Seminars in Ophthalmology

ISSN: 0882-0538 (Print) 1744-5205 (Online) Journal homepage: http://www.tandfonline.com/loi/isio20

The Effect of Corneal Epithelium on Corneal Curvature in Patients with Keratoconus Emine Kalkan Akcay, Betul Seher Uysal, Ozge Sarac, Nagehan Ugurlu, Fatma Yulek, Nurullah Cagil & Nabi Aslan To cite this article: Emine Kalkan Akcay, Betul Seher Uysal, Ozge Sarac, Nagehan Ugurlu, Fatma Yulek, Nurullah Cagil & Nabi Aslan (2014): The Effect of Corneal Epithelium on Corneal Curvature in Patients with Keratoconus, Seminars in Ophthalmology, DOI: 10.3109/08820538.2013.874490 To link to this article: http://dx.doi.org/10.3109/08820538.2013.874490

Published online: 27 Feb 2014.

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Date: 29 October 2015, At: 09:03

Seminars in Ophthalmology, Early Online, 1–8, 2014 ! Informa Healthcare USA, Inc. ISSN: 0882-0538 print / 1744-5205 online DOI: 10.3109/08820538.2013.874490

ORIGINAL ARTICLE

The Effect of Corneal Epithelium on Corneal Curvature in Patients with Keratoconus

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Emine Kalkan Akcay, Betul Seher Uysal, Ozge Sarac, Nagehan Ugurlu, Fatma Yulek, Nurullah Cagil, and Nabi Aslan Yildirim Beyazit University, Ankara Ataturk Training and Research Hospital, Ankara, Turkey

ABSTRACT Objective: To investigate the effects of corneal epithelium on corneal curvature in patients with keratoconus. Design: This is a prospective, nonrandomized study. Participants: Fifty-nine eyes of 47 patients diagnosed as keratoconus and for whom corneal collagen crosslinking (CXL) was recruited in this study. Methods: This study is a single-center clinical trial. Pregnancy, lactation, connective tissue disease, corneal thickness below 350 mm, severe dry eyes, or scar of corneal surgery were exclusion criteria. Before and during CXL procedure after removing the corneal epithelium, maximum values of corneal apical curvature, simulated keratometry 1 (Sim-K1), simulated keratometry 2 (Sim-K2), temporal and inferior curvature values, all of which are 1.5 mm from the corneal center, were calculated. These values before and after removal of epithelium were compared statistically. Results: Mean age of patients was 23.30 ± 5.5 (12–38) years. Twenty-eight (59%) were male while 19 (41%) were female. Mean values measured before and after removing the corneal epithelium were: apical curvature; 59.19 ± 7.2 (47.06–82.40) diopter (D) and 61.70 ± 8.8 (49.19–92.66) D (p = 0.001), SimK1; 47.57 ± 4.3 (39.14–64.57) D and 48.23 ± 4.3 (41.89–66.70) D (p = 0.001), SimK2; 52.04 ± 5.3 (43.56–69.34) D and 53.34 ± 5.6 (43.73–70.89) D (p = 0.001), inferior curvature; 53,85 ± 5.2 (43.47–76.56) D and 55.05 ± 5.8 (44.56–81.93) D (p = 0.002), temporal curvature 49.49 ± 5.1 (41.50–71.03) D and 51.53 ± 5.4 (41.58–73.34) D (p = 0.001), respectively. Conclusions: In keratoconus patients during CXL treatment, after removing the corneal epithelium, more steepness is detected in the curvature of the steeper area of the cornea. When evaluating patients with keratoconus, the masking effect of corneal epithelium on values of curvature should be taken into consideration. Keywords: Cornea, crosslinking, curvature, epithelium, keratoconus

INTRODUCTION

scarring are caused by this structural defect; consequently, visual and optical quality become worse.1 Histopathologic studies show that keratoconus affects all layers of cornea.5 Displacement of collagen fibers in the cornea and transformation of the corneal matrix are the important histopathological findings seen in patients with KC.6 Furthermore, it is shown that the epithelial covering cone is thinner in corneas with keratoconus as compared to normal corneas, and in severe keratoconus this severe thinning can result in breakdown of the epithelium.1,7,8 In the literature, there are some studies demonstrating that corneal epithelium shows a different thickness profile in the presence of irregular corneal

