Refracto-therapeutic surgery with excimer laser has evolved rapidly in the last decade1 to correct severe, disabling irregular astigmatism in corneal pathologies. In one of the earliest attempts to treat irregular cornea using a custom excimer laser ablations, visual symptoms were reported to resolve or decrease with both manual adjustment of laser beam placement and contoured ablation patterns.2 The initial procedures were based on Photo refractive keratectomy (PRK) and reported limited effectiveness.3 In more recent reports, Alpins and Stamatelatos4 reported that the incorporation of the corneal astigmatism data into the applied treatment parameters may improve visual and total astigmatism results in eyes with forme fruste and mild keratoconus. The correction of classical ametropias (myopia and astigmatism) in keratoconus using transepithelial PRK has been reported as less effective and less predictable than conventional PRK for naturally occurring myopia and astigmatism.3 Refracto-therapeutic ablations have evolved to the more sophisticated topography-guided5 and corneal wavefront-guided6 customized corneal ablations for irregular corneal astigmatism in keratoconus. In a latest pilot study, Shaheen et al.7 evaluated the visual, refractive, corneal topographic, and aberrometric changes after wavefront-guided Laser-in situ-keratomileusis (LASIK) or PRK using a high-resolution aberrometer to calculate the treatment for aberrated eyes. They differentiated the patients in three groups: keratoconus post-CXL group including 11 keratoconic eyes (10 patients), post-LASIK group including 5 eyes (5 patients) with previous decentered LASIK treatments, and post-RK group including 4 eyes (3 patients) with previous radial keratotomy. They reported an improvement in uncorrected and corrected distance visual acuity (UDVA and CDVA respectively) associated with a reduction in the spherical equivalent in all three groups, but was only statistically significant in the keratoconus post-CXL and post-LASIK groups (P≤.04). Similarly improvements in contrast sensitivity were observed in all three groups, but they were only statistically significant in the keratoconus post-CXL and post-LASIK groups (P≤.04).

Several combinations of therapeutic and refractive surgery approaches have been advocated. A 2-step sequential approach was proposed in the form of CXL+customized PRK. This is in comparison to the simultaneous procedures done in the form of same day phototherapeutic keratectomy (PTK)+customized PRK followed by a CXL procedure to control the progression of keratoconus.8 Another proposal is the use of simultaneous customized transepithelial PRK+CXL,9,10 which combines the refractive effect of the PRK (with epithelium removal) with the therapeutic effect of CXL.11

Topographers measure the anterior corneal surface i.e. the epithelial surface or furthermore the tear film interface which is even more regular than the epithelium. Stromal refractive surgery methods, however, use the information from corneal topography to design an ablation aimed at the stromal surface. The regrowth of epithelium after such a procedure aims to compensate for the modifications (and the induced irregularities) done in the cornea with the laser ablation. In the ideal case, the epithelial regrowth lowers the laser induced irregularities, reducing the overall corneal aberrations of the patient. On the other hand, in an unfavourable case, the internal stromal irregularities and laser induced modified stromal irregularities are compensated by the regrown epithelium in such a way that it results in complicated shapes and structures in the epithelium. These complications are comparatively controlled in a transepithelial method since the treatment is directly linked over the epithelium and the epithelium acts as a smoothing agent. Therefore, the laser ablation is aimed at inducing regularity in the epithelium first, subsequently reaching the stromal surface to remove stromal irregularity.

It is worth noticing that there are a significant number of patients treated for keratoconus with CXL in the last decade.12 These patients may still benefit from the improvements in visual outcomes through a secondary refracto-therapeutic procedure. Our aim is to analyze the improvements mainly in corrected vision after a transepithelial refractive procedure, in such patients who were previously treated for keratoconus with CXL. This study analyses a retrospective, non-comparative, consecutive case series of patients treated with reversed single-step Corneal-Wavefront guided transepithelial PRK13 after CXL, at the SEKAL Rovigo Microsurgery Centre in Rovigo, Italy, for efficacy of the procedure in improving visual outcomes in keratoconic patients. Here, the terminology “reversed single-step” outlines the pseudo-sequentialization of the Corneal-Wavefront guided and epithelial thickness profile components realized in a single step without breaks. This meant that in a counterintuitive way, the refractive correction is applied first and the epithelial profile at the end. The implications of these features are discussed later.

