Contact Lens & Anterior Eye

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1 Contact Lens & Anterior Eye 37 (2014) Contents lists available at ScienceDirect Contact Lens & Anterior Eye journal homepage: Efficacy of corneal tomography parameters and biomechanical characteristic in keratoconus detection Seyed Mahdi Ahmadi Hosseini a,b,,1, Fereshteh Abolbashari a,b,1, Hamed Niyazmand a,b, Mohammad Reza Sedaghat a,b a Refractive Errors Research Center, School of Paramedical Sciences, Mashhad University of Medical Sciences, Mashhad, Iran b Department of Ophthalmology, Mashhad Medical University, Mashhad, Iran article info abstract Article history: Received 4 March 2013 Received in revised form 11 June 2013 Accepted 4 July 2013 Keywords: Keratoconus Corneal thickness Corneal volume Corneal hysteresis Corneal resistance factor Aim: To determine the efficacy of corneal thickness parameters and corneal biomechanical properties (CBPs) in discriminating between normal and keratoconus eyes. Method: After performing a comprehensive ophthalmic examination, 50 mild to moderate keratoconus and 50 age and sex matched myopic astigmatism eyes were prospectively included in the study. The corneal topographic maps and CBP were obtained by Pentacam and Ocular response analyser, respectively. Central corneal thickness (CCT), thinnest corneal thickness (TCT), corneal thickness (CT) and percentage thickness increase (PTI) at 1, 3 and 5 mm from the thinnest point and corneal volume (CV) at 3, 5, 7 and 10 centred on thinnest point, corneal hysteresis (CH) and corneal resistance factor (CRF) were recorded. Independent t-test and receiver operating characteristic (ROC) were done with SPSS software (version 15.0, SPSS, Inc.). Results: CCT, TCT, CT at 1, 3 and 5, CV at 3, 5, 7 and 10 mm, CH and CRF were significantly lower in keratoconus eyes compared to controls (p < 0.001). In addition, PTI at 1, 3 and 5 mm from the thinnest point showed significantly higher values in keratoconus group. ROC analysis demonstrated good predictive accuracy for cut-off point values. However, the centrally located indices had higher predictive accuracy compared to the peripherally located indices. Conclusion: Although good sensitivity and specificity were found for the mentioned parameters, the centrally located indices had higher predictive accuracy compared to peripherally located indices. It is suggested to use a combination of corneal pachymetry together with CBP for more accurate detection of keratoconus British Contact Lens Association. Published by Elsevier Ltd. All rights reserved. 1. Introduction Keratoconus is a bilateral [1,2] and asymmetric [3] corneal degeneration characterized by central and para-central stromal thinning and subsequent conical ectasia. This progressive disorder is the most common corneal dystrophy with the incidence of 5 23 per 10,000 in the general population [3,4]. Keratoconus affects the vision by generating irregular astigmatism and corneal scarring. It has been proposed that the thinning of the cornea during the disease progression is related to the keratocytes apoptosis around the cone [5]. Corresponding author at: Refractive Errors Research Center, School of Paramedical Sciences, Mashhad University of Medical Sciences, Mashhad, Iran. Tel.: address: Mahdi.ahmadihosseini@yahoo.com (S.M. Ahmadi Hosseini). 1 These two authors contributed equally to the work presented here and should therefore be regarded as equivalent authors. Sometimes patients with keratoconus or other forms of ectasia, such as pellucid marginal degeneration, have poor outcomes after laser in situ keratomileusis (LASIK) and photorefractive keratectomy (PRK) [6]. Previous studies reported that 1 6% of myopic patients who have vision-correction surgery have keratoconus or are suspected of having keratoconus or other forms of corneal ectasia. The high prevalence of corneal ectasia among these candidates indicates the vital role of pre-surgical screening [7,8]. Cornea is a viscoelastic tissue and corneal hysteresis (CH) together with corneal resistance factor (CRF) are indications of corneal viscoelastic characteristics [9,10]. Hysteresis is defined as the response of a viscoelastic tissue such as cornea to the imposed stress, that is measured in millimetres of mercury (mmhg). Being knowledgeable about corneal biomechanical properties (CBPs) could be beneficial in detection of some corneal pathologies such as keratoconus, Fuch s dystrophy, keratoglobous, determination of intraocular pressure (IOP) and also prior to refractive surgeries [11,12]. Ocular response analyser (ORA) is a fairly recent advance in ophthalmic technology that could help clinicians /$ see front matter 2013 British Contact Lens Association. Published by Elsevier Ltd. All rights reserved.

