Longitudinal Changes in Ganglion Cell–Inner Plexiform Layer of Fellow Eyes in Unilateral Neovascular Age-Related Macular Degeneration

Journal Pre-proof Longitudinal changes in ganglion cell-inner plexiform layer of fellow eyes in unilateral neovascular age-related macular degeneration Min-Woo Lee, MD, Ju-mi Kim, MD, Hyung-Bin Lim, MD, Yong-Il Shin, MD, YoungHoon Lee, MD, Jung-Yeul Kim, MD, PhD PII:

S0002-9394(19)30598-7

DOI:

https://doi.org/10.1016/j.ajo.2019.12.003

Reference:

AJOPHT 11163

To appear in:

American Journal of Ophthalmology

Received Date: 16 July 2019 Revised Date:

4 December 2019

Accepted Date: 4 December 2019

Please cite this article as: Lee M-W, Kim J-m, Lim H-B, Shin Y-I, Lee Y-H, Kim J-Y, Longitudinal changes in ganglion cell-inner plexiform layer of fellow eyes in unilateral neovascular age-related macular degeneration, American Journal of Ophthalmology (2020), doi: https://doi.org/10.1016/ j.ajo.2019.12.003. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier Inc.

Abstract Purpose: To determine longitudinal changes in the ganglion cell-inner plexiform layer (GC-IPL) thickness of the fellow eyes of patients with neovascular age-related macular degeneration (AMD). Design: A prospective cohort study. Methods: Patients with unilateral neovascular AMD, unilateral polypoidal choroidal vasculopathy (PCV), and controls were included. After the initial visit, GC-IPL thickness was measured twice more with at least 1-year interval between examinations using spectral-domain OCT. Results: 27 fellow eyes of patients with unilateral choroidal neovascularization (CNV), 33 fellow eyes of patients with unilateral PCV, and 35 control eyes were enrolled. The GC-IPL thickness of the fellow eyes was 78.41 ± 9.23, 81.20 ± 5.52, and 81.60 ± 3.83 µm in the CNV, PCV, and control groups, respectively, and they showed a significant change over time (P < 0.001, P = 0.001, and P = 0.003, respectively). The reduction rate of GC-IPL thickness was -0.88, -0.41, and -0.31 µm/yr in the fellow eyes of the CNV, PCV, and control groups, respectively (CNV > PCV, control, P < 0.001). In a linear mixed model determination of factors associated with GC-IPL reduction in the fellow eyes of the CNV group, the interaction between baseline GC-IPL thickness and duration showed a significant result (P < 0.001). Conclusions: The fellow eyes of patients with neovascular AMD showed a greater reduction rate of GC-IPL thickness compared to the fellow eyes of patients with unilateral PCV and normal individuals. In patients with unilateral neovascular AMD, fellow eyes with a thicker GC-IPL at baseline showed a greater reduction in GC-IPL thickness over time.

GC-IPL thickness in the fellow eyes of neovascular AMD

Longitudinal changes in ganglion cell-inner plexiform layer of fellow eyes in unilateral neovascular age-related macular degeneration

Short title: GC-IPL thickness in the fellow eyes of neovascular AMD Min-Woo Lee1,2, MD, Ju-mi Kim1, MD, Hyung-Bin Lim, MD1, Yong-Il Shin1, MD, Young-Hoon Lee2, MD, Jung-Yeul Kim, MD, PhD1

Department of Ophthalmology, Chungnam National University College of Medicine, Daejeon, Republic of Korea1 Department of Ophthalmology, Konyang University College of Medicine, Daejeon, Republic of Korea2 Correspondence and reprint requests to: Jung-Yeul Kim, MD Department of Ophthalmology, Chungnam National University Hospital #640 Daesa-dong, Jung-gu, Daejeon, 301-721, Korea Tel: 82-42-280-8433; Fax: 82-42-255-3745; E-mail: [email protected] Keywords: AMD, CNV, PCV, ganglion cell-inner plexiform layer

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GC-IPL thickness in the fellow eyes of neovascular AMD