Keratoconus (KC) is a bilateral, slowly progressive, noninflammatory corneal dystrophy characterized by progressive corneal thinning and steepening.1 It is the most common corneal ectasia, affecting about one of 2000 people in the general population.2 It is characterized by progressive noninflamatory corneal thinning, which typically occurs in the inferior-temporal cornea.2,3 The impairment of the corneal collagen structure decreases mechanical corneal stability, which causes progressive protrusion.4 Irregular astigmatism, progressive myopia, corneal thinning, and central

Received 29 October 2013; accepted 8 December 2013; published online 18 February 2014 Correspondence: Emine Kalkan Akcay, M.D., Mutlukoy Sitesi 1957.sok. No: 7, Umitkoy, Ankara, Turkey. E-mail: [email protected]

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stromal surface.8–10 A study by Vinciguerra et al. demonstrated the flattening effect of corneal epithelial thickness on corneal curvature in patients with KC.11 An evaluation of KC progression and a laser refractive corneal surgery performed before considering the effect of corneal epithelium on corneal curvature in a patient with KC can result in an incorrect assessment.10 In this study, we aimed to investigate the effects of corneal epithelium on corneal curvature in KC patients. For this purpose, we evaluated the corneal topographical findings during CXL before and after removal of the corneal epithelium.

MATERIALS AND METHODS Fifty-nine eyes of 47 patients (28 (59%) female, 19 (41%) male) with progressive KC were included in this prospective study. The patients were chosen randomly from keratoconus patients followed by the Keratoconus and Refractive Surgery Unit of the Ophthalmology Clinic in Yildirim Beyazit University, Ataturk Education and Research Hospital. Corneal thickness (CT) below 350 mm, presence of any dry eye or corneal scar, or any corneal surgery, pregnancy, lactation, or systemic connective tissue disease were exclusion criteria from the study. Informed consent was taken from all patients for the performed procedure and usage of medical data for the aim of scientific studies. The diagnosis of KC done in all patients included in the study was by ophthalmologic examination and corneal topography (Sirius 3D Rotating Scheimpflug camera topography system). In addition to corneal topography, the diagnosis of KC was confirmed by the presence of at least one of these signs: Munson sign, corneal thinning, Fleischer ring, Vogt lines, prominent corneal nerves, Rizutti sign, and scissor reflex on retinoscopy.12 Furthermore, the diagnosis of progressive KC was made based on the presence of at least one of the following for 12 months: 1.00 D or more increase in the value of steep keratometer, 1.00 D or more increase in the value of manifested cylindric refraction, at least 0.50 D increase in the manifest refraction spherical equivalent. Before CXL, central corneal thickness (CCT) and maximum values of corneal apical curvature, superior, nasal, temporal and inferior curvature values, all of which are 1.5 mm from the corneal center, were recorded. The corneal epithelium of patients was debrided in an area 8.0–8.5 mm in diameter by applying alcohol after topical anesthesia. The topographic measurement done before the procedure was repeated. Mean epithelial thicknesses of four points (superior, inferior, nasal, and temporal) were recorded from a corneal thickness difference map. For eyes with CT above 400 mm isotonic riboflavin solution, and for

those with CT below 400 mm hipotonic riboflavin solution, was dropped once in three minutes throughout 30 minutes. Three hundred sixty-two nm UVA irradiation (3.0 mW/cm2) was applied during 30 minutes. After the procedure, a soft bandage contact lens (Pure Vision, BdL, 8.6 base curvature) was applied for five days until reepithelization of cornea was completed. Topical steroid (fluorometholone acetate) drop (Flarex, Alcon Laboratories Inc) and antibiotic (floroquinolone) drop (Exocin, Allergan Inc) were prescribed to the patients postoperatively for four times a day. Steroids were used for three weeks and antibiotics were used for two weeks. Streoids were stopped slowly. Additionally, unpreserved artificial eye tear drops (Eyestil, Teka Technical Devices Industry and Trade Incomporated Company) were applied six times a day for six months. The continuous variables were evaluated as mean ± standard deviation in statistical analysis. The paired t test was used to compare continuous variables before and after removal of epithelium. The correlation between parameters was interpreted by Pearson’s correlation coefficient. The difference was considered as statistically significant when p value was below 0.05. All analysis was made using SPSS version 17 (Statistical Package for Social Sciences Inc., Chicago, IL).

