David M.Simpson, Mount Sinai Medical Center, One Gustave L. Levy Place, Box 1052, New York, NY 10029david.simpson@mssm.edu
John-Michel Gracies, Kerr Graham, Mark Hallett, Janis Miyasaki, Markus Naumann, Barry Russman, Lance Simpson, and Yuen So
Submitted February 11, 2009
We thank Drs. Dobkin, Landau, Thach, and Sahrmann for their comments and would like to address some of their points that may lead to inaccurate conclusions. Numerous double-blind, placebo-controlled trials have demonstrated that botulinum neurotoxin (BoNT) results in improved passive mobilization and disfigurement in spasticity.
While Dr. Dobkin acknowledges that BoNT may lead to improved hygiene or ability to dress, he questions if this is “any more than a cosmetic effect for patients who pay for an anti-wrinkle drug.” It is unfortunate that he fosters the impression, frequently held by the media and public, that BoNT is predominantly a vanity drug. In contrast, the care of numerous serious disorders has been improved with BoNT.
While the correspondents question the meaningfulness of passive functional gains, cosmetic effects are often highly meaningful as they improve body image and sense of comfort. To better define the domains of function, the Disability Assessment Scale was incorporated into a large, placebo-controlled study of BoNT in spasticity with evidence of improvement. [8] BoNT in MS provides improved nursing care and perineal hygiene. [9]
Drs. Landau Thach, and Sahrmann state that no evidence supports that BoNT injection “may improve muscle weakness, soft tissue contracture, and muscle overactivity by reducing spastic co-contraction, decreasing spastic dystonia, easing muscle stretch, and increasing antagonistic torque”. However these hypotheses are increasingly supported in the literature. We have demonstrated that BoNT injection into a spastic agonist muscle decreases cocontraction of the spastic muscle and increases force developed by the antagonist. [10]. To address a point made by both correspondents, while EMG activity in spastic muscles at rest may be less than expected, even few active motor units can generate higher torque than in normal muscle.
Whether or not “reflex spasticity contributes materially to negative symptoms”, we did not assert that BoNT works by reducing spasticity. However, there is increasing evidence that BoNT may help patients with spasticity, by decreasing spastic cocontraction when attempting active movement [10,11] and spastic dystonia at rest, thus decreasing disfigurement. [12]
Physical therapy can improve motor function after stroke [13], and it is not the goal of BoNT to supplant this treatment. Patients considered for BoNT injection have goals that may be met in combination with physical therapy. The pivotal studies upon which the widely used oral agents, baclofen and tizanidine, received FDA approval for spasticity were based predominantly on patients with spinal spasticity. However, patients with spasticity resulting from brain lesions are more sensitive to the CNS depressant effects of these agents as opposed to BoNT. Our recent head-to-head, placebo-controlled trial demonstrated that BoNT is superior in safety and efficacy to tizanidine in post-stroke upper extremity spasticity. [12]
The TTA subcommittee made recommendations based on the highest quality literature, following explicit rules for evidence grading. Before the emergence of focal blocking agents, the medicines available for spastic paresis were systemic synaptic depressors. The evidence that these drugs benefited spastic patients was predominantly based on Ashworth score reduction. While Ashworth scores do not represent active function, this scale has been used throughout rehabilitation research. To acknowledge the imperfection of this tool does not negate research using it. As we stated, future studies should incorporate other outcome measures and investigate factors that predict which patient subgroups have optimal response.
References
8. Brashear A, Gordon MF, Elovic E, et al. Intramuscular injection of botulinum toxin for the treatment of wrist and finger spasticity after a stroke. N Engl J Med 2002;347:395-400.
9. Snow BJ, Tsui JK, Bhatt MH, Varelas M, Hashimoto SA, Calne DB. Treatment of spasticity with botulinum toxin: a double-blind study. Ann Neurol 1990;28:512-515.
10. Gracies JM, Lugassy M, Weisz D, at al.. Botulinum toxin dilution and endplate targeting in spasticity: A double-blind controlled study. Arch Phys Med Rehab 2008 (in press).
11. Gracies JM. Pathophysiology of Spastic Paresis. Part II. The Emergence of Muscle Overactivity. Muscle Nerve 2005;31:552-571.
12. Simpson DM, Gracies JM, Yablon SA, Barbano R, Brashear A. Botulinum Neurotoxin vs Tizanidine in Upper Limb Spasticity: A Placebo-Controlled Study. J Neurol Neurosurg Psychiatry. Online First;2008 Oct 31
13. Pak S, Patten C. Strengthening to promote functional recovery poststroke: An evidence-based review. Top Stroke Rehabil 2008;15:177-99.
Disclosures: Dr. Simpson has received speaker honoraria and research support from Allergan, Merz, and Solstice, Inc., and performs botulinum toxin injections. Dr. Gracies has received speaker honoraria and research support from Allergan, Merz, and Solstice, Inc. Dr. Graham has received speaker honoraria and research support from Allergan and performs botulinum toxin injections. Dr. Miyasaki has received research support from Boehringer Ingelheim, Huntington Study Group, NIH, Solvay, Solstice, and Teva. Dr. Naumann has received speaker honoraria from Ipsen and Allergan and performs botulinum toxin injections. Dr. Russman has received research support from Allergan and performs botulinum toxin injections. Dr. L. Simpson has received research support from Allergan. Dr. So holds financial interest in Satoris Inc., and has received research support from NIH, Pfizer, Inc., and NeurogesX, Inc.
