Journal of Refractive Surgery

Original Article Supplemental Data

Corneal Epithelial Thickness Mapping After Photorefractive Keratectomy for Myopia

Mohammad-Reza Sedaghat, MD; Hamed Momeni-Moghaddam, PhD; Mehrdad Gazanchian, MD; Dan Z. Reinstein, MD, MA(Cantab), FRCSC; Timothy J. Archer, MA(Oxon), DipCompSci(Cantab), PhD; J. Bradley Randleman, MD; Seyed Rafi Hosseini, MSc; Golshid Nouri-Hosseini, MD

Abstract

PURPOSE:

To evaluate the longitudinal changes in epithelial thickness after photorefractive keratectomy (PRK) and correlate these with refractive changes.

METHODS:

This prospective study included 52 eyes of 52 candidates for myopic PRK. Along with standard ophthalmic examinations, corneal epithelial thickness mapping by anterior segment optical coherence tomography was performed. Epithelial thickness maps of 9-mm diameter were divided into 25 sectors, including a central 2-mm zone and eight octants within para-central (2 to 5 mm), midperipheral (5 to 7 mm), and peripheral (7 to 9 mm) annular zones. All PRK treatments were performed using the Technolas Teneo 317 model 2 excimer laser (Bausch & Lomb, Rochester, NY) and an aspheric profile with a 6-mm diameter optical zone. Follow-up was at 1, 3, and 6 months.

RESULTS:

Repeated thickness measures before and after PRK at different follow-up times showed a significant difference in thickness separately in various zones (P < .001). A significant decrease in thickness was seen 1 month after PRK in all zones. Afterward, epithelial thickening continued in all zones and reached the preoperative thickness in the midperipheral and peripheral zones 6 months later, whereas the thickness in the central 5-mm zone was significantly thicker than before surgery. There was also a significant correlation between changes in spherical equivalent and epithelial thickness from before to 6 months postoperatively in the paracentral and peripheral zones.

CONCLUSIONS:

There was a marked decrease in the epithelial thickening pattern at 1 month after PRK, with gradual thickening at 3 and 6 months. Changes in epithelial thickness and spherical equivalent were significant only for the para-central peripheral zone.

[J Refract Surg. 2019;35(10):632–641.]

Abstract

PURPOSE:

To evaluate the longitudinal changes in epithelial thickness after photorefractive keratectomy (PRK) and correlate these with refractive changes.

METHODS:

This prospective study included 52 eyes of 52 candidates for myopic PRK. Along with standard ophthalmic examinations, corneal epithelial thickness mapping by anterior segment optical coherence tomography was performed. Epithelial thickness maps of 9-mm diameter were divided into 25 sectors, including a central 2-mm zone and eight octants within para-central (2 to 5 mm), midperipheral (5 to 7 mm), and peripheral (7 to 9 mm) annular zones. All PRK treatments were performed using the Technolas Teneo 317 model 2 excimer laser (Bausch & Lomb, Rochester, NY) and an aspheric profile with a 6-mm diameter optical zone. Follow-up was at 1, 3, and 6 months.

RESULTS:

Repeated thickness measures before and after PRK at different follow-up times showed a significant difference in thickness separately in various zones (P < .001). A significant decrease in thickness was seen 1 month after PRK in all zones. Afterward, epithelial thickening continued in all zones and reached the preoperative thickness in the midperipheral and peripheral zones 6 months later, whereas the thickness in the central 5-mm zone was significantly thicker than before surgery. There was also a significant correlation between changes in spherical equivalent and epithelial thickness from before to 6 months postoperatively in the paracentral and peripheral zones.

CONCLUSIONS:

There was a marked decrease in the epithelial thickening pattern at 1 month after PRK, with gradual thickening at 3 and 6 months. Changes in epithelial thickness and spherical equivalent were significant only for the para-central peripheral zone.

[J Refract Surg. 2019;35(10):632–641.]

As the outermost layer of the cornea, the epithelium has different functions, including the creation of a smooth and regular surface by changing its thickness profile or epithelial remodeling or reconstruction of the epithelial pattern.1 It is important to consider changes in the epithelial thickness profile before corneal refractive surgery. Original photorefractive keratectomy (PRK) ablation profile calculations assumed the epithelium would not change after PRK and would reconstruct with a uniform thickness.2 However, it became clear that epithelial hyperplasia after surgery was partly responsible for the observed early regression and resulting undercorrection compared to the theoretical prediction.3 When comparing the changes in corneal curvature using the Pentacam (Oculus Optikgeräte, Wetzlar, Germany) and optical coherence tomography (OCT) before and 3 months after PRK, there was an increase in the epithelial thickness in the central zone after PRK; however, other zones were not assessed.4 It was also reported that increasing the optical zone reduced the early regression because the stromal curvature was more gradual and therefore there was less epithelial thickening.5 Using confocal microscopy, it was reported that the epithelium was thinner 1 month after PRK than before surgery, which conflicts with other reports of epithelial thickening.6 However, it might be expected for the epithelium to be thinner at 1 month after PRK because the epithelium has been completely removed and is in the process of regrowing.

