Amblyopia is sub-normal visual acuity (VA) in one or both eyes that cannot be improved by optical correction in the absence of any organic disease.1 Amblyopia can be caused by strabismus, anisometropia, or deprivation early in life.2 Deprivation is known to have the strongest potential of all amblyogenic conditions.3 Structural changes in amblyopic eyes compared to control eyes have been the focus of many studies.4,5 Bilateral structural change in amblyopic patients has also been described with decreased contrast sensitivity function and the evidence of macular scotomata in fellow nonamblyopic eyes.4,5
With the advent of optical coherence tomography (OCT) in ophthalmology, there have been numerous attempts to investigate the structural differences in the macular and peripapillary retinal nerve fiber layer (RNFL) in amblyopic eyes.6–9 Recently, a number of studies have used OCT to evaluate macular thickness in amblyopic eyes; nonetheless, these studies were limited mostly to strabismic and anisometropic eyes.6–11 In addition, the majority of studies used the fellow nonamblyopic eyes as control. Studies focusing on OCT in deprivational amblyopia, per se, are very few: Kim et al. showed that macular thickness did not show any alterations in deprivational amblyopia compared to the fellow and control group.4
The present study is aimed at studying macular thicknesses at the central fovea and parafoveal locations using high-definition OCT in patients with deprivational amblyopia and comparing those measurements to those of matched controls.
Patients and Methods
This was a prospective, observational study conducted at the Department of Ophthalmology at the American University of Beirut Medical Center, Beirut, Lebanon, between October 2014 and October 2016. The study was approved by the institutional review board and adhered to the tenets of the Declaration of Helsinki. Informed assent and consent were obtained from each patient and their parents/legal guardians, respectively. Patients between the ages of 4 years and 18 years identified with deprivational amblyopia from unilateral or bilateral pediatric cataract and who had undergone cataract extraction with or without intraocular lens (IOL) implantation were approached. Patients with a history of glaucoma, retinal disease, or any type of retinal laser treatment, as well as patients not cooperative for OCT examination because of poor vision, were excluded from the study. A control group of 20 right eyes of 20 age-and gender-matched healthy subjects was created from the database of a previous study and had the same study protocol.12
All surgeries were performed by the same experienced pediatric ophthalmologist (CA). Under general anesthesia, an anterior chamber maintainer was inserted at the limbus inferotemporally and a superior limbal incision was performed for surgery. Using the vitrector (Stellaris; Bausch + Lomb, Rochester, NY), an anterior vitrectorhexis was fashioned followed by cortical aspiration, posterior capsulotomy, and limited anterior vitrectomy. In patients older than 1 year of age, primary IOL implantation was performed using the AcrySof SA60AT (Alcon; Fort Worth, TX) injectable single-piece lens before the posterior capsulotomy. In these cases, a pars plana incision would be performed to complete the posterior capsulotomy after IOL placement in the capsular bag. In one patient, a secondary IOL (AcrySof MA60BM; Alcon, Fort Worth, TX) was implanted in the ciliary sulcus. No patients required reoperation.
All patients underwent a comprehensive ophthalmologic examination. This included best-corrected VA measured on an ETDRS chart at 6 meters (and converted to logarithm of the minimal angle of resolution [logMAR] values for data analysis), extraocular motility testing, intraocular pressure measurement, fundus examination, and cycloplegic retinoscopy performed 30 minutes after pupil dilation with cyclopentolate 1% and mydriacyl 1% eye drops (instilled twice 10 minutes apart), reported as spherical equivalent (SE) refraction for analysis. Axial length (AL) measurements were obtained using the IOL Master Optical Biometer (Carl Zeiss AG, Oberkochen, Germany). Multiple AL measurements (at least three) were taken, and an average value was recorded.
Optical Coherence Tomography
After pupillary dilation, OCT images were obtained on each eye using the Cirrus 4000 high-definition spectral-domain optical coherence tomography (HD-OCT) (Cirrus HD-OCT; Carl Zeiss Meditec, Dublin, CA) by an experienced operator masked to the patient diagnosis. Two macular HD single-line enhanced-depth imaging scans in the horizontal and vertical directions were taken. Only good-quality scans defined as a signal strength of at least six and adequate foveal centration were considered. All HD scans were converted to grayscale for better visualization of the retinal layers at the fovea.
