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(Investigative Ophthalmology and Visual Science. 2007;48:661-664.)
© 2007 by The Association for Research in Vision and Ophthalmology, Inc.
DOI:  10.1167/iovs.06-0717
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Progression of Intermittent, Small-Angle, and Variable Esotropia in Infancy

Valeria L. N. Fu,1 David R. Stager,2 and Eileen E. Birch1,2

1From the Pediatric Eye Research Laboratory, Retina Foundation of the Southwest, Dallas, Texas; and the 2University of Texas Southwestern Medical Center, Dallas, Texas.


   Abstract
Top
 Abstract
Subjects and Methods
 Results
 Discussion
 References
 
PURPOSE. Esotropia (ET) in infancy may initially manifest as a small-angle, variable-angle, or intermittent deviation. Some patients experience spontaneous resolution and become orthophoric. Others progress to constant large-angle ET and require surgery. The authors examined factors that may be associated with risk for progression to constant large-angle ET.

METHODS. Seventy-seven infants who initially presented with intermittent, small (<20 prism diopter [pd]) or variable-angle ET at 2 to 12 months of age were followed up until the ET was resolved, the infants had surgery, or the parents or guardians refused surgery. All infants with refractive correction ≥+3.50 D were treated initially with glasses. Four risk factors were examined: prescription of occlusion therapy, initial visit before 6 months of age, presence of amblyopia, and abnormal stereoacuity.

RESULTS. All 12 infants with small or variable angles progressed to constant large-angle ET and surgery. ET resolved spontaneously in 44.6% (29/65) infants in whom it was intermittent. Infants with intermittent ET who received patches as initial treatment and who had abnormal stereoacuity had 3.4x (95% confidence interval [CI], 1.83–6.29) and 3.4x (95% CI, 1.66–6.78) higher risk for progression to constant large-angle ET, respectively. Neither age at initial visit nor amblyopia presented risk for progression.

CONCLUSIONS. Abnormal stereoacuity and occlusion therapy pose significant risks for progression from intermittent to constant large-angle ET. Intermittent ET that develops during the first year of life has a high likelihood of spontaneous resolution, whereas constant small-angle or variable-angle ET seldom resolves.

Esotropia (ET) in infancy may initially manifest as a small-angle, variable-angle, or intermittent deviation.1 More than 25% of patients with esodeviation at 2 to 4 months of age experience spontaneous resolution without surgery and become orthophoric by 6 months of age.2 Most of the resolved cases are infants with intermittent or variable deviations on the initial visit. Resolution rarely occurs in infants with constant esotropia ≥40 prism diopters (pd); constant ET of moderate to large angle in early infancy on repeated examination persists in 98% of patients.2 3

Surgical alignment before 6 months of age has the potential benefit of improved long-term stereopsis4 5 (Birch EE, Stager DR, manuscript submitted), but this benefit must be weighed against the possibility of spontaneous resolution. Thus, patients with large-angle constant esotropia may be candidates for early surgery, but surgery for those with small, variable, or intermittent angles may be delayed because it is difficult to predict which infants will have spontaneous resolution and which will progress and require surgery. The purpose of this study was to identify risk factors that are associated with progression to constant large-angle ET among infants who initially are treated for small-angle, variable-angle, or intermittent ET.


   Subjects and Methods
Top
 Abstract
 Subjects and Methods
Results
 Discussion
 References
 
Subjects
Seventy-seven patients were referred by 12 pediatric ophthalmologists to the Retina Foundation of the Southwest (RFSW). On the initial visit, all patients had intermittent (phoric during intervals and heterotropic during other intervals; 8–45 pd), small-angle (<20 pd), or variable-angle (6–30 pd) ET at 2 to12 months of age (6.8 ± 3.0 [mean ± SD]). Diagnosis was based on the referring pediatric ophthalmologist’s examination. Infants were followed up (at 3-month intervals for infants younger than 12 months of age; at 6-month intervals for infants older than 12 months of age) until ET resolved to orthophoria or the infants underwent eye alignment surgery. For the purpose of this study, hyperopic refers to all children with substantial hyperopia, defined here as a refractive correction of +3.5 D or greater, all whom were prescribed and wore glasses. None of the patients had known neurologic disorders. Informed consent was obtained from one or both parents before the patient’s participation. This research protocol observed the tenets of the Declaration of Helsinki and was approved by the Institutional Review Board of the University of Texas Southwestern Medical Center.

