Botulinum toxin type B for cervical dystonia
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To compare the clinical efficacy and safety of Botulinum Toxin Type B in the treatment of Cervical Dystonia.
Background
Cervical Dystonia, also called spasmodic torticollis, is a focal dystonia characterized by involuntary posture of the head away from its normal central position (Foltz 1959). It may be dominated by sustained posture, spasm, jerks or tremor, or there may be a combination of these features. This condition is frequently (70%) associated with neck or shoulder pain (Chan 1991). Disability with functional impairment and embarrassment with social withdrawal are also important incapacitating features of this movement disorder disease. Cervical dystonia is the most common form of focal dystonia with an estimate prevalence rate in Europe of 5,7/100000 (ESDE 2000), although higher rates have been reported namely in USA (8,9/100000) (Nutt 1988).
Most cases of Cervical Dystonia are idiopathic and about 12% have a family history (Jankovic 1991a). Cervical Dystonia can also be secondary to trauma or musculo‐skeletal, spinal cord, intracranial, ocular and vestibular disorders. There are also a number of cases classified as psychogenic. The pathophysiology of Cervical Dystonia is attributed to abnormal execution of motor programs (Kanovsky 2003, Klier 2002).
The natural course of Cervical Dystonia remains unclear and spontaneous remissions have been reported with an estimated prevalence of 10% (Jahnanshani 1990). However, in the vast majority, Cervical Dystonia is a life‐long disorder, and rarely it may progress to segmental or generalized dystonia.
Cervical Dystonia is classified according to the dominant head position being rotatory (simple) torticollis in the majority of cases (over 50%) (Chan 1991). Other common patterns are laterocollis, retrocollis and complex torticollis.
Botulinum toxin (BoNT) is a natural product synthesised by an anaerobic bacteria, the Clostridium botulinum responsible for the disease botulism. Different strains of Clostridium botulinum produce seven immunologically distinct forms of botulinum neurotoxin labelled A to G. These potent neurotoxins are metalloproteases that block the release of acetylcholine at the neuromuscular junction though the cleavage of different peptide bonds which are crucial components in synaptic vesicle membrane fusion. Such interference with the neuromuscular transmission results in a flaccid paralysis (Brin 2002).
These properties of the BoNT were though to have a potential therapeutic impact (Kreyden 2002) and BoNT serotype A (BoNT/A) was tested in humans for several movement disorders, namely Cervical Dystonia, in the early 1980s. Its clinically efficacy and safety were established in several RCTs (Costa 2000) and BoNT/A is now considered the first line of therapy for Cervical Dystonia.
Despite the success of BoNT/A, however, approximately 10% of treated patients develop resistance to the toxin (Greene 1994, Jankovic 1991b, Zuber 1993). A smaller proportion of patients exhibit primary resistance to BoNT/A treatment. The resistance problem has led to the study of other BoNT serotypes ‐ Type B, C and F ‐ as possible treatments options for Cervical Dystonia (Cullis 1998, Eleopra 1997, Greene 1993). At the present time BoNT serotype B (BoNT/B) is the only one of these three types that is approved in the United States and in the European Union for the treatment of Cervical Dystonia.
To address the issue of clinical efficacy and safety of BoNT/B, and to establish effect sizes in the treatment of Cervical Dystonia we systematically review the randomised controlled clinical trials that compare BoNT/B with placebo in Cervical Dystonia.
Objectives
To compare the clinical efficacy and safety of Botulinum Toxin Type B in the treatment of Cervical Dystonia.
Methods
Criteria for considering studies for this review
Types of studies
All unbiased, randomised, controlled double blind trials of BoNT/B versus placebo. Trials in which allocation is not adequately concealed will not be included.
Types of participants
The target population consists of patients with a clinical diagnosis of idiopathic focal Cervical Dystonia. Patients of all ages will be considered, whether or not they have had prior exposure to BoNT/A. All possible concomitant therapies will be accepted.
Types of interventions
Intramuscular injections of BoNT/B. All techniques (eg. EMG guided or not) and schema of administration will be considered.
