Yakov Goldich, MD, Yaniv Barkana, MD, Yariv Gerber, PhD, Adi Rasko, MD, Yair Morad, MD,Yakov Goldich, MD, Yaniv Barkana, MD, Yariv Gerber, PhD, Adi Rasko, MD, Yair Morad, MD, Morris Harstein, MD, Isaac Avni, MD, David Zadok, MD
To compare parameters of biomechanical response of the human cornea measured as corneal hysteresis (CH) and corneal resistance factor (CRF) in patients with diabetes mellitus and healthy control subjects.
SETTING: Department of Ophthalmology, Assaf Harofeh Medical Center, Zerifin, Israel.
METHODS: In the right eye of each participant, the CH, CRF, Goldmann-correlated intraocular pres-sure (IOPg), and corneal-compensated intraocular pressure (IOPcc) were measured with the Ocular Response Analyzer. Central corneal thickness (CCT) was measured by ultrasonic pachymetry and intraocular pressure by Goldmann applanation tonometry (IOP GAT). Findings were compared be-tween the 2 groups (control and diabetic).
RESULTS: Forty diabetic patients (17 women, 23 men) and 40 healthy subjects (19 women, 21 men) were prospectively recruited. The mean CH was 9.3 mm Hg G 1.4 (SD) and 10.7 G 1.6 mm Hg and the mean CRF was 9.6 G 1.6 mm Hg and 10.9 G 1.7 mm Hg in the control group and diabetic group, respectively (both P < .0001). Diabetic corneas were significantly thicker (P Z .019); the mean CCT was 530.3 G 35.9 mm in the control group and 548.7 G 33.0 mm in the diabetic group. The CH and CRF remained significantly different in multivariate analysis that included CCT. There was no statistically significant difference between the 2 groups in IOPcc, IOPg, or IOP GAT measurements.
CONCLUSIONS: Diabetes mellitus affected biomechanical parameters of the human corneas, including increased CH, CRF, and CCT. Whether this observation has implications in the clinical management and understanding of corneal ectasia and glaucoma requires further study.
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The effect of diabetes mellitus on the human cornea may have clinical significance.1 Corneal changes induced by chronic abnormal glucose metabolism have been reported in the epithelial, stromal, and
Submitted: October 22, 2008.
Final revision submitted: December 1, 2008.
Accepted: December 2, 2008.
From the Department of Ophthalmology (Goldich, Barkana, Rasko, Morad, Harstein, Avni, Zadok), Assaf Harofeh Medical Center, Zer-ifin, and the Department of Epidemiology and Preventive Medicine (Gerber), School of Public Health, Sackler Medical School, Tel Aviv University, Tel Aviv, Israel.
No author has a financial or proprietary interest in any material or method mentioned.
Corresponding author: Yakov Goldich, MD, Department of Ophthal-mology, Assaf Harofeh Medical Center, Beer Yaakov, Zerifin 70300, Israel. E-mail: email@example.com.
Q 2009 ASCRS and ESCRS Published by Elsevier Inc.
endothelial layers.2–6 Stromal changes include struc-tural alterations produced by collagen crosslinking.7 In vitro studies show that collagen crosslinking causes increased stiffness of the cornea,8,9 which in turn may affect the measurement of intraocular pressure (IOP), causing overestimation of the true IOP.10 This may also explain the observation that diabetic corneas are less susceptible to development and progression of keratoconus.11,12
Recently, the Ocular Response Analyzer (ORA, Reichert Inc.) became commercially available for in vivo measurements of the corneal biomechanical parameters of corneal hysteresis (CH) and corneal re-sistance factor (CRF) and for the noncontact assess-ment of IOP, described as Goldmann-correlated IOP (IOPg) and corneal-compensated IOP (IOPcc). The reproducibility13 and a detailed description14 of this in-strument have been published. Briefly, the instrument measures corneal response to indentation by a rapid air.
