The review question
This is an update of a Cochrane Review, We assessed the effectiveness (reduction in severity, disability, and pain) and safety of botulinum toxin type A (BtA) versus placebo (a pretend medicine) in people with involuntary positioning of the head, or cervical dystonia
Cervical dystonia, also called spasmodic torticollis, is a disorder that causes undesired, uncontrollable, often painful, abnormal placement of the head. It is a relatively uncommon condition (affecting 57 to 280 people per million) that can be very disabling, and can negatively affect a person's quality of life. In most cases, the cause is unknown; no cure exists. Since cervical dystonia is normally a long-term disorder, it requires long-term treatment.
Botulinum toxin is a powerful, natural chemical that can cause severe paralysis (an inability to move in the part of the body where it is injected) in animals and humans. It can also be used to treat many conditions, in particular, those with involuntary muscle contractions, such as cervical dystonia. Botulinum toxin is delivered by injections into the muscles that contract to produce most of the disorder symptoms. There are different types of botulinum toxin, not all are available for treating health conditions. BtA is typically considered the first treatment option in cervical dystonia.
We searched the medical literature up to July 2020. We found nine studies that compared treatment with BtA versus placebo, and included a total of 1144 participants, with on average, a moderate disease impairment. The participants remained in most of the studies for 16 to 20 weeks after the treatment. The average age of people in the studies was 52.8 years, and they had cervical dystonia for an average of 4.8 to 12.1 years before taking part in the trials. Sixty-four percent of the people in the studies were women. Eight of the nine trials were funded by drug manufacturers with possible interests in the results of the studies.
The results show that a single treatment session improved cervical dystonia symptoms, including pain, and participant's self-evaluations. However, the risk of having an unpleasant or undesirable event, particularly swallowing difficulties, tiredness, and neck weakness, was also increased. Only three studies examined the impact of BtA on quality of life, suggesting some benefit from BtA.
Certainty in the evidence
There is moderate certainty in the evidence for overall and pain improvement, and the risk of undesired events. There is high certainty in the evidence that participants reported self-evaluated improvement, and the risk that participants did not tolerate treatment.
To be included in the studies, participants must have had a history of successful treatment with BtA. People with certain types of cervical dystonia, in particular the types that make the head turn mostly backward or forward, were not allowed to participate in the studies; it is known that they do not respond as well to botulinum toxin treatment. Therefore, the conclusions from this review may not apply to all people with cervical dystonia.
We can draw no conclusions regarding long-term effects of BtA for this condition.
We are moderately certain in the evidence that a single BtA treatment session resulted in a clinically relevant reduction of cervical dystonia-specific impairment, and pain, and highly certain that it is well tolerated, compared with placebo. There is moderate-certainty evidence that people treated with BtA are at an increased risk of developing adverse events, most notably, dysphagia, neckweakness and diffuse weakness or tiredness. There are no data from RCTs evaluating the effectiveness and safety of repeated BtA injection cycles. There is no evidence from RCTs to allow us to draw definitive conclusions on the optimal treatment intervals and doses, the usefulness of guidance techniques for injection, the impact on quality of life, or the duration of treatment effect.
This is an update of a Cochrane Review first published in 2005. Cervical dystonia is the most common form of focal dystonia, and is a highly disabling movement disorder, characterised by involuntary, usually painful, head posturing. Currently, botulinum toxin type A (BtA) is considered the first line therapy for this condition.
To compare the efficacy, safety, and tolerability of BtA versus placebo, in people with cervical dystonia.
We searched Cochrane Movement Disorders' Trials Register, CENTRAL, MEDLINE, Embase, reference lists of articles, and conference proceedings in July 2020. All elements of the search, with no language restrictions, were last run in July 2020.
Double-blind, parallel, randomised, placebo-controlled trials (RCTs) of BtA versus placebo in adults with cervical dystonia.
Two review authors independently assessed records, selected included studies, extracted data using a paper pro forma, and evaluated the risk of bias. We resolved disagreements by consensus or by consulting a third review author. We performed meta-analyses using a random-effects model, for the comparison of BtA versus placebo, to estimate pooled effects and corresponding 95% confidence intervals (95% CI). We performed preplanned subgroup analyses according to BtA dose used, the BtA formulation used, and the use (or not) of guidance for BtA injections. The primary efficacy outcome was improvement in cervical dystonia-specific impairment. The primary safety outcome was the proportion of participants with any adverse event.
We included nine RCTs, with moderate, overall risk of bias, that included 1144 participants with cervical dystonia. Seven studies excluded participants with poorer responses to BtA treatment, therefore, including an enriched population with a higher probability of benefiting from this therapy. Only one trial was independently funded. All RCTs evaluated the effect of a single BtA treatment session, using doses from 150 U to 500 U of onabotulinumtoxinA (Botox), 120 U to 240 U of incobotulinumtoxinA (Xeomin), and 250 U to 1000 U of abobotulinumtoxinA (Dysport).
BtA resulted in a moderate to large improvement from the participant's baseline clinical status, assessed by the investigators, with a mean reduction of 8.09 points in the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS total score) at week four after injection (95% CI 6.22 to 9.96; I² = 0%) compared to placebo. This corresponded, on average, to a 18.4% improvement from baseline. The mean difference (MD) in TWSTRS pain subscore at week four was 2.11 (95% CI 1.38 to 2.83; I² = 0%) compared to placebo. Overall, both participants and clinicians reported an improvement of subjective clinical status. It was unclear if dropouts due to adverse events differed (risk ratio (RR) 2.51; 95% CI 0.42 to 14.94; I² = 0%) However, BtA treatment increased the risk of experiencing an adverse event (RR) 1.23; 95% CI 1.05 to 1.43; I² = 28%). Neck weakness (14%; RR 3.40; 95% CI 1.19 to 9.71; I² = 15%), dysphagia (11%; RR 3.19; 95% CI 1.79 to 5.70; I² = 0%), and diffuse weakness or tiredness (8%; RR 1.80; 95% CI 1.10 to 2.95; I² = 0%) were the most common treatment-related adverse events. Treatment with BtA resulted in a decreased risk of dropouts. We have moderate certainty in the evidence across all of the aforementioned outcomes, with the exception of subjective assessment and tolerability, in which we have high confidence in the evidence.
We found no evidence supporting the existence of a clear dose-response relationship between BtA and improvement in cervical dystonia-specific impairment, a destinction between BtA formulations, or a variation with use of EMG-guided injection for efficacy outcomes.
Due to clinical heterogeneity, we did not pool health-related quality of life data, duration of clinical effect, or the development of secondary non-responsiveness.