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Purpose To evaluate long-term, longitudinal displacement of the optic nerve head (ONH) and anterior lamina cribrosa surfaces in glaucoma patients imaged with spectral-domain optical coherence tomography (SD OCT). Design Prospective study. Participants A total of 173 eyes of 108 subjects (88 with glaucoma and 20 normal subjects) followed for a mean of 5.3 years. Methods The optic disc was imaged with SD OCT at approximately 4-month intervals, and the ONH surface depth (ONHSD), anterior lamina cribrosa surface depth (ALCSD), and prelaminar tissue thickness (PTT) were measured. The reproducibility coefficients of ONHSD, ALCSD, and PTT were calculated from 2 baseline measurements of the glaucoma group. Change in ONHSD/ALCSD/PTT was confirmed when the differences between the first baseline and the latest 2 consecutive follow-up visits were greater than the corresponding reproducibility coefficient. Factors associated with ONHSD and ALCSD changes were identified with linear mixed modeling. Main Outcome Measures Proportion of eyes with ONHSD/ALCSD change. Results Within the glaucoma group, 23.9% (33 eyes) had confirmed ONHSD change (15.2% with posterior and 8.7% with anterior displacement) and 24.6% (34 eyes) had confirmed ALCSD change (12.3% with posterior and 12.3% with anterior displacement). Some 9.4% (13 eyes) showed a decrease in PTT, and 2.2% (3 eyes) showed an increase in PTT. The specificity for detection of ONHSD/ALCSD/PTT change was 91.4% (95% confidence interval [CI], 77.6-97.0), 82.9% (95% CI, 67.3-91.9), and 94.3% (95% CI, 81.4-98.4), respectively. There were no significant differences in the proportion of eyes with visual field progression or history of filtration surgery between the groups with anterior and posterior displacement of ONH/anterior laminar surfaces (P ≥ 0.678). For each millimeter of mercury increase in the average intraocular pressure (IOP) during follow-up, the ONH and anterior laminar surfaces displaced posteriorly by 1.6 μm and 2.0 μm, respectively. An older age was associated with a decrease in magnitude of posterior displacement of the ONH and anterior laminar surfaces (P ≤ 0.009). Conclusions The ONH and anterior laminar surfaces displaced not only posteriorly but also anteriorly (with reference to Bruch's membrane opening) in a significant portion of glaucoma patients. The magnitude of change was related to age and the averaged IOP during follow-up.

Objective: To investigate the temporal relationship between optic nerve head (ONH) surface depression and retinal nerve fiber layer (RNFL) thinning measured by confocal scanning laser ophthalmoscopy (CSLO) and spectral-domain optical coherence tomography (SD-OCT), respectively, during the course of glaucoma progression. Design: Prospective, longitudinal study. Participants: A total of 146 eyes of 90 patients with glaucoma and 70 normal eyes of 35 healthy individuals followed for an average of 5.4 years (range, 48.0-76.6 months). Methods: Eyes were imaged by CSLO (Heidelberg Retinal Tomograph [HRT]; Heidelberg Engineering, GmbH, Dossenheim, Germany) and SD-OCT (Cirrus HD-OCT; Carl Zeiss Meditec AG, Dublin, CA) at approximately 4-month intervals for measurement of ONH surface topography and RNFL thickness, respectively. Significant ONH surface depression and RNFL thinning were defined with reference to Topographic Change Analysis (TCA) with HRT and Guided Progression Analysis (GPA) with Cirrus HD-OCT, respectively. The survival probabilities were compared with a Cox proportional hazards model. Main Outcome Measures: Number of eyes with progressive ONH and RNFL changes and the sequence of changes. Results: A total of 3238 OCT and 3238 CSLO images obtained in the same follow-up visits were analyzed. At a specificity of 94.3% (4 eyes showed ONH surface depression and 4 eyes showed RNFL thinning in the normal group), 57 eyes (39.0%) had ONH surface depression, 46 eyes (31.5%) had RNFL thinning, and 23 eyes (15.8%) had evidence of both in the glaucoma group. Among these 23 eyes, 19 (82.6%) had ONH surface depression detected before RNFL thinning, with a median lag time of 15.8 months (range, 4.0-40.8 months). Although only 7.0% of eyes (4/57) had RNFL thinning at the onset of ONH surface depression, 45.7% (21/46) had ONH surface depression at the onset of RNFL thinning. The survival probability of eyes with ONH surface depression was significantly worse than eyes with RNFL thinning (P = 0.002). Conclusions: With reference to the HRT TCA and OCT GPA, ONH surface depression occurred before RNFL thinning in a significant proportion of patients with glaucoma. A time window for therapeutic intervention may exist on detection of ONH surface depression before there is observable RNFL thinning in glaucoma.

Background: The loss of RGCs expressing Thy-1 after optic nerve injury has an initial phase of rapid decline followed by a longer phase with slower reduction rate. This study used longitudinal retinal imaging of mice expressing cyan fluorescent protein under control of the Thy-1 promoter (Thy1-CFP mice) to determine how the α2-adrenergic agonist brimonidine influences loss of Thy1 promoter activation. Methods. Baseline images of the fluorescent retinal neurons in 30 Thy1-CFP mice were obtained using a modified confocal scanning laser ophthalmoscope. Next, brimonidine (100 ug/kg, IP) was administered either one time immediately after optic nerve crush, or immediately after optic nerve crush and then every 2 days for four weeks. A control group received a single saline injection immediately after optic nerve crush. All animals were imaged weekly for four weeks after optic nerve crush. Loss of fluorescent retinal neurons within specific retinal areas was determined by counting. Results: At one week after optic nerve crush, the proportion of fluorescent retinal neurons retaining fluorescence was 44±7% of baseline in control mice, 51±6% after one brimonidine treatment, and 55±6% after brimonidine treatment every other day (P

