Ganglion Cell-Inner Plexiform Layer and Retinal Nerve Fiber Layer Changes in Glaucoma Suspects Enable Prediction of Glaucoma Development

Ganglion Cell-Inner Plexiform Layer and Retinal Nerve Fiber Layer Changes in Glaucoma Suspects Enable Prediction of Glaucoma Development

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Journal Pre-proof Ganglion Cell–Inner Plexiform Layer and Retinal Nerve Fiber Layer Changes in Glaucoma Suspects Enable to Predict Glaucoma Development Joong Won Shin, Kyung Rim Sung, Min Kyung Song PII:

S0002-9394(19)30538-0

DOI:

https://doi.org/10.1016/j.ajo.2019.11.002

Reference:

AJOPHT 11127

To appear in:

American Journal of Ophthalmology

Received Date: 7 June 2019 Revised Date:

25 October 2019

Accepted Date: 1 November 2019

Please cite this article as: Shin JW, Sung KR, Song MK, Ganglion Cell–Inner Plexiform Layer and Retinal Nerve Fiber Layer Changes in Glaucoma Suspects Enable to Predict Glaucoma Development, American Journal of Ophthalmology (2019), doi: https://doi.org/10.1016/j.ajo.2019.11.002. 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 Elsevier Inc. All rights reserved.

Abstract Purpose: To investigate whether progressive macular ganglion cell-inner plexiform layer (GCIPL) and peripapillary retinal nerve fiber layer (RNFL) thinning predict the development of VF defects in glaucoma suspects. Design: Retrospective cohort study Methods: This study included 541 eyes of 357 glaucoma suspects with mean followup duration of 5.7 years. Progressive GCIPL and RNFL thinning were determined using Guided Progression Analysis (GPA) in optical coherence tomography (OCT). The development of VF defect was defined as the presence of three consecutive abnormal VFs. The risk of developing VF defect was evaluated using Cox proportional hazard models. Results: Seventy-four eyes (13.7%) and 87 eyes (16.1%) showed progressive GCIPL and RNFL thinning in OCT GPA, respectively, and 40 eyes (7.4%) developed VF defects. Eyes with progressive GCIPL (hazard ratio [HR], 7.130; 95% confidence interval [CI], 3.137–16.205) and RNFL (HR, 7.525; 95% CI, 3.272–17.311) thinning showed a significantly higher risk of developing VF defects. The rate of change in the average GCIPL and RNFL thickness was significantly higher in the eyes that developed VF defects (−0.71±0.57 and −1.13±0.85 µm/year, respectively) than the eyes that did not (−0.19±0.32 and −0.27±0.64 µm/year, respectively; all p < 0.05). Progressive GCIPL (43.1±15.7 and 63.1±20.2 months, respectively; p < 0.001) and RNFL (50.9±15.9 and 66.7±19.2 months, respectively; p < 0.001) thinning were detected significantly earlier than the development of VF defects. Conclusions: Monitoring progressive change in GCIPL, as well as RNFL, effectively predicts the development of VF defects in glaucoma suspects.

Ganglion Cell–Inner Plexiform Layer and Retinal Nerve Fiber Layer Changes in Glaucoma Suspects Enable to Predict Glaucoma Development

Joong Won Shin, Kyung Rim Sung, Min Kyung Song

Department of Ophthalmology, College of Medicine, University of Ulsan, Asan Medical Center

Short title: GCIPL and RNFL thinning in glaucoma suspects

Corresponding author: Kyung Rim Sung, MD, PhD Department of Ophthalmology, College of Medicine, University of Ulsan, Asan Medical Center, 388-1 Pungnap-2-dong, Songpa-gu, Seoul 138-736, Korea Tel: 82-2-3010-3680 Fax: 82-2-470-6440 E-mail: [email protected]

