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SPECIAL ARTICLES: D. M. Simpson, J-M Gracies, H. K. Graham, J. M. Miyasaki, M. Naumann, B. Russman, L. L. Simpson, and Y. So Assessment: Botulinum neurotoxin for the treatment of spasticity (an evidence-based review): Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology Neurology 2008; 70: 1691-1698 [Abstract] [Full text] [PDF]

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Assessment: Botulinum neurotoxin for the treatment of spasticity (an evidence-based review)

Bruce H. Dobkin, MD   (11 February 2009)

Assessment: Botulinum neurotoxin for the treatment of spasticity (an evidence-based review)

William M. Landau, Shirley Sahrmann, PhD; W. Thomas Thach, MD   (11 February 2009)

Reply from the authors

David M. Simpson, John-Michel Gracies, Kerr Graham, Mark Hallett, Janis Miyasaki, Markus Naumann, Barry Russman, Lance Simpson, and Yuen So   (11 February 2009)

Assessment: Botulinum neurotoxin for the treatment of spasticity (an evidence-based review) 11 February 2009
Bruce H. Dobkin, MD, University of California Los Angeles Dept of Neurology, RNRC, 710 Westwood Plaza, Los Angeles, CA 90095 Send Correspondence to journal: Re: Assessment: Botulinum neurotoxin for the treatment of spasticity (an evidence-based review) bdobkin{at}mednet.ucla.edu Bruce H. Dobkin, MD	The Therapeutics and Technology Assessment Subcommittee of the AAN recommends that “Botulinum neurotoxin should be offered as an option for the treatment of spasticity.” [1] Despite offering a Level A rating of evidence in support, the authors noted that functional voluntary use of the affected arm after stroke and leg in cerebral palsy did not improve across their citations of trials. Quality of life was not improved by, for example, lessening joint pain. No cost-benefit analysis was offered for utility. The trials only revealed that passive range of motion or resistance to ranging a joint temporarily improved after focal injections compared to no intervention in control subjects. This finding comes from the Ashworth scale, which has high inter-rater reliability because it separates very stiff from not as stiff resistance at one joint at rest in the trials. The change may lead to an increase in mobility of a joint angle for hygiene or for pulling a shirtsleeve over a hemiplegic arm. Is that passive result any more than a cosmetic effect for patients with stroke affecting the arm who pay for an anti-wrinkle drug? The Subcommittee calls for more research to develop a tool that can measure the potential benefits of this class of drugs. The authors should clarify if the Level A evidence is based on a poor outcome measure. In addition, there is consensus that the Ashworth score is not a clinically, biologically or electrophysiologically sound surrogate for whatever aspect of the upper motor neuron syndrome it has been over-utilized to reflect. [2] The Subcommittee also calls for studies to assess optimal dosing and localization in muscle fibers of the paralytic injectable. This will not matter unless an important clinical outcome can be defined. The group also calls for better assessment of overactivity of affected muscles at rest, but no EMG activity in hypertonic muscle is found at rest. In addition, they call for head-to-head trials of the various commercial brands of toxin and longer-acting types to find improved treatments but for what clinical problem? There is a long history of research that was launched with the hope that such drugs would improve active motor function without systemic side effects. The real need is to define a clinical phenotype for which botulinum neurotoxin can serve as a therapeutic option that can yield the same or better results than physiotherapy. References 1.Simpson DM, Gracies J-M, Graham HK, et al. Assessment: Botulinum neurotoxin for the treatment of spasticity (an evidence-based review): Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 2008;70:1691-1698. 2. Dietz V, Sinkjaer T. Spastic movement disorder:impaired reflex function and altered muscle mechanics. Lancet Neurol 2007;6:725-733. Disclosure: The author reports no disclosures.
