BioMed Research International
Volume 2018 (2018), Article ID 2945751, 9 pages
https://doi.org/10.1155/2018/2945751

Clinical Study

Simultaneous Transepithelial Topography-Guided Photorefractive Keratectomy and Accelerated Cross-Linking in Keratoconus: 2-Year Follow-Up

Sibel Ahmet,¹ Alper Ağca,² Dilek Yaşa,² Ahmet Alperen Koç,³ Mesut Toğaç,¹ Yusuf Yıldırım,² Burçin Kepez Yıldız,² and Ahmet Demirok²

¹Ağrı Government Hospital, Ağrı Yolu 5. Kilometre, Doğubeyazıt, Ağrı, Turkey
²Prof. Dr. N. Resat Belger Beyoglu Eye Training and Research Hospital, Bereketzade Mah. N 2, İstanbul, Turkey
³Doç. Dr. Yaşar Eryılmaz Government Hospital, Fırat Mah, Erzurum Cad, Ağrı, Turkey

Correspondence should be addressed to Dilek Yaşa; dilekyasa2@gmail.com

Received 19 April 2018; Revised 9 August 2018; Accepted 30 September 2018; Published 15 October 2018

Academic Editor: Timothy Y. Lai

Copyright © 2018 Sibel Ahmet et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract.

Purpose. To evaluate the visual, refractive, and topographic outcomes after simultaneous topography-guided transepithelial photorefractive keratectomy (transepithelial TG-PRK) using the Amaris Excimer laser platform and accelerated corneal cross-linking (CXL) in eyes with keratoconus. Materials and Methods. Patients with 2 years of follow-up were included in this retrospective case series. Manifest refraction (MR), uncorrected (UDVA) and corrected (CDVA) distance visual acuity, corneal topography, and pachymetry were evaluated at 1, 3, 6, 12, and 24 months after surgery. The root-mean-square of total higher-order aberrations (total HOA-RMS), coma (Coma-RMS), and spherical aberration (SA-RMS) were calculated for 4- and 6-mm diameters. Results. Forty-six eyes of 46 patients were included in the study. Stromal ablation was ≤50 μ in all patients. MR was −3.78±3.26 preoperatively and −1.39±1.82 postoperatively. Significant improvements were seen in the UDVA and Coma-RMS values at 1 month, CDVA and total HOA-RMS values at 3 months, and SA-RMS values at 1 year compared to preoperative levels. UDVA values further improved after 2 years, compared to the 1-year values. No patient lost two or more lines and keratoconus progression was not observed in any patient. Conclusion. Simultaneous transepithelial TG-PRK and accelerated CXL resulted in significant gains in CDVA without compromising CXL efficacy.

1. Introduction

Keratoconus is a noninflammatory (and usually bilateral) ectatic disease of the cornea that results in localized corneal thinning and steepening. Corneal cross-linking (CXL) is the only treatment that can stop keratoconus progression [1, 2]. CXL lasts more than 60 minutes, during which riboflavin sensitization with ultraviolet-A (UVA) radiation increases the biomechanical rigidity of the anterior corneal stroma. Recently, researchers developed accelerated CXL protocols that speed up the procedure using higher-intensity radiation for a reduced period of time; these protocols can be applied in various clinical settings and effectively stabilize keratoconus [3]. However, various parameters have been used in these methods and no standard parameters for accelerated CXL have been established [3, 4].

Combining photorefractive keratectomy (PRK) with CXL or accelerated CXL offers keratoconus patients both stability and functional vision, with improvements in UDVA, CDVA, and topographic irregularity [5–8]. However, different excimer laser platforms have different ablation patterns and different algorithms for topography-guided ablation. Additionally, mechanical and laser debridement of the corneal epithelium (PRK versus transepithelial PRK) may result in different patterns of ablation and different clinical results. Therefore, clinical results with each excimer laser platform and each method of epithelial debridement should be examined separately.

Although many authors have reported the results of simultaneous TG-PRK and CXL, only a few studies reported outcomes at 2 years or beyond [9–11] and only one of them evaluated accelerated CXL with transepithelial TG-PRK [11]. In addition to these studies, Kymionis et al. [12] reported long-term results of combined transepithelial phototherapeutic keratectomy (PTK) and corneal collagen cross-linking for keratoconus (Cretan protocol). Grentzelos et al. evaluated combined transepithelial PTK and conventional PRK followed simultaneously by CXL (Cretan protocol plus) [13]. However, the accelerated cross-linking protocol that we use in combination with PRK has not been previously reported. Additionally, the Amaris platform and Optimized Refractive Keratectomy-Custom Ablation Manager (ORC-CAM) software were used in only a few studies with a limited number of patients and short follow-up periods. Camellin et al. [14] evaluated 37 eyes, but 31 of the eyes had follow-up periods that ranged from 4 months to 1 year. Müller and Lange [15] evaluated only nine eyes and the patients had follow-ups at 18 months.

The aim of this retrospective study was to evaluate the visual, refractive, and topographic outcomes, 2 years posttreatment, of keratoconic patients who were treated with a simultaneous transepithelial TG-PRK and accelerated CXL protocol in our clinic.

