Journal of Refractive Surgery

Surgical Technique 

Epithelial Photorefractive Keratectomy and Corneal Cross-linking for Keratoconus: The Tel-Aviv Protocol

Igor Kaiserman, MD, MSc, MHA; Michael Mimouni, MD; Gilad Rabina, MD

Abstract

PURPOSE:

To present the Tel-Aviv Protocol for patients with progressive keratoconus, which consists of epithelial photorefractive keratectomy (ePRK), and corneal cross-linking (CXL).

METHODS:

This was a retrospective case series of 20 consecutive patients diagnosed as having progressive keratoconus at Care-Vision Laser Centers, Tel Aviv, Israel. The Tel-Aviv Protocol included laser epithelial ablation using the EX500 excimer laser (Alcon Laboratories, Inc., Fort Worth, TX) with 50% of the manifest refractive astigmatism (on the same axis) while the spherical ablation is added so as not to exceed a total of 50-µm ablation of the epithelium and anterior stroma. Afterward, all patients underwent CXL. Data collected included thinnest corneal thickness (TCT), subjective astigmatism, mean keratometric power, maximum keratometric power (Kmax), uncorrected distance visual acuity (UDVA), and corrected distance visual acuity (CDVA).

RESULTS:

A total of 20 eyes of 20 patients with a mean age of 28.0 ± 6.5 years (range: 13 to 40 years) and a mean follow-up of 823 ± 337 days (range: 266 to 1,749 days) were included. There was a significant improvement in both UDVA (from 0.95 ± 0.73 to 0.22 ± 0.15 logMAR, P < .001) and CDVA (from 0.24 ± 0.13 to 0.13 ± 0.12 logMAR, P < .001) at the end of the follow-up period. There was a significant improvement in mean keratometry (from 46.86 ± 2.48 to 45.00 ± 2.27 diopters [D], P < .001), Kmax (from 48.18 ± 2.74 to 45.97 ± 2.55 D, P < .001), and Kmin (from 45.54 ± 2.35 to 44.03 ± 2.12 D, P < .001). TCT was significantly lower following the procedure (from 450.90 ± 35.99 to 404.90 ± 43.96 µm, P < .001). No complications and no progression in keratoconus severity were noticed during the follow-up period.

CONCLUSIONS:

The Tel-Aviv Protocol for patients with progressive keratoconus provides good improvement in visual acuity and astigmatism while halting the progression of keratoconus.

[J Refract Surg. 2019;35(6):377–382.]

Abstract

PURPOSE:

To present the Tel-Aviv Protocol for patients with progressive keratoconus, which consists of epithelial photorefractive keratectomy (ePRK), and corneal cross-linking (CXL).

METHODS:

This was a retrospective case series of 20 consecutive patients diagnosed as having progressive keratoconus at Care-Vision Laser Centers, Tel Aviv, Israel. The Tel-Aviv Protocol included laser epithelial ablation using the EX500 excimer laser (Alcon Laboratories, Inc., Fort Worth, TX) with 50% of the manifest refractive astigmatism (on the same axis) while the spherical ablation is added so as not to exceed a total of 50-µm ablation of the epithelium and anterior stroma. Afterward, all patients underwent CXL. Data collected included thinnest corneal thickness (TCT), subjective astigmatism, mean keratometric power, maximum keratometric power (Kmax), uncorrected distance visual acuity (UDVA), and corrected distance visual acuity (CDVA).

RESULTS:

A total of 20 eyes of 20 patients with a mean age of 28.0 ± 6.5 years (range: 13 to 40 years) and a mean follow-up of 823 ± 337 days (range: 266 to 1,749 days) were included. There was a significant improvement in both UDVA (from 0.95 ± 0.73 to 0.22 ± 0.15 logMAR, P < .001) and CDVA (from 0.24 ± 0.13 to 0.13 ± 0.12 logMAR, P < .001) at the end of the follow-up period. There was a significant improvement in mean keratometry (from 46.86 ± 2.48 to 45.00 ± 2.27 diopters [D], P < .001), Kmax (from 48.18 ± 2.74 to 45.97 ± 2.55 D, P < .001), and Kmin (from 45.54 ± 2.35 to 44.03 ± 2.12 D, P < .001). TCT was significantly lower following the procedure (from 450.90 ± 35.99 to 404.90 ± 43.96 µm, P < .001). No complications and no progression in keratoconus severity were noticed during the follow-up period.