Introduction Glaucoma is often a slowly progressive disease characterized by structural changes in the optic nerve head (ONH) and retinal ganglion cell (RGC), as well as their axonal loss and accompanying visual field (VF) defects. As the damage from glaucoma is irreversible, it is important to detect the disease at an early stage before significant VF loss has developed. Glaucoma suspects form the key group requiring early detection of progressive change. Progressive loss of the peripapillary retinal nerve fiber layer (RNFL) detected using optical coherence tomography (OCT) in glaucoma suspects is considered a risk factor for the development of VF defects.1, 2 Furthermore, previous studies have shown that macular damage is prevalent among patients with early glaucoma.3-5 In early glaucoma, progressive macular ganglion cell–inner plexiform layer (GCIPL) thinning is frequently detected before corresponding RNFL thinning.6 Therefore, macular imaging, in addition to peripapillary imaging, may be useful to monitor the progressive change in glaucoma suspects. Guided Progression Analysis (GPA; Carl Zeiss Meditec, Dublin, CA, USA) was developed to facilitate the tracking of structural changes in OCT. It offers an effective approach to detect progressive GCIPL and RNFL thinning in patients with established glaucoma.7-9 In addition, integrating GCIPL and RNFL GPA in glaucoma monitoring could facilitate the early detection of progressive changes.10 However, little is known about longitudinal changes in GCIPL and RNFL thicknesses using OCT GPA in glaucoma suspects. Although VF examination has commonly been used to confirm the diagnosis of glaucoma, structural damage may occur in many patients before VF defects are detectable on standard automated perimetry (SAP).11, 12 Therefore, the purpose of this study was to investigate whether progressive GCIPL and RNFL thinning are predictive of the development of VF defects in glaucoma suspects.

Methods Study Subjects This study recruited subjects from the Asan Glaucoma Progression Study, an ongoing, longitudinal, retrospective cohort study, conducted at the Asan Medical Center (Seoul, Korea). The data were collected by reviewing medical records from April 2009 and February 2019. The Institutional Review Board of Asan Medical Center approved the present study, and all procedures were carried out in accordance with the principles of the Declaration of Helsinki. The requirement for informed consent was waived owing to the retrospective nature of the study. At the baseline visit, all of the subjects underwent complete ophthalmologic examinations, including the measurement of best-corrected visual acuity (BCVA), intraocular pressure (IOP) by using Goldmann applanation tonometry, refractive error by using an autorefractor (KR-890; Topcon Corp, Tokyo, Japan), axial length (IOLMaster; Carl Zeiss Meditec), central corneal thickness (CCT; DGH-550; DGH Technology, Exton, PA, USA), slit-lamp biomicroscopy, and gonioscopy. At every 9 month follow-up visit (± 3 months), the subjects underwent stereoscopic optic disc and red-free RNFL photography (AFC-210; Nidek, Aichi, Japan), RNFL and GCIPL imaging (Cirrus HD-OCT; Carl Zeiss Meditec), and VF testing (Humphrey Field Analyzer [HFA], Swedish Interactive Threshold Algorithm [SITA] 24-2; Carl Zeiss

