Purpose
The objectives of this report are to compare optical coherence tomography (OCT) based retinal nerve fiber layer (RNFL) and ganglion cell/ inner plexiform layer (GCIPL) thickness in participants who developed primary open-angle glaucoma (POAG) in the Ocular Hypertension Treatment Study (OHTS) to RNFL and GCIPL thickness in those who did not develop POAG (ie, a parallel control group) and to elucidate the relationship between duration after reaching an OHTS POAG endpoint and RNFL and GCIPL thickness.
Design
Clinical cohort study using OCT data.
Methods
Six hundred and forty six OHTS participants who completed OHTS 3 visit OCT imaging were included. Cirrus and Spectralis parapapillary RNFL and GCIPL thickness measurements were compared between 450 eyes that developed POAG and 723 eyes in the control group that did not develop POAG.
Results
In eyes that developed POAG compared to eyes that did not develop POAG, mean global RNFL thickness was between 11.1 and 12.7 µm thinner and mean global GCIPL was between 4.5 and 7.6 µm thinner using Spectralis and Cirrus OCT, respectively (all comparisons P <.001). The 10+ years after POAG diagnosis POAG eyes had ∼10% thinner mean global RNFL thickness and GCIPL thickness than eyes with shorter durations after POAG diagnosis.
Conclusions
In the OHTS, the ocular hypertensive eyes that developed POAG had significantly thinner RNFL and GCIPL measurements compared with the ocular hypertensive eyes that did not develop glaucoma. In addition, longer duration of POAG was associated with thinner RNFL/GCIPL independent of POAG treatment status and IOP level. These results characterize the magnitude of RNFL and GCIPL thinning associated with increasing POAG duration and reinforce the role of OCT as a key tool for monitoring glaucomatous structural change in eyes with OH.
C urrently, little is known about structural changes that occur in the optic nerve and macula of glaucoma patients from the date of initial diagnosis of the disease. This is because the gold standard for the diagnosis of early glaucoma is observed progressive glaucomatous changes to the optic nerve head (ONH) and retinal nerve fiber layer (RNFL), specifically regionally, which requires longitudinal testing. , Most studies of structural defects in glaucoma are cross-sectional studies that cf measurements from healthy eyes or glaucoma suspect eyes to eyes with well-defined glaucoma. In addition, existing longitudinal studies comparing ocular tissue (eg, RNFL and ganglion cell-inner plexiform layer [GCIPL]) thinning in glaucoma patients compared to healthy controls are likely to overestimate assumed glaucomatous tissue thinning because age-specific and other comorbidities are not adequately taken into account. In many studies, healthy participants are much younger than glaucoma patients and are therefore less likely to present with disease-related defects.
The National Institutes of Health-sponsored Ocular Hypertension Treatment Study (OHTS) was completed in 3 phases (OHTS 1, 2 and 3). OHTS 1 (1994-2002) enrolled 1636 participants with ocular hypertension (OH), normal optic discs and visual fields by clinical examination and reading center assessment and tested the safety and efficacy of topical hypotensive medication in delaying or preventing POAG. OHTS 2 (2002 to 2008) tested the consequence of delaying initiation of hypotensive medication on incidence of glaucoma. In OHTS 1 and 2, all participants completed the same core examinations every 6 months and stereoscopic optic disc photography every 12 months. Between OHTS 2 and OHTS 3, protocol driven follow-up was discontinued.
OHTS 3 (2016-2019) was conducted ∼20 years after randomization to determine the severity and 20-year incidence of POAG. The protocol for POAG diagnosis by the Visual Field Reading Center, Optic Disc Reading Center and Endpoint Committee remained constant through OHTS 1, 2 and 3. ,, Diagnosis of visual field POAG required 3 consecutive abnormal visual fields with the same abnormality in the same location; optic disc POAG required 2 consecutive stereoscopic optic disc photographs to differ from baseline. The masked Endpoint Committee adjudicated whether the VF abnormality and optic disc progression were attributable to glaucoma or not and, additionally whether optic disc progression was clinically significant. Spectral domain OCT imaging was included in OHTS 3 to reflect current clinical practice and to improve our understanding of the pattern and magnitude of structural damage associated with the onset of POAG.