Alteration and reconstruction of the corneal epithelium after surgery was proposed as a reason for the early changes after PRK.7,8 Short-term refractive outcomes after PRK indicated that more than 90% of patients were within ±1.00 diopter (D) of the target, whereas this value decreased from 55% to 81% when tracking patients for a decade after surgery.9 Although epithelial hyperplasia was suggested as a cause of early refractive regression,10,11 recent studies found no significant correlation between the changes in central corneal epithelium and postoperative refractive changes; therefore, the epithelium is not a reason for long-term regression.8,12,13

The first publication of epithelial thickening after PRK used a very high-frequency (VHF) digital ultrasound (3-mm scan diameter).14 This VHF digital ultrasound system was developed further to enable epithelial thickness mapping over a 10-mm diameter, and was used to show that the epithelium remodeling was a response to the induced stromal curvature gradient.15–18 These studies showed lenticular changes after laser in situ keratomileusis (LASIK). It is expected that epithelium after PRK will behave similarly to after LASIK, responding to the stromal curvature gradient and reaching epithelial stability at 3 months.1,19

More recently, wide epithelial thickness mapping using OCT has been introduced so more studies are being done to investigate thickness variations after different corneal refractive surgery techniques. In assessment of the corneal epithelial and stromal thickness profile over the central 6 mm of the cornea 6 months after PRK using spectral-domain anterior segment OCT, Chen et al.20 found that epithelial thickness increased for 3 months after PRK, but no significant difference was detected between 3 and 6 months postoperatively. Despite the assessment of changes in corneal epithelial thickness after PRK, there is ambiguity about the relationship between epithelial thickness and spherical equivalent changes after PRK. Assessment of changes in spherical equivalent and corneal epithelial thickness profile over the central 6 mm of the cornea after PRK using anterior segment OCT showed spherical equivalent changed from −2.82 to −0.06 D after 1 month and remained stable for the remaining 5 months; in addition, thickening of corneal epithelium did not change the refractive outcomes after PRK.20

The current study was designed to evaluate the changes in epithelial thickness in a wider (9 mm) diameter at 1, 3, and 6 months after PRK. In addition, the pattern of epithelial changes and its correlation with refractive outcomes was assessed.

Patients and Methods

Patients

This longitudinal observational study included 52 eyes of 52 patients presenting to Sedaghat Eye Clinic, Mashhad, Iran, for PRK. All steps of this study followed the tenets of the Declaration of Helsinki and informed consent was obtained from all patients after an explanation of the nature and possible consequences of the study. In addition, the study was approved by the ethics committee of Mashhad University of Medical Sciences (Code Number: 951451).

Candidates for myopic PRK were included in this study. Exclusion criteria were abnormal corneal topography-tomography (steep keratometry value of 47.20 D or greater, inferior–superior index value of 1.40 D or greater, skewed radial axis index of greater than 22°, thinnest pachymetry values of less than 470 µm, difference between apex and thinnest point pachymetry of greater than 10 µm, abnormal elevation values and patterns on the front and back corneal surfaces, and Belin-Ambrósio Enhanced Ectasia Deviation Index score of greater than 1.6),21,22 family history of keratoconus, history of long-term contact lens wear for more than 2 years,23 history of previous keratorefractive surgery, history of eye diseases (eg, dry eye, vernal keratoconjunctivitis, ptosis, and corneal dystrophies), atopy, allergy, autoimmune disorders, herpetic disease, and other systemic disorders such as diabetes mellitus and hypertension, and pregnancy. Patients were asked to stop wearing their contact lenses for at least 3 to 4 weeks prior to measuring the epithelial thickness to reduce the effect of lens-induced corneal warpage as much as possible.

Preoperative and Postoperative Evaluations

Along with standard ophthalmic examinations, Scheimpflug tomography with Pentacam HR, Placido disk–based corneal topography using the TMS-4 (Tomey Corporation, Nagoya, Japan), and corneal epithelium map using anterior segment OCT (Optovue, Inc., Fremont, CA) were done for all patients. Postoperative assessments at 1, 3, and 6 months after surgery included uncorrected distance visual acuity (UDVA), cycloplegic refraction using tropicamide 1%, and corneal epithelial thickness. Mean spherical equivalent refraction was calculated for different time points, and the change in spherical equivalent refraction was calculated from preoperatively to 6 months after PRK.

OCT Epithelial Thickness Measurements

The RTVue XR OCT Avanti with AngioVue Software (Optovue, Inc.) with a corneal adaptor module was employed in the study. At each visit, the OCT imaging preceded the clinical examinations to avoid potential artifacts such as secondary to drop instillation. Images with a signal strength index of at least 30 were considered for analysis. Thickness maps are provided in eight radial meridional scans employed by the system software. Each epithelial thickness map covering the 9-mm diameter area is divided into 25 sectors, including a central 2-mm zone and eight octants equally distributed within paracentral (2 to 5 mm), midperipheral (5 to 7 mm), and peripheral (7 to 9 mm) annular zones. Mean thickness is displayed for each sector. In addition, the locations of minimum and maximum thickness are also marked.

On the typical printout, epithelial thickness values within the central 7 mm are presented, which include the superior and inferior epithelial thickness in the 2 to 7 mm zone, minimum and maximum thicknesses along with the difference between these two thicknesses, and standard deviation of thickness in the assessed 7-mm zone. From the printout, we calculated an inferior-superior index value, defined as the difference in epithelial thickness between the inferior 2 to 7 mm zone and the superior 2 to 7 mm zone.

