The African Descent and Glaucoma Evaluation Study (ADAGES) III: Contribution of Genotype to Glaucoma Phenotype in African Americans: Study Design and Baseline Data.

PURPOSE: To describe the study protocol and baseline characteristics of the African Descent and Glaucoma Evaluation Study (ADAGES) III. DESIGN: Cross-sectional, case-control study. PARTICIPANTS: Three thousand two hundred sixty-six glaucoma patients and control participants without glaucoma of African or European descent were recruited from 5 study centers in different regions of the United States. METHODS: Individuals of African descent (AD) and European descent (ED) with primary open-angle glaucoma (POAG) and control participants completed a detailed demographic and medical history interview. Standardized height, weight, and blood pressure measurements were obtained. Saliva and blood samples to provide serum, plasma, DNA, and RNA were collected for standardized processing. Visual fields, stereoscopic disc photographs, and details of the ophthalmic examination were obtained and transferred to the University of California, San Diego, Data Coordinating Center for standardized processing and quality review. MAIN OUTCOME MEASURES: Participant gender, age, race, body mass index, blood pressure, history of smoking and alcohol use in POAG patients and control participants were described. Ophthalmic measures included intraocular pressure, visual field mean deviation, central corneal thickness, glaucoma medication use, or past glaucoma surgery. Ocular conditions, including diabetic retinopathy, age-related macular degeneration, and past cataract surgery, were recorded. RESULTS: The 3266 ADAGES III study participants in this report include 2146 AD POAG patients, 695 ED POAG patients, 198 AD control participants, and 227 ED control participants. The AD POAG patients and control participants were significantly younger (both, 67.4 years) than ED POAG patients and control participants (73.4 and 70.2 years, respectively). After adjusting for age, AD POAG patients had different phenotypic characteristics compared with ED POAG patients, including higher intraocular pressure, worse visual acuity and visual field mean deviation, and thinner corneas (all P < 0.001). Family history of glaucoma did not differ between AD and ED POAG patients. CONCLUSIONS: With its large sample size, extensive specimen collection, and deep phenotyping of AD and ED glaucoma patients and control participants from different regions in the United States, the ADAGES III genomics study will address gaps in our knowledge of the genetics of POAG in this high-risk population.

Peripapillary and Macular Vessel Density in Patients with Primary Open-Angle Glaucoma and Unilateral Visual Field Loss.

PURPOSE: To characterize OCT angiography (OCT-A) vessel density of patients with primary open-angle glaucoma (POAG) with unilateral visual field (VF) loss. DESIGN: Cross-sectional study. PARTICIPANTS: A total of 33 patients with POAG with a VF defect in 1 eye (mean VF mean deviation [MD], -3.9±3.1 decibels [dB]) and normal VF in the other eye (mean VF MD, -0.2±0.9 dB) and 33 healthy eyes. METHODS: All subjects underwent OCT-A imaging, spectral-domain (SD)-OCT imaging, and VF testing. OCT-A retinal vascular measurements were summarized as whole image vessel density (wiVD), circumpapillary vessel density (cpVD), and parafoveal vessel density (pfVD). Inter-eye differences in vascular measures, as well as SD OCT retinal nerve fiber layer (RNFL), macular ganglion cell complex (mGCC) thickness, and rim area measurements in glaucoma and healthy eyes were compared. Areas under the receiver operating characteristic curves (AUROCs) were used to evaluate diagnostic accuracy for differentiating between unaffected eyes of patients with POAG and healthy eyes. MAIN OUTCOME MEASURES: Difference in OCT-A vessel density and SD OCT structural parameters between unaffected eyes of patients with POAG with the fellow affected eyes and healthy controls. RESULTS: Mean wiVD in unaffected eyes of patients with POAG (52.0%) was higher than in their fellow affected eyes (48.8%) but lower than in healthy eyes (55.9%; P < 0.001). Mean circumpapillary RNFL (cpRNFL) thickness, mGCC thickness, and rim area measurement in unaffected eyes of patients with POAG (87.5 µm, 87.7 µm, and 1.0 mm2) were also higher than those measurements in their fellow eyes (76.5 µm, 79.5 µm, and 0.8 mm2; P < 0.001) and lower than in healthy eyes (98.0 µm, 94.5 µm, and 1.4 mm2; P < 0.001). The AUROCs for differentiating unaffected eyes of patients with POAG from healthy eyes were highest for wiVD (0.84), followed by mGCC (0.78), cpRNFL (0.77), and pfVD (0.69). CONCLUSIONS: OCT-A measures detect changes in retinal microvasculature before VF damage is detectable in patients with POAG, and these changes may reflect damage to tissues relevant to the pathophysiology of glaucoma. Longitudinal studies are needed to determine whether OCT-A measures can improve the detection or prediction of the onset and progression of glaucoma.

REDUCED GANGLION CELL VOLUME ON OPTICAL COHERENCE TOMOGRAPHY IN PATIENTS WITH GEOGRAPHIC ATROPHY.

