots or the spinal cord and amputation of the femoral head, may be disfiguring, are not without risk, and spasticity can recur. Intrathecal infusion of baclofen by implanted pumps reduces spasticity, but this treatment requires close monitoring of the patient and the pump [4}.There is a need for an easily administered treatment that will control troublesome muscle spasm without producing generalized weakness or systemic effects, and injected botulinum-A toxin may meet these criteria { 5 } . Botulinum-A exotoxin is produced by the bacterium Clostvidium botulinum. When injected, in a purified form, it produces a dose-related weakness of skeletal muscle by impairing the release of acetylcholine at the neuromuscular junction [GI. Local injection of botulinum toxin selectively controls abnormal muscle activity in blepharospasm [7}, strabismus {8}, hemifacial spasm [9], spasmodic torticollis [lo], and spasmodic dysphonia 111). Injections are well tolerated, effective for about 3 months, and associated with
minimal side effects. To date, botulinum toxin has not been evaluated in spasticity. We designed a double-blind, placebo-controlled, crossover study to test the hypothesis that injection of botulinum toxin reduces spasticity of the leg adductors in multiple sclerosis.
From the Behberg Laboratory of Clinical Neuroscience, Division of Neurology, University of British Columbia, Vancouver, British Columbia, Canada.
Address correspondence to Dr Calne, Department of Medicine, University Hospital, 221 1 Wesbrook Mall, Vancouver, BC V6T 1W5, Canada.
Patients and Methods We performed a pilot study on 2 patients with multiple sclerosis and spastic contractions of the adductor muscles of the legs that made nursing difficult. Following injection of botulinurn toxin, both patients had marked reductions in adductor spasticity that lasted approximately 10 weeks. From this experience, we devised a rating scale and estimated an expected improvement on that scale of approximately 50% with a similar standard deviation. We calculated that a sample size of approximately 10 was needed to show a significant one-sided difference at p values of less than 0.05 with a power of 80%. The rating protocol is shown in the Table. We based the assessment of the degree of muscle tone on the Ashworth scale [123, modified to examine specifically the adductors. From the product of the scores for the degree of muscle tone and the spasm frequency, we derived a spasticity score. We designed the hygiene score to measure the degree to which spastic contraction made nursing care difficult. Ten patients (age 23-61 years, mean age 40.2 years; 1 man and 9 women) were recruited from two long-stay institutions. All had stable, chronic multiple sclerosis (duration of disease 9-35 years; mean duration 18.2 years), and all
Received Jan 22, 1990, and in revised form Apr 12. Accepted for publication Apr 13, 1990.
512 Copyright 0 1990 by the American Neurological Association
Rating Scales
Degree of Muscle Tone 0 No increase. 1 Increased tone, hips easily adducted to 4 5 degrees by one person. 2 Hips abducted to 45 degrees by one person with mild effort. 3 Hips abducted to 45 degrees by one person with major effort. 4 Two people required to abduct the hips to 45 degrees. Spasm Frequency Score 0 No spasms. 1 One or fewer spasms per day. 2 Between 1 and 5 spasms per day. 3 Five to less than 10 spasms per day. 4 Ten or more spasms per day, or continuous contraction. Hygiene Score 0 Independent with self-care. 1 One person is able to clean and catheterize with ease. 2 One person is able to clean and catheterize with effort. 3 One person is able to clean and catheterize only with major difficulty. 4 Two people required, but together they can clean and catheterize easily. 5 Two people clean and catheterize with difficulty.
were chair-bound or bed-bound (expanded disability status scale [13} 8.0-9.5). All had spastic contraction of adductor muscles that interfered with sitting, positioning in bed, cleaning, or urethral catheterization. Most patients had previously taken medication for the control of spasticity without success; none were on such medication during this trial. One patient had adductor tenotomy 10 years previously, but adductor spasm recurred. The injection of botulinum toxin was prepared by diluting freeze-dried toxin (supplied by Smith-Kettlewell Eye Research Institute, San Francisco, CA) with 0.9% saline to a concentration of 100 mouse units (MU)/ml. The solution was colorless and odorless, and indistinguishable from an equal quantity of isotonic saline used for the placebo injection. To minimize variation, and to ensure maximum effect from this dose of toxin, only the adductor muscles on one side were injected in each patient. On the basis of our previous experience with dystonic muscles, we chose 400 MU (160 ng) as a standard dose of botulinum toxin for each patient. The toxin was given in divided doses of 50 MU into adductor brevis (total 100 MU), adductor longus (total 100 MU), and adductor magnus (total 200 MU). The site of injection was guided by the standard locations used for elecuomyography [14). A randomized crossover design was used. The patients were examined and scored independently by two physicians “blind” to the nature of the injection (M.B. and M.V.). Choice of the first injection was made by consulting a table of random numbers. The injections were administered by B.S. who was also blinded. Follow-up assessment was performed at 2 and 6 weeks. After 3 months, the evaluation was
repeated and the crossover injection was administered. Further assessments were performed 2 and 6 weeks after the second injection. The nursing staff caring for the patients was asked to observe and record any side effects that could possibly have been due to the medication. Neither patients nor nurses were informed of the identity of the injection. Because the rating scales were noncontinuous, we used nonparametric statistical methods. To test the hypothesis that botulinum toxin reduces spasticity, we used one-sided tests of significance. The study was reviewed by the University of British Columbia Ethics Committee, and patients and relatives gave consent after a full explanation.