Introduction Age-related macular degeneration (AMD) is one of the leading causes of irreversible vision loss in older patients.1, 2 Especially neovascular AMD is an acute onset and rapidly progressing disease characterized by the growth of abnormal blood vessels into and under the retina. These vessels lead to intraretinal and subretinal accumulation of fluid and blood, which can impair visual acuity.3 As patients with unilateral neovascular AMD have a high risk of developing a similar lesion in the fellow eye, it is critical not only to manage the affected eye but also to carefully monitor the fellow eye.4-6 Polypoidal choroidal vasculopathy (PCV) has several characteristics distinct from typical AMD, such as younger age of onset, male preponderance, and high prevalence in Asians.7-9 The absence of soft drusen or subretinal drusenoid deposits (SDD) is also another feature of PCV that distinguishes it from typical AMD.10 Soft drusen and SDD can cause not only type 1 macular neovascularization or atrophy but also type 2 or 3 macular neovascularization.11, 12 In contrast, pachydrusen, based on the associated thick choroids, is known to increase the likelihood of development of type 1 macular neovasculopathy or PCV.13 Eyes with pachydrusen rarely cause retinal atrophy. Therefore, typical neovascular AMD and PCV may show different patterns of retinal change according to the different mechanisms of retinal damage. Many previous studies have reported a relationship between AMD and changes in retinal layer thickness. Lamin et al.14 reported that the ganglion cell-inner plexiform layer (GC-IPL) volumes of early and intermediate AMD eyes were reduced substantially compared to control eyes. Abdolrahimzadeh et al.15 reported ganglion cell layer thinning in the treated eyes of patients under anti-vascular endothelial growth factor therapy for unilateral exudative AMD compared to fellow early AMD eyes. In studies of the fellow eye of AMD patients, Kenmochi et al.16 reported that the retinal pigment epithelium (RPE) – cone outer segment tip (COST) was thinner in the fellow eyes of AMD patients than in control eyes. Nittala et al.17 also reported that the RPE and drusen complex layer became thinner over time in the fellow eyes of patients with unilateral neovascular AMD. However, studies for the change in the inner retina of the fellow eyes of AMD is insufficient. We therefore investigated GC-IPL changes in the fellow eyes of patients with neovascular AMD and unilateral PCV, and compared the changes with those in normal controls. We also identified factors affecting the GC-IPL reduction over time in the fellow eyes of neovascular AMD.

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GC-IPL thickness in the fellow eyes of neovascular AMD

Methods Patients This prospective, longitudinal, observational study adhered to the tenets of the Declaration of Helsinki and was approved by the Institutional Review Board of Chungnam National University Hospital, Daejeon, Republic of Korea. Patients who visited our retinal clinic were enrolled and examined between May 2013 and December 2018, and informed consent was obtained from all patients. Patients with neovascular AMD or PCV in one eye, and without signs of neovascular AMD or geographic atrophy in the fellow eye, were enrolled. The control group was comprised of patients diagnosed with unilateral epiretinal membrane, macular hole, or intraocular lens dislocation, and fellow eyes without any ophthalmic disease were analyzed. The subjects were divided into three groups: choroidal neovascularization (CNV), PCV, and control groups. All patients underwent a complete ophthalmic examination including best-corrected visual acuity (BCVA), intraocular pressure (IOP), spherical equivalent, axial length (using an IOL Master; Carl Zeiss, Jena, Germany, version 5.02), and spectral domain-optical coherence tomography (SDOCT). Drusen subtypes were determined on color photographs according to published criteria.18 We diagnosed SDD when there were 10 or more discrete areas of subretinal accumulation of whitish deposits in the color photograph. Pachydrusen was diagnosed when there were isolated or scattered yellow-white deposits that corresponded to homogenous material under the RPE as revealed by OCT. Soft drusen was diagnosed when there were homogenous sub-RPE deposits that formed mounds corresponding to yellow-white aggregates seen in the color photographs. After the initial visit, two more examinations were performed with an at least 1-year interval between them. Patients with hypertension, diabetes, any neurologic disease or ophthalmic disease that could affect GC-IPL thickness in the study eye, evidence of a neovascular lesion on fluorescein angiography in the study eye or any other feature indicating the previous presence of neovascular AMD, geographic atrophy in the study eye, intraocular surgery except cataract extraction, a BCVA < 0.7, spherical equivalent ≤ -6.0 diopters, axial length ≥ 26.0 mm, or IOP > 21 mmHg were excluded. OCT measurements OCT measurements were performed by a skilled examiner with a 512 × 128 macular cube and 200 × 200 optic cube scanning protocol using a Cirrus HD OCT (Carl Zeiss Meditec, Dublin, CA; version 10.0). The GC-IPL thickness was measured using the “Ganglion Cell Analysis” module (Fig. 1). The ganglion cell analysis algorithm automatically measured GC-IPL thickness by identifying the outer boundaries of the retinal nerve fiber layer (RNFL) and the inner plexiform layer of the macula using three-dimensional information obtained from the macular cube scan. The average GC-IPL thickness, and the thickness of six sectors (superior, superonasal, inferonasal, inferior, inferotemporal, and superonasal), were analyzed. All images were checked and verified by a masked observer (M.W.L.), and images with a signal strength < 7, any motion artifacts, involuntary saccades, obvious decentration, or segmentation errors were excluded. Statistical analysis After applying the

