The Relationship Between Asymmetries of Corneal Properties and Rates of Visual Field Progression in Glaucoma Patients.

PRéCIS:: In this study, asymmetries in corneal hysteresis (CH) between eyes of glaucoma patients were significantly associated with asymmetries in rates of visual field loss, suggesting a role of hysteresis as a risk factor for disease progression. PURPOSE: The purpose of this study was to investigate the relationship between asymmetries in rates of glaucoma progression and asymmetries of corneal properties between eyes of subjects with primary open-angle glaucoma. PARTICIPANTS AND METHODS: This prospective study followed 126 binocular subjects with glaucoma for an average of 4.3±0.8 years. CH was measured at baseline using the Ocular Response Analyzer. Standard automated perimetry (SAP) and intraocular pressure were measured at baseline and every 6 months. Rates of visual field progression were calculated using ordinary least square regression of SAP mean deviation (MD) values over time for each eye. Eyes were defined as "better" and "worse" based on the slopes of SAP MD. Pearson correlation test, and univariable and multivariable regression models were used to investigate the relationship between inter-eye asymmetry in CH and central corneal thickness and inter-eye differences in rates of visual field progression. RESULTS: Only asymmetry of CH was significantly associated with the asymmetry in SAP MD rates of change between eyes (r=0.22; P=0.01). In a multivariable model adjusting for age, race, central corneal thickness, mean intraocular pressure and baseline disease severity, CH asymmetry remained significantly associated with asymmetric progression (P=0.032). CONCLUSION: CH asymmetry between eyes was associated with asymmetry on rates of visual field change, providing further support for the role of CH as a risk factor for glaucoma progression.

Comparing the Rule of 5 to Trend-based Analysis for Detecting Glaucoma Progression on OCT.

PURPOSE: The rule of 5 is a simple rule for detecting retinal nerve fiber layer (RNFL) change on spectral-domain OCT (SD-OCT), in which a loss of 5 µm of global RNFL on a follow-up test is considered evidence of significant change when compared with the baseline. The rule is based on short-term test-retest variability of SD-OCT and is often used in clinical practice. The purpose of this study was to compare the rule of 5 with trend-based analysis of global RNFL thickness over time for detecting glaucomatous progression. DESIGN: Prospective cohort. PARTICIPANTS: A total of 300 eyes of 210 glaucoma subjects followed for an average of 5.4±1.5 years with a median of 11 (interquartile range, 7-14) visits. METHODS: Trend-based analysis was performed by ordinary least-squares (OLS) linear regression of global RNFL thickness over time. For estimation of specificity, false-positives were obtained by assessing for progression on series of randomly permutated follow-up visits for each eye, which removes any systematic trend over time. The specificity of trend-based analysis was matched to that of the rule of 5 to allow meaningful comparison of the "hit rate," or the proportion of glaucoma eyes categorized as progressing at each time point, using the original sequence of visits. MAIN OUTCOME MEASURES: Comparison between hit rates of trend-analysis versus rule of 5 at matched specificity. RESULTS: After 5 years, the simple rule of 5 identified 37.5% of eyes as progressing at a specificity of 81.1%. At the same specificity, the hit rate for trend-based analysis was significantly greater than that of the rule of 5 (62.9% vs. 37.5%; P < 0.001). If the rule of 5 was required to be repeatable on a consecutive test, specificity improved to 93.4%, but hit rate decreased to 21.0%. At this higher specificity, trend-based analysis still had a significantly greater hit rate than the rule of 5 (47.4% vs. 21.0%, respectively; P < 0.001). CONCLUSIONS: Trend-based analysis was superior to the simple rule of 5 for identifying progression in glaucoma eyes and should be preferred as a method for longitudinal assessment of global SD-OCT RNFL change over time.

Comparison of Short- And Long-Term Variability in Standard Perimetry and Spectral Domain Optical Coherence Tomography in Glaucoma.