The OHTS is uniquely positioned to address the association between RNFL and GCIPL and duration of POAG because the date of initial POAG diagnosis is precisely defined by the OHTS Endpoint Committee’s standardized assessment. This represents a significant strength of our study. In contrast, most prior studies include POAG eyes at an undetermined point in the disease course. As a result, the true onset of POAG in those cohorts is typically unknown, limiting the ability to evaluate the relationship between RNFL and GCIPL thickness and duration of disease. The clearly defined diagnosis date in OHTS allows us to quantify RNFL and GCIPL thickness as a function of the duration of POAG, and to cf these measurements to an appropriate reference group, ocular hypertensive patients who did not develop POAG. Moreover, this information can be clinically useful to indirectly separate the effects of glaucoma from those of aging in OH eyes.
Specifically, this report characterizes OHTS 3 visit OCT-measured RNFL and GCIPL thickness in OH eyes that developed POAG compared to OH eyes that did not develop POAG (No POAG eyes) during OHTS follow-up. The objectives of this study are to quantify the differences in RNFL and GCIPL thickness (1) in OH eyes that developed POAG compared to OH eyes that did not develop POAG and (2) among eyes that developed POAG, to evaluate the association between duration after incident POAG and RNFL and GCIPL thickness. We also evaluated whether these differences in RNFL and GCIPL thickness vary by (1) whether the eye developed glaucomatous optic disc damage (disc POAG) or developed visual field damage (with or without optic disc damage) and (2) race, because Black/African Americans have been shown to have early onset of glaucoma and more rapid progression.
METHODS
The current study is a clinical cohort study using OCT data. The OHTS 1 ,, (ClinicalTrials.gov Identifier: NCT00000125) was a randomized clinical trial of patients with OH designed to answer 2 primary questions: Does early ocular hypotensive treatment reduce the incidence of POAG in patients with OH and what baseline demographic and clinical factors predict which patients with OHT are at low, medium, or high risk of developing POAG. OHTS participant eyes were classified over the study duration as those diagnosed with POAG (incident POAG) and those that were not diagnosed with POAG and whether the glaucoma diagnosis was first identified by changes in the optic disc or visual field or both. Details of the original OHTS study protocol, including the protocols for all clinical tests, participants surveys, and the role of the OHTS Visual Field Reading Center, Optic Disc Reading Center, and Endpoint Committee have been described previously and were identical for the OHTS 1, OHTS 2 and OHTS 3 (as described by Kass et al 2002 and Kass et al 2021 ). The OHTS 2 was designed to determine whether delaying topical ocular hypotensive treatment by about 7 years in the Observation Group was detrimental (ie, whether delaying treatment initiated glaucomatous deterioration that was difficult to reverse).
The final study-stage, OHTS 3, included a one-time ∼20-year follow-up visit with the main objective of examining the incidence and severity of POAG in presumed surviving participants enrolled in the OHTS. Data for the OHTS 3 20-year follow-up was collected between January 7, 2016, and April 15, 2019, at 22 University-based or private research sites. Either Cirrus (Zeiss Meditec) or Spectralis (Heidelberg Engineering GmbH) optic nerve head and macula OCT measurements were obtained at the one-time OHTS 3 imaging visit based on which instrument the specific OHTS clinic used routinely for glaucoma management. , OCT imaging was not included in the OHTS phases 1 and 2 because OHTS phase 2 was conducted June 3, 2002 to December, 2008 and OCT was not FDA approved until 2008. Participant enrollment at each stage of the OHTS is shown in Figure 1 . Enrollment sample size is larger than the sample in the current report because some OCT images did not meet the quality criteria for inclusion in analyses. All stages of the OHTS were done in accordance with the Declaration of Helsinki and Institutional Review Boards and Human Subjects Committees of all study sites approved all protocols and methods.
OHTS 3 flowchart and sample sizes.