The aim of this study was to evaluate the efficacy and safety of reversed single-step Corneal-Wavefront guided transepithelial PRK treatments in keratoconic patients after CXL. Kanellopoulos also discussed and applied the possibility of reversed transepithelial PRK (although in a manual fashion) to his last series of patients as reported during ESCRS 2013 in Amsterdam.

The reversed transepithelial approach has at least three advantages in our understanding; first, the more regular epithelial surface is ablated with the complex ablation profile instead of the comparatively irregular stroma. This means that the regularity of epithelium is carried down to the stroma with a fine laser ablation profile. Second, the ablation profile calculated based on the diagnosis of essentially the corneal epithelial surface is applied directly on to the epithelium instead of the stroma. This could impart a higher coherence between the diagnosis and refractive procedure. Third, since the cooperation of the patients is likely better at the beginning of the treatment, leaving the very simple epithelial profile for the last ablation seconds reduces the impact of suboptimal centration (although with very fast treatments this may eventually be irrelevant).

Topography-guided transepithelial PRK is commonly considered a more popular choice for the treatment of keratoconus instead of the wavefront guided transepithelial PRK. However, we used the corneal wavefront guided ablation profiles, which have the same origins (topographic measurement) as topography-guided treatments but base upon the optical effects of the topography of the cornea instead of the elevation values of the cornea. We have reported refractive stability and optical benefits using the wavefront guided profiles in normal refractive procedures19 and therapeutic procedures13,26 in the past. Furthermore, the calculation of corneal asphericity as a 3-D fit renders more accurate results when it is based on the corneal wavefront aberrations rather than on the corneal topography of the principal meridians.27 The wavefront guided profiles also allow customization of the ablation profiles to minimize the tissue ablation specially critical in keratoconus cases.28–30 The use of corneal wavefront based ablation on irregular corneal surface for these keratoconic patients could be argued, however, we favoured corneal wavefront based profiles mainly due to their theoretical advantages over topography based profiles, namely customizability, tissue saving, same optical origin (as corneal topography), best attainable CDVA and the best attainable topographic regularization.

In our series, notably only two eyes (5%) needed a secondary laser retreatment for the improvement of post-operative visual acuity. These patients showed high hyperopic shift after the initial sequential treatment of CXL followed by TransPRK, and were treated with a secondary TransPRK treatment. The hyperopic shift could be attributed to excessive flattening of the cornea either post-CXL, post-TransPRK or a combination of both. These results are not reported here to maintain uniformity. Concerning defocus correction, 23 eyes (62%) were within 1.50D of attempted correction in spherical equivalent and the attempted versus achieved scattergram (Fig. 3) showed an intercept of −1.2213D consistent with the mean deviation from target of +1.09±2.36D. These results may eventually be explained by the effects of CXL therapy on progressive corneal flattening, but also the potential effects of the CXLed tissue on ablation rate.31–33 Some groups31,32 have reported reduced ablation rate in CXL corneas opposed to our clinical findings.33 Another explanation could be that the flattening of the cornea is simply due to the conus ablation which may not be well computed by the programme as it is complex to forecast this data.

The mean residual astigmatism of 2.34±1.81D can be explained by the fact that we did not attempt to correct the full astigmatism in most cases. The treatment was planned not to exceed the stromal ablation depth more than 55μm (excessively not to reduce the strength of the cornea reinforced by the CXL therapy). Furthermore, the manifest refractive astigmatism may be influenced by HOA (especially coma and trefoil), however, the observed deviation from target astigmatism was much lower (0.64±1.85D).

Generally, complete spherical and 50% astigmatic correction was targeted, but not in all cases. This decision primarily depended on the corneal thickness and the individual case. Hence, in order to avoid any confusion we analyzed achieved versus planned correction (and not manifest refraction). Although our results show significant reduction in coma and astigmatism, we cannot compare these extreme cases to the outcomes of refractive and transplant surgery in normal population. The aim of this surgery was to improve the CDVA enough to enable the use of conventional correction modalities like spectacles and increase the tolerance to contact lenses. UDVA improvement, although desirable, were only considered as secondary end point for the population in this study.