Kolmogorov-Smirnov 3

test

of

normality,

demographic

GC-IPL thickness in the fellow eyes of neovascular AMD

characteristics and ocular parameters were compared among the three groups using one-way analysis of variance and the chi-square test. Linear mixed models were performed to determine significant changes in GC-IPL thickness over time in each group, and to calculate the reduction rate of the GC-IPL thickness. The average GCIPL thickness was fitted with linear mixed models with follow-up duration, age, sex, BCVA, axial length, IOP, spherical equivalent, central macular thickness (CMT), mean RNFL thickness, and average GC-IPL thickness at baseline examination, interaction between baseline GC-IPL thickness and duration, and interaction between group and duration as fixed effects, and a random intercept was included at the eye level. Univariate and multivariate generalized linear mixed models were used to determine factors associated with GC-IPL changes over time in the CNV group. Statistical analyses were performed using SPSS version 18.0 software (IBM Corp., Armonk, NY).

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GC-IPL thickness in the fellow eyes of neovascular AMD

Results Demographics Of the 103 eyes, CNV occurred in 4 fellow eyes of the CNV group, and PCV in 1 fellow eye in the PCV group, during the follow-up period. We additionally excluded 3 eyes with much thinner GC-IPL than others in the CNV group because of the possibility that they had retinal diseases affecting the retinal layer thickness in the past. Thus, a total of 95 eyes were enrolled: 27 fellow eyes with unilateral typical CNV, 33 fellow eyes with unilateral PCV, and 35 control eyes. The mean age of the CNV, PCV, and control groups was 68.1 ± 6.9, 66.7 ± 7.3, and 68.8 ± 7.5 years, respectively (P = 0.991) (Table 1). The total follow-up period was 3.11 ± 1.16, 3.02 ± 1.09, and 3.31 ± 1.54 years in the CNV, PCV, and control groups, respectively (P = 0.680). Sex, BCVA, spherical equivalent, IOP, axial length, and follow-up period were also not significantly different among the three groups. The GC-IPL thickness of the fellow eyes was 78.41 ± 9.23, 81.20 ± 5.52, and 81.60 ± 3.83 µm in the CNV, PCV, and control groups, respectively. The fellow eyes of the CNV group showed thinner GC-IPLs than the other groups, but the difference was not significant. In the CNV group, there were 9 eyes (33.3 %) with SDD and 20 eyes (74.1 %) with soft drusen (> 63 µm). In the PCV group, there were 8 eyes (24.2 %) with pachydrusen and 2 eyes (6.1 %) with soft drusen. In the control group, small drusen (≤ 63 µm), which had little clinical significance, was observed in 6 eyes. None of the eyes showed any signs of retinal disease, and the rim area, disc area, and cup/disc ratio did not show a significant difference between the first and third visits (CNV group: P = 0.375, P = 0.059, and P = 0.408; PCV group: P = 0.334, P = 0.238, and P = 0.219; control group: P = 0.195, P = 0.222, and P = 0.736, respectively). Peripapillary RNFL and CMT of the fellow eyes of each group The mean RNFL thickness of the fellow eyes of the CNV, PCV and control groups at the first visit was 95.55 ± 9.29, 93.77 ± 7.33, and 91.60 ± 4.99 µm, respectively (P = 0.120). The mean RNFL thickness of the CNV, PCV, and control groups at the third visit was 94.31 ± 9.85, 92.80 ± 7.28, and 90.67 ± 6.06 µm, respectively, and only the fellow eyes of the CNV group showed a significant change (P = 0.011, P = 0.126, and P = 0.127, respectively). The CMT of the fellow eyes of the CNV, PCV, and control groups at the first visit was 246.52 ± 20.93, 254.87 ± 19.29, and 247.20 ± 23.21 µm, respectively (P = 0.209). The CMT at the third visit was 244.90 ± 22.67, 253.97 ± 20.98, and 247.40 ± 24.47 µm in the CNV, PCV, and control groups, respectively; CMT did not show a significant change in any group (P = 0.404, P = 0.325, and P = 0.243, respectively). The GC-IPL thickness of the fellow eyes of each group at each visit In the CNV group, the average GC-IPL thickness was 78.41 ± 9.23, 76.70 ± 9.95, and 75.41 ± 9.10 µm at visits 1 – 3, respectively, and showed a significant change over time (P < 0.001) (Table 2). The average GC-IPL thickness was 81.20 ± 5.52, 80.27 ± 5.81, and 79.87 ± 5.99 µm at visits 1 – 3, respectively, in the PCV group, and 81.60 ± 3.83, 81.17 ± 3.76, and 80.60 ± 3.72 µm, respectively, in the control group; the changes over time were significant in both groups (P = 0.001 and P = 0.003, respectively) (Fig 2). In the CNV group, the GC-IPL thickness showed significant changes over time in all sectors. In the PCV group, the GC-IPL thickness of all sectors, except the superior 5

