Keratoconus is a bilateral ectatic disorder with progressive corneal thinning and reduced uncorrected (UDVA) and corrected (CDVA) visual acuity.1 Corneal cross-linking (CXL) has dramatically changed how ectatic corneal disorders, specifically keratoconus, are treated.2 CXL is a surgical intervention that stabilizes keratoconus progression3 and, in many cases, avoids the need for more drastic interventions such as deep anterior lamellar keratoplasty or penetrating keratoplasty.4
First reported by Wollensak et al. in 2003,3 the standard CXL protocol (Dresden) consists of epithelial removal and 30 minutes of irradiation and is now considered the gold standard. Several modifications to this technique have been reported, including transepithelial5 and accelerated6 CXL. Recent evidence suggests that accelerated CXL may offer a safe and effective alternative to the standard treatment in terms of halting the progression of keratoconus and stabilizing refraction and visual acuity.5–7
Thin corneas pose a particular challenge to the clinician because corneas with a minimum thickness of less than 400 µm following epithelial removal are at an increased risk for endothelium cytotoxicity during CXL treatment.8,9 Hafezi et al.10 introduced hypo-osmolar riboflavin in 2009, leading to an increase in corneal thickness of 33 to 105 µm due to corneal swelling. Additional proposed methods for CXL in thin corneas include iontophoresis,11 stromal lenticules,12 and contact lens–assisted CXL.13 Contact lens–assisted CXL was first described in 2014 by Jacob et al.13 and increased the deepithelialized minimum corneal thickness by 96 to 124 µm without the need for corneal swelling. They later showed that a deep demarcation line is achieved without any cytotoxic effect to the corneal endothelium.14 In the aforementioned contact lens–assisted CXL, a full 30-minute irradiation protocol was used.
To the best of our knowledge, no study has reported on the outcomes of contact lens–assisted CXL for thin corneas using an accelerated CXL protocol. Therefore, the purpose of the current study was to evaluate and describe the outcomes of accelerated contact lens–assisted CXL (A-CACXL) treatment in patients with progressive keratoconus and thin corneas.
Patients and Methods
This study was approved by the institutional review board of the Ben-Gurion University of the Negev and adhered to the tenets of the Declaration of Helsinki.
This retrospective study included consecutive patients who underwent A-CACXL for progressive keratoconus from January 2015 until December 2017 at the Department of Ophthalmology, Soroka University Medical Center, Beer-Sheva, Israel. Progression was defined as a 1.50 diopters (D) increase in mean keratometric value, a 1.00 D increase in maximum keratometry, or a decrease of 5% in central corneal thickness.13,15–17 In all cases of suspected progression, a repeat examination including imaging was performed to confirm progression. Patients with a clinically significant clinical scar did not undergo this procedure. In addition, any patients who, based on planning, would have a measured minimum thickness of less than 400 µm after instilling the bandage contact lens did not undergo this procedure. Patients with a follow-up time of less than 12 months, a history of previous ocular surgery, autoimmune diseases, diabetes mellitus, or pregnancy were excluded. If both eyes of a patient met the inclusion criteria, then one of them was randomly selected to avoid biases resulting from inter-eye correlation.18 Patients were instructed to avoid eye rubbing prior to and at every follow-up visit following A-CACXL. Any patients with signs or symptoms of vernal keratoconjunctivitis were treated appropriately to reduce the chances of eye rubbing.
The medical files of all patients were reviewed, and the following data were extracted: age, gender, date of surgery, anterior/posterior mean keratometric power, anterior/posterior flat keratometric power, anterior/posterior steep keratometric power, maximum keratometric power, UDVA, CDVA, endothelial cell density, corneal resistance factor, and corneal hysteresis. Keratometry and total corneal thickness were measured with Scheimpflug-based corneal tomography (Pentacam HR; Oculus Optikgeräte, Wetzlar, Germany). The endothelial cell density was measured with automated specular microscopy (CEM-530; Nidek Corporation, Aichi, Japan). Corneal resistance factor and corneal hysteresis were measured with the Ocular Response Analyzer (ORA; Reichert Inc., Depew, NY). Extraction of data was performed by two independent investigators (RMK and AC); in case of disagreement, a third investigator (BK) was involved in the decision.
Table 1 details the characteristics of the A-CACXL methods used in this study based on previously recommended standardized terminology and protocol nomenclature.19 Briefly, the procedure was performed under sterile conditions in an operating room setting. Following topical anesthesia with 0.4% benoxinate hydrochloride drops, minimum corneal thickness was confirmed by ultrasound pachymetry (PachPen; Accutome Inc., Malvern, PA) by three repetitive measurements. Following the removal of the central 8 mm of epithelium, the minimum corneal thickness was remeasured. The A-CACXL protocol was initiated if it was less than 400 µm.