All imaging techniques were performed by the same experienced and qualified technician under supervision of an experienced corneal specialist (M-RS) between 4 PM and 8 PM during a single visit.

Surgical Technique and Postoperative Regimen

All PRK treatments were performed using the aspheric profile of the Technolas Teneo 317 model 2 laser platform (Bausch & Lomb, Rochester, NY) centered on the pupil center with an optical zone diameter of 6 mm with a transition zone between 1 and 1.5 mm. Surgery was performed under topical anesthesia by tetracaine hydrochloride 1% eye drops. The epithelium was removed mechanically with a hockey knife in a central 8-mm zone. Following the ablation, mitomycin C 0.02% (0.2 mg/mL) was applied for approximately 5 seconds per each diopter of spherical equivalent treatment. Then the eye was irrigated with 20 mL of a balanced salt solution and a bandage contact lens (Biofinity; CooperVision, Victor, NY) was used.

The postoperative treatment regimen included the following medications: 5 mg/mL levofloxacin (Oftaquix; Santen Pharmaceutical, Osaka, Japan) antibiotic eye drops were used four times daily until complete corneal reepithelialization; betamethasone 0.1% (Betasonate; Sina Daru, Tehran, Iran) steroid eye drops were administered four times daily for 2 weeks and then replaced with fluorometholone 0.1% (Allergan Ltd., Marlow, United Kingdom) four times daily for the next 3 months. Preservative-free artificial tears (Artelac Advanced; Bausch & Lomb, Montpellier, France) were administered frequently (at 1-hour intervals) in the first month, and then four times daily during the next 3 to 4 months.

Patients were seen postoperatively at 1 day and every 2 to 3 days until the epithelium had closed, at 2 weeks for the bandage contact lens removal, and then at 1, 3, and 6 months.

Statistical Analysis

Data were analyzed in SPSS.22 software (SPSS, Inc., Chicago, IL). Normality of data was assessed using the Kolmogorov–Smirnov test, and non-parametric statistics were used for variables with no Gaussian distribution. Descriptive statistics including mean and standard deviation were calculated for each of the 25 zones and plotted as for each time point. In addition, mean and standard deviation of epithelial thickness in the central (2 mm), paracentral (2 to 5 mm), mid-peripheral (5 to 7 mm), and peripheral (7 to 9 mm) zones before and after PRK were displayed in the table format and linear charts. Also, the mean thickness in the superior, inferior, temporal, and nasal (2 to 9 mm) zones of 90° before and after PRK was shown on a linear plot. The Mann–Whitney U test was used to compare the mean epithelial thickness between the inferior and superior halves separately for preoperative and postoperative follow-up visits. The Friedman test was used to compare the repeated measures means of corneal epithelial thickness in different zones and follow-up visits. Mean epithelial thickness was compared in different zones separately for each visit using the Kruskal–Wallis test. The Pearson correlation was used to assess the correlation between changes in spherical equivalent and epithelial thickness preoperatively to 6 months after PRK; this relationship was also displayed on a scatter plot. A P value of less than .05 was considered significant in all tests.

Pairwise comparisons were performed using the D Dunn–Bonferroni post-hoc test to compare the means of corneal epithelial thickness in different locations and times for 40 comparisons. Because a pairwise comparison was done on 40 pairs, the Bonferroni correction was used and a P value of less than .001 was considered significant.

Results

Demographic data are displayed in Table 1.

Patient Demographics

Table 1:

Patient Demographics

The preoperative and postoperative mean spherical equivalents at different follow-up visits are presented in Table A (available in the online version of this article). The mean and standard deviation of attempted spherical equivalent was −4.65 ± 1.69 D (95% confidence interval [CI]: −5.12 to −4.18 D). The attempted spherical equivalent was more myopic compared to the preoperative spherical equivalent, with a mean difference of 0.50 ± 0.35 D (95% CI: 0.40 to 0.60); this value was also considered as the target spherical equivalent after surgery.

SE and Cylinder Before and After PRK (n = 52 Eyes)

Table A:

SE and Cylinder Before and After PRK (n = 52 Eyes)

There was a statistically significant difference among the postoperative spherical equivalents and the target spherical equivalent using the Friedman test (chi-square (3) = 64.201, P < .001). Dunn–Bonferroni post-hoc tests showed a significant difference in the postoperative spherical equivalent relative to the target spherical equivalent between months 1 (P < .001) and 3 (P < .001), whereas the difference between month 6 (P = .215) and months 1 and 3 (P = .454) was not significant.

The Friedman test showed a statistically significant difference among the preoperative and postoperative cylinder (chi-square (3) = 31.345, P < .001). Pairwise comparisons showed a significant difference in the preoperative cylinder with the postoperative cylinder at months 3 (P = .001) and 6 (P < .001), whereas the difference among the other pairs was not statistically significant.

The typical epithelial thickness data within the central 7 mm are presented in Table 2. Comparison of the epithelial thickness in the superior and inferior portions (2 to 7 mm) before and after PRK at different follow-up times was statistically significant using the Friedman test. Although the thickness in the superior half was significantly thicker at the last follow-up visit compared to preoperatively, there was no difference for the inferior half. The standard deviation of the thickness measurement was significantly higher in all of the postoperative evaluations compared to the preoperative assessment. The Mann–Whitney U test showed that there was a significant difference in the epithelial thickness between the inferior and superior halves for before (P < .001) and 1 month after (P = .018) PRK, whereas this difference was not significant for 3 (P = .935) and 6 (P = .063) months after surgery.