GC-IPL thickness in the fellow eyes of neovascular AMD

and inferotemporal sectors, showed significant changes over time. In the control group, the GC-IPL thickness of the inferior, inferotemporal, and superotemporal sectors showed significant changes over time. The rate of reduction in GC-IPL thickness of the fellow eyes of each group The rate of reduction in the average GC-IPL thickness of the fellow eyes was -0.88, -0.41, and -0.31 µm/y in the CNV, PCV, and control groups, respectively. Also, there was a significant interaction between group and duration in linear mixed models (P = 0.001) (Table 3). According to post-hoc analysis, there was a significant difference in the change of GC-IPL thickness over time between the CNV group and the other groups. Additionally, the reduction rate of GC-IPL thickness in most sectors was greater in the CNV group than the other groups. Factors associated with GC-IPL reduction in the CNV group In the linear mixed model determination of factors associated with GC-IPL reduction in the fellow eyes of the CNV group, age, baseline mean RNFL thickness, baseline average GC-IPL thickness, and the interaction between baseline average GC-IPL thickness and duration showed significant results in univariate analysis (P = 0.014, P = 0.018, P < 0.001, and P < 0.001, respectively) (Table 4). In multivariate analysis, baseline GC-IPL thickness and the interaction between baseline GC-IPL thickness and duration showed a significant result (both P < 0.001).

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GC-IPL thickness in the fellow eyes of neovascular AMD

Discussion Changes in retinal layers, as well as a high prevalence of CNV, have been reported in the fellow eyes of patients with unilateral AMD in many recent studies.4, 6, 15-17, 19 Therefore, careful observation of structural changes in the fellow eyes of CNV patients is very important. High-resolution SD-OCT imaging allows these changes to be analyzed more accurately and efficiently. In their longitudinal study, Nittala et al.17 reported that the outer retinal layer became thinner over time in the fellow eyes of neovascular AMD patients. We assessed the longitudinal changes in the GC-IPL thickness of the fellow eyes of neovascular AMD patients, which showed thinning similar to the outer retina. We excluded 3 outlier cases showing much thinner GCIPL than other subjects in the CNV group. Although including them did not affect the result, they had relatively thinner each retinal layer as well as GC-IPL. Therefore, we could not totally rule out the possibility that they had retinal diseases affecting the retinal layer thickness such as retinal vein occlusion in the past, although they did not show any active lesion during the follow-up period. Meanwhile, the mean RNFL thickness also showed a significant change during the follow-up period in the CNV group, of approximately -1.2 µm. However, previous studies reported that the mean rate of change of RNFL thickness in normal individuals was between -0.16 and -0.52 µm/y.20-22 Therefore, the reduction of pRNFL thickness in our CNV group might have been attributable to age-related loss. Previous studies reported reticular pseudodrusen in 24% - 41% of the fellow eyes of patients with unilateral neovascular AMD.23-25 In the present study, 33.3% of the eyes had SDD, a term preferable to pseudodrusen. This rate was consistent with the results of previous studies.26 Abdolrahimzadeh et al.27 reported that GC-IPL thickness was reduced in early AMD, and was thinner in eyes with SDD compared to eyes with drusen alone. The present study also showed a greater reduction of GCIPL in the fellow eyes of the CNV group, which had a high proportion of SDD. This would be expected to result in a wider range of GC-IPL thickness values in the fellow eyes of the CNV group than the other groups, because they contained eyes without any drusen besides eyes with many SDD. Previous studies hypothesized that neuronal damage might be caused by disorganized synaptic architecture and transneuronal degeneration over time, due to chronically reduced input to the inner retina secondary to photoreceptor damage.28, 29 Additionally, in the normal fellow eyes of patients with unilateral AMD, and without any type of drusen, the tissue between the RPE line and the COST line can become atrophic.16 This atrophic change in the outer retina could cause changes in the inner retina in the fellow eyes of CNV patients, even in those without SDD. Systemic conditions such as hypertension, coronary artery disease, and atherosclerosis, which are known risk factors for AMD, may also affect GC-IPL thinning in the fellow eyes of CNV patients.30-32 Further studies with larger cohorts are needed to identify the relationship between such systemic conditions and GC-IPL changes. PCV is commonly seen in eyes with a thick choroid, and pachydrusen was also found to be associated with thick choroids.18 Baek et al.33 observed pachydrusen in 27% of the fellow eyes of unilateral PCV patients. Similarly, 24.2% of fellow eyes in our PCV group had pachydrusen. In contrast to the CNV group, the fellow eyes of the PCV group did not show a significant difference in the reduction rate of GC-IPL thickness compared to the control group. In addition to there being fewer eyes with drusen in the PCV group compared to the CNV group, pachydrusen seemed to have 7