A-CACXL was performed using a method similar to that described by Jacob et al.,13 with the main exception being the accelerated nature. Briefly, iso-osmolar 0.1% riboflavin solution (Medio-Cross 0.1%; Peschke Meditrade GmbH, Huenenberg, Switzerland) was instilled every 2 minutes for 30 minutes. At the same time, a 90-µm thick, daily disposable bandage soft contact lens, absent ultraviolet filter (SofLens; Bausch & Lomb, Bridgewater, NJ), with a 14-mm diameter and a base curve of 8.6 mm was immersed in the same iso-osmolar riboflavin solution. Adequate riboflavin penetration was confirmed by appropriate flare in the anterior chamber. The contact lens was then placed on the corneal surface and thereafter the minimum corneal thickness was remeasured to confirm that it was greater than 400 µm prior to irradiation (if not, the procedure was aborted). The cornea was then continuously irradiated at 365 nm with an intensity of 9 mW/cm2 for 10 minutes (total fluence 5.4 J/cm2) using a commercially available device (LightLink-CXL; LightMed, San Clemente, CA). During irradiation, instillation of the riboflavin solution was continued every 2 minutes above and below the contact lens, the patient was instructed to fixate on the light source, and adequate centration was constantly moni tored by the surgeon. Following irradiation, a new unsoaked bandage contact lens was placed to replace the soaked one.
The patients were prescribed topical ofloxacin 0.3% four times a day for a period of 10 to 12 days and topical dexamethasone 0.1% for a total of 1 month with gradual tapering. Patients were advised to use preservative-free artificial tears as needed. Follow-up visits were routinely performed 1 day, 1 week, and 1, 6, 12, and 24 months following treatment. The bandage contact lens was removed at the 1-week visit and corneal tomography, CDVA, corneal resistance factor, corneal hysteresis, and endothelial cell density were reassessed at the 12- and 24-month visits.
Main Outcome Measures
The main outcome measures in this study were UDVA, CDVA, and minimum corneal thickness at the last visit (12 to 34 months), as well as the occurrence of any adverse events throughout the study period. The secondary outcome measures were keratometry, corneal resistance factor, corneal hysteresis, and endothelial cell density values. Flattening following treatment was defined as a decrease of 1.00 D in maximum keratometry or 1.50 D in mean keratometry values. Contact lens wearers were instructed to remove their lenses 10 days before all evaluations.
Clinical parameters were tabulated in a spreadsheet (Excel, version 15.2; Microsoft Corporation, Redmond, WA) and analyzed with the Minitab Software, version 17 (Minitab Inc., State College, PA). Normality of the data was assessed by the Kolmogorov–Smirnov test. For the analysis of continuous data and to compare parameters before and after treatment, the paired t test was used for normally distributed variables and the non-parametric Wilcoxon signed-rank test was used for non-normally distributed variables. 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 together with their standard deviations.
Overall, 24 eyes of 24 patients were included. The mean age was 24.1 ± 8.2 years (range: 11.4 to 45.0 years); 66.6% were male (n = 16) and 33.3% were female (n = 8). The mean follow-up time was 18.2 ± 6.3 months (range: 12 to 34 months). There were 45.8% (n = 11) right eyes and 54.2% (n = 13) left eyes. A family history of keratoconus was present in 25% (n = 6). Vernal keratoconjunctivitis was present in 12.5% (3 of 24) of the entire cohort and 15.8% (3 of 19) of those who did not progress. A total of 16.7% wore rigid gas permeable contact lenses.
Major outcomes are listed in Table 2. There was no significant change in minimum corneal thickness from baseline to the last follow-up visit. There was a significant improvement in UDVA, maximum keratometry, anterior steep keratometry, anterior astigmatism, and posterior astigmatism following treatment. There was no significant change in minimum corneal thickness from baseline to the last follow-up visit.
Preoperative and Postoperative (Last Visit) Anterior Segment Variables
Flattening and Progression
Flattening of the keratectasia occurred in 45.8% of the eyes (n = 11) and progression was documented in 20.8% of the eyes (n = 5). Four of the five cases of progression had stable or improved UDVA and therefore did not undergo additional treatment. One of the five (a patient with deterioration in UDVA and keratometry values) declined further treatment. When comparing baseline parameters between the progression group and those that did not progress following treatment, no significant differences were found (Table 3).
Baseline Parameters of Eyes With and Without Progress Following Treatment
No cases were aborted following epithelium removal due to insufficient minimum corneal thickness, indicating that planning was adequate in all cases. All epithelial erosions were completely healed within 1 week. There were no cases of postoperative keratitis or corneal melting. Clinically significant stromal haze occurred in one case at 1 month following treatment and was treated with an increased frequency (every 2 hours) of topical dexamethasone 0.1% with complete resolution by 3 months. There was no significant change in endothelial cell density from baseline to the last follow-up visit (2,535 ± 317 versus 2,407 ± 319 cells/mm2, P = .10). Manual inspection of the specular microscopy revealed that there was no polymegathism or pleomorphism of the endothelial cells.
