Purpose
To investigate the relationship between corneal hysteresis (CH) and progressive retinal nerve fiber layer (RNFL) loss in a cohort of patients with glaucoma followed prospectively over time.
Design
Prospective observational cohort study.
Methods
One hundred and eighty-six eyes of 133 patients with glaucoma were followed for an average of 3.8 ± 0.8 years, with a median of 9 visits during follow-up. The CH measurements were acquired using the Ocular Response Analyzer (Reichert Instruments, Depew, New York, USA) and RNFL measurements were obtained at each follow up visit using spectral-domain optical coherence tomography (SDOCT). Random-coefficient models were used to investigate the relationship between baseline CH, central corneal thickness (CCT), average intraocular pressure (IOP), and rates of RNFL loss during follow-up, while adjusting for potentially confounding factors.
Results
Average baseline RNFL thickness was 76.4 ± 18.1 μm and average baseline CH was 9.2 ± 1.8 mm Hg. CH had a significant effect on rates of RNFL progression. In the univariable model, including only CH as a predictive factor along with time and their interaction, each 1 mm Hg lower CH was associated with a 0.13 μm/year faster rate of RNFL decline ( P = .011). A similar relationship between low CH and faster rates of RNFL loss was found using a multivariable model accounting for age, race, average IOP, and CCT ( P = .015).
Conclusions
Lower CH was significantly associated with faster rates of RNFL loss over time. The prospective longitudinal design of this study provides further evidence that CH is an important factor to be considered in the assessment of the risk of progression in patients with glaucoma.
Biomechanical properties of the cornea, such as thin central corneal thickness (CCT) and low corneal hysteresis (CH), have been identified as risk factors for primary open-angle glaucoma (POAG). This suggests that they might be important biological markers of glaucoma susceptibility. Although measurement of CCT has become an integral component of examination of patients with glaucoma and suspected glaucoma in clinical practice, recent research has suggested that CH may be a stronger indicator of glaucoma progression.
CH is a measure of the viscoelastic damping properties of the cornea, which can be estimated by analyzing the ability of the cornea to resist deformation induced by a pulse of air. CH may be evaluated in vivo using the Ocular Response Analyzer (ORA; Reichert Ophthalmic Instruments Inc, Depew, New York, USA), a device that delivers a metered air pulse to the cornea, while monitoring resulting changes in corneal curvature using a detector system. The ability of the cornea to resist deformation is thought to reflect, at least in part, the constitution of its extracellular matrix; it has been suggested that the biomechanical properties of the cornea might correlate to biomechanical properties of posterior ocular tissues, such as the lamina cribrosa and peripapillary sclera. An eye with a low CH could potentially have a lamina cribrosa that is less able to dampen pressure changes, and this might increase susceptibility to intraocular pressure (IOP)-related strain and glaucomatous damage. In support of this concept, eyes with higher CH have been reported to have greater deformation of the optic nerve surface during transient elevations of IOP.
CH has been found to be lower in glaucomatous eyes compared to normal eyes and patients with lower CH have been found to be at higher risk of progressive visual field loss. In a prospective longitudinal study, Medeiros and associates showed eyes with lower CH to have faster rates of visual field loss than those with higher CH; CH accounted for 3 times as much progression as CCT in this study. However, although previous longitudinal studies have examined the relationship between CH and functional measurements of glaucomatous damage, to our knowledge there have not been any reports on the relationship between CH and progressive structural changes to the optic nerve.
Owing to the observation that optic nerve head and retinal nerve fiber layer (RNFL) changes often occur prior to detectable visual field changes, objective assessment of structural changes may provide a more sensitive method for measuring glaucoma progression, particularly in early disease. Progressive glaucomatous structural changes can be detected by examination of optic disc stereophotographs; however, imaging devices such as optical coherence tomography (OCT) provide a more objective means to detect progression and allow calculation of rates of change over time. Although average RNFL thickness measurements have been extensively investigated in previous studies evaluating rates of glaucoma progression, it is not known whether biomechanical properties of the cornea might be related to rates of change in these structural measures.
The purpose of this study was to investigate the relationship between CH and progressive RNFL loss in a cohort of glaucomatous eyes followed over time. To our knowledge, this is the first prospective longitudinal study to examine the relationship between CH and structural changes evaluated using an imaging instrument.
