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.

A Retrospective Observational Study to Determine Baseline Characteristics and Early Prescribing Patterns for Patients Receiving Alirocumab in UK Clinical Practice.

BACKGROUND: Alirocumab is a fully human monoclonal antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9) and has been previously shown, in the phase III ODYSSEY clinical trial program, to provide significant lowering of low-density lipoprotein cholesterol (LDL-C) and reduction in risk of major adverse cardiovascular events. However, real-world evidence to date is limited. OBJECTIVE: The primary objective was to describe baseline characteristics, clinical history, and prior lipid-lowering therapy (LLT) use of patients initiated on alirocumab in UK clinical practice following publication of health technology appraisal (HTA) body recommendations. Secondary objectives included description of alirocumab use and lipid parameter outcomes over a 4-month follow-up period. METHODS: In this retrospective, single-arm, observational, multicenter study, data were collected for 150 patients initiated on alirocumab. RESULTS: Mean (standard deviation; SD) age of patients was 61.4 (10.5) years and baseline median (interquartile range; IQR) LDL-C level was 4.8 (4.2-5.8) mmol/l. Alirocumab use occurred predominantly in patients with heterozygous familial hypercholesterolemia (HeFH) (n = 100/150, 66%) and those with statin intolerance (n = 123/150, 82%). Most patients started on alirocumab 75 mg (n = 108/150 [72%]) and 35 (23.3%) were up-titrated to 150 mg. Clinically significant reductions in atherogenic lipid parameters were observed with alirocumab, including LDL-C (median [IQR] change from baseline, - 53.6% [- 62.9 to - 34.9], P < 0.001). CONCLUSION: This study highlights the unmet need for additional LLT in patients with uncontrolled hyperlipidemia and demonstrates the clinical utility of alirocumab in early real-world practice, where dosing flexibility is an important attribute of this therapeutic option.

Comparison of Digital Widefield Retinal Imaging With Indirect Ophthalmoscopy in Pediatric Patients.

BACKGROUND AND OBJECTIVE: Approximately 16,000 children in the United States lose vision each year because of retinal disease. The authors compare digital ultra-widefield (UWF) photography to indirect ophthalmoscopy in children. PATIENTS AND METHODS: Prospective, single-center study of patients ages 3 to 17 years. Retinal area during indirect ophthalmoscopy was compared with retinal area in digital UWF fundus photographs. Image quality was graded. A survey to assess the usefulness of the retinal image was obtained. RESULTS: The retinal area (mean ± standard deviation, mm2) evaluated with indirect ophthalmoscopy was 413 ± 194 mm2, compared with 652 ± 117 mm2 with widefield photography (P < .001). The difference was largest in children younger than 14. Image quality was significantly associated with patient cooperation. CONCLUSIONS: High-quality UWF photographs evaluate more peripheral retina than the in-office dilated funduscopic exam in children under 14. Photography assisted with family counseling in 17% of patients and the avoidance of examination under anesthesia in 2% of patients. [Ophthalmic Surg Lasers Imaging Retina. 2019;50:580-585.].

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.

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.

Complication rates of resident-performed cataract surgery: Impact of early introduction of cataract surgery training.

PURPOSE: To determine the effect of the early introduction of cataract surgery training on the complication rates of resident-performed cataract surgery. SETTING: University of California San Diego, San Diego, California, USA. DESIGN: Retrospective case series. METHODS: Two classes of ophthalmology residents were examined, one class with a late introduction of cataract surgery and one with an early introduction of cataract surgery. All cataract cases in which residents acted as primary surgeon were included. Patient charts were reviewed to collect data on patient characteristics, surgical details, and intraoperative and postoperative complications. RESULTS: The late-introduction cohort comprised 3 residents who performed 540 cataract cases, all during their final year of residency. The early-introduction cohort comprised 4 residents who performed 780 cataract cases beginning in the first year of residency. The late-introduction cohort had higher rates of major intraoperative complications than the early-introduction cohort (8.5% versus 3.1%) and of anterior vitrectomy (7.6% versus 2.1%) (both P < .001). Examination of the anterior vitrectomy rate as a function of experience showed the early-introduction cohort had a stable anterior vitrectomy rate of 1% to 2% throughout training, while the late-introduction cohort had a peak anterior vitrectomy rate of 12% at approximately case 20. Multivariable regression analysis showed the early-introduction cohort was independently associated with a lower rate of anterior vitrectomy (hazard ratio, 0.49; 95% confidence interval, 0.36-0.66) after adjusting for differences in patient characteristics and surgical complexity. CONCLUSIONS: Early introduction of cataract surgery training significantly decreased the rate of major intraoperative complications, specifically anterior vitrectomy, in resident-performed cataract surgeries.

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.

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.

Deep-Layer Microvasculature Dropout by Optical Coherence Tomography Angiography and Microstructure of Parapapillary Atrophy.