PURPOSE: Geographic atrophy (GA) is the sequelae of macular degeneration. Automated inner retinal analysis using optical coherence tomography is flawed because segmentation software is calibrated for normal eyes. The purpose of this study is to determine whether ganglion cell layer (GCL) volume is reduced in GA using manual analysis. METHODS: Nineteen eyes with subfoveal GA and 22 controls were selected for morphometric analyses. Heidelberg scanning laser ophthalmoscope optical coherence tomography images of the optic nerve and macula were obtained, and the Viewing Module was used to manually calibrate retinal layer segmentation. Retinal layer volumes in the central 3-mm and surrounding 6-mm diameter were measured. Linear mixed models were used for statistics. RESULTS: The GCL volume in the central 3 mm of the macula is less (P = 0.003), and the retinal nerve fiber layer volume is more (P = 0.02) in patients with GA when compared with controls. Ganglion cell layer volume positively correlated with outer nuclear layer volume (P = 0.020). CONCLUSION: The patients with geographic atrophy have a small significant loss of the GCL. Ganglion cell death may precede axonal loss, and increased macular retinal nerve fiber layer volumes are not indicative of GCL volume. Residual ganglion cell stimulation by interneurons may enable vision in patients with GA.

Frequency of Testing to Detect Visual Field Progression Derived Using a Longitudinal Cohort of Glaucoma Patients.

PURPOSE: To determine the time required to detect statistically significant progression for different rates of visual field loss using standard automated perimetry (SAP) when considering different frequencies of testing using a follow-up scheme that resembles clinical practice. DESIGN: Observational cohort study. PARTICIPANTS: One thousand seventy-two eyes of 665 patients with glaucoma followed up over an average of 4.3±0.9 years. METHODS: Participants with 5 or more visual field tests over a 2- to 5-year period were included to derive the longitudinal measurement variability of SAP mean deviation (MD) using linear regressions. Estimates of variability then were used to reconstruct real-world visual field data by computer simulation to evaluate the time required to detect progression for various rates of visual field loss and different frequencies of testing. The evaluation was performed using a follow-up scheme that resembled clinical practice by requiring a set of 2 baseline tests and a confirmatory test to identify progression. MAIN OUTCOME MEASURES: Time (in years) required to detect progression. RESULTS: The time required to detect a statistically significant negative MD slope decreased as the frequency of testing increased, albeit not proportionally. For example, 80% of eyes with an MD loss of -2 dB/year would be detected after 3.3, 2.4, and 2.1 years when testing is performed once, twice, and thrice per year, respectively. For eyes with an MD loss of -0.5 dB/year, progression can be detected with 80% power after 7.3, 5.7, and 5.0 years, respectively. CONCLUSIONS: This study provides information on the time required to detect progression using MD trend analysis in glaucoma eyes when different testing frequencies are used. The smaller gains in the time to detect progression when testing is increased from twice to thrice per year suggests that obtaining 2 reliable tests at baseline followed by semiannual testing and confirmation of progression through repeat testing in the initial years of follow-up may provide a good compromise for detecting progression, while minimizing the burden on health care resources in clinical practice.

Rates of Local Retinal Nerve Fiber Layer Thinning before and after Disc Hemorrhage in Glaucoma.

PURPOSE: To investigate longitudinal temporal and spatial associations between disc hemorrhage (DH) and rates of local retinal nerve fiber layer (RNFL) thinning before and after DHs. DESIGN: Longitudinal, observational cohort study. PARTICIPANTS: Forty eyes of 37 participants (23 with glaucoma and 17 with suspect glaucoma at baseline) with DH episodes during follow-up from the Diagnostic Innovations in Glaucoma Study and the African Descent and Glaucoma Evaluation Study. METHODS: All subjects underwent optic disc photography annually and spectral-domain optical coherence tomography (OCT) RNFL thickness measurements every 6 months. The rates of RNFL thinning were calculated using multivariate linear mixed-effects models before and after DH. MAIN OUTCOME MEASURES: Rates of global and local RNFL thinning. RESULTS: Thirty-six eyes of 33 participants with inferior or superior DHs were analyzed. The rates of RNFL thinning were significantly faster in DH quadrants than in non-DH quadrants after DH (-2.25 and -0.69 µm/year; P < 0.001). In the 18 eyes with intensified treatment after DH, the mean rate of RNFL thinning significantly slowed after treatment compared with before treatment in the non-DH quadrants (-2.89 and -0.31 µm/year; P < 0.001), but not in the DH quadrants (-2.64 and -2.12 µm/year; P = 0.19). In 18 eyes with unchanged treatment, the rate of RNFL thinning in the DH quadrant was faster after DH than before DH (P = 0.008). Moreover, compared with eyes without a treatment change, intensification of glaucoma treatment after DH significantly reduced the global, non-DH quadrants, and DH quadrant rates of RNFL thinning after DH compared with before DH (global, P = 0.004; non-DH quadrant, P < 0.001; DH quadrant, P = 0.005). In the multiple linear regression analysis, treatment intensification (ß, 1.007; P = 0.005), visual field mean deviation (ß, 0.066; P = 0.049), and difference in intraocular pressure before and after DH (ß, -0.176; P = 0.034) were associated significantly with the difference of global RNFL slope values before and after DH. CONCLUSIONS: Although the rate of RNFL thinning worsened in a DH quadrant after DH, glaucoma treatment intensification may have a beneficial effect in reducing this rate of thinning.

