Purpose

To evaluate the validity of using progressive loss of neuroretinal rim area as a surrogate end point for the development of visual field loss in glaucoma.

Design

Prospective, observational cohort study.

Participants

The study group included 492 eyes of 328 patients classified with suspected glaucoma at the baseline visit. These eyes had an average of 7.4±2.8 confocal scanning laser ophthalmoscopy (CSLO) images during a mean follow-up time of 6.6±1.6 years.

Methods

Rim area measurements were acquired with CSLO during follow-up. The visual field end point was considered the development of 3 consecutive abnormal visual fields on standard automated perimetry. Strong predictive ability and large proportion of treatment effect (PTE) explained are requisites for a suitable surrogate end point. A joint longitudinal survival model was used to evaluate the ability of rates of rim area loss in predicting visual field development, adjusting for confounding variables (baseline age, race, and corneal thickness and follow-up measurements of intraocular pressure [IOP] and pattern standard deviation). The PTE was calculated by comparing the effect of IOP on the risk of development of visual field loss when incorporating rim area loss in the same model with the effect of IOP in the model excluding rim area measurements.

Main outcome measures

Predictive strength was measured by survival-adapted R(2) and PTE.

Results

Sixty-two of 492 eyes (13%) developed visual field loss during follow-up. The mean rate of rim area change in eyes that developed visual field loss was -0.011 mm(2)/year versus -0.003 mm(2)/year in eyes that did not (P<0.001). In the multivariable model, each 0.01 mm(2)/year faster rate of rim area loss was associated with a 2.94 higher risk of visual field loss (hazard ratio, 2.94; 95% confidence interval, 1.38-6.23; P = 0.005). R(2) values were 62% and 81% for univariable and multivariable models, respectively. The PTE was 65%.

Conclusions

Progressive rim area loss was highly predictive of the development of visual field loss in glaucoma and explained a significant PTE on the clinically relevant outcome. These findings suggest that rim area measurements may be suitable surrogate end points in glaucoma clinical trials.

Purpose

To evaluate the ability of longitudinal frequency doubling technology (FDT) to predict the development of glaucomatous visual field loss on standard automated perimetry (SAP) in glaucoma suspects.

Design

Prospective, observational cohort study.

Participants

The study included 587 eyes of 367 patients with suspected glaucoma at baseline selected from the Diagnostic Innovations in Glaucoma Study (DIGS) and the African Descent and Glaucoma Evaluation Study (ADAGES). These eyes had an average of 6.7 ± 1.9 FDT tests during a mean follow-up time of 73.1 ± 28.0 months.

Methods

Glaucoma suspects had intraocular pressure (IOP) >21 mmHg or an optic disc appearance suspicious of glaucoma. All patients had normal or nonrepeatable abnormal SAP at baseline. Humphrey Matrix FDT (Carl Zeiss Meditec, Inc, Dublin, CA) testing was performed within 6 months of SAP testing. The study end point was the development of 3 consecutive abnormal SAP test results. Joint longitudinal survival models were used to evaluate the ability of rates of FDT pattern standard deviation (PSD) change to predict the development of visual field loss on SAP, adjusting for confounding variables (baseline age, mean IOP, corneal thickness, and follow-up measurements of SAP PSD).

Main outcome measures

The R(2) index was used to evaluate and compare the predictive abilities of the model containing longitudinal FDT PSD data with the model containing only baseline data.

Results

Sixty-three of 587 eyes (11%) developed SAP visual field loss during follow-up. The mean rate of FDT PSD change in eyes that developed SAP visual field loss was 0.07 dB/year versus 0.02 dB/year in those that did not (P < 0.001). Baseline FDT PSD and slopes of FDT PSD change were significantly predictive of progression, with hazard ratios of 1.11 per 0.1 dB higher (95% confidence interval [CI], 1.04-1.18; P = 0.002) and 4.40 per 0.1 dB/year faster (95% CI, 1.08-17.96; P = 0.04), respectively. The longitudinal model performed significantly better than the baseline model with an R(2) of 82% (95% CI, 74-89) versus 11% (95% CI, 2-24), respectively.

Conclusions

Rates of FDT PSD change were highly predictive of the development of SAP visual field loss in glaucoma suspects. This finding suggests that longitudinal FDT evaluation may be useful for risk stratification of patients with suspected glaucoma.

Purpose

To compare the ability of 10-2 visual field tests and central 12 locations of the 24-2 tests (C24-2) to detect central visual field progression in glaucoma eyes with early central visual field abnormalities.

Design

Observational cohort study.

