14 Laser’s Place in CXL: Excimer Laser and Refractive Surgery Combined with Corneal Cross-Linking, Femto-LASIK Combined with CXL

Anastasios John Kanellopoulos

Keywords: corneal collagen crosslinking, CXL, prophylactic CXL, LASIK, topo-guided excimer laser, corneal ectasia, femtosecond laser created corneal pocket, photorefractive CXL, LASIK-CXL, flap creation, Athens protocol

14.1 Introduction

Corneal collagen cross-linking (CXL) with riboflavin (a vitamin B2 molecule) and ultraviolet A (UVA) may nowadays be considered established options ¹ for the management of progressive keratoconus ² after more than 10 years following the introduction of the technique by the Dresden protocol. ^{3,​ 4} The procedure increases corneal resistance and inhibits progression of the ectatic disorder, ⁵ which is applicable not only in keratoconus, but also in the treatment of pellucid marginal degeneration ⁶ and induced keratectasia after laser-assisted in situ keratomileusis (LASIK). ⁷

Among the desired outcomes, however, remains not just the arrest of ectasia, but also the improvement of postoperative visual rehabilitation. Several adjuvant treatments may combine with CXL to offer a far more wider reach of options. Topography-guided photorefractive keratectomy (topo-guided PRK), transepithelial phototherapeutic keratectomy (t-PTK), intrastromal corneal ring segment (ICRS) implantation, phakic intraocular lens (p-IOL) implantation, etc., are many of the refractive options that may be combined with CXL.

Topo-guided excimer ablation combined with CXL treatment ^{8,​ 9} has been among the first of such options. A pioneering report on such options presented significant clinical improvement of a keratoconus patient who underwent topo-guided PRK 1 year after CXL. ⁸ Variations in technique have included timing of procedures (simultaneous or sequential), maximal recommended ablation depth, and the use of mitomycin C. The authors have shown that same-day simultaneous topo-guided PRK followed by CXL is more effective than sequential CXL with delayed (6 months or more) PRK in the visual rehabilitation of keratoconus. ¹⁰ Several other studies followed and confirmed the safety and/or efficacy of the simultaneous topo-guided PRK followed by CXL in patients with keratoconus and post-LASIK corneal ectasia; long-term stability of this combined procedure has also been demonstrated. ^{11,​ 12,​ 13,​ 14,​ 15}

Our team has contributed many of the evolutionary steps of the initially introduced CXL technique:

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  Higher fluence.

  
  
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  Non–dextran containing riboflavin solution.

  
  
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  Combination of CXL with topo-guided excimer normalization of ectatic corneas (the Athens Protocol [AP]).

  
  
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  Prophylactic CXL in routine myopic and hyperopic LASIK.

  
  
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  In situ CXL through a femtosecond laser–created corneal pocket.

  
  
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  Photorefractive CXL.

Specifically, we have introduced the concept of accelerated, high-fluence CXL in post-LASIK ectasia, ¹⁶ as well as the utilization of prophylactic CXL in routine LASIK, ¹⁷ and in situ femtosecond laser–assisted treatment of corneal ectasia, ² in attempting corneal deturgescence ¹⁸ in bullous keratopathy ¹⁹ and as a prophylactic intervention adjuvant to Boston keratoprosthesis surgery. ²⁰ The procedure known as the AP ²¹ involves sequentially excimer-laser epithelial debridement (50 μm), partial topography-guided excimer-laser stromal ablation, and high-fluence UVA irradiation (10 mW/cm²), accelerated (10 minutes) CXL. Corneal topography data are derived from either the Alcon/WaveLight (WaveLight AG, Erlangen, Germany) Allegro Topolyzer Vario, a wide-cone Placido corneal topographer, or the Alcon/WaveLight Oculyzer, a Pentacam Scheimpflug imaging rotating camera (Oculus Optikgeräte GmbH, Wetzlar, Germany). ²² Early results, ¹¹ as well as anterior-segment optical coherence tomography quantitative findings, ²³ are indicative of the long-term stability of the procedure. ²⁴

