Journal of Refractive Surgery

Original Article Supplemental Data

Effect of Corneal Cross-linking on Epithelial Hyperplasia and Myopia Regression After Transepithelial Photorefractive Keratectomy

David Sung Yong Kang, MD; Sun Woong Kim, MD, PhD

Abstract

PURPOSE:

To investigate the effect of accelerated corneal cross-linking (CXL) on epithelial thickness change and refractive outcome after myopic transepithelial photorefractive keratectomy (TPRK).

METHODS:

This study compared epithelial thickness changes in 49 patients undergoing TPRK-CXL with 49 patients undergoing TPRK who were matched for age and refractive error. Corneal epithelial thickness, obtained using spectral-domain optical coherence tomography preoperatively and 12 months postoperatively, was compared between the groups. Regression analysis was performed to investigate the association between changes in epithelial thickness and keratometric power. Factors affecting myopic regression (> 0.50 diopters] were evaluated using logistic regression analysis.

RESULTS:

For TPRK, the mean epithelial thickness of the center (2-mm diameter), paracenter (2- to 5-mm diameter), and pericenter (5- to 6-mm diameter) increased by 6.5 ± 3.1, 7.0 ± 2.9, and 4.9 ± 2.9 µm, respectively; increases of 4.8 ± 3.0, 5.9 ± 2.8, and 4.8 ± 2.7 µm were observed following TPRK-CXL, indicating a significant difference in the center (P = .013). Epithelial thickness increased linearly to the magnitude of myopic correction and was negatively correlated with the optical zone diameter of ablation. Change in epithelial thickness showed a linear correlation with the change in keratometric power between 1 and 12 months postoperatively, indicating regression in eyes following TPRK. Corneal epithelial thickening was significantly associated with myopic regression and simultaneous CXL tended to reduce the risk of regression.

CONCLUSIONS:

TPRK-CXL induces less epithelial hyperplasia than does TPRK, presumably owing to the effect of CXL, and the magnitude of epithelial thickening seemed to be associated with myopic regression.

[J Refract Surg. 2019;35(6):354–361.]

Abstract

PURPOSE:

To investigate the effect of accelerated corneal cross-linking (CXL) on epithelial thickness change and refractive outcome after myopic transepithelial photorefractive keratectomy (TPRK).

METHODS:

This study compared epithelial thickness changes in 49 patients undergoing TPRK-CXL with 49 patients undergoing TPRK who were matched for age and refractive error. Corneal epithelial thickness, obtained using spectral-domain optical coherence tomography preoperatively and 12 months postoperatively, was compared between the groups. Regression analysis was performed to investigate the association between changes in epithelial thickness and keratometric power. Factors affecting myopic regression (> 0.50 diopters] were evaluated using logistic regression analysis.

RESULTS:

For TPRK, the mean epithelial thickness of the center (2-mm diameter), paracenter (2- to 5-mm diameter), and pericenter (5- to 6-mm diameter) increased by 6.5 ± 3.1, 7.0 ± 2.9, and 4.9 ± 2.9 µm, respectively; increases of 4.8 ± 3.0, 5.9 ± 2.8, and 4.8 ± 2.7 µm were observed following TPRK-CXL, indicating a significant difference in the center (P = .013). Epithelial thickness increased linearly to the magnitude of myopic correction and was negatively correlated with the optical zone diameter of ablation. Change in epithelial thickness showed a linear correlation with the change in keratometric power between 1 and 12 months postoperatively, indicating regression in eyes following TPRK. Corneal epithelial thickening was significantly associated with myopic regression and simultaneous CXL tended to reduce the risk of regression.

CONCLUSIONS:

TPRK-CXL induces less epithelial hyperplasia than does TPRK, presumably owing to the effect of CXL, and the magnitude of epithelial thickening seemed to be associated with myopic regression.

[J Refract Surg. 2019;35(6):354–361.]