GC-IPL thickness in the fellow eyes of neovascular AMD

less impact on the inner retina than other drusen types, although it can affect the outer retina, similar to other drusens.33 The hypothesis; SDD or soft drusen could cause type 2 or 3 macular neovascularization, whereas pachydrusen are usually associated with type 1 macular neovascularization or PCV, which shows a greater association with the choroid than the inner retina, might be similar context.11 This may be due to the difference in the mechanism of retinal damage between SDD and soft drusen versus pachydrusen. Based on these findings, further studies are needed to clarify the mechanisms underlying retinal disease in each type of drusen. In the present study, the reduction rates of GC-IPL thickness in the fellow eyes of the PCV and control groups was -0.41 and -0.31 µm/y, respectively (P = 0.304). Leung et al.34 showed a similar result; the mean age-related loss of GC-IPL thickness was -0.318 µm/y. In our CNV group, the reduction rate was -0.85 µm/y, which was significantly greater than in the other groups. Although both AMD and PCV could affect the degree of damage to the outer retina, degenerative changes associated with aging and time factors are relatively rare in PCV patients, which might explain the lower amount of accumulated damage to the outer retina compared to AMD patients. Accordingly, GC-IPL damage due to transneuronal degeneration appeared less severe in our PCV group. Meanwhile, a change in GCIPL thickness is one of the important factors when diagnosing and analyzing the progression of glaucoma. Hollo et al.35 reported that the average ganglion cell complex reduction was -0.80 ± 0.78 µm/y for glaucomatous eyes. Another study reported -0.81 µm/y as a mean rate of GC-IPL thickness change in glaucoma patients. The similar reduction rate of GC-IPL in the fellow eyes of neovascular AMD and glaucomatous patients could be a confounding factor when assessing eyes with both diseases. Previous studies reported GC-IPL thinning in dry AMD around the fovea, and displayed an irregular ring-shaped, whereas thinning in glaucoma occurred in inferotemporal or superotemporal areas around the horizontal raphe, showing an asymmetric arcuate pattern.36, 37 Therefore, analyzing the pattern of GCIPL thinning, rather than merely determining the average thickness, would be helpful to identify the main cause of GC-IPL changes in eyes with both neovascular AMD and glaucoma. Baseline average GC-IPL thickness was the most significant factor associated with changes in GC-IPL thickness over time in the fellow eyes of the CNV group (coefficient of “interaction between duration and baseline average GC-IPL thickness” = -0.011; P < 0.001). Toto et al.38 reported that both superficial and deep retinal plexuses were altered in patients affected by not-late stage AMD. This result could be relevant to the observation that vascular diseases such as systemic hypertension, coronary, carotid, and peripheral vascular diseases, are risk factors for AMD.30 GCIPL thinning may reflect ischemic damage to the inner retina caused by alteration of the superficial retinal plexus. Additionally, a thicker GC-IPL would have a higher oxygen demand compared to a normal or thinner GC-IPL, which may result in greater sensitivity to ischemic damage. However, the temporal sequence of events between alterations in the superficial retinal plexus and GC-IPL thinning is not clear, so further longitudinal studies are needed to clarify this mechanism. Study limitations and strengths There were some limitations to this study. First, the number of subjects in each group was relatively small. Second, the follow-up period differed between groups 8

