Purpose
To determine whether corneal hysteresis and central corneal thickness are independent risk factors for glaucoma.
Design
A cross-sectional population-based cohort study.
Methods
Associations were tested between corneal hysteresis, measured in 1754 population-based subjects from the TwinsUK cohort, and glaucoma-related endophenotypes, including intraocular pressure (IOP), vertical cup-to-disc ratio, optic disc area, and optic disc cup area. Corneal hysteresis, IOP, and central corneal thickness (CCT) were measured; optic disc photographs were analyzed; and multivariable linear regression analysis was performed.
Results
Data were available on 1645 individuals. Multiple regression analysis showed corneal hysteresis to be significantly negatively associated with age (beta coefficient = −0.03, P < .00005) and IOP (beta coefficient = −0.06, P < .00005). Corneal hysteresis was also found to be associated with CCT (beta coefficient = 0.02, P < .0005). There was no significant association between corneal hysteresis and optic disc area ( P = .6), cup area ( P = .77), vertical cup-to-disc ratio ( P = .51), or spherical equivalent ( P = .08). CCT was also found to be significantly associated with IOP (beta coefficient = 3.3, P < .0005) and corneal hysteresis (beta coefficient = 9.4, P < .0005), but not with age ( P = .59) or spherical equivalent ( P = .16).
Conclusion
In this large cohort of healthy British twins, we found no relationship between corneal hysteresis or CCT and quantitative measures of optic disc cupping, suggesting that corneal hysteresis and CCT are not independent risk factors for glaucoma.
Glaucoma is the leading cause of irreversible blindness worldwide. Characteristic cupping of the optic disc is pivotal to the diagnosis of glaucoma and reflects the underlying loss of retinal ganglion cells, crucial in the pathogenesis of glaucoma. The change in optic disc appearance is one of the important factors used in monitoring glaucoma progression in individuals. There is considerable value in studying endophenotypes (such as vertical cup-to-disc ratio and intraocular pressure [IOP] for glaucoma), as they may provide more information than dichotomous disease affectation status and can be studied quantitatively in population-based studies rather than clinic-based case-control samples with potential for bias.
Hysteresis is the term that describes the ability of an elastic material to return to its natural shape after being deformed by an external force. Corneal hysteresis is the term given to a measure of viscoelasticity of the cornea, and may be associated with glaucoma. Several studies have shown corneal hysteresis to be reduced in glaucoma patients compared to normal controls. Other studies found that eyes with lower corneal hysteresis have visual fields that are more likely to worsen. It has also been shown that with increasing age, lamina cribrosa surface compliance decreases and the cornea becomes more rigid. We have previously shown that corneal hysteresis is strongly heritable. The biomechanical characteristics of the cornea and lamina cribrosa may be similar; an eye with a more deformable cornea, or one with less viscous damping, might also have an optic disc that is more vulnerable to glaucoma damage from raised IOP. There is considerable evidence to support that central corneal thickness (CCT) is a risk factor for glaucoma.
If corneal hysteresis and/or CCT are independent risk factors for glaucoma, we would expect them to be associated with other glaucoma-related quantitative endophenotypes such as vertical cup-to-disc ratio, optic disc area, and optic disc cup area. We therefore set out to examine the relationship between both corneal hysteresis and CCT and optic disc parameters in a large British population-based twin cohort.
