Penalization versus Part ... time Occlusion and Binocular Outcome in Treatment of Strabismic Amblyopia

Kurt Simons, PhD , Katherina C . Gotzler, MD, Susan Vitale, MHS

Objective: The purpose of the study is to compare the visual outcome of occlusion versus penalization treatment of strabismic amblyopia, with particular attention to binocu­larity outcome.

Design: The study design was a retrospective study. Participants: Patients with strabismic amblyopia, 75 receiving penalization alone,

87 with a history of occlusion treatment who were later treated by penalization, and 30 treated by means of part-time occlusion (2 to 6 hours/day) participated in this study.

Main Outcome Measures: Logarithm of the minimum angle of resolution (log MAR) visual acuity and binocularity index were measured.

Results: No statistically significant difference was found between outcomes for the penalization groups with and without a history of occlusion, either by univariate analysis or by multivariate analysis controlling for initial-visit age, acuity, and binocularity status. One marginally significant outcome difference was found between the pure penalization and part-time occlusion groups by univariate analysis, but no significant difference was found in the multivariate analyses controlling for the same threp. variables at the initial visit. All visual outcome differences between the pure penalization and part-time occlusion groups were less than 1 log MAR line visual acuity or less than a half-unit on the binocular­ity index.

Conclusions: The study provided no evidence of a difference in visual function outcome between penalization and occlusion, in terms of either statistical or clinical significance, although limitations of the patient samples used preclude these data from showing conclusively that there was no such difference. The lack of any other study adequately comparing these two treatment methods, in combination with the current study's demonstration of the difficulty of making adequate retrospective-based compari­son despite a large patient base (n = 1413), suggests that a large prospective, random­ized comparative treatment trial is needed. If atropine penalization, with its high acceptabil­ity to patients and parents, is found to produce results comparable with those of occlusion in cases of mild-to-moderate amblyopia, as the current and previous smaller studies suggest, then reconsideration of the standard of care for such amblyopia cases is indi­cated. Ophthalmology 1997; 104:2156-2160

Originally received: December 18. 1996. Revision accepted: May II, 1997.

Amblyopia treatment by means of pethalization dates back to at least Worth and occlusion treatment much further.! Since penalization traditionally has been viewed as useful only for occlusion treatment failures or for postocclusion acuity maintenance,! there have been few studies compar­ing these two treatment methods. One small (n = 38), retrospective study reported better lIiisual acuity outcomes in a group of children older than '6 years of age treated with atropine penalization than was obtained in a group

From the Wilmer Ophthalmological Institute, The Johns Hopkins Uni­versity School of Medicine, Baltimore, Maryland.

Supported in part by NIH grants # EY 01765 and EY 07577, and a grant from Mr. Robert Feduniak.

Reprint requests to Kurt Simons, PhD, Wilmer Ophthalmological Insti­tute B 1-35, Johns Hopkins Hospital , Balt imore, MD 21287-9009.

2156

Simons et al . Occlusion versus Penalization Treatment of Strabismic Amblyopia

of younger children who were occluded, but no statistical comparison was made.2 (The nominally more neurally plastic younger children might have been expected to produce better results.) Another small (n = 25), compara­tive study was done prospectively, with randomization and compliance monitoring, and found no difference in visual acuity outcome of the amblyopic eye between the two methods (i.e., penalization was found to be as effica­cious as occlusion).3 A recent prospective study of 36 patients with no history of amblyopia treatment came to the same conclusion, finding no statistically significant difference in outcome between the two forms of treat­ment.4

In view of evidence in animal models that unilateral or alternating occlusion during the binocular sensitive period can cause irreversible disruption ofbinocularity,5-8 binoc­ular prognosis is of particular interest in such a compari­son. Evaluation of this issue is complicated by lack of information about the human binocularity sensitive period and about the treatment implications of the already-com­promised binocularity of those with amblyopia (see re­view in preceding article9

). For instance, human infants with esotropia who undergo occlusion treatment in some cases still have at least gross stereopsis develop, even on random dot stereograms, I ,10, 11 and kittens with occlusion­induced deprivation amblyopia have been shown to be able to recover at least contour stereopsis with appropri­ately scheduled part-time reverse occlusion. 12

The current study involved retrospective analyses of two patient populations to compare the efficacy of penal­ization and occlusion, particularly regarding binocular outcome. The first analysis involved a comparison of one group of penalization patients from our previous work9

who had a history of occlusion treatment with another group who were treated solely by penalization. The sec­ond analysis compared the latter group with a group of patients for whom identical clinical measurement data were available and who had been treated by means of part-time occlusion or not.