Purpose: To apply retinal nerve fiber layer (RNFL) optical texture analysis (ROTA) to 1) investigate the association between papillomacular and papillofoveal bundle defects with 10-2 visual field (VF) sensitivity abnormalities, and 2) integrate the information from RNFL bundle defect and 24-2 VF central test locations to determine the likelihood of 10-2 VF sensitivity abnormalities., Design: Cross-sectional., Methods: A total of 841 eyes (144 healthy, 317 glaucoma suspect, and 380 glaucoma) of 442 participants were included. Eyes underwent 24-2, and 10-2 VF testing and OCT for ROTA. The borders of RNFL defects were delineated from ROTA, and the involvement of the arcuate, papillomacular, and papillofoveal bundles was determined for each eye. Multilevel logistic regression analysis was applied to evaluate the structure-function association., Results: Papillomacular (92.1%) and papillofoveal (37.9%) RNFL bundle defects were prevalent in eyes with glaucoma. A 10-2 VF location that was projected onto a papillomacular or a papillofoveal RNFL bundle defect had a significantly increased likelihood of reduced sensitivity (ORs of 18.61 at PDP < 5%, and 20.17 at TDP < 5%, respectively, P < .001 for both). When predicting the likelihood of VF abnormality in a 10-2 test location, noticeably higher odds ratios were observed when overlapping with an RNFL bundle defect, compared to when an abnormal corresponding 24-2 central point was present., Conclusions: Papillomacular and papillofoveal RNFL bundle defects are present in a considerable proportion of eyes with glaucoma. When detected, they significantly increase the likelihood of abnormality in the corresponding central VF test locations assessed by the 10-2 test., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose: We compared the effect of three different transcranial electrical stimulation (tES) protocols delivered to the occipital lobe on peripheral vision in patients with glaucoma., Methods: A double-masked, placebo-controlled study was conducted with 35 patients with glaucoma. We compared three different tES protocols: anodal transcranial direct current stimulation (a-tDCS), transcranial alternating current stimulation (tACS), and transcranial random noise stimulation (tRNS) against sham stimulation. Each patient attended four stimulation sessions (a-tDCS, tACS, tRNS, and sham) in a random order with at least 48 hours between visits. Stimulation involved placing an anodal electrode over the occipital lobe (Oz) and cathodal electrode on the cheek for 20 minutes. High-resolution perimetry (HRP) and multifocal visual evoked potential (mfVEP) measurements were made before and immediately after stimulation. Changes in HRP detection accuracy/reaction time and mfVEP signal-to-noise ratio (SNR)/latency were analyzed using linear mixed models., Results: Compared to sham, HRP detection accuracy was significantly improved after a-tDCS in both the central 20-degree (b = 0.032, P = 0.018) and peripheral analysis (b = 0.051, P = 0.002). Additionally, mfVEP SNR was significantly increased (b = 0.016, P = 0.017) and the latency was shortened (b = -1.405, P = 0.04) by the a-tDCS in the central 20-degree analysis. In the peripheral analysis, there was a trend toward an enhancement of SNR after a-tDCS stimulation (b = 0.014, P = 0.052), but it did not reach statistical significance; latency was increased after tACS (b = 1.623, P = 0.041). No significant effects were found in comparison to other active tES protocols., Conclusions: A single session of a-tDCS enhances perceptual and electrophysiologic measures of vision in patients with glaucoma. However, the small magnitude of changes observed in HRP (3.2% for accuracy in central and 5.1% in peripheral) did not exceed previous test variability and may not be clinically meaningful., Translational Relevance: a-tDCS holds promise as a potential treatment for enhancing visual function. However, future studies are needed to evaluate the long-term effects and clinical relevance of this intervention using validated measures of perimetric changes in the visual field.

Background: Glaucoma patients with irreversible visual field loss often experience decreased quality of life, impaired mobility, and mental health challenges. Perceptual learning (PL) and transcranial electrical stimulation (tES) have emerged as promising interventions for vision rehabilitation, showing potential in restoring residual visual functions. The Glaucoma Rehabilitation using ElectricAI Transcranial stimulation (GREAT) project aims to investigate whether combining PL and tES is more effective than using either method alone in maximizing the visual function of glaucoma patients. Additionally, the study will assess the impact of these interventions on brain neural activity, blood biomarkers, mobility, mental health, quality of life, and fear of falling., Methods: The study employs a three-arm, double-blind, randomized, superiority-controlled design. Participants are randomly allocated in a 1:1:1 ratio to one of three groups receiving: (1) real PL and real tES, (2) real PL and sham tES, and (3) placebo PL and sham tES. Each participant undergoes 10 sessions per block (~ 1 h each), with a total of three blocks. Assessments are conducted at six time points: baseline, interim 1, interim 2, post-intervention, 1-month post-intervention, and 2-month post-intervention. The primary outcome is the mean deviation of the 24-2 visual field measured by the Humphrey visual field analyzer. Secondary outcomes include detection rate in the suprathreshold visual field, balance and gait functions, and electrophysiological and biological responses. This study also investigates changes in neurotransmitter metabolism, biomarkers, self-perceived quality of life, and psychological status before and after the intervention., Discussion: The GREAT project is the first study to assess the effectiveness of PL and tES in the rehabilitation of glaucoma. Our findings will offer comprehensive assessments of the impact of these treatments on a wide range of brain and vision-related metrics including visual field, neural activity, biomarkers, mobility, mental health, fear of falling, and quality of life., Trial Registration: ClinicalTrials.gov NCT05874258 . Registered on May 15, 2023., (© 2024. The Author(s).)

