Correspondence
Correction
Botulinum Toxin for Spasticity after Stroke
N Engl J Med 2003; 348:258-259January 16, 2003
- Article
To the Editor:
The design of the study by Brashear et al. of botulinum toxin for stroke (Aug. 8 issue)1 fails to meet the claim of a “double-blind, placebo-controlled trial.” The investigators were open partners with the manufacturer in conducting a study in which the outcome measures were patients' reports of qualitative improvement after a dramatic injection that produces weakness. Whether the injection is paralytic or placebo, patients are likely to be biased toward reports of better performance and physicians toward observations of decreased reaction to flexor-muscle stretch. Thus, the 27 percent response to placebo is no surprise. Observation of true muscle weakness by both patients and physicians after the injection of toxin must inevitably reinforce this subjective sense of improvement.
The study lacked an essential blind crossover component. If, for example, patients were videotaped in the process of dressing on several occasions after the injection of drug and after the injection of placebo, unprejudiced observers who did not know the patients could have served to validate the presence of a therapeutic effect. Reports of conventional clinical tests of agility and coordination might have provided information about the physiologic mechanisms behind subjective improvement. Other interventions, such as physical therapy, splinting, and medication, which may affect outcomes, were not mentioned.
This study does not justify extended injections for most patients with stroke. As Rowland observes in the accompanying Perspective,2 treatment of spasticity is a popular and profitable practice. But no well-controlled outcome studies have yet shown that the suppression of reflexes by drugs (baclofen or tizanidine), surgery, or physical therapy “can significantly improve coordinated movement in hemiplegic limbs.”3-6
6 ReferencesWilliam M. Landau, M.D.
Washington University School of Medicine, St. Louis, MO 63110
landauw@neuro.wustl. edu 1
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
Full Text | Web of Science | Medline2
Rowland LP . Stroke, spasticity, and botulinum toxin. N Engl J Med 2002;347:382-383
Full Text | Web of Science | Medline3
Landau WM . Spasticity: the fable of a neurological demon and the emperor's new therapy. Arch Neurol 1974;31:217-219
Web of Science | Medline4
Burke D . Spasticity as an adaptation to pyramidal tract injury. Adv Neurol 1988;47:401-423
Medline5
Landau WM . Tizanidine and spasticity. Neurology 1995;45:2295-2296
Web of Science | Medline6
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 stroke and physicians may interpret the study of Brashear et al. as showing that functional disability decreased, so functional ability to use the hand must have increased. The authors use the term “disability” in a fashion that requires close reading. The clinical effectiveness of the intervention can be summed up as a means to loosen the wrist and finger flexors, so that the hand is easier to maintain open passively. The study was powered to detect a change of 0.5 point on the Ashworth Scale of tone — a moot change in terms of clinical effectiveness. The small absolute but statistically significant changes in scores on the Disability Assessment Scale are a subjective measure of a narrow band of disability: patients' perceptions about odd arm postures, difficulty in cleaning a clenched hand, pain possibly related to stiffness, and dressing skills not necessarily requiring the use of the affected hand. The authors offer no information about sensorimotor impairment or functionality of the hand for grasping and reaching before and after treatment. Did the subjects use the affected hand in performing daily activities before or after receiving injections?
Bruce H. Dobkin, M.D.
University of California, Los Angeles, Los Angeles, CA 90095
bdobkin@mednet.ucla. edu To the Editor:
Brashear et al. report that patients assigned to injections of botulinum toxin type A “had greater improvement in the principal target of treatment than did subjects who received placebo” but do not report the actual degree of benefit seen in each of the four measures of disability. Can they provide these data?
Manuel M. Buitrago, M.D.
Tübingen University, 72076 Tübingen, GermanyIrene Koolwijk, M.D.
Leiden University Medical Center, 2300 RC Leiden, the NetherlandsAuthor/Editor Response
In response to Dr. Landau's comments regarding our study, consideration was given to the issue of blinding. The source of funding for the study and the relationships between the investigators and the sponsor were clearly defined in our article in a manner that is consistent with the policy of the Journal. We do not believe that the results were biased.
Landau and Dobkin suggest videotaping, tests of agility, or sensorimotor or functional testing before and after injection. No data on sensorimotor impairment or specific functionality of the hand before treatment were obtained in this study. Videotaping was not used because it does not have the sensitivity to detect a change. Functional testing may not be appropriate, since negative symptoms of the upper motoneuron syndrome (e.g., weakness) prevent voluntary, goal-directed movement, irrespective of the presence or absence of spasticity.1 The Disability Assessment Scale measures a range of variables and is an appropriate first step in understanding the effects of the toxin treatment.
Clinically meaningful end points were explored in the development of this assessment scale. Input from patients and physicians indicates that for many, a primary goal is to reduce muscle tone, not necessarily to improve the active function of the affected limb.
A difference between groups in the mean change on the Ashworth Scale of tone that is smaller than that which we observed with botulinum toxin A has been considered to demonstrate the effectiveness of oral antispasticity treatment.2 With regard to concomitant medication and physical therapy, both treatment groups were asked to maintain the regimens they had been receiving before the study.
We reported the results of a single treatment with botulinum toxin A and mentioned the results of an open-label extension of the study. Readers should wait for those results to be published before concluding that our “study does not justify extended injections for most patients with stroke.”
The data requested by Drs. Buitrago and Koolwijk are listed in Table 1Table 1
Mean Scores at Base Line and Mean Change at Week 6 for All Variables According to the Disability Assessment Scale.. Pain was not a primary symptom for the majority of patients; thus, it would be inappropriate to draw population-based conclusions.We also wish to make the following corrections. The primary end point of this study, according to the protocol, was the change in the tone of the wrist flexor muscle from base line to week 6. Assessment of functional disability was an additional prespecified end point; week 6 was considered the primary end point of interest. In addition, on page 397, the fifth line of the section on “Efficacy” should read “62 in the placebo group” rather than “64 in the placebo group.”
2 ReferencesAllison Brashear, M.D.
Indiana University School of Medicine, Indianapolis, IN 46202
abrashea@iupui.edu Mark F. Gordon, M.D.
Long Island Jewish Hospital, New Hyde Park, NY 110421
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.
2
Wallace JD . Summary of combined clinical analysis of controlled clinical trials with tizanidine. Neurology 1994;44:Suppl 9:S60-S69
Web of Science | Medline