The current report investigated the differences in RNFL and GCIPL thickness measurements between eyes that developed POAG (any POAG, only optic disc POAG with no VF POAG and VF POAG with or without disc POAG) and No POAG eyes (ie, stable OH eyes). Because there was a gap in study visits between OHTS 2 and OHTS 3 of approximately 8 years, the date of POAG diagnosis in OHTS 3 was estimated using the midpoint between the participant’s last OHTS 1 or OHTS 2 visit and the OHTS 3 visit. The influence of self-reported race on these results (comparing Black/African American participants with participants of other races) also was investigated. Finally, the association between RNFL and GCIPL thickness with time after first POAG diagnosis was evaluated. For OHTS 1 and 2 POAG diagnosis date is determined by the date of the first abnormal VF or optic disc photograph that was subsequently confirmed and attributed to POAG by the OHTS Endpoint Committee and is accurate within 6 months. If a participant developed POAG in only one eye, the contralateral eye was excluded from all analyses, (ie, the contralateral eye was not included in the No POAG group). This exclusion was based on the presumption that, given the bilateral nature of glaucoma, the unaffected eye was at risk for eventual disease development. For all analyses, reported baseline measurements were measures obtained at randomization.
OCT IMAGING
The Cirrus protocol included the standard 200 × 200 optic disc-centric cube scan and the 512 × 128 macula-centric cube scan. The Spectralis protocol included the high resolution RNFL-centric circle scan and the horizontal posterior pole macula-centric scan (61 b-scans). Six hundred and fifty eight participants representing all 22 sites with OHTS 3 visits completed OCT imaging. In addition to OCT imaging obtained at the one-time OHTS 3 study visit, study centers also obtained IRB approval to submit Cirrus or Spectralis OCT images acquired during routine clinical care prior to the OHTS 3 visit to the OHTS OCT Reading Center at the University of California, San Diego (UCSD). Analysis of the longitudinal OCT data available for 306 OHTS participants is beyond the scope of this manuscript.
UNIVERSITY OF CALIFORNIA, SAN DIEGO OHTS OCT READING CENTER
As part of the current analysis, eyes from all available participants with good quality Cirrus and Spectralis OCT images according to UCSD-based OHTS OCT Reading Center (OCTRC) were included. OCTRC personnel (co-authors KAD, SV, and MH) certified OCT technicians at each site and reviewed the quality of all OCT images acquired for the OHTS 3, along with the OCT images acquired during their standard clinical care visits prior to the OHTS 3 visit.
To be included in analyses Cirrus images had a signal strength of ≥5 using software version 6.0 or higher. Images had to be well centered on the optic disc (for RNFL-centric scans) or fovea (for macula-centric scans) with vessels well aligned (for RNFL-centric scans) and with no or few identifiable artifacts. Spectralis images required a quality number ≥15 and ART Mode > 50 (for RNFL circle scans only) using software version 5.4 or higher. Images had to be well centered on the optic disc (for RNFL circle scans) or fovea (for macula scans) with vessels well aligned (for RNFL circle scans) with no or few identifiable artifacts. In some cases, reading center personnel manually corrected algorithm failures. Eighty-eight percent of Cirrus images and 87% of Spectralis OHTS 3 visit images reviewed were considered acceptable quality.
STATISTICAL ANALYSES
Data is presented as mean (95% CI) and count (%) for continuous and categorical variables, respectively. Patient and eye-level characteristics were compared across POAG diagnosis vs No POAG, duration of POAG, and race. Patient-level characteristics were compared using t-tests and ANOVA for continuous variables and Fisher’s Exact Test for categorical variables. Mean and 95% CI estimates for eye-level continuous measurements were derived from linear mixed-effects models. Linear mixed-effects models were further used to evaluate differences in sectoral thickness measurements cross-sectionally at the OHTS 3 visit across all subjects per OCT instrument and stratified by race. All mixed-effects models were fitted with a random intercept to account for between-subject variability and control for the within-subject correlation when both eyes from the same individual were included in the analysis. Analyses that evaluate differences in global and sectoral thickness measurements were adjusted for race, age, treatment status, IOP, and CCT, when appropriate. To address the effects of POAG duration, we conducted pairwise comparisons between 4 POAG duration intervals of approximately 5 years each (time after incident glaucoma) to assess global thickness differences between eyes based on the number of years from the date of their initial determination of POAG. Two-sided P -values less than.05 were considered statistically significant. The statistical analysis was performed using the R programming language (Version 4.4.0, R Foundation for Statistical Computing [2024], Vienna, Austria).
