Keratoconus is a degenerative bilateral, noninflammatory disorder characterized by ectasia, thinning, and irregular corneal topography.1 The disorder usually has onset at puberty and often progresses until the third decade of life, may manifest asymmetrically in the two eyes of the same patient, and can present with unpredictable visual acuity, particularly in relation to corneal irregularities.2 One of the acceptable options3 for progressive keratoconus management is corneal collagen cross-linking (CXL) with riboflavin and ultraviolet-A.4
To further improve the topographic and refractive outcomes, CXL can be combined with customized anterior surface normalization.5–7 Our team has developed a procedure8,9 we have termed the Athens Protocol,10 involving sequentially excimer laser epithelial debridement (50 μm), partial topography-guided excimer laser stromal ablation, and high-fluence ultraviolet-A irradiation (10 mW/cm2), accelerated (10’, or minutes) CXL. Early results11 and anterior segment optical coherence tomography quantitative findings12 are indicative of the long-term stability of the procedure.
Detailed studies on postoperative visual rehabilitation and anterior surface topographic changes by such combined CXL procedures are rare,13–16 particularly those reporting results longer than 1 year. This study aims to investigate safety and efficacy of the Athens Protocol procedure by analysis of long-term (3-year) refractive, topographic, pachymetric, and visual rehabilitation changes on clinical keratoconus management with the Athens Protocol in a large number of cases.
Patients and Methods
This clinical study received approval by the Ethics Committee of our Institution 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 clinical visit.
Patient Inclusion Criteria
Two hundred thirty-one consecutive keratoconic cases subjected to the Athens Protocol procedure between 2008 and 2010 were investigated. All procedures were performed by the same surgeon (AJK) using the Alcon/WaveLight 400 Hz Eye-Q17 or the EX500 excimer lasers.18 Inclusion criteria were clinical diagnosis of progressive keratoconus, minimum age of 17 years, and corneal thickness of at least 300 μm. All participants completed an uneventful Athens Protocol procedure and all 231 eyes were observed for up to 3 years. Exclusion criteria were systemic disease, previous eye surgery, chemical injury or delayed epithelial healing, and pregnancy or lactation (female patients).
Measurements and Analysis
Postoperative evaluation included uncorrected distance visual acuity (UDVA), manifest refraction, corrected distance visual acuity (CDVA) with this refraction, and slit-lamp biomicroscopy for clinical signs of CXL.12 For the quantitative assessment of the induced corneal changes, postoperative evaluation was performed by a Pentacam Scheimpflug imaging device (Oculyzer II, WavLight AG, Erlangen, Germany)19 and processed via Examination Software (Version 1.17r47). Specific anterior surface irregularity indices provided by the Scheimpflug imaging analysis were evaluated in addition to keratometric and pachymetric values. These indices are employed in grading and classification based on the Amsler and Krumeich criteria.20,21 These are the Index of Surface Variance, an expression of anterior surface curvature irregularity, and the Index of Height Decentration, calculated with Fourier analysis of corneal height (expressed in microns) to quantify the degree of cone decentration.22 Index of Surface Variance and Index of Height Decentration were computed for the 8-mm diameter zone.
Descriptive and comparative statistics, analysis of variance, and linear regression were performed by Minitab version 16.2.3 (MiniTab Ltd., Coventry, UK) and Origin Lab version 9 (OriginLab Corp., Northampton, MA). Paired analysis P values less than .05 were considered statistically significant. Visual acuity is reported decimally and keratometry in diopters (D). Results are reported as mean ± standard deviation and range as minimum to maximum.
The 231 eyes enrolled belonged to 84 female and 147 male participants. Mean participant age at the time of the operation was 30.1 ± 7.5 years (range: 17 to 57 years). All eyes were followed up to the 3-year follow-up.
Visual Acuity Changes
Table 1 presents preoperative and postoperative UDVA and CDVA. UDVA increased by +0.38 ± 0.31 (range: −0.34 to +1.10) and CDVA by +0.20 ± 0.21 (range: −0.32 to +0.90). Figure 1 illustrates, in the form of box plots, visual acuity gained or lost 3 years postoperatively. These graphs (the 95% median confidence range box) indicate that 95% of the cases had at least +0.1 increase in UDVA and 95% had positive change in CDVA.
Visual Acuity Data (N = 231 Eyes)
Change (gain/loss) in visual acuity, expressed as the difference of postoperative minus preoperative values (expressed decimally), showing median level (indicated by (+), average symbol (×), 95% median confidence range box (red borderline boxes), and interquartile intervals range box (black borderline boxes).
Keratometric and Anterior Surface Indices Progression
Anterior keratometry continued to flatten over the 3-year follow-up (Figure 2). Descriptive statistics for anterior keratometry, preoperatively and postoperatively, are presented in Table A (available in the online version of this article).
Anterior keratometry (K1 flat and K2 steep) as measured by the Scheimpflug device (Oculyzer II, WavLight AG, Erlangen, Germany) preoperatively up to 3 years postoperatively. All units in keratometric diopters (D).
The values for the Index of Surface Variance and the Index of Height Decentration continued to decrease over time (Figure 3, Table B, available in the online version of this article).
Anterior surface topometric indices Index of Surface Variance (no units) and Index of Height Decentration (units μm) as measured by the Scheimpflug imaging device (Oculyzer II, WavLight AG, Erlangen, Germany) preoperatively, 1 month postoperatively, and up to 36 months postoperatively.
