Abstract
Background: Botulinum toxin type A (BTA) is replacing trihexyphenidyl as the treatment of choice for idiopathic cervical dystonia (ICD), but there has never been a direct comparative study. Methods: This trial compares the effectiveness of BTA with that of trihexyphenidyl in a prospective, randomized, double-blind design. Sixty-six consecutive patients with ICD were randomized to treatment with trihexyphenidyl tablets plus placebo injection or placebo tablets plus BTA injections. Table tswere administered daily according to a fixed schedule. Dysport or saline was injected under EMG guidance at study entry and again after 8 weeks. Patients were assessed for efficacy at baseline and after 12 weeks by different clinical rating scales. Results: Sixty-four patients completed the study, 32 in each group. Mean dose of BTA was 292 mouse units (first session) and 262 mouse units (second session). Mean dose of trihexyphenidyl was 16.25 mg. The changes on the Disability section of the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS-Disability) (primary outcome), Tsui Scale, and the General Health Perception Subscale were significantly in favor of BTA. More patients treated with BTA had an improvement of at least three points on the TWSTRS-Disability (14 versus 6) and on the Tsui Scale (23 versus 12). Adverse effects were significantly less frequent in the BTA group. Conclusion: BTA is significantly more effective in the treatment of ICD, with less adverse effects.
NEUROLOGY 1996;46: 1066-1072
Idiopathic cervical dystonia (ICD), or spasmodic torticollis, is a focal dystonia of unknown etiology, characterized by sustained, involuntary contractions of the cervical muscles causing abnormal movements and head postures. [1] Patients complain of functional limitations, a painful neck, and of social embarrassment. ICD usually presents in the fourth or fifth decade of life and follows a chronic course. Sustained spontaneous remissions are rare. [2-5] The female-to-male ratio is approximately three to two. [6-8] The estimated incidence of ICD is 1.1 per 100,000, with a prevalence of 8.9 per 100,000. [9] The pathophysiology of ICD is not entirely understood. Before the introduction of botulinum toxin treatment for ICD in 1985, [10] the anticholinergic drug trihexyphenidyl was the treatment of choice. [11,12] In six open-label studies, the percentage of patients with beneficial responses to trihexyphenidyl treatment in adult-onset ICD varied between 37% and 42%. [13-18] The mean required dosage was approximately 24 mg daily, and this was accompanied by severe side effects such as dry mouth, blurred vision, and forgetfulness. These side effects were more common in the elderly and often led to withdrawal of treatment. The introduction of botulinum toxin type A (BTA), a potent biological neurotoxin that produces temporary muscle weakness by irreversible presynaptic inhibition of acetylcholine release, altered the therapeutic management of ICD. [19] Following the first placebo-controlled study of BTA treatment for ICD by Tsui et al. [20] in 1986, six other controlled trials [21-26] reported an improvement in 50 to over 80% of the patients treated with BTA, as assessed by rating scales of impairment and self-assessment.
It is not possible to compare studies of trihexyphenidyl and BTA in ICD because of differences in the selection criteria, applied methodology, and assessments used in different treatment studies. Direct comparison is important because of the much higher costs associated with BTA treatment, which already seems to have replaced trihexyphenidyl as the treatment of choice for ICD. However, there is no study in which the effects of both treatments are directly compared. In this prospective, double-blind, parallel group study, we compared treatment with BTA directly with the standard treatment of trihexyphenidyl.
Patients and methods.
Criteria for eligibility.
Patients were recruited in four centers from April 1993 to May 1994. They were eligible for this study if they had signs and symptoms of idiopathic, mainly focal, cervical dystonia. [6-8] Patients were excluded if they were under 18 years, were pregnant, or had multifocal or generalized dystonia, other neurologic disease, coagulation disorders, secondary dystonia, duration of illness less than 1 year, or previous treatment with BTA. In order to exclude other possible causes of abnormal head posture, all patients underwent ancillary examination that consisted of blood examination (ceruloplasmin, TSH, and ESR) and x-ray of the cervical spine.