RESULTS
OHTS 3 CROSS-SECTIONAL ANALYSES
A total of 1173 eyes of 646 participants had useable image data for inclusion in analyses. For Cirrus imaging, 814 eyes (of 474 participants) with good quality OCT images were included. Three hundred and twenty one (39.4%) of these eyes that developed POAG over the course of the OHTS and 493 (60.6%) did not develop POAG (No POAG eyes). For Spectralis imaging, 471 eyes (of 239 participants) with good quality images were included- 180 (38.7%) of these eyes that developed POAG and 291 (61.8%) did not develop POAG. Mean OHTS follow-up time from enrollment in OHTS 1 for eyes that developed POAG and eyes that did not develop POAG was 20.9 (95% CI: 20.7, 21.1) years and 20.6 (95% CI: 20.5, 20.8) years, respectively. At the time of OHTS 3 OCT imaging, participants who developed POAG were similar in age to those who never developed POAG (73.8 years and 73.0 years, respectively; P =.196).
OHTS 3 participant demographic, ocular characteristics and global RNFL and GCIPL thickness measurements in participants who developed POAG and those who did not develop POAG are shown in Table 1 . Mean Bruch’s membrane opening (BMO) optic disc area was significantly greater in eyes that developed POAG than in No POAG eyes (Cirrus: 1.99 mm 2 and 1.89 mm 2, respectively; P =.012 and Spectralis: 1.99 mm 2 and 1.93 mm 2, respectively; P =.043). OHTS 3 visit POAG eyes had worse mean VF mean deviation (MD) than No POAG eyes (−4.00 dB and −0.89 dB, respectively; P <.001) and worse pattern SD (PSD) (3.59 dB and 1.86 dB, respectively; P <.001). Topical ocular hypotensive treatment was prescribed to 224 of 276 participants (81.2%) who developed POAG and 241 of 370 participants (65.1%) who did not develop POAG.
Table 1
Demographic and Clinical Differences Between Primary Open Angle Glaucoma (POAG) and No POAG Participants With Cirrus And/Or Spectralis OCT Imaging.
| No POAG, (370 Subjects; 723 Eyes) | Any POAG, (276 Subjects; 450 Eyes) | P -Value | |
|---|---|---|---|
| Demographic Characteristics (Participant Level) | |||
| Self-reported sex n (%) | |||
| Female | 236 (63.8%) | 152 (55.1%) | .028 |
| Male | 134 (36.2%) | 124 (44.9%) | |
| Self-reported race n (%) | |||
| African descent | 71 (19.2%) | 84 (30.4%) | .001 |
| Other | 299 (80.8%) | 192 (69.6%) | |
| Age at OHTS 3 (years) | 72.8 (72.0, 73.7) | 73.8 (72.9, 74.8) | .133 |
| OHTS follow-up time (years) from baseline visit | 20.6 (20.5, 20.8) | 20.9 (20.7, 21.1) | .056 |
| Number of subjects receiving ocular hypotensive medication (%) | 241 (65.1%) | 224 (81.2%) | <.001 |
| OHTS 1 Baseline Clinical Characteristics (Eye Level) | |||
| Axial length (mm) | 24.0 (23.9, 24.0) | 24.0 (23.9, 24.1) | .149 |
| CCT (µm) | 578.2 (574.4, 582.1) | 576.4 (572.3, 580.6) | .454 |
| Stereo photo based vertical cup disc ratio | 0.36 (0.34, 0.38) | 0.47 (0.44, 0.49) | <.001 |
| OHTS 3 Visit Clinical Characteristics (Eye Level) | |||
| Glaucoma surgery (number of eyes [%]) | 57 (7.9%) | 154 (34.2%) | <.001 |
| 24-2 VF MD (dB) | −0.89 (−1.34, −0.44) | −4.00 (−4.51, −3.49) | <.001 |
| 24-2 VF PSD (dB) | 1.86 (1.65, 2.06) | 3.59 (3.35, 3.83) | <.001 |
| IOP (mm Hg) | 18.3 (17.8, 18.8) | 18.1 (17.5, 18.7) | .613 |
| Spherical equivalent (D) | −0.30 (−0.52, −0.08) | −0.51 (−0.75, −0.27) | .179 |