This study evaluated A-CACXL for patients with keratoconus and thin corneas. There was a significant improvement in UDVA, keratometry values, and astigmatism, with progression halted in 80% of eyes and flattening achieved in 45% of eyes. There was no evidence of endothelial cytotoxicity and the only adverse event reported was persistent clinically significant stromal haze in one case that resolved by 3 months.
In the original report on contact lens–assisted CXL, Jacob et al.13 reported that there were no cases of progression and flattening occurred in 28.5% of the eyes (n = 4). Hafezi et al.10 reported that hypo-osmolar CXL halted progression in 100% of eyes (n = 20) and flattening was achieved in 40% (n = 8). Depending on the definition of progression, baseline characteristics, and the follow-up time, there has been a wide range of progression reported despite CXL treatment in eyes with progressive keratoconus.10,13,15,20–22 The relatively high rate of progression in the current study, despite CXL treatment, may be explained by the advanced stages of the disease in this study group. For instance, in the aforementioned study by Jacob et al.,13 0% progression was reported in patients with a mean maximum keratometry of 50.90 D (> 60.00 D in the current study) and a thickness of 377.2 µm (353 µm in the current study) after epithelium removal. Indeed, Kuechler et al.22 recently reported that there is a higher incidence of progression (23% at 1 year) in eyes with maximum keratometry values greater than 58.00 D, similar to the 20% reported in the current study. In addition, it has been reported, albeit in a pediatric cohort, that patients with keratoconus who have thinner corneas are more likely to progress despite CXL treatment.23 The rate of progression might be further decreased by omitting the addition of riboflavin below the contact lens throughout the procedure because it is unclear whether or not this action may lead to a partial ultraviolet-A blocking effect. Despite the aforementioned, in the current study, a relatively high proportion of patients benefited from flattening (45%) and an additional 35% remained stable.
In the current study, there was a significant improvement in UDVA following A-CACXL (approximately two lines gained) with a non-significant improvement in CDVA. Although contradicting evidence exists regarding improvement in visual acuity following CXL, considerable evidence suggests that visual acuity may improve by approximately one to two lines.24 Furthermore, several studies have compared visual outcomes following accelerated versus standard CXL protocols. Cummings et al.25 compared accelerated and standard CXL and reported a significant improvement in UDVA at 12 months in the accelerated CXL group only. In contrast to the current study, they also reported a significant improvement in CDVA at 12 months in both groups. Similarly, Chow et al.26 reported a two-line improvement in UDVA for both accelerated and standard CXL in their study, as well as slight improvement in CDVA in both groups. However, Sadoughi et al.27 reported a non-significant improvement in both UDVA and CDVA in both the accelerated and standard CXL treatment groups of their contralateral eye study. It has been postulated that reduction of lower and higher order aberrations following CXL may explain the improvement in UDVA and CDVA, respectively.28 Although preoperative and postoperative higher order aberrations were not reported in the current study, we hypothesize that given the advanced stage of keratoconus in the current cohort, a reduction in these parameters may indeed explain the improvement in visual acuity.
There are three main methods of action when considering CXL in patients with thin corneas. The surgeon can either avoid removing tissue (eg, transepithelial),5,11 swell the tissue (eg, hypo-osmolar),10 or add a layer on top of the cornea (eg, stromal lenticule12 or contact lens–assisted13). The main disadvantage of the transepithelial techniques is that they may be of limited efficacy when compared to the standard epithelium-off techniques,29 and more high level evidence is required before such techniques may be considered as a viable alternative.30 It has been postulated that this may be due to the fact that the corneal epithelium partly absorbs ultraviolet radiation, limits the penetration of riboflavin, and reduces penetration of oxygen to the stroma.13,31,32 Hypo-osmolar riboflavin revolutionized the management of thin corneas by offering an elegant, effective, and simple solution; by swelling the stroma, the corneal thickness was efficiently increased.10 However, several potential disadvantages exist with this technique. Extended surgical time is needed to allow for the cornea to sufficiently swell. An unstable hypo-osmolar riboflavin film may result in higher irradiance at the endothelial level, increasing the potential cytotoxicity and even possible cellular toxicity due to the hypotonic nature of the solution.33 Finally, the effect of CXL on a hydrated cornea may be reduced when compared to a normal cornea due to increased space between the collagen fibers.34 With the technique proposed by Jacob et al.,13 the surgeon avoids the aforementioned potential disadvantages by removing the epithelium, thus allowing for entrance of riboflavin and penetration of ultraviolet-A and by adding a layer to the cornea rather than artificially swelling the stroma. Indeed, in the current study, the endothelial cell density remained stable following A-CACXL and there were no serious adverse events reported, supporting the safety of this technique.