The study protocol was approved by the review boards of the participating centers. Patients were provided with printed information about the study and gave their informed consent.
Randomization.
Patients were randomized to treatment with either trihexyphenidyl tablets plus placebo injections or to placebo tablets plus BTA injections. Before randomization, the neurologist assessed the patient according to the Tsui Scale [20] and the Disability section of the Toronto Western Spasmodic Torticollis Rating Scale (TW-STRS-Disability), [27,28] to obtain data about the type of dystonia and the degree of disability. Patients were asked whether their dystonia was progressive or stable in character in the last few years. Randomization was accomplished with a computer program that allowed for minimization [29] according to type of dystonia (tonic equals Tsui section D of 0 or 1 point versus clonic equals Tsui section D of 2 or 4 points), degree of disability (TWSTRS-Disability less than 16 versus TW-STRS-Disability more than equals 16), duration of illness (less than 5 years versus more than equals 5 years), and treatment center.
Treatment schedule.
If patients were already receiving trihexyphenidyl treatment prior to the study, this was gradually tapered off during 4 weeks before they entered the trial. Concurrent medication for dystonia, such as benzodiazepines, was not changed during the trial. Trial treatment consisted of tablets and injections. If tablets contained placebo, injection fluid consisted of BTA, and if tablets contained trihexyphenidyl, the injection fluid was saline. The tablets containing 2 mg trihexyphenidyl or placebo were similar in appearance and were administered according to the following schedule. The initial dosage was one-half tablet daily, which was increased by one-half tablet every 3 days to the maximal tolerated dosage. The maximum allowed dosage was three tablets four times daily by 12 weeks (24 mg per day of active treatment).
Freeze-dried BTA produced by Speywood Pharmaceuticals, UK (Dysport), was diluted to 20 mouse units per 0.1 mL of 0.9% sterile saline by an independent pharmacist and aspirated in 1-mL syringes. Placebo injections consisted of an equivalent volume of 0.9% saline. BTA or saline was injected under simultaneous EMG recording into selected cervical muscles using a hollow, teflon-coated, 27-gauge needle. Dystonic muscle activity could be verified on the monitor and by sound signal during injection. Muscles were selected for injection according to the pattern of movements and visible or palpable hypertonia or hypertrophia. The number of injection sites per muscle and the volume of fluid per injection site were left to the discretion of the physician who carried out the treatment. However, before initiation of the trial, guidelines had been formulated according to our previous experience. [30] Patients were injected when they entered the study (week 0) and after 8 weeks (week 8).
Assessment.
All patients were assessed on clinical rating scales before treatment (baseline) and after 12 weeks (week 12) by the same assessor (R.L.), who was not involved in the treatment of the patients. Scores at week 12 were compared with baseline scores. The therapeutic effect in both groups was measured by (1) the TWSTRS-Disability, (2) the Tsui Scale, (3) the Pain section of the TWSTRS (TWSTRS-Pain), and (4) the General Health Perception Subscale of the MOS-Quality of Life Scale (Dutch version). [31]
The TWSTRS-Disability is a seven-item scale that comprises an assessment of performances of daily activities that may possibly be affected by ICD. General as well as specific categories are assessed, including work performance (job or domestic), activities of daily living (feeding, dressing, hygiene), driving, reading, watching television, and leisure activities outside the home. The score range of the TWSTRS-Disability is between 0 and 33, with 33 assigned to the highest possible degree of disability. A decrease of at least three points on the TWSTRS-Disability was defined in our study as a marked clinical improvement.
The Tsui Scale is an impairment scale and evaluates the amplitude and duration of sustained posture and intermittent movements of the head, as well as the presence of shoulder elevation. The score range of the Tsui Scale is between 0 and 25. For assessment of the Tsui Scale, video recordings were performed before the first treatment and 12 weeks after the first injections. When the trial was completed, the recordings were edited into random order and scored by an assessor (J.B.), who had no knowledge of which treatment had been given and who was not involved in the treatment of the patients. According to previous reports, [21,26] a decrease of at least three points on the Tsui Scale was defined as a marked clinical improvement.