CONCLUSIONS:

The Tel-Aviv Protocol for patients with progressive keratoconus provides good improvement in visual acuity and astigmatism while halting the progression of keratoconus.

[J Refract Surg. 2019;35(6):377–382.]

Keratoconus is the most common corneal ectasia, with a prevalence of 0.3 to 250 cases per 100,000.1,2 It is a bilateral, irregular astigmatism with corneal thinning that leads to deterioration in corrected distance visual acuity (CDVA) and uncorrected distance visual acuity (UDVA).3–5

The aim of corneal cross-linking (CXL), first described by Spoerl in 1998, is to slow the progression of keratoconus.6 In 2003, the Dresden Protocol described CXL with ultraviolet-A (UV-A) for 30 minutes.7 Since then, CXL has been the main treatment for halting progression of keratoconus. In recent years, several accelerated protocols have been reported to provide comparable results to the Dresden Protocol.8–10

Despite reports of some improvement in keratometry following CXL,11–13 the benefits in terms of improvement in UDVA or CDVA are negligible.13,14 In addition, approximately 15% of patients with keratoconus cannot tolerate contact lenses despite repeated attempts.15 As such, several attempts have been made to not only prevent the progression of keratoconus but also improve visual acuity (UDVA and CDVA) in patients with keratoconus. In the Athens Protocol published in 2009, Kanellopoulos et al.16 reported that combined topography-guided photorefractive keratectomy (PRK) and CXL is more effective than CXL followed by PRK 6 months later. The long-term effects of the Athens Protocol on the cornea are still unknown because only one report (indicating no progression) regarding long-term outcomes has been published,17 and there is still a risk for progression or ectasia after this procedure. Several studies have compared manual removal of the epithelium to transepithelial phototherapeutic keratectomy (PTK) followed by CXL, and they have described mild improvement in UDVA.11,18,19

The aim of this study was to present the Tel-Aviv Protocol, using an epithelial PRK (ePRK) and combined with CXL for patients with keratoconus.

Patients and Methods

Study Participants

This retrospective study included 20 consecutive patients diagnosed as having keratoconus at Care-Vision Laser Centers, Tel Aviv, Israel. All patients underwent CXL with the Tel-Aviv Protocol, by a single surgeon (IK), who also developed the protocol. Inclusion criteria were CDVA of 20/40 or worse, spherical equivalent (SE) of −10.00 diopters (D) or less, maximum keratometric power (Kmax) of 55.00 D or less, thinnest corneal thickness (TCT) of 430 µm or greater, and Amsler–Krumeich stages of 1 to 2. Patients with a history of previous ocular surgery, a history of autoimmune diseases or diabetes, pregnancy, and TCT below 430 µm were excluded from this study.

All data for the study were collected and analyzed in accordance with the policies and procedures of the institutional review board of the Barzilai Medical Center and the tenets set forth in the Declaration of Helsinki.

Surgical Protocol

The Tel-Aviv Protocol includes removal of the epithelium by a customized refractive laser profile. A 50-µm laser ablation of the epithelium and anterior stroma is programmed in the EX500 excimer laser (Alcon Laboratories, Inc., Fort Worth, TX), which includes a myopic spherical treatment and an astigmatic treatment. The astigmatic treatment is planned as 50% of the manifest refractive astigmatism (on the same axis), whereas the spherical ablation is added so as not to exceed a total of 50-µm ablation of the epithelium and anterior stroma removal centrally. The laser epithelial removal is delivered with cyclotorsion correction and on the visual axis (not the center of the pupil) on a 6.5-mm optic zone.

After ePRK, all patients underwent CXL as described by Wollensak et al.7 Briefly, topical drops of riboflavin 0.1% with 20% dextran were instilled every 2 minutes for 30 minutes, followed by ultrasonic pachymetry. If central corneal thickness (CCT) was less than 400 µm, a hypotonic riboflavin (without dextran) was used until CCT was greater than 400 µm. Afterward, ultraviolet-A (IROC; Innocross AG, Zurich, Switzerland) was applied for 10 minutes with a total irradiance of 9 mW/cm2 (Table 1). At the end of CXL, topical moxifloxacin and dexamethasone 0.1% were used and followed by a bandaged contact lens.