Performing A-CACXL is of particular interest because it may be combined in the future with additional refractive procedures to stabilize and improve outcomes in thin corneas. For example, a recent report by Jacob et al.35 demonstrated that A-CACXL may be safely combined with corneal allogenic intrastromal ring segments in patients with keratoconus (n = 18) to improve UDVA, CDVA, and refractive outcomes. They reported no segment-induced complications and no cases of progression in their study.
This study has several limitations, the first of which is its retrospective nature. Second, there was no control arm that received 30 minutes of irradiation and as such no comment on a comparison between these two methods in thin corneas can be made. Third, this study had a relatively small sample size, but two previously reported studies on standard contact lens–assisted CXL included 10 and 14 eyes, respectively.13,14 Fourth, a substantial limitation of the current study is the higher progression rate that was reported (approximately 20%), most probably due to the advanced stage of keratoconus of many of the patients. Finally, anterior segment optical coherence tomography was not routinely performed in all of the patients following A-CACXL and so we cannot comment on the depth of the demarcation line with this method. However, Jacob et al.13 clearly demonstrated a demarcation line following contact lens–assisted CXL in their original study, which was corroborated by the findings of Malhotra et al.36
Nevertheless, to the best of our knowledge, this is the first study to report the outcomes of A-CACXL for thin corneas. This study shows that progression is halted in 80%, flattening is achieved in 45%, and there is significant improvement in UDVA and keratometry values without any evidence of damage to the corneal endothelium or permanent adverse events reported. As such, A-CACXL seems to be a viable option for patients with keratoconus and thin corneas.
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|Fluence (total) (J/cm2)||5.4|
|Soak time and interval (minutes)||30 (q2)|
|Treatment time (minutes)||10|
|Chromophore||Riboflavin (source name)|
|Chromophore carrier||5% Dextran|
|Light source||LightLink-CXL, LightMed, San Clemente, CA|
|Irradiation mode (interval)||Continuous|
|Protocol modifications||Contact lens–assisted|
|Protocol abbreviation in manuscript||A-CACXL (9*10)|
Preoperative and Postoperative (Last Visit) Anterior Segment Variables
|MCT (µm)||399.8 ± 30.7||391.0 ± 43.8||.11|
|UDVA (logMAR)||0.90 ± 0.63 (20/159 Snellen)||0.64 ± 0.47 (20/87 Snellen)||.009|
|CDVA (logMAR)||0.45 ± 0.21 (20/56 Snellen)||0.37 ± 0.23 (20/47 Snellen)||.19|
|Corneal hysteresis (mm Hg)||7.2 ± 0.7||7.8 ± 1.4||.15|
|Corneal resistance factor (mm Hg)||5.9 ± 1.3||6.3 ± 1.6||.36|
|Kmax (D)||61.20 ± 6.30||59.90 ± 5.70||.03|
|Anterior steep K (D)||55.10 ± 3.90||54.50 ± 4.10||.04|
|Anterior flat K (D)||49.50 ± 4.20||49.80 ± 3.70||.42|
|Anterior mean K (D)||52.00 ± 4.10||52.10 ± 3.80||.79|
|Poster steep K||−8.30 ± 0.90||−8.30 ± 0.90||.69|
|Posterior flat K (D)||−7.40 ± 0.80||−7.50 ± 0.80||.12|
|Anterior astigmatism (D)||5.50 ± 2.40||4.60 ± 2.10||.02|
|Posterior astigmatism (D)||0.90 ± 0.40||0.80 ± 0.40||.04|
|ECD (cells/mm2)||2,535 ± 317||2,407 ± 319||.10|
Baseline Parameters of Eyes With and Without Progress Following Treatment
|Parameter||Progression (n = 5)||No Progression (n = 19)||P|
|Age (years)||23.5 ± 5.5||24.3 ± 8.9||.81|
|Vernal keratoconjunctivitis (%)||0.0%||15.8%||1.00|
|Baseline UDVA (logMAR)||1.1 ± 1.1||0.87 ± 0.47||.61|
|Baseline CDVA (logMAR)||0.5 ± 0.2||0.5 ± 0.2||.93|
|Baseline corneal hysteresis (mm Hg)||7.1 ± 1.3||7.0 ± 0.9||.98|
|Baseline corneal resistance factor (mm Hg)||6.2 ± 2.3||5.7 ± 1.2||.71|
|Baseline Kmax (D)||61.90 ± 3.40||61.00 ± 6.90||.66|
|Baseline MCT (µm)||414.4 ± 23.2||396.2 ± 31.0||.19|