A Prospective Study of Macular Thickness in Amblyopic Children with Unilateral High Myopia

Abstract

Purpose.: To compare macular thickness of the normal fellow eye to that of the amblyopic eye using optical coherence tomography (OCT) in children with unilateral high myopia. Relationships between macular thickness and magnitude of myopic anisometropia, axial length, and visual acuity (VA) were investigated.

Methods.: Thirty-one children with a mean age of 9.56 years were recruited. Macular thickness, axial length, best-corrected VA, and refraction were measured. Paired t-test was performed to compare the macular thickness of the amblyopic eye to that of the fellow eye. Partial correlations were used to test the relationships between interocular difference in macular thickness and anisometropia, axial length, and VA.

Results.: Average (± SD) LogMAR VA in the amblyopic eye was 0.96 ± 0.31. Mean spherical equivalent in amblyopic eyes was −10.79 ± 3.40 diopters. A statistically significant difference in macular thickness was found between amblyopic and fellow eyes, with amblyopic eyes having greater foveal thickness but reduced inner and outer macular thickness. Only the nasal outer macular thickness had a statistically significant association with the magnitude of anisometropia.

Conclusions.: Amblyopic children with unilateral high myopia tend to have a thicker fovea and thinner inner and outer macula in the amblyopic eye compared to the normal fellow eye. The findings indicate that anatomic changes may be present in the retinas of amblyopic children with unilateral high myopia. Future study is warranted to determine whether the mechanism of the macular changes is due to high myopia, amblyopia, or a combination of the two.

Amblyopia is the most common cause of monocular visual impairment in children and young and middle-aged adults. ^1,2 Anisometropia as the most frequent cause of amblyopia has been evaluated in numerous studies. ^{3 –5} However, anisometropia associated with high myopia has often been excluded from those studies. The few studies investigating anisometropic amblyopia caused by unilateral high myopia have concluded that this type of amblyopia had poorer treatment outcomes. ^6,7 Underlying structural abnormalities and macular hypoplasia have been proposed as causes of the poor treatment outcomes in myopic anisometropia with limited research data to support this hypothesis. ^8,9 Knowledge of the macular structure and associated factors in amblyopia associated with unilateral high myopia will further our understanding of this type of amblyopia and may assist clinicians in predicting treatment outcomes. 

Optical coherence tomography (OCT) is a technology with good reproducibility in measuring macular thickness. ^10,11 Its application in young children has been demonstrated. ^{12 –14} Recently, macular thickness in strabismic and anisometropic amblyopia has been studied using OCT, and the results of these studies are contradictory. ^{15 –21} However, macular thickness in amblyopia associated with unilateral high myopia has not been specifically reported. 

The purpose of this study was to compare the macular thickness of the amblyopic eye to that of the fellow eye in amblyopes with unilateral high myopia. In addition, the study evaluated if there was any relationship between macular thickness and magnitude of myopic anisometropia, axial length, or visual acuity (VA). 

Methods

Study Population and Data Collection

Both the study protocol and informed consent forms were approved by the Institutional Review Board of the Illinois College of Optometry. In accordance with the guidelines of the Declaration of Helsinki, written informed consent was obtained from the parent or legal guardian of each child, and each subject gave verbal assent to participate in the study. 

A total of 31 children diagnosed with myopic anisometropic amblyopia were recruited at the Illinois Eye Institute, the teaching clinic of the Illinois College of Optometry. The characteristics of the subjects are listed in Table 1. All subjects underwent a comprehensive eye examination including VA, refraction, dilated fundus examination with indirect ophthalmoscopy, cycloplegic refraction, and A-scan ultrasound biometry. Monocular distance VA was tested at 3 meters (10 feet) using a computer-based electronic VA tester, ^22,23 which is commonly used in amblyopia studies. ^24,25 For children aged younger than 7 years, HOTV optotypes with surrounding bars were used according to the Amblyopia Treatment Study VA protocol. ²⁶ For children aged 7 years or older, single optotypes of the ETDRS acuity chart with surrounding bars were presented. Cycloplegia was induced with 1% cyclopentolate, 1% tropicamide, and 2.5% phenylephrine (1 drop each). Fixation of subjects was evaluated using visuoscopy. Due to either a blurred image through the ophthalmoscope or lack of foveal reflex, fixation was not able to be evaluated in 10 out of 31 subjects. For the remaining 21, three had eccentric fixation, five subjects had unsteady central fixation, and 13 had central steady fixation. Other than refractive error and amblyopia, all subjects had no concurrent ocular disease. The eligibility criteria are listed as follows:

•  
  Amblyopia associated with myopic anisometropia
•  
  Best-corrected VA in the amblyopic eye 20/40 to 20/400 inclusive
•  
  Best-corrected VA in the fellow normal eye ≥20/40
•  
  Interocular acuity difference ≥3 LogMAR lines

All OCT measurements (Stratus OCT3; Carl Zeiss Meditec, Dublin, CA) were performed after subjects' pupils were dilated to at least 5 mm in diameter. The measurements were done by a single skilled technician who was masked to the diagnoses of the subjects. Scans were performed using the fast macular thickness protocol, in which six 6-mm lines in a radial spoke-like pattern are obtained in a continuous automated sequence. All scans had signal strength of at least 6. In addition, all the macular images were collected using the following protocol to ensure that the foveal depression was in the center of the scan. Alignment mode was used by the technician to ensure each 6-mm line scan was through the center of the fovea. When a scan was observed to be off the center of the fovea even if the subject's fixation was accurate, the procedure of adjusting scan placement was performed to move the scan location to the center of the fovea. The following 10 parameters were measured for each subject: foveal minimum thickness, average foveal thickness, inner nasal, superior, temporal, and inferior macular thickness, outer nasal, superior, temporal, and inferior macular thickness. Figure 1A demonstrates the locations of fovea, inner macula, and outer macula. The foveal area is defined as the central circle of 1 mm diameter. Inner macula refers to the ring around the foveal area of 3 mm diameter and outer macula refers to the ring around the inner macula of 6 mm diameter.

Table 1.

 

Characteristics and Baseline Data for the Amblyopic Children with Unilateral High Myopia

Characteristic	n	Mean ± SD	Minimum	Maximum
Sex
Female	20
Male	11
Age, y		9.56 ± 3.29	5	18
Race
African American	26
Hispanic	3
Asian	2
VA, LogMAR
Amblyopic eye		0.96 ± 0.31	0.30	1.51
Fellow eye		0.16 ± 0.15	0	0.30
Refractive Error, D
Amblyopic eye		−10.79 ± 3.40	−17.50	−5.00
Fellow eye		−1.67 ± 2.90	−4.88	1.25
Anisometropia, D		9.12 ± 3.53	3.63	17.50
Axial Length, mm
Amblyopic eye		26.63 ± 1.35	24.21	29.52
Fellow eye		23.26 ± 1.08	21.53	25.48

  n = 31. SD, standard deviation; D, diopters.

Figure 1.

 

(A) Schematic diagram to demonstrate the locations of fovea, inner macula, and outer macula. (B) Schematic diagram of macular thickness of normal eyes (dashed line) versus that of amblyopic eyes with unilateral high myopia (solid line).

Data Analysis

Spherical equivalent was defined as the spherical power plus half of the minus cylinder power. VA was converted to LogMAR for analysis. The magnitude of anisometropia and interocular differences in VA, axial length, and macular thickness were obtained by subtracting the value obtained in the amblyopic eye from the value obtained in the fellow eye. The distributions of spherical equivalent, VA of the amblyopic eye, VA of the fellow eye, axial length, and macular thickness were confirmed as normally distributed by the Kolmogorov-Smirnov test. Macular thickness of the amblyopic eye was compared to that of the fellow eye using the paired t-test. Partial correlations were performed to test the relationships among macular thickness, magnitude of anisometropia, axial length, and VA while controlling for age, race, and sex. All data were analyzed using analysis software (Statistical Package for Social Sciences, SPSS version 17.0; SPSS Inc., Chicago, IL). Statistical significance was assumed at P < 0.05; however, for multiple comparisons and correlations among the 10 OCT parameters, Bonferroni's correction was applied with a resultant significance level of P < 0.005. 

Results

Table 1 shows the demographic and baseline data for all the subjects. Average (± SD) LogMAR VA in amblyopic eyes was 0.96 ± 0.31 and 0.16 ± 0.15 in the fellow eye. The mean spherical equivalent in the amblyopic eyes was −10.79 ± 3.40 diopters (D) and in the normal fellow eyes was −1.67 ± 2.90 D. The mean magnitude of anisometropia was 9.12 ± 3.53 D, ranging from 3.63 to 17.50 D. Mean axial length was 26.63 ± 1.35 mm in the amblyopic eyes and 23.26 ± 1.08 mm in the fellow eyes. Twenty-four children had pure myopic anisometropic amblyopia, and seven children had combined-mechanism amblyopia (strabismus and myopic anisometropia). 