Clinical risk factors were chosen from the data available at the time the diagnosis of esotropia was made. Four risk factors were examined to determine the risk for progression to constant large-angle ET: initial visit before 6 months of age (arbitrary value of 6 months was chosen for risk factor analysis), occlusion therapy, presence of amblyopia, and abnormal stereoacuity.

Initial visit before 6 months of age was defined as the first visit to the pediatric ophthalmologist for diagnosis.

Occlusion therapy was based on the ophthalmologist’s prescription and the parents’ reports. Prescribed occlusion regimens included patching of one eye 0.5 to 6 hours daily or alternate patching for 1 to 3 hours daily. Based on the parents’ reports, occlusion compliance was categorized as poor (<25% compliance), moderate (25%–75% compliance), and excellent (>75% compliance). Patients were categorized as "patching" if occlusion had been prescribed and compliance was rated as moderate or excellent. Patients were categorized as "no patching" if occlusion had not been prescribed or if compliance was rated as poor.

Presence of amblyopia was defined as visual acuity of either eye below the normal range according to their age. Visual acuity was evaluated with Teller Acuity Cards.

Abnormal stereoacuity was defined as stereoacuity below the normal age range with Infant Stereocards (Randot; Stereo Optical, Inc., Chicago, IL).6

Risk Factor Analysis
Relative risk (RR) was computed for all risk factors.7 Factors with 95% confidence intervals (CI) lower limit > 1.0 were deemed for study purposes to present significant risk for progression to constant large-angle ET.


   Results
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 Abstract
 Subjects and Methods
 Results
Discussion
 References
 
Small or Variable ET
Twelve infants were examined with small- or variable-angle ET. Two children (17%) were hyperopic and 10 children (83%) were nonhyperopic before surgery. All 12 (100%) progressed to constant large-angle ET and surgery. The 5 infants who initially had constant ET of <20 pd progressed to constant ET of 20 to 70 pd at 7 to 16 months of age. The 7 infants who initially had variable-angle ET progressed to constant ET at 25 to 55 pd at 9 to 17 months of age. All 12 infants underwent at least one surgical alignment (4 had one surgery, 4 had two surgeries, 3 had 3 surgeries, and 1 had 4 surgeries). After surgical treatment, the vision of 4 (33%) patients was corrected within 8 pd of orthotropia, the vision of 6 (50%) patients were corrected within 8 pd of orthotropia with postoperative spectacle correction, and the vision of 2 (17%) patients remained esotropic (10–20 pd) despite surgery and spectacle correction.

Intermittent ET
Sixty-five infants were initially examined with intermittent ET. Treatment and outcome during the follow-up period are summarized in Figure 1 . Overall, 29 (44.6%) achieved orthophoria with (n = 17) or without (n = 12) spectacle correction at 9 to 45 months of age. In the remaining 36 (55.4%) infants, constant esotropia of 10 to 90 pd developed when they were 7 to 96 months of age. Twenty-seven of the 36 children in whom constant esotropia developed underwent surgery. After surgery, the vision of 20 infants was corrected within 8 pd of orthotropia with or without postoperative spectacle correction, and 7 remained esotropic (10–25 pd). Nine children who did not undergo surgical treatment remained esotropic (8–35 pd) with or without spectacle correction.


Figure 1
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  		FIGURE 1. Flow chart of treatment and outcome during the follow-up period.

 
Because it is possible that infants with hyperopia ≥+3.50 D, all whom were treated initially with spectacles, might have a different rate of progression or different risk factors for progression than infants who were not treated with spectacles, we performed secondary subgroup analyses. Thirty-nine (60%) patients were prescribed spectacles on the initial visit; 17 of 39 (43.6%) achieved orthophoria with spectacle correction at 9 to 45 months of age. Constant ET of 10 to 50 pd developed in the remaining 22 (56.4%) infants at 7 to 96 months of age. Fifteen of 22 children underwent alignment surgery. After surgery, 1 (6.7%) was corrected within 8 pd of orthotropia, 12 (80%) were corrected within 8 pd of orthotropia with postoperative spectacle correction, and 2 (13.3%) remained esotropic (10–25 pd) despite surgery and spectacle correction. Seven (18%) children who did not have surgical treatment remained esotropic (20–35 pd) with spectacle correction.

