Epiretinal membrane (ERM) is one of the most common retinal diseases in aged persons,1 which results in blurred vision or metamorphopsia, such as macropsia and micropsia. Several theories that explain the mechanisms that cause metamorphopsia due to ERM include macular distortion, vascular leakage, edema of the inner retina, and changes in the photoreceptors,2–7 but little certain evidence supports any of these mechanisms as a direct cause of metamorphopsia. Recently, Ooto et al. evaluated the cone density of patients with ERM and central serous chorioretinopathy (CSC) using adaptive optics scanning laser ophthalmoscopy. Interestingly, a 45% to 70% lower cone density was detected in eyes with resolved CSC compared with normal eyes,8 but they found no difference in mean cone density between the eyes of patients with ERM and normal eyes.9 However, disrupted regularity of cone-packing geometry was detected in eyes with ERM, suggesting disarrangement of photoreceptor cells.
We speculated that the pattern of the photoreceptor disarrangement would determine the characteristics of metamorphopsia. Macropsia is a condition that affects human visual perception in which objects are perceived to be larger than they actually are. Theoretically, macropsia can develop when the central cone cells are concentrically displaced from their original site. Such displacement could be detected by spectral-domain optical coherence tomography (SD-OCT), which has improved the speed and sensitivity of OCT, allowing scanning at a higher resolution.10–14
Therefore, in the present study, using SD-OCT, we compared the characteristics of retinal structures in eyes with ERM according to the presence or absence of macropsia.
Patients and Methods
All investigations adhered to the tenets of the Declaration of Helsinki, and the study was approved by the Institutional Review Board and the Ethics Committee of the Catholic University of Korea. Twenty-six consecutive patients with ERM and macropsia were defined as the macropsia group, and 26 patients with ERM without macropsia were defined as the control group between June 2011 and August 2015 at Seoul Saint Mary's Hospital, Seoul, Korea. Exclusion criteria were as follows: 1) high myopia (spherical equivalent ≤ −6 diopters, axial length ≥ 26.0 mm), 2) any history of intraocular surgery of the study eye other than uncomplicated cataract surgery, 3) any history of ocular trauma to the study eye.
In the macropsia group, the diseased eye was defined as the eye that perceived the image to be larger than the fellow eye. In the control group, the eye with ERM was defined as the diseased eye when ERM was detected in one eye. In cases with bilateral ERM, the more severe eye was chosen for the diseased eye.
All patients in this study underwent a comprehensive ophthalmologic examination, including measurements of best-corrected visual acuity (BCVA), intraocular pressure, slit-lamp biomicroscopy, color fundus photography, axial length using partial coherence interferometry (IOL Master; Carl Zeiss Meidtec, Jena, Germany), and SD-OCT (Cirrus HD OCT; Carl Zeiss, Dublin, CA). BCVA was measured with the decimal system and then converted to the logarithm of the minimal angle of resolution (logMAR) units for statistical analysis.
Double Dot Chart (DDC)
We measured the degree of macropsia using previously developed method with modification.15 It consisted of one red and one green dot, diameter of 5 cm to 7 cm graded in 5-mm increments. To assess visual symptoms, patients wore the red-green glasses and were asked to choose the pair of dots that they perceived as same size at 30 cm apart. The presence and grade of macropsia was recorded (Figure 1).
Double dot chart that the authors developed, including two series of pictures. Patients were asked to wear red-green glasses and view the monitor that exhibited the chart at a 30-cm distance. Patients chose the picture that was perceived as the same size when viewed with both eyes and the grade was recorded.
SD-OCT: Outer Retinal Layer Features and Retinal Thickness Measurements
SD-OCT was performed for both eyes using high-definition (HD) five-line raster scans in same illuminance. Images with a strength less than five (on a scale from 0 to 10) were excluded.
The thicknesses of the outer nuclear layer (ONL) and inner segment / outer segment / retinal pigment epithelium (IS/OS/RPE) at the foveola were measured using a digital caliper tool built into the OCT. The total retinal layer was measured from the beginning of the hyperreflective line adjacent to vitreous to the outer margin of the RPE. The thickness of the ONL was measured as the vertical length from the external limiting membrane (ELM) to the lower edge of the highly reflective line corresponding to the OPL. The IS/OS/RPE was measured from the ELM to the bottom of RPE (Figure 2). To maximize the accuracy of measurement, all the values were evaluated independently by two of the authors (JS and JB), who were not informed of the presence of visual symptoms at that time. Each of these two authors measured numeric parameter, and the average values were used for the statistical analysis. The OCT parameters were compared to the fellow eye to calculate the ratio of interocular differences. The ratio of interocular differences was calculated as follows: Ratio of interocular difference = value from diseased eye / value from fellow eye.