Epithelium Statistics (µm) Within the Central 7 mm (n = 52 Eyes)

Table 2:

Epithelium Statistics (µm) Within the Central 7 mm (n = 52 Eyes)

The mean and standard deviations of corneal epithelial thickness in different zones in preoperative and postoperative assessments associated with pairwise comparisons are shown in Table B (available in the online version of this article).

Epithelial Thickness (µm) Before and After PRK (n = 52 Eyes)

Table B:

Epithelial Thickness (µm) Before and After PRK (n = 52 Eyes)

Comparison of the repeated epithelial thickness measures before and after PRK at different follow-up visits separately in different zones was performed using the Friedman test. There was a significant difference separately in the central (P < .001), paracentral (P < .001), midperipheral (P < .001), and peripheral (P < .001) thickness. Dunn–Bonferroni post-hoc tests showed significant differences between all pairs except before and 3 months after PRK for the central thickness, between all pairs except before and 3 months after PRK for the paracentral thickness, between all pairs except before with 6 months and 1 month with 3 months after PRK for the midperipheral thickness, and between all pairs except before with 6 months and 1 month with 3 months after PRK for the peripheral thickness.

Comparison of the epithelial thickness in different zones separately for the preoperative and postoperative measurements using the Kruskal–Wallis test provided strong evidence of a difference (P < .001) between the mean ranks of at least one pair of zones for all assessments. Dunn's pairwise tests were performed for the six pairs of zones. For the preoperative epithelial thickness, there was strong evidence (adjusted P value using the Bonferroni correction) of a difference between the peripheral zone with the central (P < .001), paracentral (P < .001), and midperipheral zones (P = .002), with no evidence of a difference between the other pairs. A significant difference was seen between the paracentral zone with the midperipheral (P = .042) and peripheral (P < .001) zones at 1 month after PRK. At 3 and 6 months postoperatively, epithelial thickness was significantly different between all zones (P < .001) except for the central zone with the paracentral and midperipheral with peripheral zones.

Figures 12 display trends in corneal epithelial thickness before and after PRK in different zones.

Line chart of mean epithelial thickness in the central (2 mm), paracentral (2 to 5 mm), midperipheral (5 to 7 mm), and peripheral (7 to 9 mm) zones separately before and after photorefractive keratectomy (n = 52 eyes).

Figure 1.

Line chart of mean epithelial thickness in the central (2 mm), paracentral (2 to 5 mm), midperipheral (5 to 7 mm), and peripheral (7 to 9 mm) zones separately before and after photorefractive keratectomy (n = 52 eyes).

Line chart of mean epithelial thickness before and after photorefractive keratectomy separately in the central (2 mm), paracentral (2 to 5 mm), midperipheral (5 to 7 mm), and peripheral (7 to 9 mm) zones (n = 52 eyes).

Figure 2.

Line chart of mean epithelial thickness before and after photorefractive keratectomy separately in the central (2 mm), paracentral (2 to 5 mm), midperipheral (5 to 7 mm), and peripheral (7 to 9 mm) zones (n = 52 eyes).

As shown in Figure 1, there was significant reduction in epithelial thickness in all zones 1 month after PRK compared to the preoperative values. After 1 month, the process of epithelial thickening continued in all zones so that 6 months later, the thickness of the midperipheral and peripheral zones reached the preoperative levels, whereas the thickness in the central 5-mm area was significantly thicker than before surgery.

Before surgery, the epithelium had a similar thickness across the central, paracentral, and midperipheral zones, but was slightly (2 µm) thinner in the peripheral zone. At the first month after surgery, the epithelium was thicker in the paracentral zone compared to the central, midperipheral, and peripheral zones, with mean differences of 1.79 ± 3.02, 2.33 ± 2.86, and 3.54 ± 4.00 µm, respectively. Between 1 and 3 months, the epithelium was thicker in the paracentral zone compared to the central, midperipheral, and peripheral zones with mean differences of 3.13 ± 10.96, 5.49 ± 9.22, and 7.18 ± 9.45 µm, respectively, and between 3 and 6 months, the epithelium was thicker in the paracentral zone compared to the central, midperipheral, and peripheral zones, with mean differences of 2.84 ± 2.72, 5.78 ± 3.59, and 7.79 ± 3.25 µm, respectively. The same thickness pattern with a marked difference was observed between the central 5 mm and outside it at 3 and 6 months after the surgery, so that the central and paracentral zones had the highest epithelial thicknesses, whereas the peripheral zone had the lowest thickness.

As shown in Figure 2, the thickest epithelium was recorded in the paracentral zone at all time points, followed by the central, midperipheral, and peripheral zones.

The mean and standard deviation of corneal epithelial thickness in the 9-mm diameter area in 25 sectors consists of a central 2-mm zone and eight sectors each in the paracentral (2 to 5 mm), midperipheral (5 to 7 mm), and peripheral (7 to 9 mm) zones before and after PRK (Figure 3).

Schematic corneas displaying mean and standard deviation of corneal epithelial thickness in 25 sectors in the 9-mm diameter area preoperatively and 1, 3, and 6 months postoperatively (n = 52 eyes).

