Association Between Ganglion Cell Complex Thinning and Vision-Related Quality of Life in Glaucoma

Key Points

Question  Are ganglion cell complex thickness changes on optical coherence tomography associated with future vision-related quality of life among patients with open-angle glaucoma?

Findings  In this analysis of a longitudinal cohort of 236 eyes in 118 patients, baseline faster ganglion cell complex thickness changes were associated with lower vision-related quality of life.

Meaning  These findings suggest assessment of ganglion cell complex thinning may be important in predicting vision-related quality of life.

Importance  Faster structural changes may be associated with worse vision-related quality of life in patients with glaucoma.

Objectives  To evaluate the association between the rate of ganglion cell complex thinning and the Vision Function Questionnaire in glaucoma.

Design, Setting, and Participants  This retrospective analysis of a longitudinal cohort was designed in October 2021. Patients were enrolled from the Diagnostic Innovations in Glaucoma Study and the African Descent and Glaucoma Evaluation Study. Two hundred thirty-six eyes of 118 patients with diagnosed or suspected glaucoma were followed up with imaging for a mean of 4.1 years from September 2014 to March 2020.

Main Outcomes and Measures  The Vision Function Questionnaire was evaluated using the 25-item National Eye Institute Visual Function at the last follow-up visit. Ganglion cell complex thickness was derived from macular optical coherence tomography scans and averaged within 3 circular areas (3.4°, 5.6°, and 6.8° from the fovea) and superior and inferior hemiregions. Linear mixed-effects models were used to investigate the association between the rate of ganglion cell complex thinning and Rasch-calibrated Vision Function Questionnaire score.

Results  The mean (SD) age was 73.2 (8.7) years, 65 participants (55.1%) were female, and 53 participants (44.9%) were African American. Race was self-reported by the participants. Mean composite Rasch-calibrated National Eye Institute Visual Function Questionnaire score was 50.3 (95% CI, 45.9-54.6). A faster annual rate of global ganglion cell complex thinning in the better eye was associated with a higher disability reflected by the composite National Eye Institute Visual Function Questionnaire score (−15.0 [95% CI, −28.4 to −1.7] per 1 μm faster; P = .03). When stratified by degrees from the fovea, the 5.6° and 6.8° areas were associated with the composite National Eye Institute Visual Function Questionnaire Rasch-calibrated score (−14.5 [95% CI, −27.0 to −2.0] per 1 μm faster; R² = 0.201; P = .03; and −23.7 [95% CI, −45.5 to −1.9] per 1 μm faster; R² = 0.196; P = .02, respectively), and −8.0 (95% CI, −16.8 to 0.8) per 1 μm faster for the 3.4° area (R² = 0.184; P = .07) after adjusting for confounding factors.

Conclusions and Relevance  These findings suggest that faster and sectoral central location of ganglion cell complex thinning provides useful information in determining the risk of vision-related quality of life in glaucoma. Monitoring macular structure may be useful for determining the risk of functional impairment in glaucoma.

As a leading cause of blindness, glaucoma impairs not only the physical function but also the mental well-being of patients worldwide.¹ In an effort to investigate quality of life in patients, the National Eye Institute Visual Function Questionnaire (NEI VFQ) was developed to evaluate vision-related health status in patients with chronic eye diseases via a self-assessment questionnaire.^2,3

The NEI VFQ has been used previously to investigate the effect of glaucoma on vision-related quality of life (VRQOL). Past studies revealed an association between glaucoma and a decreased VRQOL reflects the impaired ability to perform daily tasks and a decreased sense of independence and wellness.^4-6 The Los Angeles Latino Eye Study⁷ showed that even mild visual field (VF) damage has a significant negative effect on VRQOL in patients with glaucoma. A few studies^8-10 have also shown that faster VF loss led to a worse VRQOL outcome, implying a direct association between the functional defect caused by glaucoma and an impaired quality of life (QOL). This association underscores the importance of clinically monitoring VF changes.^8-10 This correlation is especially concerning for patients with a central VF defect,⁶ as the subjective feeling and the objective ability of the patients to maintain personal safety is highly dependent on central vision.

While the translation of a functional defect into a declined QOL is well established and expected, VF testing is subjective and prone to variability.¹¹ Moreover, adding 10-2 testing to a perimetry testing regimen to detect central visual-field defect would almost double the testing time required, which may not be feasible in clinical practice. Optical coherence tomography (OCT) thickness measurements, in contrast, tend to provide faster, more reliable, and objective results and also are well correlated with VF change in glaucoma.¹² In addition, detectable structural change often precedes functional change, so the detection of changes in the eye apparent on OCT images may allow more timely and effective intervention before actual VF loss and/or VRQOL decline occurs.^13,14

We were thus interested in investigating whether there is a correlation between VRQOL and measurements made using OCT imaging, particularly macular thickness, which is related to central vision. In this study, the association between the rate of macular ganglion cell complex (GCC) thinning and VRQOL was evaluated in patients with glaucoma.