Results The injections were easily performed and were either painless or produced discomfort only while the needle was in the muscle. No side effects attributable to the toxin were noted at any stage of the study. Five weeks after the first injection, 1 patient (age 23 years) developed left-sided numbness and hemiparesis, and she was withdrawn from the trial. The code was broken and we found that saline had been administered. The results from the remaining 9 patients have been analyzed.
Validation of Scale The scores assigned by the blind observers were in close agreement. The correlation coefficient was 0.93 for the spasticity scores and 0.81 for the hygiene scores (Spearman’s rank correlation). The mean scores of the two observers were used for further analysis. Effect on Spasticity Following botulinum toxin, there was a significant reduction in the spasticity score at 6 weeks (mean 7.9 t 4.87 to 4.7 4.31, p = 0.007, Wilcoxon signed rank test). There was no significant difference following placebo (mean 6.8 5.26 to 7.1 t 4.77). Comparison of the differences before and 6 weeks after botulinum toxin with the differences before and 6 weeks after placebo showed a significant improvement with toxin (p = 0.009) (Fig 1).The major contribution to the reduction in the spasticity score was the decrease in the muscle tone (mean 2.6 i 0.98 to 1.4 0.98, p = 0.008), with a nonstatistically significant contribution from the decrease in spasm frequency (mean 2.9 & 1.08 to 2.7 k 1.35). There was no statistical evidence for a carry-over effect (p = 0.6) El51.
*
+_
Effect on Hygiene and Putient Care There was a statistically significant improvement in the hygiene score 6 weeks after botulinum toxin (p = 0.009), and no significant difference following placebo (Fig 2). When the differences before and 6 weeks after botulinum toxin were compared with the differences before and 6 weeks after placebo, there was a significant improvement with toxin ( p = 0.02). Snow et al: Botulinum Toxin in Spasticity 513
and healed. Because this study was designed as an initial exploration of the effect of botulinum toxin on spastic muscle contraction, we chose to administer the toxin in a uniform dose injected in the same muscles in each patient. Even greater improvement may be expected when the muscles to be injected are selected according to the particular pattern of contractions in each patient. The mechanism of action of the toxin on spasticity was presumably related to the weakening of muscle contraction by blockade of the neuromuscular junctions of extrafusal fibers. It is also possible that the neuromuscular junctions of the intrafusal fibers of b muscle spindles were blocked 117. If so, this may have -10 L---i effectively dampened the stretch reflex that induces Before After Before After spastic muscle contraction. If this was a major mechaBotulinum Toxin Placebo nism, however, we expect that the spasm frequency score would have been reduced more than we obFig 1 Plot showing the change in the meun spusticity scoves 6 served in our patients. wee& after botulinum toxin and placebo in 9 patients. The The patients in this study were not troubled by pain spasticity score i.r the product of the scores f.r muscle tone and from their muscle spasms. We have treated, on an spasm frequency. open-label basis, 2 patients with severe pain related to adductor spasms. Both had marked reduction in pain and required less analgesia than previously. Botulinum toxin also produces significant pain relief in patients with spasmodic torticollis {lo]. None of our patients developed side effects attributable to botulinum toxin despite receiving much higher doses than those used in treating spasmodic torticollis. The toxin is quantified in terms of mouse units, where 1 MU is equivalent to 0.4 ng. The dose used for eye or eyelid muscles is approximately 5 to 50 MU IS-81, and doses up to 200 MU are used in the neck. A potential adverse effect in patients exposed to large doses of toxin is weakness in muscles remote from the site of injection. Dysphagia has been reported in paI tients treated with botulinum toxin for spasmodic torBefore After Before After ticollis [167. The mechanism by which botulinum toxin Botulinum Toxin Placebo produces dysphagia is not known but might involve local diffusion. Fig 2. Plot showing the change in the mean hygiene scores 6 The action of botulinum toxin persists for approxiweeks afer botulinum toxin and plucebo i n 9 patients. mately 3 months in most conditions [S, 9, 11, 173. To maintain the therapeutic effect of the toxin, repeated Discussion injections are necessary. Further work is required beWe have shown that botulinum-A toxin significantly fore establishing the long-term efficacy and safety of reduces