The corneal epithelium, which is highly reactive to irregularities and changes in the underlying stromal shape, is widely recognized to undergo remodeling in response to laser refractive surgery. Previous studies have reported substantial increases in the corneal epithelium following both laser-assisted in situ keratomileusis (LASIK) and photorefractive keratectomy (PRK), and refractive regression has been associated with postoperative epithelial hyperplasia following laser refractive surgery.1–4

Corneal cross-linking (CXL) was initially developed to prevent the progression of keratoconus and was applied for corneal ectasia.5 Recently, LASIK-Xtra has been introduced as a concurrent procedure of CXL with LASIK, and CXL has been hypothesized to be helpful in preventing ectasia and regression.6,7 Kanellopoulos and Asimellis8 showed that LASIK-Xtra induces less epithelial thickening than does LASIK, particularly in high myopic correction. Transepithelial PRK-CXL (TPRK-CXL) has also been introduced based on a concept similar to that of LASIK-Xtra, and its safety and effectiveness have been reported as comparable to those of TPRK.9 A recent report suggested a potential role of CXL in the biomechanical properties of the cornea using a dynamic Scheimpflug analyzer, but epithelial remodeling has not been observed.10 CXL also induces major epithelial remodeling11,12 and epithelial remodeling in TPRK-CXL must therefore be affected by both TPRK and CXL.

We aimed to investigate the effect of accelerated CXL on epithelial remodeling by comparing changes in epithelial thickness between TPRK and TPRK-CXL to further determine its effect on myopic regression.

Patients and Methods

Patients

This retrospective cohort comparison study included 98 eyes that had undergone uneventful TPRK (49 eyes of 49 patients) or TPRK-CXL (49 eyes of 49 patients) at Eyereum Eye Clinic (Seoul, South Korea) between June and September 2016. All surgeries were performed by the same experienced surgeon (DSYK). A complete ophthalmic examination was performed to screen for corneal abnormalities and determine patient eligibility for refractive surgery. The inclusion criteria were as follows: age 19 to 36 years, stable myopia for at least 1 year, and a corrected distance visual acuity (CDVA) of 20/25 or better. Refractive error and astigmatism were limited to make two matched groups: spherical equivalent (SE) refraction of −2.20 to −8.70 diopters (D) and refractive astigmatism of less than 4.00 D. The exclusion criteria were as follows: the use of hard contact lenses, a central corneal thickness (CCT) of less than 480 µm, a calculated postoperative residual stromal bed of less than 350 µm, and the presence of other ocular pathologic conditions such as corneal dystrophy, keratoconus, corneal opacity, or a history of previous ocular surgery. All patients were followed up for 1 year postoperatively, and the manifest refraction and keratometric values measured with Pentacam tomography (OCULUS Optikgeräte, Wetzlar, Germany) were collected at 1 month and 1 year postoperatively to estimate corneal power change. Myopic regression was estimated based on the change in SE and K values from 1 to 12 months postoperatively. The study protocol was approved by the institutional review board and was conducted according to the tenets of the Declaration of Helsinki.

Surgical Procedure

The Amaris 1050RS excimer laser system (SCHWIND eye-tech-solutions, Kleinostheim, Germany) was used to perform stromal ablation. The ablation profile was planned using the integrated Optimized Refractive Keratectomy-Custom Ablation Manager software (version 5.1; SCHWIND eye-tech-solutions). Mitomycin C 0.02% was applied to all corneas for 20 seconds, followed by thorough rinsing with a chilled balanced salt solution. For TPRK-CXL, CXL methods are summarized in Table 1. Briefly, patients were exposed to riboflavin 0.1% with hydroxypropyl methylcellulose (Vibex Rapid) placed on the corneal surface for 90 seconds, followed by thorough irrigation with 30 mL of a chilled balanced salt solution. An ultraviolet-A beam (365-nm wavelength) 9 mm in diameter was applied to the cornea in a uniform circular pattern using the KXL system (Avedro, Inc., Waltham, MA). The ultraviolet-A irradiation was performed for 90 seconds with the continuous irradiation protocol at a power of 30 mW/cm2 (total dose: 2.7 J/cm2). Mitomycin C 0.02% was then applied to all corneas for 20 seconds after cessation of ultraviolet-A irradiation and the same postoperative management was applied with TPRK. Postoperatively, one drop of topical levofloxacin 0.5% (Cravit; Santen, Osaka, Japan) was instilled at the surgical site and a bandage contact lens (Acuvue Oasys; Johnson & Johnson Vision Care, Inc., Jacksonville, FL) was placed on the cornea; the bandage contact lens was removed 4 days later after complete healing of the corneal epithelium. After surgery, topical levofloxacin 0.5% and fluorometholone 0.1% (Santen) were applied four times per day for 1 month. The dosage was tapered over 3 months.

