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Botulinum toxin type A therapy for blepharospasm

Abstract

Background

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.

Objectives

To compare the efficacy, safety, and tolerability of BtA versus placebo in people with blepharospasm.

Search methods

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.

Selection criteria

Double‐blind, parallel, randomised, placebo‐controlled trials (RCTs) of BtA versus placebo in adults with blepharospasm.

Data collection and analysis

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.

Main results

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.

Authors’ conclusions

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.

Plain language summary

Botulinum toxin type A for people with involuntary eyelid closure, or blepharospasm

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.

Authors’ conclusions

Implications for practice

In this updated Cochrane Review, we found that a single treatment session of botulinum toxin type A (BtA) is effective and well‐tolerated in the treatment of moderately impaired adults with blepharospasm. The clinical benefit includes moderate to large improvements across objective disorder‐related domains, such as severity and disability. The benefit is also meaningful when subjectively assessed by the participants.

There is no evidence regarding health‐related quality of life. Adverse events are frequent in both BtA (66 of 115 participants) and placebo groups (26 of 54 participants), but are not commonly associated with discontinuing treatment. Vision complaints (49 of 166 BtA‐treated participants) and eyelid ptosis (53 of 207 BtA‐treated participants) are the most frequent treatment‐related adverse events of special interest. We are moderately certain about the conclusions based on the evidence.

Implications for research

The net benefit of a single BtA injection in the treatment of blepharospasm is likely very positive overall.

Nonetheless, further studies are needed to establish the relative effectiveness of different doses of BtA, assessing efficacy, safety, duration of effect, and quality of life across regimens, with repeated BtA treatment sessions, and assessed under conditions more closely resembling clinical practice (pragmatic clinical trials). Because therapy typically requires optimising a dose for each person, rather than administering a fixed dose of botulinum toxin, such a line of research would be important to support physicians’ management of doses, and allow for a more solid and safe individualisation of treatment.

Future research concerning all formulations of botulinum neurotoxin should endeavour to establish clinical effectiveness, not only based on changes from baseline, but also, preferably, based on validated measures of minimal clinically important difference or change (Brożek 2006). Research is required in order to establish such a parameter for the Jankovic Rating Scale (JRS), currently the most widely used and disseminated clinical scale in the field.

It is currently uncertain whether or not the clinical effectiveness of botulinum toxin decays over time, with repeated treatment sessions, and whether a possible loss of effectiveness occurs in all clinical domains. Future studies comparing any form of BtA should address the comparative proportion of participants who develop secondary non‐responsiveness to treatment.

Finally, in conducting this systematic review, we were faced with the fact that there is no defined core outcome set in blepharospasm research, as there is for other areas (Tugwell 2007). To promote research in this field, and to support the clinical effectiveness of botulinum toxin, it would be relevant to define a set of core outcome measures, and include it in future research, via well‐established methodology, to determine the inclusion of participant‐reported outcomes (Macefield 2014).

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