Retinal Nerve Fiber Layer Optical Texture Analysis: Involvement of the Papillomacular Bundle and Papillofoveal Bundle in Early Glaucoma.

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.

Association of the CAV1-CAV2 locus with normal-tension glaucoma in Chinese and Japanese.

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 (Pmeta = .0019, OR = 4.55, I2 = 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 (Pmeta = .81, OR = 1.05; I2 = 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.

Factors governing the transduction efficiency of adeno-associated virus in the retinal ganglion cells following intravitreal injection.

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 × 109 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 × 108 vg, 1 × 108 vg, and 1 × 107 vg, respectively. Optimizing viral serotype, viral load, and promoter construct of AAV2 is important to maximize transgene expression in RGC-targeted gene therapy.

Association of the SIX6 locus with primary open angle glaucoma in southern Chinese and Japanese.

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 (Pcombined = 4.3 × 10-5, OR = 0.72, I2 = 0). Additionally, we replicated the association of one known SNP, rs33912345 (Pcombined = 0.0061, OR = 0.69, I2 = 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 (Pcombined = 0.017, OR = 0.70, I2 = 53%). All these three SNPs were significantly associated with POAG when the three cohorts were combined in meta-analysis (Pcombined<0.005). Furthermore, two haplotypes, C-C (Pcombined = 1.13 × 10-5, OR = 1.41, I2 = 0) and A-A (Pcombined = 0.045, OR = 0.68, I2 = 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.

Detection of Bruch's Membrane Opening in Healthy Individuals and Glaucoma Patients with and without High Myopia.

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, ß 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.

A common variant near TGFBR3 is associated with primary open angle glaucoma.

Primary open angle glaucoma (POAG), a major cause of blindness worldwide, is a complex disease with a significant genetic contribution. We performed Exome Array (Illumina) analysis on 3504 POAG cases and 9746 controls with replication of the most significant findings in 9173 POAG cases and 26 780 controls across 18 collections of Asian, African and European descent. Apart from confirming strong evidence of association at CDKN2B-AS1 (rs2157719 [G], odds ratio [OR] = 0.71, P = 2.81 × 10(-33)), we observed one SNP showing significant association to POAG (CDC7-TGFBR3 rs1192415, ORG-allele = 1.13, Pmeta = 1.60 × 10(-8)). This particular SNP has previously been shown to be strongly associated with optic disc area and vertical cup-to-disc ratio, which are regarded as glaucoma-related quantitative traits. Our study now extends this by directly implicating it in POAG disease pathogenesis.

Optic Nerve Head Deformation in Glaucoma: A Prospective Analysis of Optic Nerve Head Surface and Lamina Cribrosa Surface Displacement.

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.

Optic nerve head deformation in glaucoma: the temporal relationship between optic nerve head surface depression and retinal nerve fiber layer thinning.

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.

Retinal Nerve Fiber Layer Optical Texture Analysis and 10-2 Visual Field Assessment in Glaucoma.

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.

Glaucoma Rehabilitation using ElectricAI Transcranial Stimulation (GREAT)-study protocol for randomized controlled trial using combined perceptual learning and transcranial electrical stimulation for vision enhancement.

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.

Retinal nerve fiber layer progression in glaucoma: a comparison between retinal nerve fiber layer thickness and retardance.

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.

Impact of age-related change of retinal nerve fiber layer and macular thicknesses on evaluation of glaucoma progression.

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.

Anterior chamber angle imaging with swept-source optical coherence tomography: measuring peripheral anterior synechia in glaucoma.

