Purpose
To evaluate corneal biomechanical properties across the glaucoma spectrum and study the relationship between these measurements and intraocular pressure measured by Goldmann applanation tonometry (GAT-IOP) and central corneal thickness (CCT).
Design
Prospective cross-sectional study.
Methods
setting: Tertiary-care teaching institute. study population: A total of 323 eyes of 323 participants (71 normal, 101 glaucoma suspect [GS], 38 ocular hypertension [OHT], 59 primary angle-closure disease [PACD], 36 primary open-angle glaucoma [POAG], and 18 normal-tension glaucoma [NTG]) who had received no ophthalmic treatment. observation procedures: Corneal hysteresis (CH), corneal resistance factor (CRF), corneal-compensated IOP (IOPcc), and Goldmann-correlated IOP (IOPg) measured by the Ocular Response Analyzer (ORA). GAT-IOP and CCT recorded in all subjects. main outcome measures: Regression analysis used to determine the relationship between GAT-IOP, CCT, age, CRF, and CH. Bland-Altman plots used to assess agreement between IOP measured by GAT and the ORA (IOPg).
Results
CH measurements were significantly less in POAG and NTG compared to normal subjects ( P = .034 and P = .030 respectively), regardless of the IOP. The CRF was significantly less in NTG and maximum in POAG and OHT. Regression analysis with CH as dependant variable showed significant association with GAT-IOP and CRF ( P < .001) but not CCT, persisting on multivariate analysis (adjusted R 2 = 0.483). GAT-IOP correlated strongly with Goldmann-correlated IOP on the ORA (IOPg) (r = 0.82; P < .001), but limits of agreement between the measurements were poor.
Conclusions
CH and CRF may constitute a pressure-independent risk factor for glaucoma. CRF appears to influence GAT-IOP measurements more than simple geometric thickness measured by CCT. However, IOP measurements from the ORA are not interchangeable with, and are unlikely to replace, Goldmann applanation tonometry at the present time.
Glaucoma is one of the leading causes of visual impairment and blindness worldwide. Across all randomized controlled trials, lowering intraocular pressure (IOP) resulted in reduction in rates of progression to or worsening of glaucoma over 5 years. These studies confirm that 1 of the pathophysiologic bases for glaucoma is elevated IOP. Goldmann applanation tonometry (GAT) is regarded as the reference standard by which to measure IOP. However, although GAT may be less prone to biomechanical influences than Schiotz tonometry, it is known to be affected by corneal biomechanical factors such as corneal curvature, central corneal thickness (CCT), hydration, elasticity, hysteresis, and rigidity.
Previous studies in Indian eyes have demonstrated significantly thinner corneas compared to white eyes. It is now recognized that biomechanical properties of the cornea are also important, in addition to just the geometric thickness. However, there is a paucity of data regarding biomechanical properties in Indian eyes. Until recently, corneal biomechanical properties could not be measured in vivo. The Ocular Response Analyzer (ORA; Reichert Ophthalmic Instruments, Inc, Buffalo, New York, USA) is a new, noninvasive device that analyzes corneal biomechanical properties simply and rapidly. The ORA allows corneal-compensated IOP measurements and can estimate corneal hysteresis and corneal resistance. It is designed to improve the accuracy of IOP measurement by using these data to calculate a biomechanically adjusted estimate of intraocular pressure.
In this study we evaluated differences in corneal hysteresis (CH), corneal resistance factor (CRF), corneal-compensated IOP (IOPcc), and Goldmann-correlated IOP (IOPg) in Indian eyes including normal eyes, glaucoma suspects, ocular hypertensives, and both open-angle and narrow-angle glaucoma, and studied the relationship between these variables and CCT and Goldmann applanation tonometry (GAT-IOP) measurements.
Material and Methods
This was a prospective observational study including normal subjects; patients with ocular hypertension (OHT); subjects with discs suspicious for glaucoma but normal visual fields (disc suspects); and primary angle-closure disease (PACD), primary open-angle glaucoma (POAG), and normal-tension glaucoma (NTG) patients not on any treatment presenting to the Glaucoma Clinic of the Advanced Eye Centre, Postgraduate Institute of Medical Education and Research, Chandigarh, India. Normal controls were selected from age- and sex-matched healthy volunteers with no history of any ocular disease or surgery or any family history of glaucoma. Subjects fulfilling the inclusion criteria detailed below were prospectively recruited for the study.