Purpose: To explore the effects of deep optic nerve head (ONH) structures on Bruch's membrane opening (BMO)-minimum rim width (MRW) and peripapillary retinal nerve fiber layer thickness (pRNFLT) in healthy eyes., Design: Prospective cross-sectional study., Methods: Two hundred five healthy eyes of 141 subjects (mean ± standard deviation of age and axial length (AXL): 46.9 ± 10.0 years and 24.79 ± 1.15 mm) were enrolled. Best fit multivariable linear mixed models identified factors associated with BMO-MRW and pRNFLT. Explanatory variables included age, gender, AXL, BMO and anterior scleral canal opening (ASCO) area and ovality, magnitude of BMO and ASCO shift, peripapillary choroidal thickness, lamina cribrosa (LC) parameters, prelaminar thickness, and peripapillary scleral (PPS) angle., Results: Thinner BMO-MRW was associated with older age, smaller ASCO/BMO offset magnitude, larger BMO area, thinner prelaminar thickness, deeper LC, and thinner pRNFLT (P = .011, <.001, .004, <.001, <.001, <.001 respectively). Thinner pRNFLT was associated with shorter AXL, smaller ASCO area, a more posteriorly bowed PPS, shallower LC and thinner BMO-MRW. (P = .030, .002, .035, .012, <.001 respectively) CONCLUSIONS: BMO-MRW and pRNFLT were influenced by several deep ONH structures such as BMO and ASCO position shift, BMO or ASCO area, prelaminar thickness, PPS bowing and LC depth in addition to patient characteristics such as age and AXL. The degree and/or direction of associations varied between deep ONH structures and BMO-MRW or pRNFLT. Despite both BMO-MRW and pRNFLT being surrogate parameters for RGC loss, a complex relationship with ONH deep-layer morphology was indicated., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Myopia, characterized by excessive axial elongation of the eyeball, increases risks of having sight-threatening diseases and impose a financial burden to healthcare system. Although myopic control interventions showed their effectiveness in slowing progression, the efficacy varies between individuals and does not completely halt progression. The study aims to investigate the efficacy of combining 0.01% atropine administered twice daily with optical defocus for myopia control in schoolchildren., Methods and Design: This is a prospective, parallel-group, single-blinded, randomized, active-control trial (ClinicalTrials.gov identifier: NCT06358755). Myopic schoolchildren with no previous myopic control interventions aged between 7 to 12 years will be recruited. They will be randomly allocated into two groups (n = 56 per group) after baseline measurement. Both groups will receive 0.01% atropine twice per day for 18 months (one drop in the morning and the other drop at night before bedtime). Defocus incorporated multiple segments (DIMS) spectacle lenses will be prescribed in atropine plus optical defocus (ATD) treatment group while single vision spectacle lenses will be given in atropine only (AT) group. Cycloplegic refraction and axial lengths will be monitored every 6 months over 18-month study period. The primary outcomes are changes in cycloplegic refraction and axial lengths relative to the baseline over the study period., Discussion: The result will examine the combination effect of low dose atropine and myopic defocus on myopia control in a randomized controlled study. The findings will also explore the potential benefits of applying 0.01% atropine twice per day on myopic control and its potential side effects., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Chun et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Purpose: To investigate factors associated with the severity of prelaminar schisis (PLS) in heathy subjects and glaucoma patients., Design: Prospective cross-sectional study., Methods: A total of 217 eyes of 217 subjects (110 normal eyes and 107 open angle glaucoma eyes) were studied. Frequency and severity of PLS were compared between normal and glaucomatous eyes. Multivariate logistic models were used to assess factors associated with the severity of PLS. Factors considered were age, axial length, glaucomatous damage indices, Bruch membrane opening (BMO) and anterior scleral canal opening parameters, tractional forces (posterior vitreous staging and presence of Bergmeister papilla), circumpapillary choroidal thickness, lamina cribrosa (LC) parameters, and peripapillary scleral (PPS) angle., Results: The frequency of PLS was 70.9% in normal eyes and 72.0% in glaucomatous eyes. There was no difference in frequency and severity between the groups. The presence of Bergmeister papilla was the strongest predictor of a more severe PLS in both normal and glaucomatous eyes (odds ratio [OR] + 9.78, 12.5; both P < .001). A larger PPS angle in normal eyes (OR = 1.19; P = .003) and a larger BMO area and a deeper LC depth in glaucomatous eyes (OR = 1.08, 1.05; both P = .038) were associated with severity of PLS., Conclusions: The severity of PLS was strongly associated with the presence of Bergmeister papilla, suggesting a traction-related phenomenon. Correlation of PLS severity with larger BMO area and deeper LC depth, which are optic nerve head structures associated with glaucoma, suggested its possible relationship with glaucomatous damage., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose: To apply retinal nerve fiber layer (RNFL) optical texture analysis (ROTA) to investigate the prevalence, patterns, and risk factors of RNFL defects in patients with ocular hypertension (OHT) who showed normal optic disc and RNFL configuration in clinical examination, normal RNFL thickness on OCT analysis, and normal visual field (VF) results., Design: Cross-sectional study., Participants: Six hundred eyes of 306 patients with OHT., Methods: All participants underwent clinical examination of the optic disc and RNFL, OCT RNFL imaging, and 24-2 standard automated perimetry. To detect RNFL defects, ROTA was applied. The risk score for glaucoma development was calculated according to the Ocular Hypertension Treatment Study and European Glaucoma Prevention Study (OHTS-EGPS) risk prediction model. Risk factors associated with RNFL defects were analyzed using multilevel logistic regression analysis., Main Outcome Measures: Prevalence of RNFL defects., Results: The average intraocular pressure (IOP) measured from 3 separate visits within 6 months was 24.9 ± 1.8 mmHg for the eye with higher IOP and 23.7 ± 1.7 mmHg for the eye with lower IOP; the respective central corneal thicknesses were 568.7 ± 30.8 μm and 568.8 ± 31.2 μm. Of 306 patients with OHT, 10.8% (33 patients, 37 eyes) demonstrated RNFL defects in ROTA in at least 1 eye. Of the 37 eyes with RNFL defects, the superior arcuate bundle was the most frequently involved (62.2%), followed by the superior papillomacular bundle (27.0%) and the inferior papillomacular bundle (21.6%). Papillofoveal bundle defects were observed in 10.8% of eyes. The smallest RNFL defect spanned 0.0° along Bruch's membrane opening margin, whereas the widest RNFL defect extended over 29.3°. Age (years) (odds ratio [OR], 1.08; 95% confidence interval [CI], 1.03-1.13), VF pattern standard deviation (decibels [dB]) (OR, 1.82; 95% CI, 1.01-3.29), cup volume (mm 3 ) (OR, 1.24; 95% CI, 1.01-1.53), and the OHTS-EPGS risk score (OR, 1.04; 95% CI, 1.01-1.07) were associated with RNFL defects., Conclusions: A considerable proportion of patients with OHT who showed no signs of optic disc and RNFL thickness abnormalities on clinical and OCT examination exhibited RNFL defects on ROTA. Axonal fiber bundle defects on ROTA may represent the earliest discernible sign of glaucoma in the glaucoma continuum., Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article., (Copyright © 2023 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: To elucidate which swept-source optical coherence tomography (OCT)-derived optic nerve head (ONH) parameters are associated with longer axial length (AXL) in healthy myopic eyes., Design: Prospective cross-sectional observational study., Methods: Two hundred eleven healthy eyes of 140 participants (96 emmetropic-mild myopic [AXL: 22.2-24.5 mm], 83 moderately myopic [24.5-26.0 mm], and 32 highly myopic [26.0-27.4 mm] eyes) were enrolled. Bruch membrane opening (BMO), anterior scleral canal opening (ASCO) area and ovality, minimum rim width, parameters defining misalignment between the BMO and ASCO planes, OCT-defined region of perineural canal retinal epithelium atrophy and externally oblique choroidal border tissue, circumpapillary retinal nerve fiber layer thickness (cpRNFLT), circumpapillary choroidal thickness (cpChT), lamina cribrosa parameters, and peripapillary scleral (PPS) angle were calculated from BMO-centered radial scans reconstructed from 3D raster scans. Multivariate linear mixed models were used to elucidate ONH parameters that are independently associated with AXL., Results: Longer AXL was associated with a greater misalignment between ASCO and BMO planes, larger region of externally oblique choroidal border tissue, thinner cpChT, larger PPS angle, larger ASCO area, and thicker cpRNFLT (all P < .040 after Bonferroni's correction for number of included explanatory variables)., Conclusions: A greater misalignment between BMO and ASCO planes, thinner choroid, a more posteriorly bowed PPS, an enlargement of ASCO, and thicker cpRNFLT were each associated with longer AXL. An enhanced understanding of these AXL-associated configurations should provide essential information to improve our ability to detect glaucoma-induced ONH morphology in myopic eyes., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Artificial intelligence (AI) has been approved for biomedical research in diverse areas from bedside clinical studies to benchtop basic scientific research. For ophthalmic research, in particular glaucoma, AI applications are rapidly growing for potential clinical translation given the vast data available and the introduction of federated learning. Conversely, AI for basic science remains limited despite its useful power in providing mechanistic insight. In this perspective, we discuss recent progress, opportunities, and challenges in the application of AI in glaucoma for scientific discoveries. Specifically, we focus on the research paradigm of reverse translation, in which clinical data are first used for patient-centered hypothesis generation followed by transitioning into basic science studies for hypothesis validation. We elaborate on several distinctive areas of research opportunities for reverse translation of AI in glaucoma including disease risk and progression prediction, pathology characterization, and sub-phenotype identification. We conclude with current challenges and future opportunities for AI research in basic science for glaucoma such as inter-species diversity, AI model generalizability and explainability, as well as AI applications using advanced ocular imaging and genomic data., Competing Interests: Conflict of interest LP: Consultant to Eyenovia, Skye Biosciences, Character Biosciences, and Twenty Twenty. MG: Abyss Processing Pte Ltd Co-founder and Consultant. YJ: Optovue, Inc F, P; Optos, Inc. P. MS: Seymour Vision I. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be constructed as a potential conflict of interest.

