Strabismus (squint) is a misalignment of the eyes in which the visual axes deviate from bifoveal fixation (RCO 2002). It can be subdivided into esotropia (inward deviation), exotropia (outward deviation) or, less commonly, hypertropia (upward deviation), hypotropia (downward deviation) and cyclotropia (torsional deviations - inwards, incyclotorsion or out outwards, excyclotorsion). This review will specifically look at infantile esotropia (IE). Other terms that have been used to describe this condition include congenital esotropia and essential infantile esotropia.
Strabismus is present in approximately 4% of children (Vaughan 1998). The reported incidence of infantile esotropia within the first six months of life varies between 0.1% (Nixon 1985) and 1% (Friedman 1980).
Presentation and diagnosis
Infantile esotropia is a large, constant, stable angle esotropia (the angle indicates the degree/size of the squint) with an onset within the first six months of life (Kommerell 1988).
Features associated with IE include:
- alternating esotropia (can swap from one eye to the other);
- cross-fixation: taking advantage of the crossed position of the eyes so that the right eye is used to look towards the left and the left eye to look towards the right. This can be associated with the appearance of limited abduction (outward movement) of the other eye;
- manifest-latent nystagmus: oscillation of the eyes, which increases when either eye is covered;
- asymmetry of optokinetic nystagmus: a following movement followed by a rapid fixation movement in the opposite direction. This can be demonstrated by using a rotating, striped drum;
- over-acting inferior obliques: one of six muscles which move each eye. This usually occurs bilaterally (in either eye) but can be asymmetrical, leading to the development of a hypertropia in one or more positions of gaze (most prominent in adduction - inward movement of the eye);
- dissociated vertical deviation (DVD): where either eye elevates resulting in a hypertropia when the amount of light entering it is reduced (Calcutt 1993). This can also occur during a period of inattention or fatigue and can contribute to the hypertropia in adduction, since the nose can act as an occluder to the image being viewed;
- refractive error (focusing error) within normal limits;
- suppression: resulting in absence of binocular single vision (BSV) - the simultaneous use of the two eyes to give a single 3-dimensional image.
Significant amblyopia (a reduction in vision) is rare (Ansons 2001). The main reason for presentation of children with infantile esotropia is usually parental awareness of unacceptable ocular misalignment.
Treatment aims to improve ocular misalignment. However, another important issue to consider is whether such treatment facilitates and enhances the development of binocular vision. Therefore there are two aims of intervention:
1. to align the visual axes;
2. to optimise the potential for binocularity. Many authorities believe that alignment to within 10 dioptres (^) of orthotropia 'straight eyes' by two years of age offers the best prospect for the development of binocular vision (Ing 1980).
Management of the strabismus may be surgical, non-surgical or a combination of both. As with other forms of strabismus, it is important to treat any amblyopia or significant refractive error when they exist, but as stated these are unusual findings in this condition.
Surgery to correct the esotropia involves adjusting the horizontally acting extraocular muscles, and can be divided into three types:
1. unilateral surgery: weakening, usually recession, of the medial rectus which is responsible for pulling the eye in and resection (strengthening) of the lateral rectus which is responsible for pulling the eye out;
2. bilateral surgery: the medial rectus is weakened in both eyes;
3. three or more muscle surgery (horizontal): a combination of recessions and resections.
Surgical adjustment of the vertically acting muscles may also be undertaken to correct any significant hypertropia:
1. weakening of the inferior oblique muscle responsible for pulling the eye up in adduction;
2. weakening of the superior rectus, responsible for pulling the eye up in abduction, adduction and in the primary (straight ahead) position.
The age at which surgery is performed can vary and authors have used various terms to describe the timing of surgery. For example, 'ultra early' has been used to describe surgical intervention between four and six months (Helveston 1990), 'early' to describe surgery before the age of two, and 'late' to describe surgery after the age of two.