Inclusion Criteria
To be eligible for the study, subjects had to be >18 years of age, with clear cornea and clear ocular media and a minimum best-corrected visual acuity (BCVA) of 20/40. The refractive error had to have been within ±5.0 diopters (D) and astigmatism ±3.0 D.
Exclusion Criteria
Patients with coexisting ocular conditions such as diabetes or uveitis, or those who had undergone any ocular surgery or laser treatment, were excluded from the study since these conditions might influence corneal biomechanical properties as well. Patients who were receiving any ophthalmic treatment in any form, including medications for allergy and/or dry eye, were not included in the study.
Baseline Evaluation
All potential subjects underwent a comprehensive ophthalmologic examination including BCVA, IOP measured by GAT-IOP, slit-lamp biomicroscopy, gonioscopy, and stereoscopic fundus evaluation on the slit lamp using a 90.0-D lens. IOP was measured by the same investigator (A.B.). An average of 3 measurements was computed for analysis; if they differed by more than 2.0 mm Hg, a fourth reading was taken and the average of the 3 closest values was taken. Color stereoscopic optic disc photographs and red-free nerve fiber layer (NFL) photographs were taken on the Zeiss fundus camera FF 450 with Visupac System 451 (Carl Zeiss Ophthalmic Systems, GmbH, Jena, Germany). Gonioscopy was performed by an experienced gonioscopist (S.S.P., S.K.) in a semi-darkened room with minimum possible slit-lamp illumination, using a Sussman 4-mirror goniolens. Care was taken to ensure that the slit-lamp beam did not fall across the pupil, so that there was no artificial opening of the angle. The angles were graded numerically according to the Shaffer classification.
All subjects underwent baseline standard achromatic perimetry (SAP) on the Humphrey field analyzer (HFA 750 II; Carl Zeiss–Humphrey Systems, Dublin, California, USA) using the 24-2 testing protocol by SITA-standard strategy. The visual fields were considered satisfactory if false-positive and false-negative errors did not exceed 30% and fixation errors did not exceed 25%.
Eligibility Criteria
To be eligible for inclusion, patients with OHT were required to fulfill the following criteria in both eyes: BCVA 20/40 or better (refractive error ±5.0 D spherical and ±3.0 D cylinder); IOP >21 mm Hg and <32 mm Hg on at least 2 successive measurements spaced 2 weeks apart at approximately the same time of day; open angles on gonioscopy; and normal-appearing optic disc. (A normal-appearing optic disc was defined as one with no features suggestive of glaucomatous optic neuropathy such as cup-to-disc ratio >0.6, any diffuse or focal neuroretinal rim thinning, any disc hemorrhage, and/or any retinal nerve fiber layer [RNFL] defects on the red-free photograph.) Patients were included only if both observers classified the disc as “normal.” The visual fields were to be normal, which was defined as mean deviation (MD) and pattern standard deviation values within 95% confidence interval and a glaucoma hemifield test (GHT) classified as “within normal limits.”
Glaucoma suspects with suspicious-looking optic discs (disc suspects) were included if they had features suggestive of glaucomatous optic neuropathy such as cup-to-disc ratio >0.6, any diffuse or focal neuroretinal rim thinning, any disc hemorrhage, and/or any RNFL defects on the red-free photograph; IOP <21.0 mm Hg on at least 2 successive measurements spaced 2 weeks apart; open angles on gonioscopy; and normal visual fields on Humphrey SAP as described above.
PACD was defined as existing in an eye where, on gonioscopy, appositional contact between the peripheral iris and posterior trabecular meshwork was considered possible (“occludable angle”), with evidence of trabecular obstruction by the peripheral iris such as peripheral anterior synechiae and/or elevated IOP. Both primary angle closure with normal visual fields and primary angle-closure glaucoma (PACG) with glaucomatous optic neuropathy and repeatable (2 consecutive) abnormal visual field tests (defined as a pattern standard deviation outside 95% normal confidence limits and a GHT classified as “outside normal limits”) were included.