CXL Methods

Table 1:

CXL Methods

Measurement of Corneal Epithelial and Stromal Thickness

The corneal epithelial and total thickness data were obtained preoperatively and 12 months postoperatively by using the RTVue Fourier-domain optical coherence tomography (OCT) system (Optovue, Inc., Fremont, CA) with a corneal adaptor module set at a wavelength of 830 nm. The cornea was scanned in 8 meridians using a “Pachymetry + Cpwr” scan (software version A6.11.0.12) over a 6-mm diameter centered at the corneal vertex. The epithelial thickness map was generated using an automatic algorithm and was divided into a total of 17 sectors: a central 2-mm diameter zone, 8 paracentral zones within an annulus between the 2- and 5-mm diameter rings, and 8 pericentral zones within an annulus between the 5- and 6-mm diameter rings. The mean values in the 17 areas were calculated, as were the mean values in the 8 paracentral zones and 8 pericentral zones. The same investigator conducted all OCT imaging; two consecutive acquisitions were obtained and the average value was used for analysis. The thickness value for the left eye was superimposed onto the right eye values. Change in corneal epithelial thickness was obtained by subtracting the preoperative measurements from the postoperative measurements obtained at 12 months.

Statistical Analysis

Statistical analyses were performed using the Statistical Package for the Social Sciences for Windows (version 18.0; IBM Corporation, New York, NY). Only one randomly selected eye from each patient was included in the analysis to avoid bias of the relationship between bilateral eyes that could have influenced the results. A sample size calculation was conducted prior to the study to detect a 2-µm difference between groups with approximately 3 µm standard deviation. To have a type I error of 0.05 and a statistical power of 0.80, we needed 37 patients in each group. We included an additional 12 patients per group to make two groups matched for age, sex, and refractive errors. In each group, corneal epithelial thickness and other continuous clinical variables were compared using paired t tests. The difference between the two groups was compared using Student's t tests. Simple linear regression analyses were performed to investigate the influence of preoperative SE, ablation depth, preoperative epithelial thickness, and optical zone diameter for ablation on changes in epithelial thickness following surgery. A partial correlation test was conducted to evaluate the association between optical zone diameter and change in epithelial thickness after controlling for SE correction power. Multivariate logistic regression was performed to investigate the factors associated with myopic regression (> 0.50 D in keratometric change from 1 to 12 months). Statistical significance was defined as a P value of less than .05.

Results

Refractive Outcomes

The study included 98 eyes of 38 male and 60 female patients undergoing TPRK or TPRK-CXL for myopia correction with 49 eyes of 49 patients in each group. The mean age, sex ratio, preoperative SE refractive power, preoperative keratometry optical zone diameter, ablation depth, preoperative CCT, and epithelial thickness did not differ significantly between the two groups (Table 2). All eyes had a postoperative CDVA of better than 20/20, with 44 (90%) eyes after TPRK and 45 (92%) eyes after TPRK-CXL within ±0.50 D of the intended correction at 1 month. The mean postoperative refractive errors at 1 and 12 months were 0.21 ± 0.31 and 0.07 ± 0.22 D after TPRK and 0.01 ± 0.30 and 0.16 ± 0.24 D after TPRK-CXL, respectively. Comparison of changes in keratometric power showed 0.47 D of steepening (regression) in the TPRK group, whereas 0.19 D of flattening was observed in the TPRK-CXL group (Table 3).

Demographic Characteristicsa

Table 2:

Demographic Characteristics

Refractive Resultsa

Table 3:

Refractive Results

Epithelial Thickness Changes

Preoperative epithelial thickness in the 17 segments was similar in the two groups. At 12 months postoperatively, epithelium showed a statistically significant thickening in all 17 areas, with the temporal paracentral zone showing the greatest thickening in both groups (Figure 1). For TPRK, the mean epithelial thickness of the center (2 mm in diameter), paracenter (2 to 5 mm), and pericenter (5 to 6 mm) increased by 6.5 ± 3.1, 7.0 ± 2.9, and 4.9 ± 2.9 µm, respectively, and increases of 4.8 ± 3.0, 5.9 ± 2.8, and 4.8 ± 2.7 µm were observed following TPRK-CXL. The TPRK group exhibited greater thickening in the center (P < .013) than did the TPRK-CXL group and the same trend was observed in the paracenter (P = .063).

Changes in corneal epithelial thickness following transepithelial photorefractive keratectomy (TPRK) or TPRK with corneal cross-linking (TPRK-CXL). (A) TPRK induced epithelial thickening over a 6-mm diameter area, with the most thickening occurring in the temporal paracentral area (2- to 5-mm zone). (B) Concurrent CXL induced less thickening in the central (P = .013) and paracentral (overall P = .063, *< .05) sectors.