The main form of non-surgical management in IE is botulinum toxin. This drug comes from a bacterium called Clostridium botulinum, which produces toxins that can be used to block muscle contractions. The type of toxin most commonly used for injection into muscles is botulinum toxin A (Scott 1980). The toxin is injected into the medial recti to temporarily paralyse the muscles and weaken their action, allowing the antagonist muscles (the lateral recti) to act unopposed. When the paralytic effect wears off after several months, the alignment may be improved.
Rationale for a systematic review
Although previous studies have compared treatment strategies, there are currently no clinical guidelines to determine the most effective treatment or age for treatment in IE. A systematic review was needed to assess the current evidence on these issues and will be useful to ophthalmologists, orthoptists and patients (or parents of).
The primary objective of this review was to examine the effectiveness and optimal timing of surgical and non-surgical treatment options for infantile esotropia in improving ocular alignment and achieving/allowing the development of binocular single vision.
Criteria for considering studies for this review
Types of studies
We included randomised trials that met our inclusion criteria.
Types of participants
Participants in the trials were children with infantile esotropia (IE) as defined above. Participants could have received any treatment for refractive error and amblyopia but trials in which participants received prior treatment (surgical or non-surgical) for the IE were excluded.
Types of interventions
We looked at both surgical and non-surgical interventions. We examined the following comparisons:
a. any surgical intervention versus observation alone;
b. any surgical intervention versus botulinum toxin;
c. unilateral versus bilateral surgery;
d. two muscle versus three or four muscle surgery.
a. botulinum toxin versus observation alone;
b. botulinum pre-surgical treatment versus surgery alone.
3. Timing of treatment
a. ultra early versus early treatment;
b. ultra early versus late treatment;
c. early versus late treatment.
Types of outcome measures
1. Improvement in the angle of the squint.
Angle at near (and distance if possible) as measured by prism cover test, prism reflections, or synoptophore. Within 10^ (+/-) of orthotropia at six months follow up were considered a successful outcome.
2. Presence and quality of binocularity.
A wide range of tests exist to diagnose the presence and the quality of binocular vision, with a measurement of stereoacuity considered the 'gold standard'. In this review all binocular vision test results at six months follow-up will be considered but will be graded into 1) stereoacuity tests; 2) motor fusion and 3) simultaneous perception.
1. Over-correction (> 10^) of deviation.
2. Under-correction (< 10^) of deviation.
3. Number of interventions required.
Adverse effects (severe, minor)
We summarised the reported adverse effects of the various interventions such as effects from surgery (for example anterior segment ischaemia, conjunctival scarring, inflammation etc) or from botulinum toxin injections (for example spread of toxin to nearby muscles causing ptosis) and development of amblyopia. These were classified as major (requiring further intervention) and minor (requiring no further intervention).
Quality of life measures
We documented any measures of patient or parent/guardian satisfaction or quality of life.
Six months minimum follow-up period was considered.
Search methods for identification of studies
We searched the Cochrane Central Register of Controlled Trials (CENTRAL) 2013, Issue 5, part of The Cochrane Library. www.thecochranelibrary.com (accessed 10 June 2013), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE, (January 1950 to June 2013), EMBASE (January 1980 to June 2013), Latin American and Caribbean Literature on Health Sciences (LILACS) (January 1982 to June 2013), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov) and the 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 10 June 2013.
See: Appendices for details of search strategies for CENTRAL (Appendix 1), MEDLINE (Appendix 2), EMBASE (Appendix 3), LILACS (Appendix 4), mRCT (Appendix 5), ClinicalTrials.gov (Appendix 6) and the ICTRP (Appendix 7).
Searching other resources
Efforts were made to contact researchers active in this area to try and obtain unpublished studies. The Pediatric Eye Disease Investigator Group (PEDIG) were contacted in addition to Meyer et al (Meyer 1998). Meyer et al were contacted even though their study was a non-randomised trial (as stated in their protocol) because the reviewers were keen to uncover any unpublished research in this area. We manually searched the conference proceedings of the European Strabismological Association (ESA) (1975 to 1997, 1999 to 2002), International Strabismological Association (ISA) (1994) and American Academy of Paediatric Ophthalmology and Strabismus meeting (AAPOS) (1995 to 2003). We did not manually handsearch the British Orthoptic Journal as stated in our protocol as this had already been done.
