Key Points
Question
Are initial optic nerve head capillary density changes from optical coherence tomography angiography associated with visual field progression in patients with glaucoma and glaucoma suspect?
Findings
In this cohort of 167 eyes in 109 patients, faster initial capillary density loss was associated with more rapid rates of visual field progression, including a doubling of the risk of developing event progression.
Meaning
These findings suggest that monitoring of changes in optic nerve head capillary density provides complementary information to optical coherence tomography for assessing the risk of glaucoma progression.
This cohort study evaluates the association between optic nerve head capillary density loss and visual field progression.
Abstract
Importance
Rapid initial optic nerve head capillary density loss may be used to assess the risk of glaucoma visual field progression.
Objective
To investigate the association between the rate of initial optic nerve head capillary density loss from optical coherence tomography angiography (OCTA) and visual field progression.
Design, Setting, Participants
This was a retrospective study of a longitudinal cohort at a glaucoma referral center. A total of 167 eyes (96 with primary open-angle glaucoma and 71 with glaucoma suspect) of 109 patients were monitored for a mean (SD) of 5.7 (1.4) years from January 2015 to December 2022. Data analysis was undertaken in April 2023.
Main Outcomes and Measures
The rates of initial capillary density and average retinal nerve fiber layer loss were calculated from the first 3 optic nerve head OCTA and OCT scans, respectively, during the initial follow-up (mean [SD], 2.0 [1.0] years). Based on the median rate, eyes were categorized into fast and slow progressor groups. The association between initial capillary density change or retinal nerve fiber layer thinning and visual field progression was evaluated using linear-mixed and time-varying Cox models.
Results
A total of 167 eyes of 109 patients (mean [SD] age, 69.0 [11.1] years; 56 [51.4%] female and 53 [48.6%] male) were assessed. Eighty-three eyes were slow OCTA progressors, while 84 eyes were fast with mean capillary density loss of −0.45% per year and −1.17% per year, respectively (mean difference, −0.72%/year; 95% CI,−0.84 to −0.60; P < .001). Similarly, 83 eyes were slow OCT progressors, while 84 eyes were fast with mean retinal nerve fiber layer thinning of −0.09 μm per year and −0.60 μm per year, respectively (mean difference, −0.51 μm/year; 95% CI,−0.59 to −0.43; P < .001). The fast OCTA and OCT progressors were associated with more rapid visual field loss (mean difference, −0.18 dB/year; 95% CI,−0.30 to −0.06; P = .004 and −0.17 dB/year; 95% CI,−0.29 to −0.06; P = .002, respectively). Fast OCTA progressing eyes were more likely to have visual field progression (hazard ratio, 1.96; 95% CI, 1.04-3.69; P = .04). Seventeen of 52 eyes (32.7%; 95% CI, 32.5-32.8) with fast OCTA and OCT progression developed subsequent visual field likely progression.
Conclusion and Relevance
Rapid initial optic nerve head capillary density loss from OCTA was associated with a faster rate of visual field progression and a doubling of the risk of developing event progression in this study. These findings may support clinical use of OCTA and OCT optic nerve head measurements for risk assessment of glaucoma progression.
Introduction
Early detection of visual field progression is vital for effective management of glaucoma.1 Extensive research has focused on the predictive capabilities of structural optic nerve and retinal nerve fiber layer parameters and their association with visual field loss. Notably, glaucomatous eyes with rapid initial retinal nerve fiber layer loss are at higher risk of having concurrent and developing future visual field progression.2,3,4,5,6
The role of optical coherence tomography angiography (OCTA) in glaucoma is also being investigated due to its ability to provide noninvasive visualization of the retinal microvasculature. An association between glaucomatous damage and compromised ocular blood flow in both optic nerve head and macular region has been widely reported and summarized.7,8,9,10,11,12,13,14 It has also been found that rapid initial macular vessel density loss was more strongly associated with visual field progression than thinning of the macular ganglion cell complex.12 Other studies have found that peripapillary vessel density better discriminated glaucomatous from normal eyes than macular vessel density.15,16,17 Several cross-sectional studies also have shown the associations between optic nerve head vessel density and visual field loss.7,18,19,20,21,22 To our knowledge, there have been no reports on the association of initial optic nerve head capillary density with subsequent visual field progression.