Although this small series of treated eyes does not allow for definitive conclusions or evidence-based statements, our preliminary results are promising. However, there are some limitations associated with our study, mainly the lack of a control group and shorter follow up times. Mean follow-up time of 10 months could be too short for the keratoconus population, where the topographically manifest ectatic process may show much later, after the limit of the epithelial compensatory ability has been reached. In our cohort, the mean age was 35±12 years (19–64 years). The scientific evidence regarding the progression of keratoconus and efficacy of CXL with growing age might indicate against CXL treatments in older patients in our cohort.34 However, one cannot generalize that in all keratoconus patients the condition progresses similarly. In addition, in case of older patients presenting with abnormal corneas and willing to get their refractive aberrations corrected, it is imperative to reinforce the stroma before commencing any refractive procedure. However, it must be acknowledged that the efficacy of CXL treatments might be affected by the age of the patient, and a surgeon must consider the stability in the cornea after CXL before performing any refractive procedure.

It could also be argued whether the cornea is stable enough to perform a transepithelial PRK only 4 months after CXL. One can observe changes in the cornea in some patients, even after 7 years post a CXL procedure.35 In our cohort, a minimum follow up of at least four months after CXL was chosen since it was clinically observed that in general topographies become stable at least four months after conventional CXL in keratoconus patients. Furthermore, whether the cornea continues to flatten becomes less important for the results of our study, since the primary outcome in our cohort was CDVA and not UDVA, aimed at improving the patient's vision with the use of conventional correction modalities like spectacles and increasing tolerance to contact lenses.

The choice between simultaneous and sequential refracto-therapeutic treatments has been debated in the past. Simultaneous refracto-therapeutic treatments involve a same day procedure with a customized refractive treatment followed by a CXL treatment to control the progression of keratoconus. However, changes in the shape of cornea post CXL, may further manipulate the intended refractive correction. In order to avoid such an occurrence, in our cohort the refractive procedure was performed at least four months after the cornea became stable post the CXL procedure, where the corneal stability was controlled with differential topographic maps. It is well known that the epithelial thickness varies greatly in keratoconus. Treating the standard thickness of 55μm in the centre, increasing the depths towards the mid-periphery may be satisfactory for non-keratoconic eyes, but might lead to excessive removal of stromal tissue in the cone area, where the epithelial thickness normally is at its minimum (most often in the range of 40 rather than 60μm). Although the CXL procedure shall improve the keratoconic symptoms in the cornea, the use of similar epithelial profiles might affect the keratoconic eyes adversely compared to non-keratoconic eyes. However, our results suggest improved corrected vision with 41% of eyes (15 eyes), gaining two or more Snellen lines of CDVA (paired t-test P<.0001) and only 5% losing 1 line (Fig. 2). Furthermore, there were no topographic or clinical signs of keratoconus progression during the follow-up period suggesting the safety of the procedure. Haze did not pose a problem in our cohort thanks to the use of MMC with only 5 cases (13%, with traces up to grade 1) showing this problem in our analysis.

It is necessary to emphasize the compromise between the use of large optical zones, covering the scotopic pupil size (plus some tolerance for possible decentrations), and smooth transition zones.36 In our study, this compromise was realized by using a mean optical zone of 6.1±0.3mm (range 5.5–6.7mm), fully corrected central ablation zone with a multidynamic aspherical transition zone automatically provided by the laser based on the planned refractive correction (6.8±0.5mm, range 6.2–8.1mm).

Refracto therapeutic procedures have been conducted with different strategies in the past. The Athens protocol8 evaluated a series of 32 cases with corneal ectasia after LASIK that underwent combined topography-guided PRK to reduce or eliminate induced myopia and astigmatism followed by sequential, same-day ultraviolet A (UVA) CXL. Twenty-seven of 32 eyes had an improvement in UDVA and CDVA of 20/45 or better (2.25 logMAR) at last follow-up and corneal haze grade 2 was present in 2 eyes. Seventeen of 32 eyes showed improvements in UDVA and CDVA with a follow-up longer than 1.5 years. Although the comparability between our setting (naturally occurring keratoconic ectasia) and Kanellopoulos (LASIK induced iatrogenic keratectasia) may be limited, our series reports 37 eyes, with an improvement in UDVA and CDVA of 20/40 or better (+0.35 logMAR) at last follow-up, with 30 eyes showing topographic improvement, whereas 2 of the treated eyes requiring a secondary transepithelial ablation.