CXL Methods

Table 1:

CXL Methods

Patient Follow-up

Patients were treated with topical moxifloxacin for 1 week and topical dexamethasone 0.1% for a total of 1 month, with gradual tapering down. Follow-up visits were performed 1 day, 1 week, 1 month, and 3 months following the procedure, and every 6 months thereafter.

Data Collection

The medical files of all patients were reviewed and the following was extracted: age, gender, date of surgery, subjective sphere, subjective cylinder, mean keratometric power, minimum keratometric power (Kmin), Kmax, UDVA, and CDVA of the operated eye and both eyes. Safety index (CDVA after/CDVA before) and efficacy index (UDVA after/CDVA before) were calculated. Keratometry and TCT were measured with the Sirius Scheimpflug Analyzer (Costruzione Strumenti Oftalmici, Florence, Italy).

Statistical Analysis

Data were entered in a spreadsheet (Excel 15.2; Microsoft Corporation, Redmond, WA) and analyzed with SPSS statistical software (version 23.0; SPSS, Inc., Cary, NC). A paired t test was used for the analysis of continuous data and comparison of parameters before and after treatment. For statistical analyses, Snellen values were converted to logMAR units. A two-sided P value of less than .05 was considered statistically significant. Mean values are presented with standard deviations.

Results

A total of 20 eyes of 20 patients (45% female) with a mean age of 28.00 ± 6.49 years (range: 13 to 40 years) and a mean follow-up of 822.5 ± 336.7 days (range: 266 to 1,749 days) were included in the study. Changes in the assessed parameters are depicted in Table 2.

Comparison of Baseline and Postoperative Parameters

Table 2:

Comparison of Baseline and Postoperative Parameters

Change in Visual Acuity

There was a significant improvement in both UDVA (from 0.95 ± 0.73 to 0.22 ± 0.15 logMAR, P < .001) and CDVA (from 0.24 ± 0.13 to 0.13 ± 0.12 logMAR, P < .001) at the end of the follow-up period. Mean safety index was 1.31 ± 0.21 (range: 1.00 to 1.75) and mean efficacy index was 1.07 ± 0.21 (range: 0.73 to 1.64).

Change in Keratometry and TCT

There was a significant improvement in mean keratometry (from 46.86 ± 2.48 to 45.00 ± 2.27 D, P < .001), Kmax (from 48.18 ± 2.74 to 45.97 ± 2.55 D, P < .001), and Kmin (from 45.54 ± 2.35 to 44.03 ± 2.12 D, P < .001). The mean TCT was significantly lower following the procedure (450.90 ± 35.99 vs 404.90 ± 43.96 µm, P < .001). Typical examples of the change in corneal topography after ePRK-CXL are depicted in Figures 12.

A 35-year-old man (patient 1) treated with the Tel-Aviv Protocol. (A) Preoperative axial curvature and axial curvature after 750 days of follow-up. (B) Epithelial photorefractive keratectomy (ePRK) ablation depth of 51 µm (laser treatment was for −1.50 −2.00 × 125 at the 6.5-mm optical zone). During follow-up, maximum keratometric power (Kmax) reduced 2.00 diopters (D), thinnest cornea thickness (TCT) changed from 496 to 456 µm, uncorrected distance visual acuity (UDVA) improved from 2 to 0.07 logMAR and corrected distance visual acuity (CDVA) improved from 0.12 to 0.04 logMAR. Preoperative manifest refraction of −1.25 −4.00 × 125 (spherical equivalent [SE] of −3.25 D) improved to +0.25 D (SE of +0.25 D). Safety index of 1.2 and efficacy index of 1.13.

Figure 1.

