To evaluate the role of corneal hysteresis (CH) as a risk factor of central visual field (VF) progression in a cohort of glaucoma suspect and glaucoma patients.
Prospective cohort study.
Two hundred forty-eight eyes of 143 subjects who were followed for an average of 4.8 years with a minimum of 5 visits with 10-2 and 24-2 VF tests were included. Univariable and multivariable linear mixed-effects models were used to identify characteristics associated with the rate of change over time in 10-2 and 24-2 mean deviation (MD). Mixed-effects logistic regression was used to evaluate characteristics associated with an increased likelihood of event-based 10-2 VF progression based on the clustered pointwise linear regression criterion.
CH was significantly associated with 10-2 and 24-2 VF progression in the univariable trend-based analysis. In multivariable trend-based analyses, lower CH was associated with a faster rate of decline in 10-2 MD (0.07 dB/y per 1 mm Hg, P < .001) but not with 24-2 MD ( P = .490). In multivariable event-based analysis, lower CH was associated with an increased likelihood of 10-2 VF progression (odds ratio = 1.35 per 1 mm Hg lower, P = .025). Similar results were found in eyes with early glaucomatous damage at the baseline (baseline: 24-2 MD ≥ −6 dB).
Lower CH was associated with a statistically significant, but relatively small, increased risk of central VF progression on the 10-2 test grid. Given the substantial influence of central VF impairment on the quality of life, clinicians should consider using CH to assess the risk of progression in patients with primary open-angle glaucoma including those with early disease.
G laucoma is characterized by progressive retinal ganglion cell loss and commensurate visual field (VF) loss. , Assessing the possibility and rate of disease progression is of particular importance given the irreversible nature of glaucomatous damage and the potential for lifetime functional impairment. The probability and rate of disease progression varies among different individuals. Identification of baseline risk factors of disease progression allows clinicians to individualize therapy to reduce the likelihood of disease worsening. Higher intraocular pressure (IOP), older age, , decreased ocular perfusion pressure, , , presence of optic disc hemorrhage, , , thinner central corneas, , , lower corneal hysteresis (CH), focal lamina cribrosa defect, , and β-zone peripapillary atrophy , , all have been reported to be associated with glaucomatous VF progression.
Glaucomatous VF impairment affects quality of life and negatively impacts completion of everyday tasks including reading, driving, walking, and taking medications in addition to putting them at increased risk of psychiatric comorbidities including depression. Glaucoma patients with similar severity of VF damage based on the magnitudes of global VF indices may have different areas of VF damage, with some locations affecting vision-related quality of life more than others. Central VF metrics have provided a stronger association with the quality of life measures compared with those of global VF. This is particularly important considering the accumulating body of evidence regarding the presence of central VF impairment in the early stages of glaucoma.
Corneal biomechanical characteristics have been reported to affect the susceptibility of glaucoma suspects to develop a subsequent VF defect, , and it also influences the risk of progression in those with established VF damage. , CH is a biomechanical feature that defined by the viscous dampening of the anterior chamber when an air puff of varying pressure is applied to the anterior surface of the cornea, and it is hypothesized to reflect corneal extracellular matrix constituents. Considering the corneoscleral envelope as a closely linked unit, CH may provide indirect information of the structural constituents of the posterior pole related to glaucomatous damage including the lamina cribrosa and peripapillary sclera. Previous studies have shown that lower CH is a significant predictor of a faster retinal nerve fiber layer and global VF progression. However, no study has yet evaluated CH as a predictor of central VF progression in patients with glaucoma. The purpose of the current study was to investigate baseline CH as a risk factor of central VF progression in a prospective cohort of glaucoma suspect and glaucoma patients.
In this observational cohort study, participants were included from a prospective longitudinal study designed to evaluate optic nerve structure and visual function in glaucoma (Diagnostic Innovations in Glaucoma Study [DIGS] and African Descent and Glaucoma Evaluation Study [ADAGES]). Participants in these cohorts were longitudinally evaluated according to a pre-established protocol that included regular follow-up visits in which patients underwent a clinical examination and several imaging and functional tests. All participants from the DIGS and ADAGES study who met the inclusion criteria described below were enrolled in the current study. Written informed consent was obtained from all participants. The University of California, San Diego Human Subjects Committee approved all protocols, and the methods described adhered to the tenets of the Declaration of Helsinki. ADAGES and DIGS were designed with similar testing protocols, and details of the procedures in DIGS and ADAGES have been previously published.
