Structure-function analysis for macular surgery in patients with coexisting glaucoma.

PURPOSE: To develop methods to assess the effects of epiretinal membranes (ERM) and macular holes (MH) coexisting with glaucoma on pre-operative retinal structure and function and evaluate post-operative outcomes. METHODS: Seven eyes of 7 patients with glaucoma, 6 with ERMs and 1 with MH, were enrolled; 4 underwent vitrectomy for ERM and one for MH. Visual fields (VFs) and optical coherence tomography (OCT) scans were obtained pre- and post-operatively. The 10-2VF deviation map was overlayed on ganglion cell and inner plexiform layer (GCL + IPL) and retinal nerve fiber layer (RNFL) deviation maps derived from OCT macula and disc cube scans. Optic nerve circle scans were obtained to assess RNFL thickness, and OCT b-scans associated with VF defects were compared pre- and post-operatively. RESULTS: Examination of pre-operative VFs and OCT scans showed the importance of determining the extent to which glaucomatous damage contributed to VF loss; verifying automated segmentation of the GCL + IPL and RNFL; and assessing foveal anatomy. Evaluation of post-operative structure-function outcomes required correction of magnification changes in OCT scans and repeated follow-up visits to clarify the origin of VF changes. CONCLUSIONS: Pre-operative comparisons of VFs and OCT scans may be beneficial in guiding surgical planning, and evaluating outcomes, in eyes with glaucoma undergoing macular surgery.

Remote Contrast Sensitivity Testing Seems to Correlate With the Degree of Glaucomatous Macular Damage.

PRCIS: Remote contrast sensitivity (CS) testing through a free downloadable home test correlates with glaucomatous macular damage measured by 10-2 visual field (VF) testing. PURPOSE: To assess the feasibility and validity of home CS monitoring as a measure of glaucomatous damage using a free downloadable smartphone application. METHODS: Twenty-six participants were asked to remotely use the Berkeley Contrast Squares (BCS) application, a free downloadable tool that records the user's CS for varying degrees of visual acuity. An instructional video detailing how to download and use the application was sent to the participants. Subjects were asked to send logarithmic CS results with a minimum 8-week test-retest window, and test-retest reliability was measured. Results were validated against office-based CS testing that was collected within the previous 6 months. Validity analysis was also carried out to determine whether CS as measured by BCS is a good predictor of 10-2 and 24-2 VF mean deviation (MD). RESULTS: There was a high BCS test-retest reliability with an intraclass correlation coefficient score of 0.91 and a significant correlation between repeat test results and baseline test scores (Pearson, 0.86, P < 0.0001). There was significant agreement between unilateral CS scores as measured by BCS and office-based CS testing ( b = 0.94, P < 0.0001, 95% CI: 0.61 to 1.27). Unilateral CS as measured by BCS was significantly associated with 10-2 VF MD ( r2 = 0.27, P = 0.006, 95% CI: 3.7 to 20.6), but not with 24-2 VF MD ( P = 0.151). CONCLUSION: This study suggests that a free, rapid home CS test correlates with glaucomatous macular damage as measured by 10-2 VF.

Rationale and Development of an OCT-Based Method for Detection of Glaucomatous Optic Neuropathy.

A specific, sensitive, and intersubjectively verifiable definition of disease for clinical care and research remains an important unmet need in the field of glaucoma. Using an iterative, consensus-building approach and employing pilot data, an optical coherence tomography (OCT)-based method to aid in the detection of glaucomatous optic neuropathy was sought to address this challenge. To maximize the chance of success, we utilized all available information from the OCT circle and cube scans, applied both quantitative and semiquantitative data analysis methods, and aimed to limit the use of perimetry to cases where it is absolutely necessary. The outcome of this approach was an OCT-based method for the diagnosis of glaucomatous optic neuropathy that did not require the use of perimetry for initial diagnosis. A decision tree was devised for testing and implementation in clinical practice and research that can be used by reading centers, researchers, and clinicians. While initial pilot data were encouraging, future testing and validation will be needed to establish its utility in clinical practice, as well as for research.

Nicotinamide and Pyruvate for Neuroenhancement in Open-Angle Glaucoma: A Phase 2 Randomized Clinical Trial.