Methods
A total of 1754 participants were recruited from the TwinsUK Adult Twin Registry, based at St Thomas’ Hospital, London. They were unaware of any hypotheses or proposals for specific studies; only later were they invited to have an eye examination. The St Thomas’ Hospital Local Research Ethics Committee approved the study, and all the twin participants volunteered to join the TwinsUK Registry and gave informed consent to attend the hospital for phenotyping and for their data to be used for scientific research. All subjects with recorded IOP, optic disc planimetry, and CCT were included, without exclusion for other pathologies (such as early age-related macular degeneration). The study planned to exclude subjects who had corneal refractive surgery, but no participants reported having had this done. Twins were recruited for a wide range of genetic epidemiology studies; in this report the twin model is not used, but the cohort is being used to study epidemiologic factors. Both subjects within each pair of twins were used for analysis as the familial relatedness was taken into account using cluster analysis. Individuals had 2 readings done on both eyes with the Ocular Response Analyzer (ORA; Reichert, Buffalo, New York, USA). The Ocular Response Analyzer was used to measure corneal hysteresis, IOP, and CCT. All measurements were done by 1 of 3 operators. A drop of proxymethacaine 0.5% was instilled in both eyes prior to measuring CCT. For IOP, the Ocular Response Analyzer’s Goldmann-equivalent IOP was used, as this has been shown to most closely reflect Goldmann tonometry. Two measurements were performed on each eye; first and second tests were taken on 1 eye, then on the next; and if the accuracy was poor a third reading was taken. Pearson correlation coefficients between right and left eyes were calculated and as right and left eyes demonstrated significant correlation, right eye measures were arbitrarily used for further analyses. Autorefraction data were gathered using the ARM-10 Autorefractor (Nakagi, Japan) and spherical equivalent was incorporated in the regression analysis.
Simultaneous stereoscopic 15-degree optic disc photographs were taken with a Nidek 3-Dx fundus camera (Nidek, Gamagori, Japan) (early TwinsUK subjects were imaged with nonsimultaneous 30-degree stereophotographs with a Kowa camera [Kowa-Europe, Dusseldorf, Germany]). Images from both cameras were analyzed stereoscopically with custom planimetric software (StereoDx, using a Z-screen; StereoGraphics Corp, Beverly Hills, California, USA). The inner margin of the optic disc and the neuroretinal rim were delineated at the depth of the scleral plane, and images were modified for magnification using refraction and keratometry data. Data handling and preliminary analyses were undertaken using STATA (Intercooled Stata for Windows 95, Version 5.0; StataCorp, College Station, Texas, USA; 1997). Corresponding to IOP and corneal hysteresis measures, right optic disc images were used, unless poor quality (eg, cataract or other media opacities) or exclusion criteria meant left eye data were included. Optic disc data were excluded if the film photograph quality was deemed too poor. Of the 1754 twin volunteers, 102 individuals (5.8%) were excluded from the full analysis. Of the 1754 volunteers, 32 (1.8%) had poor photographs, which were not of sufficient quality for stereographic analysis, and 70 (4%) were not analyzed because of missing digitized images. In 32 of 1754 cases (1.8%) the optic disc image from the left eye was used owing to poor quality of the right.
Given that many of the optic disc endophenotypes (vertical cup-to-disc ratio, optic disc size, and optic cup areas) are correlated, multivariable linear regression was performed to analyze corneal hysteresis and CCT with respect to other glaucoma-related endophenotypes. The data points for each subject included in regression with corneal hysteresis as the dependent variable were optic disc area, optic disc cup area, vertical cup-to-disc ratio, age, IOP, and spherical equivalent, as these are known to be risk factors for glaucoma. Similarly, for CCT as dependent variable, the same measures were included in the regression analysis (with corneal hysteresis instead of CCT).
Results
Data were available on 1645 population-based subjects from the TwinsUK cohort. Average age was 57 years (range 16-83 years, standard deviation [SD]: 11.8). Of the 1645 participants available for analysis; 98% were female; 46.6% were monozygotic and 53.4% were dizygotic twins. 1.7% of the cohort had a diagnosis of glaucoma at the time of testing. These participants with glaucoma were included in the final analysis to encompass the full range of vertical cup-to-disc ratio in the study population. The mean IOP was 15.6 mm Hg (range 5.4-39.1 mm Hg, SD: 3.2), mean CCT was 544 μm (range 311-662 μm, SD: 35.1), and mean vertical cup-to-disc ratio was 0.33 (range 0.03-0.7, SD: 0.1). The means, ranges, and standard deviations for all the parameters measured are shown in Table 1 . As this is a national research cohort, subjects with elevated IOPs were referred to their local family doctor, suggesting onward referral or review, so we do not have final glaucoma specialist opinion on the etiology of elevated IOP; however, of the 2 cases that had IOPs above 30 mm Hg, neither had a known cause of secondary glaucoma and they were therefore included. Ten subjects had CCT below 450 μm; none of these reported previous refractive surgery, keratoconus, or any other corneal pathology and their removal did not alter the results, so they were included in the final analyses.