Meditec). To be included, all participating glaucoma suspects must have met the following criteria: BCVA ≥ 20/30; a spherical equivalent between −8.0 and + 3.0 diopters (D), and a cylinder correction within +3 D; and a normal anterior chamber and open angle on slit-lamp and gonioscopic examinations. A glaucoma suspect was defined as an individual with ocular hypertension (IOP > 21 mmHg) or an optic disc appearance suspicious of glaucoma (e.g., vertical cup-to-disc ratio ≥ 0.7, focal neural rim thinning, or disc hemorrhage) as determined by two experienced graders (J.W.S. and K.R.S.), without evidence of repeatable glaucomatous VF damage.1, 13 Eyes with disagreement between graders were excluded. Subjects with secondary causes of elevated IOP, or any ophthalmic or neurological disease known to affect the ONH, macular structure, or VF were excluded. All included subjects did not use IOP lowering medications at baseline. Optical Coherence Tomography Imaging The GCIPL and RNFL images were respectively obtained by using macular and optic disc cube scans with the Cirrus HD-OCT system. The macular cube scan generated a GCIPL thickness map that covered a 6 × 6 mm2 (512 × 128 pixels) area centered at the fovea. The average macular GCIPL thicknesses were measured within an annulus with inner vertical and horizontal diameters of 1 and 1.2 mm, respectively, and outer vertical and horizontal diameters of 4 and 4.8 mm, respectively. The optic disc cube scan generated the RNFL thickness map that covered a 6 × 6 mm2 (200 × 200 pixels) area centered at the optic disc. The average peripapillary RNFL thicknesses were measured in a circle, 3.46 mm in diameter. Only images with a signal strength ≥ 6 in both macular and optic disc cube scans were included. Images with motion artifacts, poor centering, or segmentation errors were checked and discarded by the operator, and re-scanning was performed during the same visit. Eyes were excluded if they had less than 6 pairs of GCIPL and RNFL images (20 eyes were excluded) or less than 3 years of follow-up duration (14 eyes were excluded). Forty-one OCT images from 23 eyes were excluded due to unmet signal strength, and 25 OCT images from 10 eyes were excluded due to uncorrectable segmentation errors. The average number of OCT examinations per eye was 8.5 (range, 6-17). In total, 4532 OCT images were included in the final analysis. Progressive Thinning in Guided Progression Analysis of the Ganglion Cell– Inner Plexiform Layer and Retinal Nerve Fiber Layer The Cirrus HD-OCT GPA (Carl Zeiss Meditec, software version 10.0) provides color-coded classification in order to facilitate the detection of progressive glaucomatous change in clinical practice. The built-in software automatically aligns, registers, and compares baseline and follow-up OCT images. Abnormal GCIPL or RNFL changes, which exceed the range of the test–retest variability, are presented using yellow and red codes in a 6 × 6 mm2 (50 × 50 superpixels) map. The “possible loss”, with a yellow code, indicates the first detection of an abnormal GCIPL or RNFL change in the GCIPL or RNFL thickness change map. The “likely loss”, with a red code, indicates that an abnormal GCIPL or RNFL change is confirmed in a subsequent follow-up examination. In the current study, progressive thinning was defined as when at least 20 contiguous pixels, coded with red, in the GCIPL or RNFL thickness change map were detected during follow-up, and the same changes were

observed in the latest follow-up visit.7-10 Trend analysis provides the rate of change in the GCIPL and RNFL thicknesses over time using linear regression. The GPA requires 2 baseline tests and at least 4 tests to determine the “likely loss” and the rate of change in thickness. Development of Visual Field Defect All VF tests were performed using the HFA with the 24-2 SITA standard strategy. Only reliable tests with false-positive or false-negative errors less than 15%, and fixation losses less than 20%, were used in the study. The first VF test was excluded from the analysis in order to reduce the learning effect. The minimal abnormality for a glaucomatous VF defect included a cluster of three or more non-edge contiguous points on a pattern deviation plot in a single hemifield (superior or inferior) with a pvalue of less than 5% (with at least one having a p-value of less than 1%); a pattern standard deviation with a p-value of less than 5%; or a glaucoma hemifield test result outside normal limits.14 The development of VF defect was defined when three consecutive VF tests met the same criterion for abnormality.12 The reference standard for glaucoma conversion was determined by the development of VF defect. When the VF defect was confirmed in three consecutive VF tests, IOP lowering agents were prescribed to the subjects. When we detected preperimetic glaucomatous change, such as progressive GCIPL or RNFL thinning, we were carefully following up the subjects without medication until they were confirmed to be perimetric glaucoma. Statistical Analysis The statistical package R version 3.5.1 (R Foundation for Statistical Computing, Vienna, Austria) was used for statistical analyses. A linear mixed effect model was used to adjust for correlation between two eyes of the same patient. The demographics and clinical characteristics were compared between eyes with and without the development of VF defects. Univariable and multivariable Cox proportional hazard models were used to evaluate the risk of developing VF defects. A shared frailty model was employed to adjust for correlation between two eyes in the time-to-event data. Kaplan–Meier survival analysis and log-rank test were used to compare the cumulative probability of developing VF defect in eyes with and without progressive GCIPL or RNFL thinning.