IMPORTANCE: Open-angle glaucoma may continue to progress despite significant lowering of intraocular pressure (IOP). Preclinical research has suggested that enhancing mitochondrial function and energy production may enhance retinal ganglion cell survival in animal models of glaucoma, but there is scant information on its effectiveness in a clinical setting. OBJECTIVE: To test the hypothesis that a combination of nicotinamide and pyruvate can improve retinal ganglion cell function in human glaucoma as measured with standard automated perimetry. DESIGN, SETTING, AND PARTICIPANTS: In this phase 2, randomized, double-blind, placebo-controlled clinical trial at a single academic institution, 197 patients were assessed for eligibility. Of these, 42 patients with treated open-angle glaucoma and moderate visual field loss in at least 1 eye were selected for inclusion and randomized. A total of 32 completed the study and were included in the final analysis. The mean (SD) age was 64.6 (9.8) years. Twenty-one participants (66%) were female. Participant race and ethnicity data were collected via self-report to ensure the distribution reflected that observed in clinical practice in the US but are not reported here to protect patient privacy. Recruitment took place in April 2019 and patients were monitored through December 2020. Data were analyzed from January to May 2021. INTERVENTIONS: Ascending oral doses of nicotinamide (1000 to 3000 mg) and pyruvate (1500 to 3000 mg) vs placebo (2:1 randomization). MAIN OUTCOMES AND MEASURES: Number of visual field test locations improving beyond normal variability in the study eye. Secondary end points were the rates of change of visual field global indices (mean deviation [MD], pattern standard deviation [PSD], and visual field index [VFI]). RESULTS: Twenty-two of 29 participants (76%) randomized to the intervention group and 12 of 13 participants (92%) randomized to placebo received their allocation, and 32 participants (32 eyes; ratio 21:11) completed the study (21 from the intervention group and 11 from the placebo group). Median (IQR) follow-up time was 2.2 (2.0-2.4) months. No serious adverse events were reported during the study. The number of improving test locations was significantly higher in the treatment group than in the placebo group (median [IQR], 15 [6-25] vs 7 [6-11]; P = .005). Rates of change of PSD suggested improvement with treatment compared with placebo (median, -0.06 vs 0.02 dB per week; 95% CI, 0.02 to 0.24; P = .02) but not MD (0.04 vs -0.002 dB per week; 95% CI, -0.27 to 0.09; P = .35) or VFI (0.09 vs -0.02% per week; 95% CI, -0.53 to 0.36; P = .71). CONCLUSIONS AND RELEVANCE: A combination of nicotinamide and pyruvate yielded significant short-term improvement in visual function, supporting prior experimental research suggesting a role for these agents in neuroprotection for individuals with glaucoma and confirming the need for long-term studies to establish their usefulness in slowing progression. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03797469.

The Role of Intraocular Pressure and Systemic Hypertension in the Progression of Glaucomatous Damage to the Macula.

PRCIS: Macular structural and functional parameters were better correlated with pressure-dependent glaucomatous damage than conventional parameters. Self-reported systemic hypertension (HTN) was not associated with structural or functional progression in this cohort. PURPOSE: The aim was to examine the relationships between intraocular pressure (IOP), systemic HTN, and glaucoma progression using structural testing with optical coherence tomography (OCT) and functional testing with visual field (VF). PATIENTS AND METHODS: A total of 191 eyes of 119 patients enrolled in a prospective, longitudinal study (Structural and Functional Progression of Glaucomatous Damage to the Macula study) with a diagnosis of glaucoma were analyzed. Patients were tested with 10-2 and 24-2 VF and spectral-domain OCT obtained at 4 to 6 month intervals. IOP from each visit was collected. Self-reported diagnoses of HTN were reported in 72 eyes (37%) in the patients included. Linear mixed effects regression was used to test the relationship between summary statistics from VF and OCT and HTN diagnosis. The goodness-of-fit of relationships was assessed with Bayesian information criterion. RESULTS: Mean follow-up IOP was most associated with the following OCT parameters: global macula ganglion cell layer (GCL), inferior macula GCL, mean macular vulnerability zone GCL, and mean less vulnerable zone macula GCL, and with the following VF parameters: 10-2 PSD and 10-2 MD. There was no significant difference in rates of progression between HTN and non-HTN patients for any OCT or VF parameter. Models with the best goodness-of-fit for the relationship between HTN and progression were the same as those observed for IOP. CONCLUSION: Macular structural and functional parameters are more sensitive to IOP in terms of glaucomatous progression when compared with more conventional parameters. While HTN was not significantly associated with progression using any parameter, macular structural and functional parameters had a better goodness-of-fit to model progression and may be useful as endpoints.

Association of Patterns of Glaucomatous Macular Damage With Contrast Sensitivity and Facial Recognition in Patients With Glaucoma.

