Corneal cross-linking (CXL) using riboflavin and ultraviolet-A radiation has become the standard of care in stabilizing ectatic corneal disease by increasing corneal rigidity.1–5 Nevertheless, CXL fails to adequately address visual rehabilitation effectively in many patients who may require but cannot tolerate contact lens fitting and use. Therefore, a series of customized anterior surface normalization techniques have been combined with CXL in an attempt to address both the progression and the underlying cornea asymmetry by further improving topographic and refractive parameters.6,7 The Athens Protocol8,9 is the first reported combined customized ablation and CXL procedure introduced by our team. It includes partial-refraction topography-guided PRK treatment followed by 50-µm phototherapeutic keratectomy (PTK) to account for epithelial removal and finally high-fluence CXL with ultraviolet-A of 6 mW/cm2 fluence (applied for 15 minutes with 0.1% riboflavin solution stromal soaking) sequentially to the excimer laser treatments the same day. The long-term visual performance measurements and the relative stability of several corneal parameters provided by extensive corneal imaging obtained perioperatively and for a few years following this procedure have been reported extensively in a larger case series study.10–14
Our and other similar studies reporting the impact of combined PRK and CXL procedures over conventional CXL alone in terms of postoperative visual rehabilitation span 1 to 2 years of follow-up.15–18 We present a prospective case series of the Athens Protocol in patients with keratoconus and report its safety, efficacy, and relative stability over a 10-year clinical observation period.
Patients and Methods
This prospective clinical study received approval from the Ethics Committee of Laservision.gr Clinical and Research Eye Institute and adhered to the tenets of the Declaration of Helsinki. Written informed consent was obtained from each participant at the time of the intervention or the first follow-up visit.
One hundred forty-four eyes treated for progressive keratoconus by means of the Athens Protocol procedure were included in this study. Visual acuity, refraction, keratometry, topography, and tomography including pachymetry and anterior surface irregularity were analyzed for 10 years. The topography device used was the Vario Topolyzer, a Placido disc–based videokeratographer (Alcon/WaveLight, Erlangen, Germany), and the Scheimpflug-based diagnostic device used was the WaveLight Oculyzer II (Alcon/WaveLight), in essence diagnostically identical to the Pentacam HD (Oculus Optikgeräte GmbH, Wetzlar, Germany).
Inclusion criteria were clinical diagnosis of progressive keratoconus, minimum age of 18 years, and corneal thickness of at least 400 µm. Exclusion criteria were underlying systemic disease, previous eye surgery, chemical injury or delayed epithelial healing, history of herpetic keratitis, corneal scarring, severe eye dryness, current corneal infection, and pregnancy or lactation for female patients.
All procedures were performed by the same surgeon (AJK) using the Alcon/WaveLight 400-Hz Eye-Q excimer laser.19,20 The topography-guided platform (named T-CAT by the manufacturer), using data from the Vario Topolyzer, was used for all cases in this study.
The same surgical procedure was applied to all patients according to the Athens Protocol, which has been reported previously.8,9 In brief, the technique includes instillation of proparacaine hydrochloride 0.5% drops (Alcaine; Alcon, Inc., Hünenberg, Switzerland), followed by a partial refraction in regard to the amount of clinical refraction treated via the topography-guided treatment of up to 50 µm in ablation depth over the cone area, followed by a PTK ablation of 7-mm diameter and 50-µm thickness to account for epithelial removal. The refractive goal was to treat up to 80% of cylinder and up to 70% sphere, not to exceed 50 µm in stromal removal as previously reported.10–13 In fact, in most cases no refractive correction was added to the topography-guided partial PRK normalization plan due to the above noted limitations. A cellulose sponge soaked in 0.02% mitomycin C solution was placed onto the ablated corneal tissue for 20 seconds following the laser ablations. Irrigation with chilled balanced salt solution was followed by corneal soaking with riboflavin (0.1% riboflavin sodium phosphate ophthalmic solution; VipeX Rapid, Avedro, Inc., Waltham, MA) for 5 minutes at 30-second intervals. Subsequently, the cornea was irradiated for 15 minutes by ultraviolet-A light (6 mW/cm2), with continued instillation of riboflavin eye drops at 2-minute intervals and total energy delivered of 5.4 Joules. A bandage soft contact lens was applied until complete reepithelialization.