Peripapillary and Macular Vessel Density in Patients with Glaucoma and Single-Hemifield Visual Field Defect.

PURPOSE: To compare hemifield differences in the vessel density of the peripapillary and macula in open-angle glaucoma eyes with visual field (VF) defect confined to one hemifield using optical coherence tomography angiography (OCT-A). DESIGN: Cross-sectional study. PARTICIPANTS: A total of 58 eyes of 58 patients with glaucoma with VF loss confined to a single hemifield and 28 healthy eyes. METHODS: Retinal vasculature information was summarized as circumpapillary vessel density (cpVD) and perifoveal vessel density (pfVD). Circumpapillary retinal nerve fiber layer (cpRNFL) and macular ganglion cell complex (mGCC) thickness were calculated using spectral domain optical coherence tomography (SD OCT). Paired and unpaired t tests were used to evaluate differences between the perimetrically affected and intact hemiretinae and healthy hemiretinae. Linear regression analyses were performed to evaluate the associations between VF measures with vascular and structural measurements. MAIN OUTCOME MEASURES: Total and hemispheric cpVD, pfVD, cpRNFL, mGCC, and mean sensitivity (MS). RESULTS: Mean cpVD and pfVD in the intact hemiretinae of glaucoma eyes (59.0% and 51.1%, respectively) were higher than in the affected hemiretinae (54.7% and 48.3%, respectively; P < 0.001) but lower than in healthy eyes (62.4% and 53.8%, respectively; P < 0.001). Similar results were noted with cpRNFL and mGCC thickness measurements (P < 0.05 for both). The strongest associations between MS in the affected hemifields were found for cpVD (r = 0.707), followed by pfVD (r = 0.615), cpRNFL (r = 0.496), and mGCC (r = 0.482) in the corresponding hemiretinae (P < 0.001 for all). Moreover, the correlations in the intact hemifields between MS with cpVD and pfVD were higher (r = 0.450 and 0.403) than the correlations between MS and cpRNFL and mGCC thickness measurements (r = 0.340 and 0.290; P values <0.05 for all). CONCLUSIONS: Reduced peripapillary and macular vessel density was detectable in the perimetrically intact hemiretinae of glaucoma eyes with a single-hemifield defect. Vessel density attenuation in both affected and intact hemiretinae was associated with the extent of VF damage in the corresponding hemifields. Optical coherence tomography angiography potentially shows promise for identifying glaucomatous damage before focal VF defects are detectable.

REPRODUCIBILITY OF VESSEL DENSITY MEASUREMENT WITH OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY IN EYES WITH AND WITHOUT RETINOPATHY.

PURPOSE: To determine the intravisit and intervisit reproducibility of optical coherence tomography angiography measurements of macular vessel density in eyes with and without retinal diseases. METHODS: Fifteen healthy volunteers and 22 patients with retinal diseases underwent repeated optical coherence tomography angiography (Angiovue Imaging System, Optovue Inc) scans after pupil dilation on 2 separate visit days. For each visit day, the eyes were scanned twice. Vessel density defined as the proportion of vessel area with flowing blood over the total measurement area was calculated using Angiovue software. Intravisit and intervisit reproducibility were summarized as coefficient of variations and intraclass correlation coefficients were calculated from variance component models. RESULTS: The coefficient of variations representing the intravisit reproducibility of the superficial macular vessel density measurements for different quadrants on 3 mm × 3-mm scans varied from 2.1% to 4.9% and 3.4% to 6.8% for healthy and diseased eyes, respectively, and for the intervisit it was 2.9% to 5.1% and 4.0% to 6.8%, respectively. The coefficient of variations were lower in healthy eyes than in diseased eyes, lower for intravisit than for intervisit, lower on 3 mm × 3-mm scans than on 6 mm × 6-mm scans, and lower for paracentral subfields than for central subfield. CONCLUSION: The evidence presented here demonstrates good reproducibility of optical coherence tomography angiography for measurement of superficial macula vessel density in both healthy eyes and eyes with diabetic retinopathy without diabetic macular edema.

Cases of advanced visual field loss at referral to glaucoma clinics - more men than women?

PURPOSE: In many medical conditions 'late presentation' of disease is more of a problem for men than women. Risk of sight loss from glaucoma is certainly greater in those detected with advanced disease. We performed a retrospective study to test the hypothesis that men are more likely than women to have advanced visual field loss at referral to glaucoma clinics. METHODS: We used 152 918 Humphrey visual fields from 32 147 patients from three regionally different hospitals in England; no other clinical data were made available apart from patient's age, sex and examination dates. The study population was defined as patients with measureable visual field loss in at least one eye at referral to glaucoma clinics. Cases of advanced visual field loss as defined by the Enhanced Glaucoma Severity Staging method at the first visit to secondary care were used as a proxy measure for late presentation of glaucoma. Age-adjusted relative risk (RR) was calculated as the ratio of the proportion of men to women with this proxy measure. RESULTS: Median (interquartile range) age and MD (worse eye) for 3733 men and 4264 women was 72 (63, 79) and 74 (64, 81) years and -6.4 (-11.7, -3.8) and -6.3 (-11.0, -3.8) dB respectively. Overall proportion of patients with advanced visual field loss at referral to glaucoma clinics was slightly higher in men (25.0%) than in women (22.3%); this difference was statistically significant (p < 0.01). Overall age-standardised RR was statistically significant (1.16; p < 0.001); a person with late presentation of glaucoma is 16% (95% confidence interval: 7-25%) more likely to be a man than a woman. CONCLUSIONS: A large number of patients with glaucomatous visual field defects are estimated to have advanced loss in at least one eye on referral to secondary care in England; risk for men more likely presenting with late disease is slightly greater than for women.