This is a retrospective, longitudinal cohort study. We selected all patients with suspected glaucoma and patients with primary open-angle glaucoma (POAG) who were enrolled in the Diagnostic Innovations in Glaucoma Study (DIGS) and African Descent and Glaucoma Evaluation Study (ADAGES) and met the inclusion criteria described below.^15,16 ADAGES and DIGS were designed with similar testing protocols, and all participants were assessed longitudinally according to established protocols consisting of regular follow-up visits with clinical examination, imaging, and functional tests.¹⁵ Data analysis for the current study was undertaken in November 2021, and written informed consent was obtained from all study participants. The University of California, San Diego Human Subject Committee approved all protocols, and the methods described adhered to tenets of the Declaration of Helsinki. Patients who participated in DIGS and ADAGES were compensated ($50) for each of their twice-yearly visits. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.

All study participants underwent annual comprehensive ophthalmologic evaluation, including best-corrected visual acuity, slit lamp biomicroscopy, dilated fundus examination, and stereoscopic optic disc photography in both eyes. Semiannual evaluations included intraocular pressure (IOP) measurement, spectral-domain OCT (Spectralis, Heidelberg Engineering) imaging, and standard automated perimetry testing with Humphrey Field Analyzer 24-2 Swedish interactive thresholding algorithm standard test (Carl Zeiss Meditec). This study included participants with at least 2 years and a minimum of 4 follow-up OCT visits who had POAG in both eyes or unilateral POAG with a diagnosis of glaucoma suspect in the contralateral eye (ie, POAG/POAG or POAG/glaucoma suspect). We defined the better eye based on a better VF mean deviation (VF MD).⁶ Glaucoma suspect eyes had either elevated IOP (≥22 mm Hg) or glaucomatous-appearing optic discs (glaucomatous optic neuropathy), without the presence of repeatable glaucomatous VF damage. Eyes classified as glaucomatous had repeatable (at least 2 consecutive) abnormal VF test results with evidence of glaucomatous optic neuropathy. Glaucomatous optic neuropathy was defined as excavation, the presence of focal thinning, notching of neuroretinal rim, or localized or diffused atrophy of the retinal nerve fiber layer (RNFL), based on masked grading of optic disc photographs by 2 graders or clinical examination by a glaucoma specialist. An abnormal VF test result was defined as a pattern standard deviation value at the 5% level or a glaucoma hemifield test result outside of normal limits. Glaucoma disease severity was classified as early (24-2 VF MD >-6 decibel [dB]) and moderate to advanced (24-2 VF MD ≤-6 dB).

Inclusion criteria at study entry also included (1) age older than 18 years, (2) open angles on gonioscopy, (3) best-corrected visual acuity of 20/40 or better, and (4) refraction plus or minus 5.0 diopters sphere and plus or minus 3.0 diopters cylinder. Exclusion criteria included (1) history of trauma or intraocular surgery (except for uncomplicated cataract or glaucoma surgery), (2) coexisting retinal disease, uveitis, or nonglaucomatous optic neuropathy, (3) other systemic or ocular diseases known to affect VF, such as pituitary lesions or demyelinating diseases, (4) significant cognitive impairment; Parkinson disease, Alzheimer disease, dementia, or a history of stroke, or (5) axial length of 27 mm or more. Those with unreliable VFs and poor-quality OCT were also excluded.

Spectralis spectral-domain OCT macula horizontal posterior pole scans acquired from September 2014 to March 2020 were used to obtain macula GCC thickness measurements. The posterior pole algorithm captures 61 horizontal B-scans (consists of 768 A-scans) spanning a 30° × 25° area parallel to the fovea–Bruch membrane opening axis. Segmentation of individual retinal layers was performed using Glaucoma Module Premium Edition software. An 8 × 8 grid of thickness measurements centered on the fovea was created, provided that sixty-four 3° × 3° superpixels was present in the central 24 × 24° of the macula. The GCC consists of the RNFL, ganglion cell layer, and inner plexiform layer. The area of the central 24 superpixels were grouped into 3 concentric circles (3.4°, 5.6°, and 6.8° from the fovea) and the mean GCC thickness was calculated for each sector.¹⁷ The mean GCC thicknesses of the superior and inferior hemiregions (each contained 12 superpixels) were also calculated. The global GCC was calculated by averaging the GCC thicknesses of the superior and inferior hemiregions (as shown in the Figure). Quality of all images was reviewed by the Imaging Data Evaluation and Analysis Reading Center in the University of California, San Diego. Segmentation of the macular layers was checked and adjusted manually, when possible. Images with noncentered scans, inaccurate segmentation that was unfixable, or a quality score of 15 dB or less were excluded from the analysis.