Macular thickness measurements are shown in Table 2. After the application of Bonferroni's correction, a statistically significant difference in macular thickness was found between amblyopic and fellow eyes, with amblyopic eyes having higher minimum foveal and average foveal thickness but lower inner and outer macular thickness. Figure 1B illustrates the difference in foveal and mid-peripheral macular thickness of the normal eyes compared to the highly myopic amblyopic eyes. A sample OCT image of our subjects is shown in Figure 2. 

Table 2.

 

Macular Thickness (μM) Comparing the Amblyopic Eyes to the Fellow Eyes

Location	Amblyopic Eye (Mean ± SD)	Fellow Eye (Mean ± SD)	P
Foveal minimum	180.97 ± 27.66	156.84 ± 18.28	0.0001*
Average foveal (1 mm)	203.58 ± 18.33	191.00 ± 15.76	0.0005*
Inner macula (3 mm)
Nasal	257.65 ± 20.73	271.71 ± 16.88	0.0003*
Superior	256.29 ± 20.66	269.97 ± 15.05	0.0013*
Temporal	243.74 ± 18.84	261.06 ± 12.94	<0.0001*
Inferior	253.03 ± 21.13	272.16 ± 17.69	<0.0001*
Outer macula (6 mm)
Nasal	245.81 ± 17.83	256.23 ± 15.48	0.0002*
Superior	231.71 ± 15.87	242.65 ± 13.76	0.0010*
Temporal	206.23 ± 14.03	222.58 ± 15.18	<0.0001*
Inferior	212.03 ± 17.25	232.16 ± 17.09	<0.0001*

  n = 31; Bonferroni's correction for multiple correlations, significant at P < 0.005. SD, standard deviation.

*  Statistical significance.

Figure 2.

 

Sample OCT images from an amblyopic subject (OD: amblyopic eye; OS: fellow eye). Subject information: 14-year-old African American female, VA OD: 20/200, OS: 20/20, 6 prism diopters constant right exotropia at distance and 8 prism diopters constant right exotropia at near. Refractive error OD: −6.00–1.25 × 165, OS: −1.25 sph.

The spherical equivalent refractive error of the amblyopic eyes was strongly correlated with the axial length (r = −0.71, P < 0.0001). Furthermore, the magnitude of anisometropia was statistically significantly correlated with the interocular difference in VA (r = −0.59, P = 0.003). While controlling for age, race, and sex, moderate correlations were found between interocular differences in all regions of outer macular thickness and the magnitude of anisometropia (Table 3); however, after Bonferroni's correction, only the nasal outer macular thickness had a statistically significant association with the magnitude of anisometropia. Interocular difference in axial length showed a moderate correlation with the nasal, superior, and temporal outer macular thickness, while interocular difference in VA correlated moderately with the inferior inner macular thickness and inferior, nasal, and temporal outer macular thickness. However, none of these correlations was statistically significant after Bonferroni's correction (Table 3). Figure 3 shows the correlations between interocular difference in macular thickness (only minimum foveal thickness and outer nasal macular thickness are shown) and magnitude of anisometropia and interocular difference in VA. 

Table 3.

 

Correlations between Interocular Difference (IOD) in Macular Thickness with Anisometropia, IOD in Axial Length, and VA

IOD in Macular Thickness	Anisometropia		IOD in Axial Length		IOD in VA
	r	P	r	P	r	P
Foveal minimum	0.13	0.547	0.08	0.72	0.19	0.40
Average foveal (1 mm)	−0.18	0.424	0.16	0.47	0.23	0.29
Inner macula (3 mm)
Nasal	0.21	0.333	−0.20	0.35	0.01	0.95
Superior	0.11	0.627	−0.15	0.49	0.03	0.90
Temporal	0.22	0.318	−0.23	0.29	−0.11	0.62
Inferior	0.36	0.091	−0.15	0.51	−0.46	0.03
Outer macula (6 mm)
Nasal	0.56	0.004*	−0.44	0.03	−0.46	0.03
Superior	0.42	0.048	−0.46	0.03	−0.22	0.31
Temporal	0.55	0.006	−0.48	0.02	−0.49	0.02
Inferior	0.30	0.170	−0.16	0.46	−0.47	0.03

 Partial correlation by controlling age, race, and sex. Bonferroni's correction for multiple correlations, significant at P < 0.005. r, correlation coefficient.

*  Statistical significance.

Figure 3.