Deep Retinal Layer Microvasculature Dropout Detected by the Optical Coherence Tomography Angiography in Glaucoma.

PURPOSE: To investigate factors associated with dropout of the parapapillary deep retinal layer microvasculature assessed by optical coherence tomography angiography (OCTA) in glaucomatous eyes. DESIGN: Cross-sectional study. PARTICIPANTS: Seventy-one eyes from 71 primary open-angle glaucoma (POAG) patients with ß-zone parapapillary atrophy (ßPPA) enrolled in the Diagnostic Innovations in Glaucoma Study. METHODS: Parapapillary deep-layer microvasculature dropout was defined as a complete loss of the microvasculature located within the deep retinal layer of the ßPPA from OCTA-derived optic nerve head vessel density maps by standardized qualitative assessment. Circumpapillary vessel density (cpVD) within the retinal nerve fiber layer (RNFL) also was calculated using OCTA. Choroidal thickness and presence of focal lamina cribrosa (LC) defects were determined using swept-source optical coherence tomography. MAIN OUTCOME MEASURES: Presence of parapapillary deep-layer microvasculature dropout. Parameters including age, systolic and diastolic blood pressure, axial length, intraocular pressure, disc hemorrhage, cpVD, visual field (VF) mean deviation (MD), focal LC defects ßPPA area, and choroidal thickness were analyzed. RESULTS: Parapapillary deep-layer microvasculature dropout was detected in 37 POAG eyes (52.1%). Eyes with microvasculature dropout had a higher prevalence of LC defects (70.3% vs. 32.4%), lower cpVD (52.7% vs. 58.8%), worse VF MD (-9.06 dB vs. -3.83 dB), thinner total choroidal thickness (126.5 µm vs. 169.1 µm), longer axial length (24.7 mm vs. 24.0 mm), larger ßPPA (1.2 mm2 vs. 0.76 mm2), and lower diastolic blood pressure (74.7 mmHg vs. 81.7 mmHg) than those without dropout (P < 0.05, respectively). In the multivariate logistic regression analysis, higher prevalence of focal LC defects (odds ratio [OR], 6.27; P = 0.012), reduced cpVD (OR, 1.27; P = 0.002), worse VF MD (OR, 1.27; P = 0.001), thinner choroidal thickness (OR, 1.02; P = 0.014), and lower diastolic blood pressure (OR, 1.16; P = 0.003) were associated significantly with the dropout. CONCLUSIONS: Systemic and ocular factors including focal LC defects more advanced glaucoma, reduced RNFL vessel density, thinner choroidal thickness, and lower diastolic blood pressure were factors associated with the parapapillary deep-layer microvasculature dropout in glaucomatous eyes. Longitudinal studies are required to elucidate the temporal relationship between parapapillary deep-layer microvasculature dropout and systemic and ocular factors.

Optical Coherence Tomography Angiography Vessel Density in Glaucomatous Eyes with Focal Lamina Cribrosa Defects.

PURPOSE: To investigate whether vessel density assessed by optical coherence tomography angiography (OCT-A) is reduced in glaucomatous eyes with focal lamina cribrosa (LC) defects. DESIGN: Cross-sectional, case-control study. PARTICIPANTS: A total of 82 patients with primary open-angle glaucoma (POAG) from the Diagnostic Innovations in Glaucoma Study (DIGS) with and without focal LC defects (41 eyes of 41 patients in each group) matched by severity of visual field (VF) damage. METHODS: Optical coherence tomography (OCT) angiography-derived circumpapillary vessel density (cpVD) was calculated as the percentage area occupied by vessels in the measured region extracted from the retinal nerve fiber layer (RNFL) in a 750-µm-wide elliptical annulus around the disc. Focal LC defects were detected using swept-source OCT images. MAIN OUTCOME MEASURES: Comparison of global and sectoral (eight 45-degree sectors) cpVDs and circumpapillary RNFL (cpRNFL) thicknesses in eyes with and without LC defects. RESULTS: Age, global, and sectoral cpRNFL thicknesses, VF mean deviation (MD) and pattern standard deviation, presence of optic disc hemorrhage, and mean ocular perfusion pressure did not differ between patients with and without LC defects (P > 0.05 for all comparisons). Mean cpVDs of eyes with LC defects were significantly lower than in eyes without a defect globally (52.9%±5.6% vs. 56.8%±7.7%; P = 0.013) and in the inferotemporal (IT) (49.5%±10.3% vs. 56.8%±12.2%; P = 0.004), superotemporal (ST) (54.3%±8.8% vs. 58.8%±9.6%; P = 0.030), and inferonasal (IN) (52.4%±9.0% vs. 57.6%±9.1%; P = 0.009) sectors. Eyes with LC defects in the IT sector (n = 33) had significantly lower cpVDs than eyes without a defect in the corresponding IT and IN sectors (P < 0.05 for all). Eyes with LC defects in the ST sector (n = 19) had lower cpVDs in the ST, IT, and IN sectors (P < 0.05 for all). CONCLUSIONS: In eyes with similar severity of glaucoma, OCT-A-measured vessel density was significantly lower in POAG eyes with focal LC defects than in eyes without an LC defect. Moreover, reduction of vessel density was spatially correlated with the location of the LC defect.