The purpose of this study was to investigate the association between the rate of initial optic nerve head capillary density loss and visual field progression in primary open-angle glaucoma and compare it to the strength of the association between circumpapillary retinal nerve fiber layer thickness loss and visual field progression.
Methods
Participants
This was a retrospective cohort study including patients with glaucoma suspect and primary open-angle glaucoma from the Diagnostic Innovations in Glaucoma Study (DIGS)23,24 who underwent OCTA and spectral-domain OCT (SD-OCT) optic nerve head imaging (Avanti [Optovue]). Patients were monitored for a mean (SD) 5.7 (1.4) years from January 2015 to December 2022, and data analysis for the current study was undertaken in April 2023. Written informed consent was obtained from all participants. Patients who participated in DIGS were compensated $50 for each of their twice-yearly visits. The Institutional Review Board at the University of California, San Diego, approved all protocols, and methods described were in agreement with the tenets of the Declaration of Helsinki.25 The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline was followed.
All participants underwent the following examinations: (1) baseline examination including ultrasound pachymetry and gonioscopy; (2) annual ophthalmologic examination including best-corrected visual acuity, slitlamp biomicroscopy, dilated fundus examination, and stereoscopic optic disc photography; and (3) semiannual examination including intraocular pressure measurement with Goldmann applanation tonometry, visual field, and OCT and OCTA in both eyes. Only participants with at least 3 OCT or OCTA scans were included. To investigate the association with visual field progression, 24-2 Swedish interactive threshold algorithm standard visual field testing on the Humphrey Field Analyzer (Carl Zeiss Meditec) was taken; tests beginning within 6 months after first OCTA and OCT visits were included. Only visual fields with good reliability index (≤33% fixation losses and false negatives, and ≤15% false positives) were included. Eyes were required to have at least 5 visual field tests and at least 2 years of follow-up.
Eyes with glaucoma suspect were defined as having glaucomatous optic neuropathy or elevated intraocular pressure of 22 mm Hg or greater without any repeatable glaucomatous visual field defect. Eyes with primary open-angle glaucoma were defined by glaucomatous optic neuropathy and repeatable glaucomatous visual field defect, which included a Glaucoma Hemifield Test outside normal limits or pattern standard deviation outside the 95% normal limits. Two masked clinical graders reviewed the presence of glaucomatous optic neuropathy based on neuroretinal rim narrowing, notching, excavation, or localized or diffuse retinal nerve fiber layer defect. According to the baseline visual field mean deviation (MD), glaucoma severity was categorized as early (24-2 visual field MD > −6 dB) and moderate to advanced (24-2 visual field MD ≤ −6 dB).
Inclusion criteria also consisted of (1) older than 18 years, (2) open angles on gonioscopy, (3) best-corrected visual acuity of 20/40 or better, and (4) refraction within 5.0 diopters spherical and within 3.0 diopters cylinder at baseline. Exclusion criteria were (1) history of trauma or intraocular surgery (except for uncomplicated cataract surgery or glaucoma surgery); (2) coexisting retinal disease, uveitis, or nonglaucomatous optic neuropathy; (3) other systemic or ocular diseases known to affect visual field performance or reliability; (4) participants with a diagnosis of Parkinson disease, Alzheimer disease, or dementia or a history of stroke; and (5) axial length of 27 mm or greater. Those with unreliable visual fields or poor-quality OCTA/OCT images were also excluded. Self-reported race data were collected via a questionnaire and reported because there are race-specific differences in visual field progression in glaucoma.26 Categories included American Indian or Alaska Native, Asian, Black or African American, Native Hawaiian or Other Pacific Islander, White, and unknown or not reported.