OBJECTIVE: To investigate the use of swept-source optical coherence tomography (OCT) for measuring the area and degree of peripheral anterior synechia (PAS) involvement in patients with angle-closure glaucoma. DESIGN: Cross-sectional study. PARTICIPANTS: Twenty-three eyes with PAS (detected by indentation gonioscopy) from 20 patients with angle-closure glaucoma (20 eyes had primary angle-closure glaucoma and 3 eyes had angle-closure glaucoma secondary to chronic anterior uveitis [n = 2] and Axenfeld-Rieger syndrome [n = 1]). METHODS: The anterior chamber angles were evaluated with indentation gonioscopy and imaged by swept-source OCT (Casia OCT, Tomey, Nagoya, Japan) in room light and in the dark using the "angle analysis" protocol, which was composed of 128 radial B-scans each with 512 A-scans (16-mm scan length). The area and degree of PAS involvement were measured in each eye after manual detection of the scleral spur and the anterior irido-angle adhesion by 2 masked observers. The interobserver variability of the PAS measurements was calculated. MAIN OUTCOME MEASURES: The agreement of PAS assessment by gonioscopy and OCT, the area and the degree of PAS involvement, and the intraclass correlation coefficient (ICC) of interobserver PAS measurements. RESULTS: The area of PAS (mean ± standard deviation) was 20.8 ± 16.9 mm(2) (range, 3.9-74.9 mm(2)), and the degree of PAS involvement was 186.5 ± 79.9 degrees (range, 42-314 degrees). There was no difference in the area of PAS (P = 0.90) and the degree of PAS involvement (P = 0.95) between images obtained in room light and in the dark. The interobserver ICCs were 0.99 (95% confidence interval [CI], 0.98-1.00) for the area of PAS and 0.99 (95% CI, 0.97-1.00) for the degree of PAS involvement. There was good agreement of PAS assessment between gonioscopy and OCT images (kappa = 0.79; 95% CI, 0.67-0.91). CONCLUSIONS: Swept-source OCT allows visualization and reproducible measurements of the area and degree of PAS involvement, providing a new paradigm for evaluation of PAS progression and risk assessment for development of angle-closure glaucoma. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Corneal thickness and elevation measurements using swept-source optical coherence tomography and slit scanning topography in normal and keratoconic eyes.

BACKGROUND: To compare corneal thickness and corneal elevation using swept source optical coherence tomography and slit scanning topography. DESIGN: Prospective study. PARTICIPANTS: 41 normal and 46 keratoconus subjects. METHODS: All eyes were imaged using swept source optical coherence tomography and slit scanning tomography during the same visit. Mean corneal thickness and best-fit sphere measurements were compared between the instruments. MAIN OUTCOME MEASURES: Agreement of measurements between swept source optical coherence tomography and scanning slit topography was analyzed. Intra-rater reproducibility coefficient and intraclass correlation coefficient were evaluated. RESULTS: In normal eyes, central corneal thickness measured by swept source optical coherence tomography was thinner compared with slit scanning topography (p < 0.0001) and ultrasound pachymetry (p = < .0001). Ultrasound pachymetry readings had better 95% limits of agreement with swept source optical coherence tomography than slit scanning topography. In keratoconus eyes, central corneal thickness was thinner on swept source optical coherence tomography than slit scanning topography (p = 0.081) and ultrasound pachymetry (p = 0.001). There were significant differences between thinnest corneal thickness, and, anterior and posterior best-fit sphere measurements between both instruments (p < 0.05 for all). Overall, reproducibility coefficients and intraclass correlation coefficients were significantly better with swept source optical coherence tomography for measurement of central corneal thickness, anterior best-fit sphere and, posterior best-fit sphere (all p < 0.001). CONCLUSIONS: Corneal thickness and elevation measurements were significantly different between swept source optical coherence tomography and slit scanning topography. With better reproducibility coefficients and intraclass correlation coefficients, swept source optical coherence tomography may provide a reliable alternative for measurement of corneal parameters.

Reverse translation of artificial intelligence in glaucoma: Connecting basic science with clinical applications.

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.

Retinal nerve fiber layer imaging with spectral-domain optical coherence tomography: a prospective analysis of age-related loss.

