Purpose

To determine whether progressive retinal nerve fiber layer (RNFL) loss occurs in the contralateral eye of patients with glaucoma showing unilateral progression according to conventional diagnostic methods.

Design

Prospective, longitudinal, observational cohort study.

Participants

Three hundred forty-six eyes of 173 patients (118 eyes with glaucoma and 228 eyes with suspect glaucoma at baseline) followed up for an average of 3.5±0.7 years.

Methods

All subjects underwent standard automated perimetry (SAP; Humphrey Field Analyzer; Carl Zeiss Meditec, Dublin, CA) and spectral-domain (SD) optical coherence tomography (OCT; Spectralis; Heidelberg Engineering, Inc., Carlsbad, CA) in both eyes at 6-month intervals. Eyes were determined as progressing by conventional methods if there was progression on masked grading of optic disc stereophotographs or SAP Guided Progression Analysis (GPA; Carl Zeiss Meditec; "likely progression"). Rates of change in SD OCT average RNFL thickness were obtained using a linear mixed effects model. Rate of global loss was calculated using a random coefficient model and compared for nonprogressing patients, progressing eyes, and fellow eyes of unilateral progressing patients.

Main outcomes measures

Rate of change in global RNFL thickness.

Results

Thirty-nine subjects showed evidence of unilateral progression by GPA, disc photographs, or both during follow-up. Mean ± standard error rate of RNFL loss in eyes progressing by conventional methods was -0.89±0.22 μm/year (P<0.001). The contralateral eyes of these subjects also showed significant loss of RNFL over time (-1.00±0.20 μm/year; P<0.001). One hundred thirty-four subjects did not show progression by conventional methods in either eye. These eyes also showed a significant decline over time in average RNFL thickness (-0.71±0.09 μm/year; P<0.001); however, the rate of change in these eyes was slower than that of the contralateral eye of patients showing unilateral progression (P<0.001).

Conclusions

Loss of RNFL thickness was seen in a substantial number of contralateral eyes of glaucoma patients showing unilateral progression by conventional methods. These findings indicate that assessment of RNFL thickness by SD OCT may show progressive glaucomatous damage that is not detected by visual fields or optic disc stereophotography.

Purpose

To evaluate the association between the rates of progressive visual field loss and the occurrence of depressive symptoms in patients with glaucoma followed over time.

Design

Prospective observational cohort study.

Participants

The study included 204 eyes of 102 patients with glaucomatous visual field defects on standard automated perimetry (SAP).

Methods

All patients had Geriatric Depression Scale (GDS) questionnaires and visual field tests obtained over a mean follow-up time of 2.2±0.6 years. Change in depressive symptoms was assessed by calculating the difference between GDS scores at the last follow-up visit from those at baseline. Rates of visual field loss were assessed by SAP. An integrated binocular visual field was estimated from the monocular SAP tests, and rates of change in mean sensitivity (MS) over time were obtained from linear mixed models. Regression models were used to investigate the association between progressive visual field loss and changes in depressive symptoms, adjusting for potentially confounding clinical and socioeconomic variables.

Main outcome measures

The association between rates of change in binocular SAP MS and change in GDS questionnaire scores.

Results

There was a significant correlation between change in the GDS scores during follow-up and change in binocular SAP sensitivity. Each 1 decibel (dB)/year change in binocular SAP MS was associated with a change of 2.0 units in the GDS scores during the follow-up period (P = 0.025). In a multivariable model adjusting for baseline disease severity, change in visual acuity, age, gender, race, Montreal Cognitive Assessment score, education, income, and comorbidity index, each 1 dB/year change in binocular SAP MS was associated with a change of 3.0 units in the GDS score (P = 0.019).

Conclusions

Faster visual field progression was associated with the occurrence of depressive symptoms in patients with glaucoma.

Purpose

To evaluate whether optic disc hemorrhages are associated with faster rates of estimated retinal ganglion cell (RGC) loss in glaucoma.

Methods

A longitudinal observational cohort study of 222 eyes of 122 patients with glaucoma recruited from the Diagnostic Innovations Glaucoma Study (DIGS) followed for an average of 3.74±0.85 years. All subjects had optical coherence tomography and standard automated perimetry during follow up. Optic disc hemorrhages were detected by masked evaluation of stereophotographs. Rates of change in estimated numbers of RGCs were determined using a previously described method. A random coefficients model was used to investigate the relationship between disc hemorrhages and rates of change in estimated RGC counts over time.

Results

19 eyes of 18 subjects had at least one disc hemorrhage during follow up. At baseline, average estimated RGC counts in eyes with and without disc hemorrhages were 677,994 cells and 682,021 cells, respectively (P = 0.929). Eyes with optic disc hemorrhages during follow-up had significantly faster rates of estimated RGC loss than eyes without disc hemorrhages (22,233 cells/year versus 10,704 cells/year, P = 0.020). The effect of disc hemorrhages on the rates of estimated RGC loss remained significant after adjusting for confounding variables.