OCTA and SD-OCT
The OCTA and OCT images were acquired simultaneously for optic nerve head capillary density and retinal nerve fiber layer thickness analysis, respectively. The AngioVue OCT system version 2018.1.0.43 then performed segmentation automatically.19 Vessel density was calculated as the percentage area occupied by flowing blood vessels, defined as pixels having decorrelation values above the threshold level in the selected region. Whole-image capillary density was obtained over the entire 4.5 × 4.5-mm2 scan field centered on the optic nerve head. The software provides capillary density through the use of a large vessel mask, which is set to detect vessels having a threshold of 3 pixels or greater (approximately ≥33 μm). Each volume contains 304 B-scans × 304 A-scans per B-scan. Optic nerve head capillary density was measured from the internal limiting membrane to the posterior boundary of retinal nerve fiber layer. Image quality review was completed on all scans according to the University of California, San Diego, Imaging Data Evaluation and Analysis Reading Center standard protocol. Trained graders, who had no knowledge as to whether the scans were from slow or fast progressors, excluded poor-quality images, defined as (1) a scan quality of less than 4, (2) poor clarity, (3) residual motion artifacts visible as irregular vessel pattern or disc boundary on the en face angiogram, (4) local weak signal, or (5) uncorrected segmentation errors. The location of the disc margin in the optic nerve head scans and segmentation were reviewed for accuracy and were adjusted manually if required.27 The retinal nerve fiber layer thickness was measured from the same optic nerve head scan. The initial rate of loss during the mean (SD) initial follow-up of 2.0 (1.0) years was calculated using the first 3 retinal nerve fiber layer and whole image capillary density measurements.
Statistical Analysis
Best-linear unbiased prediction (BLUP) was used to calculate the estimates of rates of measurement change for individual eyes. This method considered the results of the whole sample of eyes, while giving less weight to eyes that had fewer measurements or larger variability.28 The OCTA and OCT rates were divided into 2 groups based on of their corresponding rates of change. Based on the median rate of initial loss, the OCTA optic nerve head capillary density progressor eyes were categorized into fast (≤−0.75%/year) and slow (>−0.75%/year) groups.12 Similarly, the OCT progressor eyes were classified based on the median rate of thinning into fast (≤−0.33 μm/year) and slow (>−0.33 μm/year) groups.
Two methods were used to evaluate the association between initial capillary density change or retinal nerve fiber layer thinning and visual field progression. First, survival analysis was conducted, wherein event-based visual field progression was defined using Guided Progression Analysis software.29,30 This software compares individual sensitivity values on follow-up visual field visits to the values at the same location from 2 baseline visits from pattern deviation plot. The software identified progression when at least 3 locations showed a decrease beyond the expected test-retest variability at the 95% significance level. Likely progression was classified when at least 3 consecutive progressions occurred. The event date was defined as the date when likely progression was first alerted after baseline visits. Only patients with a baseline visual field MD greater than −20 dB were included, as event analysis cannot be well applied to those with visual field MD below this threshold.29,30 The time-to-event progression analysis was summarized using Kaplan-Meier survival curves.
Second, a linear mixed-effect model was produced, wherein the association of initial optic nerve head capillary density and retinal nerve fiber layer loss with the rates of visual field MD change from the entire follow-up period of 5.7 years, starting from the time that the first OCT or OCTA scan was taken, was evaluated using a linear mixed model with random intercepts and slopes. Fixed effects, including OCTA or OCT progressor groups, and the response variable, including ocular measurements, were incorporated into the models. In this model, the mean rate of change was estimated using a linear function of time, and random slopes introduced patient- and eye-specific deviations from this average evolution. Potential variables associated with the rate of visual field MD change that showed a P < .10 in the univariable analysis were also included in the multivariable model.
Descriptive statistics were calculated as the means (SDs) and categorical variables were compared using the χ2 test. Ocular parameters among groups were compared by mixed-effects model. No P values were corrected for multiple comparisons. Statistical analyses were performed using Stata version 16.0 (StataCorp). All P values were 2-sided.