Data collection and analysis
Selection of studies
Both review authors independently screened the titles and abstracts obtained by the searches to establish whether they met the criteria defined. The full copies of definitely or potentially relevant studies were obtained. Where a trial was incomplete, methodology was unclear or the data were not published, we attempted to contact the trialists.
As no trials were found in the searches we were not able to assess the quality or data. Should trials be found in the future, we will follow the steps below.
Data extraction and management
Details will be extracted from studies on the following:
1. Methods: method of allocation concealment, losses to follow up.
2. Participants: age, previous treatment, presence of co-existing ocular disease.
3. Interventions: technique used, length of follow up.
4. Outcomes: difference between intended and actual ocular alignment minimum six months. Presence and quality of binocularity.
5. Adverse events and quality of life measures.
The two review authors will independently extract data for the primary and secondary outcomes onto paper data collections forms developed by the Cochrane Eyes and Vision Group. Discrepancies will be resolved by discussion. Primary investigators will be contacted for missing data.
If future studies are included, the lead author will enter all data into Review Manager 5.1. The co-author will check the data independently in order to check for inaccuracies.
Assessment of risk of bias in included studies
We will assess study quality according to the methods set out in Chapter 8 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We will assess allocation concealment, method of allocation to treatment, documentation of exclusions, masking of outcome assessment and completeness of follow up. Trials will be graded low risk of bias, high risk of bias, and unclear: unclear or unknown risk of bias. Trials graded as high risk of bias in the area of masking of participants will still be included even where masking was not possible in the study (for example surgical versus non-surgical treatment).
Measures of treatment effect
We will use the odds ratio or relative risk for dichotomous data (for example number not achieving alignment within 10^ of orthotropia) and standardised mean difference (as different but similar instruments may have been used) for continuous data.
We will perform data analysis according to Chapter 9 of the Cochrane Handbook for Systematic Reviews of Interventions (Deeks 2011). We will summarise data from studies collecting comparable outcome measures with similar follow-up times. Studies will be assessed for heterogeneity - and statistical heterogeneity will be assessed using the Chi
We will conduct sensitivity analyses to assess the sensitivity of the effect of including studies of questionable eligibility (graded as high risk of bias) and excluding unpublished studies.
Description of studies
Results of the search
The initial electronic searches identified 280 reports of studies. After reviewing the results, all but five studies were excluded and hard copies were obtained for these five. On closer inspection, one was a randomised controlled trial but was looking at an intervention that was not included in this review (Kushner 1984) and the other four were not trials (Arnoult 1976; Birch 1995; Birch 1998; Ing 1992) (see 'Characteristics of excluded studies').
The updated search of September 2006 identified 144 reports of studies. The hard copy of one citation was obtained (Simonsz 2005) but was then excluded as it was not a randomised trial.
A further update search in September 2008 identified 134 reports of studies. The abstracts were checked but none of the references were relevant to the scope of the review.
Updated searches were run in April 2011. The electronic searches yielded a total of 240 titles and abstracts. After deduplication the Trials Search Co-ordinator scanned 171 records and discarded 133 records as they were not relevant to the scope of the review. We screened the title and abstracts of the remaining 38 reports. We obtained a hard copy of one trial (Polling 2009) but this was excluded as it only had follow-up data for three months postoperatively and studies require a minimum of six months follow-up data to be eligible for inclusion in this review.
Updated searches run in June 2013 identified 172 references. The Trials Search Co-ordinator removed 27 duplicates, scanned 145 references and removed 117 records which were not relevant to the scope of the review. We screened the remaining 28 references but did not find any trials that met the inclusion criteria for the review.
Risk of bias in included studies
No studies were found that met our inclusion criteria.
Effects of interventions
No studies were found that met our selection criteria and therefore none were included for meta-analysis.