There is a large number of reports ¹ regarding the effects of CXL with or without same-session excimer-ablation corneal normalization. There is general consensus that the intervention strengthens the cornea, helps arrest the ectasia progression, and improves corneal keratometry, 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 AP, due to the partial corneal-surface ablation; ablating a thin, ectatic cornea may sound unorthodox. However, the goal of the topo-guided ablation is to normalize the anterior cornea and thus help improve visual rehabilitation to a step beyond what a simple CXL would provide. We have investigated this over a large sample and follow-up time that permitted sensitive analysis with confident conclusion of postoperative efficacy. ²⁴ We monitored visual acuity changes, and for the quantitative assessment, we chose to standardize on one screening device, the Pentacam, and to focus on key parameters of visual acuity, keratometry, pachymetry, and anterior-surface indices. ²⁵ All these parameters reflect changes induced by the procedure and describe postoperative progression. We have further introduced two objective and sensitive anterior-surface indices, the index of height decentration (IHD) and the index of surface variance (ISV), which provide a more sensitive analysis than keratometry and visual function. ²⁶ A smaller value is indication of cornea normalization (lower IHD: cone less steep and more central; lower ISV: less irregular surface).

Our results indicated that the apparent disadvantage of thinning the cornea is balanced by a documented long-term rehabilitating improvement and synergy from the CXL component. Based on our results, the AP appears to result in postoperative improvement in both uncorrected distance visual acuity (UDVA) and corrected distance visual acuity (CDVA). Average gain/loss in visual acuity was consistently positive, starting from the first postoperative month, with gradual and continuous improvement toward the 3 years, by + 0.20 for CDVA and +0.38 for the UDVA. These visual rehabilitation improvements appear to be superior to those reported in cases of simple CXL treatment. ²⁷

Postoperatively, keratometry is reduced, for example, flat K1 meridian by –2.13 D (–5%), at the 1-month visit. In the long term, and up to 3 years, a continuous flattening is noted by –1.22 D (–3%). Likewise, for the steep K2 meridian, we observe a 1-month reduction by –3.10 D (–6%), with additional flattening of –1.32 D (–3%) over the 36 months. This progressive potential for long-term flattening has been clinically observed in many cases over at least 10 years of experience. Peer-review reports on this matter have been rare and only recent. ^{28,​ 29}

The two anterior-surface indices, IHD and ISV, also demonstrated postoperative improvement. Specifically, our data show ISV reduction by –15.39 1-month postoperatively (on average –16%), up to –6.28 (–8%) at the 3-year visit. More “dramatic” IHD changes were observed: 1-month change was –0.029 μm (–32%), followed by further reduction of –0.005 μm (–9%) at the 3-year visit. Such changes in ISV and IHD have been reported only recently. ³⁰

The initial more “drastic” change of the IHD can be justified by the chief objective of surface normalization, cone centering, ¹⁰ 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 AP includes a partial stromal excimer ablation, there is reduction of postoperative corneal thickness, manifested by the thinnest corneal thickness (TCT). Specifically, average TCT, as measured by the Pentacam, was reduced at 1 month by –97.96 μm, or –22%. What seemed to be a “surprising” result is that the cornea appears to rebound, by gradually thickening, up to 3 years postoperatively, as indicated by an average of +16.57 μm, or +4% in TCT. Postoperative corneal thickening after the 1-month “lowest thickness baseline” has also been discussed recently. ^{31,​ 32} In another recent report, ³³ the lowest TCT was noted at the 3-month interval. In that study, on 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, on 212 eyes treated with the AP 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. ³¹

It is possible, therefore, 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.