Conclusion

Eyes with disc hemorrhages showed faster rates of RGC loss compared to eyes without disc hemorrhages. These results provide further evidence that disc hemorrhages should be considered as an indicator of increased risk for faster neural loss in glaucoma.

Purpose

To evaluate the relationship between rates of change on frequency doubling technology (FDT) perimetry and longitudinal changes in quality of life (QoL) of glaucoma patients.

Design

Prospective observational cohort study.

Methods

One hundred fifty-two subjects (127 glaucoma and 25 healthy) were followed for an average of 3.2 ± 1.1 years. All subjects were evaluated with National Eye Institute Visual Function Questionnaire (NEI VFQ-25), FDT, and standard automated perimetry (SAP). Glaucoma patients had a median of 3 NEI VFQ-25, 8 FDT, and 8 SAP tests during follow-up. Mean sensitivities of the integrated binocular visual fields were estimated for FDT and SAP and used to calculate rates of change. A joint longitudinal multivariable mixed model was used to investigate the association between change in binocular mean sensitivities and change in NEI VFQ-25 Rasch-calibrated scores.

Results

There was a statistically significant correlation between change in binocular mean sensitivity for FDT and change in NEI VFQ-25 scores during follow-up in the glaucoma group. In multivariable analysis with the confounding factors, each 1 dB/year change in binocular FDT mean sensitivity corresponded to a change of 0.8 units per year in the NEI VFQ-25 scores (P = .001). For binocular SAP mean sensitivity, each 1 dB/year change was associated with 2.4 units per year change in NEI VFQ-25 scores (P < .001). The multivariable model containing baseline and rate of change information from SAP had stronger ability to predict change in NEI VFQ-25 scores compared to the equivalent model for FDT (R(2) of 50% and 30%, respectively; P = .001).

Conclusion

SAP performed significantly better than FDT in predicting change in NEI VFQ-25 scores in our population, suggesting that it may still be the preferable perimetric technique for predicting risk of disability from the disease.

Purpose

To evaluate the association between longitudinal changes in quality of life (QoL) and rates of progressive visual field loss in glaucoma.

Design

Prospective observational cohort study.

Participants

We recruited 322 eyes of 161 patients with glaucomatous visual field loss from the Diagnostic Innovations Glaucoma Study followed for an average of 3.5±0.7 years.

Methods

All subjects had National Eye Institute Visual Function Questionnaire (NEI VFQ)-25 performed annually and standard automated perimetry (SAP) at 6-month intervals. Subjects were included if they had a minimum of 2 NEI VFQ-25 and ≥5 SAP during follow-up. Evaluation of rates of visual field change was performed using the mean sensitivity (MS) of the integrated binocular visual field (BVF). Rasch analysis was performed to obtain final scores of disability as measured by the NEI VFQ-25. A joint longitudinal multivariate mixed model was used to investigate the association between change in NEI VFQ-25 Rasch-calibrated scores and change in BVF sensitivity. Potentially confounding socioeconomic and clinical variables also were analyzed.

Main outcome measures

The relationship between change in NEI VFQ-25 Rasch-calibrated scores and change in binocular SAP MS.

Results

There was a significant correlation between change in the NEI VFQ-25 Rasch scores during follow-up and change in binocular SAP sensitivity. Each 1-dB change in binocular SAP MS per year was associated with a change of 2.9 units per year in the NEI VFQ-25 Rasch scores during the follow-up period (R(2) = 26%; P<0.001). Eyes with more severe disease at baseline were also more likely to have a decrease in NEI VFQ-25 scores during follow-up (P<0.001). For subjects with the same amount of change in SAP sensitivity, those with shorter follow-up times had larger changes in NEI VFQ-25 scores (P = 0.005). A multivariable model containing baseline and rate of change in binocular MS had an adjusted R(2) of 50% in predicting change in NEI VFQ-25 scores.

Conclusions

Baseline severity, magnitude, and rates of change in BVF sensitivity were associated with longitudinal changes in QoL of glaucoma patients. Assessment of longitudinal visual field changes may help to identify patients at greater risk for developing disability from the disease.

Purpose

We examined the relationship between relative afferent pupillary defects (RAPDs) and macular structural damage measured by macular thickness and macular ganglion cell-inner plexiform layer (mGCIPL) thickness in patients with glaucoma.