Relationship between Optical Coherence Tomography Angiography Vessel Density and Severity of Visual Field Loss in Glaucoma.

PURPOSE: To evaluate the association between vessel density measurements using optical coherence tomography angiography (OCT-A) and severity of visual field loss in primary open-angle glaucoma. DESIGN: Observational, cross-sectional study. PARTICIPANTS: A total of 153 eyes from 31 healthy participants, 48 glaucoma suspects, and 74 glaucoma patients enrolled in the Diagnostic Innovations in Glaucoma Study. METHODS: All eyes underwent imaging using OCT-A (Angiovue; Optovue, Fremont, CA), spectral-domain OCT (Avanti; Optovue), and standard automated perimetry (SAP). Retinal vasculature information was summarized as vessel density, the percentage of area occupied by flowing blood vessels in the selected region. Two measurements from the retinal nerve fiber layer (RNFL) were used: circumpapillary vessel density (cpVD) (750-µm-wide elliptical annulus around the optic disc) and whole-image vessel density (wiVD) (entire 4.5×4.5-mm scan field). MAIN OUTCOME MEASURES: Associations between the severity of visual field loss, reported as SAP mean deviation (MD), and OCT-A vessel density. RESULTS: Compared with glaucoma eyes, normal eyes demonstrated a denser microvascular network within the RNFL. Vessel density was higher in normal eyes followed by glaucoma suspects, mild glaucoma, and moderate to severe glaucoma eyes for wiVD (55.5%, 51.3%, 48.3%, and 41.7%, respectively) and for cpVD (62.8%, 61.0%, 57.5%, 49.6%, respectively) (P < 0.001 for both). The association between SAP MD with cpVD and wiVD was stronger (R2 = 0.54 and R2 = 0.51, respectively) than the association between SAP MD with RNFL (R2 = 0.36) and rim area (R2 = 0.19) (P < 0.05 for all). Multivariate regression analysis showed that each 1% decrease in wiVD was associated with 0.66 decibel (dB) loss in MD and each 1% decrease in cpVD was associated with 0.64 dB loss in MD. In addition, the association between vessel density and severity of visual field damage was found to be significant even after controlling for the effect of structural loss. CONCLUSIONS: Decreased vessel density was significantly associated with the severity of visual field damage independent of the structural loss. Optical coherence tomography angiography is a promising technology in glaucoma management, potentially enhancing the understanding of the role of vasculature in the pathophysiology of the disease.

Patterns of Binocular Visual Field Loss Derived from Large-Scale Patient Data from Glaucoma Clinics.

PURPOSE: To estimate prevalence of visual field (VF) loss in superior and inferior hemifields in binocular VFs in a large sample of patients with bilateral glaucoma. DESIGN: Retrospective cohort study. PARTICIPANTS: Glaucoma patients and suspects attending 4 regionally different secondary-care eye clinics in the United Kingdom. METHODS: Binocular integrated visual fields (IVFs) using a best location method were constructed for 16 642 patients with bilateral VF loss. A significant VF defect was defined as 3 or more VF locations less than a certain sensitivity threshold, such as 20 dB. Patients were classified as having a VF defect in the inferior hemifield, superior hemifield, both hemifields, or neither hemifield. The criteria for number of locations and sensitivity threshold (in decibels) were varied across a large range of values. In addition, factor analysis was applied to the sensitivity values (in decibels) of the IVFs to determine common defect patterns in an automated fashion. MAIN OUTCOME MEASURES: Ratio of patients with binocular VF defects in the superior compared with the inferior areas of the IVF. RESULTS: Estimates of the ratio of patients having binocular VF defects in the superior compared with the inferior region of the IVF ranged from 2.1 (95% confidence interval, 2.1-2.4) to as high as 5.1 (95% confidence interval, 4.7-5.5), depending on the defect criteria used. Fewer than 10% of those patients exhibiting relatively early binocular VF loss had a defect confined to the inferior region only. Common patterns of binocular VF loss were dominated chiefly by superior hemifield defects. CONCLUSIONS: In a clinical population of patients with measurable VF loss in both eyes, superior-only binocular VF loss is more common than inferior-only loss. These estimates, derived from large collections of electronic medical records, are useful for interpreting findings about location of binocular VF loss impacting everyday activities and examining visual disability in glaucoma.