A second application of CXL combined with a refractive procedure is that of prophylactic CXL application along with LASIK, either myopic or hyperopic. ³⁴ LASIK offers predictable and stable refractive and visual outcomes. ^{35,​ 36,​ 37} Specifically in correcting moderate to high myopia (equal or more than –6.00 D in the least minus meridian of both eyes), ^{38,​ 39} there have been reports in the past indicating significant long-term regression development. ^{40,​ 41,​ 42} The work by Alió et al ⁴³ has reported that one in five or specifically the compelling percentage of 20.8% of high myopic cases required retreatment because of overcorrection/undercorrection, or regression. Our experience with high-myopic LASIK corrections is suggestive of a slight (0.5 D) trend toward long-term postoperative corneal steepening. ⁴⁴ We have been motivated, therefore, to attempt prophylactic in situ cross-linking (CXL) on the stromal bed concurrent with the LASIK, particularly in high-myopic eyes with thin residual stroma and younger patients who may not yet have exhibited ectasia risk factors. ^{45,​ 46} The application aims to enhance corneal rigidity and thus reduce the likelihood of long-term myopic shift. ^{17,​ 47,​ 48}

We have investigated up to 2-year postoperative refractive and stability results of 140 eyes subjected to femtosecond laser myopic LASIK between two groups: group A in which prophylactic high-fluence CXL is incorporated and group B, a stand-alone LASIK. ⁴⁹ The two groups in the study were by all other means matched: ablation zone, flap thickness, surgeon, lasers employed, and postoperative medication and treatment. The postoperative evaluation in the LASIK-CXL group A has not indicated any clinical or topographic evidence of complications in comparison to the stand-alone group B. Visual rehabilitation between the two groups, as expressed by CDVA and contrast sensitivity evaluation, was in similar levels in comparison to the stand-alone LASIK, without inducing any side effects or compromising visual safety. The refractive outcome, predictability, and stability were remarkable.

Comparison of the stability results between the two groups indicates that in group B there is a slight positive slope in the keratometric readings, at both the flat and the steep meridian, which is suggestive of a mild progressive corneal steepening. The recorded changes correspond to +0.57 D for the flat meridian and +0.54 D for the steep meridian. The data show a trend toward mild corneal steepening in the long-term postoperative period. Similar refractive shift has been reported previously by our team in large myopic LASIK corrections with no prophylactic CXL application. ⁴³

There is no such trend of keratometric shift in the LASIK-CXL group A (+0.03 and +0.05 D, respectively). Other differences between the two groups are the slightly increased stability of the spherical equivalent refraction, as well as the improved predictability, despite the larger range of attempted correction and increased preoperative astigmatism. It is worth noting that the mean spherical as well as cylinder error treated in group A (mean S: –6.60 D; max S: –11.50 D; mean C: –0.98 D; max C: –5.25 D) was significantly greater than in the LASIK stand-alone group (mean S: –5.14 D; max S: –9.50 D; mean C: –0.85 D; max C: –3.50 D). Despite the apparently more challenging task when compared to the stand-alone LASIK group B, the refractive results in the LASIK-CXL group were equally good and, in some cases, slightly better.

14.1.1 Aspects of Surgical Technique

In our surgical technique, it is important to avoid riboflavin immersion of the flap and its hinge. For this purpose, the flap is protected while remaining in folded shape (▶ Fig. 14.1). ⁴⁶ The reason for this is to inhibit flap CXL. However, minimal riboflavin absorption and thus cross-linking will inevitably occur as a result of osmosis during the (however short) UVA exposure duration, given the flap is in contact with the riboflavin-soaked stroma. One has to consider the following aspects: a riboflavin-presoaked flap will strongly absorb UVA (as it precedes the residual stroma along the illumination propagation path); however, it will not contribute any further to the corneal biomechanical stability and may affect negatively the postrefractive outcome, given that a 110-μm thick flap has perhaps only a 60-μm stromal (collagen) content. Cross-linking such a thin stromal layer may lead to undesirable stromal shrinking. On the collateral benefits one has to mention that a “cross-linked” flap–stromal interface might positively affect flap adherence. ⁵⁰

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