We thank Drs. Dobkin, Landau, Thach, and Sahrmann for their comments and would like to address some of their points that may lead to inaccurate conclusions. Numerous double-blind, placebo-controlled trials have demonstrated that botulinum neurotoxin (BoNT) results in improved passive mobilization and disfigurement in spasticity.
While Dr. Dobkin acknowledges that BoNT may lead to improved hygiene or ability to dress, he questions if this is “any more than a cosmetic effect for patients who pay for an anti-wrinkle drug.” It is unfortunate that he fosters the impression, frequently held by the media and public, that BoNT is predominantly a vanity drug. In contrast, the care of numerous serious disorders has been improved with BoNT.
While the correspondents question the meaningfulness of passive functional gains, cosmetic effects are often highly meaningful as they improve body image and sense of comfort. To better define the domains of function, the Disability Assessment Scale was incorporated into a large, placebo-controlled study of BoNT in spasticity with evidence of improvement. [8] BoNT in MS provides improved nursing care and perineal hygiene. [9]
Drs. Landau Thach, and Sahrmann state that no evidence supports that BoNT injection “may improve muscle weakness, soft tissue contracture, and muscle overactivity by reducing spastic co-contraction, decreasing spastic dystonia, easing muscle stretch, and increasing antagonistic torque”. However these hypotheses are increasingly supported in the literature. We have demonstrated that BoNT injection into a spastic agonist muscle decreases cocontraction of the spastic muscle and increases force developed by the antagonist. [10]. To address a point made by both correspondents, while EMG activity in spastic muscles at rest may be less than expected, even few active motor units can generate higher torque than in normal muscle. Whether or not “reflex spasticity contributes materially to negative symptoms”, we did not assert that BoNT works by reducing spasticity. However, there is increasing evidence that BoNT may help patients with spasticity, by decreasing spastic cocontraction when attempting active movement [10,11] and spastic dystonia at rest, thus decreasing disfigurement. [12]
Physical therapy can improve motor function after stroke [13], and it is not the goal of BoNT to supplant this treatment. Patients considered for BoNT injection have goals that may be met in combination with physical therapy. The pivotal studies upon which the widely used oral agents, baclofen and tizanidine, received FDA approval for spasticity were based predominantly on patients with spinal spasticity. However, patients with spasticity resulting from brain lesions are more sensitive to the CNS depressant effects of these agents as opposed to BoNT. Our recent head-to-head, placebo-controlled trial demonstrated that BoNT is superior in safety and efficacy to tizanidine in post-stroke upper extremity spasticity. [12]
The TTA subcommittee made recommendations based on the highest quality literature, following explicit rules for evidence grading. Before the emergence of focal blocking agents, the medicines available for spastic paresis were systemic synaptic depressors. The evidence that these drugs benefited spastic patients was predominantly based on Ashworth score reduction. While Ashworth scores do not represent active function, this scale has been used throughout rehabilitation research. To acknowledge the imperfection of this tool does not negate research using it. As we stated, future studies should incorporate other outcome measures and investigate factors that predict which patient subgroups have optimal response.
References
8. Brashear A, Gordon MF, Elovic E, et al. Intramuscular injection of botulinum toxin for the treatment of wrist and finger spasticity after a stroke. N Engl J Med 2002;347:395-400.
9. Snow BJ, Tsui JK, Bhatt MH, Varelas M, Hashimoto SA, Calne DB. Treatment of spasticity with botulinum toxin: a double-blind study. Ann Neurol 1990;28:512-515.
10. Gracies JM, Lugassy M, Weisz D, at al.. Botulinum toxin dilution and endplate targeting in spasticity: A double-blind controlled study. Arch Phys Med Rehab 2008 (in press).
11. Gracies JM. Pathophysiology of Spastic Paresis. Part II. The Emergence of Muscle Overactivity. Muscle Nerve 2005;31:552-571.
12. Simpson DM, Gracies JM, Yablon SA, Barbano R, Brashear A. Botulinum Neurotoxin vs Tizanidine in Upper Limb Spasticity: A Placebo-Controlled Study. J Neurol Neurosurg Psychiatry. Online First;2008 Oct 31
13. Pak S, Patten C. Strengthening to promote functional recovery poststroke: An evidence-based review. Top Stroke Rehabil 2008;15:177-99.
Disclosures: Dr. Simpson has received speaker honoraria and research support from Allergan, Merz, and Solstice, Inc., and performs botulinum toxin injections. Dr. Gracies has received speaker honoraria and research support from Allergan, Merz, and Solstice, Inc. Dr. Graham has received speaker honoraria and research support from Allergan and performs botulinum toxin injections. Dr. Miyasaki has received research support from Boehringer Ingelheim, Huntington Study Group, NIH, Solvay, Solstice, and Teva. Dr. Naumann has received speaker honoraria from Ipsen and Allergan and performs botulinum toxin injections. Dr. Russman has received research support from Allergan and performs botulinum toxin injections. Dr. L. Simpson has received research support from Allergan. Dr. So holds financial interest in Satoris Inc., and has received research support from NIH, Pfizer, Inc., and NeurogesX, Inc.