There is a large body of literature on the subject of infantile esotropia (IE), which, until recently, mainly consisted of retrospective studies, cohort studies or case series. Over recent years, more prospective studies are starting to be conducted and the results published, however, there is still a lack of randomised trials and hence it still remains difficult to resolve some of the controversies highlighted regarding management of IE. A brief summary of findings from a selection of the current literature on each of the outcome measures is given below:
Most authors agree that some form of surgical intervention is necessary to treat IE. Authors have found that a constant esotropia of > 40^ in patients aged two to four months did not spontaneously resolve (Birch 1998) or had a low likelihood of doing so (PEDIG 2002). In 1976, Arnoult et al., looked retrospectively at two groups of patients; group 1 had all undergone bimedial recessions, group 2 unilateral surgery (resection of the lateral rectus and recession of the medial rectus) (Arnoult 1976). The average angle of each group postoperatively was found to be the same, however, no statistical analysis was documented.
More recently Polling 2009, conducted a randomised trial comparing bilateral recessions to unilateral surgery for IE. Whilst the results are not suitable for inclusion for analysis in this review, the authors concluded that there no statistically significant difference between the two interventions.
Forrest 2003, published the long term outcomes of 49 patients who underwent three muscle surgery for IE and concluded from this case series, that graded, three horizontal muscle surgery has a high success rate in attaining good ocular alignment'
A randomised comparison of graded versus standard bimedial recessions (Kushner 1984), concluded that standard 10.5 mm bimedial recessions achieved a better final ocular alignment. A randomised trial of severing the check ligaments and intermuscular membranes on the medial recti during surgery found no significant difference between the two groups (Friendly 1993). Whilst bimedial rectus recessions tends to be the current method of choice, there are currently no randomised trials on different surgical approaches for IE, although many authors have stated their varying preferences.
Whilst surgical intervention for IE still seems to be the initial method of choice for the majority, a non-surgical intervention, (botulinum toxin) to alter ocular muscle alignment was first reported in Scott 1980. After this, Scott 1990, reported the results of botulinum toxin (BT) on a group of IE patients. The study found that 65% of this group achieved alignment to within 10^ of orthotropia, with just over two years follow up with no adverse effects (there was no mention of binocular state). This was in contrast to Biglan's publication a year earlier, which concluded that BT was not as successful as surgery for the treatment of IE (Biglan 1989).
Following this, Ing 1992 looked at a group of 49 patients, three years after alignment with botulinum to try and determine the effectiveness of BT in achieving binocularity. He found positive binocularity (sensory and motor fusion) in approximately half of this group. He then compared his results to another group of patients with IE aligned by surgery and concluded that botulinum was less effective than surgery in establishing binocularity (P < 0.005).
McNeer 1994 published results of 57 IE patients, all of whom received bimedial medial rectus botulinum injections. The authors concluded that, for the purpose of improving ocular alignment, BT was an effective therapy, reducing the angle of the squint, both in patients under the age of 12 months and in those under the age of 24 months. The follow-up period was a minimum of 12 months.
In 2010, a single-centre, prospective, non-randomised study (de Alba Campomanes 2010) concluded that surgery was more successful than BT in the treatment of large angle IE, however in smaller angle squints (< 30^ to 35^) it was found to be comparable to surgery. Gursoy 2012 found that there was no difference in binocular alignment with BT versus surgery and proposed that BT may be considered a primary treatment for IE.
Botulinum toxin has also been used in addition to surgery i.e. to augment surgery (bimedial recessions) for large angle IE. Lueder 2008 suggests that augmentation with BT may be more effective than bimedial recessions alone, especially in large angle squints (Lueder 2012).
The role of botulinum toxin prior to surgery was looked at retrospectively (Ruiz 2004). It was found to be effective in reducing the amount of further horizontal surgery needed however, the authors found that in children under 18 months, injection of five units of botulinum induced unbalanced DVD.
Botulinum toxin has been shown by randomised trial to be a good alternative to surgery for re-treatment of IE, being equally successful as surgery in achieving binocularity (sensory and motor fusion - not stereopsis), if carried out within six months of surgery (Tejedor 1999).
Age at intervention
The advantages and disadvantages of surgical intervention at an 'early' (< two years of age) or 'late' (> two years of age) stage have been debated in the literature. Some of these are highlighted below:
Advantages: Better potential for binocularity, reduced muscle contraction.