Materials and Methods

Best-corrected visual acuity was measured using linear Snellen optotypes or single or linear Allen figures . Visual acuity was coded as in the previous article,9 with scaling of partial-line results. As in the previous article, depth of amblyopia was defined as the logarithm of the minimum angle of resolution (logMAR) visual acuity ratio between eyes. Binocular function was tested by the Worth 4-dot test at near and at distance, and stereopsis evaluated with the Titmus stereo fly and Randot Circles stereo tests. For analysis, we once again followed the practice of the previ­ous article,9 characterizing binocularity with an index ranging from 0 to 4: 0 indicated complete suppression; 1 indicated a moderate central suppression scotoma with peripheral fusion, indicated by fusion on the Worth 4-dot test at near only; 2 indicated a small suppression scotoma and peripheral fusion and/or gross stereopsis, as shown by fusion on the Worth 4-dot test at distance or passing

the Titmus stereo fly or both; 3 indicated moderate ster­eoacuity (100-400 arc seconds) on the Randot Circles test; and 4 indicated good stereoacuity (:s70 arc seconds).

Analysis 1

A total of 163 patients with strabismic amblyopia were identified in a previous study of penalization who met inclusion criteria of no ocular or neurologic abnormality, at least 1 10gMAR line of difference in acuity between eyes at treatment onset, and adequate acuity and binocu­larity measurements obtained at the treatment onset visit, the end-of-treatment visit, and, for a subset of the patients, at a long-term follow-up visit.9 Of these 163 patients, 88 had a history of occlusion treatment under various regi­mens before penalization, whereas 75 patients in that study were treated purely with some form of penalization. Three types of penalization had been used: full-time or intermittent atropine penalization or optical penalization. To determine whether occlusion history was associated with outcome, the patients within each of these groups with a history of occlusion or attempted occlusion treat­ment were compared with the patients within that group who had been treated purely with penalization with regard to age, depth of amblyopia (defined below), binocularity index (defined below), and anisometropia, all at the initial visit. Outcome variables for the patients falling into the two categories within each group then were compared as well: depth of amblyopia and binocularity index at the end-of-treatment and long-term follow-up visits and the amount of change of the amblyopia and binocularity mea­sures between the initial visit and each of those two visits. Potentially confounding variables accounted for by multi­variate methods in this latter analysis were age, depth of amblyopia, and pretreatment binocularity status.

Analysis 2

A population of 850 patients with strabismic amblyopia treated by occlusion were identified by chart review. The same diagnostic measurements were available for these patients as for the patients of the previous study used in analysis 1,9 making adequate comparison possible. As in the case of those three groups, patients with ocular or neurologic abnormality were excluded, as were patients with less than 1 logMAR line of difference in visual acuity between eyes at the initial visit and patients for whom the diagnostic measures were not available for at least the initial- and end-of-treatment visits. A total of 30 patients (3.5%) met these inclusion criteria. An institu­tional review board-approved protocol was followed to maintain patient confidentiality.

The following data were abstracted for each patient: cycloplegic refraction at the initial visit, age, amblyopia depth, and binocularity index for each of three visits. The three visits were defined as the initial visit (i.e., when treatment was begun), the end of treatment, and again, when available, the final long-term follow-up visit (i.e., the last time patient was seen).

The 30 patients with part-time occlusions were com-

2157

Ophthalmology Volume 104, Number 12, December 1997

pared regarding status at the initial and end-of-treatment visits, and at the long-term follow-up visit when data were available. They also were compared with 75 patients drawn from all 3 groups in the previous study (full-time atropine, intermittent atropine, optical) who had been treated purely with penalization. In view of the similari­ties among the three groups in both the previous studl and in the analysis 1 results detailed below, the patients with different penalization regimens were treated as a single group in this analysis.