Figure 1.

Changes in corneal epithelial thickness following transepithelial photorefractive keratectomy (TPRK) or TPRK with corneal cross-linking (TPRK-CXL). (A) TPRK induced epithelial thickening over a 6-mm diameter area, with the most thickening occurring in the temporal paracentral area (2- to 5-mm zone). (B) Concurrent CXL induced less thickening in the central (P = .013) and paracentral (overall P = .063, *< .05) sectors.

Correlation Analysis

The changes in epithelial thickness showed a statistically significant linear association with the magnitude of preoperative refractive error and ablation depth in both groups. A negative linear correlation was also observed with preoperative epithelial thickness in the TPRK group and optic zone diameter in the TPRK-CXL group. Preoperative epithelial thickness in the TPRK-CXL group and optic zone diameter in the TPRK group showed a similar trend, although the association was not always significant (Table 4). To determine the association between optical zone diameter and epithelial thickness change after controlling for correcting refractive power, a partial correlation test was conducted, and a significant association was noted between optical zone diameter and epithelial thickness change in the TPRK-CXL group after excluding the effect of correction power (r = −0.303, P = .036). Interestingly, a significant linear correlation was observed between the change in epithelial thickness and keratometric values in the TPRK group, whereas no significant correlation was found in the TPRK-CXL group (Figure 2). Binary logistic regression analysis showed that the change in central epithelial thickness, postoperative central epithelial thickness, and CXL were significantly associated with myopic regression with odds ratios of 1.29 (P = .002), 1.23 (P = .005), and 0.106 (P = .004), respectively. Finally, the change in central epithelial thickness remained a significant risk factor associated with myopic regression with an odds ratio of 1.39 after controlling for confounding variables such as age, refractive errors, and optical zone diameter (model 1, Table A, available in the online version of this article). Interestingly, TPRK-CXL reduced the risk of myopic regression, with an odds ratio of 0.114 after controlling for the aforementioned variables (model 2, Table A).

Simple Linear Correlation Between Change in Corneal Epithelial Thickness and Various Factors

Table 4:

Simple Linear Correlation Between Change in Corneal Epithelial Thickness and Various Factors

Association between change in epithelial thickness and keratometry (K) following transepithelial photorefractive keratectomy (TPRK) or TPRK with corneal cross-linking (TPRK-CXL). (A) In the TPRK group, change in epithelial thickness showed a linear association with the observed change in keratometry from 1 month to 1 year, (B) whereas a linear association was not observed with the change in K in the TPRK-CXL group.

Figure 2.

Association between change in epithelial thickness and keratometry (K) following transepithelial photorefractive keratectomy (TPRK) or TPRK with corneal cross-linking (TPRK-CXL). (A) In the TPRK group, change in epithelial thickness showed a linear association with the observed change in keratometry from 1 month to 1 year, (B) whereas a linear association was not observed with the change in K in the TPRK-CXL group.

Factors Affecting Myopic Regression After TPRKa

Table A:

Factors Affecting Myopic Regression After TPRK

Discussion

Previous studies have reported a substantial increase in epithelial thickness following both PRK and LASIK, and epithelial hyperplasia has been associated with myopic regression following myopic laser ablation.1–3 Kanellopolous and Asimellis13 described epithelial remodeling following LASIK as a negative meniscus-like lenticular pattern, with greater thickening in the paracenter than in the center, showing results similar to those of the current study. Tang et al.14 reported that maximum epithelial thickening was noted at an annular area 3 to 4 mm in diameter and tapered off toward the periphery. Epithelial remodeling after PRK has also been reported and the overall patterns were similar.15,16 Hou et al.16 reported central epithelial thinning at 1 month and gradual thickening over 6 months with a negative meniscus-like lenticular pattern after TPRK. The current study revealed less thickening in the pericenter (5 to 6-mm annular ring) than in the paracentral area (2 to 5-mm annular ring), which is also consistent with previous findings.14,17 We suggest that variations in laser ablation profiles induce differences in the epithelial remodeling pattern. A previous report of epithelial remodeling after femtosecond laser–assisted LASIK using the same laser system demonstrated a similar pattern.17 Our results reconfirm previous findings of a linear relationship between epithelial thickening and the degree of myopic correction.14–17 Our results also suggested that larger optical zone diameter led to less epithelial thickening, which seemed to be related to previous findings that a larger optical zone induced fewer aberrations and also disturbed the corneal curvature gradient less.18 However, this association may be secondary to a lower amount of ablation and not necessarily the effect of optical zone diameter because the larger optical zone tended to be used more often for lower corrections. We therefore conducted a partial correlation test to evaluate the association between optical zone diameter and epithelial thickness change after controlling for SE correcting power. Interestingly, a significant association was noted between optical zone diameter and epithelial thickness change in the TPRK-CXL group after excluding the effect of correction power (r = −0.303, P = .036). Furthermore, epithelial changes showed better correlation (higher R2 and lower P value) with degree of myopic correction after TPRK-CXL than after TPRK alone, suggesting that CXL reduced variability in the epithelial response to TPRK.