Twenty-six (40%) of the infants who initially had intermittent ET were not initially hyperopic; rather, ET spontaneously resolved in 12 of 26 (46.2%) infants at 6 to 14 months of age. The remaining 14 (54%) infants either developed constant esotropia of 20 to 90 pd before surgery or experienced reductions in strabismic angle without surgery at 7 to 83 months of age. Twelve of the 14 children underwent alignment surgeries. After surgical treatment, 5 (42%) were corrected within 8 pd of orthotropia, 2 (16%) were corrected within 8 pd of orthotropia with postoperative spectacle correction, and 5 (42%) remained esotropic (10–21 pd) despite surgery. Two (7.6%) children who did not receive surgical treatment remained esotropic. One child, who initially had 8 to 12 pd constant esotropia, improved to intermittent esotropia; the second child’s initial angle was 20 to 25 pd constant ET but reduced to 0 to 8 pd during follow-up.

Overall rates of achieving adequate alignment through spontaneous resolution, spectacle wear, or surgery were comparable for the hyperopic and nonhyperopic children. Among the hyperopic ET group, 30 of 39 (77%) achieved adequate alignment, and among the nonhyperopic ET group,19 of 26 (73%) children achieved adequate alignment. Children with intermittent ET in their first year of life achieved a high rate of adequate alignment through spectacle correction, surgery, or spontaneous resolution.

Relative Risk for Progression
All 12 infants in the small- and variable-angle ET group progressed to large-angle esotropia and surgery, and risk factor analysis could not be conducted for this group. Among the 65 infants with intermittent ET, the relative risks of each of the factors for progression to constant large-angle ET are summarized in Table 1 . Infants who had occlusion therapy as an initial treatment had 3.4 times higher risk for progression (95% CI, 1.83–6.29) to constant large-angle ET than infants who were not patched. Infants who had abnormal stereoacuity had 3.4 times higher risk for progression (95% CI, 1.66–6.78) to constant large-angle ET than infants who had normal stereoacuity. Neither age at initial visit (RR = 1.0; 95% CI, 0.43–1.08) nor amblyopia (RR = 1.3; 95% CI, 0.81–1.99) presented significant risk for progression.


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  		TABLE 1. Relative Risk for Progression from Intermittent ET to Constant Large-Angle ET for Children

 
The relative risk associated with each of the clinical factors for progression to constant large-angle ET with or without spectacle treatment is shown in Table 1 . Among infants with hyperopia, infants who were patched as initial treatment had 4.0 times higher risk for progression (95% CI, 1.69–9.83) to constant large-angle ET than infants who were not patched. Infants who had abnormal stereoacuity had 2.6 times higher risk for progression (95% CI, 1.24–5.46) to constant large-angle ET than infants who had normal stereoacuity. Neither age at initial visit (95% CI, 0.44–1.39) nor amblyopia (95% CI, 0.61–2.07) posed significant risk for progression for infants who were hyperopic. Infants who were not initially hyperopic but who had abnormal stereoacuity had 7.1 times higher risk for progression (95% CI, 1.12–45.1) to constant large-angle ET than infants with normal stereoacuity. Infants who were patched as initial treatment had 2.8 times higher risk for progression (95% CI, 1.18–6.42) to constant large-angle ET than infants who were not patched. Among the 33 infants who had occlusion therapy, 58% (19 of 33) were prescribed part-time unilateral occlusion, 39% (13 of 33) were prescribed part-time alternate occlusion, and 3% (1 of 33) were prescribed mixed occlusion (alternate and unilateral at different times). There were no significant differences between the part-time alternate and unilateral occlusion groups in the rate of progression (P = 0.15). Age at initial visit (95% CI, 0.26–1.21) and amblyopia (95% CI, 0.77–2.94) did not pose significant risk for progression to infants who were never treated with glasses.