The VRQOL was evaluated using the 25-item NEI VFQ. This questionnaire was designed to evaluate the dimensions of self-reported vision-related health status that are relevant for patients with chronic eye diseases, including glaucoma.^2,3 The NEI VFQ consists of 25 vision-related questions that represent 11 subscales, with an additional single-item general health rating question. The 11 subscales are as follows: general vision, ocular pain, difficulty with near vision and distance activities, limitations with peripheral vision and color vision, social functioning, driving difficulties, mental health symptoms related to vision, role limitations, and dependency. Each subscale consists of 1 to 4 items. Rasch analysis locates item difficulty and person ability on a logit scale. Person disability scores measured by the NEI VFQ were linearly rescaled ranging from 0 to 100 (eg, a score of 50 is equivalent to 50% of the highest disability score).^18,19 The composite score or each subscale has a score of 100, representing the worst score on each item. Rasch analysis was conducted using Andrich rating scale models to acquire the estimates of the ability of each item, perceived ability of each participant, and the category thresholds for each response category.^9,20 Items belonging to mental health symptoms related to vision, role limitations, and dependency were excluded, as previous study showed these items belong to a separate socioemotional dimension, not directly related to visual functioning.²¹ NEI VFQ-questionnaires were completed within 1 year of the last spectral domain-OCT.

Demographic data and socioeconomic and clinical questionnaires were assessed at the time of the NEI VFQ. These questionnaires contained a survey about demographics, educational level, income, marital status, and health insurance coverage. These variables were categorized to include in the multivariable models as educational level (at least high school degree [yes/no]), income (<$25 000 per year [yes/no]), marital status (married [yes/no]), and presence of health insurance (yes/no).⁴ Race was self-reported by the participants. For comorbidities, we accounted for the presence or history of the following conditions: arthritis, asthma, cancer, depression, diabetes, heart disease, hypertension, and stroke. A simple summation score was calculated as the comorbidity index score.²²

Patient and eye characteristics data were presented as mean (95% CI) for continuous variables and count (%) for categorical variables. Estimates of rates of change for individual eyes were obtained by best linear unbiased prediction (BLUP).²³ Details about this model have been presented previously.^24,25 We were interested in whether the rates of GCC thinning associated with disability in VRQOL, and which sector of GCC parameters were associated with VRQOL subscale. Linear mixed models estimate the average rate of change in an outcome variable using a linear function of time, and participant-specific and eye-specific deviations from this average rate are introduced by random slopes. The potential predictors—self-reported age, sex, race, comorbidity index score, socioeconomic variables (education level, income, marital status, and insurance)⁵—and 24-2 VF pattern standard deviation (PSD) were introduced in the multivariable model to assess their association with patient perceptions about VRQOL. The strength of association was reported as R². Statistical analyses were performed using Stata (version 16.0; StataCorp). P values were not adjusted for multiple analyses, and a 2-sided P < .05 was considered to be statistically significant.

A total of 236 eyes of 118 participants (72 participants with bilateral POAG and 46 participants with suspected POAG/glaucoma) were included in the analysis. Mean age was 73.2 (95% CI, 71.6-74.8) years. 24-2 VF MD was −3.2 (95% CI, −4.1 to −2.3) dB for the better eye and −8.6 (95% CI, −9.9 to −7.3) dB for the worse eye, while, 24-2 VF PSD was 3.8 (95% CI, 3.2-4.3) dB for the better eye and 8.0 (95% CI, 7.3-8.8) dB for the worse eye. An average of 5.4 (95% CI, 5.1-5.7) OCT images were obtained over 4.1 (95% CI, 4.0-4.3) years of follow-up. Demographic and clinical characteristics of the participants are presented in Table 1.

Factors contributing to the NEI VFQ Rasch-calibrated composite score are summarized in Table 2. In the multivariable model, a faster rate of global GCC thinning in the better eye was associated with a higher disability of composite NEI VFQ Rasch-calibrated score (−15.0; 95% CI, −28.4 to −1.7) per 1 μm faster rate of change per year; P = .03.

