June 2015
Volume 56, Issue 6
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Retina  |   June 2015
Ganglion Cell–Inner Plexiform Layer and Peripapillary Retinal Nerve Fiber Layer Thicknesses in Age-Related Macular Degeneration
Author Affiliations & Notes
  • Eun Kyoung Lee
    Department of Ophthalmology Seoul National University College of Medicine, Seoul National University Hospital, Seoul, Korea
  • Hyeong Gon Yu
    Department of Ophthalmology Seoul National University College of Medicine, Seoul National University Hospital, Seoul, Korea
  • Correspondence: Hyeong Gon Yu, Department of Ophthalmology, Seoul National University Hospital, #101, Daehak-ro, Jongno-gu, Seoul, 110-744, Republic of Korea; hgonyu@snu.ac.kr
Investigative Ophthalmology & Visual Science June 2015, Vol.56, 3976-3983. doi:10.1167/iovs.15-17013
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      Eun Kyoung Lee, Hyeong Gon Yu; Ganglion Cell–Inner Plexiform Layer and Peripapillary Retinal Nerve Fiber Layer Thicknesses in Age-Related Macular Degeneration. Invest. Ophthalmol. Vis. Sci. 2015;56(6):3976-3983. doi: 10.1167/iovs.15-17013.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose.: To investigate changes of inner retinal layers and optic nerve head (ONH) in patients with dry age-related macular degeneration (AMD) and demonstrate the pattern of these changes.

Methods.: A total of 76 eyes classified as having dry AMD and 76 control eyes were included. Ophthalmologic evaluations included best-corrected visual acuity (BCVA) assessment, spectral-domain optical coherence tomography (SD-OCT), and Humphrey visual field (VF) test. The drusen area and volume were determined using the automated algorithm of the SD-OCT software. Macular ganglion cell–inner plexiform layer (mGCIPL) and peripapillary retinal nerve fiber layer (pRNFL) thicknesses and ONH parameters, as well as VF parameters, were compared between groups.

Results.: Macular GCIPL thickness was significantly lower in eyes with AMD than in controls (73.83 ± 7.13 vs. 82.00 ± 4.85 μm; P < 0.001), and mGCIPL thinning was observed in a ring-shaped pattern around the fovea. The pRNFL thickness was also significantly lower in eyes with AMD than in controls (88.69 ± 6.93 vs. 93.96 ± 8.33 μm; P < 0.001), but no significant difference in ONH parameters was found. An inverse correlation between drusen area and average mGCIPL thickness was found (r = −0.3253; P = 0.0064). Best-corrected visual acuity and VF parameters were worse in AMD eyes than in controls. The pattern of VF defects was mostly consistent with foveal or parafoveal scotoma.

Conclusions.: In eyes with dry AMD, mGCIPL and pRNFL thicknesses were lower than measurements in control eyes, and the average mGCIPL thickness was negatively correlated with the drusen area. However, the pattern of these changes differed from glaucomatous abnormalities.

Age-related macular degeneration (AMD) and glaucoma are leading causes of legal blindness in elderly individuals in developed countries.1,2 They have common pathogenesis of neuronal degeneration of the retina, but different retinal layers are involved. Drusen, extracellular deposits that accumulate between the retinal pigment epithelium (RPE) and the Bruch's membrane,3 are the hallmark lesions of early and intermediate AMD, and lead to outer retinal layer alterations such as photoreceptor loss and thinning of the outer nuclear layer (ONL).4 In contrast, glaucoma, which is presumed to arise from optic nerve head (ONH) damage, involves primarily the inner retinal layers. 
Although the outer retinal layers are mainly affected in AMD, inner retinal neurons may react to the photoreceptor degeneration. Studies on retinas of human retinitis pigmentosa donors showed loss of the inner nuclear layer (INL) and ganglion cell layer (GCL)5 as well as reductions in the number of ganglion cells.6 In rat models of degeneration, histochemical changes in not only the inner plexiform layer (IPL) but also the retinal ganglion cell (RGC) layer have been described.7 However, it was reported that inner retinal thickness remained unchanged in patients with AMD.4 
Recent technological advances in spectral-domain optical coherence tomography (SD-OCT) have allowed a more quantitative evaluation of drusen as well as of each retinal layer and ONH, making it possible to detect small changes in the retina and ONH. Macular ganglion cell–inner plexiform layer (mGCIPL) thickness, the combined thickness of the GCL and the IPL, has been used to monitor glaucoma patients. The ability of mGCIPL parameters to discriminate normal eyes and eyes with early glaucoma is comparable to that of the best peripapillary retinal nerve fiber layer (pRNFL) and ONH parameters.8,9 The mGCIPL parameters can be useful for glaucoma detection, especially in patients with accompanying pathologies in ONH, such as high myopia.10 Meanwhile, the drusen load (area and volume) quantified with SD-OCT represents the severity of dry AMD and can be used for monitoring AMD progression.11,12 
In the current study, it was assumed that AMD, which causes progressive degeneration of the outer retina and photoreceptor disruption, could affect inner retinal neurons. We investigated the changes of inner retinal layers and ONH in patients with dry AMD and demonstrated the pattern of these changes. Macular GCIPL and pRNFL thicknesses as well as ONH parameters were measured using Cirrus SD-OCT, and visual field (VF) sensitivities were assessed by Humphrey VF test in eyes with dry AMD; these measurements were compared with those in control eyes of individuals of a similar age. In addition, the correlation between mGCIPL thickness and the drusen load was analyzed in AMD patients. 
Methods
Participants
The study protocol was approved by the Institutional Review Board of Seoul National University Hospital and adhered to the tenets of the Declaration of Helsinki. This study comprised 76 eyes of 76 consecutive patients who presented at the Seoul National University Hospital between April 2011 and December 2013 with a diagnosis of dry AMD. The inclusion criteria for AMD participants were drusen ≥ 125 μm with or without pigmentary abnormalities as well as confluent soft drusen in the macular area (Fig. 1A). Confluent soft drusen were diagnosed via indirect fundus examination and fundus photography if they had overlapping profiles and were not scattered; at least two were always in contact with each other, but sometimes they were extensive enough to form plaques of drusenoid material.13 The exclusion criteria for the study eyes included any evidence of advanced AMD, including geographic atrophy or choroidal neovascularization (CNV) on fundus photography and SD-OCT, and any past treatment for CNV. Patients with glaucoma, high myopia (spherical equivalent ≥ −6.0 diopters or axial length [AL] ≥ 26 mm), history of pars plana vitrectomy, any other ocular disease that could interfere with visual function (e.g., comorbid maculopathy), or optical media opacity that would significantly disturb OCT image acquisition (e.g., cataract of more than Emery–Little classification grade III) were also excluded. In addition, 76 eyes of 76 healthy individuals of a similar age were included as controls. None of the eyes had glaucomatous optic disc changes (e.g., notching, rim narrowing, or RNFL defects) on fundus examination, and additional testing with stereo optic disc photography and SD-OCT confirmed normal optic disc. In the control group, if both eyes were eligible for the study, only one eye was randomly selected for inclusion. 
Figure 1
 