Results
A total of 167 eyes (including 96 eyes with primary open-angle glaucoma and 71 eyes with glaucoma suspect) from 109 patients (mean [SD] age, 69.0 [11.1] years; 56 female [51.4%] and 53 male [48.6%]; 27 Black or African American [24.8%], 13 Asian [11.9%], 66 White [60.6%], and 3 other race [2.7%], combined owing to small numbers and concealed to protect patient privacy) were included in this study. Demographic and baseline clinical characteristics are presented in Table 1. The mean (SD) baseline whole image capillary density was 42.9% (4.3), while the mean (SD) baseline visual field MD was −2.9 (3.7) dB. During the mean (SD) 5.7 (1.4) years of follow-up, a mean (SD) of 7.1 (2.1) visual field tests were included.
Table 1. Demographic and Baseline Clinical Characteristics of Participants (167 Eyes of 109 Patients).
| Characteristic | Finding, mean (SD) |
|---|---|
| Age, y | 69.0 (11.1) |
| Sex, No. | |
| Female | 56 |
| Male | 53 |
| Race, No. (%)a | |
| Black or African American | 27 (24.8) |
| Asian | 13 (11.9) |
| White | 66 (60.6) |
| Otherb | 3 (2.7) |
| Baseline IOP, mm Hg | 14.9 (4.5) |
| Diagnosis, No. of eyes (%) | |
| Primary open-angle glaucoma | 96 (57.5) |
| Glaucoma suspect | 71 (42.5) |
| Disease severity by baseline 24-2 VF MD, No. of eyes(%) | |
| Early glaucoma | 68 (70.8) |
| Moderate and advanced glaucoma | 28 (29.2) |
| Intervening cataract surgery during follow-up, No. of eyes (%) | 7 (4.2) |
| Intervening glaucoma surgery during follow-up, No. of eyes (%) | 9 (5.4) |
| Likely visual field progression, No. of eyes (%) | 37 (22.2) |
| Baseline VF MD, dB | −2.9 (3.7) |
| Baseline VF PSD, dB | 4.3 (3.6) |
| Baseline cpRNFL, μm | 81.6 (16.3) |
| Baseline wiCD, % | 42.9 (4.3) |
| Mean SSI | 62.2 (8.3) |
| Initial OCT/OCTA follow-up, y | 2.0 (1.0) |
| Follow-up, y | 5.7 (1.4) |
| No. of VF visits | 7.1 (2.1) |
Abbreviations: cpRNFL, circumpapillary retinal nerve fiber layer; IOP, intraocular pressure; MD, mean deviation; OCT, optical coherence tomography; OCTA, OCT angiography; PSD, pattern standard deviation; SSI, signal strength index; VF, visual field; wiCD, whole image capillary density.
Self-report race data were collected via questionnaire and reported because there are race-specific differences in visual field progression in glaucoma.26 Categories included American Indian or Alaska Native, Asian, Black or African American, Native Hawaiian or Other Pacific Islander, White, and unknown or not reported.
Other race groups were combined owing to small numbers and concealed to protect patient privacy.
The mean rate of capillary density loss was −0.81 (95% CI, −0.89 to −0.74) per year during the initial mean (SD) 2.0 (1.0) years of follow-up. Based on the median rate, 83 eyes were categorized as slow OCTA progressors, while 84 eyes were fast with mean capillary density loss rates of −0.45% per year and −1.17% per year, respectively. The mean difference was −0.72% per year (95% CI, −0.84 to −0.60; P < .001). Table 2 presents the characteristics of OCTA progressor eyes. The mean rate of initial retinal nerve fiber layer thinning was −0.34 μm per year (95% CI, −0.29 to −0.40). The characteristics of OCT progressor eyes are presented in the eTable in Supplement 1.