2. Materials and Methods

This retrospective study was conducted in accordance with the Declaration of Helsinki and approval was obtained from the institutional review board. The medical records of patients who underwent simultaneous transepithelial TG-PRK (Amaris 750S excimer laser platform and ORC-CAM software) and accelerated CXL (20-minute riboflavin soak, followed by 5-minute irradiation at a power of 18 mW/cm²) in our clinic between January 2015 and January 2016 were retrospectively evaluated. Patients who were older than 18 years of age and who underwent follow-up for at least 2 years were included in the study. The diagnosis of keratoconus was established using the Amsler-Krumeich classification (Table 1), based on astigmatism, corneal power, corneal transparency, and corneal thickness [16]. A Sirius 3D rotating Scheimpflug camera and topography system (Costruzioni Strumenti Oftalmici, Florence, Italy) were used to collect the measurements. The exclusion criteria were mechanical debridement of the cornea during PRK, CXL procedure with other parameters defined for this study, or associated ocular diseases that may affect measurements or visual acuity gains.

Table 1: Amsler-Krumeich clinical classification of keratoconus by stage.

Stage
Characteristics

I
Eccentric steepening

Induced myopia and/or astigmatism of ≤5.00 D

Keratometric reading ≤48.00

Vogt’s lines, typical topography

II
Induced myopia and/or astigmatism 5.00 to ≤8.00 D

Keratometric reading ≤53.00

Pachymetry ≥ 400 μm

III
Induced myopia and/or astigmatism 8.00 to ≤10.00 D

Keratometric reading >53.00

Pachymetry 200 to 400 μm

IV
Refraction not measurable

Keratometric reading >55.00 D

Central scars

Pachymetry ≤ 200 μm

The patient is at the specific stage if one of the characteristics applies. Pachymetry is measured at the thinnest site of the cornea.

D, diopters.

2.1. Preoperative and Postoperative Examinations

Preoperatively, all patients had a full ophthalmological examination, including UDVA and CDVA, manifest and cycloplegic refractions, slit-lamp evaluation, Goldman applanation tonometry, and fundoscopy examinations. Using the Sirius topography system, the following topographic and pachymetric parameters were recorded and evaluated for 4-mm pupil diameters, both preoperatively and postoperatively: minimum corneal thickness (MCT), maximum keratometry ( max), flattest keratometric reading (1), steepest keratometric reading (2), mean pupillary power (MPP), keratoconus vertex back (KVB, maximum posterior elevation), root-mean-square of the total higher-order aberrations (Total HOA-RMS), coma (Coma-RMS), and spherical aberration (SA-RMS).

Postoperatively, patients were examined on the first day after surgery and every alternating postoperative day to assess the status of corneal epithelial healing. If complete epithelialization was present, the therapeutic contact lens was removed. Afterward, the patients were examined 1, 3, 6, 12, and 24 months after surgery. UDVA and CDVA, manifest refraction (including the mean refractive spherical equivalent (MRSE)), corneal topography, and biomicroscopic examinations were performed at each visit. An automated phoropter (CV-5000, Topcon, Tokyo, Japan) and a back-illuminated 19” LED LCD monitor chart (CC-100 XP, Topcon, Tokyo, Japan) were used for visual acuity examinations. Visual acuities were converted to logMAR for statistical analysis. Corneal haze was recorded by Fantes haze grading system using slit lamp.

2.2. Surgical Technique

All PRK procedures were performed using the Schwind AMARIS 750 excimer laser platform in transepithelial PRK mode. This is a flying-spot excimer laser platform with a repetition rate of 750 Hz. The ablation profile was planned using the integrated ORC-CAM software. The treatment was planned in PRK mode to clearly see the ablation profile and stromal ablation depth. Attempted refraction was reduced to limit the ablation depth to 50 μ (over the cone) in the TG-PRK mode. These parameters were used for a transepithelial TG-PRK treatment. In the transepithelial PRK mode, the excimer laser performs epithelial and stromal ablation in one step. Mitomycin C was not used.

Transepithelial TG-PRK was followed by accelerated corneal CXL. The exposed stroma was soaked with 0.1% riboflavin (VibeX Rapid; Avedro Inc., Waltham, MA, USA) for 20 minutes, and then CXL was performed using the Avedro KXL cross-linking platform (Avedro Inc., Waltham, MA, USA) for 5 minutes at an irradiance of 18.0 mW/cm² (5.4 J/cm²). A hypotonic riboflavin solution (Peschke Trade GmbH, Huenenberg, Switzerland) was used in corneas thinner than 400 μm (1 drop every 5 seconds until the corneal thickness reaches 400 μ; online pachymetry of the excimer laser platform was used to monitor the corneal thickness). One additional drop of riboflavin was applied at 2.5 minutes during irradiation. The cornea was washed using a balanced salt solution at the end of the CXL process. A bandage contact lens (Cooper Vision, Scottsville, NY) was fitted at the end of the surgery and remained in place until full reepithelialization. The contact lens was removed after epithelial healing. All patients were treated postoperatively with topical moxifloxacin (0.5%; Alcon Laboratories, Inc, Fort Worth, TX, USA) four times daily until reepithelialization and with loteprednol etabonate (0.5%; Lotemax; Abdi İbrahim İlaç Sanayi ve Tic AŞ, İstanbul, Turkey) four times daily for 2 weeks with gradual tapering over an additional 1 week. All patients used preservative-free tear substitute for at least 1 month (Refresh Plus; Allergan, Inc., Irvine, TX).