2 S.M. Ahmadi Hosseini et al. / Contact Lens & Anterior Eye 37 (2014) Fig. 1. Corneal thickness (left) and total corneal refractive power (right) of a subject with normal eye. in vivo assessment of the corneal tissue elasticity. This instrument works by applying the jet air puff to the centre of the cornea. With an electro-optical system, the corresponding deformation of the cornea is detected. Then the difference between 2 pressures is recorded and considered as the CH. The CH is the result of the energy being absorbed or dissipated in the corneal tissue. Furthermore, the CRF is calculated using a linear combination of inward and outward applanation pressures. It is believed that the CBP is the measure of the corneal stromal characteristics [13]. The aim of this study was to evaluate the efficacy of corneal tomography parameters and CBP in discrimination between normal and keratoconic eyes. 2. Materials and methods This was a prospective comparative case series study. Subjects were selected from the patients referred to Toos ophthalmology clinic, Mashhad, Iran. All of the study procedures were conducted in accordance with the Declaration of Helsinki in 1975 and approved by the Human ethics committee of Mashhad University of Medical Sciences Subjects Keratoconus subjects were diagnosed based on biomicroscopy, keratometry, retinoscopy and topography examinations in accordance with the criteria established by the Collaborative Longitudinal Evaluation of Keratoconus (CLEK) Study [14]. In this group, subjects with any ocular pathology, corneal scar, history of surgery, dry eye and contact lens wear within the last 2 months (soft or hard) were excluded from the study. In the next step, keratoconus subjects with mild to moderate keratoconus were selected according to their mean keratometry reading (K-reading) driven from the Pentacam topographic maps (47 D < K-reading < 52 D) [15,3]. Control subjects were chosen from the candidates of refractive surgeries (PRK) with myopic astigmatism. The control group had refractive errors of myopia 4D and astigmatism 1.5D. The exclusion criteria for this group were any signs of keratoconus in slit lamp biomicroscopy, retinoscopy and topography examinations (inferior-superior localized steepening or asymmetric bow-tie pattern), history of ocular surgeries, trauma, dry eye, contact lens wear within the last 2 months or any other ocular pathology Measurements For the Pentacam measurement, the instrument was set to take 25 images per scan using the automatic release mode. Subjects were asked to sit on a chair and placed their foreheads on the headrest of the device. Then they were told to focus on the black ring at the centre of the blue LED light. An expert operator used the joy stick to align and focus the image. Once the image was stable, the instrument automatically recorded the image. Only one measurement was performed for each eye; however, if the quality specification was not white OK, the examination was repeated. The high reproducibility and repeatability of this machine has been documented previously in the measurement of anterior segment parameters [16]. The following parameters were extracted from the topographic and pachymetric maps for further analysis: central corneal thickness (CCT), thinnest corneal thickness (TCT), peripheral corneal thickness (PCT) at 1, 3 and 5 mm from the thinnest point, percentage thickness increase (PTI) at 1, 3 and 5 mm from the thinnest point and corneal volume (CV) at 3, 5, 7 and 10 mm 3 centred on the thinnest point. Figs. 1 and 2 illustrate the corneal thickness and total corneal power maps of a control subject and a subject with keratoconus, respectively. CH and CRF were measured with ORA (Reichert Ophthalmic Instruments, Depew, New York, USA). For the ORA measurement, subjects sat on a chair and placed their foreheads on the headrest of the ORA device that was made to match their height by adjusting the height of the table. To avoid startling the subjects, they were first briefed about the procedures. Then subjects were told to focus on a blinking red light on the device and the measurement was automatically done. Three consecutive ORA measurements were done for each eye and results were averaged. The quality of ORA measurement was defined as the waveform score (WS) that was graded between 0 and 10. In this experiment the measurements with the WS 5 or higher were accepted, otherwise the examination was repeated Statistical analysis Since the progression of the keratoconus is not symmetric between the 2 eyes of each subject, both eyes of the keratoconus subjects were included in this study if they met the inclusion criteria. On the other hand, only one eye of the control subjects were randomly selected for the analysis. Statistical analysis was performed with SPSS software (version 18.0, SPSS, Inc.). According to the Shapiro Wilk test, data for all the