Disadvantages: May increase the risk of amblyopia, difficulty in obtaining reliable and accurate measurements.
Advantages: Amblyopia management easier, more reliable measurements.
Disadvantages: Reduced potential for binocularity, muscle contracture can lead to mechanical component to squint.
Prospective cohort studies have found that surgical alignment is associated with better stereopsis (which is considered the 'gold' standard in binocularity) in patients who received treatment within the first 24 months of life (early) (Birch 1995; Birch 1998). Wright 1994 proposed even earlier surgery, between the age of 2.5 and three months, resulting in good binocularity, which is in agreement with Helveston's proposal of 'ultra early surgery' between four and six months.
In view of these reports of improved binocularity with surgery at less than six months of age, Ing 1995 performed a multi-centre study of the results of IE patients operated on at age six months or earlier. He included 16 patients with IE that had been surgically aligned at an average age of 4.2 months, all with a minimum of four years follow up. He concluded that surgery at less than six months of age did not lead to a better quality of binocularity than in those patients aligned at age six months. Interestingly, he concluded that binocularity remains an elusive target and a rare outcome of treatment for IE.
The early versus late strabismus surgery study (ELISS) (Simonsz 2005) was a large multi-centre, non-randomised trial, which involved 58 clinics, who recruited 231 children with IE in the "early" surgery group (six to 24 months) and 301 in the "late" group (32 to 60 months). This study found that children operated on early had better "gross" stereopsis at age six compared to the late group. This group had been operated on more frequently however and there was no significant difference in the angle of the strabismus between the two groups. In 2010, the ELISS study (Simonsz 2010) published further results, concluding that the benefit of early surgery for gross binocular vision, is balanced by a higher re-operation rate and an occasional child being operated on that would have had a spontaneous decrease without surgery. Birch 2006 looked at the long-term motor and sensory outcomes of children operated on by the age of six months and concluded that early surgery was associated with a higher prevalence of fusion and stereopsis than surgery after this age. However Polling 2009 included children who had late surgery (aged three to eight years) and concluded that 38.4% of these had some degree of gross binocular vision postoperatively.
Gerth 2008 looked at the effects that the timing on surgery for IE has on cortical visual motion processing (by measuring visually evoked potentials) and concluded that early surgery (which is defined by the authors as at or before 11 months of age) promotes the development of cortical visual motion processing compared to surgery after this age.
Studies have also looked at the effect of surgery on neuromotor development not just on vision. Both Drover 2008 and Caputo 2007 have conducted studies that look at the influence of congenital squints and surgery on such development. Both studies concluded that squint surgery is beneficial to motor function and development. This is an area for further research.
The above highlights that the current literature in the area of timing of intervention is still conflicting.
Implications for practice
As there are no randomised trials that we can include in this review at present, it has not been possible to resolve the controversies regarding type of surgery, non-surgical options and age of intervention in patients with infantile esotropia (IE). The available literature now contradicts previous suggestions that bimedial recessions is the surgical method of choice.There seems to be general agreement that any intervention should be earlier rather than later however gross binocular vision still seems possible in those receiving late intervention.
Studies of non-surgical interventions continue to be undertaken and published, mainly on the use of botulinum toxin. However, the current use of botulinum as a primary intervention for IE remains limited in comparison to surgical intervention, although McNeer and Tucker state in correspondence that BT is their primary treatment for IE (McNeer 2010).
The actual aims and outcomes of treatment are to improve ocular alignment and achieve some degree of binocularity. Most authors agree about the ocular alignment and aim for alignment within 10^ of orthotropia. However, claims of positive demonstrable binocularity after intervention vary widely. This is most likely due to the methods used to assess/confirm the presence of binocularity and the fact that claims/definition of positive stereopsis and of binocular vision can vary. The ELISS study used the term "gross" stereopsis/binocularity - very few patients in either arms of this trial actually achieved better than this level i.e. good quality binocularity. Polling's study defined positive binocularity by the presence of a bagolini cross i.e. the lowest grade of binocular vision possible. Recent multi-centre trial results still leave many questions regarding interventions for IE answered.