Table 3 summarizes the association between global or sectoral GCC slopes of better eye and NEI VFQ Rasch-calibrated score after adjusting for possible confounding factors including age, sex, race, number of glaucoma medications, visual-field PSD, education level, income, marital status, and comorbidity index. A faster annual rate of inferior GCC thinning in the better eye was associated with a higher disability of composite NEI VFQ Rasch-calibrated score (−28.4 [95% CI, −49.5 to −7.4] per 1 μm faster; P = .009) while superior was not (−7.1 [95% CI, −16.1-1.9] per 1 μm faster; P = .12). When stratified by degrees from the fovea, the 5.6° and 6.8° areas were associated with the composite NEI VFQ Rasch-calibrated score (−14.5 [95% CI, −27.0 to −2.0] per 1 μm faster; R² = 0.201; P = .03; −23.7 [95% CI, −45.5 to −1.9] per 1 μm faster; R² = 0.196; P = .02, respectively), and −8.0 (95% CI, −16.8 to 0.8) per 1 μm faster for the 3.4° area (R² = 0.184; P = .07) after adjusting for confounding factors.

This longitudinal study investigated the association between the rate of GCC thinning and VRQOL in patients with glaucoma. After adjusting for confounding factors, faster GCC thinning and lower visual acuity were associated with a lower VRQOL. Specifically, a lower VRQOL was associated weakly with GCC thinning in the 5.6° and 6.8° central macular areas.

The function and structure of the macula is crucial in glaucoma, and it is known that glaucoma progression may be missed if the central 10° of the VF and macular thickness are not monitored.²⁶ Further, it has been shown that NEI VFQ scores declined with a worsened 10-2 VF MD and with early macula damage.^6,27 Consistent with the current study, a previous study that compared retinal ganglion cell and inner plexiform thickness with VRQOL has found that the ganglion cell-inner plexiform layer loss (compared with a reference database), but not thickness, was correlated with VRQOL.²⁸ The proposed theories for this finding included the greater effect of the pattern (rather than absolute thickness measurement) of macular damage, with a higher morbidity associated with diffuse rather than focal damage. In addition, if a patient has a thicker macula at baseline, the measurement of their absolute GCC thickness during disease progression may not reflect the true extent of thinning over time and how it has affected QOL.^27,28

The current study is noteworthy in that we presented the association between the slope of GCC thinning, instead of absolute GCC thickness, and NEI VFQ scores. This approach addressed the aforementioned concern about patients with a thicker macula at baseline, whose absolute GCC thickness may not well reflect the severity of the disease. Still, our finding was not surprising, as the correlation between a thinner GCC and VF defect in glaucoma has been well established.^17,29 Furthermore, by monitoring OCT imaging measurements and advancing treatment, if needed, we speculate that the decline in VRQOL can be slowed. Interestingly, the superior GCC thinning was more associated with VRQOL decline than inferior GCC thinning in this study. This result is consistent with a previous study,¹⁰ showing association between inferior central VF loss and VRQOL change. Hood et al³⁰ also showed that that inferior macular hemiregions are more vulnerable than superior hemiregions in glaucoma. The loss of vision in the inferior area can have a significant effect on the ability to achieve daily activities, such as reading and walking down stairs.³¹

This study evaluated the rate of GCC thinning based on the sectors surrounding the fovea, which demonstrate the 5.6° and 6.8° areas were association with VRQOL. Our finding is supported by the fact that the macula vulnerability zone mainly consists of the measurement points within the 5.6° and 6.8° areas.³⁰ Moreover, Mohammadzadeh et al¹⁷ showed that the 5.6° area of GCC has a stronger association between structure and function with central VF than other sectors. Another study, by Blumberg et al,⁶ also found high association between VRQOL and central VF loss.

While there have been many studies investigating the association between functional metrics and QOL, the association between structural metrics and QOL remains unclear. Structural measures, such as GCC and RNFL, have the capability to detect glaucoma progression with greater predictability and objectivity than VF testing. Previous data are mixed as to whether RNFL thickness is associated with QOL. The cross-sectional studies by Hirneiss et al²⁸ and Prager et al³² revealed insignificant results. However, similar to the longitudinal study by Gracitelli et al,⁵ this study showed an association between the rate of RNFL thinning and change in NEI VFQ, supporting the previous finding that a faster change noticed by patients may further influence their self-reported QOL. Understanding the progression of structural changes is therefore more meaningful than absolute thickness values when assessing VRQOL, as intraindividual comparisons may be better than comparisons against a standardized set of values.