 

Scatterplots of interocular difference (IOD) in minimum foveal thickness and outer nasal macular thickness against magnitude of anisometropia and IOD in VA (LogMAR).

In an effort to ascertain whether the presence of strabismus in addition to anisometropia had an effect on macular thickness, the interocular difference in macular thickness was compared between the children with purely myopic anisometropia (n = 24) and the ones with combined mechanism amblyopia (myopic anisometropia and strabismus) (n = 7). No statistically significant differences were identified in the macular thickness of each of the regions between those two groups using t-test, equal variance not assumed. Children aged younger than 8 years (n = 15) were compared to the older children (n = 16), aged 8 to 18 years, and no statistically significant difference in macular thickness was found. The age of eight was chosen to reflect equal subject pools for statistical comparison. 

Discussion

This study found that the macular thickness in amblyopic eyes with high myopia measured by OCT was significantly different from that of the normal fellow eyes. Both foveal minimum thickness (by ∼24 μm) and average foveal thickness (by ∼13 μm) were greater in the amblyopic eyes with high myopia than in the normal fellow eyes. In contrast, both inner and outer macular thickness was thinner in the amblyopic eyes compared to that of the normal fellow eyes. Although certain macular thickness parameters had moderate correlations with the magnitude of anisometropia, interocular difference in axial length, and VA, only the outer nasal macular thickness had a statistically significant association with the magnitude of anisometropia after Bonferroni's correction. No age effect on macular thickness was revealed comparing the younger children (younger than 8 years old) to older ones (older than 8 years old). 

Previous OCT studies of macular thickness in anisometropic amblyopia have yielded inconsistent findings. ^15,16,20,21 Yoon et al. ²¹ studied 31 hyperopic anisometropic amblyopes and reported no difference in macular thickness between the amblyopic and normal fellow eyes. Average macular thickness calculated from center, inner, and outer macular regions was used in this study, which might account for their finding of no association between anisometropic amblyopia and macular thickness if the effect of amblyopia on macular thickness varies among different macular regions. Dickmann et al. ¹⁶ measured 20 mixed anisometropic amblyopes (10 with myopic anisometropia and 10 with hyperopic anisometropia) and demonstrated the same findings as Yoon et al. ²¹ However, Dickmann et al. ¹⁶ did not separate myopic from hyperopic anisometropic amblyopia nor report the macular thickness in each group. Furthermore, only foveal volume and macular thickness were reported in their study, without a breakdown of macular thickness by region. If the macular thickness values were the average of all macular regions, their study would have the same limitations as the study by Yoon et al. ²¹ In the Sydney Childhood Eye Study, Huynh et al. ¹⁵ tested 53 amblyopes with either strabismus or hyperopic anisometropia and reported that amblyopic eyes had greater foveal minimum thickness and a thinner inner macular ring than the normal fellow eyes. This is consistent with our findings, although in our study the outer macula was also thinner in the amblyopic eyes compared to the normal fellow eyes. Leone et al. ²⁷ reviewed the literature on measuring macular thickness in amblyopes and proposed that increased macular thickness found by several studies may be due to inadvertent measurement of a parafoveal eccentric point in amblyopia. To address this issue, central fixation was confirmed in each subject in our study by ensuring the location of the foveal depression at the center of the macular scan. Therefore, off-foveal fixation was highly unlikely in our study. 

Several studies specifically investigated macular thickness in strabismic amblyopia, and the results of these studies were contradictory. ^16,17,20 With 14 strabismic amblyopes, Altintas et al. ¹⁷ found no statistically significant difference in macular thickness between the amblyopic and fellow eyes though the reported average difference in foveal thickness was as high as 20 μm. Small subject numbers may have contributed to the lack of statistical significance. Dickmann et al. ¹⁶ studied macular thickness using OCT in 20 strabismic amblyopes and concluded that those with strabismic amblyopia had greater foveal volume and macular thickness in the amblyopic eye than in the normal fellow eye. Kee et al. ²⁰ compared 15 anisometropic amblyopes to six strabismic amblyopes and found strabismic amblyopes had thicker average foveae than anisometropic amblyopes. In our study, we compared macular thickness in purely myopic anisometropic amblyopia to that in combined-mechanism amblyopia (myopic anisometropia and strabismus) and did not find any significant difference in macular thickness between those two groups, which suggests that strabismus as an additional factor in myopic anisometropic amblyopia may not be a significant contributor to the changes in macular thickness. 