Importance: Facial recognition is a critical activity of daily living that relies on macular function. Glaucomatous macular damage may result in impaired facial recognition that may negatively affect patient quality of life. Objective: To evaluate the association of patterns of glaucomatous macular damage with contrast sensitivity and facial recognition among patients with glaucoma. Design, Setting, and Participants: In this prospective cohort study at a single tertiary care center, 144 eyes of 72 consecutive patients with glaucoma with good visual acuity (20/40 or better in each eye) were studied. Data were collected from March to April 2019. Exposures: Eyes with macular damage were categorized as having focal, diffuse, or mixed (focal and diffuse) damage based on optic disc and macular spectral-domain optical coherence tomography and 10-2 visual field (VF) damage. Only eyes with focal or diffuse damage were included. Higher-acuity and lower-acuity eyes were determined by 10-2 VF mean deviation (MD). Facial disability was defined as facial recognition scores at the 2% level of normal participants. Main Outcomes and Measures: (1) Monocular contrast threshold as measured by the Freiburg Visual Acuity and Contrast Test and (2) binocular facial recognition as measured by the Cambridge Face Memory Test. Results: Of the 72 included patients, 49 (68%) were White and 41 (57%) were female, and the mean (SD) age was 67.0 (11.6) years. Eyes with diffuse damage had greater contrast impairment compared with eyes with focal damage (ß = -0.5; 95% CI, -0.6 to -0.4; P < .001) after adjusting for 10-2 VF MD, 24-2 VF MD, age, presence of an early cataract, and number of drops. Similarly, Cambridge Face Memory Test scores were significantly lower in patients with diffuse rather than focal macular damage, regardless of eye (better-seeing eye: ß = 10.0; 95% CI, 2.0 to 18.2; P = .001; worse-seeing eye: ß = 5.5; 95% CI, 0.8 to 10.0; P = .23). Relative risk of facial disability was greater for patients with diffuse but not focal macular damage in the better-seeing eye (relative risk, 86.2; 95% CI, 2.7 to 2783.3; P = .01). Conclusions and Relevance: In this cohort study, diffuse rather than focal glaucomatous macular damage was associated with diminished facial recognition and contrast sensitivity. Evaluation of macular optical coherence tomography and 10-2 VF and resultant detection of diffuse macular damage may help minimize glaucoma-related visual disability.

Global optical coherence tomography measures for detecting the progression of glaucoma have fundamental flaws.

OBJECTIVE: To understand the problems involved in using global OCT measures for detecting progression in early glaucoma. SUBJECTS/METHODS: Eyes from 76 patients and 28 healthy controls (HC) had a least two OCT scans at least 1 year apart. To determine the 95% confidence intervals (CI), 151 eyes (49 HC and 102 patients) had at least two scans within 6 months. All eyes had 24-2 mean deviation ≥-6dB. The average (global) thicknesses of the circumpapillary retinal nerve fibre layer (cRNFL), GONH, and of the retinal ganglion cell layer plus inner plexiform layer (RGCLP), Gmac, were calculated. Using quantile regression, the 95% CI intervals were determined. Eyes outside the CIs were classified as "progressors." For a reference standard (RS), four experts evaluated OCT and VF information. RESULTS: Compared to the RS, 31 of the 76 (40.8%) patient eyes were identified as progressors (RS-P), and 45 patient, and all 28 HC, eyes as nonprogressors (RS-NP). The metrics missed (false negative, FN) 15 (48%) (GONH) and 9 (29%) (Gmac) of the 31 RS-P. Further, GONH and/or Gmac falsely identified (false positive, FP) 10 (22.2%) of 45 patient RS-NP eyes and 7 (25%) of the 28 HC eyes as progressing. Post-hoc analysis identified three reasons (segmentation, centring, and local damage) for these errors. CONCLUSIONS: Global metrics lead to FPs and FNs because of problems inherent in OCT scanning (segmentation and centring), and to FNs because they can miss local damage. These problems are difficult, if not impossible, to correct, and raise concerns about the advisability of using GONH and Gmac for detecting progression.

Early localized alterations of the retinal inner plexiform layer in association with visual field worsening in glaucoma patients.

Glaucoma is a chronic neurodegenerative disease of the optic nerve and a leading cause of irreversible blindness, worldwide. While the experimental research using animal models provides growing information about cellular and molecular processes, parallel analysis of the clinical presentation of glaucoma accelerates the translational progress towards improved understanding, treatment, and clinical testing of glaucoma. Optic nerve axon injury triggers early alterations of retinal ganglion cell (RGC) synapses with function deficits prior to manifest RGC loss in animal models of glaucoma. For testing the clinical relevance of experimental observations, this study analyzed the functional correlation of localized alterations in the inner plexiform layer (IPL), where RGCs establish synaptic connections with retinal bipolar and amacrine cells. Participants of the study included a retrospective cohort of 36 eyes with glaucoma and a control group of 18 non-glaucomatous subjects followed for two-years. The IPL was analyzed on consecutively collected macular SD-OCT scans, and functional correlations with corresponding 10-2 visual field scores were tested using generalized estimating equations (GEE) models. The GEE-estimated rate of decrease in IPL thickness (R = 0.36, P<0.001) and IPL density (R = 0.36, P<0.001), as opposed to unchanged or increased IPL thickness or density, was significantly associated with visual field worsening at corresponding analysis locations. Based on multivariate logistic regression analysis, this association was independent from the patients' age, the baseline visual field scores, or the baseline thickness or alterations of retinal nerve fiber or RGC layers (P>0.05). These findings support early localized IPL alterations in correlation with progressing visual field defects in glaucomatous eyes. Considering the experimental data, glaucoma-related increase in IPL thickness/density might reflect dendritic remodeling, mitochondrial redistribution, and glial responses for synapse maintenance, but decreased IPL thickness/density might correspond to dendrite atrophy. The bridging of experimental data with clinical findings encourages further research along the translational path.