Purpose: To apply retinal nerve fiber layer (RNFL) optical texture analysis (ROTA) in eyes with early glaucoma to investigate (1) the pattern of RNFL defects, (2) how often the papillomacular bundle and papillofoveal bundles are involved, and (3) the association between papillomacular and papillofoveal bundle defects and visual field (VF) sensitivity abnormalities., Design: Cross-sectional study., Participants: Two hundred four eyes with early glaucoma (VF mean deviation, ≥ -6 dB) with RNFL defects from 171 consecutively enrolled patients with glaucoma., Methods: All eyes underwent 24-2 VF testing and OCT for ROTA. The borders of RNFL defects were delineated from ROTA, and the involvement of the arcuate bundle, papillomacular bundle (i.e., bundles from the macula, excluding the fovea), and papillofoveal bundle (i.e., bundles from the fovea) was determined for each eye. Multilevel logistic regression analysis was applied to evaluate the structure-function association., Main Outcome Measures: Proportions of eyes with papillomacular or papillofoveal bundle defects., Results: Of the 204 eyes, 71.6% and 17.2% demonstrated RNFL defects involving the papillomacular and papillofoveal bundles, respectively; 25.0% showed arcuate bundle defects without involvement of papillomacular or papillofoveal bundles. The pattern of RNFL defects was diverse; the most common was concomitant involvement of the inferior arcuate bundle and the inferior papillomacular bundle (20.6%). Papillomacular or papillofoveal bundle defects were not associated with VF defects (i.e., with ≥ 3 contiguous locations with abnormal VF sensitivity in the pattern deviation probability plot) in the corresponding hemifield, although VF sensitivity of any 1 of the central 4 VF locations of the 24-2 test, which were within the macula, was more likely to be abnormal (P < 0.05 in the pattern deviation probability plot; odds ratio, 12.5; 95% confidence interval, 7.0-22.5) when the VF stimulus was projected onto a papillomacular or papillofoveal bundle defect than that projected onto an intact papillomacular or papillofoveal bundle., Conclusions: Contrary to the conventional notion that the fovea and macula are not affected until the late stages of glaucoma, papillofoveal and papillomacular bundle defects were common in early glaucoma, and they were associated with central VF sensitivity loss at the corresponding VF test locations., (Copyright © 2022 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Primary angle-closure glaucoma (PACG) is responsible for half of the glaucoma-related blindness worldwide. Cataract surgery with or without trabeculectomy has been considered to be the first-line treatment in eyes with medically uncontrolled PACG. While minimally invasive glaucoma surgery has become an important surgical approach for primary open-angle glaucoma, its indications and benefits in PACG are less clear. This review summarizes the efficacy and safety profile of minimally invasive glaucoma surgery in PACG to unfold new insights into the surgical management of PACG., Competing Interests: The authors have no funding or conflicts of interest to declare., (Copyright © 2022 Asia-Pacific Academy of Ophthalmology. Published by Wolters Kluwer Health, Inc. on behalf of the Asia-Pacific Academy of Ophthalmology.)

The clinical diagnostic evaluation of optic neuropathies relies on the analysis of the thickness of the retinal nerve fibre layer (RNFL) by optical coherence tomography (OCT). However, false positives and false negatives in the detection of RNFL abnormalities are common. Here we show that an algorithm integrating measurements of RNFL thickness and reflectance from standard wide-field OCT scans can be used to uncover the trajectories and optical texture of individual axonal fibre bundles in the retina and to discern distinctive patterns of loss of axonal fibre bundles in glaucoma, compressive optic neuropathy, optic neuritis and non-arteritic anterior ischaemic optic neuropathy. Such optical texture analysis can detect focal RNFL defects in early optic neuropathy, as well as residual axonal fibre bundles in end-stage optic neuropathy that were indiscernible by conventional OCT analysis and by red-free RNFL photography. In a diagnostic-performance study, optical texture analysis of the RNFL outperformed conventional OCT in the detection of glaucoma, as defined by visual-field testing or red-free photography. Our findings show that optical texture analysis of the RNFL for the detection of optic neuropathies is highly sensitive and specific., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Whereas lowering the intraocular pressure (IOP) can slow optic nerve degeneration in glaucoma, many patients with glaucoma continue to develop progressive loss in vision despite a significant reduction in IOP. No treatment has been shown to be effective for neuroprotection in glaucoma. We set out to conduct a randomized controlled trial to investigate whether nicotinamide riboside (NR), a nicotinamide adenine dinucleotide precursor, is effective to slow optic nerve degeneration in patients with primary open-angle glaucoma (POAG). We hypothesize that patients treated with NR have a slower rate of progressive retinal nerve fiber layer (RNFL) thinning compared with those treated with placebo., Methods: This is a randomized, double-blind, placebo-controlled, parallel-group, multi-center study including 125 patients with POAG. Patients will be randomized to receive 300 mg NR or placebo for 24 months. Clinical examination, optical coherence tomography imaging of the RNFL, and visual field (VF) test will be performed at the baseline, 1 month, 4 months, and then at 2-month intervals until 24 months. The primary outcome measure is the rate of RNFL thinning measured over 24 months. The secondary outcome measures include (1) time to VF progression, (2) time to progressive RNFL/ganglion cell inner plexiform layer (GCIPL) thinning, and (3) the rate of change of VF sensitivity over 24 months (to investigate neuroprotection) and 1 month (to investigate neuroenhancement). The rates of RNFL thinning and VF sensitivity decline between treatment groups will be compared with linear mixed modeling. Survival analysis will be performed to compare the differences in time from baseline to VF progression and time from baseline to progressive RNFL/GCIPL thinning between treatment groups using Cox proportional hazards models., Discussion: Outcome measures in glaucoma neuroprotection trials have been centered on the detection of VF progression, which may take years to develop and confirm. In addition to addressing whether NR has a neuroprotective/neuroenhancement effect in glaucoma patients, this study will demonstrate the feasibility of studying neuroprotection in a relatively short trial period (24 months) by comparing the rates of progressive RNFL thinning, a more reproducible and objective outcome measure compared with VF endpoints, between treatment groups., Trial Registration: Chinese Clinical Trial Registry 1900021998., (© 2021. The Author(s).)