Two independent raters, blinded as to whether the eye being analyzed was amblyopic, manually measured the central foveal and parafoveal thicknesses using the software caliper to determine the distance between the inner aspect of the internal limiting membrane (ILM) and the outer aspect of the retinal pigment epithelium (RPE). The ILM-RPE distance was assessed at the central foveal area (corresponding to the shallowest part of the macular pit), referred to as central macular thickness (CMT), and at 500 μm, 1,000 μm, and 1,500 μm away from the center in each of the nasal, temporal, inferior, and superior directions (Figure 1). The measurements of the two raters were then averaged after confirming good inter-observer agreement.
High-definition optical coherence tomography of the macula demonstrating the measurements (red) at the studied locations (white) on the horizontal scan
All statistical analyses were performed using GraphPad Prism version 7.0b (GraphPad Software, La Jolla, CA). The results were reported as mean ± standard deviation (SD). Interobserver agreement was evaluated with intraclass correlation coefficients and corresponding 95% confidence intervals (CI). Data normality was assessed by the D'Agostino-Pearson Omnibus K2 and Kolmogorov-Smirnov tests. Unpaired Student's t-test or Mann-Whitney U test was used to compare amblyopic to control eyes according to the data normality. Additionally, the significance of the correlation between the CMT in amblyopic eyes and age, gender, VA, refractive error, and AL was determined by the Pearson or Spearman correlation coefficients. A P value of less than .05 was considered to be statistically significant.
Thirty-four eyes of 29 subjects met our inclusion criteria, with 20 eyes from 20 controls and 14 eyes from nine patients with deprivational amblyopia. In the amblyopic group, mean age was 10.06 years ± 3.89 years, and four (44.44%) were male. The mean age at surgery was 4.64 years ± 4.31 years (range: 18 days to 12.24 years). Nine eyes had congenital cataracts, four eyes had developmental cataracts, and one eye had a traumatic cataract. The cataracts were nuclear in 10 eyes and posterior subcapsular in four eyes. Twelve eyes had primary IOL implanted during surgery, one eye had secondary IOL at a later stage, and one eye remained aphakic after cataract extraction. The patients had their OCT examination after a mean of 5.42 years ± 2.38 years from the surgery (range: 1.62 years to 8.50 years). The age- and gender-matched control group consisted of 20 right eyes from 20 patients (10 males), with a mean age of 8.96 years ± 1.89 years (Table 1). Mean logMAR visual acuity was 0.41 ± 0.53 in the amblyopic eyes and 0.03 ± 0.05 in the control eyes (P = .0028). Mean SE was −1.93 diopters (D) ± 5.01 D in the amblyopic eyes and −0.37 D ± 1.55 D in the control eyes (P = .0044). Mean AL was significantly smaller in amblyopic eyes compared to control (22.18 mm ± 0.71 mm and 23.26 mm ± 0.99mm, respectively, P = .035). Interobserver agreement for single measures absolute values was high (intraclass coefficient = 0.92; 95% CI, 0.77–0.97).
Demographic Characteristics of Study Patients and Eyes
Table 2 and Figure 2 show the thickness of the retina measured at the 13 locations for each of the amblyopic and control eyes. In amblyopic eyes, there was significant thickening of the ILM-RPE at the central fovea compared to control eyes (224.86 μm ± 34.07 μm vs. 217.80 μm ± 19.41 μm, respectively; P = .013). Albeit nonsignificant, compared to control eyes, there was a trend toward a thicker retina in amblyopic eyes in the 500 μm juxtafoveal location in each of the nasal, temporal, inferior, and superior directions. In contrast, at the 1,000 μm and 1,500 μm parafoveal areas, the amblyopic retina tended to be thinner than that of the control eyes, showing an overall steeper parafoveal descent on OCT (Figure 2).
Mean ± SD (μm) of Central and Paracentral Macular Retinal Thicknesses in Amblyopic and Control Eyes
Mean (± standard deviation) macular thicknesses of amblyopic and control eyes in the horizontal (A) and vertical (B) scans.
Assessing the correlation of the CMT of amblyopic eyes with each of gender, age, VA, SE, and AL, there was a high negative correlation with female gender (r = −0.69; 95% CI, −0.90 to −0.24; P = .011) and positive correlation with logMAR VA and SE refraction (r = 0.62; 95%CI, 0.13–0.87; P = .018 and r = 0.56; 95% CI, 0.030–0.85; P = .038, respectively). No significant correlation was found between CMT and AL in either amblyopic or control eyes. Therefore, the fovea was thicker in male patients, and those with more hyperopic SE and worse VA. However, age was not significantly correlated with the central foveal thickness in these eyes (r = −0.39; 95% CI, −0.76–0.18; P = .17).