POAG patients were included if they fulfilled the same gonioscopy and IOP features as OHT in addition to glaucomatous optic neuropathy and repeatable (2 consecutive) abnormal visual field tests as described above. Normal-tension glaucoma (NTG) had the same features as POAG except for the IOP being recorded as less than 21.0 mm Hg at all time points on a 24-hour diurnal variation test.
Patients with advanced glaucoma (MD <-12 dB) were excluded from the study.
Normal controls were included if they fulfilled the same criteria as for the OHT patients, with the exception that their IOP was recorded as ≤22.0 mm Hg on 2 successive occasions spaced 2 weeks apart at approximately the same time of day.
Only 1 eye of each patient was included in the study. If both eyes of normal and glaucoma-suspect patients were eligible for inclusion, the right eye was enrolled. If both eyes of glaucoma patients were eligible for inclusion, the worse eye was enrolled in the study.
Specialized Investigations
All eligible subjects, as defined by eligibility criteria described above, had their central corneal thickness (CCT) measured by ultrasonic pachymeter (model 200P; Sonomed, New York, New York, USA). CCT measurements were taken in the midpupillary axis by a single technician. Repeated sets of 3 readings were taken until the values differed by less than 10 μm. They were then averaged and computed for analysis. IOPcc, IOPg, CH, and CRF measurements were done using the Ocular Response Analyzer.
Ocular Response Analyzer
Reichert has produced an instrument, the Ocular Response Analyzer, that measures the corneal response to indentation by a rapid air pulse. A fully automated alignment system positions an air tube to a precise position relative to the apex of the cornea. Once aligned, a 25-millisecond air pulse applies pressure to the cornea. The air pulse causes the cornea to move inward, past applanation and into a slight concavity, before returning to normal curvature. Corneal deformation is recorded via an electro-optical infrared (IR) detection system (similar to the classical air-puff tonometers).
The ORA acquires corneal biomechanical data by quantifying this differential inward and outward corneal response to an air pulse over a time span of approximately 20 milliseconds. Once the air pulse induces the desired indentation/applanation, it symmetrically reverses, which allows the cornea to resume its original shape. Because a time lag is necessary to activate the reversal of the air pulse, the cornea actually indents mildly beyond the intended applanation point. This action permits the detection of a second applanation point, as the cornea returns from its over-applanated state. Using the first applanation pressure point (P1) and the second applanation pressure point (P2), the ORA generates 2 separate IOP output parameters (Goldmann-correlated IOP and corneal-compensated IOP) and 2 parameters that reflect biomechanical properties of the cornea (corneal hysteresis and corneal resistance factor).
Goldmann-correlated IOP (IOPg) is the average of the inward (P1) and outward (P2) applanation pressures. This parameter is closely correlated with GAT-IOP. Corneal-compensated IOP (IOPcc) is derived from both IOP and corneal biomechanical data.
During the ORA measurement process, the cornea absorbs some energy from the initial air pulse, which causes the second applanation pressure measurement to be lower than the initial measurement. The difference between the 2 pressures (P1 − P2) is corneal hysteresis (CH). This ORA parameter is thought to represent the viscoelastic nature of the cornea, or its “viscous-damping” capacity.
Corneal resistance factor (CRF) is derived from the formula P1 − kP2, where k is the constant determined from an empirical analysis of the relationship between both P1 and P2 and CCT. CRF offers a measurement of corneal resistance.
The measurement signal consists of a green symmetric curve, which corresponds to the air-pulse pressure, and a red asymmetric curve, which corresponds to applanation of the cornea via the signal produced by the IR detector. The red curve has 2 principal peaks, which correspond to points P1 and P2 on the green curve. P1 is the pressure at the first applanation event as the cornea moves inward under the increasing force of air pulse (inward applanation). P2 is the pressure corresponding to the second applanation event as the cornea returns to its normal curvature under the decreasing force of the air pulse (outward applanation). Because of the dynamic nature of the measurement process, viscous damping in the cornea causes delays in the inward and outward applanation events (energy absorption). This results in 2 different pressure values at the inward and outward events, with the second outward applanation pressure always lower than the first inward applanation pressure. Using this bidirectional applanation measurement, the ORA is able to present 4 different parameters.