Purpose: To investigate the association between the microstructure of ß-zone parapapillary atrophy (ßPPA) and parapapillary deep-layer microvasculature dropout assessed by optical coherence tomography angiography (OCT-A). Methods: Thirty-seven eyes with ßPPA devoid of the Bruch's membrane (BM) (γPPA) ranging between completely absent and discontinuous BM were matched by severity of the visual field (VF) damage with 37 eyes with fully intact BM (ßPPA+BM) based on the spectral-domain (SD) OCT imaging. Parapapillary deep-layer microvasculature dropout was defined as a dropout of the microvasculature within choroid or scleral flange in the ßPPA on the OCT-A. The widths of ßPPA, γPPA, and ßPPA+BM were measured on six radial SD-OCT images. Prevalence of the dropout was compared between eyes with and without γPPA. Logistic regression was performed for evaluating association of the dropout with the width of ßPPA, γPPA, and ßPPA+BM, and the γPPA presence. Results: Eyes with γPPA had significantly higher prevalence of the dropout than did those without γPPA (75.7% versus 40.8%; P = 0.004). In logistic regression, presence and longer width of the γPPA, worse VF mean deviation, and presence of focal lamina cribrosa defects were significantly associated with the dropout (P < 0.05), whereas width of the ßPPA and ßPPA+BM, axial length, and choroidal thickness were not (P > 0.10). Conclusions: Parapapillary deep-layer microvasculature dropout was associated with the presence and larger width of γPPA, but not with the ßPPA+BM width. Presence and width of the exposed scleral flange, rather than the retinal pigmented epithelium atrophy, may be associated with deep-layer microvasculature dropout.

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.

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.

Macular Vessel Density in Glaucomatous Eyes With Focal Lamina Cribrosa Defects.

PURPOSE: To compare optical coherence tomography angiography (OCTA) measured macular vessel density and spectral domain optical coherence tomography (SDOCT) measured macular ganglion cell complex (GCC) thickness in primary open-angle glaucoma eyes with and without focal lamina cribrosa (LC) defects. METHODS: In this cross-sectional, case-control study of patients with primary open-angle glaucoma, 46 eyes of 46 patients with LC defects and 54 eyes of 54 patients without observable LC defects were included. OCTA and SDOCT imaging were performed on the same day by the same operator. Perimetry and swept-source OCT testing used to identify LC defects were conducted within 6 months of OCTA and SDOCT testing. Global and local parafoveal vessel density and macular GCC thickness were compared between study groups. RESULTS: Glaucoma severity was similar between groups (SAP mean deviation=-5.63 and -4.64 dB for eyes with and without LC defects, respectively; P=0.40). Global and local measured parafoveal vessel density was similar between groups (all P≥0.11). GCC focal loss volume was higher in eyes with LC defects than eyes without LC defects (7.2% and 4.97%, respectively; P=0.03). In addition, GCC focal loss volume was topographically related to defect location in LC defect eyes. CONCLUSIONS: Although OCTA macular vessel density was not significantly different between eyes with and without LC defects, focal GCC loss in eyes with LC defects was different. This highlights the importance of not relying solely on vessel density measurements for determining macular changes for diagnosing and detecting glaucomatous progression.

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.

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.

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.

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.

Reproducibility and Agreement of Anterior Segment Parameter Measurements Obtained Using the CASIA2 and Spectralis OCT2 Optical Coherence Tomography Devices.

PURPOSE: To assess the reproducibility and agreement of measurement values obtained from the Tomey CASIA2 and Heidelberg Spectralis OCT2 anterior segment optical coherence tomographic devices. METHODS: Twenty eyes from 10 subjects ranging from age 28 to 45 years with no history of eye conditions or intraocular surgery were included. Two scans were obtained with each device in a standardized dark room environment after a period of dark adaptation. One anterior segment optical coherence tomography image along the horizontal (temporal nasal) meridian was analyzed per eye and per scan. Lens vault, pupil diameter, anterior chamber width, angle opening distance, trabecular iris space area, and scleral spur angle were measured using manufacturer-provided image analysis programs. Intraclass correlation coefficient (ICC) values, coefficients of variation, and Bland-Altman plots were computed to assess the intradevice correlation and interdevice agreement of measurement values. RESULTS: There was excellent intradevice reproducibility of measurement values for both the CASIA (ICC range, 0.86 to 0.99) and Spectralis (ICC range, 0.79 to 1.00). There was also excellent interdevice correlation of measurement values (ICC range, 0.78 to 0.93) for all parameters except anterior chamber width (ICC 0.20). Linear regression models and Bland-Altman plots showed that this relationship was strongest when measurement values were small. CONCLUSIONS: There is excellent intradevice reproducibility and good interdevice agreement of anterior segment parameter measurement values for the CASIA2 and Spectralis OCT2. However, the measurements obtained with each device should not be considered interchangeable.

Reproducibility of Optical Coherence Tomography Angiography Macular and Optic Nerve Head Vascular Density in Glaucoma and Healthy Eyes.