When dividing eyes with deprivational amblyopia according to amblyopia severity based on a best-corrected Snellen VA cutoff of 20/40, seven of the 14 eyes (50%) had a VA better than 20/40. In those amblyopic eyes that achieved good VA, the retina tended to be thinner at all 13 locations as compared to amblyopic eyes with visual acuity of 20/40 or worse (Figure 3). The differences were statistically significant only in the superior quadrant, at each of the 500 μm, 1,000 μm, and 1,500 μm locations (P = .038, P = .019, and P = .012, respectively).
Mean (± standard deviation) macular thicknesses of amblyopic eyes with good compared to poor visual acuity.
The present study evaluated central macular and parafoveal thicknesses on HD-OCT in eyes affected with deprivational amblyopia due to pediatric cataracts compared to age-matched controls. It affirmed a significantly thicker fovea in amblyopic eyes compared to matched normal controls. A trend was seen in all quadrants of increased thickness at the 500 μm location and decreased thickness at the 1,000 μm and 1,500 μm location among amblyopic eyes. Gender, VA, and refractive errors were statistically significantly correlated with the central thickness.
With the advent of OCT use in ophthalmology, many attempts were carried out to search for structural differences in the macula of eyes affected with amblyopia in general and to a much lesser extent with deprivational amblyopia.6,9–11,13,14 To our knowledge, only one similar study by Kim et al. was performed evaluating peripapillary RNFL and macular thickness on OCT in pediatric patients (mean age 7.21 years ± 2.46 years) with unilateral congenital cataracts who underwent cataract surgery.4 They found no significant differences comparing CMT in eyes with deprivational amblyopia to control eyes, although the former tended to have an increased CMT.4 However, they used the 200 μm × 200μm macular cube scan and its automated central, inner, and outer (nasal, temporal, superior, and inferior) macular thicknesses, in contrast to our measurements using HD-OCT single line scans. Although they also investigated the influence of the severity of amblyopia among other factors, they did so only on the nasal peripapillary RNFL (which was significantly increased in amblyopes in their study) but found no significant association.
Previous studies investigating macular thickness in amblyopia demonstrated that the inner quadrant of the macula tended to be thicker among affected eyes.6,13 We showed a similar trend at the central and 500 μm parafoveal locations. This could suggest signs of immaturity of the amblyopic fovea as compared to controls, as observed in our earlier works on anisometropic and strabismic amblyopia.13,14 It seems amblyopia due to deprivation results in similar quantitative and qualitative changes in the foveal center. Maldonato et al. reported several signs of foveal immaturity in neonates, including a shallow foveal pit and a thin photoreceptor layer at the foveal center, with persistence of the inner retinal layers in the fovea of immature neonates compared with adults.15 We noted similar findings in amblyopic eyes and believe that foveal immaturity could represent the primary change in amblyopia rather than a quantitative consequence of retrograde axonal degradation. In fact, after stratification by severity of amblyopia, we found a thicker macula among patients with worse VA in agreement with the above argument, yet other studies reported no significant differences comparing amblyopic eyes to normal controls.6,9,16 Our results are also in agreement with our previous study that amblyopic eyes had a flatter central configuration with attenuation of the “classic” foveal contour over the 500 μm area around the foveal pit. Interestingly, however, the amblyopic retina tapers more rapidly farther away from the central fovea while keeping a foveal-to-parafoveal thickness ratio greater than that of control eyes.13
Retinal and macular thicknesses are known to vary with gender, with women tending to have thinner retinas according to earlier studies.12,17–19 We found similar results, with female gender significantly associated with a thinner central macula. A more hyperopic refractive error and logMAR VA were also positively correlated with CMT, which was reported in several other studies.20,21 Whereas eyes with more myopic SE and longer AL are known to have a thinner retina,22,23 in our series, amblyopic eyes had a thicker fovea despite a mean SE of −1.93 D ± 5.01 D; however, amblyopic eyes had a shorter anteroposterior diameter as well, which could represent a potential confounder. In agreement with others, we also found that positive SE of amblyopic eyes was significantly associated with increased CMT. Our study showed no correlation between age and macular thickness; this can be attributed to the fact that our age range was limited, with most of our study population being either young or adolescent (range: 4 years to 18 years), and thus age did not influence OCT readings. Interestingly, there was no correlation between AL and CMT in both amblyopic and control eyes, but this could be due to our study's limited sample size.