The TWSTRS-Pain consists of a severity score for the patient's usual, worst, and best pain in the last week, as well as a duration component and an assessment of the contribution of pain to disability. The score range of the TWSTRS-Pain is between 0 and 20, with 20 assigned to the highest possible experienced pain.
The General Health Perception Subscale of the MOS-Quality of Life Scale is the five-item subscale of the 20-item MOS questionnaire concerning general health perception. The scores on this subscale were transformed linearly to a 100-point scale, with 100 assigned as the best possible score.
The primary outcome measure was the difference between the two treatment groups with regard to the change on the TWSTRS-Disability. Secondary outcomes were as follows: (1) difference between the number of patients who had an improvement of at least three points on the TWSTRS-Disability, (2) difference between changes on the Tsui Scale, (3) difference between the number of patients who had an improvement of at least three points on the Tsui Scale, (4) difference between changes on the TWSTRS-Pain, and (5) difference between changes on the General Health Perception Subscale of the Dutch MOS-Quality of Life Scale.
Adverse effects.
When patients experienced effects considered as adverse, they informed their neurologist. All adverse effects were recorded during the trial. According to the nature of the side effect, the physician advised the patient to adjust the tablet schedule or reduced the BTA dosage at the second treatment.
Statistical analysis.
Patients who left the study before they received trial treatment were excluded from further analysis. All patients who received any study medication were included in the final analysis (intention to treat).
Wilcoxon's signed rank test was used for analysis of differences between treatment groups of changes on (1) the TWSTRS-Disability (primary outcome measure), (2) the Tsui Scale, (3) the TWSTRS-Pain, and (4) the General Health Perception Subscale of the MOS-Quality of Life Scale. Yates' corrected chi-square test or, if appropriate, Fisher's exact two-tailed test were used for analysis of the differences between the treatment groups of (1) the number of patients who had an improvement of at least three points on the TWSTRS-Disability, (2) the number of patients who had an improvement of at least three points on the Tsui Scale, and (3) the number of adverse effects. A p value below 0.05 was defined as statistically significant.
Results.
Patients.
Sixty-six patients were enrolled in the trial, 33 patients in each treatment group. Table 1 shows the clinical characteristics according to assigned treatment. The treatment groups were well matched with respect to most relevant variables. The number of patients with a duration of illness more than equals 5 years, a TWSTRS-Disability score more than equals 16, and a Tsui D section score of 2 or 4 was slightly, but not significantly, higher in the BTA group. There was a significant excess of patients with a progressive type of cervical dystonia in the trihexyphenidyl group (p equals 0.003).
Table 1. Clinical characteristics on entry of 66 enrolled patients according to assigned treatment
Two patients dropped out before they received trial treatment, one in each treatment group, because of the occurrence of a colon carcinoma in one patient and withdrawal of cooperation in the other. The remaining 64 patients completed the trial and have been included in the analysis of efficacy and safety.
Treatment administration.
Thirty-two patients received BTA treatment. The mean total dose of BTA was 292 mouse units (range, 38 to 440) at the first treatment session (week 0) and 262 mouse units (range, 36 to 440) at the second treatment session (week 8). In one center, the BTA was erroneously diluted to 10 mouse units per 0.1 mL of 0.9% sterile saline, and the patients received one-half the proposed dose. The five patients allocated to BTA in that center received a significantly lower dose compared with patients in other centers. They received a mean dose of 109 mouse units (range, 38 to 180) at the first and 120 mouse units (range, 36 to 230) at the second treatment session. In both treatment sessions the splenius capitis was the most frequently injected muscle, followed by the sternocleidomastoid and semispinalis muscles. The mean interval between the two treatment sessions was 60 days (range, 49 to 63).