PURPOSE: Optical coherence tomography angiography (OCT-A) is a noninvasive technology that allows visualization of retinal blood vessels. It is important to determine reproducibility of measurements as low precision can impair its diagnostic capabilities. The purpose of this study is to determine intravisit and intervisit reproducibility of optic nerve head (ONH) and macular vessel density measurements with OCT-A. PATIENTS AND METHODS: Fifteen healthy volunteers and 14 glaucoma patients completed 2 OCT-A (AngioVue; Optovue Inc.) scanning sessions on each of 2 separate days to assess intravisit and intervisit reproducibility. A series of ONH and macula scans were acquired at each session. Vessel density (%), the proportion of vessel area over the total measurement area was calculated. Reproducibility was summarized using coefficients of variation (CV) and intraclass correlation coefficients calculated from variance component models. RESULTS: In healthy eyes, the CV of intravisit and intervisit global vessel density measures ranged from 1.8% to 3.2% in ONH scans and 2.5% to 9.0% in macular scans. In glaucoma eyes, the CV of intravisit and intervisit global vessel density measures ranged from 2.3% to 4.1% in ONH scans and 3.2% to 7.9% in macular scans. CVs were lower for global than sectorial measures. Global OCT-A ONH intraclass correlation measurements for the retinal nerve fiber layer in healthy eyes were lower (range: 0.65 to 0.85) than in glaucoma eyes (range: 0.89 to 0.94). Scan size did not make large differences in measurement CVs. CONCLUSIONS: Reproducibility of OCT-A ONH and macula vessel density measurements is good. Moreover, glaucoma patients have sparser vessel density with poorer reproducibility than healthy subjects.

Progressive Macula Vessel Density Loss in Primary Open-Angle Glaucoma: A Longitudinal Study.

PURPOSE: To characterize the rate of macula vessel density loss in primary open-angle glaucoma (POAG), glaucoma-suspect, and healthy eyes. DESIGN: Longitudinal, observational cohort from the Diagnostic Innovations in Glaucoma Study. METHODS: One hundred eyes (32 POAG, 30 glaucoma-suspect, and 38 healthy) followed for at least 1 year with optical coherence tomography angiography (OCT-A) imaging on at least 2 visits were included. Vessel density was calculated in the macula superficial layer. The rate of change was compared across diagnostic groups using a multivariate linear mixed-effects model. RESULTS: Baseline macula vessel density was highest in healthy eyes, followed by glaucoma-suspect and POAG eyes (P < .01). The rate of vessel density loss was significantly different from zero in the POAG, but not in the glaucoma-suspect or healthy eyes. The mean rate of change in macula whole en face vessel density was significantly faster in glaucoma eyes (-2.23%/y) than in glaucoma-suspect (0.87%/y, P = .001) or healthy eyes (0.29%/y, P = .004). Conversely, the rate of change in ganglion cell complex (GCC) thickness was not significantly different from zero in any diagnostic group, and no significant differences in the rate of GCC change among diagnostic groups were found. CONCLUSIONS: With a mean follow-up of less than 14 months, eyes with POAG had significantly faster loss of macula vessel density than either glaucoma-suspect or healthy eyes. Serial OCT-A measurements also detected glaucomatous change in macula vessel density in eyes without evidence of change in GCC thickness.

Impact of Normal Aging and Progression Definitions on the Specificity of Detecting Retinal Nerve Fiber Layer Thinning.

PURPOSE: To evaluate the specificity of current definitions used to identify progressive change of the average peripapillary retinal nerve fiber layer (RNFL) thickness measurements obtained on optical coherence tomography (OCT) imaging. DESIGN: Prospective observational cohort study. METHODS: Setting: University of California, San Diego. STUDY POPULATION: Seventy-five eyes from 45 normal participants. OBSERVATION PROCEDURE: Patients were seen at an average of 5.7 visits over 3.2 years, to determine the age-related average RNFL thickness changes and longitudinal measurement variability. Slope and variability estimates were used to reconstruct "real-world" OCT imaging measurements with computer simulations. MAIN OUTCOME MEASURE: False-positive rates for progression in normal eyes using different definitions. RESULTS: The estimated normal average RNFL thickness change over time was -0.54 ± 0.23 µm/year (P < .001). Even with a recent definition of progression that appeared to guarantee a high level of specificity by accounting for normal aging (requiring a significant negative slope that was more negative than the 5% lower limit of aging), 18% simulated normal eyes were still falsely identified as having progressed after 5 years of annual testing in a clinical practice scenario. However, this was reduced to 8% and 4% when trend-based analysis of progression was performed after adjustments using the mean and 5% lower limit of normal rates of aging, respectively. CONCLUSIONS: This study highlights how current definitions for detecting RNFL thinning have an unacceptably poor level of specificity, and that more stringent definitions are required to avoid misleading interpretations of progression on OCT imaging in clinical practice.