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CORNEAL BIOMECHANICAL PARAMETERS IN DIABETES
pulse using an electrooptical system. The air puff in-dents the cornea, passing a defined point of applana-tion and into a slight concavity. After reaching the pressure peak, the pressure of the air pulse decreases and the cornea returns to its normal configuration, again passing the defined point of applanation. An electrooptical system monitors the entire process and calculates the above parameters. Corneal hysteresis represents the absolute difference between the 2 pres-sure values causing force-in (P1) and force-out (P2) ap-planations and provides a measure of viscous damping of the cornea. The CRF is derived from the formula (P1 kP2), where k is a constant. The constant k was de-termined from an empirical analysis of the relationship between both P1 and P2 and the central corneal thick-ness (CCT) to develop a parameter more strongly asso-ciated with CCT than CH (Luce D. IOVS 2006; 47:ARVO E-Abstract 2266). The IOPg is the average of the 2 IOP measurements at the applanation points. The IOPcc is a pressure measurement that uses the in-formation provided by CH to provide an IOP that is less affected by CCT or corneal curvature.14,15
The aim of this study was to compare the parame-ters of biomechanical response of corneas of diabetic patients and healthy controls and to test our study hy-pothesis that the diabetic cornea is stiffer than the healthy one.
PATIENTS AND METHODS
Diabetic patients and healthy subjects (control group) from the ophthalmology outpatient clinic of the Assaf Harofeh Medical Center were prospectively enrolled. For this study, a patient was defined as diabetic if he or she had a refer-ring-physician diagnosis of diabetes and was taking antidia-betic medication. Patients and subjects with any type of known corneal disease, glaucoma, contact lenses, or chronic use of topical ocular medications were excluded, as were those who had any type of eye surgery.
This study was approved by the Institutional Ethics Committee of Assaf Harofeh Medical Center, and written informed consent was obtained from each participant after the nature and intent of the study had been fully explained. The study protocol was consistent with the tenets of the Dec-laration of Helsinki. All participants had assessment with the ORA that included measurement of noncontact IOP, CH, and CRF. The same examiner performed all assessments. Briefly, each patient was seated and asked to fixate on a tar-get light and the measurement was taken. A noncontact probe scanned the central corneal area and released an air puff. Measured IOP, CH, and CRF values were displayed on the monitor of the computer. For each patient, 3 readings of good quality were obtained; good-quality images were de-fined as having a waveform with 2 distinct, nearly symmet-rical peaks. Irreproducible out-of-scale measurements were excluded from the analysis. The mean values of each param-eter were used for statistical evaluation.13
After the noncontact part of study assessments was fin-ished, topical anesthesia of oxybuprocaine hydrochloride 0.4% drops (Localin) was administered. The CCT was
measured by the ORA-attached handheld ultrasonic pachy-meter. The probe was gently placed in a perpendicular orientation on the central corneal. The results of the CCT reading were displayed on the computer. Finally, applana-tion tonometry was performed once with the Goldmann applanation tonometer (IOP GAT). One examiner, who was masked to the previously recorded ORA data, performed all measurements.
Data are presented as frequency or mean G standard de-viation. Independent-samples t tests were used to assess dif-ferences between the compared groups in CH, CRF, CCT, IOPcc, IOPg, and IOP GAT. Linear regression was used to evaluate the differences in CH and CRF after accounting for age, sex, IOP GAT, and CCT. A 2-tailed P value of 0.05 was selected for the threshold of statistical significance. Be-cause 6 measurements were compared between cases and controls, to avoid multiple-comparison problems, a Bonfer-roni correction was performed and an a level of 0.0085 was applied for each test. Analyses were performed using SPSS for Windows (version 14, SPSS, Inc.).
Forty diabetic patients and 40 healthy subjects were in-cluded in the study (Table 1). There were no statisti-cally significant differences between the 2 groups in age or sex distribution (PO.23). Only the right eye was examined.