Results A total of 541 eyes of 357 glaucoma suspects (208 men and 149 women) were included in this study. The mean follow-up period was 5.7 ± 1.4 years (range, 3.1–9.4 years). At the baseline visit, the mean age, refractive error, axial length, CCT, IOP, average GCIPL and RNFL thicknesses, VF mean deviation (MD), and the proportion of ocular hypertension were 58.9 ± 13.6 years, −1.29 ± 3.16 D, 24.38 ± 1.65 mm, 537.4 ± 41.7 µm, 16.2 ± 3.9 mmHg, 78.6 ± 7.0 µm, 86.9 ± 10.5 µm, −0.79 ± 1.34 dB, and 15.3%, respectively. Sensitivity and Specificity of Guided Progression Analysis for Detecting Development of Visual Field Defect in Glaucoma Suspects The development of VF defect was detected in 40 eyes (7.4%) during the follow-up period. The clinical characteristics of eyes with and without the development of VF

defect are summarized in Table 1. Eyes that demonstrated the development of VF defects had a longer follow-up duration and thinner average GCIPL and RNFL thicknesses at baseline examination compared to eyes without. The GPA detected progressive GCIPL and RNFL thinning in 74 eyes (13.7%) and 87 eyes (16.1%), respectively (Figure 1). Fifty-one eyes (9.4%) showed both progressive GCIPL and RNFL thinning. The sensitivity and specificity of progressive GCIPL thinning for detecting the development of VF defects were 72.5% (29/40 eyes) and 91.0% (456/501 eyes), respectively, and those of progressive RNFL thinning were 77.5% (31/40 eyes) and 88.8% (445/501 eyes), respectively. The rate of change in the average GCIPL and RNFL thickness was significantly higher in eyes that developed VF defects (−0.71 ± 0.57 µm/year and −1.13 ± 0.85 µm/year, respectively) than eyes that did not (−0.19 ± 0.32 µm/year and −0.27 ± 0.64 µm/year, respectively; all p < 0.05). Spatial Distribution of Visual Field Defect and Correspondence with Progressive Ganglion Cell–Inner Plexiform Layer and Retinal Nerve Fiber Layer Change Figure 2 shows the frequency and distribution of VF abnormality on a pattern deviation plot in 24-2 VF when the development of VF defects was first detected. Among 40 eyes with the development of VF defects, initial VF defect was most frequently detected in the superonasal test point within parafoveal VF (16 eyes, 40%). However, regional involvement of VF defect was more frequent in nasal VF (22.5%) than in parafoveal VF (18.8%). Among 36 eyes with progressive GCIPL or RNFL thinning and the development of VF defects, spatial correspondence between progressive structural and functional changes were observed in 33 eyes (91.6%); 21 eyes (58.3%) had inferior GCIPL or RNFL progression and development of superior VF defect, and 12 eyes (33.3%) had superior GCIPL or RNFL progression and development of inferior VF defect.

Temporal Relationship among Progressive Ganglion Cell–Inner Plexiform Layer, Retinal Nerve Fiber Layer, and Visual Field Change Among 29 eyes with progressive GCIPL and VF change, progressive GCIPL thinning was detected before the development of VF defects in 24 eyes (82.8%), whereas the development of VF defect was detected before progressive GCIPL thinning in 5 eyes (17.2%). The first detection of progressive GCIPL thinning was significantly earlier than that of the development of VF defect (43.1 ± 15.7 and 63.1 ± 20.2 months, respectively; p < 0.001). Among 31 eyes with progressive RNFL and VF change, 23 eyes (74.2%) showed progressive RNFL thinning before the development of VF defect, 6 eyes (19.4%) showed the development of VF defect before progressive RNFL thinning, and 2 eyes (6.4%) showed progressive RNFL and VF change simultaneously. The first detection of progressive RNFL thinning was significantly earlier than that of the development of VF defect (50.9 ± 15.9 and 66.7 ± 19.2 months, respectively; p < 0.001). Among 24 eyes with progressive GCIPL, RNFL, and VF change, 11 eyes (45.8%) showed progressive GCIPL thinning before progressive RNFL thinning, 6 eyes (25.0%) showed progressive RNFL thinning before progressive GCIPL thinning, and 7 eyes (29.2%) showed progressive GCIPL and RNFL thinning simultaneously. There was no significant difference in the first detection between progressive GCIPL and RNFL thinning (44.3 ± 15.1 and 49.6 ±