A 35-year-old man (patient 1) treated with the Tel-Aviv Protocol. (A) Preoperative axial curvature and axial curvature after 750 days of follow-up. (B) Epithelial photorefractive keratectomy (ePRK) ablation depth of 51 µm (laser treatment was for −1.50 −2.00 × 125 at the 6.5-mm optical zone). During follow-up, maximum keratometric power (Kmax) reduced 2.00 diopters (D), thinnest cornea thickness (TCT) changed from 496 to 456 µm, uncorrected distance visual acuity (UDVA) improved from 2 to 0.07 logMAR and corrected distance visual acuity (CDVA) improved from 0.12 to 0.04 logMAR. Preoperative manifest refraction of −1.25 −4.00 × 125 (spherical equivalent [SE] of −3.25 D) improved to +0.25 D (SE of +0.25 D). Safety index of 1.2 and efficacy index of 1.13.

A 27-year-old woman (patient 9) treated with the Tel-Aviv Protocol. (A) Preoperative axial curvature and axial curvature after 476 days of follow-up. (B) Epithelial photorefractive keratectomy (ePRK) ablation depth of 57 µm (laser treatment was for −2.00 −2.00 × 20 at 6.5-mm optical zone). During follow-up, maximum keratometric power (Kmax) reduced 3.00 diopters (D), thinnest corneal thickness (TCT) changed from 445 to 388 µm, uncorrected distance visual acuity (UDVA) improved from 2 to 0.3 logMAR, and corrected distance visual acuity (CDVA) improved from 0.39 to 0.17 logMAR. Preoperative manifest refraction of −2.00 −4.50 × 20 (spherical equivalent [SE] of −4.25 D) improved to +0.75 −2.50 × 180 (SE of −0.50 D). Safety index of 1.75 and efficacy index of 1.25.

Figure 2.

A 27-year-old woman (patient 9) treated with the Tel-Aviv Protocol. (A) Preoperative axial curvature and axial curvature after 476 days of follow-up. (B) Epithelial photorefractive keratectomy (ePRK) ablation depth of 57 µm (laser treatment was for −2.00 −2.00 × 20 at 6.5-mm optical zone). During follow-up, maximum keratometric power (Kmax) reduced 3.00 diopters (D), thinnest corneal thickness (TCT) changed from 445 to 388 µm, uncorrected distance visual acuity (UDVA) improved from 2 to 0.3 logMAR, and corrected distance visual acuity (CDVA) improved from 0.39 to 0.17 logMAR. Preoperative manifest refraction of −2.00 −4.50 × 20 (spherical equivalent [SE] of −4.25 D) improved to +0.75 −2.50 × 180 (SE of −0.50 D). Safety index of 1.75 and efficacy index of 1.25.

Change in Manifest Refraction

There was a significant reduction in both sphere (from −1.49 ± 2.80 to −0.23 ± 1.47 D, P = .01) and cylinder (from −2.92 ± 1.03 to −1.20 ± 0.82 D, P < .001). Figure 3 demonstrates double-angle plots before and after the Tel-Aviv Protocol.

Double-angle plot before and after Tel-Aviv Protocol. ATR = against-the-rule; D = diopters; WTR = with-the-rule

Figure 3.

Double-angle plot before and after Tel-Aviv Protocol. ATR = against-the-rule; D = diopters; WTR = with-the-rule

Discussion

In this study, we describe the Tel-Aviv Protocol (ePRK-CXL) for progressive keratoconus. The purpose of ePRK-CXL is to slow the progression of keratoconus, reduce astigmatism (including irregular astigmatism), and improve UDVA and CDVA of the operated eye without excessively thinning or weakening the cornea. In this study, with an average follow-up of more than 2 years, UDVA of the operated eye improved from 0.95 ± 0.73 to 0.22 ± 0.15 logMAR (P < .001) and Kmax was reduced from 48.18 ± 2.74 to 45.97 ± 2.55 D (P < .001).