Assessment: Botulinum neurotoxin for the treatment of spasticity (an evidence-based review) 11 February 2009
William M. Landau, Washington University School of Medicine 660 South Euclid Avenue, Campus Box 8030 ,St. Louis, MO 63110, Shirley Sahrmann, PhD; W. Thomas Thach, MD Send Correspondence to journal: Re: Assessment: Botulinum neurotoxin for the treatment of spasticity (an evidence-based review) landauw{at}neuro.wustl.edu William M. Landau, et al.	Advocacy of botulinum for spasticity fails claimed “evidence-based” standards: unconflicted, objective measures, blinded controls, independent replication. [1] Unlike symptomatic headache, spasticity has a scientific definition: “motor disorder characterized by velocity–dependent increase in tonic stretch reflexes (‘muscle tone’) with exaggerated tendon jerks, resulting from hyperexcitability of the stretch reflex as one component of the upper motor neuron syndrome [UMNS, all morbid effects of forebrain disconnection from spinal cord/brainstem]. … negative symptoms [are] the pattern of weakness and loss of dexterity caused by withdrawal of the influence of these descending motor pathways.” [3] Thus, spasticity is only the product of professional examination, neither cause nor synonym of UMNS, and not consistently correlated with severity of motor performance disability. [4-7, e1-e3] Deficient deftness and force result directly from impaired control of recruitment and firing frequency of motoneurons that comprise the final common path for a specific task. [e4-e16] Most weakness is neither attributable to mistaken reflex opposition [e17] nor myopathic failure. [e18] At rest spastic muscle is flaccid and electromyographically silent. [e4] Even the chronic decerebrate state has passive limb postures with brisk tendon jerks. [e19-e22] The assessors state “Resistance to passive movement has not been shown to correlate with active function,” but accept the subjective non- parametric Ashworth spasticity scale, “global satisfaction scores,” and “passive function” by “subjects, family members, or clinicians”: truly placebo by acclamation. Subjective labels for clumsiness like “stiffness/ tightness” are not evidence for curable reflex mechanism. Their advertisement “for patients and families” that botulinum injections “block nerve signals that cause muscle spasms or pain” is deceptively misleading. The only certain effect is weakness of injected muscle for all activities, voluntary, involuntary, and reflex. No evidence supports their presumptive speculation that paralytic 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. Measurements for comfort/nursing care by paralysis of certain muscles were not ascertained. Substantive performance gain in adults is yet to be proved. Cerebral palsy impairs projections from corticospinal neurons, basal ganglia, and often cerebellum/brainstem. [e-16] Deficits of gait, limb growth, dexterity, and speech are not simply juvenile spasticity. Whether prescription botulinum beyond research protocols improves operative morbidity and permanent functional outcome also remains still to be seen. [e23] The false premise that reflex spasticity contributes materially to negative symptoms is unnecessary. Objective measures of botulinum efficacy for any UMNS impairment merit Cochrane collaboration standard evaluation. References 3. Lance JW. Symposium Synopsis. In: Feldman RG, Young RR, Koella WP, ed. Spasticity: Disordered Motor Control. Chicago: Year Book, 1980:485. 4. Twitchell TE. The restoration of motor function following hemiplegia in man. Brain 1951;74;443-480. 5. Landau WM, Weaver RA, Hornbein TF. Fusimotor nerve function in man: Differential nerve block studies in normal subjects and in spasticity and rigidity. Arch Neurol 1961:3:10-23. 6. Landau WM. Clinical Neuromythology II. Parables of palsy pills and PT pedagogy: a spastic dialectic. Neurology 1988;38:1496-1499. 