2.3. Statistical Analysis

Statistical analysis was performed using IBM SPSS Statistics 20 software (IBM Corp, Armonk, NY, USA). The distribution of the variables was assessed using the Shapiro–Wilk test. The mean and standard deviation (SD) were used for normal distributions in descriptive statistics; median, minimum, and maximum values were used ​​for nonnormal distributions. Visual acuity measurements were converted to logMAR for statistical analysis. The dependent-samples -test was used for the variables with normal distributions and the Wilcoxon test was used for the variables with nonnormal distributions. The level of statistical significance was set at .

3. Results

Forty-six eyes from 46 patients were included in the study. Thirty (65%) patients were male and 16 (35%) patients were female. The mean age was 26±5 years (min: 18 years; max: 39 years). All had stage 1 or 2 keratoconus as defined based on the Amsler-Krumeich classification (20 eyes Grade 1, 26 eyes Grade 2). Demographic data and patient characteristics are shown in Table 2.

Table 2: Preoperative patient characteristics.

Median
Minimum
Maximum

UDVA (logMAR)
0.70
0.15
1.30

CDVA (logMAR)
0.40
0.00
1.00

SPH (D)
-1.62
-8.00
1.50

CYL (D)
-2.50
-5.00
0.00

MRSE (D)
-3.31
-12.63
0.25

Mean ± SD
Minimum
Maximum

PACHYMETRY (μm)
470.02 ± 31.55
406
529

(D)
54.90 ± 4.81
47.34
64.71

K₁ (D)
45.50 ± 2.84
40.57
55.60

K₂ (D)
48.72 ± 3.08
43.83
58.57

MPP (D)
45.98 ± 2.87
41.52
53.72

KVB (μm)
66.72 ± 31.94
11
139

HOA-RMS (4 mm) (μm)
1.04 ± 0.57
0.15
2.58

COMA-RMS (4 mm) (μm)
0.91 ± 0.54
0.10
2.35

SA-RMS (4 mm) (μm)
0.19 ± 0.16
0.01
0.71

HOA-RMS (6 mm) (μm)
2.52 ± 1.25
0.43
5.83

COMA-RMS (6 mm) (μm)
2.17 ± 1.21
0.29
5.50

SA-RMS (6 mm) (μm)
0.52 ± 0.51
0.03
1.90

UDVA: uncorrected distance visual acuity; CDVA: corrected distance visual acuity; SPH: sphere; CYC: cylinder; MRSE: spherical equivalent of manifest refraction; SD: standard deviation; : steepest keratometry; K₁: flat keratometry; K2: steep keratometry; MPP: mean pupillary power (4.5 mm diameter ); KVB: keratoconus vertex back (posterior elevation); HOA-RMS: root-mean-square of total higher-order aberrations; Coma-RMS: root-mean-square of coma; SA-RMS: root-mean-square of spherical aberration.

Table 3 shows the attempted correction and ablation characteristics. Table 4 shows the visual acuity and manifest refraction values during follow-up. At the end of 24 months, on average, UDVA improved to 0.40 logMAR (max: 0.00, min: 1.00), compared with the preoperative UDVA of 0.70 logMAR (max: 0.15, min: 1.30). Additionally, on average, CDVA improved to 0.15 logMAR (max: 0.00, min: 1.00) at 24 months postsurgery compared with the presurgery value of 0.40 logMAR (max: 0.00, min: 1.00).

Table 3: Attempted correction and ablation charactheristics.

Mean ± SD
Median
Minimum/Maximum

Optical zone diameter (mm)
5.93 ± 0.58
6
5/7

Transition zone diameter (mm)
0.72 ± 0.29
0.63
0.33/1.46

Total ablation zone (mm)
6,65 ± 0,71
6,63
5.33/8.23

Maximum ablation depth (μ)
76± 35
85
16/138

Central ablation depth (μ)
48 ± 28
62
2/96

Minimum ablation depth (μ)
35± 28
56
0.003/61

Ablation volume (μm³)
1745 ±1239
2001
183/4232

Attempted sphere (D)
-1.15 ± 1.51
-1.00
-4.87/1.30

Attempted cylinder (D)
-1.10 ± 0.75
-0.81
-2.99/0

: ablation profile was evaluated by the surgeon. Maximum ablation depth was limited to 50 μ over the cone. Paracentral ablation was not limited.

Table 4: Visual acuity and manifest refraction during follow-up.

Preoperative
1 month
3 months
6 months
12 months
24 months

UDVA (logMAR)

Mean±SD
0.77 ± 0.40
0.55 ± 0.31
0.49 ± 0.28
0.48 ± 0.28
0.48 ± 0.33
0.42 ± 0.29

Median
0.70
0.52
0.52
0.52
0.40
0.40

Min/Max
0.15/1.30
0.10/1.30
0.00/1.30
0.00/1.30
0.00/1.30
0.00/1.00

p value (preop)
-
<0.001
<0.001
<0.001
<0.001
<0.001

p value (previous)
-
-
0.033
0.475
0.687
0.042

CDVA (logMAR)