Measurement Protocol
Eligible patients were recruited and the ORA measurements were done before Goldmann applanation tonometry on a designated day. Three good-quality waveform scans, defined by the manufacturer as having symmetry in height between the 2 peaks of the waveform, were saved. Good-quality profiles required relatively equal, well-defined inward and outward applanation spike heights that were located above the pressure curve, and relatively smooth raw applanation signals. Readings were examined graphically, and those with poor-quality applanation signals (multiple applanation spikes or asymmetric signals) were discarded. Mean ORA values were calculated from all good-quality measurements for use in statistical analyses. IOPcc, IOPg, CH, and CRF were recorded.
Central Corneal Thickness
All eligible subjects had their CCT measured by ultrasonic pachymeter (model 200P, Sonomed). Repeated sets of 3 readings were taken until the values differed by less than 10 μm. They were then averaged and computed for analysis.
All parameters were recorded on prospectively filled data forms.
Statistical Methods
The results were analyzed using SPSS for Windows software, Version 19.0 (SPSS Inc, Chicago, Illlinois, USA). Analysis of variance with post hoc Dunnett T3 comparisons was used to assess the differences in all measurements between normal subjects, glaucoma suspects, and OHT, PACG, and POAG patients. Linear regression analysis was done to study the relationship between CCT, GAT-IOP, age, corneal hysteresis, and CRF. Multiple regression analysis was done using CH as the dependant variable and then using GAT-IOP as dependant variable. Multivariate analysis was done for those variables found to be significantly associated with CH and GAT-IOP respectively. Bland-Altman plots were constructed to assess the agreement between IOP measurements by the GAT and the ORA. Independent samples t test and Pearson correlation was done for inter-eye comparison of corneal hysteresis measurements in normal subjects.
Results were considered significant at P < .05.
Results
Data from 323 eyes of 323 subjects were analyzed. Of these, 71 were normal, 101 were glaucoma suspects with suspicious discs, 38 were OHT, 59 were PACD, 36 were POAG, and 18 were NTG eyes. There were 180 male and 143 female subjects, with mean age 51.9 ± 15.2 years and 45.7 ± 15.7 years respectively.
GAT-IOP, CCT measurements, and ORA data are shown in Table 1 . POAG and OHT patients had significantly raised IOP compared to the other groups ( P < .001). NTG patients had significantly thin corneas compared to all other groups ( P < .001), where the CCT was similar.
| Diagnosis | GAT-IOP (mm Hg) | CCT (μm) | CH (mm Hg) | CRF (mm Hg) | IOPcc (mm Hg) | IOPg (mm Hg) |
|---|---|---|---|---|---|---|
| Normal (n = 71) | ||||||
| Mean ± SD | 13.7 ± 2.4 a | 530.7 ± 33.4 | 9.5 ± 1.4 | 9.2 ± 1.5 | 15.6 ± 3.4 | 13.9 ± 3.6 |
| (95% CI) | (13.1; 14.3) | (522.8; 538.6) | (9.2; 9.8) | (8.8; 9.6) | (14.8; 16.4) | (13.1; 14.8) |
| Glaucoma suspect (n = 101) | ||||||
| Mean ± SD | 15.4 ± 3.4 | 518.7 ± 37.3 | 8.9 ± 1.7 | 9.3 ± 1.6 | 18.8 ± 9.8 | 15.9 ± 4.35 |