Reoperations for Complications Within 90 Days After Glaucoma Surgery.

OBJECTIVE: To describe reoperations in the operating room for complications encountered within 90 days after glaucoma surgery at a single institution over a 2-year period. DESIGN: Retrospective case series. SUBJECTS: Adult patients who have undergone glaucoma surgery including a tube shunt, trabeculectomy with mitomycin C, trabectome, or transcleral cyclophotocoagulation from June 1, 2015 to August 30, 2017 at a single institution. METHODS: These patients were then examined for postoperative complications that required reoperations within the first 90 days including revision of the tube shunt, revision of the trabeculectomy, drainage of the choroidal, or placement of a tube shunt. MAIN OUTCOME MEASURES: Percentage of reoperations for complications within the first 90 days after glaucoma surgery and surgical indications for these reoperations. RESULTS: A total of 622 glaucoma procedures were performed on 600 eyes in 525 patients over a 2-year period from June 1, 2015 to June 30, 2017 by 4 glaucoma surgeons at a single institution. Of these, 275 (44%) were trabeculectomy with mitomycin C, 253 (41%) were the placement of a tube shunt, 33 (5%) were cyclophotocoagulation, and 61 (10%) were trabectome procedures. Postoperative complications requiring reoperations within 90 days developed in 15 patients (2.4%) overall including 7 patients (2.5%) in the trabeculectomy with mitomycin C group and 8 patients (3.1%) in the tube shunt group. Five patients developed bleb leaks, 3 patients developed serous choroidal effusions, 3 patients had tube exposure, 1 patient had tube retraction, 1 patient had persistent iritis from iris touching the tube, and 1 had encapsulation around the tube. The rate of reoperation for complications was similar between the tube group and the trabeculectomy group (P=0.67, χ test). There were no complications requiring reoperations in 90 days for transcleral cyclophotocoagulation or trabectome. CONCLUSIONS: Early postoperative complications requiring reoperations within the first 90 days after glaucoma surgery were low and comparable with previous studies. Common indications for reoperation within 90 days include wound leak and tube shunt-related issues.

Macular Damage in Glaucoma is Associated With Deficits in Facial Recognition.

PURPOSE: This report examines the relationship between glaucomatous macular damage and facial recognition. In addition, it assesses the role of contrast sensitivity (CS) as an intermediary step in the causal pathway between macular damage and impairment of facial recognition. DESIGN: Prospective cross-sectional study. METHODS: This study was conducted in a single tertiary care center. The study population included 144 eyes of 72 participants with a diagnosis of open angle glaucoma in one or both eyes and a visual acuity of 20/40 or better in each eye. The presence or absence of macular damage was determined by comparing corresponding regions of the retinal nerve fiber layer and the retinal ganglion cell layer with spectral-domain optical coherence tomography with the 10-2 visual field (VF). Better and worse eye was determined by 10-2 VF mean deviations (MDs). Interventions were 1) macular function as measured by 10-2 VF and 2) CS as measured by the Freiburg Visual Acuity and Contrast Test (FrACT). The primary outcome measure was the Cambridge Face Memory Test (CFMT) score. RESULTS: Regardless of eye, there was a significant correlation between facial recognition and 10-2 VF MD (P < .0001 better, worse eye). The 10-2 VF MD remained a significant predictor of facial recognition after adjusting for potential confounders including glaucoma severity, CS, age, and visual acuity (P = .004 better eye, P = .019 worse eye). CONCLUSIONS: Even with good central visual acuity, patients with glaucomatous macular damage exhibit diminished facial recognition, which is partly mediated through diminished CS.

Disc Hemorrhages Are Associated With the Presence and Progression of Glaucomatous Central Visual Field Defects.