Subjects underwent annual comprehensive ophthalmologic examinations, including a review of medical history, best-corrected visual acuity, slitlamp biomicroscopy, IOP measurement, dilated funduscopic examination, stereoscopic optic disc photography, and standard automated perimetry using Swedish Interactive Threshold Standard Algorithm (Humphrey Field Analyzer; Carl Zeiss Meditec). Semiannual examinations included standard automated perimetry (10-2 VF and 24-2 VF) and IOP measurement. Only subjects with open angles on gonioscopy at baseline were included. Subjects were excluded if they had a baseline best-corrected visual acuity <20/40, axial length of more than 26.5 mm, baseline 24-2 mean deviation (MD) of worse than −20 dB, or any ocular or systemic disease that could affect the optic nerve or VF.
The study included eyes diagnosed as glaucoma or glaucoma suspect with baseline CH measurements and a minimum follow-up time of 2.5 years with a minimum of five 10-2 and 24-2 VF tests. Eyes were classified as glaucomatous if they had repeatable (≥2 consecutive) abnormal VF test results or evidence of glaucomatous optic neuropathy defined as excavation, the presence of focal thinning, notching of the neuroretinal rim, or localized or diffuse atrophy of the retinal nerve fiber layer based on masked grading of optic disc photographs by 2 graders or clinical examination by a glaucoma specialist. An abnormal VF test was defined as a pattern standard deviation (PSD) outside of the 95% normal confidence limits or a Glaucoma Hemifield Test result outside normal limits. Glaucoma suspects were defined as those having elevated IOP (≥22 mm Hg) or suspicious-appearing optic discs without the presence of repeatable glaucomatous VF damage.
standard automated perimetry
The 10-2 and 24-2 VF tests were considered unreliable and excluded if there was >33% fixation losses, >33% false-positive errors, or >33% false-negative errors. Experienced graders at the University of California, San Diego Visual Field Assessment Center reviewed the results, excluding tests with eyelid or rim artifacts, fatigue or learning effects, inappropriate fixation, or evidence that the VF results were caused by a disease other than glaucoma (eg, homonymous hemianopia) or inattention. Patients with glaucoma were stratified into 2 groups based on the severity of their VF damage. Patients with baseline 24-2 MD > −6.0 dB were classified as mild glaucoma, and patients with baseline 24-2 MD ≤ −6.0 were classified as moderate-to-severe glaucoma.
10-2 regions proposed by Hood and associates were divided into 5 zones: the superior nasal (zone 1), superior temporal (zone 2), superior temporal band (zone 3), inferior temporal (zone 4), and inferior nasal (zone 5). For the calculation of the mean sensitivity in each zone, threshold sensitivity values in decibels (dB) were used. The zonal mean sensitivity measurements were calculated as the average threshold sensitivity values of all points tested in that region.
Central visual field progression
Different trend-based and event-based analyses that were used to characterize progression in the 10-2 VF tests are described below.
Best linear unbiased prediction (trend-based)
Estimates of rates of change for individual eyes in different zones were obtained by best linear unbiased prediction (BLUP). Ordinary least-squares estimates can be imprecise in eyes with just a few measurements available over time or with large intraindividual variability. Individual ordinary least-squares estimates (ie, individual regression lines) also do not take into account the information provided by the whole population, whereas BLUPs are shrinkage estimates that take into account the results obtained by evaluating the whole sample of eyes, giving less weight to estimates obtained from eyes with few measurement occasions or large intraindividual variability (ie, more “noise”). In eyes with a large number of measurements over time, BLUP and ordinary least-squares estimates give similar results. BLUPs have been used to estimate individual rates of structural change measured by different instruments in glaucoma and to measure the rate of cognitive change in longitudinal models. ,
Clustered pointwise linear regression (event-based)
Regression of VF parameters over time has been used to identify VF deterioration and to estimate the magnitude of VF loss. Regression of individual locations or of clusters provided more information about the location of VF loss than regression of global indices. , A VF test point was flagged as worsening if it showed a significant negative slope faster than −1 dB/y, with a significance level of P < .01. , Per de Moraes and associates, a progression event in 10-2 VF was defined when ≥3 test points located in the same latent class analysis derived 10-2 VF sector progressed faster than −1.0 dB/y at P < .01 over the follow-up period.
Corneal hysteresis measurements
CH measurements were acquired at the baseline visit using the Ocular Response Analyzer (Reichert Ophthalmic Instruments Inc). A trained technician obtained 3 measurements from each eye, and the average of 3 measurements was calculated for analysis. The Ocular Response Analyzer determines corneal biomechanical properties using an applied force-displacement relationship. Details of its operation have been previously described. In brief, within a 20-ms time frame, a metered air pulse is delivered to the eye, causing the cornea to move inward in a concave fashion (past a first applanation point), and then the cornea returns (past a second applanation point) to its initial position. An electro-optical collimation detector system monitors the corneal curvature in the central 3.0-mm diameter during the measurement period and defines 2 peaks produced by the applanation events. CH is the difference between these 2 applanation pressures measured in millimeters of mercury. CH thus relates to the viscous dampening ability of the cornea. The device provides a waveform score to reflect the quality of measurements. Three measurements were obtained for each eye in each visit, and the average of the qualified measurements with a waveform score greater than 4 was considered for analysis. Baseline VF tests were chosen as those closest to the baseline CH measurement date.