Representative cases of dry age-related macular degeneration (AMD). Left eye of a 72-year-old woman with a visible confluent soft drusen in the macular area on a fundus photograph (A). A spectral-domain optical coherence tomography (SD-OCT) macular scan showed multiple contiguous drusen (B) and successful segmentation and measurement of macular GCIPL thickness with the ganglion cell analysis algorithm (C). Long thin white arrows indicate OCT scan direction. (D) Surface rendering of the retinal pigment epithelium (RPE) segmentation. (E) Retinal thickness map. (F) Drusen thickness map.
Figure 1
 
Representative cases of dry age-related macular degeneration (AMD). Left eye of a 72-year-old woman with a visible confluent soft drusen in the macular area on a fundus photograph (A). A spectral-domain optical coherence tomography (SD-OCT) macular scan showed multiple contiguous drusen (B) and successful segmentation and measurement of macular GCIPL thickness with the ganglion cell analysis algorithm (C). Long thin white arrows indicate OCT scan direction. (D) Surface rendering of the retinal pigment epithelium (RPE) segmentation. (E) Retinal thickness map. (F) Drusen thickness map.
All patients underwent comprehensive ophthalmologic examinations. Examinations included measurement of best-corrected visual acuity (BCVA), intraocular pressure (IOP; by Goldmann applanation tonometry), noncycloplegic refraction (Autorefractor KR-8900; Topcon Corporation, Tokyo, Japan), and axial length (Axis II PR; Quantel Medical, Inc., Bozeman, MT, USA). Slit-lamp biomicroscopy, indirect fundus examination, fundus photography (Vx-10; Kowa Optimed, Tokyo, Japan), and fluorescein angiography (Vx-10; Kowa Optimed) were also performed. Best-corrected visual acuity measurements were made using a Snellen chart and were converted to logarithm of the minimum angle of resolution (logMAR) units for statistical analyses. Refraction data were converted to spherical equivalent (SE) for analyses. 
Macula and Optic Disc Spectral-Domain Optical Coherence Tomography Imaging
Spectral-domain OCT (Cirrus; Carl Zeiss Meditec, Dublin, CA, USA) was performed to obtain two scans: one macular scan (Macular cube 200 × 200 protocol) and one pRNFL scan (Optic disc cube 200 × 200 protocol). The macular cube scan was obtained using a 5-line raster scan mode with a length of 6 mm (128 lines, 512 A-scans per line). The built-in ganglion cell analysis (GCA) algorithm (Cirrus OCT software, ver. 6.0) detected and measured mGCIPL thickness within a 6 × 6 × 2-mm cube in an elliptical annulus around the fovea (dimensions: vertical inner and outer radii of 0.5 and 2.0 mm, respectively; horizontal inner and outer radii of 0.6 and 2.4 mm, respectively). The GCA algorithm identified the outer boundary of the RNFL as well as the outer boundary of the IPL. The difference between the RNFL and IPL outer boundary segmentations yielded the combined thickness of the GCL and IPL (Figs. 1B, 1C).8 The mGCIPL thickness was then analyzed according to eight parameters: average, minimum, and in six sectors (superonasal, superior, superotemporal, inferotemporal, inferior, and inferonasal). Images with a signal strength of less than six, blinking artifacts, and algorithm segmentation failures were excluded from analyses. The following ONH parameters were also automatically measured by the built-in analysis algorithm (Cirrus OCT software, ver. 6.0): rim area, disc area, average cup-to-disc (C/D) ratio, vertical C/D ratio, and cup volume. The pRNFL thickness within a 3.46-mm-diameter circle (256 A-scans) automatically positioned around the optic disc was measured and analyzed according to 17 parameters: average, 4 quadrants (superior, inferior, temporal, and nasal), and 12 clock-hour sectors. The pRNFL thickness in a 6 × 6-mm2 area around the optic disc cube was measured by 200 × 200 axial scans for generation of the deviation map. For the clock-hour pRNFL thickness, 12 sectors of 30° were defined in clockwise order for both eyes. Clock-hour 1 in the right eye corresponded to clock-hour 11 in the left eye, clock-hour 2 in the right eye corresponded to clock-hour 10 in the left eye, and so on. The mGCIPL and pRNFL thicknesses as well as the ONH parameters were compared between the two groups. 
The drusen area and volume data used in this study for analysis were automatically generated by the Cirrus OCT software algorithm from the cube scans (Figs. 1D–F). The drusen thickness map was defined as the difference between the actual RPE segmentation and the RPE floor.11 This drusen thickness map is generated from each of the 40,000 data points and was automatically calculated as previously reported.11 Drusen area and volume measurements were obtained for the macular area within circles centered on the fovea with diameters of 5 mm. This was chosen to correspond to the area in which the GCA algorithm measures mGCIPL thickness. The drusen area values were square root transformed according to the scaling properties.11 
Humphrey Visual Field Examination
Visual field analysis was performed using the Swedish Interactive Threshold Algorithm (SITA) standard of the Humphrey Visual Field (HVF) Analyzer II 750 instrument (Carl Zeiss Meditec) and the central full-threshold 30-2 program (Figs. 2A–C). Only reliable visual fields (fixation losses, false positives, and false negatives all ≤ 20%) were included in the analysis. As the GCA thickness map covered a radial area between 2.1° and 8.3° from the fovea, with the ellipse extending in the vertical direction between 1.7° and 7°, the macular VF was projected centrally on the Humphrey 30-2 SITA map. Macular VF mean sensitivity (MS), expressed in decibels (dB), was determined using the HVF and was defined as the average of the differential light sensitivity obtained at 12 points area representing the macula.14 Macular VF MS as well as visual field index (VFI), mean deviation (MD), and pattern standard deviation (PSD) were compared between the two groups. 
Figure 2
 
Images from the same subject shown in Figure 1. (A) Circle: The visual field sensitivity values of the area used for ganglion cell analysis. The macular visual field mean sensitivity for this patient was 26.33 dB. (B, C) The visual field pattern deviation map demonstrates a parafoveal scotoma. (D) A ganglion cell–inner plexiform layer (GCIPL) thickness map (the denser the orange/yellow ring, the thicker the GCIPL) revealed an irregular ring-shaped area of thinning in the GCIPL around the fovea. A GCIPL deviation map (E) and a GCIPL macular sector map (F) showed decreased GCIPL thickness around the fovea in a ring shape (red: below percentile 1; yellow: below percentile 5). (GI) Peripapillary retinal nerve fiber layer (pRNFL) analysis revealed decreased temporal pRNFL thickness, which was especially pronounced in the 3 o'clock sector in this patient.
Figure 2
 
Images from the same subject shown in Figure 1. (A) Circle: The visual field sensitivity values of the area used for ganglion cell analysis. The macular visual field mean sensitivity for this patient was 26.33 dB. (B, C) The visual field pattern deviation map demonstrates a parafoveal scotoma. (D) A ganglion cell–inner plexiform layer (GCIPL) thickness map (the denser the orange/yellow ring, the thicker the GCIPL) revealed an irregular ring-shaped area of thinning in the GCIPL around the fovea. A GCIPL deviation map (E) and a GCIPL macular sector map (F) showed decreased GCIPL thickness around the fovea in a ring shape (red: below percentile 1; yellow: below percentile 5). (GI) Peripapillary retinal nerve fiber layer (pRNFL) analysis revealed decreased temporal pRNFL thickness, which was especially pronounced in the 3 o'clock sector in this patient.
Statistical Analysis
The Student's t-test and χ2 test were used to compare ocular parameters in eyes with AMD and control eyes. Factors related to mGCIPL thickness in the AMD group were identified using univariate and multivariate linear regression analyses, with mGCIPL thickness as the dependent variable. Variables with a significance level of P < 0.15 in the univariate analyses were included in the multivariate analysis. Associations between the drusen area and drusen volume as well as the drusen area and mGCIPL thickness were analyzed using the Pearson test. All statistical analyses were performed using SPSS software for Windows version 21.0 (SPSS, Inc., Chicago, IL, USA). The statistical significance level was set at P < 0.05. 
Results
Subject Baseline Characteristics
Seventy-six patients (18 men [23.7%], 58 women [76.3%]) were included in the AMD group, and 76 patients (28 men [36.8%], 48 women [63.2%]) were included in the control group. The mean age was 73.14 ± 6.75 years in the AMD group and 73.07 ± 6.74 years in the control group. Table 1 summarizes the patient demographics and baseline clinical characteristics. There were no statistically significant differences between the two groups in sex, age, IOP, SE, axial length, or proportion of pseudophakic eyes. 
Table 1
 