PRECIS: In this prospective cohort study, disc hemorrhages were associated with more severe central damage on 24-2 and 10-2 visual fields (VFs), and faster progression globally on 24-2 VFs and centrally on 10-2 VFs. PURPOSE: To study the relationship between disc hemorrhage (DH) and the presence and progression of glaucomatous central VF damage. METHODS: Cross-sectional and longitudinal analyses were performed on data from the African Descent and Glaucoma Evaluation Study (ADAGES) cohort. Two masked investigators reviewed disc photographs for the presence and location of DH. 24-2 central VF damage was based on the number of test locations within the central 10 degrees of the 24-2 field pattern deviation and their mean total deviation (MTD). 10-2 central VF damage was based on pattern deviation and MTD. Main outcome measures were the association between DH and presence of central VF damage and between DH and worsening of VF. RESULTS: DH was detected in 21 of 335 eyes (6.2%). In the cross-sectional analysis, DH was significantly associated with more severe central damage on 24-2 [incidence rate ratio=1.47; 95% confidence interval (CI)=1.02-2.12; P=0.035] and 10-2 VFs (incidence rate ratio=1.81; 95% CI=1.26-2.60; P=0.001). In the longitudinal analysis, DH eyes progressed faster than non-DH eyes based on 24-2 global MTD rates (difference in slopes, ß=-0.06; 95% CI=-0.11 to -0.01; P=0.009) and 10-2 MTD rates (ß=-0.10; 95% CI=-0.14 to -0.06; P< 0.001), but not 24-2 central MTD rates (ß=-0.02; 95% CI=-0.078 to 0.026; P=0.338). CONCLUSION: DH was associated with the presence and progression of central VF defects. DH identification should prompt intensive central VF monitoring and surveillance with 10-2 fields to detect progression.

Detection of Progression With 10-2 Standard Automated Perimetry: Development and Validation of an Event-Based Algorithm.

PURPOSE: To describe the development of a new algorithm for detecting progressive changes in 10-2 visual field (VF) tests using event-based analysis and to test its validity in a second, independent glaucoma cohort. DESIGN: Prospective cohort study. METHODS: Patients with established open-angle glaucoma from the Macular Assessment and Progression Study (MAPS; development cohort, n = 151), and the African Descent and Glaucoma Evaluation Study (ADAGES; validation cohort, n = 52) were evaluated. The 10-2 VF results from MAPS were obtained during 4 test-retest sessions within a 4-month period. For the validation analysis, 10-2 VF results from ADAGES performed on at least 5 visits were used. The event-based pointwise changes on 10-2 tests in the validation cohort were determined using 2 progression criteria: at least 3 progressing VF locations on 2 or 3 consecutive tests ("possible" or "likely" progression). Linear mixed-effects models were used to evaluate VF progression. RESULTS: In the validation cohort, the mean (SD) follow-up time was 2.3 (0.7) years. The number of eyes experiencing 10-2 VF progression based on "possible" and "likely" progression was 36 (54.5%) and 11 (16.6%), respectively. Eyes experiencing "possible" progression had MD changes (-0.60 dB/year [95% confidence interval (CI): -0.93 to -0.28]) faster than those not meeting this criterion (P < .001), whereas for those with "likely" progression the difference was -0.91 dB/year (95% CI: -1.26 to -0.56, P < .001). CONCLUSIONS: A new event-based progression algorithm using the 10-2 VF can identify eyes experiencing more rapid MD progression and may be used as a tool to assess progressive macular functional changes in glaucoma.

Eye-Drop Abstinence in Glaucoma Patients Admitted to the Hospital Service: A Single Institution Assessment.

PURPOSE: Anecdotally, many patients admitted to an inpatient general medicine service do not have their glaucoma eye drops started. The purpose of this study was to determine the extent of eye-drop abstinence after inpatient admission. DESIGN: Retrospective, cross-sectional, hospital-based study. PARTICIPANTS: Four hundred seventy-five patients admitted to the general medicine regional hospital service from January 2016 through February 2018 with a known past medical diagnosis of or active outpatient medications for glaucoma. METHODS: The combination of an administrative database and cross-referenced patient charts were reviewed for demographic data, past medical problems, inpatient orders, intake history and physical, length of stay, and admitting diagnosis. MAIN OUTCOME MEASURES: The effect of (1) outpatient glaucoma drops reconciliation and (2) recognition of glaucoma as a pertinent past medical problem in a patient's intake history and physical on inpatient eye-drop administration. The overall rate of eye-drop abstinence also was recorded. RESULTS: Of 475 patients, 46.3% were women, with an average age of 80.2 years (standard deviation, 11.1 years). Average length of stay was 4.61 days (standard deviation, 3.7 days). In total, 63.8% achieved successful administration of medication on the hospital floor, resulting in a 36.2% eye-drop abstinence rate during the hospital stay. Three hundred eighty-six of 475 patients (81.3%) achieved successful glaucoma medication reconciliation. Patients with successful reconciliation had a significantly different rate of eye-drop administration (73.3% vs. 21.0%; P ≤ 0.001). Recognition of glaucoma in the history and physical occurred in only 42.5% of patients. There was a significant difference in eye-drop administration when glaucoma was included in the history and physical (75.7% vs. 55.0%; P ≤ 0.001). CONCLUSIONS: Glaucoma treatment incurs a high rate of medication noncompliance, especially in the elderly. The present study demonstrates that more than one third of patients admitted to an academic medical center do not receive their glaucoma medications. Patients discharged to nursing homes, subacute rehabilitation, and assisted living facilities rely on appropriate discharge medication reconciliation, resulting in forced abstinence during transition of care. An emphasis on appropriate medical reconciliation and recognition of glaucoma as a pertinent past medical problem will improve rates of eye-drop discontinuation on inpatient admission significantly.