Methods
This was an observational cohort study of participants from a prospective longitudinal study designed to evaluate optic nerve structure and visual function in glaucoma (Diagnostic Innovations in Glaucoma Study [DIGS], clinicaltrial.gov identifier: NCT00221897 , National Eye Institute) conducted at the Hamilton Glaucoma Center, University of California, San Diego (UCSD). Participants in the DIGS were longitudinally evaluated according to a pre-established protocol that included regular follow-up visits in which patients underwent clinical examination and several other imaging and functional tests. Written informed consent was obtained from all participants and the institutional review board (IRB #140276). The UCSD Human Subjects Committee approved all protocols, and the methods described adhered to the tenets of the Declaration of Helsinki. Subjects were followed at 6-month intervals.
At each visit during follow-up, subjects underwent a comprehensive ophthalmologic examination, including review of medical history, best-corrected visual acuity, slit-lamp biomicroscopy, IOP measured using Goldmann applanation tonometry (GAT; Haag-Streit, Konig, Switzerland), gonioscopy, dilated funduscopic examination, stereoscopic optic disc photography, standard automated perimetry (SAP), and retinal nerve fiber layer assessment with spectral-domain OCT (SDOCT) (software version 5.4.7.0; Heidelberg Engineering, Dossenheim, Germany). All patients also had CCT measurements obtained by a trained technician using ultrasound pachymetry (Pachette GDH 500; DGH Technology, Inc, Philadelphia, Pennsylvania, USA). Only subjects with open angles on gonioscopy were included. Subjects were excluded if they presented best-corrected visual acuity <20/40, spherical refraction outside ±5.0 diopters or cylinder correction outside 3.0 diopters, or any other ocular or systemic disease that could affect the optic nerve or the visual field.
The study included 186 eyes from 133 patients diagnosed with glaucoma, as determined on the baseline visit. Eyes were classified as glaucomatous if they had repeatable (at least 3 consecutive) abnormal visual field test results on the baseline visits or a glaucomatous-appearing optic disc based on masked stereophotograph assessment. An abnormal visual field was defined as a pattern standard deviation (PSD) outside of the 95% normal confidence limits or a Glaucoma Hemifield Test (GHT) result outside normal limits. Signs of glaucomatous damage to the optic nerve were considered diffuse or localized neuroretinal rim loss, excavation, and RNFL defects. Each participant was required to have a minimum of 4 SDOCT examinations during a minimum 2 years follow-up. Each patient was treated at the discretion of the attending ophthalmologist.
Standard Automated Perimetry
SAP visual field tests were performed using the 24-2 Swedish interactive threshold algorithm on the Humphrey Field Analyzer II (Carl Zeiss Meditec, Inc, Dublin, California, USA). All visual fields were evaluated by the UCSD Visual Field Assessment Center. Visual fields with more than 33% fixation losses or false-negative errors, or more than 15% false-positive errors, were excluded.
Spectral-Domain Optical Coherence Tomography Retinal Nerve Fiber Layer Assessment
Spectralis SDOCT was used to obtain average circumpapillary RNFL thickness measurements from a 3.45-mm circle centered on the optic disc. The circle scan consisted of 1536 A-scan points. Details of the operation of the Spectralis SDOCT have been described previously. All SDOCT (Heidelberg Engineering, GmBH, Dossenheim, Germany) images were reviewed by the UCSD Imaging Data Evaluation and Analysis Center to ensure that the scan was centered, that the signal strength was more than 15 dB, and that there were no artifacts. Scans that were inverted or clipped or those that showed coexistent retinal pathologic abnormalities were excluded. The RNFL segmentation algorithm also was checked for errors.
Corneal Hysteresis Measurements
CH measurements were acquired at the baseline visit using the ORA. A trained technician obtained 3 measurements from each eye and the average of 3 measurements was calculated for analysis. The ORA determines corneal biomechanical properties using an applied force-displacement relationship. Details of its operation have been previously described. During an ORA measurement, a precisely metered air pulse is delivered to the eye, causing the cornea to move inward, past a first applanation, and move into a slight concavity. Milliseconds after the first applanation, the air pump generating the air pulse is shut down and the pressure applied to the eye decreases in an inverse-time, symmetrical fashion. As the pressure decreases, the cornea passes through a second applanated state while returning from concavity to its normal convex curvature. The 2 applanations take place within approximately 20 ms, a time sufficiently short to ensure that ocular pulse effect, or eye position, do not change during the measurement process. An electro-optical collimation detector system monitors the corneal curvature in the central 3.0 mm diameter throughout the 20 ms measurement period, based on the reflection of light from the cornea. When the cornea is flat (applanated), the reflection of light is maximal, generating a peak. A filtered version of the detector signal defines 2 precise applanation times corresponding to 2 well-defined peaks produced by inward and outward applanation events. Two corresponding pressures of an internal air supply plenum are determined from the applanation times derived from the detector applanation peaks. These 2 pressures are defined as the intersection of a vertical line drawn through the peaks of the applanation curve with the plenum pressure curve. The 2 applanation pressures are different primarily because of the biomechanical properties of the cornea. The difference between the 2 applanation pressures is the CH, measured in mm Hg, and is related to the viscous damping property of the cornea. The device provides a waveform score to reflect the quality of measurements. Only measurements associated with a waveform score greater than 4 were considered for inclusion. Baseline OCT and SAP tests were chosen as those closest to the baseline CH measurement date.