Demographics and Baseline Clinical Characteristics of the Study Participants
Table 1
 
Demographics and Baseline Clinical Characteristics of the Study Participants
Macular GCIPL and Peripapillary RNFL Thicknesses in Dry AMD
Table 2 presents mGCIPL, pRNFL, and ONH parameters for the AMD and control groups. There was no difference in OCT signal strength of the eyes in both scans between the two groups. The average mGCIPL thickness in eyes with dry AMD was significantly less than that in control eyes (73.83 ± 7.13 vs. 82.00 ± 4.85 μm; P < 0.001). The mean reduction in average mGCIPL thickness in the AMD group was 10%. Macular GCIPL parameters including minimum thickness and thicknesses in all six sectors were significantly less in the AMD group than in the control group (all P < 0.001). Thinning of the mGCIPL associated with confluent soft drusen in the macular area was mainly located around the fovea in a ring-shaped pattern (Figs. 2D–F). Also, the average pRNFL thickness in eyes with dry AMD was significantly less than that in control eyes (88.69 ± 6.93 vs. 93.96 ± 8.33 μm; P = 0.001) with 5.6% of mean reduction. In quadrant sector analysis, pRNFL thickness was less than that of control eyes in the superior, inferior, and temporal quadrants (P = 0.018, P = 0.001, and P = 0.045, respectively). In clock-hour sector measurements, pRNFL thickness was significantly less than that of control eyes in the 6/6, 8/4, 9/3, and 11/1 o'clock sectors (P = 0.003, P = 0.014, P = 0.008, and P = 0.022, respectively) (Figs. 2G–I). On the other hand, ONH parameters including rim area, disc area, average C/D ratio, vertical C/D ratio, and cup volume did not differ significantly between the AMD and control groups. In the AMD group, the average pRNFL thickness was positively correlated with the average mGCIPL thickness (r = 0.3257; P = 0.0134). However, a significant correlation was not found between the average pRNFL thickness and the drusen area on the 5-mm circle (r = −0.1158; P = 0.3910) (Supplementary Table S1). 
Table 2
 
Spectral-Domain Optical Coherence Tomography Measurements in Eyes With Dry Age-Related Macular Degeneration and Age-Matched Healthy Controls
Table 2
 
Spectral-Domain Optical Coherence Tomography Measurements in Eyes With Dry Age-Related Macular Degeneration and Age-Matched Healthy Controls
Factors Affecting Macular GCIPL Thickness in Dry AMD
We found a strong correlation between the drusen area and drusen volume (r = 0.9638; P < 0.0001, Fig. 3A). Drusen area on the 5-mm circle was negatively correlated with the average mGCIPL thickness, meaning that eyes with a larger drusen area had a thinner mGCIPL thickness in patients with AMD (r = −0.3253; P = 0.0064, Fig. 3B). Given this finding and given that when the drusen area rather than the square root of the drusen area (data not shown, r = −0.2944; P = 0.0141) was plotted versus the average mGCIPL thickness, an improved correlation was observed, only the drusen area was used for regression analysis. Univariate and multivariate regression analyses were performed using mGCIPL thickness as the dependent variable in the AMD group (Table 3). In the multivariate analysis, only the drusen area on the 5-mm circle (P = 0.006) was significantly associated with mGCIPL thickness. No significant associations were identified between mGCIPL thickness and age, sex, IOP, SE, axial length, or disc parameters including rim area, disc area, average C/D ratio, vertical C/D ratio, and cup volume. 
Figure 3
 
(A) Scatterplots showing correlation between drusen volume and drusen area. (B) Univariate linear regression analysis of average ganglion cell–inner plexiform layer (GCIPL) thickness versus drusen area on the 5-mm circle. Pearson's correlation coefficient (r) and P values for the slope of the regression line are noted.
Figure 3
 
(A) Scatterplots showing correlation between drusen volume and drusen area. (B) Univariate linear regression analysis of average ganglion cell–inner plexiform layer (GCIPL) thickness versus drusen area on the 5-mm circle. Pearson's correlation coefficient (r) and P values for the slope of the regression line are noted.
Table 3
 
Univariate and Multivariate Linear Regression Analyses Using the Macular Ganglion Cell–Inner Plexiform Layer Thickness as the Dependent Variable in Eyes With Dry Age-Related Macular Degeneration
Table 3
 
