Amblyopia is defined as low visual acuity in one or both eyes associated with the presence of strabismus, anisometropia, or deprivation during the critical period of visual development.1 Decreased visual input from the amblyopic eye might lead to significant changes in the visual pathway, including the visual cortex, the lateral geniculate nucleus, and the retina. Amblyopia is generally attributed to abnormal development of the visual cortex.
Experimentally induced blurring during development was shown to cause a selective loss of neurons in the visual cortex and experimentally induced strabismus disrupted binocular connections of cortical neurons.2 Histologic study of the lateral geniculate nucleus of monkeys with strabismic, anisometropic, and visual deprivation amblyopia revealed a marked shrinkage of cells that receive input from the amblyopic eye.3,4 Similar results in the lateral geniculate nucleus in human anisometropic amblyopia5 and strabismic amblyopia6 have been reported.
Retinal involvement in the amblyopic eye is controversial. Ikeda and Tremain7 reported that in a group of cats reared with convergent strabismus without alternating fixation, sustained-X cells in the area centralis of the squinting eye showed significantly poorer spatial resolution and reduced contrast sensitivity compared with cells in the area centralis of the normal eye. On the contrary, Cleland et al.8 did not find any deficit in the spatial resolution of retinal ganglion cells in cats with strabismic amblyopia. Several experiments have shown retinal ganglion cell loss,9 mean nucleolar volume diminution, and internal plexiform layer thinning after light deprivation in rats and cats.10 Von Noorden et al. reported a decrease in size and density of parafoveal retinal ganglion cells after long-term (24 months) visual deprivation by performing unilateral eyelid suture in Macaca mulatta.11 Arden and Wooding12 reported reduced pattern electroretinogram results in amblyopic participants, whereas Hess et al.13 observed no change when factors such as optical focus, fixation alignment, and fixation stability had been individually optimized.
Optical coherence tomography (OCT) uses a scanning interferometer and a near-infrared (820 nm) light beam to obtain cross-sectional retinal images with an axial resolution of 10 μm depending on the optical reflectivity of each retinal structure.14 Typically, retinal nerve fiber layer (RNFL) thickness is measured by using a circle centered on an optic disc with a diameter of 3.46 mm. An algorithm in the commercial software estimates the boundaries of RNFL and RNFL thickness using the reflected light beam. Using OCT, some studies found no differences between the amblyopic and fellow eyes,15–21 whereas some found thicker RNFL in anisometropic amblyopic eyes.22,23
The purpose of this study was to compare the RNFL thickness measurements of strabismic eyes, anisometropic amblyopic eyes, and control eyes using OCT (OCT version 3.0; Zeiss Humphrey, Dublin, CA).
Patients and Methods
This study was performed on 40 healthy children and 65 children who were diagnosed as having either strabismus or anisometropic amblyopia. Clinical examinations included best-corrected visual acuity, refraction error, slit-lamp examination, extraocular movements, intraocular pressure, and funduscopy. Patients with a neurological disease or ocular diseases such as glaucoma, nystagmus, and peripapillary chorioretinal atrophy and patients who were too young to cooperate were excluded from the study.
Amblyopia was defined as interocular best-corrected visual acuity difference of 2 or more lines using Snellen chart at 6 meters. Anisometropia was defined as a spherical equivalent difference between the two eyes of 2 diopters (D) or more, and with no heterotropia in the alternate cover test. The anisometropic group included myopic and hypermetropic anisometropic amblyopic participants. Patients with interocular astigmatism difference of more than 1 D were excluded from the study. Strabismic amblyopes had esotropia or exotropia of at least 10 prism D in the alternate cover test and a spherical difference between the two eyes of less than 1 D. Informed consent was obtained from the parents of the 105 children.
OCT images were obtained using time-domain OCT after pupillary dilatation with 1% cyclopentolate hydrochloride. Fast RNFL scan protocol comprised three peripapillary scans, each consisting of 256 test points measured along a circle having a nominal diameter of 3.46 mm centered on the optic disc. To ensure high quality of RNFL images, at least three scans were taken and the one with best centration, focus, and higher signal was used for analysis. The instrument software calculates average thickness values from the three scans for each quadrant (superior, nasal, inferior, and temporal), each clock hour, and average RNFL.