Estimated Utility of the Short-term Assessment of Glaucoma Progression Model in Clinical Practice.

IMPORTANCE: Clinical trials of glaucoma therapies focused on protecting the optic nerve have required large sample sizes and lengthy follow-up to detect clinically relevant change due to its slow rate of progression. Whether shorter trials may be possible with more frequent testing and use of rate of change as the end point warrants further investigation. OBJECTIVE: To describe the design for the Short-term Assessment of Glaucoma Progression (STAGE) model and provide guidance on sample size and power calculations for shorter clinical trials. DESIGN, SETTING, AND PARTICIPANTS: A cohort study of patients with mild, moderate, or advanced open-angle glaucoma recruited from the Diagnostic Innovations in Glaucoma Study at the University of California, San Diego. Enrollment began in May 2012 with follow-up for every 3 months for 2 years after baseline examination. Follow-up was concluded in September 2016. Data were analyzed from July 2019 to January 2021. Visual fields (VF) and optic coherence tomography (OCT) scans were obtained at baseline and for 2 years with visits every 3 months. EXPOSURES: Glaucoma was defined as glaucomatous appearing optic discs classified by disc photographs in at least 1 eye and/or repeatable VF damage at baseline. MAIN OUTCOMES AND MEASURES: Longitudinal rates of change in retinal nerve fiber layer (RNFL) thickness and VF mean deviation (MD) are estimated in study designs of varying length and observation frequency. Power calculations as functions of study length, observation frequency, and sample size were performed. RESULTS: In a total referred sample of 97 patients with mild, moderate, or advanced glaucoma (mean [SD] age, 69 [11.4] years; 50 [51.5%] were female; 19 [19.6%]), over the 2-year follow-up, the mean VF 24-2 MD slope was -0.32 dB/y (95% CI, -0.43 to -0.21 dB/y) and the mean RNFL thickness slope was -0.54 µm/y (95% CI, -0.75 to -0.32 µm/y). Sufficient power (80%) to detect similar group differences in the rate of change in both outcomes was attained with total follow-up between 18 months and 2 years and fewer than 300 total participants. CONCLUSIONS AND RELEVANCE: In this cohort study, results from the STAGE model with reduction of the rate of progression as the end point, frequent testing, and a moderate effect size, suggest that clinical trials to test efficacy of glaucoma therapy can be completed within 18 months of follow-up and with fewer than 300 participants.

Classification of primary angle closure spectrum with hierarchical cluster analysis.

PURPOSE: To classify subjects with primary angle closure into clusters based on features from anterior segment optical coherence tomography (ASOCT) imaging and to explore how these clusters correspond to disease subtypes, including primary angle closure suspect (PACS), primary angle closure glaucoma(PACG), acute primary angle closure (APAC) and fellow eyes of APAC and reveal the factors that become more predominant in each subtype of angle closure. METHOD: A cross-sectional study of 248 eyes of 198 subjects(88 PACS eyes, 53 PACG eyes, 54 APAC eyes and 53 fellow eyes of APAC) that underwent complete examination including gonioscopy, A-scan biometry, and ASOCT. An agglomerative hierarchical clustering method was used to classify eyes based on ASOCT parameters. RESULTS: Statistical clustering analysis produced three clusters among which the anterior segment parameters were significantly different. Cluster 1(43 eyes) had the smallest anterior chamber depth(ACD) and area, as well as the greatest lens vault (p<0.001 for all). Cluster 2(113 eyes) had the thickest iris at 2000 microns(p = 0.048), and largest iris area(p<0.001), and the deepest ACD (p<0.001). Cluster 3(92 eyes) was characterized by elements of both clusters 1 and 2 and a higher iris curvature(p<0.001). There was a statistically significant difference in the distribution of clusters among subtypes of angle closure eyes(p<0.001). Although the patterns of clusters were similar in PACS and PACG eyes, with the majority of the eyes classified into cluster 2(55%, and 62%, respectively), the highest proportion of APAC and fellow eyes were assigned to clusters 1(44%) and 3 (51%), respectively. CONCLUSION: Hierarchical cluster analysis identified three clusters with different features. Predominant anatomical components are different among subtypes of primary angle closure.

Progression of Primary Open-Angle Glaucoma in Diabetic and Nondiabetic Patients.

PURPOSE: To compare the rates of visual field (VF) loss and retinal nerve fiber layer (RNFL) thinning in primary open-angle glaucoma (POAG) patients with or without type 2 diabetes mellitus (DM). DESIGN: Cohort study. METHODS: A total of 197 eyes (55 eyes of 32 POAG patients with DM in POAG/DM group and 142 eyes of 111 age-matched POAG patients without DM in POAG/DM- group) were included from the Diagnostic Innovations in Glaucoma Study (DIGS). Type 2 DM participants were defined by self-report of DM history and use of antidiabetic medication. The rates of VF loss and RNFL loss were compared in POAG eyes with and without DM using univariate and multivariable mixed-effects models. RESULTS: The median (interquartile range) follow-up was 5.7 years (4.0, 6.4). The mean rate of global RNFL loss in the POAG/DM group was 2-fold slower than in the POAG/DM- group overall (-0.40 µm/year vs -0.83 µm/year, respectively P = .01). Although a slower rate of VF mean deviation and pattern standard deviation loss was found in the POAG/DM group compared to the POAG/DM- group, the difference was not statistically significant. CONCLUSIONS: POAG patients with treated type 2 DM, who had no detectable diabetic retinopathy, had significantly slower rates of RNFL thinning compared to those without diagnosed DM.