Total retinal layer (TNL), outer nuclear layer (ONL), and inner segment / outer segment / retinal pigment epithelium (IS/OS/RPE) junction were measured using a built-in caliper tool in optical coherence tomography.
The ELM, IS/OS junction, and cone outer segment tips (COST) line were defined as “intact” when the hyperreflective line showed a continuous hyperreflective signal without disruption within a 3-mm width zone. This line was graded as attenuated if the intensity of the line within the 3-mm width zone was below 50%. When there was disagreement in the presence of disruption of ELM, IS/OS junction, and COST line, the third opinion was invited (WKL).
Inter- and intraexaminer measuring consistency was determined by having both examiners measure the thickness of ONL and IS/OS/RPE in the same image repetitively (10 times each). The bias for each measurement was calculated as the mean difference in data between measurement and examiners; the paired t-test determined whether levels of bias were significantly different from zero, as previously described.16 The limits of agreement (LoA), encompassing 95% of differences between two measurements (mean ± [1.96 x SD]), were established using the standard deviation of differences. Wilcoxon signed-rank test was used to analyze differences in continuous variables between the diseased eye and control eye pairs, whereas the Mann-Whitney U test was used for comparison between the two groups. Chi-square tests were used to compare frequencies of disruption of ELM, IS/OS junction, and COST line between eyes. For all analyses, P value less than .05 was considered significant. All statistical analyses were performed using SPSS statistical software (version 12.0; SPSS, Chicago, IL).
The patient characteristics are described in Table 1. Twelve male and 14 female patients with a mean age of 72.31 years ± 7.91 years (range: 60 years to 82 years) were enrolled in the macropsia group, and 11 males and 15 females with a mean age of 66.80 years ± 7.72 years (range: 57 years to 79 years) were enrolled in the control group. BCVA was 0.18 logMAR ± 0.11 logMAR (range: 0 logMAR to 0.3 logMAR) for the macropsia group and 0.23 logMAR ± 0.17 logMAR (range: 0 logMAR to 0.4 logMAR) for the control group. There was no difference in the BCVA between two groups. The sex, age, and the baseline BCVA were not significantly different between the two groups (P = .577, P = .102, and P = .273, respectively). Among those 26 patients with macropsia and ERM, 11 patients underwent pars plana vitrectomy with membrane peeling, and 15 patients were followed regularly.
Clinical Characteristics of Enrolled Patients
No subjects showed any difficulty in testing using the DDC. Twenty-six patients in the macropsia group showed positive results with the double dot test. The mean grade of DDC was 2.30 ± 0.80 (range: 1 to 4). None of the control group had positive DDC results.
No statistically significant bias was evident with respect to inter- and intraexaminer measurements of ONL and IS/OS/RPE (Table 2). SD-OCT findings of each group are described in Table 3. The ONL in the diseased eyes was significantly thicker in the macropsia group than in the control group (287.96 μm ± 92.02 μm for the macropsia group and 227.88 μm ± 86.01 μm for the control group, P = .020), whereas these two groups did not differ significantly in the thickness of ONL in the control eye (126.81 μm ± 50.56 μm for the macropsia group and 130.04 μm ± 77.19 μm for the control group, P = .860). The ratio of interocular difference missed statistical significance (2.53 μm ± 1.12 μm for the macropsia group and 2.02 μm ± 0.97 μm for the control group, P = .086). The thickness of IS/OS/RPE in the diseased eye was significantly thicker in the macropsia group than in the control group (P < .001), whereas these two groups did not differ significantly in the thickness of IS/OS/RPE in the control eye (P = .161). The ratio of interocular difference was significantly higher in the macropsia group than in the control group (1.59 μm ± 0.48 μm for the macropsia group and 1.07 μm ± 0.21 μm for the control group, P < .001).
Repeatability for the Inter- and Intraexaminer Measurements
SD-OCT Findings of Enrolled Patients
No eye showed disrupted ELM or IS/OS junction, regardless of the presence of ERM or macropsia. A disrupted COST line was detected from 88.46% of diseased eyes and 38.46% of the other eyes in the macropsia group (P < .001). However, in the control group, the frequency of disruption of the COST line did not differ significantly between eyes (50.00% for diseased eyes and 30.77% for control eyes, P = .252).