SPSS software version 16.0 (SPSS, Inc., Chicago, IL) was used for statistical analyses. Analysis of variance was used to compare the differences between the three groups. Paired sample t test or Wilcoxon signed rank test were used to determine whether differences between values of the amblyopic eyes and nonamblyopic eyes were significant. The correlation between RNFL and refraction was evaluated using nonparametric Spearman correlation coefficient. A P value less than .05 was considered statistically significant.
The control group included 40 healthy subjects (20 boys, 20 girls) with a mean age of 12.42 ± 4.0 years (range: 5 to 18 years), the strabismic group included 15 boys and 20 girls with a mean age of 11.34 ± 4.53 years (range: 6 to 18 years), and the anisometropic group included 16 boys and 14 girls, with a mean age of 12.87 ± 4.4 years (range: 5 to 18 years). There were no differences according to age and gender among the three groups (P = .33 and .68, respectively). The spherical equivalent refraction ranged between +1.50 and +8.50 D in the hypermetropic anisometropic group (n = 22), −1.50 and −6.50 D in the myopic anisometropic group (n = 8), and −1.00 and +1.00 D in the strabismic group. The control group included emmetropic subjects. In the strabismic group, none of the RNFL thickness parameters differed between the amblyopic eyes and fellow eyes (P > .05) (Table 1). In the hyperopic anisometropic group, only temporal RNFL thickness was lower in amblyopic eyes (66.32 ± 16.84 μm) compared to their fellow eyes (71.23 ± 15.00 μm) (P = .03) (Table 1), whereas in the myopic anisometropic group, there were no significant inter-eye differences in RNFL thickness parameters except superior RNFL thickness, which was significantly lower in the amblyopic eyes (112.12 ± 18.54 μm) than their fellow eyes (123.12 ± 20.85 μm) (P = .05) (Table 1). RNFL thickness parameters did not differ between the amblyopic eyes and the right eyes of the control subjects (P > .05). Using the nonparametric Spearman correlation coefficient, RNFL measurements showed a significant correlation with spherical equivalent in the anisometropic group (Table 2, Figure 1).
Table 1: Retinal Nerve Fiber Layer Thickness in the Three Groups
Table 2: Relationship Between Optical Coherence Tomography Parameters and the Spherical Equivalence of the Amblyopic Eye
Figure 1. Relationship between spherical equivalence and average retinal nerve fiber layer (RNFL) thickness in the anisometropic group.
Peripapillary RNFL may be examined objectively and quantitatively with imaging technologies including scanning laser polarimeter and OCT. Baddini-Caramelli et al.24 and Colen et al.25 measured the RNFL thickness of patients with unilateral strabismic amblyopia using scanning laser polarimetry and reported no differences in RNFL measurements between amblyopic and normal eyes. In a study performed on anisometropic, strabismic, and combined amblyopic eyes using the GDx Nerve Fiber Analyzer (Carl Zeiss Meditec, Inc., Dublin, CA), Bozkurt et al.26 found no differences in the retardation measurements of the RNFL between amblyopic and normal eyes.
Using OCT, Altintas et al.15 found no differences in the thickness of the RNFL between the amblyopic and nonamblyopic eyes in a small group of subjects with strabismus. Kee et al.17 found no significant differences in RNFL thickness between the amblyopic eyes and their fellow eyes or healthy children, but RNFL was found to be thicker in eyes with anisometropic amblyopia than in eyes with strabismic amblyopia. In the Sydney Childhood Eye Study,18 65 of 4,118 children (1.8%) had amblyopia. They found no significant differences in RNFL measurements among amblyopic eyes, fellow eyes, or normal eyes of healthy children. Using OCT, Walker et al.21 reported that no significant difference was found in peripapillary RNFL thickness between the amblyopic eyes and fellow eyes in adult amblyopic patients. Miki et al.19 evaluated 26 patients with persistent amblyopia and 25 patients who had recovered from amblyopia and showed that there were no differences in RNFL thickness measurements between the affected and fellow eyes. In a recent study performed on 14 strabismic, 31 anisometropic amblyopic, and 20 nonamblyopic anisometropic patients, no statistically significant differences were found between the amblyopic eyes and the fellow eyes using spectral-domain OCT.20
Contrary to the above-mentioned studies, Yen et al.22 studied 18 patients with refractive amblyopia, 20 patients with strabismic amblyopia, and 17 patients with anisometropia without amblyopia using OCT and found that mean RNFL thickness of the amblyopic eyes (142.2 ± 18.6 μm) was thicker than their fellow eyes (129.7 ± 18.5 μm) in patients with refractive amblyopia. They suggested that the process of postnatal reduction of ganglion cells requires sharply focused objects as appropriate stimuli and refractive amblyopia affects the process of postnatal reduction of ganglion cells so the RNFL thickness measured thicker than the normal eye. Similar to this study, Yoon et al.23 reported that RNFL thickness in amblyopic eyes was significantly thicker than in normal eyes in subjects with hyperopic anisometropic amblyopia.