Understanding the effect of concurrent CXL on TPRK is not simple. A combined effect of CXL and TPRK is exerted on the overall epithelial remodeling pattern. We investigated the effect of CXL on epithelial remodeling and regression by comparing two matched surgical groups differing only in the application of CXL. Although epithelial hyperplasia has been addressed as one of the causative factors leading to myopic regression, a direct relationship between change in epithelial thickness and refractive change has not been well documented. Our results demonstrated a significant linear relationship between the magnitude of epithelial thickening and change in keratometric values in the TPRK group. The absence of this linear association in the TPRK-CXL group may be evidence of a counteracting CXL effect on epithelial thickening. Our data therefore suggested that CXL suppressed corneal reshaping toward steepening (myopic regression) at the 1-year follow-up after TPRK. Furthermore, CXL showed a slight but significant flattening effect from 1 month to 1 year (Table 3). A corneal flattening effect after accelerated CXL has never been addressed, and this needs to be further validated. Corneal steepening at 1 month and gradual flattening thereafter are not uncommon findings after CXL in keratoconus,19,20 and similar patterns of corneal reshaping might be possible in accelerated CXL in laser ablation of the cornea for myopic correction. The epithelial remodeling pattern of CXL itself has never been investigated for patients without keratoconus and is difficult to predict. Epithelial remodeling after standard CXL in keratoconus has been reported, and epithelial decrease has been noted with a greater smoothing effect.11,12 The combined effect of CXL and LASIK has been reported to induce less epithelial thickening compared with LASIK alone.8 Based on the available evidence, we presumed that accelerated CXL played a role in suppressing epithelial hyperplasia after myopic laser ablative surgery and reduced variability in the epithelial response. Stromal stiffening may be related to the reduced driving force of epithelial hyperplasia.

Previous studies have demonstrated good repeatability for the RTVue anterior segment OCT system for the measurement of epithelial and corneal thickness after LASIK and small incision lenticule extraction surgery, as well as normal eyes (within-subject standard deviation (Sw): 0.7 to 0.9).17,21,22 We assessed the intra-user repeatability in 30 eyes that had undergone TPRK at 1, 3, 6, and 12 months postoperatively by calculating Sw, the coefficient of variation, and the intraclass correlation coefficient for the three consecutive measurements, and found good repeatability for epithelial thickness measurements at 12 months postoperatively (Sw: 0.76 at 12 months and 0.70 at preoperative measurements; Table B, available in the online version of this article). Notably, epithelial thickness measurement becomes challenging after TPRK at early postoperative times. After 6 months, the repeatability did not differ from the preoperative measurement. Hence, we considered epithelial thickness measurement at 1 year to define the magnitude of epithelial hyperplasia. For refractive data analysis, we compared postoperative refractive results at 1 month and 1 year to estimate myopic regression. It would be ideal if we also had analyzed change in epithelial thickness for the same time scale, but we analyzed epithelial thickness change from baseline to postoperative 1-year measurement due to the aforementioned poor repeatability issue at 1 month. Taking previous findings showing that epithelial thickness recovered to the pre-operative level at 3 weeks,23 our approximation may be acceptable.