3 28 S.M. Ahmadi Hosseini et al. / Contact Lens & Anterior Eye 37 (2014) Fig. 2. Corneal thickness (left) and total corneal refractive power (right) of a subject with keratoconus eye. parameters were normally distributed. Independent Student t-test was used to compare the mentioned parameter between control and keratoconus eyes. Then the Receiver operating characteristic (ROC) was performed to estimate the area under the curve, cut-off values, sensitivity and specificity for the significant parameters. A Bonferroni correction was used to control type I error. A p < 0.05 was considered statistically significant. 3. Results 3.1. Subjects This study evaluated 50 eyes of 50 control subjects (31 males, 19 females) with the mean ± standard deviation (SD) age of 25.2 ± 2.5 years. Keratoconus group comprised 50 eyes of 42 patients (26 males, 16 females) with the mean ± SD age of ± 3.3 years. There were 21 right eyes (42%) and 29 left eyes (58%). Two studied groups were age and sex matched (Chi-square, p > 0.05) Comparison between normal and keratoconus groups The mean CCT was ± 33 m and ± 30 m in control group and keratoconus group, respectively. The mean TCT was ± 79 m in control eyes and ± 28 m in keratoconus eyes. The CCT (t-test, p = 0.000) and TCT (t-test, p = 0.000) were significantly higher in the control group than in the keratoconus group. There was a gradual increase in CT from the thinnest point of the cornea to the periphery. Corneal thickness at 1, 3 and 5 mm were significantly lower in the keratoconus group compared to the control group (t-test, p < 0.05). The mean ± SD values for CCT, TCT, and PCT at 1, 3 and 5 mm from the thinnest point in 2 groups are summarized in Table 1. The mean PTI in keratoconus eyes was significantly Table 2 Mean ± standard of percentage thickness increase from the thinnest point. PTI 1 (%) 1.4 ± ± PTI 3 (%) 15.5 ± ± PTI 5 (%) 20.4 ± ± PTI 1, percentage thickness increase at 1 mm; PTI 3, percentage thickness increase at 3 mm; PTI 5, percentage thickness increase at 5 mm. higher compared to control eyes at all eccentricities (t-test, p < 0.05) (Table 2). The mean total CV (CV at 10 mm 3 centred on the thinnest point) was 58.3 ± 3.2 mm 3 in the keratoconus and 61.2 ± 3.2 mm 3 in the control group (t-test, p = 0.000). CV distribution at all eccentricities was significantly lower in the keratoconus eyes compared to the controls (t-test, p < 0.001). Table 3 indicates the mean ± SD and the significant level of the independent student t-test for CV distribution between 2 studied groups. CH (t-test, p = 0.008) and CRF (t-test, p = 0.003) were significantly lower in the keratoconus eyes compared to the controls. The mean CH was 10.0 ± 1.8 mmhg in the control and 8.46 ± 1.6 mmhg in the keratoconus group. The mean CRF was 10.4 ± 1.9 mmhg and 7.63 ± 1.5 mmhg in the control and the keratoconus group, respectively. On the whole, our findings showed significantly lower values of CT, CV, CH and CRF and significantly higher PTI in the keratoconus eyes compared to the control eyes Receiver operating characteristics The area under the curve was statistically significant for all of the measured parameters (p < 0.001). ROC curve analysis indicated good predictive accuracy for all of the cut-off point values. Table 4 Table 1 Mean ± standard of corneal thickness. CCT ( m) ± ± TCT ( m) ± ± CT1( m) ± ± CT3( m) ± ± CT5( m) ± ± CCT, central corneal thickness; CT 1, corneal thickness at 1 mm; CT 3, corneal thickness at 3 mm; CT 5, corneal thickness at 5 mm; TCT, thinnest corneal thickness. Table 3 Mean ± standard of corneal volume distribution. CV3(mm 3 ) 3.9 ± ± CV5(mm 3 ) 11.5 ± ± CV7(mm 3 ) 24.9 ± ± CV 10 (mm 3 ) 61.2 ± ± CV 3, corneal volume at central 3 mm; CV 5, corneal volume at central 5 mm; CV 7, corneal volume at central 7 mm; CV 10, corneal volume at central 10 mm.