PURPOSE: To assess short- and long-term variability on standard automated perimetry (SAP) and spectral domain optical coherence tomography (SD-OCT) in glaucoma. DESIGN: Prospective cohort. METHODS: Ordinary least squares linear regression of SAP mean deviation (MD) and SD-OCT global retinal nerve fiber layer (RNFL) thickness were fitted over time for sequential tests conducted within 5 weeks (short-term testing) and annually (long-term testing). Residuals were obtained by subtracting the predicted and observed values, and each patient's standard deviation (SD) of the residuals was used as a measure of variability. Wilcoxon signed-rank test was performed to test the hypothesis of equality between short- and long-term variability. RESULTS: A total of 43 eyes of 43 glaucoma subjects were included. Subjects had a mean 4.5 ± 0.8 SAP and OCT tests for short-term variability assessment. For long-term variability, the same number of tests were performed and results annually collected over an average of 4.0 ± 0.8 years. The average SD of the residuals was significantly higher in the long-term than in the short-term period for both tests: 1.05 ± 0.70 dB vs. 0.61 ± 0.34 dB, respectively (P < 0.001) for SAP MD and 1.95 ± 1.86 µm vs. 0.81 ± 0.56 µm, respectively (P < 0.001) for SD-OCT RNFL thickness. CONCLUSIONS: Long-term variability was higher than short-term variability on SD-OCT and SAP. Because current event-based algorithms for detection of glaucoma progression on SAP and SD-OCT have relied on short-term variability data to establish their normative databases, these algorithms may be underestimating the variability in the long-term and thus may overestimate progression over time.

Corneal Biomechanics and Visual Field Progression in Eyes with Seemingly Well-Controlled Intraocular Pressure.

PURPOSE: To investigate the incidence and risk factors for glaucomatous visual field progression in eyes with well-controlled intraocular pressure (IOP). DESIGN: Prospective cohort. PARTICIPANTS: A total of 460 eyes of 334 patients with glaucoma under treatment. METHODS: Study subjects had a mean follow-up of 4.3±0.8 years. Patients were classified as well controlled if all IOP measurements were less than 18 mmHg. Rates of visual field progression were calculated using ordinary least-squares linear regression of standard automated perimetry (SAP) mean deviation (MD) values over time. Progression was defined as a significantly negative MD slope (alpha = 0.05). MAIN OUTCOME MEASURES: Rates of SAP MD change; mean and peak IOP, and IOP fluctuation; and corneal biomechanics: corneal hysteresis (CH), central corneal thickness (CCT), and corneal index. RESULTS: Of the 179 eyes with well-controlled IOP, 42 (23.5%) demonstrated visual field progression. There was no significant difference between progressing and stable patients in baseline MD (-6.4±7.1 decibels [dB] vs. -6.0±6.2 dB; P = 0.346), mean IOP (11.7±2.0 mmHg vs. 12.1±2.3 mmHg; P = 0.405), IOP fluctuation (1.6±0.6 mmHg vs. 1.6±0.5 mmHg; P = 0.402), or peak IOP (14.3±1.9 mmHg vs. 14.6±2.1 mmHg; P = 0.926). Progressing eyes had significantly lower CH (8.6±1.3 mmHg vs. 9.4±1.6 mmHg; P = 0.014) and thinner CCT (515.1±33.1 µm vs. 531.1±42.4 µm; P = 0.018, respectively) compared with stable eyes. In the multivariate analysis, a 1 standard deviation lower corneal index, a summation of normalized versions of CH and CCT, resulted in a 68% higher risk of progression (odds ratio, 1.68; 95% confidence interval, 1.08-2.62; P = 0.021). CONCLUSIONS: Approximately one-quarter of eyes with well-controlled IOP may show visual field progression over time. Thin cornea and low CH are main risk factors.

Detecting Retinal Nerve Fibre Layer Segmentation Errors on Spectral Domain-Optical Coherence Tomography with a Deep Learning Algorithm.