Types of outcome measures
For each trial, the number of patients originally allocated at random to each treatment group will be identified. Outcome information will be sought regarding the number of patients in each treatment group that had each outcome considered.
The primary outcome will be:
Improvement in symptomatic rating scales (all).
Secondary Outcomes:
1.Changes in subjective evaluation of clinical status both by patients and clinicians;
2.Changes in pain scores;
3.Changes in quality of life assessments,
4.Adverse reactions (frequency and severity), including deterioration in dystonia severity.
Search methods for identification of studies
The review will draw on the search strategy developed for the Movement Disorders Group as a whole. As BoNT was first used therapeutically in 1977, searches will be conducted from that year. Relevant trials will be identified according to the following search strategy:
1.Cochrane Movement Disorders Group Specialised Register (see Review Group details for more information);
2.Cochrane Controlled Trials Register (Central/CCTR in The Cochrane Library, Issue 3, 2002);
3.MEDLINE (1977‐6/2002);
4.EMBASE (1977‐6/2002);
Titles, keywords and abstracts of the citations downloaded from the electronic searches will be screened, and full copies of reports of potentially suitable trials will be obtained for further assessment.
The search strategy will also include:
5.Reference lists of located trials and BoNT review articles;
6.Handsearch of Movement Disorders Journal and international congress of movement disorders and botulinum toxins (1985‐6/2002);
7.Personal communication with other researchers in the field;
8.Contact with the drug manufacturer (Elan Pharmaceuticals, Inc) in order to obtain additional assistance.
Authors of published trials will be contacted for further information and unpublished data if necessary.
The search strategy for MEDLINE and Central/CCTR is given below. The search strategy will be modified for EMBASE.
1.botulin$ and tox$ and B.tw
2.neurobl$ or myobl$.tw
3.or/1‐2
4.cervical dystonia/
5.torticollis/
6.cervic$ and dysto$.tw
7.torticol$.tw
8.or/4‐7
9.3 and 8
10.limit 9 to human
Data collection and analysis
Three reviewers (Costa J, Borges A, Espírito‐Santo C) will independently assess the studies identified by the search strategy in order to identify potentially suitable trials for the review according to the criteria outlined above. Disagreements about inclusions will be resolved by discussion.
The full papers will be independently assessed for methodological quality by extracting details of randomisation methods, blinding of treatments and assessments, whether intention‐to‐treat analysis is possible from the published data, whether treatment groups are comparable with regard to demographics and clinical characteristics, the number of patients excluded or lost to follow‐up, definition of outcomes, and entry and exclusion criteria.
Sources of bias looked for will include: 1) selection bias, including randomisation and by chance differences in groups due to small sample sizes; 2) performance bias; 3) attrition bias; 4) detection bias; 5) selective reporting of results.
Data on the number of patients with each outcome or event, by allocated treatment group, irrespective of compliance, and whether or not the patient was subsequently deemed ineligible or otherwise excluded from treatment or follow‐up, will be sought to allow an "intention‐to‐treat" analysis.
Eligible data will be abstracted by two reviewers (Costa J, Ferreira JJ) onto standardised forms independently, cross‐checked for accuracy and amalgamated. Disagreements about inclusion will be resolved by discussion.
All results will be expressed as ordinal data. The various rating scales used will be dichotomised using each author's own criteria for improvement or no improvement. If these criteria are not described, improvement will be defined, as any beneficial change from baseline and no improvement will be defined as no improvement from baseline and include any deterioration from baseline. Authors will be asked to provide individual patient data in cases were results are only presented as mean values for groups in order to dichotomise the results.
Statistical analysis will be performed by means of the statistical software provided by the Cochrane Collaboration. Heterogeneity between trial results will be tested using a standard chi‐squared test. The results will be reported as odds ratios (and 95% confidence intervals) for dichotomous outcomes, using the Peto fixed‐effects method. The significance of any differences between odds ratios will be calculated using a standard method (Altman 1996). Additionally the results of the rating scales will also be analysed as continuous variables using the standardised mean difference (and 95% confidence intervals). Descriptive summary of the results will be provided where it is not possible to combine outcome data from different studies.