All patients were prescribed topical antibiotics: moxifloxacin 0.5% (Vigamox; Alcon Laboratories, Inc., Ft. Worth, TX) four times a day for 10 days and corticosteroid eye drops (dexamethasone 0.1%, Maxidex; Alcon Laboratories, Inc.) four times a day for 1 month to be followed by a second topical corticosteroid (rimexolone 0.5%, Lotemax; Bausch & Lomb, Rochester, NY) two times a day for the second month postoperatively. Additionally and for the first 2 postoperative months, all patients used autologous serum eye drops (two times a day), and oral vitamin C (1,000 mg/day). Protection from all-natural light using sunglasses and a cap outdoors during the day was strictly advised.
Postoperative evaluation included uncorrected distance visual acuity (UDVA), manifest refraction, corrected distance visual acuity (CDVA), and slit-lamp biomicroscopy for clinical signs of CXL. For the quantitative assessment of the induced corneal keratometric and pachymetric changes, postoperative evaluation was performed by a Pentacam Scheimpflug imaging device (Oculyzer II; WaveLight AG, Erlangen, Germany). A specific anterior surface irregularity index provided by the Scheimpflug imaging analysis was evaluated in addition to keratometric and pachymetric values. This is the index of height decentration, calculated with Fourier analysis of corneal height for the 8-mm diameter zone to quantify the degree of cone decentration.
Descriptive and comparative statistics, analysis of variance, and linear regression were performed by Minitab version 16.2.3 (MiniTab Ltd., Coventry, United Kingdom), using the paired-samples t test and its non-parametric equivalent (Wilcoxon signed-rank test) for variables with no Gaussian distribution to analyze the change before and after the Athens Protocol. A P value of less than .05 was considered significant in all tests. Visual acuity is reported in decimals and keratometry in diopters (D). Results are reported as mean ± standard deviation.
A total of 144 eyes of 40 female and 90 male participants were included in the study. Mean participant age at the time of the operation was 29 ± 5 years (range: 19 to 53 years). All eyes were followed up for 10 years. Preoperative and postoperative visual acuity, pachymetric, keratometric, and topometric asymmetry parameters are shown in Table 1.
Refractive, Pachymetric, and Topographic Parameters (Mean ± Standard Deviation)
Visual Acuity Changes
Mean UDVA showed a statistically significant improvement from preoperatively to 1 year and slightly increased at 10 years, which was significant compared to preoperative values (P < .01) but not 1-year values (P = .52). At 10 years, UDVA improved more than two lines in 45%. No eyes lost more than one line (Figure 1). Mean CDVA also increased significantly at 1 year. At 10 years, it increased compared to preoperative values (P < .01) but was unchanged from 1 year (P = .63). Ten years postoperatively, CDVA was increased more than two lines in 37.5%. No eyes lost more than one line (Figure 1).
Changes in uncorrected (UDVA) and corrected (CDVA) distance visual acuity 10 years postoperatively. The x axis denotes the changes in reading Snellen charts lines and the y axis shows the percentage of patients.
Keratometric and Topometric Indices Stabilization and Improvement
Mean flat (K1) and steep (K2) keratometry decreased (normalized) significantly postoperatively (Figure 2). The mean value for the index of height decentration continued to decrease over time. In total, 136 eyes (94.4%) showed no further keratoconic progression (Figure 3), 3 eyes (2.1%) showed minimal progression as documented by corneal topography but no further thinning, and 5 eyes showed progressive “overcorrection” or “hyperopic” shift, in regard to what was planned at the 10-year follow-up (Figure 4).