In this study we developed a deep learning (DL) algorithm that detects errors in retinal never fibre layer (RNFL) segmentation on spectral-domain optical coherence tomography (SDOCT) B-scans using human grades as the reference standard. A dataset of 25,250 SDOCT B-scans reviewed for segmentation errors by human graders was randomly divided into validation plus training (50%) and test (50%) sets. The performance of the DL algorithm was evaluated in the test sample by outputting a probability of having a segmentation error for each B-scan. The ability of the algorithm to detect segmentation errors was evaluated with the area under the receiver operating characteristic (ROC) curve. Mean DL probabilities of segmentation error in the test sample were 0.90 ± 0.17 vs. 0.12 ± 0.22 (P < 0.001) for scans with and without segmentation errors, respectively. The DL algorithm had an area under the ROC curve of 0.979 (95% CI: 0.974 to 0.984) and an overall accuracy of 92.4%. For the B-scans with severe segmentation errors in the test sample, the DL algorithm was 98.9% sensitive. This algorithm can help clinicians and researchers review images for artifacts in SDOCT tests in a timely manner and avoid inaccurate diagnostic interpretations.

Mobile Telephone Use and Reaction Time in Drivers With Glaucoma.

Importance: Combining mobile telephone use with driving is not unusual. However, distracted driving limits driving performance because of limited capacity for persons to divide attention. Objectives: To investigate the frequency of mobile telephone use while driving and to assess whether patients with glaucoma had a disproportionate decrease in driving performance while conversing on a mobile telephone compared with healthy participants. Design, Setting, and Participants: Cross-sectional study of surveys collected from 112 patients with glaucoma and 70 control participants investigating mobile telephone use while driving. A randomly selected subgroup of 37 patients with glaucoma and 28 controls drove in a driving simulator to investigate peripheral event detection performance during distracted driving at the Visual Performance Laboratory, Duke University, Durham, North Carolina. Data collection was performed from December 1, 2016, through April 30, 2017. Exposures: Participants answered a survey and submitted to a driving simulation test with and without mobile telephone use. Main Outcomes and Measures: Survey answers were collected, and distracted driving performance, assessed by reaction time to peripheral stimuli, was analyzed. Results: Of the 182 participants who answered the survey, the 112 participants with glaucoma included 56 women (50.0%) and had a mean (SD) age of 73.6 (9.6) years. The 70 controls included 49 women (70.0%) and had a mean (SD) age of 68.4 (10.9) years. When asked about mobile telephone use while driving, 30 patients with glaucoma (26.8%) admitted rarely using and 2 (1.8%) sometimes using it. In the control group, 20 participants (28.6%) admitted rarely using and 2 (2.9%) sometimes using the telephone while driving (P = .80). Reaction times to peripheral stimuli were significantly longer among patients with glaucoma compared with controls during mobile telephone use (median [interquartile range], 1.86 [1.42-2.29] seconds vs 1.14 [0.98-1.59] seconds; P = .02). Compared with driving performance while not using a mobile telephone, the mean (SD) increase of 0.85 (0.60) second in reaction time while conversing on the mobile telephone among patients with glaucoma was significantly greater than the mean (SD) increase of 0.68 (0.83) second for controls (P = .03). Conclusions and Relevance: This study's findings indicate that patients with glaucoma use mobile telephones while driving as frequently as healthy participants. However, the findings also suggest that patients with glaucoma may experience a greater decline than healthy participants in their ability to detect peripheral events while driving when also talking on a mobile telephone. Patients with glaucoma should be informed that they may have a higher driving risk that may be worsened by distractions, such as mobile telephone use.

Visual Crowding in Glaucoma.

