Corneal biomechanical metrics in thin cornea of normal, keratoconus suspect and keratoconus in Egyptian population

Background To assess and compare corneal hysteresis (CH) and corneal resistance factor (CRF) in normal thin (NT) healthy corneas with central corneal thickness (CCT) 470-500 µm with matched thickness in keratoconus (KC) and keratoconus suspect (KCS) eyes. Methods A total of 66 eyes in three groups were included prospectively: NT, KCS and KC groups based on clinical examination and topography. Corneal hysteresis (CH) and corneal resistance factor (CRF) were measured by the ocular response analyzer. CH and CRF were compared between the three groups and statistically analyzed by variances test. Results The mean CRF and respectively. Within only CRF NT and (P there was no statistically significant difference NT between each groups (P >

2 Abstract Background To assess and compare corneal hysteresis (CH) and corneal resistance factor (CRF) in normal thin (NT) healthy corneas with central corneal thickness (CCT) 470-500 µm with matched thickness in keratoconus (KC) and keratoconus suspect (KCS) eyes.

Methods
A total of 66 eyes in three groups were included prospectively: NT, KCS and KC groups based on clinical examination and topography. Corneal hysteresis (CH) and corneal resistance factor (CRF) were measured by the ocular response analyzer. CH and CRF were compared between the three groups and statistically analyzed by variances test.

Results
The three groups consisted of 32 NT, 19 KCS, and 15 KC. The mean CH measured was 8.55± 1.77, 9.03± 1.119 and 8.06 ± 0.85 mm Hg in NT, KCS and KC eyes, respectively.
The mean CRF was 8.39 ± 1.47, 8.27 ± 1.09 and 7.24 ± 1.27 mm Hg in NT, KCS and KC eyes, respectively. Within range of central corneal thickness (470 -500 µm), only mean CRF was statistically significantly different between the NT and KC (P < 0.05); there was no statistically significant difference between NT and KCS, nor the mean CH between each groups (P > 0.05).

Conclusions
CRF only can be helpful in differentiating KC from NT eyes; however, it's not valuable for detecting KCS which is the main concern for refractive surgery. No benefit from CH in differentiating between the study groups. Further investigations & work focusing on more accurate tests for identifying KCS are still needed. Background 3 Central corneal thickness (CCT) is a biometric factor, [1] with a wide range of variability in healthy eyes, the cause of which is believed to result from different amounts of collagen fibrils and interfibrillar substance in the corneal stromal matrix. [2] It is a measure of tissue mass and represent an indicator of corneal rigidity. Also, CCT changes among ethnic groups and show strong heritability among families. [3] The development of a test for reliable assessment of corneal rigidity and its response to excimer laser ablation was a vital point in the development of refractive surgery. This was a challenging issue until 2005, when the Ocular Response Analyzer (ORA) appeared in the market with its uses in ophthalmology medicine. [4] The ORA has an infrared electro-optical system that monitors corneal deformations. It delivers a precisely metered collimated air pulse to the eye. The cornea suffers an inward movement, passing a first applanation state before assuming a concave shape. The air pressure progressively declines after this first applanation and the cornea passes through a second applanation state while returning to its normal convex curvature. The test plots a waveform that contains two peaks, corresponding to the inward and outward applanation moments.
Using this bidirectional applanation measurement, the ORA is able to present the four original parameters. Corneal hysteresis (CH) is the difference between these two pressure values, which represents the corneal viscoelastic damping. The mean of these two pressures is the Goldmann-correlated IOP (IOPg). The Corneal-compensated IOP (IOPcc) is a pressure measurement that uses the CH to determine an IOP value that is less affected by corneal properties, such as CCT. Corneal Resistance Factor (CRF) is calculated using a proprietary algorithm and represent overall cornea resistance. [5][6][7] In the present study, we investigated the corneal biomechanical metrics in healthy eyes 4 (NT) with CCT 470 to 500 µm and compared them with thickness matched keratoconus Two consecutive ORA measurements were made and the best waveform score from each patient was included in the analysis of the study. The ORA is a noncontact tonometer with automated eye centration alignment. Subjects were seated on a chair and instructed to place their foreheads on the headrest of the ORA device, and were instructed about a noncontact probe that would move toward the eye and emit a gentle puff of air. They were asked to fix on a blinking red light in the machine.
Thereafter, the ORA was activated, and the air puff was emitted onto the center of the cornea. Only, the reliable ORA readings with good score were obtained & stored.
The manufacturer defined good-quality readings as both force-in and force-out applanation signal peaks on the ORA waveform being fairly symmetrical in height. The ORA displayed a graphic representation of the corneal response after each measurement ( Figure 4).
The figures (5, 6, and 7) represent the ORA signals provided from our three study groups.
The red curve is the "dynamic map" of the cornea obtained during the rapid in/out deformation. That dynamic process generated two signal peaks that defined the two applanation states. The difference between these inward and outward motion applanation pressures (P1 and P2) was called corneal hysteresis (CH).
The ORA software utilized the CH to generate two additional parameters: the corneal-6 compensated IOP (IOPcc) and the corneal resistance factor (CRF). A Goldmann-correlated IOP (IOPg) was also provided by the machine.