Table 2. Characteristics of Eyes Categorized by Optical Coherence Tomography Angiography (OCTA) Progressor Group.
| Characteristic | Mean (95% CI) | P value | ||
|---|---|---|---|---|
| Slow OCTA (83 eyes of 51 patients)a | Fast OCTA (84 eyes of 58 patients)a | Difference (95% CI) | ||
| Initial capillary density change, %/y | −0.45 (−0.50 to −0.40) | −1.17 (−1.26 to −1.08) | −0.72 (−0.84 to −0.60) | <.001 |
| Initial RNFL thinning, μm/y | −0.26 (−0.32 to −0.20) | −0.42 (−0.51 to −0.34) | −0.16 (−0.28 to −0.05) | .004 |
| Baseline age, mean (SD), y | 68.4 (9.3) | 69.5 (12.5) | 2.5 (−1.3 to 6.2) | .19 |
| Sex, No. | ||||
| Female | 30 | 26 | NA | .15 |
| Male | 21 | 32 | NA | |
| Race, No.b | ||||
| Black or African American | 16 | 11 | NA | .21 |
| Asian | 6 | 7 | NA | |
| White | 29 | 37 | NA | |
| Otherb | 0 | 3 | NA | |
| Self-reported HTN, No. (%) | 29 (56.9) | 39 (67.2) | NA | .26 |
| Self-reported diabetes, No. (%) | 8 (16.0) | 7 (12.1) | NA | .58 |
| Axial length, mm | 24.5 (24.3 to 24.8) | 24.3 (24.0 to 24.6) | −0.2 (−0.7 to 0.2) | .26 |
| CCT, μm | 542.6 (534.6 to 550.5) | 529.3 (519.9 to 538.8) | −13.2 (−27.8 to 1.3) | .08 |
| Baseline IOP, mm Hg | 15.4 (14.5 to 16.4) | 14.3 (13.3 to 15.3) | −1.1 (−2.8 to 0.5) | .16 |
| Mean IOP during follow-up, mm Hg | 15.6 (14.8 to 16.4) | 14.8 (13.9 to 15.6) | −0.8 (−2.2 to 0.5) | .24 |
| No. of eyes with glaucoma | 32 | 64 | NA | <.001 |
| No. of eyes suspected of having glaucoma | 51 | 20 | NA | |
| Disease severity at baseline (24-2 VF MD), No. of eyes (%) | ||||
| Early glaucoma | 27 (84.4) | 41 (64.1) | NA | .04 |
| Moderate and advanced glaucoma | 5 (15.6) | 23 (35.9) | NA | |
| Intervening cataract surgery during follow-up, No. of eyes (%) | 3 (3.6%) | 4 (4.8%) | NA | .71 |
| Intervening glaucoma surgery during follow-up, No. of eyes (%) | 6 (7.2%) | 3 (3.6%) | NA | .30 |
| Likely visual field progression, No. of eyes (%) | 13 (15.7%) | 24 (28.6%) | NA | .05 |
| Baseline VF MD, dB | −1.2 (−1.7 to −0.7) | −4.5 (−5.4 to −3.6) | −3.3 (−4.3 to −2.3) | <.001 |
| Baseline VF PSD, dB | 2.7 (2.2 to 3.2) | 5.8 (4.9 to 6.6) | 3.1 (2.1 to 4.0) | <.001 |
| Mean SSI | 62.7 (61.0 to 64.5) | 61.7 (59.9 to 63.6) | −1.0 (−3.6 to 1.6) | .44 |
| Follow-up, y | 5.7 (5.4 to 6.0) | 5.6 (5.3 to 5.9) | −0.1 (−0.6 to 0.4) | .75 |
| No. of VF visits | 7.2 (6.7 to 7.6) | 7.0 (6.5 to 7.5) | −0.2 (−0.9 to 0.5) | .60 |
Abbreviations: CCT, central corneal thickness; HTN, hypertension; IOP, intraocular pressure; MD, mean deviation; NA, not applicable; PSD, pattern standard deviation; RNFL, retinal nerve fiber layer; SSI, signal strength index; VF, visual field.
Rates of capillary density change: slow = slower than −0.75%/year; fast = faster than −0.75%/year.