Purpose: Crowding refers to the phenomenon in which objects that can be recognized when viewed in isolation are unrecognizable in clutter. Crowding sets a fundamental limit to the capabilities of the peripheral vision and is essential in explaining performance in a broad array of daily tasks. Due to the effects of glaucoma on peripheral vision, we hypothesized that neural loss in the disease would lead to stronger effects of visual crowding. Methods: Subjects were asked to discriminate the orientation of a target letter when presented with surrounding flankers. The critical spacing value (scritical), which was required for correct discrimination of letter orientation, was obtained for each quadrant of the visual field. scritical values were correlated with standard automated perimetry (SAP) mean sensitivity (MS) and optical coherence tomography (OCT) retinal nerve fiber layer (RNFL) thickness measurements. Results: The study involved 13 subjects with mild glaucomatous visual field loss and 13 healthy controls. Glaucomatous eyes had significantly greater (worse) scritical than controls (170.4 ± 27.1 vs. 145.8 ± 28.0 minimum of visual angle, respectively; P = 0.007). scritical measurements were significantly associated with RNFL thickness measurements (R2 = 26%; P < 0.001) but not with SAP MS (P = 0.947). Conclusions: In glaucoma patients, a pronounced visual crowding effect is observed, even in the presence of mild visual field loss on standard perimetry. scritical was associated with the amount of neural loss quantified by OCT. These results may have implications for understanding how glaucoma patients are affected in daily tasks where crowding effects may be significant.

Association between Rates of Visual Field Progression and Intraocular Pressure Measurements Obtained by Different Tonometers.

PURPOSE: To investigate the associations between intraocular pressure (IOP) measurements obtained by different tonometric methods and rates of visual field loss in a cohort of patients with glaucoma followed over time. DESIGN: Prospective, observational cohort study. PARTICIPANTS: This study included 213 eyes of 125 glaucomatous patients who were followed for an average of 2.4±0.6 years. METHODS: At each visit, IOP measurements were obtained using Goldmann applanation tonometry (GAT), the Ocular Response Analyzer (ORA) (Reichert, Inc., Depew, NY), corneal-compensated IOP (IOPcc), and the ICare Rebound Tonometer (RBT) (Tiolat, Oy, Helsinki, Finland). Rates of visual field loss were assessed by standard automated perimetry (SAP) mean deviation (MD). Linear mixed models were used to investigate the relationship between mean IOP by each tonometer and rates of visual field loss over time, while adjusting for age, race, central corneal thickness, and corneal hysteresis. MAIN OUTCOME MEASURES: Strength of associations (R2) between IOP measurements from each tonometer and rates of SAP MD change over time. RESULTS: Average values for mean IOP over time measured by GAT, ORA, and RBT were 14.4±3.3, 15.2±4.2, and 13.4±4.2 mmHg, respectively. Mean IOPcc had the strongest relationship with SAP MD loss over time (R2 = 24.5%) and was significantly different from the models using mean GAT IOP (R2 = 11.1%; 95% confidence interval [CI] of the difference, 6.6-19.6) and mean RBT IOP (R2= 5.8%; 95% CI of the difference, 11.1-25.0). CONCLUSIONS: Mean ORA IOPcc was more predictive of rates of visual field loss than mean IOP obtained by GAT or RBT. By correcting for corneal-induced artifacts, IOPcc measurements may present significant advantages for predicting clinically relevant outcomes in patients with glaucoma.

What Is the Amount of Visual Field Loss Associated With Disability in Glaucoma?