Our study limitations include the small sample size, due to the rarity of deprivational amblyopia and the younger age of those patients. Thus, further studies with a larger sample size should be undertaken. In addition, the majority of our study patients had to be old enough to cooperate with OCT testing; the younger preverbal and uncooperative children had to be excluded. However, with the development of portable OCT machines, this may be circumvented. Many of our patients were tested at an older age and, thus, it would be difficult to relate the OCT changes to a certain age or to extrapolate them longitudinally. A prospective study following macular thickness on OCT of patients with amblyopia before and after treatment would potentially directly resolve the relation between the severity of amblyopia and macular thickness. Lastly, because of the rarity of the condition, our inclusion of both eyes of patients with bilateral deprivational amblyopia could present another limitation, but repeating the same analysis while selecting the more amblyopic eye of the patients with bilateral amblyopia yielded similar non-significant results.
In conclusion, our study is one of a few on the topic of retinal changes on OCT in the rare condition of deprivational amblyopia. It demonstrated that CMT was significantly increased among amblyopic eyes compared to control eyes and this correlated with the severity of amblyopia. Parafoveal thicknesses at 500 μm in all four quadrants showed a similar increase and those at 1,000 μm and 1,500 μm showed a decrease but without statistical significance. Male gender, poor VA, and hyperopic refractive errors were positively correlated with CMT.
- von Noorden GK. Amblyopia: A multidisciplinary approach. Proctor lecture. Invest Ophthalmol Vis Sci. 1985;26(12):1704–1716.
- von Noorden GK. Classification of amblyopia. Am J Ophthalmol. 1967;63(2):238–244. doi:10.1016/0002-9394(67)91543-7 [CrossRef]
- Wiesel TN, Hubel DH. Effects of visual deprivation on morphology and physiology of cells in the cat's lateral geniculate body. J Neurophysiol. 1963;(26):978–993. doi:10.1152/jn.19184.108.40.2068 [CrossRef]
- Kim YW, Kim SJ, Yu YS. Spectral-domain optical coherence tomography analysis in deprivational amblyopia: A pilot study with unilateral pediatric cataract patients. Graefes Arch Clin Exp Ophthalmol. 2013;251(12):2811–2819. doi:10.1007/s00417-013-2494-1 [CrossRef]
- Leguire LE, Rogers GL, Bremer DL. Amblyopia: The normal eye is not normal. J Pediatr Ophthalmol Strabismus. 1990;27(1):32–38; discussion 39.
- Huynh SC, Samarawickrama C, Wang XY, et al. Macular and nerve fiber layer thickness in amblyopia: The Sydney Childhood Eye Study. Ophthalmology. 2009;116(9):1604–1609. doi:10.1016/j.ophtha.2009.03.013 [CrossRef]
- Yen MY, Cheng CY, Wang AG. Retinal nerve fiber layer thickness in unilateral amblyopia. Invest Ophthalmol Vis Sci. 2004;45(7):2224–2230. doi:10.1167/iovs.03-0297 [CrossRef]
- Repka MX, Goldenberg-Cohen N, Edwards AR. Retinal nerve fiber layer thickness in amblyopic eyes. Am J Ophthalmol. 2006;142(2):247–251. doi:10.1016/j.ajo.2006.02.030 [CrossRef]
- Kee SY, Lee SY, Lee YC. Thicknesses of the fovea and retinal nerve fiber layer in amblyopic and normal eyes in children. Korean J Ophthalmol. 2006;20(3):177–181. doi:10.3341/kjo.2006.20.3.177 [CrossRef]
- Altintas O, Yüksel N, Ozkan B, Caglar Y. Thickness of the retinal nerve fiber layer, macular thickness, and macular volume in patients with strabismic amblyopia. J Pediatr Ophthalmol Strabismus. 2005;42(4):216–221.
- Quoc EB, Delepine B, Tran THC. [Thickness of retinal nerve fiber layer and macular volume in children and adults with strabismic and anisometropic amblyopia]. J Fr Ophtalmol. 2009;32(7):488–495. doi:10.1016/j.jfo.2009.06.002 [CrossRef]
- Al-Haddad C, Barikian A, Jaroudi M, Massoud V, Tamim H, Noureddin B. Spectral domain optical coherence tomography in children: Normative data and biometric correlations. BMC Ophthalmol. 2014;14:53. doi:10.1186/1471-2415-14-53 [CrossRef]
- Al-Haddad CE, El Mollayess GM, Mahfoud ZR, Jaafar DF, Bashshur ZF. Macular ultrastructural features in amblyopia using high-definition optical coherence tomography. Br J Ophthalmol. 2013;97(3):318–322. doi:10.1136/bjophthalmol-2012-302434 [CrossRef]
- Al-Haddad CE, Mollayess GMEL, 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(12):1696–1699. doi:10.1136/bjo.2010.195081 [CrossRef]
- Maldonado RS, O'Connell R V, Sarin N, et al. Dynamics of human foveal development after premature birth. Ophthalmology. 2011;118(12):2315–2325. doi:10.1016/j.ophtha.2011.05.028 [CrossRef]
- Xu J, Lu F, Liu W, Zhang F, Chen W, Chen J. Retinal nerve fibre layer thickness and macular thickness in patients with esotropic amblyopia. Clin Exp Optom. 2013;96(3):267–271. doi:10.1111/cxo.12001 [CrossRef]
- Aguirre F, Mengual E, Hueso JR, Moya M. Comparison of normal and amblyopic retinas by optical coherence tomography in children. Eur J Ophthalmol. 20(2):410–418.