Univariate and Multivariate Linear Regression Analyses Using the Macular Ganglion Cell–Inner Plexiform Layer Thickness as the Dependent Variable in Eyes With Dry Age-Related Macular Degeneration
Visual Function in Dry AMD
The mean logMAR BCVA in the AMD group (0.12 ± 0.09) was significantly worse than that in control eyes (0.05 ± 0.08; P < 0.001; Table 4). Visual field MD values (−2.65 ± 1.94 dB) were lower and VF PSD values (3.33 ± 2.02 dB) were greater in AMD eyes than in control eyes (MD: −0.94 ± 1.78 dB, P < 0.001; PSD: 2.38 ± 1.37 dB, P = 0.012). Also, the mean VFI (95.84 ± 3.56%) and VF MS values (28.59 ± 2.23 dB) were significantly lower in AMD eyes than in control eyes (VFI: 98.44 ± 2.14%, P < 0.001; VF MS: 30.73 ± 1.75 dB, P < 0.001) (Fig. 2A). The characteristic VF defect in AMD eyes was mostly consistent with foveal or parafoveal scotoma (Figs. 2B, 2C). In the AMD group, significant correlations were not found between the VF MS and the average mGCIPL thickness (r = 0.0959; P = 0.5169) or drusen area on the 5-mm circle (r = −0.1748; P = 0.2348) (Supplementary Table S1). 
Table 4
 
Visual Function in Eyes With Dry Age-Related Macular Degeneration and Age-Matched Healthy Controls
Table 4
 