RESULTS The mean age of patients recruited in this study was 23.30 ± 5.5 (12–38) years (59% female and 41% male). A significant decrease was detected in mean CCT measured before removing the corneal epithelium compared to mean central stromal thickness (CST) measured just after removing it (p = 0.001). Table 1 shows preoperatively the mean apical curvature, which significantly increased after removing the epithelium (p = 0.001) (Figures 1, 2). Similarly, the mean preoperative SimK1 (p = 0.001), SimK2 (p = 0.001), temporal curvature (p = 0.001), and inferior curvature (p = 0.002) significantly increased after removing the epithelium (Figure 3). However, the decreases in the mean superior curvature (p = 0.25) and the nasal curvature (p = 0.15) were not statistically significant (Table 1). The mean epithelial thickness of inferior and temporal points 1.5 mm away from the corneal center measured before and after removing the corneal epithelium was lower than the superior and nasal points’ thicknesses (Table 2). There was a negative moderate correlation between the preoperative apical curvature and preoperative CCT (r = 0.578, p = 0.001) (Figure 4). Additionally, a negative correlation was present between the mean post-debridement apical curvature and post-debridement CST (r = 0.508, p = 0.001) (Figure 5). Seminars in Ophthalmology

Corneal Epithelium in Keratoconus

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TABLE 1. The variation of corneal curvature measured by corneal topography*. Pre-CXL with Epithelium Measurement

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CCT, mm AC, D SimK1, D SimK2, D SC, D IC, D TC, D NC, D

Pre-CXL without Epitelium

Average

min

max

Average

Min

max

p Value

442.8 ± 43.20 59.19 ± 7.2 47.57 ± 4.3 52.04 ± 5.3 41.95 ± 4.9 53.85 ± 5.2 49.49 ± 5.1 43.59 ± 3.3

352 47.06 39.14 43.56 28.02 43.47 41.50 29.48

550 82.40 64.57 69.34 56.68 76.56 71.03 51.99

422 ± 39.87 61.70 ± 8.8 48.23 ± 4.3 53.34 ± 5.6 41.28 ± 8.0 55.05 ± 5.8 51.53 ± 5.4 43.03 ± 4.8

343 49.19 41.89 43.73 12.75 44.56 41.58 25.76

527 92.66 66.70 70.89 58.74 81.93 73.34 51.62

0.001 0.001 0.001 0.001 0.25 0.002 0.001 0.15

* = Sirius 3D Rotating Scheimpflug camera topografic system; CXL = Corneal collagen crosslinking; CCT = Central corneal thickness; AC = Apical maximum curvature; SimK1 = Simulated keratometry 1; SimK2 = Simulated keratometry 2; D = Diopters; SC = Superior Curvature; IC = Inferior Curvature; TC = Temporal Curvature; NC = Nasal Curvature.

DISCUSSION In this study, 59 eyes with keratoconus were examined. Anterior and posterior surface keratometer measurements were done with a Sirius 3D Rotating Scheimpflug camera topography system, which is found to be repeatable and reliable.19 After removal of the corneal epithelium in keratoconic eyes during CXL, an increase was detected on apical curvature, SimK1, and SimK2. There was also an increase of curvature on more perpendicular inferior and temporal points. Preoperative and post-debridement pacimetric differences of superior and nasal 1.5 mm points, which are flatter in comparison to temporal and inferior points, were lower. The corneal epithelium affects the refractive power of the cornea and hence its contribution to ocular refraction.10 This effect is produced by the difference in the refractive index between the air-eye tear film membrane and the epithelial-stromal index (1.40 versus 1.3777).13 Vogt et al. described, for the first time, the complete or partial masking effect of the corneal epithelium in patients with irregular stromal surface in 1921.14 This compensatory mechanism has been observed in patients who had irregular astigmatism, myopic and hypermetropic excimer laser surgery, and radial keratotomy. It has also been known that epithelial thickness is important in refractive and lens surgery.7,15 Irregular epithelial thickness can result in a detrimental defect or an unpredictable efficacy in refractive surgery due to the masking of stromal irregularity by the epithelium.15 Simon et al. performed keratometric measurements from 10 eyes received from a human eye bank before and after removing the corneal epithelium and demonstrated the change in corneal power and axis of astigmatism.16 The masking effect of the epithelium should also be considered in a distinction between frank keratoconus and forme fruste keratoconus.13 In the case of performing transepithelial phototherapeutic keratectomy (PTK) and CXL in !