In the statistical analysis, two-tailed t tests for paired data were used for evaluation of mean change pretreat­ment to post-treatment, the Kruskal-Wallis test was used for comparing median outcomes among treatment groups, Fisher's exact test was used to compare proportions be­tween treatment groups, and multivariate relationships were assessed by means of multiple linear or multiple logistic regression.

Results

Analysis 1

With one exception, patients in the full-time atropine, intermittent atropine, and optical penalization groups with a history of occlusion treatment were not found by univar­iate analysis to differ significantly from the patients in each of those groups, respectively, who had been treated purely by penalization regarding age, depth of amblyopia, binocularity index, or amount of anisometropia at the initial visit, depth of amblyopia, or binocularity index at the later visits. The exception was that in the optical penalization group, patients with a history of occlusion had a marginally, significantly (P < 0.02) larger mean amount of anisometropia than did those treated only by penalization.

We then assessed the effect of history of occlusion on the outcome variables in each of the three treatment groups, adjusting for the potentially confounding vari­ables of age, depth of amblyopia, and binocularity index at the initial visit in a multivariate model. The outcome variables analyzed were amblyopia depth and presence or absence of any degree of binocularity at the end-of­treatment and long-term follow-up visits. Once again, there were no significant differences in outcome between patients in the occlusion and no-occlusion history catego­ries in any of the three penalization treatment groups. In summary, treatment outcome after penalization was not found to differ significantly whether the patients had a history of occlusion or not.

Analysis 2

Patients in the part-time occlusion group were treated by regimens varying from 2 to 6 hours of occlusion per day and, in some cases, with a variable number of hours per

2158

day over a course of treatment. Results are summarized in Table 1.

All visual outcome differences between the penaliza­tion-only and part-time occlusion groups were less than 1 10gMAR line acuity or less than a half unit on our binocularity index (Table 1). Univariate and multivariate approaches were used to compare the two groups. The groups were quite similar as to age and visual status at the initial visit (Table 1), with none of the differences being statistically significant. The only statistically sig­nificant outcome difference between these two groups by univariate analysis was a borderline significant greater degree of improvement of the visual acuity status (i.e., depth of amblyopia) in the penalization-only group be­tween the initial and long-term follow-up visits (Table 1). Multivariate analysis was made of the outcome vari­ables (i.e., amblyopia depth and presence or absence of binocularity at any level at the end-of-treatment and long­term follow-up visits) in the two treatment groups control­ling for age, depth of amblyopia, and binocularity index at the initial visit. No significant differences were found.

Discussion

The current study found no substantial evidence that pe­nalization treatment of strabismic amblyopia produces different outcome on either monocular (i.e., visual acuity) or binocularity measures than does occlusion treatment. The only exception to this finding was a marginally, statis­tically significant greater amount of amblyopia reduction found by univariate analysis in the penalization-only than in the part-time occlusion group between the initial and long-term follow-up visits (Table 1). However, this differ­ence was not found in the multivariate analysis controlling for age and visual status at the initial visit. Even the differences found by univariate analysis were so small­less than 1 10gMAR line on the amblyopia depth measure and less than a half step on the binocularity index (Table I)-that they would be considered clinically insignifi­cant.

Our study has several limitations, however, that pre­vent a definitive conclusion. In analysis 1, in keeping with a difficulty confronting previous studies,13 patients classified as occlusion treatment failures may in fact have been compliance failures rather than true occlusion treat­ment failures. (It has been reported anecdotally that pa­tients in whom (full-time) occlusion was carried out cor­rectly showed no further improvement from subsequent penalization, although no explicit data were reported to support this conclusion.14) To the extent that some of the patients in the current study had not in fact experienced intended occlusion, of course, our analysis does not repre­sent an evaluation of the effects of true occlusion.