Diffuse Macular Damage in Mild to Moderate Glaucoma Is Associated With Decreased Visual Function Scores Under Low Luminance Conditions.

PURPOSE: Glaucoma patients commonly report increasing visual problems under low luminance or glare conditions, yet there is limited understanding of the structural basis of visual functional losses. This report examines the relationship between glaucomatous macular damage, assessed using structure-function correlation, and visual difficulty under low luminance conditions, as measured by Low Luminance Questionnaire (LLQ). DESIGN: Observational cohort study. METHODS: Setting: Tertiary care referral center. PARTICIPANTS: A total of 252 eyes of 126 participants with mild or moderate open-angle glaucoma (24-2 mean deviation [MD] better than -12 dB) selected from a consecutive sample. PREDICTOR: Focal and diffuse macular defects were identified based on corresponding abnormal regions on probability maps from spectral-domain optical coherence tomography (SDOCT) optic disc and macular cube scans, and 10-2 and 24-2 visual fields (VF). MAIN OUTCOME MEASURE: LLQ scores. RESULTS: Eighty-two of the 126 (65%) better eyes (defined by 24-2 VF MD) had evidence of macular damage, while the remaining 44 did not have macular damage. Of the 82 with damage, 33 (40%) had diffuse damage and 49 (60%) had focal damage. After adjusting for 24-2 MD and age in the multivariable regression, diffuse macular damage remained a significant predictor of the LLQ subscales "difficulty with extreme lighting" (P = .0024), ''difficulty with low lighting" (P = .037), and "diminished mobility"; (P = .042). In contrast, there was no significant difference in LLQ scores in any subscale between participants with focal macular damage and those without macular damage. CONCLUSION: Mild diffuse glaucomatous macular damage, as detected by abnormal topographic regions on measures of structure and function, is associated with decreased LLQ scores.

Structure-Function Agreement Is Better Than Commonly Thought in Eyes With Early Glaucoma.

Purpose: To assess the agreement between structural (optical coherence tomography [OCT]) and functional (visual field [VF]) glaucomatous damage with an automated method and deviation/probability maps, and to compare this method to a metric method. Methods: Wide-field spectral-domain OCT scans, including the disc and macula, and 24-2 and 10-2 VFs were obtained from 45 healthy control (H) eyes/individuals, and 53 eyes/patients with 24-2 mean deviation (MD) better than -6 dB diagnosed as "definite glaucoma" (DG) by experts. Abnormal structure-abnormal function (aS-aF) agreement was assessed with an automated topographic (T) method based upon VF pattern deviation and OCT probability maps. Results were compared to a metric (M) method optimized for accuracy, (abnormal 24-2 glaucoma hemifield test [GHT] or pattern standard deviation [PSD], or 10-2 PSD AND abnormal OCT [quadrant]). Results: For the T-method, 47 (88.7%) of the 53 DG eyes showed aS-aF agreement, compared to 2 (4.5%) of the 45 H eyes. The aS-aF agreement for these two H eyes was easily identified as mistaken, and did not replicate on a subsequent test. Without the 10-2, the aS-aF agreement decreased from 47 to 34 (64.2%) of 53 DG eyes. For the M-method, 37 (69.8%) of the 53 DG eyes showed aS-aF agreement, while omitting the 10-2 VF resulted in agreement in only 33 (62.3%) eyes. Conclusions: There is good agreement between structural and functional damage, even in eyes with confirmed early glaucomatous damage, if both 24-2 and 10-2 VFs are obtained, and abnormal locations on the VFs are compared to abnormal regions seen on OCT macular and disc scans. This can be done in an objective, automated fashion. (ClinicalTrials.gov number, NCT02547740.).