Statistical Analysis
The evaluation of the effect of CH measurements on rates of change in RNFL thickness was performed using linear mixed models with random intercepts and random slopes. In linear mixed models, the average evolution of the outcome variable (RNFL 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 RNFL 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. Several different predictors were investigated in this study, including baseline age, race, baseline CH, average GAT IOP, and CCT. We initially constructed univariable models containing only 1 putative predictor along with its interaction with time. Subsequently, more complex models containing multiple predictors and interactions were constructed to evaluate the effect of certain predictors while adjusting for potentially confounding factors. Similar models have been used previously to evaluate the role of CH as a risk factor for the rate of visual field progression in a cohort of patients with glaucoma followed prospectively over time.
All statistical analyses were performed with commercially available software (STATA, version 13; Stata Corp LP, College Station, Texas, USA). The alpha level (type I error) was set at 0.05.
Results
The study included 186 eyes of 133 patients with glaucoma followed for an average of 3.8 ± 0.8 years (range, 2.0–5.2 years). Included eyes had a median of 9 (range, 4–18) SDOCT tests during follow-up. Table 1 shows baseline clinical and demographic information for eyes included in the study. Baseline CH was 9.2 ± 1.8 mm Hg. Figure 1 shows distribution of corneal hysteresis values at baseline for all 186 eyes included in the study during follow-up.
| Glaucomatous Eyes (N = 186 Eyes, 133 Subjects) | |
|---|---|
| Age (y) | 68.3 ± 10.0 |
| Sex, n (%) | |
| Female | 65 (49%) |
| Ancestry, n (%) | |
| European | 74 (56%) |
| African | 47 (35%) |
| Other | 12 (9%) |
| RNFL thickness (μm) | 76.4 ± 18.1 |
| Baseline PSD (dB) | 5.3 ± 3.7 |
| Baseline mean deviation (dB) | −5.3 ± 5.8 |
| Baseline VFI (%) | 86.7 ± 17.1 |
| Baseline CH (mm Hg) | 9.2 ± 1.8 |
| Follow-up (y) | 3.8 ± 0.8 |
| Average GAT IOP (mm Hg) | 13.8 ± 3.7 |
| CCT (μm) | 533 ± 42 |
Table 2 shows the effect of each putative predictive factor on the rates of RNFL loss over time according to the univariable models. Baseline CH had a significant effect on rates of RNFL progression over time ( P = .011) ( Table 2 ). That is, lower values of CH were associated with faster loss of RNFL thickness. Each 1 mm Hg lower CH was associated with an additional RNFL loss of 0.13 μm/year. Average GAT IOP also was significantly associated with rates of RNFL change over time, with each 1 mm Hg higher average GAT IOP associated with a 0.06 μm/year faster rate of RNFL loss. Being of African-American ancestry was also associated with faster rates of RNFL loss in the univariable analysis; however, age and CCT were not.
| Parameter | Effect on Baseline (Intercept) | Effect on Change Over Time | ||
|---|---|---|---|---|
| β 1 (SE) a | P | β 2 (SE) a | P | |
| Baseline age (per year older) | −0.42 (0.13) | .001 | 0.004 (0.01) | .655 |
| Race (African-American) | 8.04 (2.59) | .002 | −0.44 (0.14) | .002 |
| Baseline CH (per mm Hg lower) | 0.92 (0.71) | .197 | −0.13 (0.05) | .011 |
| Average GAT IOP (per mm Hg higher) | 1.38 (0.33) | <.001 | −0.06 (0.03) | .017 |
| CCT (per 100 μm thinner) | 3.91 (3.08) | .206 | 0.07 (0.22) | .735 |
a The coefficient β 1 corresponds to the effect of each predictive factor on the baseline CH measurements. Negative values correspond to lower CH measurements at baseline. Coefficient β 2 corresponds to the effect on change over time. Negative values correspond to faster RNFL decline over time. Refer to the equation presented in “Materials and Methods.” Variables were centered at their mean values.
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