PURPOSE: To propose a new methodology for classifying patient-reported outcomes in glaucoma and for quantifying the amount of visual field damage associated with disability in the disease. DESIGN: Cross-sectional study. METHODS: A total of 263 patients with glaucoma were included. Vision-related disability was assessed by the National Eye Institute Visual Function Questionnaire (NEI VFQ-25). A latent class analysis (LCA) model was applied to analyze NEI VFQ-25 data and patients were divided into mutually exclusive classes according to their responses to the questionnaires. Differences in standard automated perimetry (SAP) mean deviation (MD) and integrated binocular mean sensitivity (MS) values between classes were investigated. The optimal number of classes was defined based on goodness-of-fit criteria, interpretability, and clinical utility. RESULTS: The model with 2 classes, disabled and nondisabled, had the best fit with an entropy of 0.965, indicating excellent separation of classes. The disabled group had 48 (18%) patients, whereas 215 (82%) patients were classified as nondisabled. The average MD of the better eye in the disabled group was -5.98 dB vs -2.51 dB in the nondisabled group (P < .001). For the worse eye, corresponding values were -13.36 dB and -6.05 dB, respectively (P < .001). CONCLUSION: Application of an LCA model allowed categorization of patient-reported outcomes and quantification of visual field levels associated with disability in glaucoma. A damage of approximately -6 dB for SAP MD, indicating relatively early visual field loss, may already be associated with significant disability if occurring in the better eye.

Macular Pigment and Visual Function in Patients With Glaucoma: The San Diego Macular Pigment Study.

Purpose: Although recent studies have shown that macular pigment (MP) is significantly lower in glaucoma patients, this relationship merits further investigation. Methods: This cross-sectional study included 85 glaucoma patients and 22 controls. All subjects had standard automated perimetry (SAP) and retinal nerve fiber layer (RNFL) thickness measurements. Intake of lutein (L) and zeaxanthin (Z) was estimated using a novel dietary screener. The Heidelberg Spectralis dual-wavelength autofluorescence (AF) technology was employed to study the relationship between MP and glaucoma. The association between MP volume and glaucoma was investigated using linear regression models accounting for potential confounding factors. Results: Glaucoma patients had significantly worse SAP mean deviation (MD) and lower RNFL thickness in the study eye compared to control subjects (P < 0.001 for both). MP (volume) was comparable between groups (P = 0.436). In the univariable model, diagnosis of glaucoma was not associated with MP volume (R2 = 1.22%; P = 0.257). Dietary intake of L and Z was positively and significantly related to MP in the univariable (P = 0.022) and multivariable (P = 0.020) models. Conclusions: These results challenge previous studies that reported that glaucoma is associated with low MP. Dietary habits were found to be the main predictor of MP in this sample. Further research is merited to better understand the relationship between glaucoma, MP, and visual performance in these patients.

A Prospective Longitudinal Study to Investigate Corneal Hysteresis as a Risk Factor for Predicting Development of Glaucoma.

PURPOSE: To investigate the role of corneal hysteresis (CH) as a risk factor for development of glaucoma. DESIGN: Prospective observational cohort study. METHODS: Two hundred and eighty-seven eyes of 199 patients suspected of having glaucoma were followed for an average of 3.9 ± 1.8 years. All eyes had normal visual fields at baseline. Development of glaucoma was defined as occurrence of 3 consecutive abnormal standard automated perimetry tests during follow-up, defined as pattern standard deviation (PSD) < 5%, and/or Glaucoma Hemifield Test outside normal limits. Measurements of CH were acquired at baseline using the Ocular Response Analyzer (ORA). Univariable and multivariable Cox regression models were used to investigate baseline factors associated with development of visual field loss over time. RESULTS: Fifty-four (19%) eyes developed repeatable visual field defects during follow-up. Measurements of CH at baseline were significantly lower in patients who developed glaucoma vs those who did not (9.5 ± 1.5 mm Hg vs 10.2 ± 2.0 mm Hg; P = .012). Each 1-mm Hg lower CH was associated with an increase of 21% in the risk of developing glaucoma during follow-up (95% confidence interval [CI]: 1.04-1.41; P = .013). In a multivariable model adjusting for age, intraocular pressure, central corneal thickness, PSD, and treatment, CH was still predictive of development of glaucoma (hazard ratio = 1.20; 95% CI: 1.01-1.42; P = .040). CONCLUSION: Baseline lower CH measurements were significantly associated with increased risk of developing glaucomatous visual field defects over time. The prospective longitudinal design of this study supports a role of CH as a risk factor for developing glaucoma.