| (95% CI) | (14.8; 16.2) | (511.4; 526.1) | (8.6; 9.2) | (8.9; 9.6) | (16.9; 20.7) | (15.1; 16.8) |
| OHT (n = 38) | ||||||
| Mean ± SD | 22.2 ± 3.5 | 537.7 ± 46.0 | 9.2 ± 1.9 | 11.1 ± 2.6 | 23.6 ± 5.5 | 22.3 ± 5.3 |
| (95% CI) | (21.05; 23.3) | (522.6; 552.8) | (8.5; 9.8) | (10.2; 11.9) | (21.9; 25.5) | (20.6; 24.1) |
| PACD (n = 59) | ||||||
| Mean ± SD | 16.2 ± 3.9 | 525.0 ± 38.3 | 9.3 ± 1.5 | 9.9 ± 2.4 | 19.3 ± 4.7 | 17.9 ± 5.1 |
| (95% CI) | (15.1; 17.2) | (515.0; 535) | (8.9; 9.7) | (9.3; 10.5) | (18.0; 20.5) | (16.6; 19.2) |
| POAG (n = 36) | ||||||
| Mean ± SD | 23.6 ± 12.4 | 523.5 ± 35.5 | 7.9 ± 2.8 a | 11.1 ± 2.4 | 26.2 ± 15.6 | 24.3 ± 14.7 |
| (95% CI) | (19.5; 27.8) | (511.5; 535.5) | (6.9; 8.8) | (10.3; 11.9) | (20.9; 31.5) | (19.4; 29.3) |
| NTG (n = 18) | ||||||
| Mean ± SD | 14.6 ± 4.5 a | 496.4 ± 18.8 a | 8.0 ±1.6 a | 7.8 ± 1.5 a | 16.6 ±3.9 | 14.0 ±4.8 |
| (95% CI) | (12.4; 16.8) | (487.1; 505.8) | (7.2; 8.8) | (7.04; 8.5) | (14.7; 18.6) | (11.7; 16.4) |
| Overall (n = 323) | ||||||
| Mean ± SD | 16.8 ± 6.2 | 524.0 ± 37.7 | 8.9 ± 1.9 | 9.7 ± 2.2 | 19.5 ± 8.8 | 17.4 ± 7.3 |
| (95% CI) | (16.2; 17.6) | (519.9; 528.2) | (8.8; 9.1) | (9.4; 9.9) | (18.5; 20.4) | (16.6; 18.2) |
Corneal hysteresis measurements were significantly less in POAG and NTG compared to normal subjects ( P = .034 and P = .030 respectively), in whom it was maximum. There was no significant difference in CH between normal subjects and disc suspects, OHT, or PACD ( Table 1 ).
The CRF measurement was significantly less in NTG compared to all other groups, and significantly greater in POAG and OHT groups compared to the others.
There was no significant difference in corneal thickness or biomechanical properties between normal subjects, disc suspects, and PACD.
Bivariate correlations showed significant correlations between IOP, CCT, CH, and CRF, but when controlling for CH and CRF, CCT no longer correlated to the GAT-IOP (r = −0.04; P = .478). CRF correlated significantly to the CCT even after correcting for the CH (r = 0.355; P < .001).
Regression analysis with CH as the dependant variable ( Table 2 ) showed a significant association with GAT-IOP and CRF ( P < .001) but not CCT (adjusted R 2 = 0.483). According to this model, multiple regression analysis showed that the coefficient beta for GAT-IOP was −0.214 and for CRF was 0.581, indicating that for every mm Hg increase in GAT-IOP, the CH would decrease by 0.214, and for every unit increase in CRF, CH would be expected to increase by 0.581 ( Table 2 ). A regression slope calculated between CH and GAT-IOP showed the equation to be CH = 10.26 − 0.11 × IOP (R 2 = 0.130; Figure 1 ) . GAT-IOP and CRF remained strongly associated with CH on multivariate analysis also.
| Model | Factors | Unstandardized Coefficient B | Standardized Coefficient Beta | Significance |
|---|---|---|---|---|
| Multiple regression | GAT-IOP | −0.214 | −0.709 | <.001 |
| CCT | 0.002 | 0.034 | .435 | |
| CRF | 0.581 | 0.676 | <.001 | |
| Multivariate analysis a dependent variable | Mean square | F b | ||
| CH | GAT-IOP | 9.365 | 11.06 | <.001 |
| CRF | 7.121 | 8.41 | <.001 |
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