Table 2 shows CH, CRF, IOPcc, IOPg, GAT IOP, and CCT measurements in the diabetic group and control group. Corneal hysteresis, CRF, and CCT were statis-tically significantly greater in the diabetic group. Fig-ures 1 to 3 show the distribution of these parameters in the 2 groups. A multivariate analysis that included sex, age, GAT IOP, and CCT, which was performed to examine whether the differences in corneal biome-chanical parameters reflected the effect of confound-ing factors, showed that CH remained statistically significantly different between the 2 groups (P!.001). The IOPg, IOPcc, and IOP GAT values were not statistically significantly different between the diabetic group and control group (Table 2 and Figure 4).
Table 1. Clinical characteristics.
Group Characteristic Diabetic Control Eyes (n) 40 40 Mean age (y) G SD 60.9 G 12.4 63.8 G 9.0Sex, n (%) Male 17 (42.5) 19 (47.5) Female 23 (57.5) 21 (52.5).
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Table 2. Study parameters and their statistical distribution.
Mean G SD Parameter Diabetic Group Control Group P Value*
CH (mm Hg) 10.7 G 1.6 9.3 G 1.4 .0001CRF (mm Hg) 10.9 G 1.7 9.6 G 1.6 !.0001IOPcc (mm Hg) 16.6 G 4.4 17.7 G 4.9 .31IOPg (mm Hg) 16.6 G 4.3 16.1 G 4.9 .66IOP GAT (mm Hg) 15.0 G 3.2 14.2 G 3.4 .25CCT (mm) 548.7 G 33.0 530.3 G 35.9 .019
CCT Z central corneal thickness; CH Z corneal hysteresis; CRF Z corneal resistance factor; IOPcc Z corneal-compensated intraocular pressure; IOPg Z Goldmann-correlated intraocular pressure; IOP GAT
Z Goldmann applanation tonometer intraocular pressure *t test
(mmHg) 16.00 14.00 15.00 Factor 12.00 13.00 Resistance 11.00 10.00 9.00 Corneal 8.00 6.00 7.00
Figure 2. Box-and-whisker plots (smallest, median, and largest values with interquartile range) showing CRF in the control group and diabetic group.
The results in our study show that the CCT, CH, and CRF in diabetic eyes were significantly higher than in nondiabetic eyes. Corneal structural integrity and stiffness may be described using anatomical and biomechanical parameters. Anatomical properties customarily include CCT and biomechanical parame-ters may be presented through the CH and CRF pa-rameters measured by the ORA. The relationship between these factors and their relative contribution to corneal elasticity and stiffness are not clearly understood.16,17
Diabetes mellitus has a significant effect on morpho-logic, metabolic, physiologic, and clinical aspects of the human cornea.1 A previous study18 using ultra-sound pachymetry found that the CCT was increased in diabetic eyes. Hyperglycemia was shown to influ-ence corneal biomechanical properties by inducing stromal collagen crosslinking through glycosylation and lysyl oxidase enzymatic activity.19 Both increased thickness of nonedematous cornea and crosslinking of
14.00 (mmHg) 13.00 12.00 11.00 Hysteresis 8.00 10.00 9.00
Figure 1. Box-and-whisker plots (smallest, median, and largest values with interquartile range) showing CH in the control group and diabetic group.
collagen fibers may eventually result in increased cor-neal stiffness.9 Keratoconus is characterized by thin-ning and increased distensibility of the corneal stroma that consists predominantly of collagen fi-bers.20 Any further change in the arrangement of these fibers may influence stromal, and thus corneal, stiff-ness. It was recently shown that keratoconus progres-sion may be slower in diabetic eyes, probably due to
biomechanical corneal changes.11,12 Previous studies of keratoconic eyes21–23 found that low CH, CRF,
and CCT values were well correlated with the ectatic corneas. The increased CH, CRF, and CCT values in the diabetic patients in our study may implicate increased corneal stiffness and explain this diabetic protective phenomenon.
One possible weakness of our study was the lack of specific consideration of the severity and duration of diabetes, as can be assessed by the presence of diabetic neuropathy, retinopathy, nephropathy, and measure-ments of glycolated hemoglobin. Considering the marked heterogeneity of diabetes, the measured
(µm) 650 600 Thickness 550 Corneal 500 Central 450 400 Control Diabetic
Figure 3. Box-and-whisker plots (smallest, median, and largest values with interquartile range) showing CCT in the control group and diabetic group.