OBJECTIVE: To investigate age-related changes of the retinal nerve fiber layer (RNFL) imaged by a spectral-domain optical coherence tomography (OCT). DESIGN: Prospective, cross-sectional, and longitudinal studies. PARTICIPANTS: One hundred normal individuals were recruited for cross-sectional analysis, 35 of whom were randomly selected for longitudinal analysis. METHODS: The circumpapillary average and quadrant RNFL thicknesses were measured by the Cirrus HD-OCT. In the longitudinal study, participants were followed at 4-month intervals for a mean of 30 months (range, 24-41 months) for RNFL and visual field measurements. Cross-sectional RNFL data were analyzed with multiple linear regression models with adjustment of spherical error, optic disc area, and signal strength. Longitudinal RNFL measurements were analyzed with linear mixed models with fixed coefficients on follow-up duration, baseline RNFL thickness, spherical error, optic disc area, and signal strength. Factors influencing the rate of change of RNFL measurements were analyzed in the interaction terms with "duration" in the linear mixed models. MAIN OUTCOME MEASURES: Rates of change of average and quadrant RNFL thicknesses. RESULTS: In the cross-sectional analysis, significant negative correlations were found between age and average (-0.33 µm/year; P = 0.011), inferior (-0.45 µm/year; P = 0.037), and temporal (-0.31 µm/year; P = 0.046) RNFL thicknesses. In the longitudinal analysis, the mean rates of change of average, superior, and inferior RNFL thicknesses were -0.52 (95% confidence interval [CI], -0.86 to -0.17), -1.35 (95% CI, -2.05 to -0.65) and -1.25 µm/year (95% CI, -1.78 to -0.71), respectively, after adjusting for baseline RNFL thickness, spherical error, disc area, and signal strength. There was no detectable RNFL reduction in the nasal and temporal quadrants. The only significant factor influencing the rates of change of RNFL measurements was the baseline RNFL thickness. A greater baseline RNFL thickness was associated with a faster rate of change. CONCLUSIONS: Progressive, age-related decline of RNFL thickness can be detected with longitudinal OCT imaging. Rate estimates derived from trend analysis for detection of glaucomatous RNFL progression should be interpreted with reference to the normal ranges of age-related reduction, particularly when the baseline RNFL measurement is large.

Minimally Invasive Glaucoma Surgery in Primary Angle-Closure Glaucoma.

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.

Comparison of retinal nerve fiber layer imaging by spectral domain optical coherence tomography and scanning laser ophthalmoscopy.

OBJECTIVE: To compare the area and the angular width of localized retinal nerve fiber layer (RNFL) defects imaged by confocal scanning laser ophthalmoscopy (CSLO) and optical coherence tomography (OCT) and to evaluate their agreement. DESIGN: Cross-sectional study. PARTICIPANTS: Fifty-one eyes of 41 glaucoma patients. METHODS: Sixty-one distinctive, localized RNFL defects (17 superior and 44 inferior RNFL defects) detected in RNFL photographs imaged by a CSLO were identified. These patients underwent RNFL imaging with a spectral-domain OCT. The RNFL thickness deviation maps (50×50 pixels) generated by the OCT revealed the locations of abnormal RNFL thicknesses with abnormal pixels denoted in red (RNFL thickness less than the lower 99% normal distribution) or yellow (RNFL thickness less than the lower 95% normal distribution). The RNFL thickness deviation maps were aligned and overlaid with the corresponding CSLO RNFL photographs. The area and the angular width of RNFL defects from the corresponding retinal regions in the CSLO RNFL photographs and the OCT RNFL thickness maps were measured and compared. Their agreement was analyzed with the Bland-Altman plot. MAIN OUTCOME MEASURES: The area and the angular width of RNFL defects and the agreement of RNFL defects measurements between OCT images and CSLO RNFL photographs. RESULTS: The area and the angular width of RNFL defects measured with the CSLO RNFL photographs were 1.11 ± 0.57 mm² and 23.80 ± 10.38°, respectively, which were significantly smaller than those measured by the OCT RNFL thickness deviation map when abnormal RNFL thickness was defined as less than the lower 95% centile ranges (2.27 ± 0.92 mm² and 74.16 ± 28.74°, respectively; both P < 0.001). When abnormal RNFL thickness was defined as less than the lower 99% centile ranges, a significant difference in angular width (42.11 ± 22.19°; P<0.001), but not in area (1.19 ± 0.68 mm²; P = 0.444) was found between the 2 imaging methods. Bland-Altman plots revealed that a larger RNFL defect was associated with a greater difference in angular width between OCT and CSLO RNFL photography measurements. CONCLUSIONS: The agreement of RNFL defect measurements between CSLO RNFL photography and OCT was poor. The OCT RNFL thickness deviation map could reveal additional RNFL abnormalities not detectable by CSLO RNFL photography. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Comparison of two novel swept-source optical coherence tomography devices to a partial coherence interferometry-based biometer.

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.