Figure 3.

Schematic corneas displaying mean and standard deviation of corneal epithelial thickness in 25 sectors in the 9-mm diameter area preoperatively and 1, 3, and 6 months postoperatively (n = 52 eyes).

The pattern of epithelial thickening after PRK showed a marked decrease in epithelial thickness 1 month after surgery, with gradual thickening at 3 and 6 months after surgery. The epithelial thickness reached the preoperative values after 6 months in the midperipheral and peripheral zones, whereas in the central and paracentral zones it exceeded those preoperative values.

Figure 4 illustrates the epithelial thickness in the superior, inferior, temporal, and nasal zones of 45°.

Line chart of preoperative and postoperative mean epithelial thickness in the superior, inferior, nasal, and temporal zones of 45° (2 to 9 mm) (n = 52 eyes).

Figure 4.

Line chart of preoperative and postoperative mean epithelial thickness in the superior, inferior, nasal, and temporal zones of 45° (2 to 9 mm) (n = 52 eyes).

Preoperative epithelial thickness was the thinnest in the superior zone (2 to 9 mm), followed by the temporal, nasal, and inferior zones. One month after PRK, the temporal zone experienced the lowest reduction, whereas the nasal zone had the largest change. Following the 1-month time point, the epithelial thickness increased in all zones; this increasing trend continued with the highest slope for the temporal zone and the lowest slope for the superior zone during the time interval of 3 to 6 months after PRK.

The Friedman test showed a statistically significant difference in the repeated epithelial thickness measurements before and 1, 3, and 6 months after surgery in the superior (chi-square (3) = 46.108, P < .001), temporal (chi-square (3) = 53.630, P < .001), inferior (chi-square (3)= 47.594, P < .001), and nasal (chi-square (3)= 51.677, P < .001) zones (P < .001). Pairwise comparisons using the Dunn–Bonferroni post-hoc tests showed significant differences in the thickness between all pairs except before and 3 months after PRK (P = 1.00) for the superior zone, between all pairs except before with 6 months (P = 1.00) and 1 with 3 months (P = 1.00) after PRK for the inferior zone, and between all pairs except before with 3 (P = .108) and 6 (P = .596) months for the nasal zone, between all pairs except before with 3 months after PRK (P = 1.00).

There was no significant correlation between changes in spherical equivalent and epithelial thickness from preoperatively to 6 months postoperatively in the central (rs = 0.296, P = .080) and midperipheral (rs = −0.154, P = .371) zones. However, there was a significant correlation between changes in spherical equivalent and epithelial thickness in the paracentral (rs = 0.437, P = .008) and peripheral (rs = −0.497, P = .002) zones (Figure 5).

Scatter plots of changes in epithelial thickness in different zones and changes in spherical equivalent from preoperatively to 6 months after photorefractive keratectomy (n = 52 eyes).

Figure 5.

Scatter plots of changes in epithelial thickness in different zones and changes in spherical equivalent from preoperatively to 6 months after photorefractive keratectomy (n = 52 eyes).

Discussion

The results showed an initial decrease in epithelial thickness at 1 month followed by a gradual increase at 3 and 6 months after PRK. Six months after surgery, the thickness in the midperipheral and peripheral zones reached preoperative levels, whereas in the central and paracentral zones, it was thicker than the preoperative values. The spherical equivalent was also highest at 1 month after surgery and gradually decreased. The changes in the epithelial thickness in the central and paracentral zones were greater than in the midperipheral and peripheral zones, but there were no statistically significant differences between the central and paracentral zones or the midperipheral and peripheral zones in terms of epithelial thickness changes. This pattern of epithelial thickening resembled a lenticular shape and mirrors the 6-mm ablation zone, which conforms to the central and paracentral zones in the current study.

A significant correlation was found between the changes in epithelial thickness and spherical equivalent in the paracentral and peripheral zones from preoperatively to 6 months after PRK. Increased epithelial thickness changes in the paracentral zone were associated with increased spherical equivalent changes. Changes in thickness in the peripheral zone were accompanied by a decrease in spherical equivalent. These changes may be attributed to the curvature gradient, which is higher for higher corrections, so that further epithelial remodeling (both central thickening and peripheral thinning) increases the refractive effect.

The study of epithelial thickness changes after refractive surgery has been widespread in recent years due to advances in epithelial corneal thickness measuring equipment. The role of the corneal epithelium in determining the refractive status of the eye and the mechanism of its reconstruction and repair after corneal refractive surgery has been investigated.6 Assessing the epithelial thickness by confocal microscopy through focusing in 17 patients before and 1 month after PRK showed that the mean epithelial thickness was 51 ± 4.0 µm before surgery and 45 ± 10 µm 1 month after surgery.6 This change in epithelial thickness 1 month after surgery is in line with the current results.

In a study by Ivarsen et al.,12 the overall thickness of the cornea, epithelium, and stroma was measured by confocal microscopy through focusing before and after PRK at different intervals up to 3 years. The pre-operative epithelial thickness was 47 ± 4 µm, which decreased 1 week after PRK and then increased to reach the initial level 6 months after the operation. This increase continued until 1 year after surgery and then remained the same. These findings indicate a marked epithelial recovery after PRK similar to the current study. Moreover, they showed that changes in refraction after PRK did not correlate with epithelial changes. Similar to the current results, the epithelial thickness after PRK is first reduced and then increased and reaches the preoperative level at approximately 6 months after surgery. On the other hand, they did not find any correlation between refractive and epithelial thickness changes, whereas the current study showed a significant negative correlation between spherical equivalent changes and changes in paracentral zone thickness at 1 to 3 months after PRK.