Visual Function in Eyes With Dry Age-Related Macular Degeneration and Age-Matched Healthy Controls
Discussion
The current study demonstrated that both mGCIPL thickness and pRNFL thickness were lower in eyes with dry AMD when compared to control eyes. Because the purpose of our study was to investigate changes of inner retinal layers in AMD patients, we included only eyes with dry AMD associated with confluent soft drusen. Those with early AMD were excluded due to the possible insignificant change, and those with advanced AMD were excluded owing to potential influence of geographic atrophy or CNV. The mean reduction in average mGCIPL thickness was 10% and that in average pRNFL thickness was 5.6% compared with controls. These findings suggest that there is damage to the inner retinal layers in eyes with dry AMD. Despite changes in mGCIPL and pRNFL thicknesses, structural alterations in the optic disc were not observed. This is the first study to evaluate mGCIPL and pRNFL thickness as well as ONH parameters in eyes with dry AMD. 
Importantly, the present study highlights the distinctive patterns of mGCIPL and pRNFL changes and VF defects in dry AMD, which differ from those of glaucomatous structural changes. Firstly, mGCIPL thinning observed in AMD eyes in the current study was seen around the fovea and displayed an irregular ring-like shape, while the thinning observed in eyes with glaucomatous damage is predominantly located in the inferotemporal or superotemporal area around the horizontal raphe and displays an asymmetric arcuate pattern.15 Secondly, pRNFL thinning in the 8/4 and 9/3 o'clock sectors was prominent in AMD eyes, while the temporal pRNFL is less susceptible to glaucomatous damage when compared to the superior and inferior regions. Thirdly, the characteristic VF defect in AMD eyes in the current study was mainly either a foveal or parafoveal scotoma, while VF defects present in glaucoma are usually arcuate scotomas and nasal steps,16 and parafoveal VF loss is generally considered to occur in association with advanced glaucoma.17,18 Additionally, the typical structural alterations of the optic disc observed in glaucoma, classically described as disc cupping, notching of the neuroretinal rim, or vertical elongation of the cup,19 were not found in eyes with AMD in the current study. These results suggest that when OCT is used to evaluate glaucoma patients, mGCIPL and pRNFL thinning due to AMD should be considered. 
Our study found an inverse relationship between drusen load and average mGCIPL thickness. We propose that the thinning of the mGCIPL observed in eyes with dry AMD may have occurred as a result of several mechanisms. Firstly, RGC damage may be caused by disorganized synaptic architecture and transneuronal degeneration in eyes with AMD. Evidence of some dystrophic ganglion cells and changes in glial cell immunoreactivity of Müller cells in human AMD-afflicted retinas has been reported.20 In the retinal degeneration (rd) mouse, synaptogenesis was altered not only in the OPL,21 but also in the IPL.22 Secondly, microvascular abnormalities in the GCL, IPL, and INL could affect the thickness of the mGCIPL. A number of changes in the retinal vasculature of the dystrophic Royal College of Surgeons (RCS) rat have been described previously.23 The loss of RGCs may be attributed to vascular abnormalities in the inner retinal layers that are caused by longstanding outer retinal degeneration in AMD. Lastly, mechanical tension on the inner retina caused by the elevation of the RPE and outer retina over drusen could possibly lead to RGC damage. Mechanical pressure may cause severe morphological changes in multiple retinal layers, which could result in RGC injury and a subsequent decrease in mGCIPL thickness. 
The current finding of mGCIPL thinning in dry AMD is consistent with a previously published study describing mGCIPL abnormalities in various ocular conditions. Hwang24 reported that mGCIPL thinning was observed around the fovea in a ring-shaped area in conditions associated with early macular degeneration. Although an exact definition of early macular degeneration was not provided in that study, the pattern of mGCIPL abnormalities described agrees with the current finding of ring-shaped thinning of the mGCIPL in dry AMD. On the other hand, it was also reported that despite thinning of the photoreceptor layer, inner retinal thickness remained unchanged over drusen in nonneovascular AMD eyes.4 This discrepancy may be explained by differences in the definition of the inner retina. The inner retina was defined as the sum of the RNFL, GCL, IPL, INL, and OPL thicknesses in the previous study, while the current study examined the thickness of the GCL and IPL only. Meanwhile, several other investigators have demonstrated the morphology of the ONH and pRNFL thickness in advanced and exudative AMD, respectively. Law et al.25 reported that eyes with large areas of geographic atrophy or disciform AMD have optic disc structural alterations that resemble glaucomatous optic neuropathy, while Rimayanti et al.26 showed that the values of ganglion cell complex components were significantly decreased in eyes with exudative AMD when compared to normal eyes, although the pRNFL thickness did not differ significantly. Although these findings are inconsistent with those observed in the current study, the study subjects were different from ours, and our study comprised those with dry AMD with confluent soft drusen in the macular area; therefore, these series are not directly comparable. 