Figure 3 shows representative SD-OCT findings in patients with or without macropsia. Patients with macropsia complained that each eye perceived different image sizes, and we found that the eye with macropsia tended to have a thicker ONL and IS/OS/RPE than the fellow eye (Figures 3A and 3B). These differences were not detected in the control group (Figures 3C and 3D).
Optical coherence tomography (OCT) findings of patients with epiretinal membrane and macropsia. (A) OCT findings from an 82-year-old male with macropsia. The logMAR best-corrected visual acuity (BCVA) for the eye with macropsia was 20/25. (B) A 74-year-old female with macropsia. Her BCVA was 20/20 for the eye with macropsia. (C) A 74-year-old female without macropsia. Her BCVA was 20/25 for her diseased eye. (D) A 68-year-old female without macropsia. His BCVA was 20/40 for her diseased eye.
In this study, we found that patients with macropsia had thicker IS/OS/RPE and more frequently disrupted COST line in the diseased eye than in the fellow eye. Previously, Tsunoda et al. reported the presence of highly reflective foveal regions in patients with vitreomacular traction or ERM and suggested that these regions indicate an inward traction of retina on the fovea.17 They hypothesized that these highly reflective foveal regions resulted from the changes in the alignment of the outer segments. The ONL contains the nucleus of cone and rod photoreceptor cells, and the outer segment is where photons are captured and phototransduction cascade begins. Based on these findings, we speculated that the contractive nature of ERM in these patients resulted in the centralization of photoreceptor cells, which makes the location of these cells more central than the original location. Accordingly, the OS of centrally moved photoreceptor cells capture more central light stimulus than the paired retinal corresponding photoreceptor cells in the fellow eye. As a result, the eyes with ERM may perceive an object larger than its actual size.
It has been suggested that the continuous IS/OS junction might represent an intact photoreceptor layer,18 and that a continuous ELM is a sign of intact photoreceptor cell body and muller glial cells.19,20 We observed no patient with a disrupted IS/OS junction or ELM in either eye in the present study. However, disruption of the COST line was most often detected in the diseased eye of patients with macropsia. The COST line, also known as the interdigitation line, seems to indicate an early sign of photoreceptor damage. It has been speculated that the tractional force generated by ERM may alter the interface between photoreceptor and RPE without severe damage to photoreceptor or RPE cells themselves.21,22 In a previous study, disruption of the COST line was detected in 48% of eyes with ERM, which is similar to the prevalence that we observed in the control group of this study.19 However, disruption of the COST line was detected in 88.46% of the diseased eyes of patients with macropsia, which suggests an altered microstructural interface between photoreceptor and RPE cells, which might result from or result in the centralization of photoreceptor cells in the present study.
Ooto et al.9 previously reported that the eyes with ERM were associated with microfolds of photoreceptor cells from their study that used adaptive optics scanning laser ophthalmoscopy. However, there was no significant difference in the cone density from patients with or without metamorphopsia. We presume that the metamorphopsia involves diverse cone photoreceptor changes resulting from ERM, and the patients with macropsia or micropsia would exhibit different cone photoreceptor changes.
Of interest, Okamoto et al. reported that 55% of patients with macular hole (MH) complain of micropsia.23 We speculated that patients with ERM usually complain of macropsia, whereas patients with MH complain of micropsia because photoreceptor cells are stretched away from their original location in patients with MH and move more centrally in patients with ERM. They reported that this anisekonia was improved after MH closure. In contrast, most patients who underwent pars plana vitrectomy for ERM removal stated that the macropsia did not significantly improve after surgery, even though their visual acuity improved (within 12 months of postoperative follow-up). We speculated that the eyes with macropsia may indicate the advanced stage of ERM with irreversible retinal structural changes.
Although we found the characteristic findings in macropsia caused from ERM, the results that can directly indicate that the foveal morphologic findings cause macropsia are lacking. Further study is warranted to understand the detailed mechanism.
