**Purpose**:
The purpose of this study was to identify the relationship between aniseikonia scores in the vertical and horizontal meridians and the foveal microstructure on vertical and horizontal spectral-domain optical coherence tomography (SD-OCT) in patients with idiopathic epiretinal membrane (ERM).

**Methods**:
All patients (*n* = 65) with unilateral ERM were examined, and the aniseikonia scores in the vertical (VAS) and horizontal (HAS) meridians were determined using the New Aniseikonia Test. Vertical and horizontal images passing through the fovea were obtained by axial SD-OCT in both eyes. The thicknesses of the ganglion cell layer + inner plexiform layer, inner nuclear layer (INL), and outer retinal layer were measured on the SD-OCT images, and color histograms were analyzed using Photoshop software.

**Results**:
Of the 65 ERM patients, 81.5% (53 patients) had macropsia. The VAS and HAS were equal in 52.8% (28 patients). Multiple regression analysis revealed significant correlations between the VAS and vertical INL thickness (*R* = 0.388, *P* = 0.001) and between the HAS and horizontal INL thickness (*R* = 0.349, *P* = 0.001). The difference between VAS and HAS was proportional to the ratio of the vertical INL thickness to horizontal INL thicknesses (*R* = 0.370, *P* < 0.001).

**Conclusions**:
Eyes with ERM mostly presented macropsia. The aniseikonia scores in the vertical and horizontal meridians correlate well with INL thickness on the vertical and horizontal directions of SD-OCT images, respectively. Aniseikonia induced by ERM may be related to the INL thickening detected with SD-OCT.

^{1}Although previous study samples have been small, 78–100% of ERM patients reportedly have aniseikonia.

^{2–6}Aniseikonia is an ocular condition characterized by a significant difference between the eyes in the perceived size of images. ERM-induced aniseikonia is presumably due to compression or stretching forces that cause an abnormal distribution of the retinal receptors,

^{3}creating a perceived image that is larger or smaller in size. Recently, adaptive optics-scanning laser ophthalmoscopy (AO-SLO) of eyes with ERM showed microfolds in the foveal photoreceptor layer, suggesting shrinkage of the ERM might cause contraction in the photoreceptor layer, thus producing microfolds.

^{7}Patients with ERM exhibit more severe aniseikonia and are at greater risk of binocularity loss and developing asthenopia and impaired vision quality.

^{5}

^{8}The size of each eye's semicircle is adjusted until the shape is perceived as a perfect circle. The NAT presents two series of matched semicircles (vertical and horizontal) at random, and the aniseikonia scores are measured in the vertical and horizontal meridians. A recent study used the NAT to examine the relationship between the aniseikonia scores and retinal microstructures in patients with ERM.

^{6}However, only one report investigated the relationship between the aniseikonia scores and retinal microstructures, and the study only used the mean aniseikonia scores. In contrast, numerous studies have examined the relationship between metamorphopsia and ERM.

^{9–14}Furthermore, these studies measured the differing metamorphopsia between horizontal and vertical lines.

^{9–12}Metamorphopsia, which is a symptom described as perceived distortion of objects, is different from aniseikonia. However, both aniseikonia and metamorphopsia have a similar development mechanism, which reflects abnormal distribution of photoreceptors.

^{6}There is usually metamorphopsia, together with aniseikonia from retinal distortion caused by the ERM. Reportedly, the horizontal metamorphopsia scores increase according to ERM severity but do not change with the vertical metamorphopsia scores, and the horizontal metamorphopsia scores are significantly larger than the vertical metamorphopsia scores in advanced stages of ERM.

^{9}However, there are no known studies evaluating the correlation between the vertical meridian and horizontal meridian aniseikonia scores and the ERM microstructure.

^{15}Therefore, we investigated the difference in the aniseikonia scores between the horizontal and vertical meridians and the relationship between aniseikonia and ERM microstructures.

^{16}:

*J*

_{0}= −

*C*/2 × cos2α, where

*C*is negative cylindrical power and α is the cylindrical axis.

*J*

_{0}refers to cylinder power set at orthogonal 90 and 180 meridians, representing Cartesian astigmatism. This notation allows a direct comparison to be made of the subject's astigmatism separately for the horizontal and vertical meridians.

^{17}

**Figure 1**

**Figure 1**

*U*test. Univariate and stepwise multiple linear regression analyses were used to assess the relationship between possible influencing factors and vertical or horizontal aniseikonia scores. All variables with

*P*< 0.10 in the univariate analysis were included in the multiple regression model. Multicollinearity was evaluated among predictor variables by using the variance inflation factor. We used variance inflation factor >10 as a guide for exploring alternative models. The associations between the DAS and the ratio of the GCL + IPL, INL, and outer retinal layer thickness were evaluated using the Spearman rank correlation test. All tests of associations were considered statistically significant at

*P*< 0.05. The analyses were performed using SPSS version 18.0 for Windows (SPSS, Inc., Chicago, IL, USA).

**Table 1**

**Table 2**

*R*= 0.241,

*P*= 0.015), vertical INL thickness (

*R*= 0.333,

*P*= 0.001), horizontal GCL + IPL thickness (

*R*= 0.227,

*P*= 0.024), and horizontal INL thickness (

*R*= 0.231,

*P*= 0.021) on univariate analysis. The HAS also correlated with the vertical GCL + IPL thickness (

*R*= 0.217,

*P*= 0.030), vertical INL thickness (

*R*= 0.235,

*P*= 0.017), horizontal GCL + IPL thickness (

*R*= 0.193,

*P*= 0.046), and horizontal INL thickness (

*R*= 0.312,

*P*= 0.002) on univariate analysis. However, the aniseikonia score did not correlate with the vertical and horizontal outer retinal layer thicknesses (Table 2). Multiple linear regression analysis was performed using the vertical GCL + IPL thickness, vertical INL thickness, horizontal GCL + IPL thickness, and horizontal INL thickness as predictors. A significant positive correlation was seen between the VAS and vertical INL thickness (

*R*= 0.388,

*P*= 0.001) on multiple linear regression analysis, but no correlation was observed between the VAS and horizontal INL thickness. A positive correlation was also seen between the HAS and horizontal INL thickness (

*R*= 0.349,

*P*= 0.001) on multiple linear regression analysis, but not between HAS and vertical INL thickness. Our multicollinearity check did not reveal any problems, with all predictor variables in the multivariate models having a variance inflation factor < 3.