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progressive KC patients, a little ablation was also inadvertently done from the stroma under the thin corneal cone, unlike cases of CXL with mechanical debridement of the epithelium. The epithelium on flattened stroma will be thicker, having a more flattening effect on the cornea. When evaluating the long-term efficacy of CXL, these factors should be kept in mind since the flattening effect may be caused by both CXL and increased epithelial thickness masking the real corneal curvature.17,18 In summary, the steepness of the cornea was increased after scraping off the epithelium in flatter meridians and points in corneas with KC. Additionally, the epithelial thicknesses of steeper points were thinner than those of flatter points. All these signs demonstrate the effect of the epithelium on total corneal power and the masking effect of the epithelium on the curvature of corneas with KC. As far as we know, the only study investigating the in-vivo intraoperative keratometric changes belongs to Vinciguerra et al.11 To examine intraoperative and postoperative efficacy of CXL on 28 eyes with progresive KC, they performed topographic analysis before and after epithelial scraping during CXL. They detected an increase in apical keratometry and keratometry of the steepest meridian after removing the corneal epithelium. They proposed these signs as evidence of flattening and corrective effects of the epithelium on corneal irregularity.11 In our study, 59 eyes with KC were examined topographically and, apart from the previously mentioned studies, the keratometric changes of superior, inferior, nasal, and temporal points were evaluated as well. There are many studies performing pachymetric measurements to detect epithelial features of corneas with KC. In one study, Haque et al. detected that, in patients with KC, the central epithelial thickness measured by three different intraoperative topographic methods was 4.7 mm (8.9%) thinner than the control group. There was no difference in pachymetric

FIGURE 1. Topographic images of the patient with KC before removing the corneal epithelium.

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FIGURE 2. Topographic images of the patient with KC just after removing the corneal epithelium.

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Corneal Epithelium in Keratoconus

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FIGURE 3. Differential maps before and after removal of the corneal epithelium.

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Corneal Epithelium in Keratoconus TABLE 2. Epithelial thicknesses at points 1.5 mm from the central cornea, measured by taking the difference in stromal and corneal thicknesses.

Mean Epi, mm SD

Superior

Inferior

Temporal

Nasal

33.71 13.16

27.16 13.3

23.81 13.4

32.66 12.8

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Epi = Epithelial thickness; SD = Standard deviation.

FIGURE 4. Correlation graphic of preoperative curvature (AC) and central corneal thickness (CCT).

apical

FIGURE 5. Correlation graphic of post-debridement apical curvature (AC) and central stromal thickness (CST).

measurements done in the temporal and nasal sides, which were 3.5 mm away from the corneal center.20 The mean epithelial thicknesses in our study was lower than other studies, such as Haque et al. and !

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Reinstein et al., which showed that the epithelium was thin only over the cone and thicker around the cone. This might be because of the influence on the data due to the different cone locations or it may partly be due to measurement errors, since obtaining a reliable topography after epithelial removal can be quite difficult, and there may be edema, hydration effects, etc., on the cornea. The masking effect of the epithelium is supported by statistically significant differences between preoperative and post-debridement measurements in our study, in which we took the points 1.5 mm nasal and temporal points apart from the central cornea (as in most cases including cone). In one study, Reinstein et al. revealed B scan images of keratoconic corneas, epithelial thickness, and axial curvature maps by Artemis (ArcScan, Morrison, CO), a very high-frequency digital ultrasound. They showed that the conal protrusion in the posterior surface of the cornea was more clearly visible than the one in the anterior surface and that the central epithelium was thin while the epithelium surrounding the cone was thick. The thinnest epithelial point was located in the inferotemporal zone in 74% of the cases.8 Haque et al. presented the same results by comparing keratoconic corneas with normal and rigid gas-permeable lens users pachymetrically.21 In our study, the increase detected in anterior curvature and steepness of inferior and temporal curvatures after removing the epithelium supports these studies. There are some limitations in the present study. First, the evaluated points’ epithelium thicknesses were measured with the subtraction technique, which it is not a direct measurement as with optical coherence tomography (OCT) or ultrahigh-frequency (UHF) ultrasound. Second, there can be some hydration changes in the cornea during CXL because of the instilled drugs during the procedure. Before and after epithelial removal, the corneal conditions were not equivalent. Third and last, during CXL after the removal of the epithelium, intrasession repeatibility of the measurements was not performed. Despite these limitations, we believe that this study provided information about the effects of the corneal epithelium on corneal curvature in keratoconus patients. In conclusion, in this study topographic variations were recorded intraoperatively in keratoconic eyes, showing that the corneal epithelium affects the conal curvature, masking its real value. With removing the epithelium, a significant increase was seen in the value of the steepest keratometry and apical keratometry. This can be explained by the fact that the epithelium is thinner in the steepest areas of the stroma. As a result, the epithelium behaves as a flattening factor in the cone and shows the real value of curvature to be lower than normal.