Association of Macular Visual Field Measurements With Glaucoma Staging Systems.

Importance: Macular function is important for daily activities but is underestimated when tested with 24-2 visual fields, which are often used to classify glaucoma severity. Objective: To test the hypothesis that current glaucoma staging systems underestimate glaucoma severity by not detecting macular damage. Design, Setting, and Participants: This cross-sectional study was carried out in a glaucoma referral practice. The eyes of participants with manifest glaucoma and 24-2 mean deviation (MD) better than -6 dB were included. All participants were tested with 24-2, 10-2 visual fields, and spectral-domain optical coherence tomography of the optic disc and macula. Exposures: Macular damage was based on the topographic agreement between visual field results and retinal ganglion cell plus inner plexiform layer probability plots. Classifications from the Hodapp-Parrish-Anderson (HPA), visual field index (VFI), and Brusini staging systems were examined and compared with visual field and spectral-domain optical coherence tomography results. Main Outcomes and Measures: The association between the presence of macular damage and glaucoma severity scores. Results: Fifty-seven eyes of 57 participants were included; 33 participants (57%) were women, and 43 (75%) were white. Their mean (SD) age was 57 (14) years. Forty-eight of the eyes (84% [95% CI, 72%-92%]) had macular damage by the study definition. These had a 24-2 MD mean (SD) of -2.5 (1.8); corresponding results for the 10-2 MD were -3.0 (2.4) dB and for the VFI were 94.2% (4.5%). The HPA system classified 70% (95% CI, 55%-83%) of eyes with macular damage as having early defects; the VFI system classified 81% (95% CI, 67%-91%) of eyes with macular damage as having early defects, and the Brusini system 68% (95% CI, 53%-81%). Conclusions and Relevance: These findings suggest that current glaucoma staging systems based on 24-2 (or 30-2) visual fields underestimate disease severity and the presence of macular damage. If these results are confirmed and generalizable to other participants, new systems using macular measures (from 10-2 and spectral-domain optical coherence tomography results) might improve staging of glaucoma severity.

T-Lymphocyte Subset Distribution and Activity in Patients With Glaucoma.

Purpose: Besides glia-driven neuroinflammation, growing evidence from analysis of human blood samples, isolated autoantibodies, and postmortem tissues also support systemic immune responses during neurodegeneration in glaucoma patients. To explore the T-cell-mediated component of systemic immunity, this study analyzed T lymphocytes in patients' blood. Methods: Blood samples were collected from 32 patients with glaucoma and 21 nonglaucomatous controls, and mononuclear cells were isolated by Histopaque density gradient centrifugation. T-cell subset distribution was analyzed by multicolor flow cytometry after helper (Th) and cytotoxic fractions, and Th subpopulations, were stained with antibodies to CD4, CD8, or distinctive markers, such as IFN-γ (for Th1), IL-4 (for Th2), IL-17A (for Th17), and CD25/FoxP3 (for T regulatory cells [Tregs]). In addition, proliferative activity and cytokine secretion of T cells were analyzed after in vitro stimulation. Results: Analysis of T-cell subset distribution detected a glaucoma-related shift. Despite similar frequencies of CD4+ or CD8+ T cells, or Th1, Th2, or Th17 subsets in glaucoma and control groups, glaucomatous samples exhibited a trend toward decreased frequency of CD4+ (or CD8+)/CD25+/FoxP3+ Tregs within the entire CD4+ (or CD8+) population (P < 0.001). Furthermore, CD4+ T cells in glaucomatous samples presented a greater stimulation response (∼3-fold) as characterized by increased proliferation and proinflammatory cytokine secretion (P < 0.05). Conclusions: These findings suggest that the immunity activated in glaucoma may not be counterbalanced by an efficient immune suppression. More work is encouraged to determine whether shifted T-cell homeostasis may contribute to neurodegeneration in glaucoma, and/or whether T-cell subset imbalance may serve as a biomarker of autoimmune susceptibility.

Macular Damage, as Determined by Structure-Function Staging, Is Associated With Worse Vision-related Quality of Life in Early Glaucoma.