17.2 months, respectively; p = 0.214). Figure 3 shows representative cases temporal relationship among progressive GCIPL, RNFL, and VF change. Risk of Developing Visual Field Defect in Eyes with Progressive Ganglion Cell– Inner Plexiform Layer and Retinal Nerve Fiber Layer Thinning Kaplan-Meier survival analysis revealed that eyes with progressive GCIPL or RNFL thinning had a significantly greater probability of the development of VF defects (all p < 0.001, Figure 4). Table 2 shows the results of the Cox proportional hazard model for the risk of development of VF defect. In the univariable Cox proportional hazard model, progressive GCIPL (hazard ratio [HR], 7.431; 95% confidence interval [CI], 3.291-16.780; p<0.001) and RNFL (HR, 7.449; 95% CI, 3.271-16.960; p<0.001) thinning were significantly associated with the risk of developing VF defect. The baseline average GCIPL thickness (HR, 0.947; 95% CI, 0.894–1.003; p = 0.062) showed marginal statistical significance. In the multivariable model, eyes with progressive GCIPL (HR, 7.130; 95% CI, 3.137–16.205; p < 0.001) and RNFL (HR, 7.525; 95% CI, 3.272–17.311; p < 0.001) thinning showed a significantly higher risk of developing VF defect after adjusting for the baseline average GCIPL thickness.

Discussion According to the clinical guidelines for glaucoma suspects suggested by the American Academy of Ophthalmology and the United Kingdom National Institute for Health and Clinical Care Excellence, the examinations of IOP, VF, optic disc, and RNFL are recommended in clinical practice to determine if damage has occurred.15, 16 Although a growing body of evidence has recently suggested that macular imaging is essential for monitoring patients with established glaucoma,6-8, 10 there is limited empirical evidence for a macular assessment in the follow-up of glaucoma suspects. In the current study, we showed the validity of macular imaging in glaucoma suspects by using OCT GPA. In 541 eyes of 357 glaucoma suspects, OCT GPA detected progressive GCIPL thinning in 74 eyes (13.7%) during the mean follow-up of 5.7 years. The sensitivity and specificity of GCIPL GPA for detecting the development of VF defects were 72.5% and 91.0%, respectively. Eyes with progressive GCIPL thinning had a 7.130-fold increase in the risk of developing VF defects compared to eyes without. In addition, progressive GCIPL thinning was detected significantly earlier than the development of VF defects. Our findings suggest that macular GCIPL assessment in monitoring glaucoma suspects may be effective for the early detection of glaucomatous conversion. In glaucoma suspects, the early diagnosis of glaucoma is important to commence proper treatment and minimize the risk of irreversible VF loss. The role of RNFL measurement in following glaucoma suspects has been well defined.15 Increased RNFL atrophy was associated with an increased risk of the development of VF loss.2, 17 Furthermore, Miki et al.1 showed that a 1-µm/year faster rate of RNFL loss corresponded to a 2.05-fold higher risk of developing VF defects in glaucoma suspects. In glaucoma suspects, the assessment of RNFL thickness has the potential to detect glaucomatous damage before the appearance of VF defects.18 Previous studies have shown that GCIPL measurement is also valuable in monitoring suspected or manifest glaucoma. In a study of 513 eyes of 309 participants with suspected and preperimetric glaucoma followed up for 41 months, Zhang et al.19 reported that the most accurate predictors of developing glaucoma