The thinnest corneal decreased as a result of excimer laser ablation but then stabilized over time without additional thinning (Table 2).
Thinnest Corneal Thickness Measured by the Scheimpflug Device (N = 231 Eyes) (μm)
Many reports describe the effects of CXL with or without same-session excimer laser ablation corneal normalization.3 There is general consensus that the intervention strengthens the cornea, helps arrest the ectasia progression, and improves corneal keratometric values, refraction, and visual acuity.
The key question is the long-term stability of these induced changes. For example, is the cornea ‘inactive’ after the intervention and, if not, is there steepening or flattening and/or thickening or thinning? These issues are even more applicable in the case of the Athens Protocol, due to the partial corneal surface ablation. Ablating a thin, ectatic cornea may sound unorthodox. However, the goal of the topography-guided ablation is to normalize the anterior cornea and thus help improve visual rehabilitation to a step beyond that a simple CXL would provide.
This study aims to address some of the above issues. The large sample and follow-up time permit sensitive analysis with confident conclusion of postoperative efficacy. We monitored visual acuity changes and for the quantitative assessment we chose to standardize on one Scheimpflug screening device and to focus on key parameters of visual acuity, keratometry, pachymetry, and anterior surface indices.23 All of these parameters reflect changes induced by the procedure and describe postoperative progression. However, variations in the two anterior surface indices (Index of Surface Variance and Index of Height Decentration) may provide a more valid analysis than keratometry and visual function.24 Our results indicate that the apparent disadvantage of thinning the cornea is balanced by a documented long-term rehabilitating improvement and synergy from the CXL component.
Visual Acuity Changes
Based on our results, the Athens Protocol appears to result in postoperative improvement in both UDVA and CDVA. 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. These visual rehabilitation improvements appear to be superior to those reported in cases of simple CXL treatment.25
However, it is noted that the visual acuity presented with large variations. The standard deviation of UDVA was ±0.20 preoperatively and ±0.28 postoperatively. Likewise, the standard deviation of CDVA was ±0.23 preoperatively and ±0.20 postoperatively.
We theorize that the reason for visual acuity in keratoconic cases having such large fluctuations (and often being unexpectedly good) can be attributed to a ‘multifocal’ and ‘soft’ (ie, adaptable) cornea, in addition to advanced neural processing in the individual visual system. However, these ‘advantages’ are essentially negated with CXL treatment, which stiffens the cornea. Over time, possibly due to further topography improvement and adaptation to the partially normalized cornea, a noteworthy improvement in visual acuity is observed.
Keratometric and Anterior Surface Indices Progression
After the 1-month visit, keratometric values are reduced. This progressive potential for long-term flattening has been clinically observed in many cases over at least 10 years. Peer-reviewed reports on this matter have been rare and only recent.26,27
The two anterior surface indices, Index of Surface Variance and Index of Height Decentration, also demonstrated postoperative improvement. A smaller value is indication of corneal normalization (lower Index of Surface Variance, less irregular surface, lower Index of Height Decentration, cone less steep and more central). These changes are therefore suggestive of corneal topography improvement, in agreement with other smaller sample studies.13 Such changes in Index of Surface Variance and Index of Height Decentration have been reported only recently.28
The initial more ‘drastic’ change of the Index of Height Decentration can be justified by the chief objective of surface normalization, cone centering,6 which is noted even by the first month. The subsequent surface normalization, as also indicated by keratometric flattening, suggests further anterior surface improvement.
As expected by the fact that Athens Protocol includes a partial stromal excimer ablation, there is reduction of postoperative corneal thickness, manifested by the thinnest corneal thickness. What seemed to be a ‘surprising’ result is that the cornea appears to rebound, by gradually thickening, up to 3 years postoperatively. Postoperative corneal thickening after the 1-month ‘lowest thickness baseline’ has also been discussed recently.29,30 In another report,31 the lowest thinnest corneal thickness was noted at the 3-month interval. In that study of 82 eyes treated only with CXL, the average cornea thickened by +24 μm after 1 year compared to the 3-month baseline. In our study of 212 eyes treated with the Athens Protocol procedure, the cornea thickening rate after the baseline first postoperative month was approximately half (+12 μm over the first year), in agreement with a recent publication.29
Therefore, it is possible that stromal changes initiated by the CXL procedure are not just effective in halting ectasia, but are prompting corneal surface flattening and thickening, which appears to be longer lasting than anticipated.
We note, however, that CXL alone results not just in corneal reshaping, but also in stromal density and refractive index, both possibly influencing the reported thickness by the Scheimpflug device. Therefore, true corneal thickness differences may not be accurately explored by Scheimpflug imaging due to the principle of operation (densitometry), which has been our clinical experience with abnormal density corneas (ie, corneal scars or arcus senilis corneas). Further studies of corneal thickness chances by modalities, such as anterior segment optical coherence tomography, which currently also measure epithelial thickness,32 may be warranted. In addition, corneal biomechanical analysis and corneal volume studies may be necessary to further validate such findings.
Our study indicates a significant improvement in all parameters studied. The changes induced by the procedure indicate a consistent trend toward improved visual rehabilitation, corneal flattening (validating ectasia arrest), and anterior surface improvement. The Athens Protocol procedure demonstrates impressive refractive, keratometric, and topometric results. Progressive potential for long-term flattening documented in this study suggests employment of caution in the surface normalization process to avoid overcorrection.