- Wang XM, Cui DM, Zhen L, et al. Characteristics of the macula in amblyopic eyes by optical coherence tomography. Int J Ophthalmol. 2012;5(2):172–176.
- Adhi M, Aziz S, Muhammad K, Adhi MI. Macular thickness by age and gender in healthy eyes using spectral domain optical coherence tomography. PLoS One. 2012;7(5):e37638. doi:10.1371/journal.pone.0037638 [CrossRef]
- Song AP, Wu XY, Wang JR, Liu W, Sun Y, Yu T. Measurement of retinal thickness in macular region of high myopic eyes using spectral domain OCT. Int J Ophthalmol. 2014;7(1):122–127.
- Hashimoto S, Yasuda M, Ninomiya T, et al. Foveal and macular thickness in a Japanese population: The Hisayama Study. Ophthalmic Epidemiol. 2016;23(3):202–208. doi:10.3109/09286586.2015.1136651 [CrossRef]
- Huynh SC, Wang XY, Rochtchina E, Mitchell P. Distribution of macular thickness by optical coherence tomography: Findings from a population-based study of 6-year-old children. Invest Ophthalmol Vis Sci. 2006;47(6):2351–2357. doi:10.1167/iovs.05-1396 [CrossRef]
- Song WK, Lee SC, Lee ES, Kim CY, Kim SS. Macular thickness variations with sex, age, and axial length in healthy subjects: A spectral domain-optical coherence tomography study. Invest Ophthalmol Vis Sci. 2010;51(8):3913–3918. doi:10.1167/iovs.09-4189 [CrossRef]
Demographic Characteristics of Study Patients and Eyes
|Amblyopic Eyes (n = 14)||Control Eyes (n = 20)||P Value|
|Gender (Male / Female)||4 / 5||10 / 10||—|
|Eyes (Left / Right)||8 / 6||20 / 0||—|
|Age (Mean ± SD, Years)||10.06 ± 3.89||8.96 ± 1.89||.45|
|Visual Acuity (Mean ± SD, logMAR)||0.41 ± 0.53||0.03 ± 0.05||.0028|
|Spherical Equivalent (Mean ± SD, D)||−1.93 ± 5.01||−0.37 ± 1.55||.0044|
|Axial Length (Mean ± SD, mm)||22.18 ± 0.71||23.26 ± 0.99||.035|
Mean ± SD (μm) of Central and Paracentral Macular Retinal Thicknesses in Amblyopic and Control Eyes
|Location||Amblyopic Eyes (n = 14)||Control Eyes (n = 20)||P Value|
|Central Macula||224.86 ± 34.07||217.80 ± 19.41||.013|
|Nasal||500 μm||294.07 ± 28.15||291.90 ± 24.03||.81|
|1,000 μm||339.86 ± 33.64||344.65 ± 18.84||.60|
|1,500 μm||332.79 ± 40.59||346.35 ± 17.22||.19|
|Temporal||500 μm||293.21 ± 32.04||287.25 ± 22.16||.53|
|1,000 μm||324.50 ± 36.01||329.70 ± 17.00||.65|
|1,500 μm||311.43 ± 45.82||322.35 ± 13.35||.32|
|Inferior||500 μm||306.29 ± 29.70||302.45 ± 28.20||.86|
|1,000 μm||338.21 ± 35.30||351.25 ± 18.87||.47|
|1,500 μm||312.21 ± 38.95||338.70 ± 17.07||.013|
|Superior||500 μm||316.36 ± 29.02||307.70 ± 23.98||.35|
|1,000 μm||346.71 ± 36.82||355.15 ± 18.79||.90|
|1,500 μm||328.29 ± 41.24||340.45 ± 20.21||.88|