In this study, we showed no differences in average RNFL thickness measurements between amblyopic eyes and fellow eyes. Only temporal RNFL thickness parameter in hyperopic anisometropia and superior RNFL thickness parameter in myopic anisometropia were found to be significantly lower in the amblyopic eyes compared to the nonamblyopic eyes. In the anisometropic group, mean RNFL thickness showed a significant correlation with refraction.
In the anisometropic group, we believe that the thinning of the RNFL is related to myopia rather than to amblyopia. Budenz et al.27 reported that larger and more myopic eyes had a statistically lesser mean RNFL thickness. One possibility is that OCT measurements affected optically by greater axial length and higher myopia produced apparently thinner RNFL as an artifact. Another possibility is that using fixed scan circle may be associated with false thinner RNFL thickness in a larger optic disc associated with myopia and with false thicker RNFL thickness in a small optic disc associated with hypermetropia. Further studies taking into account the optic disc size and not using fixed scan circle should be performed for measuring RNFL thickness.
Amblyopia is not associated with a decrease in RNFL thickness in strabismic or anisometropic amblyopia. In the anisometropic group, the inter-eye differences in RNFL thickness parameters seem to be related to the refraction differences between the amblyopic and fellow eyes.
- von Noorden GK. Classification of amblyopia. Am J Ophthalmol. 1967;63:238–244.
- Kiorpes L, Kiper DC, O’Keefe LP, Cavanaugh JR, Movshon JA. Neuronal correlates of amblyopia in the visual cortex of macaque monkeys with experimental strabismus and anisometropia. J Neurosci. 1998;18:6411–6424.
- von Noorden GK. Histological studies of the visual system in monkeys with experimental amblyopia. Invest Ophthalmol. 1973;12:727–738.
- von Noorden GK, Middleditch PR. Histology of the monkey lateral geniculate nucleus after unilateral lid closure and experimental strabismus: further observations. Invest Ophthalmol. 1975;14:674–683.
- von Noorden GK, Crawford ML, Levacy RA. The lateral geniculate nucleus in human anisometropic amblyopia. Invest Ophthalmol Vis Sci. 1983;24:788–790.
- von Noorden GK, Crawford ML. The lateral geniculate nucleus in human strabismic amblyopia. Invest Ophthalmol Vis Sci. 1992;33:2729–2732.
- Ikeda H, Tremain KE. Amblyopia occurs in retinal ganglion cells in cats reared with convergent squint without alternating fixation. Exp Brain Res. 1979;35:559–582 doi:10.1007/BF00236772 [CrossRef] .
- Cleland BG, Crewther DP, Crewther SG, Mitchell DE. Normality of spatial resolution of retinal ganglion cells in cats with strabismic amblyopia. J Physiol. 1982;326:235–249.
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- von Noorden GK, Crawford ML, Middleditch PR. Effect of lid suture on retinal ganglion cells in Macaca mulatta. Brain Res. 1977;122:437–444 doi:10.1016/0006-8993(77)90455-3 [CrossRef] .
- Arden GB, Wooding SL. Pattern ERG in amblyopia. Invest Ophthalmol Vis Sci. 1985;26:88–96.
- Hess RF, Baker CL Jr, Verhoeve JN, Keesey UT, France TD. The pattern evoked electroretinogram: its variability in normals and its relationship to amblyopia. Invest Ophthalmol Vis Sci. 1985;26:1610–1623.
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- Repka MX, Goldenberg-Cohen N, Edwards AR. Retinal nerve fiber layer thickness in amblyopic eyes. Am J Ophthalmol. 2006;142:247–251 doi:10.1016/j.ajo.2006.02.030 [CrossRef] .