Competing Interests: None

To evaluate the repeatability and agreement of corneal and biometry measurements obtained with two swept-source optical coherence tomography (SSOCT) and a partial coherence interferometry-based device. This is a cross-sectional study. Forty-eight eyes of 48 patients had three consecutive measurements for ANTERION (Heidelberg Engineering, Germany), CASIAII (Tomey, Japan) and IOLMaster500 (Carl Zeiss Meditec, USA) on the same visit. Mean keratometry (Km), central corneal thickness (CCT), anterior chamber depth (ACD) and axial length (AL) were recorded. Corneal astigmatic measurements were converted into vector components-J0 and J45. Intra-device repeatability and agreements of measurements amongst the devices were evaluated using repeatability coefficients (RCs) and Bland-Altman plots, respectively. All devices demonstrated comparable repeatability for Km (p ≥ 0.138). ANTERION had the lowest RC for J0 amongst the devices (p ≤ 0.039). Systematic difference was found for the Km and J0 obtained with IOLMaster500 compared to either SSOCTs (p ≤ 0.010). The ACD and AL measured by IOLMaster500 showed a higher RC compared with either SSOCTs (p < 0.002). Systematic difference was found in CCT and ACD between the two SSOCTs (p < 0.001), and in AL between ANTERION and IOLMaster500 (p < 0.001), with a mean difference of 1.6 µm, 0.022 mm and 0.021 mm, respectively. Both SSOCTs demonstrated smaller test-retest variability for measuring ACD and AL compared with IOLMaster500. There were significant disagreement in keratometry and AL measurements between the SSOCTs and PCI-based device; their measurements should not be considered as interchangeable., (© 2021. The Author(s).)

The crystalline lens plays an important role in the pathophysiology of primary angle closure and primary angle-closure glaucoma. The aging process is associated with a progressive enlargement of the lens, resulting in greater iridolenticular and iridotrabecular contact, which exacerbates both pupillary block and appositional angle closure, irrespective of the cataract status of the lens. Cataract surgery has been shown to widen the angle and reduce intraocular pressure in eyes with primary angle closure or primary angle-closure glaucoma. Recently, clear lens phacoemulsification has been suggested as a treatment modality in such eyes. We review the literature on clear lens extraction in eyes with angle closure and discuss its efficacy, safety, and indications. Although it is evident that clear lens extraction is beneficial in eyes with primary angle closure and primary angle-closure glaucoma, it is technically challenging and should be performed by experienced surgeons who not only master the procedure but are also able to deal with potential complications. Since the follow-up of the reviewed studies is relatively short, long-term follow-up (>10 years) of patients who undergo this procedure is needed to evaluate the safety and confirm the early benefits reported., (Copyright © 2020. Published by Elsevier Inc.)

Background: The CAV1-CAV2 locus has been associated with primary open-angle glaucoma (POAG) and intraocular pressure. However, its association with normal-tension glaucoma (NTG) was inconclusive. Therefore, we evaluated this association in Chinese and Japanese., Methods: Two single-nucleotide polymorphisms (SNPs, rs4236601 and rs1052990) from previous genome-wide association studies of POAG were genotyped in a total of 2220 study subjects: a Hong Kong Chinese cohort of 537 NTG patients and 490 controls, a Shantou Chinese cohort of 102 NTG and 731 controls and an Osaka Japanese cohort of 153 NTG and 207 controls. Subgroup analysis by gender was conducted. Outcomes from different cohorts were combined using meta-analysis., Results: SNP rs4236601 was significantly associated with NTG in the two Chinese cohorts (P meta = .0019, OR = 4.55, I 2 = 0). In contrast, rs4236601 was monomorphic in the Osaka cohort. The association of rs1052990 was insignificant in a meta-analysis combining Chinese and Japanese cohorts (P meta = .81, OR = 1.05; I 2 = 64%), and the OR tended towards opposite directions between Chinese (OR = 1.26) and Japanese (OR = 0.69). Gender-specific effects of the SNPs were not statistically significant in the logistic regression or Breslow-day tests of ORs (P > .05), although rs4236601 was significant in males (P = .0068; OR = 10.30) but not in females (P = .14; OR = 2.65) in the meta-analysis of Chinese subjects., Conclusions: In this study, we confirmed the association of rs4236601 at the CAV1-CAV2 locus with NTG in Chinese. SNP rs4236601 is monomorphic, and rs1052990 tends towards a different direction in the Japanese cohort. Further studies are warranted to verify the ethnic difference and gender-specific effects of this locus., (© 2020 Royal Australian and New Zealand College of Ophthalmologists.)

Objectives: To evaluate the diagnostic accuracy of rapid assessment of avoidable blindness (RAAB)., Design: Population-based diagnostic accuracy study., Methods: A total of 2145 (95.3%, 2145/2250) subjects aged 50 years and older who participated in the RAAB survey were included. All the recruited participants underwent ophthalmic examination according to the RAAB protocol and then were reexamined with instruments in a mobile eye clinic set up in a village center on the same day. Examination in the mobile clinic included standardized visual acuity (VA) tests using logMAR charts, refraction, slit-lamp biomicroscopy, and dilated fundal examination with a binocular indirect ophthalmoscope. Blindness and economic blindness were defined as VA in the better-seeing eye <3/60 and <6/60, respectively. Visual impairment (VI) was defined as VA <6/18 in the better eye. The primary cause of blindness and VI was defined according to the cause of VI in the participant's better eye., Main Outcome Measures: The sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), and area under the curve (AUC) of receiver operating characteristics of RAAB for detection of blindness and the principal causes of VI., Results: A total of 1816 subjects (84.7%), including 686 men (37.8%) and 1130 women (62.2%), underwent ophthalmic examination in the mobile eye clinic. The mean (±standard deviation) age was 64.4 ± 9.6 years. The sensitivities, specificities, AUC, PLR, and NLR of RAAB were 90.3%, 99.3%, 0.948, 124.0, and 0.10, respectively, for detection of blindness (presenting visual acuity, PVA <3/60); 89.5%, 98.7%, 0.940, 69.2, and 0.11, respectively, for detection of economic blindness (PVA <6/60); and 90.3%, 97.7%, 0.940, 38.7, and 0.10, respectively, for detection of VI (PVA <6/18). The sensitivities, specificities, AUC, PLR, and NLR were 90.5%, 98.1%, 0.943, 48.1, and 0.10; and 60.4%, 98.7%, 0.796, 46.4, and 0.40 for detection of VI (PVA <6/18) owing to cataract and refractive error, respectively., Conclusion: The diagnostic performances of RAAB were high for detecting the prevalence of blindness, VI, and VI owing to cataract., (Copyright © 2019. Published by Elsevier Inc.)