Association between Rates of Retinal Nerve Fiber Layer Thinning and Previous Disc Hemorrhage in Glaucoma.

PURPOSE: To investigate the relationship between previous disc hemorrhage (DH) and subsequent rates of retinal nerve fiber layer (RNFL) thinning. DESIGN: Longitudinal, observational cohort study. PARTICIPANTS: Twenty-eight patients with glaucoma and patients with suspected glaucoma who had a history of DH in 1 eye (unilateral DH), but not in the fellow eye, enrolled in the Diagnostic Innovations in Glaucoma Study and the African Descent and Glaucoma Evaluation Study were included. METHODS: All subjects underwent annual optic disc photography and semiannual spectral-domain OCT RNFL thickness measurements. Multivariable linear mixed-effects models were used to investigate the relationship between the presence of previous DH and RNFL thinning rates while adjusting for potential confounding factors, such as race, age, mean intraocular pressure (IOP), baseline disease severity, and central corneal thickness (CCT). The relationship between the timing of DH and the rates of RNFL thinning also was investigated in eyes with a history of DH. MAIN OUTCOME MEASURES: Rates of global and local RNFL thinning. RESULTS: Previous DH was significantly associated with faster RNFL thinning rates globally (-0.39 µm/year faster, P = 0.010), in DH quadrants (-0.77 µm/year faster, P = 0.012), and non-DH quadrants (-0.49 µm/year faster, P = 0.038) after adjustment for race, mean IOP, baseline age, baseline standard automated perimetry mean deviation, and CCT. Higher IOP was also significantly associated with faster thinning rates globally (-0.07 µm/year faster per 1 mmHg higher, P = 0.047) and in DH quadrants (-0.10 µm/year faster per 1 mmHg higher, P = 0.044). In eyes with a history of DH, the time elapsed from the latest DH episode to the first OCT examination was not significantly associated with the rate of RNFL thinning. CONCLUSIONS: A history of DH is an independent risk factor for faster rates of RNFL thinning in non-DH quadrants and in DH quadrants; this risk is present even in eyes that exhibited DH several years earlier.

Optical Coherence Tomography Angiography Macular Vascular Density Measurements and the Central 10-2 Visual Field in Glaucoma.

PURPOSE: To evaluate the association between macula vascular density assessed by optical coherence tomography angiography (OCT-A) and central visual field (VF) threshold sensitivities in healthy, glaucoma suspect, and glaucoma patients. METHODS: A total of 185 eyes from 38 healthy participants, 31 glaucoma suspects, 72 mild glaucoma patients, and 44 moderate/severe glaucoma patients from the Diagnostic Innovations in Glaucoma Study who underwent OCT-A images of the macula and 10-2 VF testing were enrolled in this observational cross-sectional study. The relationship between central VF mean sensitivity (MS) and superficial macula whole-image vessel density (wiVD), and the relationship between the MS of the 4 central points of the 10-2 VF (MS4) and parafoveal vessel density (pfVD), were assessed using linear regression models. RESULTS: Mean wiVD (52.5%, 49.8%, 49.4% and 45.2%, respectively) and mean pfVD (54.9%, 52.1%, 51.8% and 47.7%, respectively) were found to be significantly higher in healthy eyes and glaucoma suspect eyes compared with glaucoma eyes with mild and moderate/severe disease [analysis of covariance (ANCOVA) P<0.001]. The univariate associations between 10-2 MS and wiVD (R=26.9%) and between 10-2 MS4 and pfVD (R=16.8%) were statistically significant (P<0.001 for both). After adjusting for scan quality, age, sex and intraocular pressure, superficial macula wiVD and pfVD were still independently associated with central VF loss. Macula wiVD performed better [area under the receiver operator characteristic (AUROC)=0.70] than ganglion cell complex thickness (AUROC=0.50) for differentiating between glaucoma suspect and healthy eyes (P=0.010). CONCLUSIONS: Loss of OCT-A macula vessel density is associated with central 10-2 VF defects. Macula vessel density is a clinically relevant parameter that may enhance monitoring of glaucoma suspects and patients.

Optic disc microvasculature dropout in primary open-angle glaucoma measured with optical coherence tomography angiography.