7. Landau WM, Hunt CC. Dorsal rhizotomy, a treatment of unproven efficacy. J Child Neurol 1990;5:174-178. [ REFERENCES e1-e23 will be considered as DATA SUPPLEMENT electronic REFERENCE material] ***** e1. Landau WM. Muscle tone: hypertonus, spasticity, rigidity. In: Elsevier’s Encyclopedia of Neuroscience, 3rd Edition 2001;1-5. e2. Sommerfeld DK, Eek EU, Svensson AK, et al. Spasticity after stroke: its occurrence and association with motor impairments and activity limitations. Stroke 2004;35:134-139. e3. Landau WM. Letter to the Editor: Spasticity after stroke, Why bother? Stroke 2004; 35:1787-1788. e4. Hoefer PF, Putnam TJ. Action potentials of muscles in “spastic” conditions. Arch Neurol Psychiatr 1940;43:1-22. e5. McComas AJ, Sica, REP, Upton ARM, et al. Functional changes in motoneurons of hemiparetic patients. J Neurol Neurosurg Psychiat 1973;36:183-193. e6. Young RR, Shahani BT. A clinical neurophysiological analysis of single motor unit discharge patterns in spasticity. In: Feldman RG, Young RR, Koella WP, ed. Spasticity: Disordered Motor Control. Chicago: Year Book, 1980:219-231. e7. Petajan JH. Motor unit control in spasticity. In: Feldman RG, Young RR, Koella WP, ed. Spasticity: Disordered Motor Control. Chicago: Year Book, 1980:233-247. e8. Grimby L, Hannerz J, Rånlund T. Disturbances in the voluntary recruitment order of anterior tibial motor units in spastic paraparesis upon fatigue. J Neurol Neurosurg Psychiat 1974;37:40-46. e9. Rosenfalck A, Andreassen S. Impaired regulation of force and firing pattern of single motor units in patients with spasticity. J Neurol Neurosurg Psychiat 1980;43:907-916. e10. Tang A, Rymer WZ. Abnormal force-EMG relations in paretic limbs of hemiparetic human subjects. J Neurol Neurosurg Psychiat 1981;44:690- 698. e11. Fitts SS, Hammond MC, Kraft GH, et al. Quantification of gaps in the EMG interference pattern in chronic hemiparesis. Electroenceph Clin Neurophysiol 1989; 73:225-232. e12. Gemperline JJ, Allen S, Walk D, et al. Characteristics of motor unit discharge in subjects with hemiparesis. Muscle Nerve 1995;18:1101- 1114. e13. Frontera WR, Grimby L, Larsson L. Firing rate of the lower motoneuron and contractile properties of its muscle fibers after upper motoneuron lesion in man. Muscle Nerve 1997;20:938-947. e14. Frascarelli M, Mastrogregori L, Conforti L. Initial motor unit recruitment in patients with spastic hemiplegia. Electromyogr Clin Neurophysiol 1998;38:267-271. e15. Canning CG, Ada L, O’Dwyer NJ. Abnormal muscle activation characteristics associated with loss of dexterity after stroke. 2000; J Neurol Sci 2000;176:45-56. e16. Rose J, McGill KC. Neuromuscular activation and motor-unit firing characteristics in cerebral palsy. Dev Med Child Neurol 2005;47:329-336. e17. Sahrmann SA, Norton BJ. The relationship of voluntary movement to spasticity in the upper motor neuron syndrome. Ann Neurol 1977;2:460-465. e18. Landau WM and Sahrmann SA. Preservation of directly stimulated muscle strength in hemiplegia due to stroke. Arch Neurol 2002;59:1453- 1457. e19. Feldman MH. The decerebrate state in the primate. I. Studies in Monkeys. Arch Neurol 1971;25:501-516. e20. Feldman MH, Sahrmann S. The decerebrate state in the primate. II. Studies in Man. Arch Neurol 1971;25:517-525. e21. Feldman MH. Physiological observations in a chronic case of “locked-in” syndrome. 1971;21:460-478. e22. Bazett HC, Penfield WG. A study of the Sherrington decerebrate animal in the chronic as well as the acute condition. Brain 1922;45:185- 265. e23. Moore AP, Ade-Hall RA, Tudor Smith C, et al. Two-year placebo- controlled trial of botulinum toxin A for leg spasticity in cerebral palsy. Neurology 2008;71:122-128. Disclosure: The authors report no disclosures.
Reply from the authors 11 February 2009
David M. Simpson, Mount Sinai Medical Center One Gustave L. Levy Place, Box 1052, New York, NY 10029, John-Michel Gracies, Kerr Graham, Mark Hallett, Janis Miyasaki, Markus Naumann, Barry Russman, Lance Simpson, and Yuen So Send Correspondence to journal: Re: Reply from the authors david.simpson{at}mssm.edu David M. Simpson, et al.	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.