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- Huynh SC, Samarawickrama C, Wang XY, et al. Macular and nerve fiber layer thickness in amblyopia: The Sydney Childhood Eye Study. Ophthalmology. 2009;116:1604–1609 doi:10.1016/j.ophtha.2009.03.013 [CrossRef] .
- Miki A, Shirakashi M, Yaoeda K, et al. Retinal nerve fiber layer thickness in recovered and persistent amblyopia. Clin Ophthalmol. 2010;4:1061–1064 doi:10.2147/OPTH.S13145 [CrossRef] .
- Al-Haddad CE, Mollayess GM, Cherfan CG, Jaafar DF, Bashshur ZF. Retinal nerve fibre layer and macular thickness in amblyopia as measured by spectral-domain optical coherence tomography. Br J Ophthalmol. 2011;95:1696–1699 doi:10.1136/bjo.2010.195081 [CrossRef] .
- Walker RA, Rubab S, Voll AR, Erraguntla V, Murphy PH. Macular and peripapillary retinal nerve fibre layer thickness in adults with amblyopia. Can J Ophthalmol. 2011;46:425–427.
- Yen MY, Cheng CY, Wang AG. Retinal nerve fiber layer thickness in unilateral amblyopia. Invest Ophthalmol Vis Sci. 2004;45:2224–2230 doi:10.1167/iovs.03-0297 [CrossRef] .
- Yoon SW, Park WH, Baek SH, Kong SM. Thicknesses of macular retinal layer and peripapillary retinal nerve fiber layer in patients with hyperopic anisometropic amblyopia. Korean J Ophthalmol. 2005;19:62–67 doi:10.3341/kjo.2005.19.1.62 [CrossRef] .
- Baddini-Caramelli C, Hatanaka M, Polati M, Umino AT, Susanna R Jr, . Thickness of the retinal nerve fiber layer in amblyopic and normal eyes: scannig laser polarimetry study. J AAPOS. 2001;5:82–84 doi:10.1067/mpa.2001.112678 [CrossRef] .
- Colen TP, de Faber JT, Lemij HG. Retinal nerve fiber layer thickness in human strabismic amblyopia. Binocul Vis Strabismus Q. 2005;15:141–146.
- Bozkurt B, Irkec M, Orhan M, Karaagaoglue E. Thickness of the retinal nerve fiber layer in patients with anisometropic and strabismic amblyopia. Strabismus. 2003;11:1–7 doi:10.1076/stra.22.214.171.12491 [CrossRef] .
- Budenz DL, Anderson DR, Varma R, et al. Determinants of normal retinal nerve fiber layer thickness measured by Stratus OCT. Ophthalmology. 2007;114:1046–1052 doi:10.1016/j.ophtha.2006.08.046 [CrossRef] .
Retinal Nerve Fiber Layer Thickness in the Three Groups
|Group||Amblyopic Eyes (μm)||Fellow Eyes (μm)||P|
| Superior||123.11 ± 22.55||120.94 ± 22.90||.52|
| Nasal||80.94 ± 22.18||74.77 ± 23.51||.33|
| Inferior||126.86 ± 26.41||127.03 ± 30.05||.96|
| Temporal||74.46 ± 21.18||75.86 ± 14.26||.28|
| Average thickness||101.34 ± 13.74||99.65 ± 15.22||.33|
| Superior||120.09 ± 25.75||127.32 ± 15.52||.38|
| Nasal||82.59 ± 24.98||82.00 ± 21.27||.86|
| Inferior||139.55 ± 21.92||132.45 ± 21.76||.08|
| Temporal||66.32 ± 16.84||71.23 ± 15.00||.03|
| Average thickness||102.16 ± 13.62||103.24 ± 10.10||.94|
| Superior||112.12 ± 18.54||123.12 ± 20.85||.05|
| Nasal||77.00 ± 19.06||78.75 ± 12.96||.73|
| Inferior||123.13 ± 18.64||135.75 ± 17.18||.07|
| Temporal||80.63 ± 18.65||79.00 ± 13.23||.50|
| Average thickness||98.12 ± 9.29||104.25 ± 9.53||.07|
Relationship Between Optical Coherence Tomography Parameters and the Spherical Equivalence of the Amblyopic Eye
|RNFL Thickness (μm)||Spherical Equivalence (D)|
|Hyperopic Anisometropic Group||Myopic Anisometropic Group|