Mean±SD
0.36 ± 0.23
0.31 ± 0.27
0.27 ± 0.24
0.26 ± 0.23
0.21 ± 0.21
0.20 ± 0.21

Median
0.40
0.22
0.22
0.22
0.15
0.15

Min/Max
0.00/1.00
0.00/1.00
0.00/1.00
0.00/1.00
0.00/1.00
0.00/1.00

p value (preop)
-
0.125
0.013
0.007
<0.001
<0.001

p value (previous)
-
-
0.010
0.100
0.003
0.067

MRSE (D)

Mean±SD
−3.78±3.26
−1.69±1.82
−1.41±2.20
−1.42±2.00
−1.42±1.84
−1.39±1.82

Median
−3.31
−1.19
−1.06
−1.00
−1.25
−1.25

Min/Max
−12.63/0.25
−8.25/1.38
−8.25/1.38
−8.25/1.38
−5.50/1.38
−5.50/1.38

p value (preoperative)
-
<0.001
<0.001
<0.001
<0.001
<0.001

p value (previous)
-
-
0.115
0.537
0.871
0.465

SD: standard deviation; min: minimum; max: maximum; UDVA: uncorrected distance visual acuity; CDVA: corrected distance visual acuity; MRSE: spherical equivalent of manifest refraction.

: compared to preoperative visit.

: compared to previous visit.

While there was no statistically significant difference in the mean CDVA value at 1 month, statistically significant improvements were observed at 3, 6, 12, and 24 months postsurgery, compared to preoperative values. There was also a statistically significant improvement in the MR at 1 month.

The pre- and postoperative corneal topography parameters are shown in Table 5. The changes in K1, K2, and MPP were statistically significant at all visits compared to the preoperative values.

Table 5: Corneal topography parameters during follow-up.

Preoperative
1 month
3 months
6 months
12 months
24 months

(D)

Mean±SD
54.90 ± 4.81
53.30 ± 5.25
52.54 ± 5.58
51.98 ± 5.00
52.55 ± 5.30
52.42 ± 5.37

Min/Max
47.34/64.71
45.89/63.01
40.19/68.66
40.19/62.95
43.64/63.20
43.64/63.05

p (preoperative)
-
0.202
0.011
<0.001
<0.001
<0.001

p (previous)
-
-
0.71
0.243
0.512
0.124

K₁ (D)

Mean±SD
45.50 ± 2.84
43.53 ± 3.79
43.31 ± 2.25
43.32 ± 2.25
43.81 ± 2.97
43.77 ± 2.94

Min/Max
40.57/55.60
34.00/49.49
38.88/47.07
38.88/47.07
40.19/53.25
40.07/53.25

p (preoperative)
-
0.006
<0.001
<0.001
<0.001
<0.001

p (previous)
-
-
0.253
0.820
0.733
0.096

K₂ (D)

Mean±SD
48.72 ± 3.08
47.20 ± 3.55
46.79 ± 3.01
46.81 ± 3.00
47.28 ± 3.51
47.25 ± 3.48

Min/Max
43.83/58.57
42.25/55.37
40.99/51.96
40.99/51.96
42.03/58.31
41.85/58.31

p (preoperative)
-
0.025
<0.001
<0.001
<0.001
<0.001

p (previous)
-
-
0.409
0.188
0.300
0.503

MPP (D)

Mean±SD
45.98 ± 2.87
44.32 ± 3.49
44.27 ± 3.55
44.24 ± 3.47
44.19 ± 2.96
44.15 ± 2.86

Min/Max
41.52/53.72
37.63/52.47
38.04/58.00
38.04/58.00
39.87/51.82
39.87/51.82

p (preoperative)
-
0.013
0.018
0.016
<0.001
<0.001

p (previous)
-
-
0.319
0.620
0.388
0.519

KVB (m)

Mean±SD
66.72±31.94
62.75±27.37
74.68±34.52
73.68±34.74
78.56±32.55
78.45±32.03

Min/Max
11/139
16/110
12/183
12/183
32/151
32/151

p (preoperative)
-
0.882
0.003
0.004
<0.001
<0.001

p (previous)
-
-
0.112
0.387
0.670
0.823

SD: standard deviation; min: minimum; max: maximum; : steepest keratometry; K₁: flat keratometry; K2: steep keratometry; MPP: mean pupillary power (4.5 mm diameter); KVB: keratoconus vertex back (posterior elevation).

: compared to preoperative visit.

: compared to previous visit.

Table 6 shows the preoperative and postoperative corneal pachymetry values. The mean preoperative pachymetry (thinnest) was 470.02 ± 31.55 μm (min: 406, max: 529) and it was 414.94 ± 45.22 μm (min: 311, max: 496) at 24 months after surgery (p<0.001).

Table 6: Preoperative and postoperative pachymetry.

Corneal pachymetry

Preoperative
1 Month
3 Months
6 Months
12 Months
24 Months

Mean±SD
470±32
403±51
401±46
404±47,11
415±46
415±45

Range (Min/Max)
406/529
313/479
318/480
318/480
311/496
311/496

p
-
<0.001
<0.001
<0.001
<0.001
<0.001

p
-
-
0.272
0.137
0.301
0.803

SD: standard deviation; Min: minimum; Max: maximum

: compared to preoperative visit; paired samples t-test, two-tailed.

: compared to previous visit; paired samples t-test, two-tailed.

The changes in the patients’ higher-order aberrations during follow-up are summarized in Tables 7 and 8. Two years after surgery, statistically significant changes were found in the total HOA-RMS, Coma-RMS, and SA-RMS values at both the 4-mm and 6-mm diameters.