Importance: Clinical assessment of vision-related disability is hampered by the lack of instruments to assess visual performance in real-world situations. Interactive virtual reality (VR) environments displayed in a binocular stereoscopic VR headset have been designed, presumably simulating day-to-day activities to evaluate vision-related disability., Objective: To investigate the application of VR to identify vision-related disability in patients with glaucoma., Design, Setting, and Participants: In a cross-sectional study, 98 patients with glaucoma and 50 healthy individuals were consecutively recruited from a university eye clinic; all participants were Chinese. The study was conducted between August 30, 2016, and July 31, 2017; data analysis was performed from December 1, 2017, to October 30, 2018., Exposures: Measurements of visual acuity, contrast sensitivity, visual field (VF), National Eye Institute 25-item Visual Function Questionnaire Rasch score, and VR disability scores determined from 5 VR simulations: supermarket shopping, stair and city navigations in daytime, and stair and city navigations in nighttime. Duration required to complete the simulation, number of items incorrectly identified, and number of collisions were measured to compute task-specific and overall VR disability scores. Vision-related disability was identified when the VR disability score was outside the normal age-adjusted 95% confidence region., Main Outcomes and Measures: Virtual reality disability score., Results: In the 98 patients with glaucoma, mean (SD) age was 49.8 (11.6) years and 60 were men (61.2%); in the 50 healthy individuals, mean (SD) age was 48.3 (14.8) years and 16 were men (32.0%). The patients with glaucoma had different degrees of VF loss (122 eyes [62.2%] had moderate or advanced VF defects). The time required to complete the activities by patients with glaucoma vs healthy individuals was longer by 15.2 seconds (95% CI, 5.5-24.9 seconds) or 34.1% (95% CI, 12.4%-55.7%) for the shopping simulation, 72.8 seconds (95% CI, 23.0-122.6 seconds) or 33.8% (95% CI, 10.7%-56.9%) for the nighttime stair navigation, and 38.1 seconds (95% CI, 10.9-65.2 seconds) or 30.8% (95% CI, 8.8%-52.8%) for the nighttime city navigation. The mean (SD) duration was not significantly different between the glaucoma and healthy groups in daytime stair (203.7 [93.7] vs 192.9 [89.1] seconds, P = .52) and city (118.7 [41.5] vs 117.0 [52.3] seconds, P = .85) navigation. For each decibel decrease in binocular VF sensitivity, the risk of collision increased by 15% in nighttime stair (hazard ratio [HR], 1.15; 95% CI, 1.08-1.22) and city (HR, 1.15; 95% CI, 1.08-1.23) navigations. Fifty-eight patients (59.1%) with glaucoma had vision-related disability in at least 1 simulated daily task; a higher proportion of patients had vision-related disability in nighttime city (27 of 88 [30.7%]) and stair (27 of 90 [30.0%]) navigation than in daytime city (7 of 88 [8.0%]) and stair (19 of 96 [19.8%]) navigation. The overall VR disability score was associated with the National Eye Institute 25-item Visual Function Questionnaire Rasch score (R2 = 0.207)., Conclusions and Relevance: These findings suggest that vision-related disability is associated with lighting condition and task in patients with glaucoma. Virtual reality may allow eye care professionals to understand the patients' perspectives on how visual impairment imparts disability in daily living and provide a new paradigm to augment the assessment of vision-related disability.

Investigation of neurodegeneration in glaucoma, a leading cause of irreversible blindness worldwide, has been obfuscated by the lack of an efficient model that provides chronic, mild to moderate elevation of intraocular pressure (IOP) with preservation of optical media clarity for long term, in vivo interrogation of the structural and functional integrity of the retinal ganglion cells (RGCs). Here, we designed and formulated an injectable hydrogel based on in situ cross-linking of hyaluronic acid functionalized with vinyl sulfone (HA-VS) and thiol groups (HA-SH). Intracameral injection of HA-VS and HA-SH in C57BL/6J mice exhibited mild to moderate elevation of IOP with daily mean IOP ranged between 14 ± 3 and 24 ± 3 mmHg, which led to progressive, regional loss of RGCs evaluated with in vivo, time-lapse confocal scanning laser ophthalmoscopy; a reduction in fractional anisotropy in the optic nerve and the optic tract projected from the eye with increased IOP in diffusion tensor magnetic resonance imaging; a decrease in positive scotopic threshold response in electroretinography; and a decline in visual acuity measured with an optokinetic virtual reality system. The proportion of RGC loss was positively associated with the age of the animals, and the levels and the duration of IOP elevation. The new glaucoma model recapitulates key characteristics of human glaucoma which is pertinent to the development and pre-clinical testing of neuroprotective and neuroregenerative therapies. STATEMENT OF SIGNIFICANCE: A new model to study chronic neurodegeneration in glaucoma has been developed via intracameral injection of a specifically designed hyaluronic acid functionalized with vinyl sulfone and thiol groups for cross-linking. Intracameral injection of the chemically cross-linked hydrogel generates mild to moderate IOP elevation, resulting in progressive degeneration of the retinal ganglion cells, optic nerve, and optic tract, and a decline in visual function. The model recapitulates the key features of neurodegeneration in human glaucoma, which will facilitate and expedite the development of neuroprotective and neuroregenerative therapies., (Copyright © 2019 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Glaucoma is a leading cause of blindness characterized by progressive degeneration of retinal ganglion cells (RGCs). A well-established risk factor for the development and progression of glaucoma is elevation of intraocular pressure (IOP). However, how elevated IOP leads to RGC degeneration remains poorly understood. Here, we fabricate a facile, tunable hydrostatic pressure platform to study the effect of increased hydrostatic pressure on RGC axon and total neurite length, cell body area, dendritic branching, and cell survival. The hydrostatic pressure can be adjusted by varying the height of a liquid reservoir attached to a three-dimensional (3D)-printed adapter. The proposed platform enables long-term monitoring of primary RGCs in response to various pressure levels. Our results showed pressure-dependent changes in the axon length, and the total neurite length. The proportion of RGCs with neurite extensions significantly decreased by an average of 38 ± 2% (mean ± SEM) at pressures 30 mmHg and above (p < 0.05). The axon length and total neurite length decreased at a rate of 1.65 ± 0.18 μm and 4.07 ± 0.34 μm, respectively (p < 0.001), for each mmHg increase in pressure after 72 hours pressure treatment. Dendritic branching increased by 0.20 ± 0.05 intersections/day at pressures below 25 mmHg, and decreased by 0.07 ± 0.01 intersections/day at pressures above 25 mmHg (p < 0.001). There were no significant changes in cell body area under different levels of hydrostatic pressure (p ≥ 0.05). Application of this model will facilitate studies on the biophysical mechanisms that contribute to the pathophysiology of glaucoma and provide a channel for the screening of potential pharmacological agents for neuroprotection.