Methods

A cross-sectional study was done of 106 glaucoma patients and 85 healthy individuals from the Diagnostic Innovations in Glaucoma Study. All subjects underwent standard automated perimetry (SAP) and optic nerve and macular imaging using Cirrus Spectral Domain Optical Coherence Tomography (SDOCT). Glaucoma was defined as repeatable abnormal SAP or progressive glaucomatous changes on stereo photographs. Pupil responses were assessed using an automated pupillometer, which records the magnitude of RAPD (RAPD score), with additional RAPD scores recorded for each of a series of colored stimuli (blue, red, green, and yellow). The relationship between RAPD score and intereye differences (right minus left eye) in circumpapillary retinal nerve fiber layer (cpRNFL) thickness, mGCIPL, macular thickness, and SAP mean deviation (MD), was examined using linear regression.

Results

There was fair correlation between RAPD score and asymmetric macular structural damage measured by intereye difference in mGCIPL thickness (R(2) = 0.285, P < 0.001). The relationship between RAPD score and intereye difference in macular thickness was weaker (R(2) = 0.167, P < 0.001). Intereye difference in cpRNFL thickness (R(2) = 0.350, P < 0.001) and SAP MD (R(2) = 0.594, P < 0.001) had stronger association with RAPD scores compared to intereye difference in mGCIPL and macular thickness.

Conclusions

Objective assessment of pupillary responses using a pupillometer was associated with asymmetric macular structural damage in patients with glaucoma.

Purpose

To evaluate the relationship between intraocular pressure (IOP) and rates of retinal nerve fiber layer (RNFL) thickness change over time measured by spectral-domain (SD) optical coherence tomography (OCT).

Design

Observational cohort study.

Participants

The study involved 547 eyes of 339 patients followed up for an average of 3.9±0.9 years. Three hundred eight (56.3%) had a diagnosis of glaucoma and 239 (43.7%) were considered glaucoma suspects.

Methods

All eyes underwent imaging using the Spectralis SD OCT (Heidelberg Engineering GmbH, Heidelberg, Germany), along with IOP measurements and standard automated perimetry (SAP). Glaucoma progression was defined as a result of "Likely Progression" from the Guided Progression Analysis software for SAP. Linear mixed models were used to investigate the relationship between average IOP during follow-up and rates of RNFL thickness change, while taking into account potential confounding factors such as age, race, corneal thickness, and baseline disease severity.

Main outcome measures

The association between IOP and rates of global and sectorial RNFL thickness loss measured by SD OCT.

Results

Forty-six eyes (8.4%) showed progression on SAP during follow-up. Rates of global RNFL thickness change in eyes that progressed by SAP were faster than in those that did not progress (-1.02 vs. -0.61 μm/year, respectively; P = 0.002). For progressing eyes, each 1-mmHg higher average in IOP during follow-up was associated with an additional average loss of 0.20 μm/year (95% confidence interval [CI]: 0.08 to 0.31 μm/year; P < 0.001) of global RNFL thickness versus only 0.04 μm/year (95% CI: 0.01 to 0.07 μm/year; P = 0.015) for nonprogressing eyes. The largest associations between IOP and rates of RNFL change were seen for measurements from the temporal superior and temporal inferior sectors, whereas the smallest association was seen for measurements from the nasal sector.

Conclusions

Higher levels of IOP during follow-up were associated with faster rates of RNFL loss over time measured by SD OCT. These findings support the use of SD OCT RNFL thickness measurements as biomarkers for the evaluation of the efficacy of IOP-lowering therapies to slow down the rate of disease progression.

Importance

Evaluation of structural optic nerve damage is a fundamental part of diagnosis and management of glaucoma. However, the relationship between structural measurements and disability associated with the disease is not well characterized. Quantification of this relationship may help validate structural measurements as markers directly relevant to quality of life.

Objective

To evaluate the relationship between rates of retinal nerve fiber layer (RNFL) loss and longitudinal changes in quality of life in glaucoma.

Design, setting, and participants

Observational cohort study including 260 eyes of 130 patients with glaucoma followed up for a mean (SD) of 3.5 (0.7) years. All patients had repeatable visual field defects on standard automated perimetry (SAP) at baseline. The 25-item National Eye Institute Visual Function Questionnaire (NEI VFQ-25) was performed annually, and spectral-domain optical coherence tomography and SAP were performed at 6-month intervals. A joint model was used to investigate the association between change in NEI VFQ-25 Rasch-calibrated scores and change in RNFL thickness, adjusting for confounding socioeconomic and clinical variables.

Main outcomes and measures

Association between change in binocular RNFL thickness (RNFL thickness in the better eye at each point) and change in NEI VFQ-25 scores.

Results

Progressive binocular RNFL thickness loss was associated with worsening of NEI VFQ-25 scores over time. In a multivariable model adjusting for baseline disease severity and the rate of change in binocular SAP sensitivity, each 1-μm-per-year loss of RNFL thickness was associated with a decrease of 1.3 units (95% CI, 1.02-1.56) per year in NEI VFQ-25 scores (P < .001). After adjusting for the contribution from SAP, 26% (95% CI, 12%-39%) of the variability of change in NEI VFQ-25 scores was associated uniquely with change in binocular RNFL thickness. The P value remained less than .001 after adjusting for potential confounding factors.