Self-reported race data were collected via questionnaire and reported because there are race-specific differences in visual field progression in glaucoma.26 Categories included American Indian or Alaska Native, Asian, Black or African American, Native Hawaiian or Other Pacific Islander, White, and unknown or not reported.
Other race groups were combined owing to small numbers and concealed to protect patient privacy.
Factors contributing to the rate of visual field MD change over time are summarized in Table 3. In the univariable model, the fast OCTA progressor group showed faster annual visual field MD loss (−0.25 dB/year; 95% CI, −0.32 to −0.17 vs −0.08 dB/year; 95% CI, −0.15 to 0.00; mean difference, −0.17 dB/year; 95%CI, −0.28 to −0.06; P = .002). Similarly, the fast OCT progressor had a faster annual visual field MD loss (−0.25 dB/year; 95% CI, −0.33 to −0.18 vs −0.07 dB/year; 95% CI, −0.15 to 0.00; mean difference, −0.18 dB/year; 95% CI,−0.29 to −0.07; P = .001). In multivariable model 1, fast OCTA progression was associated with faster visual field MD loss (−0.18 dB/year; 95% CI, −0.30 to −0.06; P = .004). Similarly, in multivariable model 2, fast OCT progression was associated with faster visual field MD loss (−0.17 dB/year; 95% CI, −0.29 to −0.06; P = .002). After adjustment for covariates, the rate of initial capillary density loss showed stronger association with visual field MD loss (r2 = 0.16; P < .001) than the rate of initial retinal nerve fiber layer thinning (r2 = 0.11; P < .001), as shown in the eFigure in Supplement 1.
Table 3. Factors Associated With the Rate of Visual Field Mean Deviation Change Over Time by Univariable and Multivariable Mixed Model Analysis.
| Factor | Univariable model | Multivariable model 1 | Multivariable model 2 | |||
|---|---|---|---|---|---|---|
| β (95% CI) | P value | β (95% CI) | P value | β (95% CI) | P value | |
| Overall | ||||||
| Intercept | NA | NA | −6.48 (−11.41 to −1.54) | .01 | −6.78 (−11.93 to −1.62) | .01 |
| Age, per 10 y older | 0.01 (−0.05 to 0.06) | .76 | 0.01 (−0.06 to 0.08) | .81 | −0.01 (−0.07 to 0.05) | .77 |
| Female sex | 0.05 (−0.06 to 0.16) | .37 | NA | NA | NA | NA |
| Black or African American race | 0.12 (−0.01 to 0.25) | .06 | 0.10 (−0.04 to 0.23) | .16 | 0.09 (−0.03 to 0.21) | .15 |
| Self-reported diabetes | 0.07 (−0.10 to 0.24) | .43 | NA | NA | NA | NA |
| Self-reported hypertension | 0.10 (−0.01 to 0.21) | .09 | 0.09 (−0.05 to 0.23) | .22 | 0.09 (−0.04 to 0.23) | .17 |
| Axial length, per 1 mm longer | −0.03 (−0.08 to 0.02) | .22 | NA | NA | NA | NA |
| CCT, per 100 μm thinner | −0.03 (0.11 to −0.17) | .69 | NA | NA | NA | NA |
| Baseline IOP, per 1 mm Hg higher | 0.00 (−0.02 to 0.01) | .52 | NA | NA | NA | NA |
| Mean IOP during follow-up, per 1 mm Hg higher | 0.00 (−0.02 to 0.01) | .56 | −0.01 (−0.02 to 0.00) | .23 | 0.00 (−0.02 to 0.01) | .60 |
| Intervening cataract surgery during follow-up | −0.02 (−0.32 to 0.29) | .92 | NA | NA | NA | NA |
| Intervening glaucoma surgery during follow-up | 0.12 (−0.16 to 0.41) | .40 | NA | NA | NA | NA |
| Follow-up period, per 1 y longer | 0.02 (−0.03 to 0.06) | .44 | NA | NA | NA | NA |
| No. of VF follow-up visits | −0.02 (−0.04 to 0.01) | .22 | NA | NA | NA | NA |
| Mean SSI, per 1 higher | 0.00 (−0.01 to 0.01) | .60 | NA | NA | NA | NA |
| OCT progressor group | ||||||
| Intercept (baseline: slow) | −0.07 (−0.15 to 0.00) | .05 | NA | NA | NA | NA |
| Fast-slow | −0.18 (−0.29 to −0.07) | .001 | NA | NA | −0.17 (−0.29 to −0.06) | .002 |
| OCTA progressor group | ||||||
| Intercept (baseline: slow) | −0.08 (−0.15 to 0.00) | .05 | NA | NA | NA | NA |
| Fast-slow | −0.17 (−0.28 to −0.06) | .002 | −0.18 (−0.30 to −0.06) | .004 | NA | NA |
Abbreviations: CCT, central corneal thickness; IOP, intraocular pressure; NA, not applicable; SSI, signal strength index; VF, visual field.