PURPOSE: To evaluate microvasculature dropout in the optic disc (Mvd-D) using optical coherence tomography angiography (OCTA) and investigate factors associated with Mvd-D in primary open-angle glaucoma (POAG) eyes. METHODS: One hundred twenty-three eyes of 123 POAG patients were included from the Diagnostic Innovations in Glaucoma Study. The 3.0×3.0-mm optic nerve head OCTA scans were acquired using a spectral-domain OCT instrument. Images with whole-signal-mode were evaluated. Eyes were classified into 3 categories (Mvd-D, pseudo-Mvd-D, and no Mvd-D). Mvd-D and pseudo-Mvd-D had complete loss of OCTA signals on the temporal side of the optic disc on the en face projection image. They were distinguished base on the visualization of the anterior lamina cribrosa in the horizontal B-scans of that area. No Mvd-D was defined when no complete signal loss of OCTA signals was observed. Covariates including focal lamina cribrosa defects assessed by swept-source OCT and microvasculature dropout in the parapapillary region (Mvd-P) were analyzed. RESULTS: Forty-two, 37, and 44 eyes were identified as having Mvd-D, pseudo-Mvd-D, and no Mvd-D, respectively. The eyes with Mvd-D showed significantly lower intraocular pressure, worse visual field mean deviation, larger cup-to-disc ratio, thinner circumpapillary retinal nerve fiber layer (cpRNFL), and lower circumpapillary vessel density within the RNFL than the eyes with pseudo-Mvd-D or the eyes without Mvd-D. Multivariable logistic regression analysis showed significant associations of Mvd-D with larger cup-to-disc ratio (OR, 1.08; P = 0.001), worse visual field mean deviation (OR, 1.09; P = 0.048), higher prevalence of focal lamina cribrosa defect (OR, 9.05; P = 0.002), and higher prevalence of Mvd-P (OR, 10.33; P <0.001). CONCLUSIONS: OCTA-derived Mvd-D was strongly associated with the presences of Mvd-P and focal lamina cribrosa defects, and these 3 findings were topographically associated with each other.

Retinal Nerve Fiber Layer Features Identified by Unsupervised Machine Learning on Optical Coherence Tomography Scans Predict Glaucoma Progression.

Purpose: To apply computational techniques to wide-angle swept-source optical coherence tomography (SS-OCT) images to identify novel, glaucoma-related structural features and improve detection of glaucoma and prediction of future glaucomatous progression. Methods: Wide-angle SS-OCT, OCT circumpapillary retinal nerve fiber layer (cpRNFL) circle scans spectral-domain (SD)-OCT, standard automated perimetry (SAP), and frequency doubling technology (FDT) visual field tests were completed every 3 months for 2 years from a cohort of 28 healthy participants (56 eyes) and 93 glaucoma participants (179 eyes). RNFL thickness maps were extracted from segmented SS-OCT images and an unsupervised machine learning approach based on principal component analysis (PCA) was used to identify novel structural features. Area under the receiver operating characteristic curve (AUC) was used to assess diagnostic accuracy of RNFL PCA for detecting glaucoma and progression compared to SAP, FDT, and cpRNFL measures. Results: The RNFL PCA features were significantly associated with mean deviation (MD) in both SAP (R2 = 0.49, P < 0.0001) and FDT visual field testing (R2 = 0.48, P < 0.0001), and with mean circumpapillary RNFL thickness (cpRNFLt) from SD-OCT (R2 = 0.58, P < 0.0001). The identified features outperformed each of these measures in detecting glaucoma with an AUC of 0.95 for RNFL PCA compared to an 0.90 for mean cpRNFLt (P = 0.09), 0.86 for SAP MD (P = 0.034), and 0.83 for FDT MD (P = 0.021). Accuracy in predicting progression was also significantly higher for RNFL PCA compared to SAP MD, FDT MD, and mean cpRNFLt (P = 0.046, P = 0.007, and P = 0.044, respectively). Conclusions: A computational approach can identify structural features that improve glaucoma detection and progression prediction.

The Association Between Macula and ONH Optical Coherence Tomography Angiography (OCT-A) Vessel Densities in Glaucoma, Glaucoma Suspect, and Healthy Eyes.

PURPOSE: To evaluate strength of associations between optical coherence tomography (OCT)-angiography vessel density (VD) measurements in the macula and peripapillary region of the optic nerve head (ONH) with standard structural OCT thickness measures. MATERIALS AND METHODS: This cross-sectional study included 333 eyes of 219 primary open-angle glaucoma patients, 41 glaucoma suspects, and 73 healthy participants from the Diagnostic Innovations in Glaucoma Study (DIGS) with good quality OCT angiography images. The strength of associations between microvasculature measures in the ONH retinal nerve fiber layer (RNFL) and superficial macula layer was assessed using linear regression models. Associations between ONH and macula VD, and circumpapillary (cp) RNFL thickness and macular ganglion cell complex (mGCC) measures were also evaluated. RESULTS: The strength (r) of associations among VD and thickness measures of ONH and macula ranged from 14.1% to 69.4%; all were statistically significant (P<0.001). The association between ONH and macula whole-image VD (r=41.0%) was significantly weaker than the relationship between mGCC and cpRNFL thickness (r=69.4%, P<0.001). Although both cpRNFL and mGCC thicknesses tended to be more strongly associated with ONH VD (r=39.2% and 26.7%, respectively) than macula VD (r=27.5% and 17.7%, respectively), differences did not reach statistical significance (P=0.050 and P=0.113, respectively). CONCLUSIONS: The strength of the association of VD with cpRNFL and mGCC thicknesses varies by retinal layer. The weaker association of macula VD compared with ONH VD with tissue thickness may be due to differences in micorovasculature between the macula and ONH.