were focal RGC loss at baseline, followed closely by focal RNFL loss. In addition, Hou et al.10 reported the efficacy of integrating GCIPL and RNFL measurements in following patients with manifest glaucoma. In the current study, we found that progressive GCIPL thinning, as well as progressive RNFL thinning, was predictive of the development of VF defects in glaucoma suspects. In facilitating the early detection of VF conversion in glaucoma suspects, it would be required to monitor both the macula and peripapillary areas. A previous study of 151 patients with early glaucoma (VF MD, -3.4 dB) over a 3year follow-up period demonstrated that progressive macular GCIPL thinning was frequently detected before corresponding peripapillary RNFL thinning.6 In a recent study of 231 eyes of 136 glaucoma patients (VF MD, -9.6 dB) with a mean follow-up period of 5.8 years, Hou et al.10 reported that 19 eyes showed GCIPL thinning detected before RNFL thinning, and 13 eyes showed RNFL thinning detected before GCIPL thinning, among the 35 eyes demonstrated to have both progressive RNFL and GCIPL thinning. In the current study, we found similar findings in eyes with suspected glaucoma. Among 24 eyes with progressive GCIPL, RNFL, and VF change, eyes with progressive GCIPL thinning detected before progressive RNFL thinning (11 eyes, 45.8%) were observed more than eyes with progressive RNFL thinning detected before progressive GCIPL thinning (6 eyes, 25.0%). However, there was no significant difference in the first detection between progressive GCIPL and RNFL thinning, although progressive GCIPL thinning was detected slightly earlier than progressive RNFL thinning (44.3 ± 15.1 and 49.6 ± 17.2 months, respectively; p = 0.214). Early glaucomatous damage to the macula may be overlooked in the 24-2 VF test. Indeed, De Moraes et al.20 showed that 79 of 200 (39.5%) eyes with suspected glaucoma classified as normal on the 24-2 VF test were classified as abnormal on the 10-2 VF test. Furthermore, Traynis et al.4 reported that in early glaucoma, 16% of eyes with normal 24-2 VF results have defects on the 10-2 VF test. In the current study, we observed 40 eyes (7.4%) that showed abnormality on the 24-2 VF test; however, this value may have been underestimated since the 10-2 VF test was not performed. In contrast, we found 74 eyes (13.7%) with macular GCIPL progression and 87 eyes (16.1%) with peripapillary RNFL progression. Shin et al.21 reported that the macular GCIPL parameters were more valuable than the peripapillary RNFL parameters for detecting early glaucoma in eyes with parafoveal VF loss, and that the RNFL parameters were better than the GCIPL parameters in eyes with peripheral VF loss. Although the 10-2 VF test can provide valuable information relating to macular damage, in clinical practice, it is challenging to perform multiple VF tests. Therefore, macular evaluation using OCT may be a good alternative to the 10-2 VF test. In the current study of glaucoma suspects, the rate of change in average GCIPL and RNFL thickness was faster in eyes with the development of VF defects (-0.71 µm/year and -1.13 µm/year, respectively) than in eyes without (-0.19 µm/year and 0.27 µm/year, respectively); these findings are consistent with previous studies in eyes with suspected glaucoma. Indeed, in a study of 43 glaucoma suspects and 29 glaucomatous eyes over a 4.4-year follow-up period, the rate of macular thickness loss in progressing eyes was faster than that in non-progressing eyes.22 Furthermore, in a study of 454 eyes of 294 glaucoma suspects with median follow-up of 2.2 years, the rate of average RNFL loss was significantly faster in eyes that developed VF defects compared with eyes that did not (-2.02 µm/year and -0.82 µm/year,

respectively).1 Hammel et al.23 reported that the rate of change in average GCIPL thickness was -0.14 µm/year in 56 eyes of 28 healthy participants at a median followup of 1.7 years. Considering that the higher rate of change in average RNFL thickness is predictive of conversion to glaucoma in glaucoma suspects,1 the rate of change in average GCIPL thickness could also be an entirely predictable consequences of the development of glaucoma. Avoiding false identification of progressive thinning in glaucoma suspects is important as it has the potential to lead to unnecessary treatments, as well as the potential adverse effects of IOP-lowering agents. A recent study reported excellent specificities for GCIPL and RNFL GPA (95.5% and 91.0%, i.e., false-positive rates of 4.5% and 9.0%, respectively) in 67 eyes of 36 healthy participants over a mean follow-up period of 7.8 years.10 However, no guidelines are available to distinguish glaucomatous progressive thinning from false-positive findings in eyes with suspected or established glaucoma. Our findings should be interpreted with caution considering the potential of false-positive results. Further investigation is needed for the factors affecting the false-positive results in progressive GCIPL and RNFL thinning. In conclusion, monitoring both the macular and peripapillary area using OCT provides an effective approach to predict the development of VF defect in glaucoma suspects. Progressive GCIPL and RNFL thinning were detected significantly earlier than the development of VF defects. In glaucoma suspects, the early diagnosis of glaucoma is important to commence proper treatment and minimize the risk of irreversible VF loss. Macular GCIPL measurement, as well as RNFL, may be useful ancillary tools in the serial observation of glaucoma suspects for the early detection of glaucoma development.