| OHTS 3 OCT | |||
| Cirrus | |||
| N (participants/ eyes) | 256/493 | 218/321 | |
| Signal strength | 7.8 (7.6, 7.9) | 7.5 (7.4, 7.6) | .007 |
| RNFL mean global thickness (µm) | (464 eyes) | (299 eyes) | |
| 84.7 (83.4, 86.0) | 72.0 (70.5, 73.5) | <.001 | |
| GCIPL mean global thickness (µm) | (449 eyes) | (274 eyes) | |
| 74.4 (73.3, 75.4) | 66.8 (65.6, 68.1) | <.001 | |
| Bruch’s membrane opening area (mm 2) | 1.89 (1.84, 1.94) | 1.99 (1.93, 2.05) | .012 |
| Spectralis | |||
| N (participants/ eyes) | 147/291 | 92/180 | |
| Quality score | 74.7 (69.1, 80.3) | 78.2 (71.9, 84.4) | .256 |
| RNFL mean global thickness (µm) | (291 eyes) | (180 eyes) | |
| 90.2 (88.4, 92.1) | 79.1 (76.9, 81.3) | <.001 | |
| GCIPL mean global thickness (µm) | (193 eyes) | (139 eyes) | |
| 70.0 (68.5, 71.4) | 65.5 (63.8, 67.1) | <.001 | |
| Bruch’s membrane opening area (mm 2) | 1.93 (1.87, 1.98) | 1.99 (1.93, 2.05) | .043 |
Mean global RNFL and GCIPL were significantly thinner in POAG eyes compared to No POAG eyes (RNFL: Cirrus 12.7 µm thinner, Spectralis 11.1 µm thinner; GCIPL: Cirrus 7.6 µm thinner, Spectralis 4.5 µm thinner; P <.001 for all comparisons) ( Table 1 ).
Table 2 shows optic disc area, mean global RNFL thickness and mean global GCIPL thickness by 3 diagnostics criteria (optic disc POAG, VF POAG, and Any POAG) for Cirrus and Spectralis. For both instruments, global RNFL and GCIPL were significantly thicker in POAG eyes diagnosed by optic disc deterioration than POAG eyes diagnosed by VF (Cirrus RNFL 8.5 thicker and GCIPL 5.5 um thicker; both P -values <.001). Similar differences in RNFL and GCIPL thickness by POAG type were found for Spectralis. Sectoral/regional RNFL and GCIPL comparisons among the above-described groups for Cirrus and Spectralis are shown in Supplemental Tables 1 and 2, respectively.
TABLE 2
Cirrus and Spectralis Disc Area, Retinal Nerve Fiber Layer (RNFL) Thickness and Ganglion Cell Inner Plexiform Layer (GCIPL) Thickness in No POAG Eyes, POAG by Optic Disc Damage Only and POAG by Visual Field Damage With or Without Optic Disc Damage.
| No POAG | POAG Optic Disc Damage Only | POAG Visual Field Damage (With or Without Optic Disc Damage) | P -Value | Any POAG | P -Value (vs No POAG) | |
|---|---|---|---|---|---|---|
| Cirrus OCT | ||||||
| N (participants/ eyes) | 256/ 493 | 115/ 165 | 103/ 156 | 218/ 321 | ||
| Disc area (mm 2) | 1.9 (1.8, 1.9) | 2.0 (1.9, 2.0) | 2.0 (1.9, 2.1) | .029 | 2.0 (1.9, 2.0) | .012 |
| Mean global RNFL thickness (µm) | 84.7 (83.4, 85.9) | 76.2 (74.4, 78.0) | 67.7 (65.9, 69.5) | <.001 | 72.0 (70.5, 73.5) | <.001 |
| Mean global GCIPL thickness (µm) | 74.4 (73.3, 75.4) | 69.3 (67.8, 70.8) | 63.8 (62.2, 65.4) | <.001 | 66.8 (65.6, 68.1) | <.001 |
| Spectralis OCT | ||||||
| N (participants/ eyes) | 147/ 291 | 49/ 100 | 43/ 80 | 92/ 180 | ||
| Disc area (mm2) | 1.9 (1.9, 2.0) | 2.0 (1.9, 2.1) | 2.0 (1.9, 2.0) | .075 | 2.0 (1.9, 2.1) | .033 |
| Mean global RNFL thickness (µm) | 90.6 (88.8, 92.3) | 84.2 (81.7, 86.7) | 72.7 (69.8, 75.7) | <.001 | 79.6 (77.4, 81.8) | <.001 |
| Mean global GCIPL thickness (µm) | 70.3 (68.9, 71.7) | 67.4 (65.6, 69.2) | 62.5 (60.4, 64.6) | <.001 | 65.6 (64.0, 67.3) | <.001 |
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