In analysis 2, the use of part-time rather than full-time occlusion in the sample of patients with occlusion means that all the patients had more binocular than occluded (monocular) visual experience during the course of treat­ment. Whether this binocular experience served to main­tain binocularity analogous to the binocularity maintained

Simons et al . Occlusion versus Pen alization Treatment of Strabismic Amblyopia

Table 1. M ean and Mean Differences of T reatment Groups (Analysis 2) [Range in Brackets]

Size of Mean Differences

Penalization Only Part-time Between Measure Group n Occlusion Group n Groups

Age (yrs) At initial visit 5.6 [2.4 to 12.2] 75 5.0 [2.5 to 7.8] 30 0.6 At end of treatment 7.2 [3.1 to 13.3] 75 6.6 [2.9 to 9.6] 30 0.6 At long-term follow-up 9. 7 [3.4 to 16.7] 39 9.5 [4.0 to 16.5] 17 0.2

Treatment duration (yrs) 1.6 [0.02 to 6. 1] 75 1.6 [J to 5.1] 30 0 Long-term follow-up duration (yrs) 2.4 [0.1 to 9.2] 39 2.9 [0.8 to 7.5] 17 0.5 Interocular acuity difference (in 10gMAR lines)

At initial visit 2.9 [1 to 10.7] 75 2.8 [1 to 10] 30 0.1 At end of treatment 0.7 [- 1.8 to 7.0] 75 0.9 [0 to 6.0] 30 0. 2 At long-term follow-up 0.8 [- 1.2 to 7.3] 39 0.5 [0 to 3.0] 17 OJ Amount of improvement:

Initial to end-of-treatment visit 2.2 [-1.5 to 6.4] 75 1.9 [-2 .5 to 7.8] 30 0.2 Initial to long-term (ollow-up-treatment visits 2.2 [- 2 to 4.6] 39 1.3 [- 1 to 5. 1] 17 0.9* End-of-treatment to long-term follow-up visit 0.2 [- 3 to 1.9] 39 0. 1 [.3 to 6.0] 17 0. 1

Binocularity index (Grades 0-4) At initial visit 1.5 [0 to 4] 71 1.7 [0 to 4] 30 0.2 At end of treatment 2. 1 [0 to 4] 74 2.3 [0 to 4] 30 0.2 At long-term follow-up 2.4 [0 to 4] 39 2.8 [0 to 4] 17 0.4 Amount of improvement

Initial to end-of-treatment visit 0.6 [- 2 to 4] 70 .59 [- 2 to 4] 30 0.01 Initial to long-term (allow-up-treatment visits 0.77 [- 2 to 4] 39 .89 [- 1 to 3] 18 0. 12 End-of-treatment to long-term follow-up visit 0.33 [-3 to 4] 39 .67 [- 1 to 3] 18 OJ4

Anisometropia (amblyopic-better eye refractive difference in diopters, SE)

At initial visit 0.3 [+ 2 to - 1.25] 53 0. 1 [+5.0 to - 2.0] 30 0.2

SE = spherical equiva lent; nla = not applicable; Binocularity index: 0 = suppression ; 1 = peripheral fusion; 2 = central fusion; 3 = steroacuity of 100 to 400"; 4 = stereoacui ty of s70".

* Significant d ifference (P < 0.05).

in penalization or whether the binocular experience com­promised binocularity through restimulation of the' 'am­blyopiagenic factor" I of strabismus is difficult to say. To the extent that thi s binocular experience enhanced binocularity, however, it reduced the visual experience difference between occlusion and penalization and, hence, the basis for detecting a difference between them.

A second possible shortcoming of analysis 2 was that the part-time occ lusion sample of patients able to meet the study criteria comprised only 3.5% of a prac­tice population of 850 cases. This is testimony to the difficulty of making a treatment comparison of the kind attempted here on the basis of data obtained retrospec­tively.

A third possible shortcoming of the present study involves the question of whether bias may have been introduced by the selection criteria themselves. We at­tempted to control for this problem as much as possible by using the total population of patients available from all the practice fil es that served as sources of patient records. This en sured that the only selection constraint outside of possible limiting characteristics from the practices themselves was the study's inclusion cri teri a. However, these criteria limited the sample to patients

old enough at their fi rs t visit to cooperate with standard clinical testing of vi sual acuity and binocularity. As reviewed briefly in the previous article,9 thi s age limita­tion may have constrained the responsiveness of the visual system to any treatment, because of reduced neu­ral plasticity.