Implications for research
There is clearly a need for good quality trials to be conducted in various areas of IE, in order to improve the evidence base for the management of this condition. The trials need to be carefully planned, using standardised outcomes - an agreement is needed as to what constitutes 'positive binocularity' and what is considered a 'success' in terms of surgical alignment. Ideally quality of life measures would be incorporated into these trials.
The Cochrane Eyes and Vision Group developed and executed the electronic searches. We are grateful to Lorraine Cassidy for her input in to the protocol. We thank Carrie MacEwen, Catey Bunce, Suzanne Brodney-Folse and Roberta Scherer for their peer review comments. Finally we thank Sarah Hatt and Anupa Shah for their assistance throughout the review process.
Richard Wormald (Co-ordinating Editor for CEVG) acknowledges financial support for his CEVG research sessions from the Department of Health through the award made by the National Institute for Health Research to Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology for a Specialist Biomedical Research Centre for Ophthalmology. The views expressed in this publication are those of the authors and not necessarily those of the Department of Health.
Data and analyses
This review has no analyses.
Appendix 1. CENTRAL search strategy
#1 MeSH descriptor: [Esotropia] explode all trees
#3 convergen* near strabism*
#4 internal near strabism*
#5 #1 or #2 or #3 or #4
Appendix 2. MEDLINE (OvidSP) search strategy
1 randomized controlled trial.pt.
2 (randomized or randomised).ab,ti.
9 exp animals/
10 exp humans/
11 9 not (9 and 10)
12 8 not 11
13 exp esotropia/
15 (strabism$ adj3 convergen$).tw.
16 (strabism$ adj3 internal).tw.
18 12 and 17
The search filter for trials at the beginning of the MEDLINE strategy is from the published paper by Glanville et al (Glanville 2006).
Appendix 3. EMBASE (OvidSP) search strategy
1 exp randomized controlled trial/
2 exp randomization/
3 exp double blind procedure/
4 exp single blind procedure/
7 (animal or animal experiment).sh.
9 7 and 8
10 7 not 9
11 6 not 10
12 exp clinical trial/
13 (clin$ adj3 trial$).tw.
14 ((singl$ or doubl$ or trebl$ or tripl$) adj3 (blind$ or mask$)).tw.
15 exp placebo/
18 exp experimental design/
19 exp crossover procedure/
20 exp control group/
21 exp latin square design/
23 22 not 10
24 23 not 11
25 exp comparative study/
26 exp evaluation/
27 exp prospective study/
28 (control$ or propspectiv$ or volunteer$).tw.
30 29 not 10
31 30 not (11 or 23)
32 11 or 24 or 31
33 exp convergent-strabismus/
35 (strabism$ adj3 convergen$).tw.
36 (strabism$ adj3 internal).tw.
38 32 and 37
Appendix 4. LILACS search strategy
infantile or congenital and esotrop$ or converge$ or internal and strabism$
Appendix 5. metaRegister of Controlled Trials search strategy
Appendix 6. ClinicalTrials.gov search strategy
Appendix 7. ICTRP search strategy
Last assessed as up-to-date: 10 June 2013.
Protocol first published: Issue 3, 2004
Review first published: Issue 1, 2005
Contributions of authors
Conceiving the review: SE
Designing the review: SE
Co-ordinating the review: SE
Undertaking manual searches: SE, AS
Screening search results: SE, AS
Organising retrieval of papers: SE
Screening retrieved papers against inclusion criteria: SE, AS
Appraising quality of papers: SE, AS
Extracting data from papers: SE, AS
Writing to authors of papers for additional information: SE
Providing additional data about papers: SE
Obtaining and screening data on unpublished studies: SE
Data management for the review: SE
Entering data into RevMan: SE, AS
Analysis of data: SE, AS
Interpretation of data: SE, AS
Writing the review: SE
Securing funding for the review:
Performing previous work that was the foundation of current study: SE
Declarations of interest
Medical Subject Headings (MeSH)
MeSH check words