Continuous and categorical data were presented as mean (95% confidence interval) and count (%). Statistically significant differences in characteristics between glaucoma suspect and glaucoma patients were determined by 2-sample t tests for continuous variables and the Fisher exact test for categorical variables. Eye characteristics were compared using linear mixed-effects models with random intercepts to account for within-subject variability. In the trend-based analysis, VF trajectories were estimated using linear mixed-effects models with random eye-within-patient intercepts and independent random slopes-within-eye. The details on the use of these models for evaluation of rates of change in glaucoma and to model longitudinal processes have been published. , , In linear mixed models, the average evolution of the outcome variable (VF measurements) is described using a linear function of time, and random intercepts and random slopes introduce subject- and eye-specific deviations from this average evolution. The model can account for the fact that different eyes can have different rates of VF loss over time, while also accommodating correlations between both eyes of the same individual. , Interaction terms between time and putative predictors (eg, CH) can be included in the model to test whether there is a significant effect of the putative predictor on changes of the outcome variable over time. Multivariable models were fit after including all variables with a P value of ≤.10 in univariable analysis. In addition to age, demographic characteristics, and follow-up duration, all models were adjusted for both mean IOP during follow-up , and positive history of disc hemorrhage , , because of their reported associations with glaucomatous VF progression. In the event-based analysis, univariable and multivariable mixed-effects logistic regression models were used to identify characteristics associated with an increased likelihood of 10-2 VF progression defined by the clustered pointwise linear regression (PLR) criterion. Linear mixed-effect models with random intercepts and random slopes were used to compare the rates of 10-2 MD loss and age-adjusted zonal rates of mean sensitivity loss between 2 groups of eyes divided based on baseline CH (CH ≥ 10 mm Hg and CH < 10 mm Hg). All statistical analyses were performed with commercially available software (STATA, version 17.0; Stata Corp LP). The alpha level (type I error) was set at 0.05.
A total of 248 eyes (71 glaucoma suspect, 177 glaucoma) of 143 patients were included in this prospective cohort study. The cohort included 72 females (50.3%) and 99 non-African descent (69.2%) participants. The mean (95% confidence interval) baseline age at the study entry was 68.4 (67.1, 69.7) years, the average follow-up duration of eyes was 4.8 (4.7, 4.9) years, and the average number of visits was 7.8 (7.5, 8.1). A total of 76.6% of study participants were already on ocular hypotensive eye drops at the study entry. Specifically, 63.3% of participants were using prostaglandin analogs at the beginning of the follow-up. Glaucoma eyes had lower baseline IOP, lower mean IOP during follow-up, worse baseline 24-2 and 10-2 MDs, and higher baseline 24-2 and 10-2 PSDs (all P values <.05) than glaucoma suspect eyes. Other characteristics including axial length, central corneal thickness, CH, positive history of disc hemorrhage, follow-up duration, and number of test visits were similar between glaucoma suspect and glaucoma eyes (all P values >.05) ( Table 1 ). Figure 1 shows the distribution of baseline CH measurements for all 248 eyes included in the study during follow-up.