The Kaplan-Meier analyses of likely visual field progression events for both OCTA and OCT progressor groups are presented in Figure 1. Eyes with faster initial OCTA progression were more likely to have event-based visual field progression, with a hazard ratio of 1.96 (95% CI, 1.04-3.69; P = .04). There was a trend of association between the faster initial OCT progression and event-based visual field progression (hazard ratio, 1.70; 95% CI, 0.88-3.30; P = .15). The proportions of eyes with visual field Guided Progression Analysis likely progression in the OCT and OCTA progressor groups are presented in Figure 2. While 17 of 52 eyes (32.7%; 95% CI, 32.5-32.8) that were categorized as fast OCTA and fast OCT progressors developed future visual field likely progression, 7 of 32 eyes (21.9%; 95% CI, 21.7-22.0) that were fast OCTA but slow OCT progressors developed this event.
Figure 1. Survival of Visual Field Progression From Guided Progression Analysis.
OCT indicates optical coherence tomography; OCTA, OCT angiography; HR, hazard ratio.
Figure 2. Proportions of Eyes With Likely Visual Field (VF) Progression From Guided Progression Analysis.
OCT indicates optical coherence tomography; OCTA, OCT angiography.
Discussion
This cohort study explored the association between initial optic nerve head capillary density loss and future visual field progression. We classified eyes with glaucoma based on the median rate of OCT or OCTA measurement change during the initial 2 years into fast and slow progressors groups. Fast OCTA progressors were associated with faster rate of visual field MD loss, and were twice as likely to develop visual field event-based progression than slow OCTA progressors. Fast initial OCT progression was also associated with faster rate of visual field MD loss. One-third of eyes that had fast initial OCT and OCTA progression developed future visual field likely progression. A previous study12 also demonstrated that rapid initial macular vessel density loss was more strongly associated with visual field progression than thinning of the macular ganglion cell complex. Along with OCT, the current findings support the consideration of potential use of OCTA for risk assessment of glaucoma progression. However, studies with longer follow-up are needed to ascertain whether these results will provide clinically relevant outcomes for patients with glaucoma.
Several large-scale studies have shown the structural-functional correlation between retinal nerve fiber layer and visual field progression.2,3,4 However, progression monitoring by retinal nerve fiber layer may be subject to the floor effect. As OCTA parameters reach the measurement floor later than OCT parameters, they can be particularly useful in more advanced stages of glaucoma. However, since OCTA measurements are more variable than OCT, the number of steps available for clinical assessment of progression is smaller.31 Optic nerve head vessel density was also found to be associated with visual field progression across all stages of glaucoma, while retinal nerve fiber layer thickness showed association with visual field progression only in the early stage.32 Moreover, the structural-functional association between optic nerve head vessel density and visual field MD has been reported in several studies,7,18,19,20,21,22 even more so than the association between retinal nerve fiber layer and visual field MD.7,18,19 Of note, the aforementioned studies were mostly performed in a parallel or cross-sectional design, while our study aimed to simulate a typical clinical practice scenario for monitoring and predicting glaucoma progression.