Table 7: Higher-order aberration values (4 mm) during follow-up.

Preoperative
1 month
3 months
6 months
12 months
24 months

HOA-RMS (m)

Mean±SD
1.04 ± 0.57
0.76 ± 0.58
0.61 ± 0.38
0.62 ± 0.39
0.64 ± 0.42
0.63 ± 0.41

Min/Max
0.15/2.58
0.18/2.28
0.15/1.84
0.15/1.84
0.16/1.95
0.16/1.80

p (preoperative)
-
0.153
<0.001
<0.001
<0.001
<0.001

p (previous)
-
-
0.141
0.763
0.982
0.027

COMA-RMS (m)

Mean±SD
0.91 ± 0.55
0.57 ± 0.50
0.45 ± 0.35
0.47 ± 0.35
0.50 ± 0.39
0.49 ± 0.38

Min/Max
0.10/2.35
0.06/1.69
0.03/1.64
0.03/1.64
0.03/1.69
0.03/1.52

p (preoperative)
-
0.024
<0.001
<0.001
<0.001
<0.001

p (previous)
-
-
0.240
<0.001
0.750
0.064

SA-RMS (m)

Mean±SD
0.19 ± 0.16
0.24 ± 0.29
0.11 ± 0.16
0.11 ± 0.16
0.13 ± 0.10
0.13 ± 0.10

Min/Max
0.01/0.71
0.01/1.04
−0.40/0.62
−0.40/0.62
0.00/0.44
0.02/0.45

p (preoperative)
-
0.687
0.087
0.073
0.008
0.006

p (previous)
-
-
0.101
0.645
0.820
0.518

SD: standard deviation; min: minimum; max: maximum; HOA-RMS: root-mean-square of total higher-order aberrations; Coma-RMS: root-mean-square of coma; SA-RMS: root-mean-square of spherical aberration.

: compared to preoperative visit.

: compared to previous visit.

Table 8: Higher-order aberration values (6 mm) during follow-up.

Preop
1 month
3 months
6 months
12 months
24 months

HOA-RMS (m)

Mean±SD
1.04 ± 0.57
0.76 ± 0.58
0.61 ± 0.38
0.62 ± 0.39
0.64 ± 0.42
0.63 ± 0.41

Min/Max
0.15/2.58
0.18/2.28
0.15/1.84
0.15/1.84
0.16/1.95
0.16/1.80

p (preoperative)
-
0.153
<0.001
<0.001
<0.001
<0.001

p (previous)
-
-
0.141
0.763
0.982
0.027

COMA-RMS (m)

Mean±SD
0.91 ± 0.55
0.57 ± 0.50
0.45 ± 0.35
0.47 ± 0.35
0.50 ± 0.39
0.49 ± 0.38

Min/Max
0.10/2.35
0.06/1.69
0.03/1.64
0.03/1.64
0.03/1.69
0.03/1.52

p (preoperative)
-
0.024
<0.001
<0.001
<0.001
<0.001

p (previous)
-
-
0.240
<0.001
0.750
0.064

SA-RMS (m)

Mean±SD
0.19 ± 0.16
0.24 ± 0.29
0.11 ± 0.16
0.11 ± 0.16
0.13 ± 0.10
0.13 ± 0.0

Min/Max
0.01/0.71
0.01/1.04
−0.40/0.62
−0.40/0.62
0.00/0.44
0.02/0.45

p (preoperative)
-
0.687
0.087
0.073
0.008
0.006

p (previous)
-
-
0.101
0.645
0.820
0.518

SD: standard deviation; min: minimum; max: maximum; HOA-RMS: root-mean-square of total higher-order aberrations; Coma-RMS: root-mean-square of coma; SA-RMS: root-mean-square of spherical aberration.

: compared to preoperative visit.

: compared to previous visit.

At 24 months after surgery, no patient had corneal melting, scarring, or perforation; HSV reactivation; or keratoconus progression. No patient experienced a clinically significant complication. Two years after surgery, there was an area of corneal opacity in 7 (15%) of the eyes. However, none of these patients had a decrease in CDVA (Table 8).

Two years after surgery, no patient lost ≥2 line of CDVA. The change in CDVA lines is shown in Figure 1.

Figure 1: Change in corrected distance visual acuity (CDVA).

4. Discussion

Although some CXL protocols result in more cross-linking and a greater increase in Young’s modulus [17], less corneal cross-linking (a smaller increase in Young’s modulus) may still have the same clinical effect (in terms of disease stabilization). In other words, the optimum CXL parameters to produce the clinically desired effect (in terms of stabilization or prophylaxis) are not known. For prophylactic CXL performed simultaneously with PRK, the issue becomes more complicated because defining the optimum prophylactic parameters is a greater challenge when even the optimum stabilizing parameters are not defined. Additionally, most eyes with stable keratoconus are also stable after a PRK procedure even if cross-linking is not applied, which further increases the complexity of this issue [18, 19]. Consistent with published reports, keratoconus progression was not seen in any patient during the postoperative follow-up period in our study [5–15, 18–21]. It should be noted that a non-TG PRK is associated with a decrease in HOA and an increase in CDVA [19], and we believe that non-TG PRK is a valuable option for some patients to limit the ablation depth and to use a less complicated ablation profile. With so many parameters (PRK, transepithelial-PRK, TG-PRK, and transepithelial TG-PRK in combination with different CXL protocols) and a relatively stable disease, the optimum parameters for PRK and simultaneous CXL are difficult to determine without large-scale, comparative, randomized trials with an extended duration of follow-up to establish the long-term stability of this procedure in keratoconus treatment. Although these large-scale studies have not been performed, we believe that each study with different parameters adds valuable information to get closer to identifying the optimum parameters.