Purpose: To study the roles of sequence alterations in the optineurin ( OPTN ) gene-coding region in normal-tension glaucoma (NTG) among Chinese patients., Methods: Genomic DNA was extracted from 190 NTG patients and 201 control subjects. The thirteen exons of OPTN were amplified by polymerase chain reaction and analyzed by direct sequencing. Detected sequence changes were compared between NTG patients and control subjects., Results: Seven sequence changes in OPTN were identified in both NTG patients and control subjects. Among them, c.464G>A (T34 T), c.509C>T (T49T), c.806G>A (V148V), and c.959T>C (P199P) were synonymous codon changes, whilst c.655T>A (M98K), c.1996G>A (R545Q), and c.1582T>C (I407T) were missense changes. Two previously reported heterozygous mutations, c.458G>A (E50K) in exon 4 and c.691&#95;692insAG in exon 6, were not found in this study. Out of these seven OPTN sequence variants, c.464G>A (T34T) was significantly associated with NTG in both the allelic and genotypic association analyses (allelic association: p = 0.0001, OR = 2.20, 95% CI: 1.46-3.31; genotypic association: p = 0.0001), whereas the association of other variants with NTG did not reach statistical significance ( p > 0.05). Variants c.1582 T>C (I407T) and c.806G>A (V148V) were identified in one and two NTG patients, respectively, but not in the control subjects., Conclusions: This study confirmed the association of the OPTN T34T variant with NTG, suggesting that OPTN is a susceptibility gene for NTG in Chinese. Moreover, a variant with amino acid change (I407T) was identified in NTG but not in controls. Further studies are warranted to assess whether this variant is a causative mutation for NTG.

Efficient transduction of the retinal ganglion cells (RGCs) is a prerequisite to maximize therapeutic outcomes in any form of gene therapy for optic neuropathies. Whereas subretinal injection of adeno-associated virus 2 (AAV2) has been well-characterized, the serotype, viral load, and promoter combinations that govern RGC transduction efficiency following intravitreal injection remains poorly understood. We evaluated the transduction efficiency of seven AAV2 serotypes (AAV2/1, AAV2/2, AAV2/4, AAV2/5, AAV2/6, AAV2/8, and AAV2/9) for the RGCs at 4 weeks following intravitreal injection in C57BL/6J mice. Intravitreal injection of 1 × 10 9  vg of AAV2/2 with eGFP driven by the CMV promoter attained a higher transduction efficiency for the RGCs (60.0 ± 4.2%) compared with the six other AAV2 serotypes with eGFP driven by the same promoter injected at the same viral load ( < 3.0%). Reporter driven by the CAG promoter had a lower transduction efficiency (up to 42.0 ± 5.8%) compared with that driven by the CMV reporter (60.0 ± 4.2%, p ≤ 0.024). There was a viral dose-dependent transduction effect of AAV2/2-CMV-eGFP and the transduction efficiency was 40.2 ± 3.9%, 16.6 ± 4.2%, and 2.6 ± 0.2% when the viral load decreased to 5 × 10 8  vg, 1 × 10 8  vg, and 1 × 10 7  vg, respectively. Optimizing viral serotype, viral load, and promoter construct of AAV2 is important to maximize transgene expression in RGC-targeted gene therapy.

The purpose of the study was to evaluate the association profiles of the SIX6 locus with primary open-angle glaucoma (POAG) in southern Chinese and Japanese. In this study, we tested single marker and haplotype-based associations of 11 tagging single nucleotide polymorphisms (SNPs) covering the SIX6 locus with POAG in a Hong Kong Chinese cohort (N = 1402). A novel SNP (i.e., rs12436579) and two SNPs (i.e., rs33912345 and rs10483727) from previous genome-wide association studies were further tested in a Chinese cohort from Shantou (N = 888) and a Japanese cohort from Osaka (N = 463). Results from the three cohorts were meta-analysed using a random-effect model. We found rs12436579, which has not been previously reported, was associated with POAG in Hong Kong and Shantou Chinese (P combined  = 4.3 × 10 -5 , OR = 0.72, I 2  = 0). Additionally, we replicated the association of one known SNP, rs33912345 (P combined  = 0.0061, OR = 0.69, I 2  = 45%), with POAG in the Chinese cohorts but not in the Japanese cohort (P > 0.6). Another known SNP, rs10483727, was nominally associated with POAG in the two Chinese cohorts (P combined  = 0.017, OR = 0.70, I 2  = 53%). All these three SNPs were significantly associated with POAG when the three cohorts were combined in meta-analysis (P combined <0.005). Furthermore, two haplotypes, C-C (P combined  = 1.13 × 10 -5 , OR = 1.41, I 2  = 0) and A-A (P combined  = 0.045, OR = 0.68, I 2  = 70%), defined by rs33912345-rs12436579 were associated with POAG in Chinese but not in Japanese. In conclusion, this study confirmed the association between two GWAS SNPs in SIX6 (rs33912345 and rs10483727) and POAG. Also, a SNP, rs12436579, not associated with POAG before, was found to be associated with POAG in Chinese. Further studies are warranted to elucidate the role of this novel SNP in POAG., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Purpose: To determine the proportions of eyes with indiscernible Bruch's membrane opening (BMO) in glaucoma patients and healthy individuals with and without high myopia and to investigate factors contributing to indiscernible BMO., Design: Cross-sectional study., Participants: Five hundred eyes from 315 participants, including 212 high myopic eyes (axial length [AL], ≥26 mm) from 80 glaucoma patients and 60 healthy individuals and 288 non-high myopic eyes (AL, <26 mm) from 96 glaucoma patients and 88 healthy individuals., Methods: The optic disc was imaged by the Spectralis OCT (Heidelberg Engineering, Heidelberg, Germany) using 24 equally spaced radial B-scans. The BMO was located independently by 2 trained observers and was recorded as discernible or indiscernible over 48 meridians in each eye. The BMO of a meridian was determined to be indiscernible when both observers failed to identify its location. The agreement between the observers was evaluated with κ statistics. Factors associated with indiscernible BMO were identified with multivariable, multilevel logistic regression modeling., Main Outcome Measures: Proportions of eyes with indiscernible BMO and hazard ratios (HRs) of factors associated with indiscernible BMO., Results: The agreement for assessment of BMO visibility between the observers was good (κ, 0.631; 95% confidence interval, 0.602-0.661). In the groups with and without high myopia, 32.1% and 8.2% of glaucomatous eyes had 1 or more meridians with indiscernible BMO, respectively. In the healthy eyes, the respective proportions were 28.0% and 3.9%. The proportions were significantly higher in eyes with high myopia compared to eyes without high myopia in the glaucoma group (P < 0.001) and the healthy group (P < 0.001). The temporal meridian, followed by the inferotemporal and superotemporal meridians, of the optic disc were the most frequent locations with indiscernible BMO. Increased AL, advanced glaucoma, β parapapillary atrophy, and young age were associated with an increased HR of indiscernible BMO (P ≤ 0.032)., Conclusions: A significant proportion of high myopic eyes have indiscernible BMO at the temporal, superotemporal, and inferotemporal meridians of the optic disc, which may compromise the measurement of neuroretinal rim in the diagnostic evaluation of glaucoma., (Copyright © 2018 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

The advent of optical coherence tomography angiography (OCT-A) provides a new opportunity to visualize the retinal vasculature in a non-invasive and dye-free manner which may help identify vascular abnormalities in glaucoma. While a reduction in retinal and optic nerve head vessel densities and blood flow indexes measured by OCT-A has been demonstrated in patients with glaucoma in many studies, it is unclear whether OCT-A provides additional information for the detection and monitoring of glaucoma compared with OCT measurements such as retinal nerve fiber layer thickness, neuroretinal rim width, and ganglion cell inner plexiform layer thickness. Longitudinal studies are needed to elucidate whether vascular abnormalities detected by OCT-A are a cause or a consequence of optic nerve damage in glaucoma., Competing Interests: Competing interests: KW declares that he has no competing interests. CL has received speaker honoraria from Carl Zeiss Meditec and Heidelberg Engineering and research support from Carl Zeiss Meditec.No competing interests were disclosed.Competing interests: Gábor Holló is an unpaid consultant of Optovue and Zeiss (both companies produce OCT angiography instruments).