To best evaluate visual field progression, a sufficient number of reliable visual field tests is needed, including at baseline.33 We included the results from the initial 3 OCT or OCTA visits instead of relying solely on 1 baseline test. Although opting for more frequent testing may increase the predictability of visual field progression, such a testing paradigm may not be feasible in clinical practice. In our study, the OCTA slope derived within 2 years of follow-up was associated with visual field progression over an extended period of 5.7 years.
We found that eyes with faster initial OCTA progression were likely to develop rapid visual field MD loss and event progression in the future. Previous studies have also found an association between optic nerve head vessel density and visual field MD.7,20,21,22 Yarmohammadi et al7 reported that each 1% decrease in optic nerve head vessel density was associated with 0.66 dB of visual field MD deterioration. However, these studies were cross-sectional and did not provide information on future progression. Moreover, even though assessing the percentage of vessel density loss may be useful, the duration of vessel density loss is another important clinical factor to consider. For example, patients who have 1% loss of vessel density in 1 year may require more urgent and intense treatment than those with 1% loss of vessel density in 5 years. Based on the results of our study, eyes with an initial rate of capillary density loss faster than −0.75% per year should be monitored more carefully, as they had a two-fold higher risk of developing event progression and rapid visual field MD loss in the future compared to eyes that progressed at a slower rate.
Faster initial OCT retinal nerve fiber layer progression was also associated with the rate of future visual field MD loss, and the magnitude of the variability explained by the model was similar in OCT and OCTA. Our result is consistent with findings by Swaminathan et al,5 which used different cutoffs for defining OCT progressors. Our study also demonstrated a trend of association between eyes with faster OCT progression and future event progression. Similarly, Yu et al4 found that retinal nerve fiber layer thinning detected by Cirrus trend progression analysis and event determined progression from Guided Progression Analysis was concurrently associated with likely visual field event progression with a hazard ratio of 8.4 (95% CI, 3.30-21.61).
Limitations
Our study has several limitations. First, our cohort included patients previously treated for glaucoma, so the course of visual field loss might have been affected by prior treatments in some eyes. Second, the single site evaluated could lead to selection bias and also limit the generalizability of the results. Third, our cohort included only 28 eyes with moderate to advanced glaucoma. Furthermore, advanced glaucoma eyes with visual field MD worse than −20 dB were excluded. Therefore, our results may not be generalizable to these patients. Fourth, compared to OCT, OCTA has been shown to have greater intra- and inter-visit variability.34,35 Including a higher number of OCTA scans might yield more accurate results. However, approximately one-third of OCTA scans were excluded due to poor quality, consistent with what was reported from a prior study.27 Fifth, the relatively limited follow-up period and the relatively few numbers of eyes might lead to relatively wide CI around the findings. Furthermore, the multiplicity of investigations, such that 99% CI might be more appropriate. The clinical relevance of these findings remains uncertain.
Conclusions
In conclusion, fast initial capillary density loss was associated with faster rate of visual field progression and a greater chance of developing event visual field progression over an extended follow-up. One-third of eyes that had fast initial OCT and OCTA progression developed future visual field likely progression. Both trend and event analysis findings support the consideration of potential clinical use of OCTA along with OCT for estimating the risk of glaucoma progression.
eTable. Characteristics of Eyes Categorized by Optical Coherence Tomography (OCT) Progressor Group.
eFigure. Association of the Rate of Visual Field Mean Deviation (MD) Loss and the Rate of Capillary Density Loss and Retinal Nerve Fiber Layer Thinning.
Data sharing statement
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
eTable. Characteristics of Eyes Categorized by Optical Coherence Tomography (OCT) Progressor Group.
eFigure. Association of the Rate of Visual Field Mean Deviation (MD) Loss and the Rate of Capillary Density Loss and Retinal Nerve Fiber Layer Thinning.
Data sharing statement