|Glaucoma Suspect||Glaucoma||P Value|
|At the patient level||143||40 (28.0)||103 (72.0)|
|Male (%)||71 (49.7)||19 (47.5)||52 (50.5)|
|Female (%)||72 (50.3)||21 (52.5)||51 (49.5)|
|Non-African American (%)||99 (69.2)||27 (67.5)||72 (69.9)|
|African American (%)||44 (30.8)||13 (32.5)||31 (30.1)|
|Self-reported DM (%)||23 (16.1)||6 (15.0)||17 (16.5)||>.99|
|Self-reported HTN (%)||89 (62.2)||24 (60.0)||65 (63.1)||.848|
|Systolic blood pressure (mm Hg)||130.2 (126.9, 133.4)||131.9 (125.0, 138.8)||129.5 (125.9, 133.1)||.511|
|Diastolic blood pressure (mm Hg)||76.6 (74.7, 78.5)||78.6 (74.8, 82.4)||75.8 (73.6, 78.1)||.207|
|At the eye level||248||71 (28.6)||177 (71.4)|
|Baseline age (y)||68.4 (67.1, 69.7)||64.9 (62.4, 67.5)||69.8 (68.3, 71.2)||.119|
|Axial length (mm)||24.09 (23.97, 24.21)||24.23 (23.98, 24.48)||24.03 (23.89, 24.17)||.362|
|CCT (µm)||543.3 (537.2, 549.4)||561.0 (549.7, 572.2)||537.0 (529.9, 544.1)||.213|
|Baseline IOP (mm Hg)||14.6 (14.1, 15.1)||16.0 (15.2, 16.9)||13.9 (13.3, 14.5)||.012|
|Mean IOP during follow-up (mm Hg)||14.7 (14.2, 15.2)||16.4 (15.5, 17.3)||14.0 (13.5, 14.5)||<.001|
|CH (mm Hg)||9.62 (9.40, 9.84)||10.12 (9.70, 10.54)||9.42 (9.17, 9.67)||.291|
|History of DH (%)||32 (12.9)||7 (9.9)||25 (14.1)||.317|
|Baseline 24-2 MD (dB)||−3.31 (−3.85, −2.78)||−0.40 (−0.74, −0.05)||−4.48 (−5.15, −3.82)||<.001|
|Baseline 24-2 PSD (dB)||4.28 (3.83, 4.72)||1.74 (1.61, 1.87)||5.29 (4.74, 5.85)||<.001|
|Baseline 10-2 MD (dB)||−2.87 (−3.44, −2.29)||−0.50 (−0.81, −0.18)||−3.82 (−4.57, −3.06)||<.001|
|Baseline 10-2 PSD (dB)||3.59 (3.08, 4.10)||1.29 (1.22, 1.36)||4.51 (3.84, 5.18)||<.001|
|10-2 Follow-up (y)||4.8 (4.7, 4.9)||5.0 (4.9, 5.2)||4.7 (4.6, 4.9)||.079|
|Visits of 10-2 visual field||7.8 (7.5, 8.1)||7.4 (7.0, 7.9)||8.0 (7.6, 8.3)||.842|
Table 2 shows the results of univariable and multivariable trend-based analysis of the characteristics associated with the rate of change in 10-2 VF MD over time. In the univariable analysis, male gender, higher baseline 10-2 PSD, worse baseline 24-2 MD, higher baseline 24-2 PSD, and lower baseline CH were associated with a faster rate of 10-2 VF progression (all P values <.05). Results of the multivariable analysis showed that lower mean IOP during follow-up (β = −0.02 dB/y per 1 mm Hg higher, P = .043), worse baseline 24-2 MD (β = −0.02 dB/y per 1 dB worse, P = .004), and lower baseline CH (β = −0.07 dB/y per 1 mm Hg lower, P < .001) were significantly associated with a faster rate of 10-2 VF progression.
|Variables||Univariable Model||Multivariable Model|
|β (95% CI)||P Value||β (95% CI)||P Value|
|Age, per 10 y older||−0.05 (−0.11, 0.01)||.102||−0.02 (−0.09, 0.05)||.561|
|Sex: F/M||0.13 (0.00, 0.26)||.049||0.04 (−0.10, 0.18)||.586|
African American/Non-African American
|−0.01 (−0.15, 0.13)||.889||−0.02 (−0.17, 0.12)||.762|
|Axial length, per 1 mm longer||0.01 (−0.06, 0.07)||.790||—||—|
|CCT, per 10 µm thinner||0.00 (−0.02, 0.01)||.844||—||—|
|Self-reported diabetes||−0.07 (−0.25, 0.11)||.433||—||—|
|Self-reported hypertension||0.06 (−0.08, 0.19)||.412||—||—|
|Baseline systolic blood pressure, per 10 mm Hg higher||0.00 (−0.04, 0.03)||.827||—||—|
|Baseline diastolic blood pressure, per 10 mm Hg higher||0.00 (−0.05, 0.05)||.992||—||—|
|Baseline IOP, per 1 mm Hg higher||0.00 (−0.02, 0.01)||.612||—||—|
|Mean IOP during follow-up, per 1 mm Hg higher||−0.01 (−0.03, 0.01)||.277||−0.02 (−0.04, 0.00)||.043|
|History of disc hemorrhage||−0.11 (−0.25, 0.02)||.096||−0.12 (−0.25, 0.02)||.093|
|Baseline MD 10-2, per 1 dB worse||−0.01 (−0.02, 0.00)||.111||—||—|
|Baseline PSD 10-2, per 1 dB higher||−0.01 (−0.02, 0.00)||.036||—||—|
|Baseline MD 24-2, per 1 dB worse||−0.02 (−0.03, −0.01)||.002||−0.02 (−0.03, −0.01)||.004|
|Baseline PSD 24-2, per 1 dB higher||−0.02 (−0.03, 0.00)||.007||—||—|
|CH, per 1 mm Hg lower||−0.07 (−0.11, −0.04)||<.001||−0.07 (−0.11, −0.03)||<.001|
|Follow-up duration, per 1 y longer||0.04 (−0.04, 0.11)||.363||0.02 (−0.06, 0.10)||.628|