The purpose of CXL is to slow the progression of keratoconus and, based on previous results, it has little to no influence on visual acuity. Previous studies found that after CXL with manual epithelium removal there is a mild change in visual acuity that ranges from −0.14 to +0.12 logMAR.12–14,20–22 In addition, there are complications that may influence visual acuity such as halos, corneal edema, haze, infectious keratitis, recurrent corneal erosions, and inflammatory reaction.12,13,20,22,23

Patients' contact lens intolerance and the will to gain better UDVA after CXL have led to new surgical techniques of CXL combined with PTK or PRK. In 2009, Kanellopoulos et al.16 published the Athens Protocol. In this study, they used topography-guided PRK after epithelium removal with a 50-µm planned stromal removal. Later, Stojanovic et al.24 recommended a maximum stromal ablation of 60 µm after epithelium removal and a minimal postoperative corneal thickness of 400 µm. Lin et al.25 reported that the refractive treatment was limited by a minimum residual stromal depth of 300 µm and maximum stromal ablation depth of 80 µm. Few studies have compared manual removal of the epithelium to removal by PRK. Kymionis et al. published the Cretan Protocol (a combination of transepithelial PTK and CXL) in 201418 and the Cretan Protocol plus (simultaneous conventional PRK followed by CXL) in 2017.26 The epithelium was removed using transepithelial PTK. The Cretan Protocol included 23 eyes and Kymionis et al. found an improvement in UDVA from 0.99 ± 0.57 logMAR preoperatively to 0.61 ± 0.36 logMAR at the last follow-up, and the mean steep keratometry changed from 53.39 ± 7.14 to 49.99 ± 4.36 D at the last follow-up.18 Kapasi et al.11 found CDVA improvement of 2.30 ± 0.96 lines for the PTK group in comparison to 0.00 ± 0.33 lines in the manual removal of the epithelium group. The Tel-Aviv Protocol (ePRK-CXL) demonstrated similar improvement in UDVA to previous protocols, with an average change from 1.00 ± 0.71 logMAR preoperatively to 0.20 ± 0.08 logMAR postoperatively.

The Athens Protocol aims to improve corrected vision in patients with keratoconus by a limited topography-guided PRK ablation of the stroma. Kanellopoulos et al. examined 325 eyes, with 3 years of follow-up, divided into two groups. The first group underwent CXL with topography-guided PRK performed 6 months later and the second group underwent CXL with topography-guided PRK on the same day. Mean UDVA improved from 0.9 ± 0.3 to 0.49 ± 0.25 logMAR and mean reduction in keratometry was 2.75 ± 1.30 D. They concluded that same-day topography-guided PRK and CXL appears to be superior to CXL with later PRK in the visual rehabilitation of progressing keratoconus.16 Sakla et al.27 examined 85 eyes of 66 patients, with 1-year follow-up. They performed manual removal of the epithelium followed by partial topography-guided PRK, which included correction of up to 70% of astigmatism and some of the sphere component without exceeding 50-µm ablation in planned stromal removal. They found improvement of UDVA from preoperative 0.86 ± 0.39 to 0.46 ± 0.49 logMAR and reduction in Kmax from 48.10 ± 3.68 to 46.05 ± 3.94 D. Thereafter, several small studies demonstrated similar results.28–30 After a 3-year follow-up, Kanellopoulos and Asimellis17 concluded that the Athens Protocol demonstrates safe and effective results as a keratoconus management option. As far as we know, this is the only long-term follow-up of the Athens Protocol and the long-term effects of this procedure on the cornea are still unknown. Other published complications of the Athens Protocol include haze in 5% to 30% of the cases.28,29

According to previous studies, after CXL with manual removal of the epithelium (without laser ablation) there is a thinning of 0 to 50 µm in CCT.15,31,32 Using the Tel-Aviv Protocol, TCT was reduced by a similar amount of 46 µm (from 450.90 ± 35.99 to 404.90 ± 43.96 µm, P < .001), with no keratoconus progression during the 2-year follow-up time. In comparison, the mean CCT after 3 years follow-up of the Athens Protocol reduced 81 µm, from 451.91 ± 40.02 µm preoperatively to 370.52 ± 58.21 µm postoperatively.17,28,30 It is worth noting that many of the other studies on CXL combined with PRK did not publish preoperative or postoperative CCT and reported that no ectasia cases were noted.16,17,27–30

The Athens Protocol and similar recent studies showed an improvement of 0.5 logMAR in UDVA and reduction of 2.00 D in Kmax, but a reduction of 81 µm in CCT was induced. With the Tel-Aviv Protocol, similar refractive and topographic improvements were noticed but a change of only 46 µm in CCT, similar to CCT after CXL with manual epithelial removal. Thus, the Tel-Aviv Protocol presents a good combination of visual acuity and astigmatism improvement with a smaller reduction in corneal thickness.