Statistical Analysis
Data were statistically described in terms of mean standard deviation ( SD), median and range, or frequencies and percentages when appropriate. Comparison of numerical variables between the study groups was done using independent samples t test. For comparing categorical data, Chi square (2) test was performed. Fisher's exact test was used instead when the expected frequency is less than 5. Comparison of the continuous variables was done by One-way ANOVA with Bonferroni correction for post-hoc analysis.
The predictive ability of the ORA parameters was analyzed using Receiver operating

Results
A total of 66 eyes were enrolled in our study, of which 32 eyes showed normal thin corneas, 15 eyes with keratoconus suspect, and 19 eyes with frank keratoconus.
The age of our study groups ranged from 18 to 35 years, with an average of 29.59 ± 3.02 years for Group (NT) and 26.86± 5.42 for Group (KCS) and 30.26 ± 3.85 for Group (KC).
( Table 1) Our study included forty eyes of male patients and twenty six eyes of female patients. The gender distribution is summarized in Table 2.
The central corneal thickness ranged from 470 to 500 µm, with an average of 492.90 ± 7 8.07 µm for group (NT) and 488.53 ± 9.47 µm for group (KCS) and 486.10 ± 9.41 µm for group (KC). The difference between the three groups was statistically insignificant (pvalue = 0.057). (Table 3) The mean CH of the study groups was 8

Discussion
Forme fruste keratoconus (FFKC) and keratoconus suspect (KCS) diagnosis remain a dilemma, despite the advances in using topographic and tomographic tools; there is no specific accepted consensus for categorizing an eye as KCS [8]. . Many cases of post refractive corneal ectasia still reported,that is why searching for a supplementary investigation to detect FFKC and KCS is needed. For decision making to perform corneal ablation procedure in these cases, the surgeon should depend on analysis of multiple investigations & parameters. [9][10][11][12][13] Ocular response analyzer (ORA) represents a relatively new perspective for in vivo measurement of corneal biomechanics; since its development by Luce [5] many studies have evaluated the ORA parameters (CH and CRF) for detecting keratoconus (KC) and keratoconus suspect (KCS) and normal thin (NT) eyes. [14][15][16][17][18] Other reports have determined that CH and CRF are significantly lower in KC eyes than in NT eyes and reported CH and CRF as poor properties for discriminating mild KC from NT eyes. [6,[19][20] In spite of the various studies performed to evaluate the ORA accuracy for detecting KC and KCS from NT eyes, the diagnostic performance of the CH and CRF remains of limited 8 value and the role of CCT as a confounding factor is not yet clearly defined. [6,[14][15][16][17][18] The current study tried to reveal the diagnostic value of ORA as an auxiliary test to differentiate thin corneas with different topographic diagnoses (KC, KCS and NT). Our results showed that only the mean CRF was significantly lower in KC eyes compared to NT ones, but no significant difference was seen in CCT, CH and CRF parameters of KCS eyes compared with NT eyes.
Various studies have assessed the CH and CRF between NT and KC eyes. Fontes et al 6 found significantly lower CH and CRF in KC in comparison to NT eyes. However we found that only the CRF was significantly lower in KC than NT eyes, with no significance to CH.
Our study shows comparable results to Galletti JG et al [20] which prove that corneal resistance factor was better than CH for detecting keratoconic corneas once the effect of CCT on ORA measurements was considered, even for topographically unaffected fellow The present study also demonstrated that the mean CH, CRF and CCT in KCS did not differ from NT eyes. Using the principle Orbscan criterion to identify KCS that was a difference of 1.5 diopters or greater between superior and inferior corneal curvature, did not find any significant difference between groups. Saad et al used a computer-based calculation from Nidek OPD scan videokeratographer, found a significant difference between NT and KCS first, which failed to remain significant after controlling for CCT. [21] A possible hypothesis for this finding might be the mysterious role of corneal thickness on corneal biomechanics. CH and CRF are known to be highly correlated to corneal thickness. 9 [6,[22][23] As corneal thickness decreases significantly in keratoconic eyes [24] and usually is within NT limits in KCS and NT eyes, any changes in CH and CRF could be related to the changes in CCT. After controlling for the CCT in our study, only CRF differences between NT and KC remained significant. The CCT between NT and KCS were not significantly different, therefore, could not play a confounding role.
However, our results are not in agreement with a number of previous studies. Schweitzer et al [16] used the NT fellow eye of a manifest keratoconic with KISA index of <60% for defining KCS. They found a significant difference between NT and KCS eyes which remained significant after controlling for CCT in the thinner groups. Johnson et al [14] used the keratoconus severity score (KSS) score developed by the collaborative longitudinal evaluation of KC study group to define and grade the severity of KCS also found a significant difference between KCS and NT eyes after adjustment for CCT, age and sex.
The KCS grading of severity performed in this study has made the comparison of their result with other studies directly impossible. This discrepancy between the studies may be caused by the various definitions of KCS used in different studies; therefore the use of a unified grading scale for defining KCS in future studies is highly useful for comparing the results.
As the receiver operating characteristic (ROC) curve analysis between KC and NT eyes showed, selecting the cutoff points for CH (8.4) and CRF (7.6) provided that 84.2% sensitivity and 46.8% specificity for CH, and 78.95% sensitivity and 68.09% specificity for CRF. Because there was no significant difference between KCS and NT eyes in CH and CRF, the ROC curve analysis was only done for NT and KC group and the KCS were not included in the present study. The ROC curve analysis performed in the Fontes et al study [7] showed a poor overall predictive value of CH (74.83%) and CRF (76.97%) with the cutoff points of 9.64 mmHg and 9.60 mmHg respectively.