Another interesting finding of the present study is that pRNFL thinning was most obvious in the 6/6, 8/4, 9/3, and 11/1 o'clock sectors. These findings can be explained in terms of the structure–function relationships of the macular region. The axons of the RGCs within the macular region are assumed to be located mainly in the temporal sectors of the ONH; therefore, preferential thinning in the papillomacular fiber bundle is understandable. No significant differences in pRNFL thickness between AMD eyes and controls were found in the 7/5 and 10/2 o'clock sectors; the reason for this is not known at present. The fact that the average pRNFL thickness was positively correlated with the mGCIPL thickness in eyes with AMD is not surprising, as these two measurements are closely related.27,28 Our study found no significant correlation between the average pRNFL thickness and the drusen area on the 5-mm circle. This might be attributable to the fact that the average pRNFL thickness represents the whole retinal area while the measurement of drusen area was obtained for the macular area within 5 mm of the center of the fovea. Also, it may be related to the fact that many factors are associated with pRNFL thickness. Our findings also show that, despite mGCIPL and pRNFL thinning, structural alterations of the optic disc did not occur. This indicates that confluent soft drusen-associated mGCIPL and pRNFL thinning precedes measurable changes in optic disc configuration. Nevertheless, if dry AMD progresses to advanced AMD with associated alterations such as geographic atrophy, measurable changes in optic disc architecture could occur, as presented in a previous report by Law et al.25 Furthermore, our study showed that visual functions including macular VF MS were significantly impaired in AMD eyes as compared to controls, confirming the results of previous reports.29,30 Even though most of the dry AMD patients maintained good visual acuity, our data allow us to confirm definitively that eyes with dry AMD have inner retinal damage and actual impairment of macular function. The findings that no significant correlations were found between the VF MS and the average mGCIPL thickness or drusen area on the 5-mm circle might be attributable to the fact that the VF MS could also be affected by other factors, such as photoreceptor disruption or RPE atrophy. 
There are several limitations to our study. Firstly, GCA algorithm segmentation failure occurs often during Cirrus OCT imaging in eyes with dome-shaped drusen, resulting in erroneous measurements of mGCIPL thickness. Even though we excluded cases with artifacts from the analysis, this may have given rise to selection bias and influenced the results of our study. Secondly, quantitative analyses of the disrupted photoreceptor layer or the RPE atrophy were not included in our study. Additional studies evaluating both the inner and outer retina, including photoreceptor structure and RPE, are needed to draw more definitive conclusions regarding changes in mGCIPL thickness and visual function in eyes with AMD. Lastly, because we excluded patients with known glaucoma in current study, the observed finding may not reflect the real clinical situation. Further studies with a general population are required to allow extrapolation of our results. 
In conclusion, the average mGCIPL and pRNFL thicknesses were lower in eyes with dry AMD as compared to control eyes. The average mGCIPL thickness was negatively correlated with the drusen area. Despite changes in mGCIPL and pRNFL thicknesses, optic disc structural alterations were not detected. The pattern of abnormalities in mGCIPL and pRNFL as well as the VF defects observed differed from glaucomatous abnormalities. Inner retinal damage may have had an impact on decreased visual function in eyes with dry AMD. 
Acknowledgments
Disclosure: E.K. Lee, None; H.G. Yu, None 
References
Rahmani B, Tielsch JM, Katz J, et al. The cause-specific prevalence of visual impairment in an urban population. The Baltimore Eye Survey. Ophthalmology. 1996; 103: 1721–1726.
Sommer A, Tielsch JM, Katz J, et al. Racial differences in the cause-specific prevalence of blindness in east Baltimore. N Engl J Med. 1991; 325: 1412–1417.
Pauleikhoff D, Barondes MJ, Minassian D, Chisholm IH, Bird AC. Drusen as risk factors in age-related macular disease. Am J Ophthalmol. 1990; 109: 38–43.