- Fraser-Bell S, Guzowski M, Rochtchina E, Wang JJ, Mitchell P. Five-year cumulative incidence and progression of epiretinal membranes: the Blue Mountains Eye Study. Ophthalmology. 2003;110(1):34–40. doi:10.1016/S0161-6420(02)01443-4 [CrossRef]
- Watanabe A, Arimoto S, Nishi O. Correlation between metamorphopsia and epiretinal membrane optical coherence tomography findings. Ophthalmology. 2009;116(9):1788–1793. doi:10.1016/j.ophtha.2009.04.046 [CrossRef]
- Arroyo JG, Irvine AR. Retinal distortion and cotton-wool spots associated with epiretinal membrane contraction. Ophthalmology. 1995;102(4):662–668. doi:10.1016/S0161-6420(95)30989-X [CrossRef]
- Matsumoto C, Arimura E, Okuyama S, Takada S, Hashimoto S, Shimomura Y. Quantification of metamorphopsia in patients with epiretinal membranes. Invest Ophthalmol Vis Sci. 2003;44(9):4012–4016. doi:10.1167/iovs.03-0117 [CrossRef]
- Arimura E, Matsumoto C, Okuyama S, Takada S, Hashimoto S, Shimomura Y. Retinal contraction and metamorphopsia scores in eyes with idiopathic epiretinal membrane. Invest Ophthalmol Vis Sci. 2005;46:2961–2966. doi:10.1167/iovs.04-1104 [CrossRef]
- Niwa T, Terasaki H, Kondo M, Piao CH, Suzuki T, Miyake Y. Function and morphology of macula before and after removal of idiopathic epiretinal membrane. Invest Ophthalmol Vis Sci. 2003;44(4):1652–1656. doi:10.1167/iovs.02-0404 [CrossRef]
- Krøyer K, Jensen OM, Larsen M. Objective signs of photoreceptor displacement by binocular correspondence perimetry: A study of epiretinal membranes. Invest Ophthalmol Vis Sci. 2005;46(3):1017–1022. doi:10.1167/iovs.04-0952 [CrossRef]
- Ooto S, Hangai M, Sakamoto A, et al. High-resolution imaging of resolved central serous chorioretinopathy using adaptive optics scanning laser ophthalmoscopy. Ophthalmology. 2010;117(9):1800–1809. doi:10.1016/j.ophtha.2010.01.042 [CrossRef]
- Ooto S, Hangai M, Takayama K, et al. High-resolution imaging of the photoreceptor layer in epiretinal membrane using adaptive optics scanning laser ophthalmoscopy. Ophthalmology. 2011;118(7):873–881. doi:10.1016/j.ophtha.2010.08.032 [CrossRef]
- van Velthoven ME, Faber DJ, Verbraak FD, van Leeuwen TG, de Smet MD. Recent developments in optical coherence tomography for imaging the retina. Prog Retin Eye Res. 2007;26(1):57–77. doi:10.1016/j.preteyeres.2006.10.002 [CrossRef]
- Schmidt-Erfurth U, Leitgeb RA, Michels S, et al. Three-dimensional ultrahigh-resolution optical coherence tomography of macular diseases. Invest Ophthalmol Vis Sci. 2005;46(9):3393–3402. doi:10.1167/iovs.05-0370 [CrossRef]
- Srinivasan VJ, Wojtkowski M, Witkin AJ, et al. High-definition and 3-dimensional imaging of macular pathologies with high-speed ultrahigh-resolution optical coherence tomography. Ophthalmology. 2006;113(11):2054.e1–14. doi:10.1016/j.ophtha.2006.05.046 [CrossRef]
- Ko TH, Fujimoto JG, Schuman JS, et al. Comparison of ultrahigh- and standard-resolution optical coherence tomography for imaging macular pathology. Ophthalmology. 2005;112(11):1922.e1–15. doi:10.1016/j.ophtha.2005.05.027 [CrossRef]
- Oh J, Smiddy WE, Flynn HW Jr, Gregori G, Lujan B. Photoreceptor inner/outer segment defect imaging by spectral domain OCT and visual prognosis after macular hole surgery. Invest Ophthalmol Vis Sci. 2010;51(3):1651–1658. doi:10.1167/iovs.09-4420 [CrossRef]
- Ugarte M, Williamson TH. Aniseikonia associated with epiretinal membranes. Br J Ophthalmol. 2005;89(12):1576–1580. doi:10.1136/bjo.2005.077164 [CrossRef]
- Bland JM, Altman DG. Statistical methods for assessing agreement between two methods of clinical measurement. Lancet. 1986;1(8476):307–310. doi:10.1016/S0140-6736(86)90837-8 [CrossRef]