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DECLARATION OF INTEREST The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

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REFERENCES 1. Rabinowitz YS. Keratoconus. Surv Ophthalmol 1998;42: 297–319. 2. Prisant O, Legeais JM, Renard G. Superior Keratoconus. Cornea 1997;16:693–694. 3. Auffarth GU, Wang L, Vo¨lcher HE. Keratoconus evaluation using the orbscan topography system. J Cataract Refract Surg 2000;26:222–228. 4. Andreassen TT, Simonsen AH, Oxlund H. Biomechanical properties of keratoconus and normal corneas. Exp Eye Res 1980;31:435–441. 5. Yue BY, Sugar J, Schrode K. Histochemical studies of keratoconus. Curr Eye Res 1988;7:81–86. 6. Meek KM, Tuft SJ, Huang Y, et al. Changes in collagen orientation and distribution in keratoconus corneas. IOVS 2005;46:1948–1956. 7. Reinstein DZ, Archer TJ. Epithelial thickness in normal cornea: Three-dimensional display with very high frequency ultrasound. J Refract Surg 2008;24:571–581. 8. Reinstein DZ, Gobbe M, Archer TJ, et al. Epithelial, stromal, and total corneal thickness in keratoconus: Three-dimensional display with artemis very-high frequency digital ultrasound. J Refract Surg 2010;26:259–271. 9. Reinstein DZ, Archer TJ. Combined artemis very highfrequency digital ultrasound-assisted transepithelial phototherapeutic keratectomy and wave front-guided treatment following multiple corneal refractive procedures. J Cataract Refract Surg 2006;32:1870–1876. 10. Kannelopoulos AJ, Aslanides IM, Asimellis G. Correlation between epithelial thickness in normal corneas, untreated ectatic corneas, and ectatic corneas previously treated with

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CXL: Is overall epithelial thickness a very early ectasia prognostic factor? Clinical Ophthalmology 2012;6:789–800. Vinciguerra P, Albe` E, Trazza S, et al. Intraoperative and postoperative effects of corneal collagen cross-linking on progressive keratoconus. Arch Ophthalmol 2009; 127(10):1258–1265. Romero-Jimenez M, Santodomingo-Rubido J, Wolffsohn JS. Keratoconus: A review. Cont Lens Anterior Eye 2010;33: 157–166. Patel S, Marshall J, Fitzke III FW. Refractive index of the human corneal epithelium and stroma. J Refract Surg 1995; 11:100–105. Vogt A. Textbook and Atlas of Atlas of Slit Lamp Microscopy of the Living Eye. Bonn, Germany: Wayenborgh Editions, 1981. Reinstein DZ, Archer TJ, Gobbe M. Refractive and topographic errors in topography-guided ablation produced by epithelial compensation predicted by 3D Artemis VHF digital ultrasound stromal and epithelial thickness mapping. J Refract Surg 2012;28:657–663. Simon G, Ren Q, Kervick GN, Parel JM. Optics of the corneal epithelium. Refract Corneal Surg 1993;9:42–50. Kapasi M, Baath J, Mintsioulis G, et al. Phototherapeutic keratectomy versus mechanical epithelial removal followed by corneal collagen crosslinking for keratoconus. Can J Ophthalmol 2012;47:344–347. Kymionis GD, Grentzelos MA, Kounis GA, et al. Combined transepithelial phototherapeutic keratectomy and corneal collagen cross-linking for progressive keratoconus. Ophthalmology 2012;119:1777–1784. Montalban R, Alio JL, Javaloy J, Pinero D. Intrasubject repeatability in keratoconus-eye measurements obtained with a new Scheimpflug photography-based system. J Catarct Refract Surg 2013;39(2):211–218. Haque S, Simpson T, Jones L. Corneal and epithelial thickness in keratoconus: A comparison of ultrasonic pachymetry, Orbscan II, and optical coherence tomography. J Refract Surg 2006;22:486–493. Haque S, Jones L, Simpson T. Thickness mapping of the cornea and epithelium using optical coherence tomography. Optom Vis Sci 2008;85:963–976.

Seminars in Ophthalmology

The Effect of Corneal Epithelium on Corneal Curvature in Patients with Keratoconus.

To investigate the effects of corneal epithelium on corneal curvature in patients with keratoconus...
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