Conclusions and relevance

Progressive binocular RNFL thickness loss was associated with longitudinal loss in quality of life, even after adjustment for progressive visual field loss. These findings suggest that rates of binocular RNFL change are valid markers for the degree of neural loss in glaucoma with significant relationship to glaucoma-associated disability.

Purpose

To evaluate the relationship between intraocular pressure (IOP) and rates of retinal nerve fiber layer (RNFL) thickness change over time measured by spectral-domain (SD) optical coherence tomography (OCT).

Design

Observational cohort study.

Participants

The study involved 547 eyes of 339 patients followed up for an average of 3.9±0.9 years. Three hundred eight (56.3%) had a diagnosis of glaucoma and 239 (43.7%) were considered glaucoma suspects.

Methods

All eyes underwent imaging using the Spectralis SD OCT (Heidelberg Engineering GmbH, Heidelberg, Germany), along with IOP measurements and standard automated perimetry (SAP). Glaucoma progression was defined as a result of "Likely Progression" from the Guided Progression Analysis software for SAP. Linear mixed models were used to investigate the relationship between average IOP during follow-up and rates of RNFL thickness change, while taking into account potential confounding factors such as age, race, corneal thickness, and baseline disease severity.

Main outcome measures

The association between IOP and rates of global and sectorial RNFL thickness loss measured by SD OCT.

Results

Forty-six eyes (8.4%) showed progression on SAP during follow-up. Rates of global RNFL thickness change in eyes that progressed by SAP were faster than in those that did not progress (-1.02 vs. -0.61 μm/year, respectively; P = 0.002). For progressing eyes, each 1-mmHg higher average in IOP during follow-up was associated with an additional average loss of 0.20 μm/year (95% confidence interval [CI]: 0.08 to 0.31 μm/year; P < 0.001) of global RNFL thickness versus only 0.04 μm/year (95% CI: 0.01 to 0.07 μm/year; P = 0.015) for nonprogressing eyes. The largest associations between IOP and rates of RNFL change were seen for measurements from the temporal superior and temporal inferior sectors, whereas the smallest association was seen for measurements from the nasal sector.

Conclusions

Higher levels of IOP during follow-up were associated with faster rates of RNFL loss over time measured by SD OCT. These findings support the use of SD OCT RNFL thickness measurements as biomarkers for the evaluation of the efficacy of IOP-lowering therapies to slow down the rate of disease progression.

Importance

Individuals of African descent have been reported to be at higher risk for becoming visually impaired from glaucoma compared with individuals of European descent.

Objective

To investigate racial differences in longitudinal visual field variability and their impact on time to detect visual field progression.

Design, setting, and participants

This multicenter prospective observational cohort study included 236 eyes of 173 individuals of European descent and 235 eyes of 171 individuals of African descent followed up for a mean (SD) time of 7.5 (3.4) years.

Main outcomes and measures

Differences in test-retest variability and simulated time to detect progression in individuals of African descent and of European descent with glaucoma. Standard automated perimetry mean deviation values were regressed over time for each eye, and SD of the residuals was used as a measure of variability. Distributions of residuals were used in computer simulations to reconstruct "real-world" standard automated perimetry mean deviation trajectories under different assumptions about rate of change and frequency of testing. Times to detect progression were obtained for the simulated visual fields.

Results

Among the 344 patients, the mean (SD) age at baseline was 60.2 (10.0) and 60.6 (9.0) years for individuals of African descent and of European descent, respectively; 94 (52%) and 86 (48%) of individuals of African descent and of European descent were women, respectively. The mean SD of the residuals was larger in eyes of individuals of African descent vs those of European descent (1.45 [0.83] dB vs 1.12 [0.48] dB; mean difference: 0.33 dB; 95% CI of the difference, 0.21-0.46; P < .001). The eyes in individuals of African descent had a larger increase in variability with worsening disease (P < .001). When simulations were performed assuming common progression scenarios, there was a delay to detect progression in eyes of individuals of African descent compared with those of European descent. For a scenario with baseline mean deviation of -10 dB and rate of change of -0.5 dB/y, detection of progression in individuals of African descent was delayed by 3.1 (95% CI, 2.9-3.2) years, when considered 80% power and annual tests.

Conclusions and relevance

Patients of African descent with glaucoma showed increased visual field variability compared with those of European descent, resulting in delayed detection of progression that may contribute to explain higher rates of glaucoma-related visual impairment in individuals of African descent compared with those of European descent with glaucoma.