To the Editor: The design of the study by Brashear et al. ofbotulinum toxin for stroke (Aug. 8 issue)1 fails to meet theclaim of a "double-blind, placebo-controlled trial." The investigatorswere open partners with the manufacturer in conducting a studyin which the outcome measures were patients' reports of qualitativeimprovement after a dramatic injection that produces weakness.Whether the injection is paralytic or placebo, patients arelikely to be biased toward reports of better performance andphysicians toward observations of decreased reaction to flexor-musclestretch. Thus, the 27 percent response to placebo is no surprise.Observation of true muscle weakness by both patients and physiciansafter the injection of toxin must inevitably reinforce thissubjective sense of improvement.
The study lacked an essential blind crossover component. If,for example, patients were videotaped in the process of dressingon several occasions after the injection of drug and after theinjection of placebo, unprejudiced observers who did not knowthe patients could have served to validate the presence of atherapeutic effect. Reports of conventional clinical tests ofagility and coordination might have provided information aboutthe physiologic mechanisms behind subjective improvement. Otherinterventions, such as physical therapy, splinting, and medication,which may affect outcomes, were not mentioned.
This study does not justify extended injections for most patientswith stroke. As Rowland observes in the accompanying Perspective,2treatment of spasticity is a popular and profitable practice.But no well-controlled outcome studies have yet shown that thesuppression of reflexes by drugs (baclofen or tizanidine), surgery,or physical therapy "can significantly improve coordinated movementin hemiplegic limbs."3,4,5,6
William M. Landau, M.D. Washington University School of Medicine St. Louis, MO 63110 landauw{at}neuro.wustl.edu
References
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. [Free Full Text]
Rowland LP. Stroke, spasticity, and botulinum toxin. N Engl J Med 2002;347:382-383. [Free Full Text]
Landau WM. Spasticity: the fable of a neurological demon and the emperor's new therapy. Arch Neurol 1974;31:217-219. [Free Full Text]
Burke D. Spasticity as an adaptation to pyramidal tract injury. Adv Neurol 1988;47:401-423. [Medline]
Landau WM. Tizanidine and spasticity. Neurology 1995;45:2295-2296. [Free Full Text]
Landau WM. Muscle tone: hypertonus, spasticity, rigidity. In: Adelman G, Smith BH, eds. Encyclopedia of neuroscience. 3rd ed. New York: Elsevier Science, 2001.
To the Editor: Patients with chronic hemiplegic effects of strokeand physicians may interpret the study of Brashear et al. asshowing that functional disability decreased, so functionalability to use the hand must have increased. The authors usethe term "disability" in a fashion that requires close reading.The clinical effectiveness of the intervention can be summedup as a means to loosen the wrist and finger flexors, so thatthe hand is easier to maintain open passively. The study waspowered to detect a change of 0.5 point on the Ashworth Scaleof tone — a moot change in terms of clinical effectiveness.The small absolute but statistically significant changes inscores on the Disability Assessment Scale are a subjective measureof a narrow band of disability: patients' perceptions aboutodd arm postures, difficulty in cleaning a clenched hand, painpossibly related to stiffness, and dressing skills not necessarilyrequiring the use of the affected hand. The authors offer noinformation about sensorimotor impairment or functionality ofthe hand for grasping and reaching before and after treatment.Did the subjects use the affected hand in performing daily activitiesbefore or after receiving injections?
Bruce H. Dobkin, M.D. University of California, Los Angeles Los Angeles, CA 90095 bdobkin{at}mednet.ucla.edu
To the Editor: Brashear et al. report that patients assignedto injections of botulinum toxin type A "had greater improvementin the principal target of treatment than did subjects who receivedplacebo" but do not report the actual degree of benefit seenin each of the four measures of disability. Can they providethese data?
Manuel M. Buitrago, M.D. Tübingen University 72076 Tübingen, Germany
Irene Koolwijk, M.D. Leiden University Medical Center 2300 RC Leiden, the Netherlands
The authors reply: In response to Dr. Landau's comments regardingour study, consideration was given to the issue of blinding.The source of funding for the study and the relationships betweenthe investigators and the sponsor were clearly defined in ourarticle in a manner that is consistent with the policy of theJournal. We do not believe that the results were biased.
Landau and Dobkin suggest videotaping, tests of agility, orsensorimotor or functional testing before and after injection.No data on sensorimotor impairment or specific functionalityof the hand before treatment were obtained in this study. Videotapingwas not used because it does not have the sensitivity to detecta change. Functional testing may not be appropriate, since negativesymptoms of the upper motoneuron syndrome (e.g., weakness) preventvoluntary, goal-directed movement, irrespective of the presenceor absence of spasticity.1 The Disability Assessment Scale measuresa range of variables and is an appropriate first step in understandingthe effects of the toxin treatment.
Clinically meaningful end points were explored in the developmentof this assessment scale. Input from patients and physiciansindicates that for many, a primary goal is to reduce muscletone, not necessarily to improve the active function of theaffected limb.
A difference between groups in the mean change on the AshworthScale of tone that is smaller than that which we observed withbotulinum toxin A has been considered to demonstrate the effectivenessof oral antispasticity treatment.2 With regard to concomitantmedication and physical therapy, both treatment groups wereasked to maintain the regimens they had been receiving beforethe study.
We reported the results of a single treatment with botulinumtoxin A and mentioned the results of an open-label extensionof the study. Readers should wait for those results to be publishedbefore concluding that our "study does not justify extendedinjections for most patients with stroke."
The data requested by Drs. Buitrago and Koolwijk are listedin Table 1. Pain was not a primary symptom for the majorityof patients; thus, it would be inappropriate to draw population-basedconclusions.
Table 1. Mean Scores at Base Line and Mean Change at Week 6 for All Variables According to the Disability Assessment Scale.
We also wish to make the following corrections. The primaryend point of this study, according to the protocol, was thechange in the tone of the wrist flexor muscle from base lineto week 6. Assessment of functional disability was an additionalprespecified end point; week 6 was considered the primary endpoint of interest. In addition, on page 397, the fifth lineof the section on "Efficacy" should read "62 in the placebogroup" rather than "64 in the placebo group."
Allison Brashear, M.D. Indiana University School of Medicine Indianapolis, IN 46202 abrashea{at}iupui.edu
Mark F. Gordon, M.D. Long Island Jewish Hospital New Hyde Park, NY 11042
Editor's note: The study was supported by Allergan. Drs. Brashearand Gordon have received research grants and honorariums forspeeches from Allergan.
References
Mayer NH, Esquenazi A, Childers MK. Common patterns of clinical motor dysfunction. In: Mayer NH, Simpson DM, eds. Spasticity: etiology, evaluation, management, and the role of botulinum toxin. New York: WE MOVE, 2002:16-26.
Wallace JD. Summary of combined clinical analysis of controlled clinical trials with tizanidine. Neurology 1994;44:Suppl 9:S60-S69. [Medline]
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