4 S.M. Ahmadi Hosseini et al. / Contact Lens & Anterior Eye 37 (2014) Table 4 Receiver operating characteristic curve analysis for the keratoconus versus normal. Parameters AUC Cutoff Value Sensitivity (%) Specificity (%) CCT ( m) TCT( m) CT1( m) CT3( m) CT5( m) PTI 1 (%) PTI 3 (%) PTI 5 (%) CV3(mm 3 ) CV5(mm 3 ) CV7(mm 3 ) CV 10 (mm 3 ) CH (mmhg) CRF (mmhg) AUC, area under curve; SE, standard error. * p <.05, statistically significant. demonstrates the cut-off point values in addition to the sensitivity and specificity for each parameter. 4. Discussion Keratoconus typically starts at puberty and progresses until the third or fourth decade of the life [17]. Previous investigations have suggested various reasons such as increasing in keratocytes apoptosis around the cone area, fragmentation of the corneal basal epithelial membrane, degenerative changes of the basal epithelial cells and disintegrated Bowman s layer [5,18,19] for the changes in the corneal tissue of the keratoconus patients. The ectasia progression after refractive surgeries in patients with keratoconus or other forms of corneal ectasia has been reported in previous studies [6]. Therefore, detection of early stages of the keratoconus is crucial for screening of the refractive surgeries candidates. The present study evaluated the efficacy of corneal tomography parameters and CBP in detection of mild-moderate keratoconus. This study showed that corneal pachymetry parameters measured by the Pentacam could be used in differentiating between mildmoderate keratoconus and PRK candidates. Based on the ROC curve analysis, the overall predictive accuracy of the centrally located indices (CCT, TCT, CT 1, PTI 1 and CV 3) were higher compared to the peripherally located indices for keratoconus detection. The vital role of corneal thickness parameters in keratoconus detection is evident. Nowadays, the measurement of corneal thickness parameters is widely applied in preoperative examinations of refractive surgeries candidates [20 22]. Our findings about corneal thickness agree with those of preceding studies [21]. Ucakhan et al. evaluated the efficacy of the corneal thickness parameters measured with the Pentacam for better discrimination between mild-moderate keratoconus and myopic subjects [21]. In the present study, the mean values of CCT in both control and keratoconus groups are in line with the results of Ucakhan et al. study [21]. The mean CCT and TCT were m and m in their control and m and m in their keratoconus group. Similar to the current study, the ROC curve analysis in their study showed overall good predictive accuracy of CCT and TCT (AUC 0.832, 0.896, respectively) [21]. Ambrosio et al. evaluated the corneal tomography parameters in mild-moderate keratoconus using the Pentacam [22]. The authors reported significant lower corneal thickness and volume with 0.4 mm steps in the keratoconus eyes compared to the controls. However, they did not present the cut-off point values for their studied parameters. The mean CV at 3, 5 and 7 mm 3 were 3.3, 1.1 and 22.4 mm 3, respectively. These values were lower in comparison with the result of the present study. The difference between 2 studies could be confined to the higher severity of the keratoconus eyes in their study population. In a recent study, Abolbashari et al. evaluated the corneal thickness and total corneal volume of the keratoconus eyes in a sample of Asian population using the Pentacam [23]. They found progressively lower corneal volume with progression of the disease [23]. As discussed, we found significant differences for corneal volume distribution between the studied groups. ROC curve analysis showed good predictive accuracy for corneal volume. It should be mentioned that when the diameter of the volume circle became larger, the predictive accuracy got lower. For instance, the predictive accuracy of CV at 3 mm 3 (sensitivity: 83.4%, specificity: 80.6%) was higher compared to CV at 7 mm 3 (sensitivity: 68.9%, specificity: 67.1%). Hence, it seems that Pentacam Scheimpflug system provides valuable and accurate information about