Thirty-two patients received trihexyphenidyl treatment. The dosage was gradually increased to a mean maximal tolerated daily dose of 16.25 mg (range, 4 to 24). Two patients in the trihexyphenidyl treatment group discontinued treatment before assessment at the end of the trial period (week 12). One of these patients increased the dosage to 8 mg per day by 8 weeks and then stopped taking tablets because of forgetfulness. The other patient reached a total daily dose of 20 mg by 8 weeks and discontinued because of the occurrence of a stomatitis. The scores of these patients were included in the analysis (intention to treat). Nine patients reached the maximum daily dose of 24 mg trihexyphenidyl; all except one experienced several adverse effects.
Before breaking the trial code, we asked the patients to which treatment group they thought they were assigned. Twenty-three patients (71%) in the trihexyphenidyl group and 24 patients (75%) in the BTA group predicted the correct treatment. The physicians answered this question correctly in 23 patients (71%) in the trihexyphenidyl group and in 13 patients (41%) in the BTA group.
Treatment outcomes.
The treatment outcomes on the different rating scales are summarized in Table 2.
Table 2. Treatment outcomes according to assigned treatment
Primary outcome measure.
Changes on the TWSTRS-Disability are shown in Figure 1. Improvement in the BTA group was higher than in the trihexyphenidyl group (p equals 0.0097). The median improvement in the trihexyphenidyl treatment group was 0 points versus 2 points in the BTA treatment group (95% CI for difference in median: 1 to 4). Following completion of the study, an excess of patients with a progressive type of cervical dystonia was found in the trihexyphenidyl group. Therefore, a nonparametric analysis of variance was used to explore the possibility that this imbalance confounded the results of the study. After correction for the excess of the progressive type of dystonia in the trihexyphenidyl group, the treatment effect was similar in size and remained statistically significant (p equals 0.0087).
Figure 1. Changes on the TWSTRS-Disability according to assigned treatment (lines represent median change in each group).
Secondary outcome measures.
An improvement of at least three points on the TWSTRS-Disability was seen in six patients (18.8%) in the trihexyphenidyl group versus 14 patients (42.8%) in the BTA group (p equals 0.059); difference 24% (95% CI: minus 0.7 to 45.5).
The difference between the treatment groups of changes on the Tsui Scale is shown in Figure 2. Again, the BTA group improved significantly more than the trihexyphenidyl group (p equals 0.0009). The median improvement in the trihexyphenidyl group was 0 points versus 5 points in the BTA group (95% CI for difference in median: 2 to 7). Twelve patients (37.5%) in the trihexyphenidyl group versus 23 patients (71.9%) in the BTA group showed an improvement on the Tsui Scale of at least three points (p equals 0.012); difference 34.4% (95% CI: 17.0 to 57.1).
Figure 2. Changes on the Tsui Scale according to assigned treatment (lines represent median change in each group).
Improvement on the TWSTRS-Pain was superior in the BTA group. The median improvement on the TWSTRS-Pain was one point in the trihexyphenidyl group versus three points in the BTA group. The difference, however, did not reach significance.
The trihexyphenidyl group showed a median deterioration of four points on the General Health Perception Subscale of the MOS-Quality of Life Scale versus a median improvement of two points in the BTA group (95% CI for difference in median: 4 to 12). The difference was statistically significant (p equals 0.0023).
For all these secondary outcome measures, the treatment effect did not change when data were corrected for the excess of the progressive type of the dystonia in the trihexyphenidyl group.
Adverse effects.
The reported adverse effects are shown in Table 3. Patients in the trihexyphenidyl group experienced a total of 76 adverse effects, in contrast to 31 in the BTA group (p less than 0.0001). Frequently reported adverse effects in the trihexyphenidyl group were dry mouth in 25 patients (78%), forgetfulness in 15 (48%), and general fatigue in seven (22%). The frequency of these specific adverse effects was significantly higher in the trihexyphenidyl group compared with the BTA group. Blurred vision, dizziness, and depression were reported in both treatment groups, with an excess in the trihexyphenidyl group. The rates of pain at the injection sites and dyspepsia were equal in both groups. Three patients in the BTA group reported weakness of neck muscles, and one patient experienced dysphagia.