Participants

Three-hundred eyes of 180 participants with glaucoma or ocular hypertension.

Methods

Participants with both 10-2 and 24-2 tests performed on ≥3 visits over ≥1-year period were included to estimate the longitudinal variability of 10-2 and C24-2 visual field mean deviation (MD). The variability estimates were then used to reconstruct real-world visual field results by computer simulations, in a scenario where eyes had a baseline 10-2 and C24-2 MD was -2 dB and exhibited various rates of change (-0.25, -0.50, -0.75 and -1.00 dB/year), and the time to detect these changes were evaluated using trend-based analyses.

Main outcome measures

Time required to detect progression.

Results

Overall, the time to detect central visual field progression was reduced by 7-9% using the 10-2 compared to C24-2 MD values, equivalent to a total reduction of 0.1-0.3 dB lost. For example, 90% of eyes with a central 10-2 or C24-2 MD loss of -0.50 dB/year would be detected after 5.0 and 5.5 years of semi-annual testing respectively, or after 3.4 and 3.7 years respectively for eyes with a -1.00 dB/year loss.

Conclusions

Trend-based analyses using 10-2 MD resulted in a mild reduction (7-9%) in the time to detect central visual field progression compared to C24-2 MD in glaucoma eyes with early central visual field abnormalities. Further studies are needed to determine whether other progression analyses can better exploit the increased sampling of 10-2 tests. These findings provide evidence-based guidance on the potential value-add of 10-2 testing in the clinical management of glaucoma patients.

Purpose

To estimate retinal ganglion cell (RGC) losses associated with visible glaucomatous localized retinal nerve fiber layer (RNFL) defects.

Design

Observational cross-sectional study.

Methods

A multicenter study of 198 normal eyes (138 subjects) and 66 glaucomatous eyes (55 subjects) recruited from the Diagnostic Innovations in Glaucoma Study and the African Descent and Glaucoma Evaluation Study. All eyes underwent standard automated perimetry (SAP), spectral-domain optical coherence tomography, and fundus stereophotography within 6 months. Glaucomatous eyes were included if localized RNFL defects were detected by masked grading of stereophotographs. The number of RGCs in each sector of a structure-function map was estimated using a previously published model combining RGC estimates from SAP and spectral-domain optical coherence tomography. The estimated percentage loss of RGCs (combined structure-function index) was calculated.

Results

In glaucomatous eyes, there were 136 sectors with visible RNFL defects and 524 sectors without visible RNFL defects. The most common sectors with visible RNFL defects were inferior and inferotemporal sectors, followed by superior and supertemporal sectors. Eyes with visible RNFL defects had a mean estimated RGC count of 657,172 cells versus 968 883 cells in healthy eyes (P < .001). The average combined structure-function index in sectors with a visible RNFL defect (59 ± 21%) was significantly higher than in sectors without a visible RNFL defect in glaucomatous eyes (15 ± 29%; P < .001) and higher than in healthy eyes (1 ± 13%; P < .001).

Conclusions

Although visible localized RNFL defects often are considered an early sign of glaucoma, this study indicates that they are likely to be associated with large neuronal losses.

PURPOSE: To uncover the mechanism of subconjunctival outflow in human patients. DESIGN: Cross-sectional study. SUBJECTS/PARTICIPANTS AND/OR CONTROLS: Fifteen subjects receiving subconjunctival anesthesia prior to intravitreal injection for routine clinical care. METHODS: Anterior segment OCT (AS-OCT) was performed in patients with various instances of conjunctival edema or subconjunctival fluid. Other subjects received a subconjunctival mixture of 0.005% indocyanine green and 2% lidocaine. After subconjunctival injection of the tracer/anesthetic mixture, blebs and associated outflow pathways were angiographically imaged and the time for appearance recorded. The pattern and structure of outflow pathways were studied using AS-OCT. Angiographic and AS-OCT results were compared to trabecular/conventional outflow imaging which demonstrates veins. MAIN OUTCOME MEASURES: Ocular surface lymphangiography and AS-OCT images. RESULTS: AS-OCT of the conjunctiva in a normal eye demonstrated thin non-edematous conjunctiva with absent intraconjunctival lumens or subconjunctival fluid. Subjects with a history of trabeculectomy, subconjunctival drug injection, or chemosis demonstrated thickened conjunctiva and intraconjunctival luminal pathways that contained valve-like structures. Tracer-based studies in patients demonstrated blebs with irregular subconjunctival bleb-related outflow patterns that arose in a time-dependent fashion. These angiographic pathways were luminal on OCT, sausage-shaped, and contained intraluminal valve-like structures. This was in contrast to trabecular/conventional outflow imaging where pathways were classically Y-shaped, of even-caliber, and lacked valve-like structures. DISCUSSION: Outflow pathways were seen in cases of conjunctival edema and after subconjunctival tracer injection. These pathways were lymphatic based upon pattern and structural study. Better understanding of bleb-related lymphatic outflow may lead to improved bleb-requiring glaucoma surgeries and subconjunctival drug delivery.