In this study, we evaluated same-day simultaneous TG-transepithelial-PRK and accelerated CXL treatment in 46 patients with frequent follow-up visits for 2 years. A different accelerated CXL protocol was used with a reduced soak time, which was previously not used in combination with PRK. All patients were examined four times during the first year and all patients were examined at 2 years. This follow-up schedule is routine in our refractive surgery clinic, which is in a tertiary referral eye hospital. Every patient was examined by an ophthalmology resident first, then a specialist, and then a faculty member. Thus, although the number of patients was not high, there were no missing pieces of data during the 2-year follow-up, and early changes in visual acuity and corneal topography parameters, including high-order aberrations, during the first year are described clearly.

A reduction in HOA after TG-PRK in keratoconus eyes (with or without the addition of CXL) is not surprising and is a consistent finding in published studies. In this study, total HOA was significantly lower than its preoperative levels and total HOA at 24 months was significantly lower than it was 12 months after surgery. Coma, which is usually a significant aberration in keratoconus eyes, was reduced significantly at the 1-month visit. The mean manifest refraction was −3.78±3.26 D preoperatively and −1.39±1.82 D postoperatively; however, the results were distributed over a wide range and MRSE has, by definition, limited value in describing refractive error in a patient with irregular astigmatism. Additionally, it is difficult to perform subjective refraction in patients with irregular astigmatism because large dioptric changes may induce only a minor change in the patient’s visual acuity, and therefore it is common for patients’ verbal responses to be inconsistent. With these limitations in mind, MRSE values were significantly decreased after the treatment (p<0.001). As a result of the decreased MRSE and HOA values, both UDVA and CDVA improved significantly after TG-transepithelial PRK and accelerated CXL. The mean CDVA at 3 months was better than that at 1 month (p=0.01) and mean CDVA at 12 months was better than that at 6 months (p=0.003). The effect of simultaneous UDVA treatment was more striking than its effect on CDVA. The best way to assess mean line loss or gains in a group of patients is to evaluate logMAR visual acuity. An improvement of 1 log unit (a 0.1 increase in the logMAR value) means a loss of one ETDRS line. It also means that the minimum angle of resolution is multiplied by 1.2589¹. However, a 3-log-unit improvement (0.3 decrease in logMAR) means that the minimum angle of resolution is multiplied by 1/1.2589³, resulting in a 50% decrease in the minimum angle of resolution (doubling of visual acuity). The mean UDVA improvement in this study was 3.5 log units (0.77 logMAR preoperatively and 0.42 logMAR postoperatively). Additionally, UCVA values at 24 months were better than UCVA values at 12 months (p=0.04). These changes in CDVA and UDVA show that corneal remodeling and visual acuity improvement continues during the first 2 years after surgery.

To the best of our knowledge, only a few transepithelial TG-guided PRK-CXL studies report outcomes at 2 years or beyond. With the exception of the study performed by Kanellopoulos et al., all of the studies had fewer patients than this study. Additionally, the CXL protocol (accelerated or not), PRK or PTK method (transepithelial or not, topography guided or not, excimer laser platform), or both differed between our study and the other studies in the literature [9–15].

Alessio et al. [9] reported outcomes after a 2-year follow-up of simultaneous transepithelial TG-PRK and CXL in 17 eyes. They performed CXL in one eye and simultaneous TG-PRK and CXL on the contralateral eye; however, they used a standard protocol for CXL (30-minute soak, 30-minute irradiation at 5.4 J/cm²) and they used the iVIS Suite custom ablation system and Corneal Interactive Programmed Topographic Ablation (CIPTA) planning software for transepithelial TG-PRK. Consistent with our study, they reported that an improvement in visual acuity continued beyond 1 year after the operation. Kontadakis et al. [10] reported outcomes of a 3-year follow-up after simultaneous TG-PRK and CXL in 30 eyes. Their results are consistent with our study and report an improvement of 2.7 log units in UDVA and an improvement of 0.9 log units in CDVA at 3 years. However, in contrast to our study, they used the standard CXL protocol (30-minute riboflavin-A soak, 30-minute irradiation at 5.4 J/cm²). A solid-state excimer laser with a wavelength of 213 nm with a Pulzar Z1 Excimer laser platform was used for a transepithelial custom ablation profile. Kymionis et al. [12] reported the outcomes of simultaneous transepithelial PTK (Allegretto Wavelight excimer laser, Wavelight Laser Technologie AG) and the standard CXL protocol in 23 eyes (16 of these eyes had follow-up periods of more than 2 years). In addition to that, Grentzelos et al. reported that combined transepithelial PTK and conventional PRK followed simultaneously by CXL (Cretan protocol plus) results in favorable outcomes in keratoconus patients [13]. Kanellopoulos et al. [11] reported the largest series with the longest follow-up using accelerated CXL and transepithelial TG-PRK. The term “accelerated” has a broad definition and different protocols of accelerated cross-linking have been used to treat keratoconus. Kanellopoulos et al. used a 30-minute riboflavin soak and an irradiation power of 10 mW/cm² in contrast to our study (20-minute riboflavin soak and an irradiation power of 18 mW/cm²). Consistent with our study, the average gain/loss in visual acuity was consistently positive, starting from the first postoperative month, with gradual and continuous improvement toward the 3-year visit. Although we used a different CXL protocol and a different ablation pattern (Schwind Amaris ORC-CAM), our results are comparable to the studies above [9–13].