GC-IPL thickness in the fellow eyes of neovascular AMD

because of the limitations imposed by clinic-based recruitment, but they did not show a significant difference. Third, we could not analyze outer retinal layers, such as the photoreceptor layer or RPE, because the Cirrus HD OCT instrument could only measure the macular, peripapillary RNFL, and GC-IPL thicknesses by autosegmentation. Longitudinal analysis of both the inner and outer retina would be meaningful in future studies. The strength of this study is that this prospective study determined the longitudinal change of GC-IPL thickness in fellow eyes of neovascular AMD, PCV, and control groups, and compared the 3 groups over 2 years. We also identified factors associated with GC-IPL changes over time in the fellow eyes of neovascular AMD. In conclusion, the fellow eyes of patients with unilateral neovascular AMD, which have a high probability of SDD or soft drusen, showed a greater reduction rate in GC-IPL thickness compared to the fellow eyes of patients with unilateral PCV and normal individuals. In addition, the fellow eyes with a thicker GC-IPL at baseline showed a greater reduction of GC-IPL thickness over time in patients with unilateral neovascular AMD. We suggest that physicians should be aware of the susceptibility to inner retinal damage of patients with neovascular AMD, even in eyes without an AMD lesion, to ensure appropriate management of any changes in retinal thickness.

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GC-IPL thickness in the fellow eyes of neovascular AMD

ACKNOWLEDGEMENT A. Funding/Support : None B. Financial Disclosures : None C. Contributions to Authors in each of these areas Design and conduct of the study (M.W.L., J.Y.K.); Collection of data (M.W.L., J.M.K., J.Y.K.); Analysis and interpretation of data (M.W.L., H.B.L., J.Y.K.); Writing the article (M.W.L., J.Y.K.); Critical revision of the article (M.W.L., Y.H.L., Y.I.S., J.Y.K.); Final approval of the article (M.W.L., J.M.K., H.B.L., Y.I.S., Y.H.L., J.Y.K.); D. Other Acknowledgment: None

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GC-IPL thickness in the fellow eyes of neovascular AMD

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GC-IPL thickness in the fellow eyes of neovascular AMD

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GC-IPL thickness in the fellow eyes of neovascular AMD

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GC-IPL thickness in the fellow eyes of neovascular AMD

Figure Legends Figure 1. The thickness of ganglion cell-inner plexiform layer (GC-IPL) using spectral domain-optical coherence tomography. (Top) Horizontal and vertical B-scan of macula. The GC-IPL is autosegmented and designated using yellow and purple lines. (Bottom) The significance map of the GC-IPL shows the average, minimum, and sixsector GC-IPL thickness. S, superior; ST, superotemporal; IT, inferotemporal; I, inferior; IN, inferonasal; SN, superonasal. Figure 2. Line graphs showing the mean and sectoral ganglion cell-inner plexiform layer (GC-IPL) thickness at each visit. The mean and all sectoral GC-IPL thicknesses were thinner in the fellow eyes of the choroidal neovasculopathy (CNV) group than the fellow eyes of the polypoidal choroidal vasculopathy (PCV) and control groups. The differences between the fellow eyes of the CNV group and the other 2 groups tended to increase over time.