Purpose

To compare the ability of 10-2 visual field tests and central 12 locations of the 24-2 tests (C24-2) to detect central visual field progression in glaucoma eyes with early central visual field abnormalities.

Design

Observational cohort study.

Participants

Three-hundred eyes of 180 participants with glaucoma or ocular hypertension.

Methods

Participants with both 10-2 and 24-2 tests performed on ≥3 visits over ≥1-year period were included to estimate the longitudinal variability of 10-2 and C24-2 visual field mean deviation (MD). The variability estimates were then used to reconstruct real-world visual field results by computer simulations, in a scenario where eyes had a baseline 10-2 and C24-2 MD was -2 dB and exhibited various rates of change (-0.25, -0.50, -0.75 and -1.00 dB/year), and the time to detect these changes were evaluated using trend-based analyses.

Main outcome measures

Time required to detect progression.

Results

Overall, the time to detect central visual field progression was reduced by 7-9% using the 10-2 compared to C24-2 MD values, equivalent to a total reduction of 0.1-0.3 dB lost. For example, 90% of eyes with a central 10-2 or C24-2 MD loss of -0.50 dB/year would be detected after 5.0 and 5.5 years of semi-annual testing respectively, or after 3.4 and 3.7 years respectively for eyes with a -1.00 dB/year loss.

Conclusions

Trend-based analyses using 10-2 MD resulted in a mild reduction (7-9%) in the time to detect central visual field progression compared to C24-2 MD in glaucoma eyes with early central visual field abnormalities. Further studies are needed to determine whether other progression analyses can better exploit the increased sampling of 10-2 tests. These findings provide evidence-based guidance on the potential value-add of 10-2 testing in the clinical management of glaucoma patients.

Precis

In this longitudinal prospective cohort study of open-angle glaucoma patients, intraocular pressure (IOP) parameters (mean, fluctuation, and maximum) had a similar effect on glaucomatous progression in the central and peripheral visual field (VF) regions.

Purpose

To study the effects of IOP on rates of glaucomatous central versus peripheral VF progression.

Methods

The African Descent and Glaucoma Evaluation Study (ADAGES) is a longitudinal prospective cohort study that recruited patients from 3 centers. A sample of those with established glaucoma were included in this study. The mean peripheral sensitivity (MPS) and the mean central sensitivity (MCS) were defined based upon the average total deviation of the peripheral and central (10 degrees) points of the 24-2 VF, respectively. Progression was based upon central and peripheral change from linear mixed-effects models. The relationships between VF progression and IOP mean, maximum, and fluctuation as continuous variables were also investigated. Main outcome measures were MPS and MCS progression rates.

Results

A total of 452 eyes of 344 patients were studied. The mean number of VFs (SD) for each eye was 13.3 (6.4) over 9.1 (3.7) years. The mean baseline MD was -5.1 (3.9) dB and the mean rate of MD change was -0.26 dB/y [95% confidence interval (CI): -0.33 to -0.20, P<0.001]. Mean rates of MPS (-0.27 dB/y, 95% CI: -0.33 to -0.22, P<0.001) and MCS change (-0.26 dB/y, 95% CI: -0.31 to -0.21, P<0.001) were similar (P=0.351). Mean, fluctuation, and maximum IOP were significantly associated with MPS and MCS (all P<0.025).

Conclusions

The effect of IOP parameters on VF progression was statistically similar between central and peripheral VF regions.

Purpose

To compare race-related differences in estimated rate of change of Bruch's membrane opening-minimum rim width (BMO-MRW) and circumpapillary retinal nerve fiber layer thickness (RNFLT) in healthy, glaucoma suspect, and glaucoma eyes of individuals of European (ED) and African descent (AD).

Design

Prospective cohort study.

Methods

This study investigated rate of change of BMO-MRW and RNFLT in 124 healthy, 227 glaucoma suspect, and 177 glaucoma eyes followed for approximately 3 years and tested with optical coherence tomography every 6 months. Suspect eyes had a history of untreated intraocular pressure (IOP) ≥ 22 mm Hg or suspicion of glaucoma by optic disc photograph assessment without repeatable abnormal standard automated perimetry (SAP) results. Glaucoma eyes had repeatable abnormal SAP results (GHT ONL or PSD ≤ 5%). Mixed-effects models were used to estimate the rate of change after controlling for age, mean follow-up IOP, central corneal thickness, axial length, and BMO area.