The application of digital imaging technologies including confocal scanning laser ophthalmoscopy (CSLO), optical coherence tomography (OCT), and scanning laser polarimetry (SLP) has significantly improved the detection of optic nerve head (ONH) deformation and progressive retinal nerve fiber layer (RNFL) thinning for assessment of glaucoma progression. Algorithms for change analysis such as topographic change analysis and guided progression analysis perform event analysis of serial ONH surface height topology maps and RNFL thickness/RNFL retardance maps, respectively, providing a topographical display of the location of significant change. With spectral-domain OCT, it is feasible to delineate and measure the lamina cribrosa surface depth in addition to ONH surface depth and RNFL thickness. Growing evidence from experimental and clinical studies indicates that ONH and lamina cribrosa deformation can be observed prior to detectable RNFL thinning and functional loss in glaucoma. These findings lend support to the notion that upon detection of ONH/lamina cribrosa deformation, a time window for therapeutic intervention for better outcomes may exist. The ONH and the lamina cribrosa are therefore important targets for monitoring glaucoma progression. This review summarizes the latest findings comparing the performance of OCT, CSLO, and SLP for detection of progressive ONH and RNFL damages in glaucoma patients and the clinical implication and limitations of studying the morphological alteration of the ONH, lamina cribrosa, and RNFL in the assessment of glaucoma progression., Competing Interests: Conflicts of interest: The author has received speaker honorarium from Carl Zeiss Meditec and Heidelberg Engineering, and research support from Carl Zeiss Meditec and Optovue (Fremont, California, USA).

Objective: To investigate the performance of spectral-domain optical coherence tomography (OCT) and scanning laser polarimetry to detect progressive retinal nerve fiber layer (RNFL) changes and to determine whether reduction of the RNFL retardance occurred before thinning of the RNFL in glaucoma., Design: Prospective, longitudinal study., Participants: One hundred eighty-four eyes of 116 glaucoma patients and 43 normal eyes of 23 healthy individuals., Methods: Patients were followed up every 4 months for at least 36 months with RNFL retardance (GDx Enhanced Corneal Compensation; Carl Zeiss Meditec) and RNFL thickness (Cirrus HD-OCT; Carl Zeiss Meditec) measured in the same visit. Progressive RNFL retardance and thickness changes were evaluated with event-based analysis (Guided Progression Analysis; Carl Zeiss Meditec) with reference to the RNFL retardance change map and the RNFL thickness change map, respectively. The area and frequency distribution of RNFL changes were examined by overlaying the RNFL retardance change maps and the RNFL thickness change maps in the latest follow-up. The agreement of RNFL retardance and RNFL thickness progression was evaluated with κ statistics., Main Outcome Measures: Number of eyes with progressive RNFL changes over time., Results: A total of 2472 OCT thickness maps and 2472 RNFL retardance maps were collected and reviewed with a mean follow-up of 55.1 months. Twenty-seven eyes (14.6%; 26 glaucoma patients) showed progressive RNFL thinning, whereas 8 eyes (4.3%; 8 glaucoma patients) showed progressive reduction of RNFL retardance. Seven eyes (3.8%; 7 glaucoma patients) had progression that was detected by both instruments, all with progressive RNFL thinning detected before progressive reduction of RNFL retardance became evident, and the mean lag time was 13.4 months (range, 4.0-37.6 months). The agreement between RNFL thickness and RNFL retardance progression was fair (κ, 0.357). Progressive loss of RNFL thickness was observed most frequently at the inferotemporal 223° to 260°, whereas the inferotemporal 227° to 263° and superior 56° to 117° were observed most commonly for progressive loss of RNFL retardance. In the normal group, no eyes showed reduction in RNFL thickness or retardance., Conclusions: At a comparable level of specificity, progressive RNFL thinning was detected more often than progressive reduction of RNFL retardance. For eyes with progressive loss of RNFL thickness and RNFL retardance, the former preceded the latter., (Copyright © 2013 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Objective: To investigate the impact of age-related change of macular and circumpapillary retinal nerve fiber layer (RNFL) measurements on evaluation of glaucoma progression., Design: Prospective, longitudinal study., Participants: A total of 150 eyes of 90 patients with glaucoma and 72 eyes of 40 normal individuals., Methods: Both eyes were imaged by the Cirrus HD-OCT (Carl Zeiss Meditec, Dublin, CA; optic nerve head and macular scans were taken every 4 months for a mean of 45.8 months (range, 35.4-60.6 months). The mean age-related rates of change of macular (including the ganglion cell and inner plexiform layer [GCIPL], inner retina [IR], outer retina [OR], and total macular thicknesses) and circumpapillary RNFL measurements were estimated with linear mixed models in the normal group. Macular and RNFL progression were then evaluated in individual eyes in the glaucoma group, with trend analysis before and after accounting for age-related change using the lower 95% confidence intervals (CIs) of the mean age-related rates of change as cutoffs. The survival probability was evaluated with the Kaplan-Meier estimator, and the agreement of progression detection among the structural parameters was calculated with Kappa statistics., Main Outcome Measures: Detection of glaucoma progression and survival probability of macular and RNFL parameters., Results: Before accounting for age-related change, 50.0% (75 eyes) showed progression by the GCIPL thickness, 50.0% (75 eyes) showed progression by the IR thickness, 30.0% (45 eyes) showed progression by the total macular thickness, 27.3% (41 eyes) showed progression by the circumpapillary RNFL thickness, and 10.0% (15 eyes) showed progression by the OR thickness. The survival probability of GCIPL and IR thicknesses were significantly worse compared with circumpapillary RNFL thickness (P ≤ 0.001). After accounting for age-related change, the proportions decreased to 14.7%, 20.0%, 16.0%, 26.7%, and 1.3%, respectively, with the circumpapillary RNFL thickness demonstrating the worst survival probability. The agreement of progression detection between RNFL and macular measurements was poor with (kappa range, -0.055 to 0.185) or without (kappa range, -0.046 to 0.173) taking age-related change into consideration., Conclusions: Age-related change of macular and circumpapillary RNFL measurements can be detected in normal eyes and can affect the analysis of glaucoma progression. The impact is more substantial in analyzing macular progression than circumpapillary RNFL progression., (Copyright © 2013 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)