Repeatability of Corneal Epithelial Thickness Measurement Using RTVue Before and After TPRK

Table B:

Repeatability of Corneal Epithelial Thickness Measurement Using RTVue Before and After TPRK

We have reported a relatively small but statistically significant difference (1.76 µm in the center) in epithelial thickening following TPRK or TPRK-CXL. Post-hoc actual statistical power calculation from 49 patients in each group given real mean difference and standard deviation revealed 0.78 with type I error 0.05. The small magnitude of difference, which is less than resolution of the current OCT device, may underestimate the clinical significance of our finding. However, Ge et al.24 demonstrated that the axial resolution of different OCT devices did not affect the measurement results of corneal epithelial thickness, although higher resolution could yield better image quality that allowed for higher precision. We hope future technologies with higher resolution will evaluate corneal epithelial thickness more accurately and confirm our finding.

Epithelial hyperplasia has been suggested as being responsible for perceived myopic regression after refractive surgery, but we did not observe a substantial magnitude of regression in the current study. This could be a limitation of addressing the effect of CXL on the suppression of regression. Studies using long-term follow-up of patients with a greater degree of myopia and a consequent increased possibility of regression may be warranted to confirm this effect.

This study demonstrated that the increase in epithelial thickness was proportional to the amount of myopia correction and ablation depth after TPRK and that concurrent CXL reduced postoperative epithelial thickening. Reduced epithelial hyperplasia in TPRKCXL seems to be associated with a decreased tendency toward myopic regression because of the inclusion of CXL.