Schuman SG, Koreishi AF, Farsiu S, et al. Photoreceptor layer thinning over drusen in eyes with age-related macular degeneration imaged in vivo with spectral-domain optical coherence tomography. Ophthalmology. 2009; 116: 488–496, e482.
Santos A, Humayun MS, de Juan E,Jr, et al. Preservation of the inner retina in retinitis pigmentosa. A morphometric analysis. Arch Ophthalmol. 1997; 115: 511–515.
Stone JL, Barlow WE, Humayun MS, de Juan E,Jr, Milam AH. Morphometric analysis of macular photoreceptors and ganglion cells in retinas with retinitis pigmentosa. Arch Ophthalmol. 1992; 110: 1634–1639.
Lund RD, Coffey PJ, Sauve Y, Lawrence JM. Intraretinal transplantation to prevent photoreceptor degeneration. Ophthalmic Res. 1997; 29: 305–319.
Mwanza JC, Oakley JD, Budenz DL, et al. Macular ganglion cell-inner plexiform layer: automated detection and thickness reproducibility with spectral domain-optical coherence tomography in glaucoma. Invest Ophthalmol Vis Sci. 2011; 52: 8323–8329.
Mwanza JC, Durbin MK, Budenz DL, et al. Glaucoma diagnostic accuracy of ganglion cell-inner plexiform layer thickness: comparison with nerve fiber layer and optic nerve head. Ophthalmology. 2012; 119: 1151–1158.
Choi YJ, Jeoung JW, Park KH, Kim DM. Glaucoma detection ability of ganglion cell-inner plexiform layer thickness by spectral-domain optical coherence tomography in high myopia. Invest Ophthalmol Vis Sci. 2013; 54: 2296–2304.
Gregori G, Wang F, Rosenfeld PJ, et al. Spectral domain optical coherence tomography imaging of drusen in nonexudative age-related macular degeneration. Ophthalmology. 2011; 118: 1373–1379.
Yehoshua Z, Wang F, Rosenfeld PJ, et al. Natural history of drusen morphology in age-related macular degeneration using spectral domain optical coherence tomography. Ophthalmology. 2011; 118: 2434–2441.
Klein ML, Ferris FL,III, Armstrong J, et al. Retinal precursors and the development of geographic atrophy in age-related macular degeneration. Ophthalmology. 2008; 115: 1026–1031.
Lee EK, Yu HG. Ganglion cell-inner plexiform layer thickness after epiretinal membrane surgery: a spectral-domain optical coherence tomography study. Ophthalmology. 2014; 121: 1579–1587.
Hwang YH, Jeong YC, Kim HK, Sohn YH. Macular ganglion cell analysis for early detection of glaucoma. Ophthalmology. 2014; 121: 1508–1515.
Varma R, Ying-Lai M, Francis BA, et al. Prevalence of open-angle glaucoma and ocular hypertension in Latinos: the Los Angeles Latino Eye Study. Ophthalmology. 2004; 111: 1439–1448.
Park SC, De Moraes CG, Teng CC, et al. Initial parafoveal versus peripheral scotomas in glaucoma: risk factors and visual field characteristics. Ophthalmology. 2011; 118: 1782–1789.
Jung KI, Park HY, Park CK. Characteristics of optic disc morphology in glaucoma patients with parafoveal scotoma compared to peripheral scotoma. Invest Ophthalmol Vis Sci. 2012; 53: 4813–4820.
Jonas JB, Budde WM. Diagnosis and pathogenesis of glaucomatous optic neuropathy: morphological aspects. Prog Retin Eye Res. 2000; 19: 1–40.
Ramirez JM, Ramirez AI, Salazar JJ, de Hoz R, Trivino A. Changes of astrocytes in retinal ageing and age-related macular degeneration. Exp Eye Res. 2001; 73: 601–615.
Blanks JC, Adinolfi AM, Lolley RN. Photoreceptor degeneration and synaptogenesis in retinal-degenerative (rd) mice. J Comp Neurol. 1974; 156: 95–106.
Strettoi E, Porciatti V, Falsini B, Pignatelli V, Rossi C. Morphological and functional abnormalities in the inner retina of the rd/rd mouse. J Neurosci. 2002; 22: 5492–5504.
Villegas-Perez MP, Lawrence JM, Vidal-Sanz M, Lavail MM, Lund RD. Ganglion cell loss in RCS rat retina: a result of compression of axons by contracting intraretinal vessels linked to the pigment epithelium. J Comp Neurol. 1998; 392: 58–77.
Hwang YH. Patterns of macular ganglion cell abnormalities in various ocular conditions. Invest Ophthalmol Vis Sci. 2014; 55: 3995–3996.
Law SK, Sohn YH, Hoffman D, et al. Optic disk appearance in advanced age-related macular degeneration. Am J Ophthalmol. 2004; 138: 38–45.
Rimayanti U, Kiuchi Y, Yamane K, et al. Inner retinal layer comparisons of eyes with exudative age-related macular degeneration and eyes with age-related macular degeneration and glaucoma. Graefes Arch Clin Exp Ophthalmol. 2014; 252: 563–570.
Koh VT, Tham YC, Cheung CY, et al. Determinants of ganglion cell-inner plexiform layer thickness measured by high-definition optical coherence tomography. Invest Ophthalmol Vis Sci. 2012; 53: 5853–5859.
Mwanza JC, Durbin MK, Budenz DL, et al. Profile and predictors of normal ganglion cell-inner plexiform layer thickness measured with frequency-domain optical coherence tomography. Invest Ophthalmol Vis Sci. 2011; 52: 7872–7879.
Midena E, Segato T, Blarzino MC, Degli Angeli C. Macular drusen and the sensitivity of the central visual field. Doc Ophthalmol. 1994; 88: 179–185.
Midena E, Degli Angeli C, Blarzino MC, Valenti M, Segato T. Macular function impairment in eyes with early age-related macular degeneration. Invest Ophthalmol Vis Sci. 1997; 38: 469–477.
Figure 1
 