- Tsunoda K, Watanabe K, Akiyama K, Usui T, Noda T. Highly reflective foveal region in optical coherence tomography in eyes with vitreomacular traction or epiretinal membrane. Ophthalmology. 2012;119(3):581–587. doi:10.1016/j.ophtha.2011.08.026 [CrossRef]
- Shimoda Y, Sano M, Hashimoto H, Yokota Y, Kishi S. Restoration of photoreceptor outer segment after vitrectomy for retinal detachment. Am J Ophthalmol. 2010;149(2):284–290. doi:10.1016/j.ajo.2009.08.025 [CrossRef]
- Wakabayashi T, Fujiwara M, Sakaguchi H, Kusaka S, Oshima Y. Foveal microstructure and visual acuity in surgically closed macular holes: spectral-domain optical coherence tomographic analysis. Ophthalmology. 2010;117(9):1815–1824. doi:10.1016/j.ophtha.2010.01.017 [CrossRef]
- Wakabayashi T, Oshima Y, Fujimoto H, et al. Foveal microstructure and visual acuity after retinal detachment repair. Ophthalmology. 2009;116(3):519–528. doi:10.1016/j.ophtha.2008.10.001 [CrossRef]
- Shimozono M, Oishi A, Hata M, et al. The significance of cone outer segment tips as a prognostic factor in epiretinal membrane surgery. Am J Ophthalmol. 2012;153(4):698–704. doi:10.1016/j.ajo.2011.09.011 [CrossRef]
- Itoh Y, Inoue M, Rii T, Hirota K, Hirakata A. Correlation between foveal cone outer segment tips line and visual recovery after epiretinal membrane surgery. Invest Ophthalmol Vis Sci. 2013;54(12):7302–7308. doi:10.1167/iovs.13-12702 [CrossRef]
- Okamoto F, Sugiura Y, Moriya Y, et al. Aniseikonia and foveal microstructure in patients with idiopathic macular hole. Ophthalmology. 2016;123(9):1926–1932. doi:10.1016/j.ophtha.2016.05.051 [CrossRef]
Clinical Characteristics of Enrolled Patients
|Macropsia Group (n = 26)||Control Group(n = 26)||P Value|
|Male, No. (%)||12 (46.2)||11 (42.3)||.577a|
|Age, Years (Range)||72.31 ± 7.91 (60–82)||66.80 ± 7.72 (57–79)||.102b|
|BCVA, LogMAR (Range)||0.18 ± 0.11 (0–0.3)||0.23 ± 0.17 (0–0.4)||.273b|
|Duration of Macropsia, Months (Range)||27.70 ± 20.58 (4–64)||0 (0)||-|
|Double Dot Test, Positive (%)||26 (100)||0 (0)||-|
Repeatability for the Inter- and Intraexaminer Measurements
|Measurement||Mean Difference||SD of the Differences||95% LoA|
|ONL||Interexaminer comparisons||4.80||2.49||−0.08, +9.68|
|Intraexaminer comparisons||2.56||1.95||−1.26, +6.38|
|IS/OS/RPE||Interexaminer comparisons||2.30||1.64||−0.91, +5.51|
|Intraexaminer comparisons||1.33||0.91||−0.45, +3.11|
SD-OCT Findings of Enrolled Patients
|Macropsia group (N = 26)||Control group (N = 26)||P Value* Between the Two Groups|
|Mean TRL ± SD (range)|
| Diseased eye, μm‡||432.38 ± 111.42 (240–776)||473.60 ± 138.95 (185–661)||.247a|
| The other eye, μm||243.38 ± 39.10 (181–362)||261.04 ± 79.17 (190–446)||.323a|
| Ratio†||1.83 ± 0.59 (0.86–3.64)||1.94 ± 0.79 (0.72–3.73)||.576a|
P Value From Interocular Difference||< .001b||< .001b|
|Mean ONL ± SD (Range)|
| Diseased eye, μm‡||287.96 ± 92.02 (90–497)||227.88 ± 86.01 (83–465)||.020a|
| The other eye, μm||126.81 ± 50.56 (80–289)||130.04 ± 77.19 (77–454)||.860a|
| Ratio†||2.53 ± 1.12 (0.67–4.92)||2.02 ± 0.97 (0.59–3.84)||.086a|
P Value From Interocular Difference||< .001b||< .001b|
|Mean IS/OS/RPE ± SD (Range)|
| Diseased eye, μm ‡||33.42 ± 10.52 (18–59)||23.44 ± 5.80 (14–28)||< .001a|
| The other eye, μm||20.88 ± 1.53 (17–24)||21.84 ± 2.56 (18–26)||.116a|
| Ratio†||1.59 ± 0.48 (0.95–2.79)||1.07 ± 0.21 (0.94–1.83)||< .001a|
P Value From Interocular Difference||<.001b||.161b|
|Disruption of COST Line, Yes|
| Diseased eye,‡ n (%)||23 (88.46)||13 (50.00)||.006c|
| The other eye, n (%)||10 (38.46)||8 (30.77)||.771c|
P Value From Interocular Difference||< .001c||.252c|