ACKNOWLEDGMENTS/DISCLOSURE

a. Funding/Support: None

b. Financial Disclosures: None

c. Other Acknowledgments: None

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Figure captions Figure 1. A proportional Venn diagram showing the number of eyes with progressive ganglion cell-inner plexiform layer (GCIPL), retinal nerve fiber layer (RNFL) thinning, and the development of visual field (VF) defects in glaucoma suspects. Figure 2. A frequency and distribution of VF abnormality on a pattern deviation plot in 24-2 visual field (VF) when the development of VF defects was first detected. Among 40 eyes with the development of VF defects, nasal (dotted triangle) and parafoveal (dotted circle) VF involvement were 22.5% and 18.8%, respectively. Figure 3. (Top) Case example of a 64-year-old woman who demonstrated progressive ganglion cell-inner plexiform layer (GCIPL) thinning (August 31, 2012) before progressive retinal nerve fiber layer (RNFL) thinning (December 2, 2013). The development of visual field (VF) defect, which was defined as the presence of three consecutive abnormal VFs, was detected on December 12, 2018, approximately 6 years after the first detection of the progressive structural change. (Bottom) Case example of a 66-year-old man showed progressive RNFL thinning (June 3, 2013) before progressive GCIPL thinning (March 3, 2014). The development of VF defect was confirmed on December 8, 2014, approximately 18 months after the first detection of the progressive structural change. Figure 4. Kaplan-Meier curves stratified according to the presence of progressive ganglion cell-inner plexiform layer (GCIPL) and retinal nerve fiber layer (RNFL) thinning in glaucoma suspects. The statistical endpoint was defined as the time of the first detection of the development of visual field (VF) defect. Eyes with progressive GCIPL and RNFL thinning had a greater cumulative probability of development of VF defect than eyes without (p < 0.001, log-rank test).

Table 1. Clinical characteristics in eyes with and without the development of visual field defect All

Age (years) Refractive error (D) Axial length (mm) Central corneal thickness (µm) Follow-up duration (years) Ocular hypertension Intraocular pressure (IOP, mmHg) Baseline IOP Mean follow-up IOP Peak follow-up IOP Range of follow-up IOP Fluctuation of follow-up IOP Visual field measurement Baseline MD (dB) Baseline PSD (dB) Final MD (dB) Final PSD (dB) Rate of change in MD (dB/year) Rate of change in PSD (dB/year) Macular GCIPL measurement Baseline average GCIPL thickness (µm) Final average GCIPL thickness (µm) *Rate of change in average GCIPL thickness (µm/year) Peripapillary RNFL measurement Baseline average RNFL thickness (µm) Final average RNFL thickness (µm) *Rate of change in average RNFL thickness (µm/year)

(n=541) 58.9 ± 13.6 -1.29 ± 3.16 24.38 ± 1.65 537.4 ± 41.7 5.7 ± 1.4 83 (15.3)

Eyes with VFD (n=40) 60.4 ± 13.4 -1.02 ± 3.14 24.30 ± 1.77 530.4 ± 41.5 7.7 ± 1.3 10 (25.0)

Eyes without VFD (n=501) 58.8 ± 13.7 -1.31 ± 3.16 24.39 ± 1.65 537.9 ± 41.7 5.6 ± 1.3 73 (14.6)