References

  1. Ivarsen A, Fledelius W, Hjortdal JO. Three-year changes in epithelial and stromal thickness after PRK or LASIK for high myopia. Invest Ophthalmol Vis Sci. 2009;50:2061–2066. doi:10.1167/iovs.08-2853 [CrossRef]
  2. Patel SV, Erie JC, McLaren JW, Bourne WM. Confocal microscopy changes in epithelial and stromal thickness up to 7 years after LASIK and photorefractive keratectomy for myopia. J Refract Surg. 2007;23:385–392. doi:10.3928/1081-597X-20070401-11 [CrossRef]
  3. Spadea L, Fasciani R, Necozione S, Balestrazzi E. Role of the corneal epithelium in refractive changes following laser in situ keratomileusis for high myopia. J Refract Surg. 2000;16:133–139.
  4. Reinstein DZ, Ameline B, Puech M, Montefiore G, Laroche L. VHF digital ultrasound three-dimensional scanning in the diagnosis of myopic regression after corneal refractive surgery. J Refract Surg. 2005;21:480–484.
  5. Wollensak G. Crosslinking treatment of progressive keratoconus: new hope. Curr Opin Ophthalmol. 2006;17:356–360. doi:10.1097/01.icu.0000233954.86723.25 [CrossRef]
  6. Rajpal RK, Wisecarver CB, Williams D, et al. Lasik Xtra((R)) provides corneal stability and improved outcomes [published online ahead of print October 26, 2018]. Ophthalmol Ther.
  7. Kanellopoulos AJ, Asimellis G, Karabatsas C. Comparison of prophylactic higher fluence corneal cross-linking to control, in myopic LASIK, one year results. Clin Ophthalmol. 2014;8:2373–2381. doi:10.2147/OPTH.S68372 [CrossRef]
  8. Kanellopoulos AJ, Asimellis G. Epithelial remodeling after femtosecond laser-assisted high myopic LASIK: comparison of stand-alone with LASIK combined with prophylactic high-fluence cross-linking. Cornea. 2014;33:463–469. doi:10.1097/ICO.0000000000000087 [CrossRef]
  9. Lee H, Yong Kang DS, Ha BJ, et al. Comparison of outcomes between combined transepithelial photorefractive keratectomy with and without accelerated corneal collagen cross-linking: a 1-year study. Cornea. 2017;36:1213–1220.
  10. Lee H, Roberts CJ, Ambrosio R Jr, Elsheikh A, Kang DSY, Kim TI. Effect of accelerated corneal crosslinking combined with transepithelial photorefractive keratectomy on dynamic corneal response parameters and biomechanically corrected intraocular pressure measured with a dynamic Scheimpflug analyzer in healthy myopic patients. J Cataract Refract Surg. 2017;43:937–945. doi:10.1016/j.jcrs.2017.04.036 [CrossRef]
  11. Rocha KM, Perez-Straziota CE, Stulting RD, Randleman JB. Epithelial and stromal remodeling after corneal collagen cross-linking evaluated by spectral-domain OCT. J Refract Surg. 2014;30:122–127. doi:10.3928/1081597X-20140120-08 [CrossRef]
  12. Haberman ID, Lang PZ, Broncano AF, Kim SW, Hafezi F, Randleman JB. Epithelial remodeling after corneal crosslinking using higher fluence and accelerated treatment time. J Cataract Refract Surg. 2018;44:306–312. doi:10.1016/j.jcrs.2017.12.021 [CrossRef]
  13. Kanellopoulos AJ, Asimellis G. Longitudinal postoperative lasik epithelial thickness profile changes in correlation with degree of myopia correction. J Refract Surg. 2014;30:166–171.
  14. Tang M, Li Y, Huang D. Corneal epithelial remodeling after LASIK measured by Fourier-domain optical coherence tomography. J Ophthalmol. 2015;2015:860313. doi:10.1155/2015/860313 [CrossRef]
  15. Chen X, Stojanovic A, Liu Y, Chen Y, Zhou Y, Utheim TP. Postoperative changes in corneal epithelial and stromal thickness profiles after photorefractive keratectomy in treatment of myopia. J Refract Surg. 2015;31:446–453. doi:10.3928/1081597X-20150623-02 [CrossRef]
  16. Hou J, Wang Y, Lei Y, Zheng X, Zhang Y. Corneal epithelial remodeling and its effect on corneal asphericity after transepithelial photorefractive keratectomy for myopia. J Ophthalmol. 2016;2016:8582362. doi:10.1155/2016/8582362 [CrossRef]
  17. Ryu IH, Kim BJ, Lee JH, Kim SW. Comparison of corneal epithelial remodeling after femtosecond laser-assisted LASIK and small incision lenticule extraction (SMILE). J Refract Surg. 2017;33:250–256. doi:10.3928/1081597X-20170111-01 [CrossRef]
  18. Mok KH, Lee VW. Effect of optical zone ablation diameter on LASIK-induced higher order optical aberrations. J Refract Surg. 2005;21:141–143.
  19. Hersh PS, Greenstein SA, Fry KL. Corneal collagen crosslinking for keratoconus and corneal ectasia: one-year results. J Cataract Refract Surg. 2011;37:149–160. doi:10.1016/j.jcrs.2010.07.030 [CrossRef]
  20. Chang CY, Hersh PS. Corneal collagen cross-linking: a review of 1-year outcomes. Eye Contact Lens. 2014;40:345–352. doi:10.1097/ICL.0000000000000094 [CrossRef]
  21. Kanellopoulos AJ, Asimellis G. In vivo three-dimensional corneal epithelium imaging in normal eyes by anterior-segment optical coherence tomography: a clinical reference study. Cornea. 2013;32:1493–1498. doi:10.1097/ICO.0b013e3182a15cee [CrossRef]
  22. Ma XJ, Wang L, Koch DD. Repeatability of corneal epithelial thickness measurements using Fourier-domain optical coherence tomography in normal and post-LASIK eyes. Cornea. 2013;32:1544–1548. doi:10.1097/ICO.0b013e3182a7f39d [CrossRef]
  23. Kaluzny BJ, Szkulmowski M, Bukowska DM, Wojtkowski M. Spectral OCT with speckle contrast reduction for evaluation of the healing process after PRK and transepithelial PRK. Biomed Opt Express. 2014;5:1089–1098. doi:10.1364/BOE.5.001089 [CrossRef]
  24. Ge L, Yuan Y, Shen M, Tao A, Wang J, Lu F. The role of axial resolution of optical coherence tomography on the measurement of corneal and epithelial thicknesses. Invest Ophthalmol Vis Sci. 2013;54:746–755. doi:10.1167/iovs.11-9308 [CrossRef]

CXL Methods

ParameterVariable
Treatment targetProphylaxis
Fluence (total) (J/cm2)2.7
Soak time (minutes)1.5
Intensity (mW)30
Treatment time (minutes)1.5
Epithelium statusRemoved during TPRK
ChromophoreRiboflavin
Chromophore carrierHydroxypropyl methylcellulose
Chromophore osmolarityIso-osmolar
Chromophore concentration0.1%
Light sourceKXL system (Avedro)
Irradiation mode (interval)Continuous
Protocol modificationsCombined with TPRK
Protocol abbreviation in manuscriptTPRK-CXL (30*1.5)