Results

A race-related difference in rate of change of global BMO-MRW but not average RNFLT in suspect eyes was observed. Rate of change of BMO-MRW was -1.82 μm/year and -2.20 μm/year in ED and AD suspect eyes, respectively (P = .03). Rate of change of RNFLT was -0.64 μm/year and -0.75 μm/year in ED and AD suspect eyes, respectively (P = .75). No race-related differences in change rate were found in healthy or glaucoma eyes.

Conclusion

Race is an important consideration when assessing structural change, particularly minimum rim width, in glaucoma suspect eyes. Differences in rate of structural change may help explain racial disparities in glaucoma susceptibility.

Purpose

To compare spectral-domain optical coherence tomography (SD-OCT) standard structural measures and a new three-dimensional (3D) volume optic nerve head (ONH) change detection method for detecting change over time in severely advanced-glaucoma (open-angle glaucoma [OAG]) patients.

Methods

Thirty-five eyes of 35 patients with very advanced glaucoma (defined as a visual field mean deviation < -21 dB) and 46 eyes of 30 healthy subjects to estimate aging changes were included. Circumpapillary retinal fiber layer thickness (cpRNFL), minimum rim width (MRW), and macular retinal ganglion cell-inner plexiform layer (GCIPL) thicknesses were measured using the San Diego Automated Layer Segmentation Algorithm (SALSA). Progression was defined as structural loss faster than 95th percentile of healthy eyes. Three-dimensional volume ONH change was estimated using the Bayesian-kernel detection scheme (BKDS), which does not require extensive retinal layer segmentation.

Results

The number of progressing glaucoma eyes identified was highest for 3D volume BKDS (13, 37%), followed by GCPIL (11, 31%), cpRNFL (4, 11%), and MRW (2, 6%). In advanced-OAG eyes, only the mean rate of GCIPL change reached statistical significance, -0.18 μm/y (P = 0.02); the mean rates of cpRNFL and MRW change were not statistically different from zero. In healthy eyes, the mean rates of cpRNFL, MRW, and GCIPL change were significantly different from zero. (all P < 0.001).

Conclusions

Ganglion cell-inner plexiform layer and 3D volume BKDS show promise for identifying change in severely advanced glaucoma. These results suggest that structural change can be detected in very advanced disease. Longer follow-up is needed to determine whether changes identified are false positives or true progression.

Purpose

To evaluate the validity of using progressive loss of neuroretinal rim area as a surrogate end point for the development of visual field loss in glaucoma.

Design

Prospective, observational cohort study.

Participants

The study group included 492 eyes of 328 patients classified with suspected glaucoma at the baseline visit. These eyes had an average of 7.4±2.8 confocal scanning laser ophthalmoscopy (CSLO) images during a mean follow-up time of 6.6±1.6 years.

Methods

Rim area measurements were acquired with CSLO during follow-up. The visual field end point was considered the development of 3 consecutive abnormal visual fields on standard automated perimetry. Strong predictive ability and large proportion of treatment effect (PTE) explained are requisites for a suitable surrogate end point. A joint longitudinal survival model was used to evaluate the ability of rates of rim area loss in predicting visual field development, adjusting for confounding variables (baseline age, race, and corneal thickness and follow-up measurements of intraocular pressure [IOP] and pattern standard deviation). The PTE was calculated by comparing the effect of IOP on the risk of development of visual field loss when incorporating rim area loss in the same model with the effect of IOP in the model excluding rim area measurements.

Main outcome measures

Predictive strength was measured by survival-adapted R(2) and PTE.

Results

Sixty-two of 492 eyes (13%) developed visual field loss during follow-up. The mean rate of rim area change in eyes that developed visual field loss was -0.011 mm(2)/year versus -0.003 mm(2)/year in eyes that did not (P<0.001). In the multivariable model, each 0.01 mm(2)/year faster rate of rim area loss was associated with a 2.94 higher risk of visual field loss (hazard ratio, 2.94; 95% confidence interval, 1.38-6.23; P = 0.005). R(2) values were 62% and 81% for univariable and multivariable models, respectively. The PTE was 65%.

Conclusions

Progressive rim area loss was highly predictive of the development of visual field loss in glaucoma and explained a significant PTE on the clinically relevant outcome. These findings suggest that rim area measurements may be suitable surrogate end points in glaucoma clinical trials.