**Table 3**

**Figure 2**

**Figure 2**

^{2–6}The aniseikonia scores ranged from 2% to 19% in the present study, which is consistent with findings in previous reports.

^{2–6}The ERM with macular contraction is considered a representative macropsia disorder. Presumably, the compression caused by shrinkage of ERM results in a more packed distribution of retinal receptors; as a result, incoming light stimulates more receptors, and the image appears larger.

^{3,7}

^{6}Aniseikonia measured by computerized NAT was considered reproducible and reliable according to previous reports.

^{3,18}Validation studies of computerized NAT revealed 0.990 ± 0.005 horizontal and 0.991 ± 0.004 vertical correlation coefficients and 0.985 ± 0.111 horizontal and 0.989 ± 0.102 vertical slope, suggesting a small underestimation.

^{3}Yoshida et al.

^{18}also reported that the aniseikonia measured with the NAT was 1.4% less than when measured with the phase difference haploscope, with no significant difference in the horizontal and vertical directions. Previous reports suggest that the small NAT underestimation is clinically insignificant, and there is quite good agreement in the vertical and horizontal directions. Therefore, we suggest the NAT used in this study is a reliable method for measuring aniseikonia. We could not calibrate the NAT personally, however, lending a level of uncertainty to our NAT-determined aniseikonia score.

^{19,20}More than 2.0 D of anisometropia was excluded from the study to minimize anisometropia-induced aniseikonia. We believe aniseikonia was not related to the spherical equivalent or the difference of spherical equivalent between both eyes. To account for patients' astigmatism, we applied the vectorial notation of spherical-cylindrical refraction, but found no correlation between aniseikonia scores and astigmatism.

^{6}We also observed an association between vertical and horizontal INL thickness and vertical and horizontal aniseikonia scores, respectively. The consistency between this and a previous study suggests that the INL change may be one of the important etiologies of aniseikonia. We hypothesized how morphologic alterations mostly involving the INL could displace the structure of photoreceptors, leading to aniseikonia. First, aniseikonia might be caused by a spherical lensing effect of microcystic changes in the INL. Microcystic changes, predominantly involving the INL, may result from a mechanical stretch threshold for which cell loss occurs and are a common SD-OCT finding in ERM.

^{21,22}In our study, 39 of the 53 ERM patients with macropsia (73.6%) exhibited microcystic changes in the INL on SD-OCT (Fig. 3). In addition, the AO-SLO imaging revealed extra microcystic changes not seen on SD-OCT.

^{23}Cynthia et al.

^{23}observed the cones underlying the microcystic change appeared more tightly packed in the AO-SLO and suggested paraxial optical ray tracing modeling the microcystic change as a spherical lens. Based on this modeling, we postulated the light rays bending of the path caused by the cyst might stimulate more photoreceptors. Thus, the magnification lens effect of INL microcystic change might lead to macropsia. Moreover, aniseikonia is known to be not reduced after surgery, although the INL thickness was significantly decreased than preoperative values.

^{6}INL microcystic changes are also observed after membrane removal.

^{21}Therefore, this postulation might explain why aniseikonia did not change after surgery. Second, the correlation between the aniseikonia scores and INL thickness may be coincidental. The INL is the location of many early inflammatory and tractional pathologic spaces.

^{24}In the process of transmission of contraction force of an ERM to the photoreceptor layer, INL thickening may occur, but abnormal distribution of photoreceptor cells might eventually occur, resulting in aniseikonia. Because current SD-OCT image does not represent photoreceptor disarrangement, we could not observe the correlation between the aniseikonia scores and photoreceptor disarrangement; thus, the observed relationship between the aniseikonia scores and INL thickness may have been artifactual. Previous evidence supports our suggestion that disarrangement of photoreceptor cells correlates with the severity of metamorphopsia using AO-SLO in eyes with ERM.

^{7}

**Figure 3**

**Figure 3**

^{10,11}Metamorphopsia is a type of distorted vision in which a grid of straight lines appears wavy, whereas aniseikonia is an ocular condition in which the perceived size of images differs significantly. Thus, if the sensory retina is contracted in the vertical direction, the photoreceptor layer would also be compressed vertically, eventually increasing the vertical macropsia. Therefore, we speculated that when the retinal structures contracted vertically, the INL would exhibit greater thickening on vertical OCT, and eventually, the VAS would increase.

**Figure 4**

**Figure 4**

**Figure 5**

**Figure 5**

^{25}where the mean difference between the actual thickness (Spectralis OCT) and predicted thickness ranged from 0.65 to 1.01 μm.

^{26}A prior report demonstrated that changes in INL thickness before and 6 months after ERM removal were a small but significant 7.6 μm.

^{14}Thus, we suggest the difference between vertical and horizontal INL (75 pixels) is meaningful with regard to the accuracy of OCT measurements.

**H. Chung**, None;

**G. Son**, None;

**D.J. Hwang**, None;

**K. Lee**, None;

**Y. Park**, None;

**J. Sohn**, None

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