Seiler et al.33 used customized irradiation patterns, instead of homogeneous irradiation, on the cornea during CXL. Their results showed that Kmax decreased −1.70 ± 2.00 D in the customized CXL group in comparison to −0.90 ± 1.30 D in the standard CXL. They concluded that customized CXL had a shorter epithelial healing time, a stronger flattening effect, and better regularization of the cornea compared to the standard CXL. Later, more studies on customized CXL demonstrated similar results.34–36

Epithelial thickness at the cone area was measured in previous studies between 30 and 38 µm and thicker in the surrounding area.37,38 In the Tel-Aviv Protocol, a total corneal ablation of 50 µm was performed. Thus, we believe that an ablation of approximately 12 to 20 µm was performed on the anterior stroma, specifically in the area of the cone that is the area mostly responsible for the visual aberrations. Furthermore, this astigmatic removal of epithelium and Bowman's layer might result in an astigmatic CXL effect, similar to what Seiler et al.33,35 showed in their studies about customized CXL. We believe ePRK-CXL results in better visual acuity in comparison to standard CXL in part due to the customized CXL effect.

This study has several limitations, including the relatively small number of patients, its retrospective nature, using a single arm without comparison to other existing keratorefractive surgical techniques for keratoconus (eg, Athens Protocol and Cretan Protocol), and lack of the epithelial map prior to surgery and during the follow-up.

The Tel-Aviv Protocol of ePRK-CXL for patients with progressive keratoconus provides improvement in visual acuity and astigmatism without increasing the risk of progression or ectasia and without excessively thinning the cornea. A large-scale prospective study is needed to properly and rigorously assess this potential new treatment for appropriate patients with keratoconus.

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CXL Methods

ParameterVariable
Treatment targetKeratoconus
Fluence (total) (J/cm2)5.4
Soak time and interval (minutes)30 (q2)
Intensity (mW)9
Treatment time (minutes)10
Epithelium statusOff
ChromophoreRiboflavin (VibeXTM)
Chromophore carrierDextran
Chromophore osmolarityIso-osmolar
Chromophore concentration0.1%
Light sourceIROC (Innocross AG, Zurich, Switzerland)
Irradiation modeContinuous
Irradiation zoneCentral 7 mm

Comparison of Baseline and Postoperative Parameters

ParameterPreoperative (Mean ± SD)Postoperative (Mean ± SD)Pa
Mean K (D)46.86 ± 2.4845.00 ± 2.27< .001
K minimum (D)45.54 ± 2.3544.03 ± 2.12< .001
K maximum (D)48.18 ± 2.7445.97 ± 2.55< .001
Thinnest corneal thickness (µm)450.90 ± 35.99404.90 ± 43.96<.001
UDVA (logMAR)0.95 ± 0.730.22 ± 0.15< .001
Sphere (D)−1.49 ± 2.800.23 ± 1.47.01
Cylinder (D)−2.92 ± 1.03−1.20 ± 0.82< .001
CDVA (logMAR)0.24 ± 0.130.13 ± 0.12< .001
Authors

From the Department of Ophthalmology, Barzilai Medical Center, Ashkelon, Israel (IK); the Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheba, Israel (IK); Care-Vision Laser Centers, Tel Aviv, Israel (IK); the Department of Ophthalmology, Rambam Health Care Campus, Haifa, Israel (MM); Bruce and Ruth Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel (MM); and the Department of Ophthalmology, Tel Aviv Sourasky Medical Center, affiliated to the Sackler Faculty of Medicine, Tel Aviv University, Israel (GR).

The authors have no financial or proprietary interest in the materials presented herein.

AUTHOR CONTRIBUTIONS

Study concept and design (IK, GR); data collection (GR); analysis and interpretation of data (IK, MM, GR); writing the manuscript (IK, MM, GR); critical revision of the manuscript (IK, GR); statistical expertise (MM); supervision (IK)

Correspondence: Igor Kaiserman, MD, MSc, MHA, Department of Ophthalmology, Barzilai Medical Center, Ashkelon, Israel. E-mail: igor@prof-or.com

Received: December 10, 2018
Accepted: May 09, 2019

10.3928/1081597X-20190514-01

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