Mean anterior flat (K1), and steep (K2) and maximum (Kmax) keratometry as measured by the Scheimpflug device (Oculyzer II; WaveLight AG, Erlangen, Germany) preoperatively up to 10 years postoperatively. All units in keratometric diopters (D). AP = Athens Protocol
Case 1. (A) Preoperative Pentacam (Oculyzer II; WaveLight AG, Erlangen, Germany) images reveal inferocentral steep cone (Kmax: 50.60 D; Rx: −2.75 −2.50 × 20; CDVA: 20/32; UDVA: 20/200). (B) One year following Athens Protocol applied to the left eye, the Pentacam shows greater symmetry and reduced steepness of corneal shape (Kmax: 44.90 D; Rx: −1.75 DS; CDVA: 20/20; UDVA: 20/32). (C) At 5 years postoperatively, the keratometric power and shape shows no significant difference (Kmax: 43.80 D; Rx: −0.50 −0.25 × 120; CDVA: 20/20; UDVA: 20/20). (D) At 10 years postoperatively, keratometric values and shape remain stable (Kmax: 44.40 D; Rx: −0.50 DS; CDVA: 20/20; UDVA: 20/20). Kmax = maximum keratometry; D = diopters; Rx = refraction; CDVA = corrected distance visual acuity; UDVA = uncorrected distance visual acuity; DS = diopters sphere
Case 2. (A) Preoperative Pentacam (Oculyzer II; WaveLight AG, Erlangen, Germany) images reveal inferocentral steep cone (Kmax: 53.10 D; Rx: −0.50 −2.00 × 135; CDVA: 20/20). (B) One year following Athens Protocol applied to the left eye, the Pentacam shows superior steepening (Kmax: 47.2 D) with a reduced inferocentral reading (K: 43.50 D; Rx: +1.00 −0.75 × 140; CDVA: 20/32; UDVA: 20/40). (C) At 4 years postoperatively, Pentacam reveals an inferocentral flattening (K: 39.30 D), whereas the superior corneal power remains stable (Kmax: 46.70 D; Rx: +1.50 −2.25 × 135; CDVA: 20/32; UDVA: 20/40). (D) At 10 years postoperatively, the inferocentral corneal power shows flattening (Kmin: 34.80 D), whereas the superior (Kmax) readings are 46.60 D (Rx: +4.75 −1.75 × 75; CDVA: 20/50; UDVA: 20/63). Kmax = maximum keratometry; D = diopters; Rx = refraction; CDVA = corrected distance visual acuity; UDVA = uncorrected distance visual acuity; DS = diopters sphere
Corneal Pachymetry Changes
Mean corneal thickness at the thinnest point significantly decreased from 413.71 ± 33.19 µm (range: 352 to 435 µm) to 378.41 ± 40.11 µm (range: 317 to 423 µm) (P < .01) at 1 year postoperatively and slightly increased (without statistical significance) over the 10-year follow-up (391.35 ± 39.17 µm; range: 367 to 435 µm). This was a result of excimer laser ablation but then stabilized over time without any additional thinning (Table 1).
The 10-year follow-up data reported herein favorably address the safety and long-term efficacy of the Athens Protocol applied, because it appears to result in statistically significant postoperative improvement in both UDVA and CDVA, which remain stable long term. Average gain/loss in visual acuity was consistently positive, starting as previously reported9 from the first postoperative month, with gradual slight improvement when comparing the 1-year visit as a landmark to the 10-year follow-up. Visual function and keratometric parameter improvements appear to be superior to those reported in cases of conventional CXL treatment alone.
How much the cone flattens when the two procedures are combined, resulting in obvious synergy, remains unknown and unpredictable.21,22 The flattening effect in many cases far surpasses what would be expected if CXL was employed alone and followed at a later time by a topography-guided PRK procedure. A minority of cases demonstrated over-flattening and a hyperopic refractive shift than what was expected. Nevertheless, it is usually only possible to treat a small amount of cylinder and/or sphere anyway, because the topography-guided normalization may remove close to 50 µm from the cone center even without a refractive component added to it (with sphere and cylinder set to 0). Our initial suggestion was to treat maximally up to 50 µm on the thinnest part of the cornea. Even in cases with significant thinning, and even when employing optical zones of less than 6 mm (not an available option in the United States with current Food and Drug Administration approval), due to the limitations of the preoperative pachymetry and the necessary residual bed, the attempted refractive diopters in the ablation may be as low as 0.50 D of sphere and/or cylinder or even none. Even in such cases, the normalization of the cone and the synergy observed with the CXL component may result in 5.00 and even 10.00 D of flattening.
The Athens Protocol appears to be a safe, effective, and predictable alternative to conventional CXL for progressive keratoconus in patients who are poorly tolerant to rigid contact lens use, by both addressing corneal ectasia stabilization and significantly “reversing” the impact on visual function related to corneal irregularity that occurs with this disease.
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Refractive, Pachymetric, and Topographic Parameters (Mean ± Standard Deviation)
|1 Year||10 Years|
|UDVA (decimal)||0.19 ± 0.17||0.53 ± 0.21||0.55 ± 0.19||< .01||< .01||.52|
|CDVA (decimal)||0.59 ± 0.21||0.80 ± 0.17||0.81 ± 0.19||< .01||< .01||.63|
|CCT (µm)||468.74 ± 35.05||391.14 ± 40.07||395.42 ± 32.21||< .01||< .01||.31|
|IHD (µm)||0.117 ± 0.061||0.072 ± 0.038||0.074 ± 0.031||< .01||< .01||.62|
|K1 (D)||44.82 ± 2.95||41.33 ± 3.77||40.64 ± 2.95||< .01||< .01||.08|
|K2 (D)||50.57 ± 2.80||45.87 ± 2.70||44.00 ± 3.22||< .01||< .01||< .01|
|Kmax (D)||53.43 ± 2.97||46.17 ± 1.18||44.75 ± 2.14||< .01||< .01||< .01|