Diffuse corneal haze, which emerges in a few days after CXL in virtually all eyes, generally resolves over time. It is identified as a dust-like change in the stroma. In addition, some patients suffer from scarring that persists and can decrease visual acuity. However, these two words— “haze” and “scar”—are sometimes used interchangeably in the literature [19, 22]. No histopathological studies have evaluated these two types of opacities (haze and scar) after cross-linking and the distinction between a very mild superficial scar and a dense localized haze is not clear in the literature. In our clinical practice, we prefer to use the word “scar” to define a localized area of dense corneal opacity (an opaque patch) that is usually accompanied by a localized decrease in corneal thickness in the early postoperative period that may distort the topographical pattern. Similar to haze, the scars also fade appreciably within the first postoperative year. The effect of the opacity (haze or scar) depends on its location, severity, and the corresponding change in topography [23]. To avoid confusion, in this study we report persistent (2 years) localized corneal opacities as a complication. Two years postoperatively, seven patients (15%) in our study had still mild localized areas of central/paracentral corneal opacities. However, CDVA was increased in all of these patients (Table 9).

Table 9: Preoperative and postoperative (2 years) DCVA in eyes with a localized corneal opacity.

Preoperative CDVA
Postoperative CDVA

0.4
0.9

0.6
0.6

0.7
0.4

0.7
1.0

0.4
0.1

0.3
0.7

0.8
0.9

The most important limitation of this study is its retrospective nature and lack of a control group. In addition, slit-lamp examinations were performed by different residents at different visits. These should be considered when interpreting the results. For example, there was no objective measure of corneal haze before and after treatment because it was not a routine part of our preoperative and postoperative examinations. In addition to that, endothelial cell density (ECD) was not assessed in our patients after the operation; as a result, it was not possible to report ECD changes. Despite these limitations, this retrospective case series describes, for the first time, the clinical results of transepithelial TG-PRK using the Amaris excimer laser platform and ORC-CAM’s ablation profile with a simultaneous accelerated CXL protocol in keratoconus patients, and a relatively high number of patients were included with a long follow-up.

In conclusion, we found that the transepithelial TG-PRK with the Amaris Excimer laser platform and simultaneous accelerated CXL (20-minute riboflavin soak time, 5-minute 18 mW/cm² UVA irradiation) was safe and effective for treating keratoconus patients. However, large-scale, comparative, randomized trials are required to determine the optimum parameters and most suitable patients.

Data Availability

The data used to support the findings of this study are available from the corresponding author upon request.

Ethical Approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Consent

For this type of study, formal consent is not required.

Conflicts of Interest

The authors declare that there are no conflicts of interest regarding the publication of this article.

Authors’ Contributions

Sibel Ahmet, Alper Ağca, Yusuf Yıldırım, and Ahmet Demirok were involved in conceptualization of the manuscript and design of the study; Ahmet Alperen Koç, Mesut Toğaç, Dilek Yaşa, and Burçin Kepez Yıldız were involved in acquisition, analysis, and interpretation of data; Ahmet Alperen Koç, Mesut Toğaç, Dilek Yaşa, and Burçin Kepez Yıldız were involved in drafting the manuscript; Sibel Ahmet, Alper Ağca, Yusuf Yıldırım, and Ahmet Demirok were involved in critical review and revision of the manuscript for important intellectual content. All authors read and approved the final manuscript.

References

F. Raiskup, A. Theuring, L. E. Pillunat, and E. Spoerl, “Corneal collagen crosslinking with riboflavin and ultraviolet-a light in progressive keratoconus: ten-year results,” Journal of Cataract & Refractive Surgery, vol. 41, no. 1, pp. 41–46, 2015.

G. Wollensak, E. Spoerl, and T. Seiler, “Stress-strain measurements of human and porcine corneas after riboflavin-ultraviolet-A-induced cross-linking,” Journal of Cataract & Refractive Surgery, vol. 29, no. 9, pp. 1780–1785, 2003.

M. Tomita, M. Mita, and T. Huseynova, “Accelerated versus conventional corneal collagen crosslinking,” Journal of Cataract & Refractive Surgery, vol. 40, no. 6, pp. 1013–1020, 2014.

Y. Yıldırım, O. Olcucu, Z. K. Gunaydin et al., “Comparison of Accelerated Corneal Collagen Cross-linking Types for Treating Keratoconus,” Current Eye Research, vol. 42, no. 7, pp. 971–975, 2017.

A. M. Al-Amri, “5-year follow-up of combined non-topography guided photorefractive keratectomy and corneal collagen cross linking for keratoconus,” International Journal of Ophthalmology, vol. 11, no. 1, pp. 48–52, 2018.