   Discussion
Top
 Abstract
 Subjects and Methods
 Results
 Discussion
References
 
All 12 infants with small- or variable-angle ET progressed to a constant large-angle ET that was treated surgically. This finding suggested that the rate of spontaneous resolution of esotropia in infancy that initially manifested with a small or variable angle was low. On the other hand, intermittent ET that initially manifested at 2 to 12 months of age showed a relatively high rate of spontaneous resolution (19%) and a high rate of excellent response to spectacle correction (26%); intermittent ET resolved spontaneously or with spectacle correction in almost 45% of infants.

In this study, we examined the relative risk for progression from intermittent ET during infancy to constant large-angle ET from prescription of occlusion therapy, initial visit before 6 months of age, presence of amblyopia, and abnormal stereoacuity for infants with intermittent ET. Overall, occlusion therapy and abnormal stereoacuity posed significant risks for progression. These factors are possibly interrelated.

Alternate and monocular occlusion have been shown to disrupt binocular interaction in animal studies, and monocularly deprived cats are unable to discriminate stereoscopically with random-dot stereograms after part-time alternate occlusion8 9 or monocular occlusion.10 11 Tychsen et al.12 also showed that full-time alternate occlusion from birth to age 9 months produced stereoblindness and small-angle infantile ET in monkeys. However, all infants in the present study were prescribed part-time occlusion (1–3 hours daily). Part-time occlusion therapy, however, may be sufficient to degrade stereoacuity or to produce stereoblindness.

An alternative to occlusion is the use of atropine or optical penalization methods. It has been suggested that these methods may be less damaging to binocular function because they allow for binocular vision at some viewing distances. However, Simons et al.13 found no difference in binocular outcomes between atropine penalization and occlusion therapy. The PEDIG Amblyopia Treatment Study (a randomized clinical trial of patching versus atropine)14 15 also reported no difference in binocular outcomes at 6 months or 2 years after treatment.16

Age at initial visit did not pose a significant risk for progression to constant large-angle ET. This was surprising because a recent PEDIG natural history study of esotropic infants found that younger age at the initial visit was strongly associated with an increased probability of spontaneous resolution.2 They attributed this higher risk to the association between age at initial visit and immaturity of the ocular motor system. Although age at initial visit was similar in our study (3.7 ± 2.7 months) and the PEDIG study (3.2 ± 0.9), we found no such association. In our study, all 65 infants had intermittent ET. In PEDIG study, only 19% of infants had intermittent ET. The mixed groups of infantile esotropia in PEDIG study may only reflect the natural history of the general population of infants with ET, not any specific group of ET such as intermittent ET.

Amblyopia was not found to pose a significant risk for progression to constant large-angle ET. It was evaluated by forced-choice preferential-looking grating acuity (Teller Acuity Cards). This form of acuity testing may be less sensitive to strabismic amblyopia than recognition acuity tests.17 18 Hence, it is possible that our ability to examine this risk factor was limited by inaccurate classification of infants as nonamblyopic, with the result that only a small number of infants (17/66) were classified as amblyopic.

In conclusion, the present study identified occlusion therapy and abnormal stereoacuity as the primary risk factors for progression from intermittent ET in infancy to constant large-angle ET. Patients with intermittent ET during the first year of life have a high likelihood (44.6%) of spontaneous resolution or resolution with spectacle correction alone. However, constant small- or variable-angle ET seldom resolves; all 12 infants in the present study progressed to constant large-angle ET.


   Footnotes
 
Supported in part by National Institutes of Health Grants EY05236 (EEB).

Submitted for publication June 27, 2006; revised August 25 and September 7, 2006; accepted November 30, 2006.

Disclosure: V.L.N. Fu, None; D.R. Stager, None; E.E. Birch, None

The publication costs of this article were defrayed in part by page charge payment. This article must therefore be marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.

Corresponding author: Valeria L. N. Fu, Retina Foundation of the Southwest, 9900 N. Central Expressway, Suite 400, Dallas, TX 75231; vfu{at}retinafoundation.org.


   References
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 Abstract
 Subjects and Methods
 Results
 Discussion
 References
 

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