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Table 1. Demographics and baseline characteristics of fellow eyes of the unilateral CNV, unilateral PCV, and control groups CNV (n = 27) PCV (n=33) Control (n = 35) P-value Age (yrs, mean ± SD) 68.1 ± 6.9 66.7 ± 7.3 68.8 ± 7.5 0.944 Sex (men, %) 7 (25.9) 15 (50.0) 13 (43.3) 0.210 Laterality (right, %) 15 (55.6) 12 (40.0) 15 (50.0) 0.792 BCVA 0.00 ± 0.09 -0.01 ± 0.06 0.00 ± 0.04 0.684 (logMAR, mean ± SD) SE (D, mean ± SD) 0.00 ± 1.06 0.16 ± 1.31 0.47 ± 1.03 0.287 IOP (mmHg, mean ± 15.7 ± 2.1 15.7 ± 2.2 14.6 ± 3.0 0.298 SD) Axial length 23.4 ± 0.7 23.7 ± 0.9 23.4 ± 0.7 0.096 (mm, mean ± SD) Interval 1st – 2nd visit 1.56 ± 0.70 1.56 ± 0.61 1.59 ± 0.79 0.770 (y, mean ± SD) Interval 2nd – 3rd visit 1.55 ± 0.54 1.46 ± 0.62 1.72 ± 0.93 0.423 (y, mean ± SD) Total follow-up period 3.11 ± 1.16 3.02 ± 1.09 3.31 ± 1.54 0.680 (y, mean ± SD) < 0.001 Subretinal drusenoid 9 (33.3 %) 0 (0 %) 0 (0 %) deposit (n, %) Soft drusen (> 63 µm) 20 (74.1 %) 2 (6.1 %) 0 (0 %) < 0.001 (n, %) Pachydrusen (n, %) 0 (0 %) 8 (24.2 %) 0 (0 %) < 0.001 Average GC-IPL 78.41 ± 9.23 81.20 ± 5.52 81.60 ± 3.83 0.139 thickness (µm, mean ± SD) 95.55 ± 9.29 93.77 ± 7.33 91.60 ± 4.99 0.120 Mean RNFL thickness (µm, mean ± SD) CMT (µm, mean ± SD) 246.52 ± 254.87 ± 247.20 ± 23.21 0.209 20.93 19.29 ONH parameters Rim area (mean ± SD, 1.38 ± 0.23 1.28 ± 0.26 1.27 ± 0.21 0.178 2 mm ) Disc area (mean ± SD, 2.11 ± 0.36 2.01 ± 0.43 1.89 ± 0.37 0.107 2 mm ) Cup/disc ratio (mean ± 0.54 ± 0.17 0.57 ± 0.13 0.53 ± 0.16 0.604 SD) Values in boldface(P < 0.05) are statistically significant. CNV, choroidal neovasculopathy; PCV, polypoidal choroidal vasculopathy; BCVA, best-corrected visual acuity; logMAR, logarithm of the minimum angle of resolution; SE, spherical equivalent; IOP, intraocular pressure;GC-IPL, ganglion cell-inner plexiform layer; RNFL, retinal nerve fiber layer; CMT, central macular thickness; ONH, optic nerve head; SD, standard deviation;.

Table 2. Ganglion cell-inner plexiform layer thickness of the fellow eyes of the unilateral typical CNV, PCV, and control groups at each visit CNV group PPCV group PControl Pvalue value group value First 78.41 ± 9.23 81.20 ± 5.52 81.60 ± 3.83 average Second 76.70 ± 9.95 <0.001 80.27 ± 5.81 0.001 81.17 ± 3.76 0.003 average Third 75.41 ± 9.10 79.87 ± 5.99 80.60 ± 3.72 average Sector First S 78.40 ± 10.80 81.43 ± 5.80 81.93 ± 4.18 Second S 76.93 ± 10.73 <0.001 80.90 ± 6.90 0.201 81.80 ± 4.59 0.384 Third S 75.11 ± 10.17 80.80 ± 6.20 81.50 ± 4.31 First SN 82.44 ± 8.46 83.17 ± 5.62 83.63 ± 5.14 Second SN 80.85 ± 7.43 0.001 82.07 ± 6.03 0.005 83.50 ± 5.04 0.230 Third SN 79.59 ± 8.60 81.80 ± 5.80 82.57 ± 4.98 First IN 80.48 ± 8.48 81.47 ± 6.97 81.90 ± 5.10 Second IN 78.52 ± 8.41 0.001 79.77 ± 6.44 0.002 81.47 ± 5.10 0.086 Third IN 77.59 ± 7.16 78.43 ± 7.76 80.10 ± 6.09 First I 75.67 ± 10.90 79.23 ± 7.42 78.87 ± 4.61 Second I 75.11 ± 10.14 <0.001 77.73 ± 5.98 0.008 77.80 ± 5.47 <0.001 Third I 73.44 ± 10.02 77.63 ± 6.70 77.77 ± 5.23 First IT 77.52 ± 11.72 81.77 ± 6.26 82.20 ± 4.61 Second IT 75.37 ± 12.97 <0.001 81.47 ± 6.34 0.095 81.37 ± 4.59 <0.001 Third IT 73.89 ± 13.63 80.83 ± 7.16 80.93 ± 4.22 First ST 75.30 ± 13.31 79.73 ± 6.66 81.43 ± 6.53 Second ST 73.89 ± 13.85 <0.001 79.47 ± 7.26 0.031 80.93 ± 7.04 0.033 Third ST 73.70 ± 13.48 79.70 ± 8.03 80.67 ± 7.05 Values are presented as mean ± SD (µm). Values in boldface (P < 0.05) are significant changes over time in linear mixed models. CNV, choroidal neovasculopathy; PCV, polypoidal choroidal vasculopathy; S, superior; SN, superonasal; IN, inferonasal; I, inferior; IT, inferotemporal; ST, superotemporal;

