The Verplancke Study
Using a randomized, double-blind, placebo-controlled, parallel-group design, Verplancke et al. (2005) compared BoNT-A and placebo in combination with serial casting to prevent worsening of lower-limb spasticity in patients with traumatic brain injury. Thirty-five patients were selected to receive physiotherapy without casting, gastrocnemius and soleus injections of saline with casting, or gastrocnemius and soleus injections of BoNT-A with casting (total dose: 200 units, diluted at 50 units/ml).
Improvement in the mean angle of ankle dorsiflexion for the patients receiving BoNT-A plus casting was 13.59 degrees (range, -10 to +20 degrees), compared with 11.69 degrees (range, -22 to +22 degrees) for the saline-plus-casting group and 4.59 degrees (range, -20 to +26 degrees) for the physiotherapy group. There was no significant difference between the casting groups.
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Baseline Modified Ashworth Scale scores were significantly reduced for both casting groups at week 12 (at the study exit) (saline, P < .03; BoNT-A, P = .04). The BoNT-A group with casting experienced greater improvement at week 12 on the Glasgow Outcome Scale (4.1), compared with either the saline-plus-casting group (3) or the physiotherapy group (2.8), with scores of 1-3 indicating severe disability); however, the differences were not significant.
No patients in the BoNT-A group with casting required rescue treatment because of their greatly reduced range of motion; however, about 30% of patients in the other treatment groups did need it.
The BoNT-A patients with casting reported only one treatment-related ADE—transient flu-like symptoms. The study represented Level 1b-minus evidence and was downgraded because of incomplete reporting of statistical analyses.
The studies reviewed in this article—except Brashear’s trial in 2004, which used BoNT-B (Myobloc)—reported significant reductions in BoNT-dependent muscle tone. Tone reduction, although not a therapeutic goal, is an important part of a comprehensive spasticity-management program aimed at achieving functional outcomes such as improved gait, hygiene, and pain reduction. Ideally, this systematic review would culminate with a meta-analysis of the studies identified by the search methodology. However, statistical pooling of the results from these studies requires a high level of homogeneity of effect measures for all of the studies. Even though the identified trials, individually, were of relatively high quality (six Level 1b studies and three studies slightly downgraded to Level 1b-minus, according to the OCEBM criteria), the large degree of heterogeneity between the studies precluded pooling of the study data to improve the power of the analysis.
Function-based outcome measures yielded mixed results. The 2002 Brashear study showed significant improvement in patient- and caregiver-selected functional goals (on the Disability Assessment Scale) following BoNT-A treatment.
Kirazli et al. (1998) observed significant improvement in ambulation (walking velocity) in patients receiving BoNT-A, but other investigators did not discern any significant treatment benefit from BoNT-A in standard functional assessments. Subjective global assessments of treatment outcomes by patients and physicians tended to be significantly better for BoNT-A patients than controls, but differences between groups in standard quality-of-life measures were not observed.
Perhaps these findings underscore the fact that monotherapy with BoNT-A (or any relevant treatment option) is insufficient for managing spasticity in some patients and that it should therefore be incorporated into an overall treatment program that includes physical and occupational therapies, oral medications, intrathecal baclofen, phenol injections, and surgery. We endorse the treatment algorithm put forth by the Spasticity Study Group in 1997 and updated in 2002 (see Figure 1, page 672). We note that no current evidence exists to support the use of BoNT to prevent the onset of spasticity.
A wide variety of BoNT-A concentrations (18-100 units/ml) were used in these studies. EMG was used primarily to identify muscles, but electrical stimulation and surface landmarks were also used. Because of this heterogeneity, we could not definitively determine an optimal concentration of BoNT-A or a preferred method of muscle localization to treat spasticity.
BoNT-A was well tolerated; most treatment-related ADEs were mild to moderate and then resolved. Transient injection-site pain was the most commonly reported ADE. No serious treatment-related events were reported except for individual incidents of arm pain and hematoma, neither of which prompted discontinuation from the study. There were no significant between-group (BoNT vs. control) differences in the incidence of ADEs, although dry mouth occurred in 89% of subjects in the BoNT-B group, in contrast to 20% of patients in the placebo group.
Of the nine studies, six were classified as Level 1b, and three studies were Level 1b-minus, according to the OCEBM level of evidence criteria with the evidence supporting a recommendation grade of A (see Tables 3 to 5).
Our Neurotoxin Spasticity Consensus Group acknowledges that several clinical trials using BoNT-A (Dysport) to treat adult focal spasticity have been published. Although this treatment is currently not available in the U.S., we recognize that these studies generally support our conclusions for BoNT-A (Botox).
- Level 1b evidence supports the efficacy and safety of BoNT-A (Botox) for the treatment of focal spasticity in adults, as measured by the Ashworth or Modified Ashworth Scales.
- Based on the reviewed evidence, patients in whom improvement in passive range of motion would be expected to provide functional benefit and/or facilitate care, would be considered the best candidates for BoNT-A treatment.
- The majority of the evidence reviewed addresses spas-ticity secondary to stroke. Patients with spasticity from other causes (traumatic brain injury, MS, and spinal cord injury) were included in some studies, and they experienced similar treatment outcomes. Despite a lack of randomized, controlled trials focused on patients with spas-ticity from non-stroke causes, it is reasonable to expect that they would similarly benefit from BoNT-A treatment.
- Because only one small study evaluated the use of BoNT-B (Myobloc/Neurobloc) in the treatment of adult focal spasticity, no definite conclusions about its use in this indication can be made.
- No serious treatment-related ADEs were seen with the use of BoNT-A. Apcalis Oral Jelly
- Based on the conclusions of this review, we endorse the treatment algorithm put forth by the Spasticity Study Group in 1997 and updated in 2002.