Although previous studies raised questions about the validity of using separate subscales items included in the NEI VFQ,^21,33 this approach allows clinicians to understand the relative contributions of physical and mental conditions. In earlier studies, decline in near vision, peripheral vision, driving, role limitations, and dependency were suggested to correlate with VF loss in glaucoma.³¹ In the current subscale analysis, near vision, peripheral vision, social function, and driving were among the VRQOL measures most affected by GCC thinning. Reduced peripheral vision often is a major cause behind traffic crashes and other traumatic injuries in patients with glaucoma. Notably, social function, which is closely related to mental wellness, was associated with the rates of global and sectoral GCC thinning. This association reached significance even more uniformly than other subscales, showing the profound ways in which glaucoma can influence our patients’ social interactions.

This study had limitations. First, like all other questionnaires, VRQOL is a subjective evaluation. Using a more objective test may provide a more accurate representation of disability with daily life in glaucoma. Second, we did not collect information on ocular surface diseases that may affect VRQOL. However, since the number of glaucoma eye drops was associated with severity of ocular surface disease,³⁴ it was adjusted in the analysis. Third, owing to the complicated nature of QOL, there may be residual confounding factors that were not adjusted. Fourth, the Rasch score is a normalized score calculated based on the best and worst NEI-VFQ questionnaire results obtained in each individual study population, and our study included many cases of glaucoma in relatively early stages. Therefore, concern about the generalizability of our findings owing to potential selection bias should be noted. Last, the data were collected prior to the study design. Therefore, we cannot eliminate the possibility that biases associated with data selection may affect the results.

In conclusion, a faster rate and central location of GCC thinning was associated, but weakly, with lower VRQOL in patients with glaucoma. Understanding how structural changes influence VRQOL is vital for understanding which patients may need more frequent observation and additional treatment to prevent visual disability and reduced quality of life.

Accepted for Publication: May 1, 2022.

Published Online: June 30, 2022. doi:10.1001/jamaophthalmol.2022.2140

Corresponding Author: Robert N. Weinreb, MD, Shiley Eye Institute, University of California, San Diego, 9500 Campus Point Dr, La Jolla, CA 92093-0946 (rweinreb@health.ucsd.edu).

Author Contributions: Drs Nishida and Moghimi are co–first authors and had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Nishida, Moghimi, Mohammadzadeh, Liebmann, Weinreb.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Nishida, Moghimi, Mohammadzadeh, Wu, Yamane, Weinreb.

Critical revision of the manuscript for important intellectual content: Nishida, Moghimi, Wu, Yamane, Kamalipour, Micheletti, Liebmann, Fazio, Girkin, Zangwill, Weinreb.

Statistical analysis: Nishida, Moghimi, Wu, Kamalipour, Mahmoudinezhad.

Obtained funding: Liebmann, Fazio, Zangwill, Weinreb.

Administrative, technical, or material support: Liebmann, Zangwill, Weinreb.

Supervision: Moghimi, Yamane, Zangwill, Weinreb.

Conflict of Interest Disclosures: Dr Liebmann reported nonfinancial support from Bausch & Lomb, Carl Zeiss Meditec, Heidelberg Engineering, Novartis, Optovue, and Reichert Technologies; grants from the National Eye Institute and Research to Prevent Blindness; and personal fees from Alcon, Allergan, Carl Zeiss Meditec, and Heidelberg Engineering. Dr Fazio reported grants from the National Eye Institute, EyeSight Foundation of Alabama, and Research to Prevent Blindness and personal fees from Heidelberg Engineering. Dr Girkin reported grants from the National Eye Institute, EyeSight Foundation of Alabama, and Research to Prevent Blindness and personal fees from Heidelberg Engineering. Dr Zangwill reported grants from the National Eye Institute; grants and nonfinancial support from Heidelberg Engineering; and nonfinancial support from Carl Zeiss Meditec, Optovue, and Topcon. Dr Zangwill is a consultant for Abbvie. Dr Weinreb reported grants from the National Eye Institute and National Institute of Minority Health and Health Disparities, as well as nonfinancial support from Heidelberg Engineering, Carl Zeiss Meditec, Konan Medical, Optovue, Centervue, and Topcon; and personal fees from Abbvie, Aerie Pharmaceuticals, Allergan, Eyenovia, Nicox, and Topcon; and he also is a consultant for Toromedes, Iantrek, IOPtic, and Implandata; all outside the submitted work. No other disclosures were reported.

Funding/Support: National Eye Institute (R01EY029058, R01EY11008, R01EY19869, R01EY027510, R01EY026574, R01EY018926, and P30EY022589); an unrestricted grant from Research to Prevent Blindness; EyeSight Foundation of Alabama; UC Tobacco-Related Disease Research Program (T31IP1511); and grants for participants’ glaucoma medications from Novartis/Alcon Laboratories Inc, Allergan, Akorn, Pfizer, Merck, and Santen.

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.