A. J. Kanellopoulos and P. S. Binder, “Collagen cross-linking (CCL) with sequential topography-guided PRK: a temporizing alternative for keratoconus to penetrating keratoplasty,” Cornea, vol. 26, no. 7, pp. 891–895, 2007.

I. Knezović, M. B. Višnjić, and H. Raguž, “Partial topography-guided photorefractive keratectomy followed by corneal cross linking in the management of progressive keratoconus: our initial ten-month results,” Acta clinica Croatica, vol. 54, no. 2, pp. 193–200, 2015.

G. D. Kymionis, G. A. Kontadakis, G. A. Kounis et al., “Simultaneous topography-guided PRK followed by corneal collagen cross-linking for keratoconus,” Journal of Refractive Surgery, vol. 25, no. 9, pp. S807–S811, 2009.

G. Alessio, M. L'Abbate, C. Sborgia, and M. G. La Tegola, “Photorefractive keratectomy followed by cross-linking versus cross-linking alone for management of progressive keratoconus: Two-year follow-up,” American Journal of Ophthalmology, vol. 155, no. 1, pp. 54–65, 2013.

G. A. Kontadakis, V. P. Kankariya, K. Tsoulnaras, A. I. Pallikaris, A. Plaka, and G. D. Kymionis, “Long-Term Comparison of Simultaneous Topography-Guided Photorefractive Keratectomy Followed by Corneal Cross-linking versus Corneal Cross-linking Alone,” Ophthalmology, vol. 123, no. 5, pp. 974–983, 2016.

A. J. Kanellopoulos and G. Asimellis, “Keratoconus management: long-term stability of topography-guided normalization combined with high-fluence CXL stabilization (The Athens Protocol),” Journal of Refractive Surgery, vol. 30, no. 2, pp. 88–93, 2014.

G. D. Kymionis, M. A. Grentzelos, V. P. Kankariya et al., “Long-term results of combined transepithelial phototherapeutic keratectomy and corneal collagen crosslinking for keratoconus: Cretan protocol,” Journal of Cataract & Refractive Surgery, vol. 40, no. 9, pp. 1439–1445, 2014.

M. A. Grentzelos, G. A. Kounis, V. F. Diakonis et al., “Combined transepithelial phototherapeutic keratectomy and conventional photorefractive keratectomy followed simultaneously by corneal crosslinking for keratoconus: Cretan protocol plus,” Journal of Cataract & Refractive Surgery, vol. 43, no. 10, pp. 1257–1262, 2017.

M. Camellin, J. M. Guidotti, and S. Arba Mosquera, “Corneal-Wavefront guided transepithelial photorefractive keratectomy after corneal collagen cross linking in keratoconus,” Journal of Optometry, vol. 10, no. 1, pp. 52–62, 2017.

T. M. Müller and A. P. Lange, “Topography-Guided PRK and Crosslinking in Eyes with Keratoconus and Post-LASIK Ectasia,” Klinische Monatsblätter für Augenheilkunde, vol. 234, no. 4, pp. 451–454, 2017.

K. Kamiya, R. Ishii, K. Shimizu, and A. Igarashi, “Evaluation of corneal elevation, pachymetry and keratometry in keratoconic eyes with respect to the stage of Amsler-Krumeich classification,” British Journal of Ophthalmology, vol. 98, no. 4, pp. 459–463, 2014.

A. Hammer, O. Richoz, S. A. Mosquera, D. Tabibian, F. Hoogewoud, and F. Hafezi, “Corneal biomechanical properties at different corneal cross-linking (CXL) irradiances,” Investigative Ophthalmology & Visual Science, vol. 55, no. 5, pp. 2881–2884, 2014.

E. Chelala, H. El Rami, A. Dirani, A. Fadlallah, O. Fakhoury, and E. Warrak, “Photorefractive keratectomy in patients with mild to moderate stable keratoconus: A five-year prospective follow-up study,” Clinical Ophthalmology, vol. 7, pp. 1923–1928, 2013.

E. A. Kasparova and A. A. Kasparov, “Six-year experience with excimer laser surgery for primary keratoconus in Russia.,” Journal of refractive surgery (Thorofare, N.J. : 1995), vol. 19, no. 2, pp. S250–254, 2003.

H. Khakshoor, F. Razavi, A. Eslampour, and A. Omdtabrizi, “Photorefractive keratectomy in mild to moderate keratoconus: Outcomes in over 40-year-old patients,” Indian Journal of Ophthalmology, vol. 63, no. 2, pp. 157–161, 2015.

G. Cennamo, A. Intravaja, D. Boccuzzi, G. Marotta, and G. Cennamo, “Treatment of keratoconus by topography-guided customized photorefractive keratectomy: Two-year follow-up study,” Journal of Refractive Surgery, vol. 24, no. 2, pp. 145–149, 2008.

F. Raiskup, A. Kißner, A. Hoyer, E. Spörl, and L. E. Pillunat, “Corneal scar development after cross-linking in keratoconus,” Der Ophthalmologe, vol. 107, no. 9, pp. 837–842, 2010.

F. Raiskup, A. Hoyer, and E. Spoerl, “Permanent corneal haze after riboflavin-UVA-induced cross-linking in keratoconus,” Journal of Refractive Surgery, vol. 25, no. 9, pp. S824–S828, 2009.