The review question
We reviewed the evidence about the effect of botulinum toxin type A (BtA) in people with involuntary eyelid closure, or blepharospasm. This is an update of a previous Cochrane Review and we assessed the effectiveness and safety of BtA versus placebo (a pretend medicine) in blepharospasm.
Background
Blepharospasm is a dysfunction of the eyelids that presents as involuntary eyelid closure, due to contractions of the eye muscles. Botulinum toxin type A (BtA) is a powerful, natural chemical that can cause severe paralysis (an inability to move the part of the body in which 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 blepharospasm. Botulinum toxin is delivered by injections into the muscles that contract to produce most of the disorder-related symptoms. There are different types of botulinum toxin, not all are available for treating health conditions. BtA is typically considered the first main treatment option for people with blepharospasm.
Study characteristics
We searched the medical literature in July 2020 and found three studies that compared treatment with BtA with placebo (injection with a liquid that will not treat the problem). These studies included a total of 313 participants, who had, on average, a moderate impairment. Most (66%) of the people in the studies were women. All trials were funded by drug manufacturers with possible interests in the results of the studies.
Key results
The results show that a single treatment session (where both eyelids were injected with BtA multiple times) improved the severity of blepharospasm symptoms, disability, and number of involuntary movements. We did not find an increased risk of any unpleasant or undesirable event, though we did find a larger risk of vision complaints and eyelid drooping in people who took BtA. Participants felt that BtA was better than placebo. The BtA effect lasted for around 10 weeks. No study examined the effect of BtA on quality of life.
Certainty in the evidence
The certainty in the evidence varies from low to high. We can draw no conclusions regarding long-term effects of BtA for this condition.
We are moderately certain that a single BtA treatment resulted in a clinically relevant reduction of blepharospasm-specific severity and disability, and have low certainty that it is well tolerated, when compared with placebo. There is low-certainty evidence that people treated with BtA are not at an increased risk of developing adverse events, though BtA treatment likely increases the risk of visual complaints and eyelid ptosis. 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, or the impact on quality of life.
This is an update of a Cochrane Review first published in 2005. Blepharospasm is the second most common form of focal dystonia. It is a disabling disorder, characterised by chronic, intermittent or persistent, involuntary eyelid closure, due to spasmodic contractions of the orbicularis oculi muscles. Currently, botulinum toxin type A (BtA) is considered the first line of therapy for this condition.
To compare the efficacy, safety, and tolerability of BtA versus placebo in people with blepharospasm.
We searched Cochrane Movement Disorders' Trials Register, CENTRAL, MEDLINE, Embase, reference lists of included articles, and conference proceedings. We ran all elements of the search, with no language restrictions, in July 2020.
Double-blind, parallel, randomised, placebo-controlled trials (RCTs) of BtA versus placebo in adults with blepharospasm.
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 did not carry out any prespecified subgroup analyses. The primary efficacy outcome was improvement on any validated symptomatic rating scale. The primary safety outcome was the proportion of participants with any adverse event.
We included three RCTs, assessed at low to moderate overall risk of bias, which randomised 313 participants with blepharospasm. Two studies excluded participants with poorer prior responses to BtA treatment, therefore, they included an enriched population with a higher probability of benefiting from this therapy. All trials were industry-funded. All RCTs evaluated the effect of a single BtA treatment session.
BtA resulted in a moderate to large improvement in blepharospasm-specific severity, with a reduction of 0.93 points on the Jankovic Rating Scale (JRS) severity subscale at four to six weeks after injection (95% confidence interval (CI) 0.61 to 1.25; I² = 9%) compared to placebo. BtA was also resulted in a moderate to large improvement in blepharospasm-specific disability and blepharospasm-specific involuntary movements at four to six weeks after injection (disability: 0.69 JRS disability subscale points, 95% CI 0.18 to 1.19; I² = 74%; blepharospasm-specific involuntary movements: standardised mean difference (SMD) 0.79, 0.31 to 1.27; I² = 58%) compared to placebo. BtA did not show a risk of adverse events (risk ratio (RR) 1.18, 95% CI 0.87 to 1.60; I² = 0%). However, BtA increased the risk of vision complaints and eyelid ptosis (vision complaints: RR 5.73, 95% CI 1.79 to 18.36; I² = 51%; eyelid ptosis: RR 4.02, 95% CI 1.61 to 10.00; I² = 39%). There was no distinction between BtA and placebo in the number of participants who dropped out of the trial.
A single trial estimated the duration of effects to be 10.6 weeks (range 6.1 to 19.1).
We found no evidence supporting the existence of a clear dose-response relationship with BtA. We found no data reporting the impact of BtA on health-related quality of life, or the development of secondary non-responsiveness.