Representative cases of dry age-related macular degeneration (AMD). Left eye of a 72-year-old woman with a visible confluent soft drusen in the macular area on a fundus photograph (A). A spectral-domain optical coherence tomography (SD-OCT) macular scan showed multiple contiguous drusen (B) and successful segmentation and measurement of macular GCIPL thickness with the ganglion cell analysis algorithm (C). Long thin white arrows indicate OCT scan direction. (D) Surface rendering of the retinal pigment epithelium (RPE) segmentation. (E) Retinal thickness map. (F) Drusen thickness map.
Figure 1
 
Representative cases of dry age-related macular degeneration (AMD). Left eye of a 72-year-old woman with a visible confluent soft drusen in the macular area on a fundus photograph (A). A spectral-domain optical coherence tomography (SD-OCT) macular scan showed multiple contiguous drusen (B) and successful segmentation and measurement of macular GCIPL thickness with the ganglion cell analysis algorithm (C). Long thin white arrows indicate OCT scan direction. (D) Surface rendering of the retinal pigment epithelium (RPE) segmentation. (E) Retinal thickness map. (F) Drusen thickness map.
Figure 2
 
Images from the same subject shown in Figure 1. (A) Circle: The visual field sensitivity values of the area used for ganglion cell analysis. The macular visual field mean sensitivity for this patient was 26.33 dB. (B, C) The visual field pattern deviation map demonstrates a parafoveal scotoma. (D) A ganglion cell–inner plexiform layer (GCIPL) thickness map (the denser the orange/yellow ring, the thicker the GCIPL) revealed an irregular ring-shaped area of thinning in the GCIPL around the fovea. A GCIPL deviation map (E) and a GCIPL macular sector map (F) showed decreased GCIPL thickness around the fovea in a ring shape (red: below percentile 1; yellow: below percentile 5). (GI) Peripapillary retinal nerve fiber layer (pRNFL) analysis revealed decreased temporal pRNFL thickness, which was especially pronounced in the 3 o'clock sector in this patient.
Figure 2
 
Images from the same subject shown in Figure 1. (A) Circle: The visual field sensitivity values of the area used for ganglion cell analysis. The macular visual field mean sensitivity for this patient was 26.33 dB. (B, C) The visual field pattern deviation map demonstrates a parafoveal scotoma. (D) A ganglion cell–inner plexiform layer (GCIPL) thickness map (the denser the orange/yellow ring, the thicker the GCIPL) revealed an irregular ring-shaped area of thinning in the GCIPL around the fovea. A GCIPL deviation map (E) and a GCIPL macular sector map (F) showed decreased GCIPL thickness around the fovea in a ring shape (red: below percentile 1; yellow: below percentile 5). (GI) Peripapillary retinal nerve fiber layer (pRNFL) analysis revealed decreased temporal pRNFL thickness, which was especially pronounced in the 3 o'clock sector in this patient.
Figure 3
 
(A) Scatterplots showing correlation between drusen volume and drusen area. (B) Univariate linear regression analysis of average ganglion cell–inner plexiform layer (GCIPL) thickness versus drusen area on the 5-mm circle. Pearson's correlation coefficient (r) and P values for the slope of the regression line are noted.
Figure 3
 
(A) Scatterplots showing correlation between drusen volume and drusen area. (B) Univariate linear regression analysis of average ganglion cell–inner plexiform layer (GCIPL) thickness versus drusen area on the 5-mm circle. Pearson's correlation coefficient (r) and P values for the slope of the regression line are noted.
Table 1
 
Demographics and Baseline Clinical Characteristics of the Study Participants
Table 1
 
Demographics and Baseline Clinical Characteristics of the Study Participants
Table 2
 
Spectral-Domain Optical Coherence Tomography Measurements in Eyes With Dry Age-Related Macular Degeneration and Age-Matched Healthy Controls
Table 2
 
Spectral-Domain Optical Coherence Tomography Measurements in Eyes With Dry Age-Related Macular Degeneration and Age-Matched Healthy Controls
Table 3
 
Univariate and Multivariate Linear Regression Analyses Using the Macular Ganglion Cell–Inner Plexiform Layer Thickness as the Dependent Variable in Eyes With Dry Age-Related Macular Degeneration
Table 3
 
Univariate and Multivariate Linear Regression Analyses Using the Macular Ganglion Cell–Inner Plexiform Layer Thickness as the Dependent Variable in Eyes With Dry Age-Related Macular Degeneration
Table 4
 
Visual Function in Eyes With Dry Age-Related Macular Degeneration and Age-Matched Healthy Controls
Table 4
 
Visual Function in Eyes With Dry Age-Related Macular Degeneration and Age-Matched Healthy Controls
Supplement 1
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