Some reports do advocate for simultaneous CXL concurrent with refractive correction as compared to sequential CXL therapy followed by refractive correction (as in our case). Kanellopoulos et al.8 studied a total of 325 eyes with keratoconus divided into two groups (n=127 eyes for the sequential group, and n=198 eyes for the simultaneous group). At the last follow-up in the sequential group, the mean UDVA improved to 0.49±0.25 logMAR, and the mean CDVA improved to 0.16±0.22 logMAR. Mean reduction in spherical equivalent refraction was 2.50±1.20D and mean haze score was 1.2±0.5. In the simultaneous group, the mean UDVA improved to 0.3±0.2 logMAR, and the mean CDVA improved to 0.11±0.16 logMAR. Mean reduction in spherical equivalent refraction was 3.20±1.40D and mean haze score was 0.5±0.3. Statistically, the simultaneous group did better (P<.05) in all fields evaluated, with improvement in UDVA and CDVA, a greater mean reduction in spherical equivalent refraction, keratometry, and less corneal haze. Compared to this study, our smaller sample sized sequential setting showed that the mean UDVA improved from 1.0±0.6 logMAR to +0.4±0.4 logMAR, and mean CDVA improved from +0.4±0.20 logMAR to +0.2±0.2 logMAR at the last follow-up. Mean reduction in spherical equivalent refraction was −1.09±2.36D, and mean haze score was 0.1±0.2.

Kymionis et al.37 compared the outcomes of corneal collagen cross-linking (CXL) for the treatment of progressive keratoconus using transepithelial PTK (t-PTK) versus mechanical epithelial debridement. In group 1 (t-PTK), logarithm of the minimum angle of resolution mean UDVA and mean CDVA improved from 0.99±0.71 and 0.30±0.26 preoperatively to 0.63±0.42 (P=0.02) and 0.19±0.18 (P=0.008) at 12 months postoperatively, respectively. In group 2 (mechanical debridement), neither mean UDVA nor mean CDVA demonstrated a significant improvement at 12 months postoperatively (P>0.05). In group 1, mean corneal astigmatism improved from −5.84±3.80 diopters (D) preoperatively to −4.31±2.90D (P=0.015) at the last follow-up, whereas in group 2 there was no significant difference at the same postoperative interval (P>0.05). They concluded that epithelial removal using t-PTK during CXL results in better visual and refractive outcomes in comparison with mechanical epithelial debridement.

A recent report3 suggests that non-topographic transepithelial PRK with simultaneous crosslinking improves vision, and may offer an alternative to keratoplasty in contact lens intolerant keratoconus. The most notable finding of this series was a significant improvement in vision, both corrected and unaided. The proportion of eyes achieving a functional threshold of 0.1 logMAR (Snellen 6/8.5) increased from 22 to 64%, a significant proportion who might otherwise have to consider keratoplasty. Notably, even in cases with residual refractive errors, these were easily correctable with glasses or soft contact lenses rather than rigid lenses, with benefits in wear time and tolerance. These visual acuity improvements compare favourably to those described in published series of topographically guided excimer treatments. By comparison, current studies of CXL alone demonstrate a modest and unpredictable improvement in visual function in just over half of the cases, with the remainder remaining stable, but a proportion also worsening in terms of visual acuity. Also in this series, correction of topographic parameters was not directly targeted by the technique; however, there was a significant improvement in topographic parameters.

Further analysis of the postoperative night vision complaints and the analysis of post-operative outcomes according to optical zone size are also of interest. Long-term follow-up on these eyes will help determine whether these results also show improved stability over time. We are aware that a laser treatment on an unstable cornea could lead to a dehiscence in future but one must weigh the advantage of a fast and easy procedure with improved visual quality to the possible variation (but not certain risk) of astigmatism in the future.

The reduction of preoperative astigmatism to moderate values postoperatively, with significant reduction in HOA in our cohort suggests that reversed single-step Corneal-Wavefront guided transepithelial PRK ablation profiles with AMARIS yield good visual, optical, and refractive results for the correction of refracto-therapeutic problems in keratoconic patients.

None.

Camellin concept, performing the treatments, reviewing the article. Guidotti concept, reviewing the article. Arba Mosquera writing the article, providing statistical expertise.

Arba Mosquera is employee of SCHWIND eye tech solutions manufavuter of the SCHWIND AMARIS used in this study.