| Measure | Mean | Minimum | Maximum | Standard Deviation |
|---|---|---|---|---|
| Age (y) | 57 | 16 | 83 | 11.8 |
| CH (mm Hg) | 10.2 | 4.6 | 25.3 | 1.6 |
| IOP (mm Hg) | 15.6 | 5.4 | 39.1 | 3.2 |
| CCT (μm) | 544 | 311 | 662 | 35.1 |
| Optic disc area (mm 2 ) | 2.6 | 0.6 | 5.3 | 0.65 |
| Cup area (mm 2 ) | 1.4 | 0.1 | 4.4 | 1.4 |
| VCDR | 0.33 | 0.03 | 0.7 | 0.1 |
| SE (diopters) | −0.45 | −14.5 | 8.1 | 2.87 |
Right/left eye correlations were as follows: IOP, 0.81 ( P < .001); corneal hysteresis, 0.88 ( P < .001); CCT, 0.83 ( P < .001). Corneal hysteresis was correlated with CCT ( r = 0.41, P < .0001), IOP ( r = −0.12, P < .0001), and age ( r = −0.25, P < .0001) and was at borderline significance with optic disc area ( r = −0.04, P = .08) but not with other optic disc endophenotypes. CCT was, as expected, significantly correlated with IOP ( r = 0.30, P < .0001), age ( r = −0.09, P < .0001), and corneal hysteresis ( r = 0.41, as above), and with optic disc area ( r = −0.07, P = .002), but not with vertical cup-to-disc ratio or cup area. Using multivariable regression analysis, corneal hysteresis was found to be significantly negatively associated with age (beta coefficient = −0.03, P < .00005) and IOP (beta coefficient = −0.06, P < .00005). Corneal hysteresis was also found to be associated with CCT (beta coefficient = 0.02, P < .0005). There was no significant association between corneal hysteresis and optic disc area ( P = .62), cup area ( P = .77), or vertical cup-to-disc ratio ( P = .51). There was also no association between corneal hysteresis and spherical equivalent ( P = .07). The R 2 value for these was 0.28. These results are shown in more detail in Table 2 . CCT was also found to be significantly associated with IOP (beta coefficient = 3.3, P < .0005) and corneal hysteresis (beta coefficient = 9.4, P < .0005), but not with age ( P = .59) or spherical equivalent ( P = .16) ( Table 3 ). The R 2 value for these was 0.33. There was no significant association with the glaucoma-related optic disc parameters when multivariable analysis was used. Regression analyses using optic disc parameters as the dependent variables did not show any difference in relative results; the measures of vertical cup-to-disc ratio, disc area, and cup area were not associated with corneal hysteresis or CCT in the models.
| Parameter | Coefficient | P Value | 95% Confidence Interval |
|---|---|---|---|
| Age (y) | −0.03 | <.0005 | −0.03 to −0.02 |
| IOP (mm Hg) | −0.06 | .001 | −0.09 to −0.03 |
| CCT (μm) | 0.02 | <.0005 | 0.021 to 0.025 |
| Optic disc area (mm 2 ) | −0.04 | .62 | −0.19 to 0.11 |
| Cup area (mm 2 ) | 0.04 | .77 | −0.25 to 0.35 |
| VCDR | −0.66 | .51 | −2.62 to 1.29 |
| SE (diopters) | 0.02 | .07 | −0.002 to 0.05 |
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