What is the aim of this review?
The aim of this Cochrane Review was to find out how well botulinum toxin works as a treatment for strabismus. Cochrane researchers collected and analysed all relevant studies to answer this question and included six studies.
The evidence as to the benefits and harms of using botulinum toxin for strabismus is uncertain.
What was studied in the review?
Strabismus occurs when the eyes are not aligned. Usually one eye turns inwards or outwards. Less frequently one eye turns upwards or downwards. It is commonly known as "squint".
Strabismus can lead to blurred vision or double vision. In children it can affect the long term development of vision in the affected eye. There are many causes of strabismus. In most cases, there are problems with the muscles or nerves around the eye.
Doctors can use botulinum toxin to stop individual muscles around the eye working for a while. This may help the eyes become more aligned and may lead to less blurred or double vision. One problem with using botulinum toxin is that it can result in a droopy eyelid (ptosis).
What are the main results of the review?
The review shows that:
• using botulinum toxin in children requiring primary treatment or retreatment for strabismus may make no difference, or slightly reduce the chances of recovering correct alignment of the eyes compared with surgery (low-certainty evidence);
• using botulinum toxin in adults with strabismus may decrease the chances of recovering correct alignment of the eyes compared with surgery (low-certainty evidence);
• people with sixth nerve palsy receiving botulinum toxin may have a similar or small increased chance of correct alignment of eyes compared with no treatment (low-certainty evidence);
• the evidence on using botulinum toxin with surgery, compared with surgery alone, was very uncertain (very low-certainty evidence);
• ptosis occurred commonly in people receiving botulinum toxin in these studies. The number of people affected ranged from 1 in 10 to 1 in 2 people. Everyone recovered when treatment stopped. Ptosis occurred less frequently when treated with botulinum toxin combined with sodium hyaluronate compared to botulinum toxin alone.
How up-to-date is this review?
The Cochrane researchers searched for studies that had been published up to 11 July 2016.
Most published literature on the use of botulinum toxin in the treatment of strabismus consists of retrospective studies, cohort studies or case reviews. Although these provide useful descriptive information, clarification is required as to the effective use of botulinum toxin as an independent treatment modality. Six RCTs on the therapeutic use of botulinum toxin in strabismus, graded as low and very low-certainty evidence, have shown varying responses. These include a lack of evidence for effect of botulinum toxin on reducing visual symptoms in acute sixth nerve palsy, poor response in people with horizontal strabismus without binocular vision, similar or slightly reduced achievement of successful ocular alignment in children with esotropia and potential increased achievement of successful ocular alignment where surgery and botulinum toxin are combined. Further high quality trials using robust methodologies are required to compare the clinical and cost effectiveness of various forms of botulinum toxin (e.g. Dysport, Xeomin, etc), to compare botulinum toxin with and without adjuvant solutions and to compare botulinum toxin to alternative surgical interventions in strabismus cases with and without potential for binocular vision.
The use of botulinum toxin as an investigative and treatment modality for strabismus is well reported in the medical literature. However, it is unclear how effective it is in comparison to other treatment options for strabismus.
The primary objective was to examine the efficacy of botulinum toxin therapy in the treatment of strabismus compared with alternative conservative or surgical treatment options. This review sought to ascertain those types of strabismus that particularly benefit from the use of botulinum toxin as a treatment option (such as small angle strabismus or strabismus with binocular potential, i.e. the potential to use both eyes together as a pair). The secondary objectives were to investigate the dose effect and complication rates associated with botulinum toxin.
We searched CENTRAL (which contains the Cochrane Eyes and Vision Trials Register) (2016, Issue 6), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to July 2016), Embase (January 1980 to July 2016), Latin American and Caribbean Literature on Health Sciences (LILACS) (January 1982 to July 2016), the ISRCTN registry (www.isrctn.com/editAdvancedSearch), ClinicalTrials.gov (www.clinicaltrials.gov), and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 11 July 2016. We handsearched the British and Irish Orthoptic Journal, Australian Orthoptic Journal, proceedings of the European Strabismological Association (ESA), International Strabismological Association (ISA) and International Orthoptic Association (IOA) (www.liv.ac.uk/orthoptics/research/search.htm) and American Academy of Paediatric Ophthalmology and Strabismus meetings (AAPOS). We contacted researchers who are active in this field for information about further published or unpublished studies.
We included randomised controlled trials (RCTS) of any use of botulinum toxin treatment for strabismus.
Two review authors independently selected studies and extracted data. We used standard methods expected by Cochrane and assessed the certainty of the evidence using GRADE. We defined ocular alignment as an angle of deviation of less than or equal to 10 prism dioptres.
Six RCTs were eligible for inclusion. We judged the included studies as at a mixture of low, unclear and high risk of bias. We did not consider any of the included studies as at low risk of bias for all domains.
Two trials conducted in Spain (102 people, number of eyes not specified) compared botulinum toxin with surgery in children that required retreatment for acquired or infantile esotropia. These two studies provided low-certainty evidence that children who received botulinum toxin may have a similar or slightly reduced chance of achieving ocular alignment (pooled risk ratio (RR) 0.91, 95% confidence interval (CI) 0.71 to 1.16), binocular single vision (RR 0.88, 95% CI 0.63 to 1.23), sensory fusion (RR 0.88, 95% CI 0.63 to 1.23) and stereopsis (RR 0.86, 95% CI 0.59 to 1.25) compared with children who received surgery. One trial from Canada compared botulinum toxin with surgery in 30 adults (30 eyes) with horizontal strabismus and reported a reduced chance of ocular alignment with botulinum toxin (RR 0.38, 95% CI 0.17 to 0.85; low-certainty evidence).
One trial in the UK suggested that botulinum toxin may result in a similar or slightly improved chance of ocular alignment in people with acute onset sixth nerve palsy compared with observation (RR 1.19, 95% CI 0.96 to 1.48; 47 participants, low-certainty evidence).
Very low-certainty evidence from one trial from Brazil suggested that adjuvant botulinum toxin in strabismus surgery may increase the chances of ocular alignment compared with strabismus surgery alone (RR 1.83, 95% CI 0.41 to 8.11; 23 participants).
One trial from China of 47 participants (94 eyes) suggested that people receiving botulinum toxin combined with sodium hyaluronate may have a similar or slightly reduced chance of achieving ocular alignment compared with botulinum toxin alone (RR 0.81, 95% CI 0.36 to 1.82; low-certainty evidence).
Reported complications in people given botulinum toxin in the included trials included ptosis (range 9% to 41.66%) and vertical deviation (range 8.3% to 18.51%). Ptosis occurred less frequently when treated with botulinum toxin combined with sodium hyaluronate compared to botulinum toxin alone.