Table 3. Reported adverse effects according to assigned treatment
Discussion.
The overall treatment response was significantly better in the BTA group than in the trihexyphenidyl group, as demonstrated by different levels of measurement according to the International Classification of Impairments, Disabilities and Handicaps of the World Health Organization. [32] Impairments reflect organ dysfunction or abnormalities of body structure. Disabilities refer to the consequence of impairments in terms of patients' functional performance of common daily activities, whereas handicaps are concerned with the social disadvantages resulting from impairments and disabilities. Instead of a handicap scale, we used a quality-of-life scale to assess the consequences of impairments and disabilities on the general health experienced by the patients. Our results showed that the improvement of BTA on the level of impairments (Tsui Scale) was strong enough to generate an improvement in functional performance on common daily activities (TWSTRS-Disability) and in experienced general health (General Health Perception). The number of patients with marked improvements was also higher in the BTA group than in the trihexyphenidyl group. In our opinion, any decrease on the TWSTRS-Disability is clinically relevant, but a decrease of at least three points on this scale can be considered a marked improvement. Forty-three percent of the patients treated with BTA showed such an improvement versus 19% in the trihexyphenidyl group. There was improvement of at least three points on the Tsui Scale, which is generally considered as marked clinical improvement, [21,26] in 72% of the patients treated with BTA versus 38% of the patients in the trihexyphenidyl group. Hence, the efficacy was greater in the BTA group assessed on impairment as well as on disability level. In most previous reports, [20,23-25] BTA injections showed a strong reduction in neck pain compared with placebo. Moore et al. [26] found a greater reduction in pain in the BTA group compared with placebo, but the difference was not significant. Although in our study there was a greater improvement in pain in the BTA group, the difference between treatment groups did not reach significance. The greater improvement in the general health perception in the BTA group is probably also caused by the lower frequency of adverse effects associated with this treatment. Two patients in the trihexyphenidyl group discontinued their medication because of severe side effects, whereas none of the patients in the BTA group requested discontinuation of their treatment after the first BTA injections.
As mentioned, in one of the collaborating centers, BTA was erroneously diluted to 10 instead of 20 mouse units per 0.1 mL. Patients in this center received significantly less BTA. If all nine patients treated with BTA or trihexyphenidyl in this center were excluded from analysis, the difference between the two treatment groups with regard to the change on the TWSTRS-Disability scale increased further.
The clinical characteristics of the study population are comparable with those of general ICD patients, and therefore we believe that our results are relevant to the general population with this disorder.
A theoretical disadvantage of this study could have been that adverse effects of trihexyphenidyl would confound the blindness of the trial. However, to avoid this bias, the assessments were performed by an assessor who was not involved in the treatment of the patients. Thus, we believe that the differences between the treatments noted in this study were not biased in this way. Furthermore, it is possible that the duration of the study has not been long enough for some patients to achieve the maximum benefit from trihexyphenidyl as improvement may sometimes be delayed by many weeks. [18,33]
Because of important differences in selection criteria, applied methodology, and assessment, studies on the effectiveness of trihexyphenidyl in cervical dystonia can hardly be compared with studies on BTA treatment. However, previous reports [13-18,20-26] have suggested that BTA might be more effective than trihexyphenidyl in improving abnormal posture and head movements. Because of the higher costs of BTA treatment and the required experience in specialized centers, this difference in beneficial effect should also be demonstrable in functional performance and in general health experienced by the patients. This study confirms the clinical experience that BTA is more effective than trihexyphenidyl in the treatment of cervical dystonia. Since there is a clear difference between the treatment groups in terms of improvement of disability and experienced general health, intramuscular injections with BTA should be considered as the treatment of choice for cervical dystonia.
Acknowledgments
The authors are grateful to Prof. M. Vermeulen and Dr. M. Aramideh for their helpful comments during protocol and manuscript preparation.
- Copyright 1996 by Advanstar Communications Inc.
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