Demographic Characteristicsa

CharacteristicTPRK (n = 49)TPRK-CXL (n = 49)P
Male:female (No.)19:3019:301.000
Age (y)24.54 ± 3.57 (20 to 35)25.80 ± 4.54 (19 to 35).126
Mean SE (D)−5.47 ± 1.36 (−2.25 to −7.44)−5.45 ± 1.64 (−2.19 to −8.69).946
Optical zone (mm)6.62 ± 0.24 (6.0 to 7.3)6.60 ± 0.28 (6.0 to 7.4).742
Planned ablation depth (µm)101.47 ± 17.52 (49.1 to 134.7)101.83 ± 21.12 (58.9 to 136.5).928
Preoperative CCT (µm)552.9 ± 24.73 (503 to 607)545.6 ± 28.38 (490 to 619).176
Preoperative central epithelial thickness (µm)52.9 ± 3.3 (46 to 61)52.6 ± 2.8 (46 to 60).557
Preoperative K (D)43.40 ± 1.30 (41.50 to 45.80)43.70 ± 1.30 (41.00 to 46.70).355

Refractive Resultsa

ParameterTPRK (n = 49)TPRK-CXL (n = 49)P
1 month SE (D)0.21 ± 0.310.01 ± 0.30.001
1 month K (D)37.7 ± 1.5038.5 ± 1.62.028
1 year SE (D)0.07 ± 0.220.16 ± 0.24.046
1 year K (D)38.2 ± 1.5338.3 ± 1.64.835
Change in SE (1 m to 1 y) (D)−0.15 ± 0.270.16 ± 0.35< .001
Change in K (1 m to 1 y) (D)0.47 ± 0.49−0.19 ± 0.44< .001

Simple Linear Correlation Between Change in Corneal Epithelial Thickness and Various Factors

ParameterTPRK (n = 49)TPRK-CXL (n = 49)


R2BPR2BP
Ablation depth
  Central0.0840.064.0450.1350.054.009
  Paracentral0.0360.029.1900.0780.038.052
Spherical equivalent
  Central0.130−1.005.0110.228−0.912.001
  Paracentral0.081−0.614.0450.183−0.758.002
Preoperative epithelial thickness
  Central0.111−0.379.0190.030−0.188.236
  Paracentral0.149−0.366.0060.050−0.235.122
Optical zone diameter
  Central0.063−4.033.0810.256−6.080< .001
  Paracentral0.018−1.628.3650.201−4.998.001

Factors Affecting Myopic Regression After TPRKa

ParameterCrudeModel 1Model 2



OR (95% CI)POR (95% CI)POR (95% CI)P
Epi change1.29 (1.09 to 1.52).0021.39 (1.14 to 1.70).001
CXL0.11 (0.02 to 0.50).0040.11 (0.02 to 0.54).006
Age0.96 (0.83 to 1.10).5210.94 (0.80 to 1.11).4460.95 (0.80 to 1.12).552
Spherical1.07 (0.75 to 1.51).7241.36 (0.68 to 2.69).3831.08 (0.55 to 2.09).831
Cylinder1.50 (0.78 to 2.88).2261.35 (0.59 to 3.17).4801.48 (0.65 to 3.36).354
Optical zone2.37 (0.28 to 20.4).4323.11 (0.04 to 230).6061.34 (0.03 to 70.9).884

Repeatability of Corneal Epithelial Thickness Measurement Using RTVue Before and After TPRK

TimeCenter (2 mm)

SwCVICC
Preoperative0.711.330.941
1 month1.853.890.772
3 months0.941.810.971
6 months0.801.420.972
12 months0.761.250.966
Authors

From Eyereum Eye Clinic, Seoul, South Korea (DSYK); and the Department of Ophthalmology, Yonsei University Wonju College of Medicine, Wonju, Gangwon-do, South Korea (SWK).

Dr. Kang has received personal fees from Avedro, Inc., SCHWIND eye-tech-solutions, and Carl Zeiss Meditec. The remaining author has no financial or proprietary interest in the materials presented herein.

AUTHOR CONTRIBUTIONS

Study concept and design (DSYK, SWK); data collection (DSYK); analysis and interpretation of data (SWK); writing the manuscript (DSYK, SWK); critical revision of the manuscript (SWK); statistical expertise (SWK); administrative, technical, or material support (DSYK)

Correspondence: Sun Woong Kim, MD, PhD, Department of Ophthalmology, Yonsei University, Wonju College of Medicine, 20, Ilsan-ro, Wonju, Gangwon-do, 26426, South Korea. E-mail: eyedockim@yonsei.ac.kr

Received: September 14, 2018
Accepted: April 22, 2019

10.3928/1081597X-20190422-01

Sign up to receive

Journal E-contents