P

0.537 0.601 0.941 0.425 <0.001 0.078

16.2 ± 3.9 14.7 ± 2.5 18.6 ± 4.9 6.9 ± 4.7 2.1 ± 1.2

16.7 ± 5.8 14.9 ± 2.5 19.5 ± 5.5 7.9 ± 5.4 2.3 ± 1.3

16.1 ± 3.7 14.7 ± 2.5 18.5 ± 4.8 6.9 ± 4.7 2.1 ± 1.2

0.295 0.388 0.098 0.077 0.118

-0.79 ± 1.34 1.84 ± 0.88 -0.88 ± 1.83 2.02 ± 1.43 0.09 ± 0.34 0.03 ± 0.22

-0.93 ± 1.20 1.84 ± 0.61 -3.05 ± 3.16 4.89 ± 3.42 -0.31 ± 0.37 0.40 ± 0.49

-0.79 ± 1.36 1.86 ± 1.06 -0.71 ± 1.57 1.84 ± 0.94 0.11 ± 0.32 0.01 ± 0.16

0.493 0.772 <0.001 0.021 <0.001 <0.001

78.6 ± 7.0 77.4 ± 7.5 -0.23 ± 0.37

74.8 ± 7.3 71.0 ± 7.9 -0.71 ± 0.57

78.9 ± 6.9 77.9 ± 7.2 -0.19 ± 0.32

<0.001 <0.001 <0.001

86.9 ± 10.5 85.1 ± 10.5 -0.33 ± 0.70

83.2 ± 8.8 76.9 ± 9.9 -1.13 ± 0.85

87.2 ± 10.5 85.7 ± 10.3 -0.27 ± 0.64

0.010 <0.001 <0.001

Data are mean ± standard deviation or no. (%). MD = mean deviation; PSD = pattern standard deviation; GCIPL = ganglion cell-inner plexiform layer; RNFL = retinal nerve fiber layer. *Rates of change in GCIPL and RNFL thicknesses were determined using Guided Progression Analysis.

Table 2. Univariable and multivariable Cox proportional hazard models for the risk of development of visual field defect in glaucoma suspects Univariable model

Progressive GCIPL thinning

Hazard ratio (95% CI) 7.431 (3.291-16.780)

p <0.001

Progressive RNFL thinning

7.449 (3.271-16.960)

<0.001

Age (years)

1.005 (0.975-1.037)

0.731

Sex

0.910 (0.464-1.781)

0.782

Refractive error (D)

1.037 (0.902-1.193)

0.608

Axial length (mm)

0.886 (0.595-1.320)

0.553

Central corneal thickness (µm)

0.997 (0.989-1.006)

0.533

Follow-up duration (years)

1.056 (0.642-1.737)

0.830

Baseline IOP (mmHg)

1.016 (0.935-1.104)

0.706

Mean follow-up IOP (mmHg)

1.074 (0.944-1.221)

0.278

Peak follow-up IOP (mmHg)

1.003 (0.969-1.038)

0.874

Range of follow-up IOP (mmHg)

0.996 (0.963-1.031)

0.835

Fluctuation of follow-up IOP

0.993 (0.871-1.133)

0.922

Baseline VF MD (dB)

1.042 (0.857-1.267)

0.678

Baseline GCIPL thickness (µm)

0.947 (0.894-1.003)

0.062

Baseline RNFL thickness (µm)

0.987 (0.958-1.018)

0.422

Multivariable model 1 with progressive GCIPL thinning included Hazard ratio (95% CI) 7.130 (3.137-16.205)

0.968 (0.912-1.028)

p

Multivariable model 2 with progressive RNFL thinning included Hazard ratio (95% CI)

p

<0.001

0.298

7.525 (3.272-17.311)

<0.001

0.951 (0.898-1.007)

0.083

GCIPL = ganglion cell-inner plexiform layer; RNFL = retinal nerve fiber layer; CI = confidence interval; IOP = intraocular pressure; VF MD = visual field mean deviation.

In this retrospective long-term study, 541 eyes of 357 glaucoma suspects with mean follow-up duration of 5.7 years were analyzed. Progressive ganglion cell-inner plexiform layer (GCIPL) and retinal nerve fiber layer (RNFL) thinning were detected significantly earlier than the development of visual field (VF) defects. Monitoring progressive change in GCIPL, as well as RNFL, effectively predicts the development of VF defects in glaucoma suspects.