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(mmHg) 35 30 Pressure 25 Intraocular 20 15 10 5 control diabetic IOPg control diabetic control diabetic IOPcc GAT IOPcc IOPg IOP IOP GAT
Figure 4. Box-and-whisker plots (smallest, median, and largest values with interquartile range) showing IOPcc, IOPg, and IOP GAT in the control group and diabetic group.
differences between the 2 groups may have been dis-proportionately influenced by the most severely af-fected patients in the study group. Some correlation between duration and severity of diabetes and corneal morphological abnormalities has been shown,4,6 and further evaluation of such a correlation with corneal viscoelastic changes may be appropriate.
Recently, more advanced analysis of the raw ORA data in addition to the CH and CRF parameters in bio-mechanical evaluation has been suggested. This analy-sis is performed using graphically presented waves, including comparison of signal peak amplitudes and shape,24 width of infrared peaks at their mid-height point, and the slope of the air pulse during the 2 appla-nation events (Glass DH, et al. IOVS 2008; 49:ARVO E-Abstract 646). Once the accuracy and reliability of these analytic tools are established, they can potentially be used for further evaluation of the influence of diabetes.
Corneal viscoelasticity may define corneal response to applanation forces during ocular tonometry. Bro-man et al.25 showed that corneal thickness and CH
can influence IOP measurements. Several popula-tion-based studies26–29 found consistently higher IOP
measurements in diabetic patients than in nondiabetic individuals. In our study, diabetic patients tended to have higher IOP GAT values than control subjects, al-though the difference was not statistically significant. This may reflect the small size of the study popula-tions: Assuming a standard deviation of 3.0 mm Hg for IOP GAT; a sample size of about 800 subjects would be required to detect a difference of 0.6 mm Hg between the compared groups29 given a significance level of 5% and a statistical power of 80%. In our study, the ORA noncontact IOP measurements were also not statistically significantly different between the 2 study groups.
It has been suggested that regardless of IOP, a thin-ner cornea is a risk factor for development of open-angle glaucoma30 and for increased severity of glaucomatous damage at initial presentation.31 Cong-don et al.32 showed that low CH by itself was associ-ated with increased glaucomatous injury. Plausibly, both higher CCT and higher CH may be associated with some protection against glaucoma. The results of the Ocular Hypertension Treatment Study (OHTS)33 suggest there may be some protective effect of diabetes on the progression to open-angle glau-coma. Although this finding has been much debated, the results in our study may support it. Increased cor-neal stiffness, in addition to and independent of in-creased thickness, may cause overestimation of IOP when measured by GAT.34 This overestimation may explain the apparent protective role of diabetes on pro-gression to open-angle glaucoma reported in the OHTS. An additional theoretical hypothesis involves biomechanical changes that occur in the lamina cribro-sa in diabetic patients. The same processes that lead to increased corneal stiffness in diabetes may happen in other eye structures containing collagen fibers. Burgoyne et al.,35 in their recent review, showed that increased compliance (ie, decreased stiffness) of the lamina cribrosa might be associated with increased glaucomatous damage. Lesk et al.36 report an associa-tion between corneal thickness and lamina cribrosa stiffness, with less stiffness in eyes with thinner corneas, thus allowing greater lamina cribrosa displacement and increased axonal injury after IOP fluctuations. Increased corneal stiffness may be associated with increased stiff-ness of lamina cribrosa and thus provide protection against glaucomatous injury.
In summary, our study showed that persons with diabetes mellitus had increased CCT, CH, and CRF, possibly reflecting greater stiffness of diabetic corneas. Whether this observation has implications in the clin-ical management and understanding of corneal ectasia and glaucoma requires further investigation.
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Yakov Goldich, MD
Department of Ophthalmology, Assaf
Harofeh Medical Center, Zerifin, Israel
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