leg adductor spasticity in multiple sclerosis. the higher doses of toxin used in spasticity of the lower This is the first demonstration of such an effect, and it limbs. opens up new possibilities for the application of botBotulinum toxin represents a new approach to the ulinum toxin in clinical practice. treatment of spasticity with important differences to The ease of patient care, as measured by the hygiene systemic drug treatment. Systemic drugs remain the score, improved signlficantly following treatment with best treatment for the patient with generalized spasticbotulinum toxin. The greatest clinical benefit occurred ity in whom overall reduction in muscle tone is rein patients with the highest initial scores. In 2 patients, quired. In contrast, botulinum toxin is potentially more beneficial for patients with isolated troublesome one nurse was able to perform care that required two nurses before treatment. In another patient, a chronic muscle contractions. Potential applications would be in perineal excoriation became accessible to treatment patients with adductor spasticity making care of the
L
u
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~
~
~
514 Annals of Neurology Vol 28 No 4 October 1990
perineum difficult, patients at risk for soft-tissue necrosis from pressure between the legs, and patients with flexion and adduction of the hip causing pressure necrosis over the head of the femur. A further application may be in patients who depend on spastic extension of the legs to facilitate weight bearing yet have debilitating contractions in other muscle groups. The generalized effect of systemic drugs can block the helpful spasticity, while botulinum toxin would treat the troublesome contractions without affecting the useful spasticity. In summary, botulinum-A toxin reduced spastic muscle contractions. The toxin was easily administered and was not associated with adverse effects. Within the strict protocol of this study, there was an improvement in the ease of nursing care following injection of the toxin. This improvement may be expected to be even greater as we gain more experience in the use of botulinum-A toxin for spasticity. This study was supported by the British Columbia Health Care Research Foundation, the New Zealand Neurological Foundation, and the Dystonia Medical Research Foundation. Dr Alan Scott of the Smith-Kettlewell Eye Institute, San Francisco, gave helpful advice and support for this study. Dr Michael Schulzer helped with statistical analysis. We thank the staff, and the patients and their relatives of Pearson Hospital and Buchanan Court for their cooperation.
References 1. Young RR, Delwade PJ. Drug therapy: spasticity (first of two parts). N Engl J Med 1981;304:28-33 2. Young RR, Delwade PJ. Drug therapy: spasticity (second of two parts). N Engl J Med 1981;3096-99
3. h c e GP. Pharmacotherapy of spasticity: some theoretical and practical considerations. Can J Neurol Sci 1987;14(suppl):510512 4. Penn RD, Savoy SM, Corcos D, et al. Intrathecal baclofen for severe spinal spasticity. N Engl J Med 1989;320:1517-1521 5 . Scott AB, Rosenbaum AL, Collins CC. Pharmacologic weakening of extraocular muscles. Invest Ophthalmol 1973;12:924927 6. Kao I, Drachman DB, Price DL. Botulinum toxin: mechanism of presynaptic blockade. Science 1976;193:1256-1258 7. Scott AB, Kennedy RA, Stubbs HA. Botulinum toxin injection as a treatment for blepharospasm. Arch Ophthalmol 1985; 103:347-350 8. Scott AB. Botulinum toxin injection of eye muscles to correct strabismus. Trans Am Ophthalmol SOC1981;79:734-770 9. Mauriello JA Jr. Blepharospasm, Meige syndrome, and hemifacial spasm: treatment with botulinum toxin. Neurology 1985; 35:1499-1500 10. Tsui JK, Eisen A, Stoessel J, et al. Double-blind study of botulinum toxin in spasmodic torticollis. Lancet 1986;2:245257 11. Ludlow CL, Naunton RF, Sedory SE, et al. Effects of botulinum toxin on specch in adduccor spasmodic dystonia. Neurology 1988;38:1220-1225 12. Ashworth B. Preliminary trial of carisoprodol in multiple sclerosis. Practitioner 1964;192:540-542 13. Kurtzke JF. Rating neurologic improvement in multiple sclerosis: an expanded disability rating scale (EDSS). Neurology 1983;33:1444-1452 14. Delagi EF, Perotto A, Iazzetti J, Morrison D. Anatomic guide for the electromyographer. Springfield: Charles C Thomas, 1980
15. Armitage P, Berry G. Statistical methods in medical research. Oxford: Blackwell Scientific, 1987:222-226 16. Stell R, Thompson PD, Marsden CD. Botulinum toxin in spasmodic torticollis. J Neurol Neurosurg Psychiatry 1988;51:92092 3 17. Tsui JK, Fross RD, Calne S, Calne DB. Local treatment of spasmodic torticollis with botulinum toxin. Can J Neurol Sci 1987;141533-535
Snow et al: Botulinum Toxin in Spasticity
515