the corneal thickness parameters in keratoconus eyes that could be beneficial in monitoring and management of this disorder. Human cornea is known to have a viscoelastic nature and external forces might alter the shape of the corneal surface. There are 2 main measurable parameters that present the viscoelastic characteristics of the corneal tissue. The first one introduces the proportionality between the magnitude of the tissue deformation and the applied force known as the static resistance. The second parameter describes the dependence on time of the relationship between corneal tissue deformation and applied force known as the viscous resistance. The ORA is a machine that provides reproducible data on viscoelastic characteristics of the cornea [24]. In 2010, Piñero et al. [25] assessed the corneal biomechanical properties in the keratoconus eyes. In their study, the mean CH and CRF were 8.1 ± 1.4 mmhg and 7.1 ± 1.6 mmhg, respectively, that were lower values compared to the findings of the present study (CH = 8.46 ± 1.6 mmhg, CRF = 7.63 ± 1.5 mmhg). Higher values of these parameters in the current study could be due to inclusion of the severe keratoconus patients in the aforementioned study. Previous studies demonstrated significant role of anterior 120 m of the corneal stroma in determination of the corneal biomechanical characteristics and corneal stability [26]. Biomechanical instability of the cornea in keratoconic corneas has been reported to be due to alteration of the regular orthogonal arrangement of the stromal fibrils [27]. It is believed that the mostly affected corneal layer in the keratoconus eyes is the stroma [5]. So any changes in corneal layers especially stroma, that is supposed to be approximately 90% of the total corneal thickness, could affect the corneal elasticity and CBP. In another study, Fontes et al. evaluated the efficacy of the corneal biomechanics in discrimination between normal and keratoconus corneas [28]. their mean CH and CRF were 8.23 mmhg and mmhg, respectively that are in agreement with the findings of the current study [28]. Overall, it seems that the predictive accuracy of the CH and CRF is not good enough for keratoconus detection. It is suggested to use a combination of corneal pachymetry parameters and corneal biomechanics for better and more accurate detection of the keratoconus patients. In conclusion, this study showed that corneal parameters in the mild-moderate keratoconus eyes significantly different from the control eyes. The keratoconus eyes had lower CT and CV distribution compared to the controls. Although good sensitivity and specificity was found for the mentioned parameters, the centrally located indices had higher predictive accuracy compared to the peripherally located indices. It is suggested to use a combination of corneal pachymetry parameters and corneal biomechanics for better and more accurate detection of keratoconus patients. It could be concluded that corneal parameters obtained from the Pentacam and ORA might be helpful in discrimination of the keratoconus from the normal corneas.

5 30 S.M. Ahmadi Hosseini et al. / Contact Lens & Anterior Eye 37 (2014) Funding The authors did not receive any financial support from any public or private sources. Conflict of interest The authors have no financial or proprietary interest in a product, method, or material described here. References [1] Zadnik K, Barr JT, Gordon MO, Edrington TB. Biomicroscopic signs and disease severity in keratoconus. Collaborative Longitudinal Evaluation of Keratoconus (CLEK) Study Group. Cornea 1996;15(2):139. [2] Kennedy R, Bourne W, Dyer J. A 48-year clinical and epidemiologic study of keratoconus. American Journal of Ophthalmology 1986;101(3): 267. [3] Chopra I, Jain AK. Between eye asymmetry in keratoconus in an Indian population. Clinical and Experimental Optometry 2005;88(3): [4] Rabinowitz YS. Keratoconus. Survey of Ophthalmology 1998;42(4): [5] Meek KM, Tuft SJ, Huang Y, et al. Changes in collagen orientation and distribution in keratoconus corneas. 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