In contrast with the current study, Kaluzny et al.24 reported thicker central epithelial thickness in the first 2 weeks after PRK, which returned to preoperative values after 3 weeks and remained stable for up to 3 months. It does not seem likely that the epithelial thickness would increase in the first 2 weeks after PRK given that the epithelium has been completely removed during the procedure and is therefore in the process of regrowing. There are differences between their study and the current study and other studies already described in sample size (20 eyes of 10 patients vs 52 eyes of 52 patients) and follow-up length (3 vs 6 months), but it seems possible that subtle differences among the devices used (or OCT measurement systems) do not allow universal predictions.

Chen et al.20 reported no significant difference between the epithelial thickness in the center of the cornea and the paracentral zones before the surgery. The epithelial thickness was thinner in the superior zone than in the inferior zone, the temporal zone was thinner than the nasal zone, and the thickness of these zones 1 month after PRK was greater than before PRK; this increase in thickness continued until 3 months. The highest increase in thickness was seen between 1 and 3 months with no significant change during 3 to 6 months. Spherical equivalent remained constant 1 month after PRK, and no significant correlation was found between epithelial thickening and postoperative refractive changes. The greatest change in epithelial thickness was observed in the temporal zone, which had the least thickness before surgery. In contrast, in the current study the epithelial thickness 1 month after surgery was less than preoperative values and the thickness changes followed a similar trend at 1 to 3 months and 3 to 6 months after surgery. Preoperatively, the epithelial thickness was thinnest in the superior zone and thickest in the inferior zone, whereas it was thinnest in the superior zone and thickest in the temporal zone at all follow-up times. Epithelial thickness asymmetry in the superior and inferior zones can be justified by the upper eyelid function and the role of gravity in the lacrimal layer when measured by OCT. However, the relationship between changes in the postoperative thickness and preoperative thickness is not yet clearly understood. Chen et al.20 justified this phenomenon based on the windshield effect and corneal configuration changes following the stromal ablation, which allows the epithelium to thicken more in these zones.

The lack of difference in the central epithelial thickness and the mean of all zones in the two sexes was confirmed in a study conducted in Egypt25 and is contrary to the findings that reported a thicker epithelium in males.20,26 Geographical and hereditary factors may play a role in determining the corneal epithelial thickness, considering the fact that both studies in which the epithelium was thicker in men were performed in China.

A previous study using OCT showed that after PRK, epithelium in the paracentral zone becomes thicker compared to the central zone,20,27 whereas the current study shows that the increase in epithelial thickness in the central and paracentral zones was greater than the midperipheral and peripheral zones. The thickest epithelium paracentrally was most likely due to the aspheric ablation profile with a paracentral spherical aberration precompensation component, which creates a subsurface central island. Therefore, change in the epithelial thickness after PRK in our study follows a lenticular pattern that is consistent with the results obtained by Reinstein et al.1 using a VHF ultrasound device after myopic LASIK. One point of difference with their study is the time to epithelial thickness stabilization, which was 3 months in their study compared to 6 months after PRK in the current study. This appears to show that epithelial remodeling takes longer after surface ablation, which may be expected given that the epithelium is completely removed during a surface ablation procedure.

Corneal epithelial thickness in normal eyes ranged from 48.3 to 58.4 µm in various studies,20,28–32 which is similar to the range of preoperative thickness (47.72 to 58.36 µm) obtained in the current study. The difference in thickness in various studies can be attributed to the measurement technique. Measuring by VHF ultrasound or confocal microscopy through focusing requires the use of immersion oil to exclude the tear film thickness, whereas OCT does not exclude this confounding factor and the tear film thickness is included on the measured epithelial layer. Other causes of differences in postoperative thickness among the various studies include the degree of myopia, the ablated zone, and the epithelium removal method (mechanical, alcohol, or laser) in PRK.

A literature review of epithelial thickness measurement using anterior segment OCT in a 9-mm corneal diameter revealed that there was only one study on the measurement of epithelial thickness in this diameter. Hashmani et al.33 mentioned that wide corneal epithelial mapping had a good repeatability in measuring the epithelial thickness of the central and peripheral zones, and the central zone was thicker than all peripheral zones except the nasal zone in healthy individuals with refractive errors between +5.00 and −6.00 D. One of the strengths of the current study was measurement of the epithelial thickness in a wider diameter of the cornea (9 mm) compared to all previous studies, which measured the epithelial changes in a 6-mm corneal diameter.

Limitations of this study include the assessment of epithelial changes after PRK and the fact that other corneal refractive surgeries such as LASIK and small incision lenticule extraction were not investigated. Another weakness was the lack of a longer follow-up period (eg, 1 year), which might better reflect long-term changes. However, most repair and remodeling of the corneal epithelium took place during the first 6 months of surgery and the epithelial thickness does not change significantly from 6 months to 1 year after surgery.1

For future studies, comparing epithelial changes is recommended in this wide diameter in various surgical techniques such as PRK, LASIK, and small incision lenticule extraction. There may be a difference between PRK and LASIK because Bowman's layer has been removed. Also, in the early period (1 to 2 months), the epithelium is still regrowing after PRK, whereas it is remodeling after LASIK.