PURPOSE: Macular damage is common early in glaucoma and has previously been identified as a significant factor affecting vision-related quality of life (VRQoL) across the spectrum of glaucomatous damage. This report uses structure-function correlation to identify early macular damage and assess its relationship with the National Eye Institute Visual Function Questionnaire (NEI VFQ-25). DESIGN: Cohort study. METHODS: Setting: Institutional. STUDY POPULATION: Eighty-eight eyes of 44 participants with early open-angle glaucoma (24-2 mean deviation [MD] better than -6 dB). OBSERVATION PROCEDURE: Focal and diffuse macular defects were identified based on corresponding abnormal regions on probability maps from spectral-domain optical coherence tomography (SD-OCT) optic disc and macular cube scans, and 10-2 and 24-2 visual fields (VF). MAIN OUTCOME MEASURE: VRQoL, as measured by the NEI VFQ-25. RESULTS: Twenty-five of 44 (57%) "worse" eyes (defined by 24-2 VF MD) and 13 of 44 (31%) "better" eyes had macular damage. Mean (±standard deviation) MD of worse and better eyes were -3.03 dB (±2.3) and -1.15 dB (±1.7), respectively. Compared to those without macular damage, lower NEI VFQ-25 scores were seen in patients with macular damage in the worse eye (85.4 [± 9.0] vs 94.6 [± 3.3]; P = .0001) and the better eye (84.8 [± 11.1] vs 91.3 [± 6.3]; P = .017). Arcuate damage outside the macula did not affect VRQoL (better eye, P = .40; worse eye, P = .87). CONCLUSIONS: Early glaucomatous macular damage, as detected by abnormal topographic regions on measures of structure and function, is associated with decreased VRQoL. Arcuate damage outside the macula does not have an association with VRQoL in early glaucoma.

Oxidative Stress-Related Molecular Biomarker Candidates for Glaucoma.

Purpose: Glaucoma-related molecular biomarkers can improve clinical testing to diagnose the disease early, predict its prognosis, and monitor treatment responses. Based on the evidence of increased oxidative stress in glaucomatous tissues, this study analyzed oxidative stress-related biomarker candidates in blood and aqueous humor samples with or without glaucoma. Methods: The blood and aqueous humor samples collected from carefully selected groups of 96 patients with glaucoma and 64 healthy subjects without glaucoma were included in the study. The samples were analyzed for protein carbonyls and advanced glycation end products (AGEs) through ELISA-based quantification assays. To allow proper comparisons, the Goldmann-Witmer coefficient that reflects the ratio of aqueous humor to blood values corrected to total protein concentration in individual samples was calculated. Results: Blood and aqueous humor levels of protein carbonyls and AGEs were found significantly higher in glaucomatous samples compared with age-matched nonglaucomatous controls (P < 0.001). The glaucoma-related increase in protein carbonyls and AGEs was more prominent in aqueous humor samples than blood samples (2.6-fold versus 1.9-fold for protein carbonyls, and 3.1-fold versus 1.9-fold for AGEs; P < 0.001). Comparison of the Goldmann-Witmer coefficients indicated greater values for protein carbonyls (1.37 ± 0.3 vs. 3.07 ± 0.8) and AGEs (1.2 ± 0.3 vs. 3.2 ± 1.1) in the glaucoma group (P < 0.001). Conclusions: Findings of this study encourage further validation studies of oxidative stress-related biomarkers in glaucoma. Analysis of protein carbonyls and AGEs in longitudinal studies of larger and heterogeneous patient cohorts should better assess the value of these promising candidates as molecular biomarkers of glaucoma for clinical predictions.

Hybrid Deep Learning on Single Wide-field Optical Coherence tomography Scans Accurately Classifies Glaucoma Suspects.

PURPOSE: Existing summary statistics based upon optical coherence tomographic (OCT) scans and/or visual fields (VFs) are suboptimal for distinguishing between healthy and glaucomatous eyes in the clinic. This study evaluates the extent to which a hybrid deep learning method (HDLM), combined with a single wide-field OCT protocol, can distinguish eyes previously classified as either healthy suspects or mild glaucoma. METHODS: In total, 102 eyes from 102 patients, with or suspected open-angle glaucoma, had previously been classified by 2 glaucoma experts as either glaucomatous (57 eyes) or healthy/suspects (45 eyes). The HDLM had access only to information from a single, wide-field (9×12 mm) swept-source OCT scan per patient. Convolutional neural networks were used to extract rich features from maps derived from these scans. Random forest classifier was used to train a model based on these features to predict the existence of glaucomatous damage. The algorithm was compared against traditional OCT and VF metrics. RESULTS: The accuracy of the HDLM ranged from 63.7% to 93.1% depending upon the input map. The retinal nerve fiber layer probability map had the best accuracy (93.1%), with 4 false positives, and 3 false negatives. In comparison, the accuracy of the OCT and 24-2 and 10-2 VF metrics ranged from 66.7% to 87.3%. The OCT quadrants analysis had the best accuracy (87.3%) of the metrics, with 4 false positives and 9 false negatives. CONCLUSIONS: The HDLM protocol outperforms standard OCT and VF clinical metrics in distinguishing healthy suspect eyes from eyes with early glaucoma. It should be possible to further improve this algorithm and with improvement it might be useful for screening.