In conclusion , although the current study does not resolve the matter, it adds to previous evidence2

-4 that

use of atropine penalization as a primary treatment of mild-to-moderate amblyopia may produce both monoc­ular and binocular results at least comparable to those of traditional occlusion. If so, there may be reason to reconsider whether atropine penalization is a viable al­ternative to occlusion as the standard of care for ambly­opia at those leve ls or, indeed, whether such penaliza­tion may be preferable to occlusion in view of its high acceptability to both patients and parents,4.9 solving the classic problem of obtaining compliance in occlusion treatment.' 3 However, adequate re-evaluation of the standard of care will require a large, randomized, pro­spective study comparing these two techniques.

Acknowledgment. The authors thank Stuart Dankner, MD, for providing access to his patient records, which provided the part-time occlusion group sample.

2159

Ophthalmology Volume 104, Number 12, December 1997

References

l. von Noorden GK. Binocular vision and ocular motility: theory and management of strabismus, 5th ed. St Louis: Mosby, 1996.

2. Ron A, Nawratzki 1. Penalization treatment of amblyopia: a follow-up study of two years in older children. J Pediatr Ophthalmol Strabismus 1982; 19: 137-9.

3. Doran RML, Yarde S, Starbuck A. Comparison of treat­ment methods in strabismic amblyopia. In: Campos EC, ed. Strabismus and Ocular Motility Disorders: Proceedings of the Sixth Meeting at the International Strabismological Association, Australia, 1990. Houndmills, Basingstoke, Hampshire: Macmillan Press, Scientific & Medical, 1991, 1990; chap. 5.

4. Foley-Nolan A, McCann A, O'Keefe M. Atropine penali­sation versus occlusion as the primary treatment for ambly­opia. Br J Ophthalmol 1997;81 :54-7.

5. Mitchell DE, Timney B. Postnatal development of function in the mammalian visual system. In: Handbook of physiol­ogy: a critical, comprehensive presentation of physiological knowledge and concepts. Bethesda, MD: American Physio­logical Society; Baltimore: Dist. by Williams & Wilkins, 1984; Sect. 1, v. III, pt. 1, chap. 12.

6. Timney B. The effects of early and late monocular depriva­tion on binocular depth perception in cats. Brain Res 1983;283:235-43.

2160

7. Timney B. Effects of brief monocular deprivation on binoc­ular depth perception in the cat: a sensitive period for the loss of stereopsis. Vis Neurosci 1990;5:273-80.

8. Altmann L, Luhmann HJ, Greuel JM, Singer W. Functional and neuronal binocularity in kittens raised with rapidly al­ternating monocular occlusion. J Neurophysiol 1987; 58:965-80.

9. Simons K, Stein L, Sener EC, Vitale SH, Guyton DL. Full­time atropine, intermittent atropine, and optical penalization and binocular outcome in treatment of strabismic amblyo­pia. Ophthalmology 1997. In press.

10. Birch EE, Stager DR, Berry P, Everett ME. Prospective assessment of acuity and stereopsis in amblyopic infantile esotropes following early surgery. Invest Ophthalmol Vis Sci 1990;3 1:758-65.

11. Birch EE, Stager DR, Everett ME. Random dot stereoacuity following surgical correction of infantile esotropia. J Pedi­atr Ophthalmol Strabismus 1995;32:231-5.

12. Mitchell DE, Ptito M, Lepore F. Depth perception in mon­ocularly deprived cats following part-time reverse occlu­sion. Eur J Neurosci 1994;6:967 -72.

13. Simons K. Preschool vision screening: rationale, methodol­ogy and outcome. Surv Ophthalmol 1996;41:3-30.

14. Gregersen E, Pontoppidan J, Rindziunski E. Penalization where conventional occlusion treatment fails. In: Fells P, ed. The Second Congress of the International Strabismolog­ical Association. Marseille: Diffusion Generale de Li­brairie, 1976;74-9.