Table 3. Reduction rate in the ganglion cell-inner plexiform layer thickness of the fellow eyes of the CNV, PCV, and control groups CNV PCV Control *P-value (post-hoc) Average -0.88 -0.41 -0.31 < 0.001 (95% CI) (-1.10 to -0.67) (-0.65 to -0.17) (-0.51 to -0.12) (CNV > PCV, control) Superior -0.98 -0.19 -0.14 < 0.001 (95% CI) (-1.32 to -0.65) (-0.50 to 0.11) (-0.45 to 0.18) (CNV > PCV, control) Superonasal -0.90 -0.43 -0.33 0.047 (CNV (95% CI) (-1.40 to -0.40) (-0.72 to -0.14) (-0.62 to -0.05) > PCV, control) Inferonasal -0.82 -0.98 -0.56 0.225 (95% CI) (-1.27 to -0.38) (-1.57 to -0.39) (-1.32 to 0.20) -0.50 -0.45 0.265 Inferior -0.77 (95% CI) (-1.14 to -0.41) (-0.85 to -0.14) (-0.69 to -0.22) Inferotemporal -1.02 -0.25 -0.56 0.008 (CNV (95% CI) (-1.41 to -0.63) (-0.54 to -0.05) (-0.78 to -0.33) > PCV, control) Superotemporal -0.63 0.01 -0.24 0.034 (CNV (95% CI) (-0.96 to -0.31) (-0.44 to 0.46) (-0.45 to -0.02) > PCV, control) CI, confidence interval; CNV, choroidal neovasculopathy; PCV, polypoidal choroidal vasculopathy. * P value for interaction between group and duration in linear mixed models. Values in boldface(P < 0.05) are statistically significant.

Table 4. Univariate and multivariate linear mixed-effect model determination of factors associated with changes in the GC-IPL thickness in the fellow eyes of the CNV group Univariate Multivariate Estimate (95 % CI) P Estimate (95 % CI) P value value Age -0.63 (-1.12 to -0.14) 0.014 -0.05 (-0.12 to 0.02) 0.162 Sex -5.98 (-14.24 to 2.26) 0.379 BCVA -27.82 (-67.16 to 11.52) 0.158 Axial length 2.77 (-2.51 to 8.05) 0.290 IOP -0.29 (-2.16 to 1.58) 0.775 SE -0.82 (-4.42 to 2.78) 0.644 Baselin CMT 0.11 (-0.07 to 0.29) 0.229 Baselin mean 0.45 (0.08 to 0.82) 0.018 0.04 (-0.01 to 0.09) 0.122 RNFL thickness Baseline GC1.00 (0.96 to 1.05) < < 1.02 (0.96 to 1.07) IPL thickness 0.001 0.001 Baseline GC- -0.011 (-0.014 to -0.008) < -0.011 (-0.014 to < IPL thickness 0.001 0.008) 0.001 × duration Baseline GC-IPL thickness × duration means interaction between 2 factors. Values in boldface (P < 0.05) are statistically significant. CI, confidence interval; BCVA, best-corrected visual acuity; IOP, intraocular pressure; SE, spherical equivalent; CMT, central macular thickness; RNFL, retinal nerve fiber layer; GC-IPL, ganglion cell-inner plexiform layer; CNV, choroidal neovasculopathy.

Highlights The fellow eyes of patients with neovascular AMD showed a greater reduction rate of GC-IPL thickness compared to the fellow eyes of patients with PCV, which tended severe in eyes with thicker GC-IPL at baseline.

Table of contents statement The fellow eyes of patients with unilateral neovascular age-related macular degeneration (AMD) showed a greater reduction rate in ganglion cell-inner plexiform layer (GC-IPL) thickness compared to the fellow eyes of patients with unilateral polypoidal choroidal vasculopathy and normal individuals. In addition, the fellow eyes with a thicker GC-IPL at baseline showed a greater reduction of GC-IPL thickness over time in patients with unilateral neovascular AMD. So physicians should be aware of the susceptibility to inner retinal damage of patients with neovascular AMD, even in eyes without an AMD lesion, to ensure appropriate management of any changes in retinal thickness.