It is well established that amblyopia has a deleterious effect on both the cell growth of the lateral geniculate nucleus and the distribution of cortical neurons. ^{28 –30} However, possible involvement of the retina in amblyopia has been controversial. ^{31 –36} While several electrophysiological studies showed that pattern electroretinograms and electro-oculograms in amblyopic eyes were reduced compared with normal eyes, ^35,36 other studies have not concurred. ^33,34 With OCT, the retinal structure can be measured reliably. ^10,11 Huynh et al. ¹⁵ have proposed that arrest of normal postnatal changes in amblyopic eyes could affect the normal maturation of the macula, including movement of Henle's fibers away from the foveola, and result in an increased foveal thickness measured by OCT. Furthermore, they found that central macula and foveal minimum tended to be thicker in untreated compared to treated amblyopic eyes; thus, they suggested that the macular thickness changes occur after the onset of amblyopia. Liu et al. ¹⁹ reported that amblyopes who failed to achieve normal VA after treatment showed a thicker fovea. The amblyopia treatment history in our subjects varied from no previous treatment to noncompliance with past treatment. Thus, the effect of amblyopia treatment on macular thickness could not be evaluated in our study. To confirm whether the change in macular thickness in amblyopic eyes occurs before, concurrently with, or after the onset of amblyopia, a longitudinal study measuring macular thickness before and after the onset of amblyopia is needed. 

The association between myopia and macular thickness has been reported by several authors. ^{37 –42} Earlier studies reported myopia had no effect on macular thickness. ³⁷ More recent studies have shown that myopia, especially high myopia (<−5.00 D), was associated with macular thickness change. ^{38 –42} Luo et al. ⁴⁰ found that outer macular thickness was thinner in moderate myopia compared to both low myopia and non-myopia; however, they did not find any difference in either the foveal or inner macular thickness among no, low, and moderate myopia. Lam et al. ⁴² reported a thicker fovea and thinner outer macula associated with myopia but no change in inner macular thickness comparing myopia (including low, moderate, and high myopia) to non-myopia. Wu et al. ³⁸ found a thicker fovea and thinner inner and outer macular in high myopia than non-myopia. Furthermore, they postulated that mechanical stretching of the sclera resulting from increased axial length in myopia was the underlying mechanism of a shallow fovea and a thinner peripheral macula. If myopia were associated with a shallow fovea, foveal morphology of myopes would be expected to be different from that of emmetropes. However, Dubis et al. ⁴³ studied foveal pit morphology in 22 myopes and 39 emmetropes. They found no difference in foveal depth, diameter, and slope between those two groups. We have attempted to enroll age-matched control children who had bilateral equal, high myopia, and were non-amblyopic (VA of 20/25 or better) with the myopia magnitude matching that of our amblyopic subjects (mean refractive error, −10.79 D). However, within a two-year period, only two control subjects were identified. Thus, we were not able to determine whether macular characteristics in our amblyopes with unilateral high myopia were due to amblyopia, high myopia, or a combination of the two. It is our assumption that if myopia were the major reason for the differences in macular thickness, we would not expect our findings to have concurred with those in the Sydney Childhood Eye Study, since the refractive error in their subjects' amblyopic eyes was hyperopic (∼+2.00 D). ¹⁵ Nonetheless, further studies are needed to identify the underlying mechanism for macular anomalies in amblyopic children with unilateral high myopia. 

To the best of our knowledge, this is the first study to measure the macular thickness in amblyopia associated with unilateral high myopia. In conclusion, we found a thicker central macula and thinner peripheral macula in the amblyopic eyes with high myopia compared to the normal fellow eyes. The findings in the present study may help clinicians and scientists to understand the pattern of regional variations in macular thickness in amblyopia with unilateral high myopia. Future study is warranted to determine whether the mechanism of the macular changes is due to high myopia, amblyopia, or both, and to determine whether the macular anomalies in amblyopia can be modified by amblyopia treatment. 

Footnotes

 Presented in part at the annual meeting of the Association for Research in Vision and Ophthalmology, Fort Lauderdale, Florida, May 2009.

Footnotes

 Supported by the Illinois Society for the Prevention of Blindness, CIBA Vision, and Illinois College of Optometry Faculty Research Fund.

Footnotes

 Disclosure: Y. Pang, None; G.W. Goodfellow, None; C. Allison, None; S. Block, None; K.A. Frantz, None

The authors thank Rebecca Tudor for her assistance in performing OCT on all subjects in this study and Ruth Trachimowicz for her helpful comments and suggestions. The authors also thank Li Deng at the New England College of Optometry and Susan Kelly at the Illinois College of Optometry for their advice on statistical analysis.