The current study showed the epithelium thickened gradually at 3 and 6 months after PRK to reach the preoperative levels and even more than that in the central and paracentral zones. Moreover, changes in the epithelial thickness in the central and paracentral zones were greater than in the midperipheral and peripheral zones, but there was no significant difference in terms of epithelial thickness changes between the central and paracentral and the midperipheral and peripheral zones. This pattern of epithelial thickening resembled a lenticular shape. A significant direct correlation was found between the changes in epithelial thickness and spherical equivalent in the paracentral zone from preoperatively to 6 months postoperatively and an inverse correlation was seen for the peripheral zone.

References

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Patient Demographics

CharacteristicValue
Patients/eyes52/52
Mean age (range) (years)27.70 (18 to 47)
Gender (male:female)18:34
Cylinder, mean ± SD (95% CI) (D)−0.99 ± 1.10 (−1.29 to −0.68)
SE, mean ± SD (95% CI) (D)−4.15 ± 1.87 (−4.67 to −3.63)
UDVA, mean ± SD (95% CI) (logMAR)0.94 ± 0.23 (0.88 to 1.00)
CDVA, mean ± SD (95% CI) (logMAR)0.01 ± 0.03 (0.00 to 0.02)
Keratometry, mean ± SD (95% CI) (D)43.97 ± 1.40 (43.58 to 44.36)
Central pachymetry, mean ± SD (95% CI) (µm)528 ± 32 (519 to 537)

Epithelium Statistics (µm) Within the Central 7 mm (n = 52 Eyes)

AreaMean ± SD (95% CI)Friedman Test [Pairwise Comparisons]

Preop (1)1 Month Postop (2)3 Months Postop (3)6 Months Postop (4)
9 mm52.35 ± 2.36 (51.70 to 53.01)47.74 ± 4.54 (46.47 to 49.00)51.58 ± 4.06 (50.44 to 52.71)54.24 ± 3.20 (53.24 to 55.24)(chi-square (3) = 72.422, P < .001)
Within-eye SD1.73 ± 0.58 (1.57 to 1.89)5.52 ± 1.97 (4.97 to 6.07)4.08 ± 1.40 (3.68 to 4.46)4.50 ± 1.44 (4.05 to 4.95)(chi-square (3) = 88.077, P < .001); [2,4: 0.546, 3,4: 0.546, Other pairs: < .05]
Minimum–maximum−9.08 ± 3.43 (−10.03 to −8.12)−30.6 ± 10.43 (−33.5 to −27.69)−19.63 ± 8.35 (−21.96 to −17.31)−18.81 ± 4.99 (−20.36 to −17.25)(chi-square (3) = 93.239, P < .001); [3,4: 1.00, Other pairs: < .05]
I-S value (2 to 7 mm)2.84 ± 2.03 (1.78 to 3.90)1.78 ± 6.10 (0.32 to 3.89)−0.21 ± 2.53 (−1.60 to 1.17)0.35 ± 8.58 (−2.35 to 3.06)(chi-square (3) = 27.707, P < .001); [1,4: 0.769, 1,2: 1.00, 2.4: 1.00, Other pairs: < .05]

SE and Cylinder Before and After PRK (n = 52 Eyes)

SEMean ± SD (95% CI)
Preoperative (D)−4.15 ± 1.87 (−4.67 to −3.63)
Preoperative cylinder (D)−0.99 ± 1.09 (−1.29 to −0.68)
1 month postoperative SE (D)+1.23 ± 0.66 (+1.04 to +1.41)
1 month postoperative cylinder (D)−0.51 ± 0.55 (−0.67 to −0.36)
3 months postoperative SE (D)+0.97 ± 0.53 (+0.82 to +1.12)
3 months postoperative cylinder (D)−0.32 ± 0.35 (−0.41 to −0.22)
6 months postoperative SE (D)+0.70 ± 0.54 (+0.53 to +0.86)
6 months postoperative cylinder (D)−0.24 ± 0.28 (−0.32 to −0.15)
1 month postoperative SE – target SE+0.72 ± 0.53 (+0.57 to +0.87)
3 months postoperative SE – target SE+0.46 ± 0.37 (+0.36 to +0.57)
6 months postoperative SE – target SE+0.16 ± 0.43 (+0.03 to +0.29)

Epithelial Thickness (µm) Before and After PRK (n = 52 Eyes)

AreaMean ± SD (95% CI)Friedman Test [Pairwise Comparisons]

Preop (1)1 Month Postop (2)3 Months Postop (3)6 Months Postop (4)
Superior (2 to 7 mm)51.62 ± 2.59 (50.89 to 52.34)47.35 ± 5.25 (45.88 to 48.81)51.98 ± 3.52 (51 to 52.96)53.90 ± 2.38 (53.16 to 54.65)(chi-square (3) = 53.926, P < .001); [1,3: 1.00, Other pairs: < .05]
Inferior (2 to 7 mm)54.46 ± 2.84 (53.67 to 55.25)49.13 ± 5.6 (47.58 to 50.69)51.77 ± 3.62 (50.76 to 52.78)54.26 ± 8.51 (51.61 to 56.91)(chi-square (3) = 57.759, P < .001); [1,4: 1.00, 2,3: 0.835, Other pairs: < .05]
Minimum48.12 ± 2.89 (47.31 to 48.92)32.15 ± 9.08 (29.63 to 34.68)41.77 ± 5.92 (40.12 to 43.42)45.07 ± 3.42 (44.01 to 46.14)(chi-square (3) = 83.678, P < .001); All pairs: < .05]
Maximum56.23 ± 7.67 (54.1 to 58.37)62.75 ± 7.46 (60.67 to 64.83)60.38 ± 9.70 (57.68 to 63.09)63.64 ± 4.55 (62.23 to 65.06)(chi-square (3) = 36.756, P < .001); [2,3: 1.00, 2,4: 0.187, 3,4: 0.208 Other pairs: < .05]
Central (a) (2 mm)53.19 ± 2.79 (52.41 to 53.97)47.9 ± 4.68 (46.6 to 49.21)52.63 ± 8.03 (50.4 to 54.87)56.45 ± 8.94 (53.67 to 59.24)(chi-square (3) = 82.163, P < .001) [1,3: 1.00, Other pairs: < .05]
Paracentral (b) (2 to 5 mm)53.26 ± 2.67 (52.52 to 54.00)49.69 ± 4.55 (48.43 to 50.96)55.76 ± 9.33 (53.17 to 58.36)58.28 ± 3.25 (57.27 to 59.29)(chi-square (3) = 78.229, P < .001) [1,3: 1.00, Other pairs: < .05]
Midperipheral (c) (5 to 7 mm)52.72 ± 2.49 (52.03 to 53.42)47.36 ± 4.92 (45.99 to 48.73)50.27 ± 3.36 (49.33 to 51.21)52.49 ± 2.97 (51.57 to 53.42)(chi-square (3) = 62.203, P < .001) [1,4: 1.00, 2,3: .096, Other pairs: < .05]
Peripheral (d) (7 to 9 mm)50.99 ± 2.35 (50.33 to 51.64)46.15 ± 5.34 (44.66 to 47.64)48.58 ± 3.35 (47.65 to 49.51)51.68 ± 8.63 (48.99 to 54.37)(chi-square (3) = 54.942, P < .001) [1,4: 1.00, 2,3: .282, Other pairs: < .05]
Kruskal–Wallis test [pairwise comparisons](chi-square (3) = 24.371, P < .001) [a,b: 1.00; a,c: 1.00; b,c: 1.00; Other pairs: < .05](chi-square (3) = 18.280, P < .001) [a,b: 0.271; a,c: 1.00; a,d: .166; c,d: .790, Other pairs: < .05](chi-square (3) = 74.709, P < .001) [a,b: .780; c,d: .203, Other pairs: < .05](chi-square (3) = 83.649, P < .001) [a,b: 1.00; c,d: .285, Other pairs: < .05]
Authors

From the Eye Research Center (M-RS), the Department of Optometry, School of Paramedical Sciences (HM-M), School of Medicine (MG), and Student Research Committee (MG, GN-H), Mashhad University of Medical Sciences, Mashhad, Iran; the Health Promotion Research Center, Zahedan University of Medical Sciences, Zahedan, Iran (HM-M, SRH); London Vision Clinic, London, United Kingdom (DZR, TJA); Columbia University Medical Center, New York, New York (DZR); Sorbonne Université, Paris, France (DZR); Biomedical Science Research Institute, Ulster University, Coleraine, United Kingdom (DZR); and Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio (JBR).

Supported in part by an unrestricted grant to Cole Eye Institute, Cleveland Clinic from Research to Prevent Blindness, Inc.

Dr. Reinstein is a consultant for Carl Zeiss Meditec (Jena, Germany) and has a proprietary interest in the Artemis Insight 100 technology (ArcScan, Inc., Morrison, Colorado) through patents administered by the Cornell Center for Technology Enterprise and Commercialization (CCTEC), Ithaca, New York. The remaining authors have no financial or proprietary interest in the materials presented herein.

Dr. Randleman did not participate in the editorial review of this manuscript.

The authors thank the personnel of Sedaghat Eye Clinic, the participants who made this study possible, and the Deputy of Research of Mashhad University of Medical Sciences (Grant No. 951451).

AUTHOR CONTRIBUTIONS

Study concept and design (M-RS, HM-M, JBR); data collection (HM-M, MG, GN-H); analysis and interpretation of data (M-RS, HM-M, MG, DZR, TJA, JBR, SRH, GN-H); writing the manuscript (M-RS, HM-M, MG, TJA, GN-H); critical revision of the manuscript (M-RS, HM-M, MG, DZR, JBR, SRH, GN-H); statistical expertise (HM-M, MG, DZR, TJA, SRH, GN-H); administrative, technical, or material support (HM-M, MG, GN-H); supervision (M-RS, HM-M)

Correspondence: Hamed Momeni-Moghaddam, PhD, Sedaghat Eye Clinic, Molla-Sadra 2 Str., Ahmadabad Blvd., Mashhad, Iran. E-mail: hmomeni_opt@yahoo.com

Received: June 18, 2019
Accepted: August 26, 2019

10.3928/1081597X-20190826-03

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