Saudi Journal for Health Sciences

: 2018  |  Volume : 7  |  Issue : 1  |  Page : 7--13

Visual and refractive outcomes of combined excimer laser ablation with accelerated corneal collagen cross-linking in subclinical keratoconus

Talal A Althomali 
 Ophthalmology Department, Medical College, Taif University, Taif, Saudi Arabia

Correspondence Address:
Talal A Althomali
Taif University, P.O. Box 795, Code 21944, Taif
Saudi Arabia


Purpose: The purpose of the study was to evaluate efficacy, safety, and stability of visual and refractive outcomes of combined photorefractive keratectomy (PRK) with accelerated corneal collagen cross-linking (CXL) in subclinical keratoconus. Materials and Methods: This retrospective study included 140 eyes (75 patients) with subclinical keratoconus which underwent simultaneous topography-guided PRK with acceleratedCXL (2.7 J/cm2). Outcome measures were pre- and postoperative uncorrected distance visual acuity (UDVA) and corrected distance visual acuity (CDVA), manifest refraction, and keratometry. Results: Refractive and keratometric parameters demonstrated statistically significant improvement from baseline to postoperative 12 months. UDVA of ≥20/20 was achieved in 90.7% (127/140) eyes and ≥20/40 in 96.4% (135/140) eyes at last follow-up. Regarding refractive outcomes, 94.3% (132/140) eyes were within ± 1.00 D of attempted refractive correction and 82.9% (116/140) eyes had astigmatism of ≤0.25D postoperatively as compared to 22.9% (32/140) eyes at preoperative levels. Regarding safety, 90.7% (127/140) eyes maintained their preoperative CDVA and 7.2% (10/140) eyes lost ≥2 lines of CDVA. Complications included corneal haze in 7.14% (10/140) and corneal ectasia in 0.7% (1/140) eyes. Conclusion: During the 12-month follow-up, combined topography-guided PRK and accelerated CXL provided good visual and refractive outcomes offering spectacle independence in subclinical keratoconus eyes; however, development of one case of ectasia (0.7%) indicates compromised safety and seems to suggest that utilizing 2.7 J/cm2 energy for CXL procedure may not be adequate.

How to cite this article:
Althomali TA. Visual and refractive outcomes of combined excimer laser ablation with accelerated corneal collagen cross-linking in subclinical keratoconus.Saudi J Health Sci 2018;7:7-13

How to cite this URL:
Althomali TA. Visual and refractive outcomes of combined excimer laser ablation with accelerated corneal collagen cross-linking in subclinical keratoconus. Saudi J Health Sci [serial online] 2018 [cited 2022 Aug 19 ];7:7-13
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Full Text


Excimer laser surgeries correct refractive error by corneal tissue ablation which also leads to the weakening of the biomechanical strength of the cornea and therefore increase the risk of developing postoperative keratectasia. The incidence of postrefractive surgery ectasia is greatly enhanced by the presence of conditions associated with low residual stromal bed thickness (<250 μm) either from excessive ablation (high myopia) or thick flap creation, or presence of preexisting topographic abnormalities such as subclinical keratoconus.[1] Due to increased risk of postrefractive surgery ectatic complications, subclinical keratoconus is considered as a contraindication to laser in situ keratomileusis (LASIK).[2] There are reports which suggest that patients with preoperative risk factors could be offered photorefractive keratectomy (PRK) as an alternative to LASIK;[3] however, the risk of progression to keratoconus after PRK still prevails.[1],[2],[3] As such, general consensus has been that excimer laser ablation procedures should be avoided in eyes with subclinical keratoconus.

In recent years, riboflavin-ultraviolet A (UVA) corneal collagen cross-linking (CXL) has been successfully used to halt the progression of keratoconus. In highly irregular corneas with keratoconus or post-LASIK ectasia, the combination of topography-guided PRK with CXL has been found to significantly decrease corneal irregularity and improve visual acuity as well as halt the progression of keratoconus at the same time.[4],[5] The use of prophylactic accelerated CXL in combination with LASIK has also been evaluated in a population at risk but with no corneal abnormalities and found to be safe and effective with respect to the refractive and keratometric outcomes.[6],[7]

Due to the successful use of CXL alone or in combination with topography-guided PRK in eyes with manifest keratoconus, there has been a revival of interest about the possibility of performing laser vision correction safely in eyes with subclinical keratoconus. In patients with subclinical keratoconus, simultaneous CXL with PRK may offer both spectacle/contact lens freedom and stability of their ectatic disorder at the same time. The current study aimed at evaluating the visual, refractive, and safety outcomes in patients with subclinical keratoconus, who have undergone combined, same-day, topography-guided PRK followed by accelerated CXL.

 Materials and Methods

This retrospective study comprised of consecutive patients who underwent simultaneous topography-guided PRK with accelerated CXL for subclinical keratoconus between January 2011 and February 2013 and completed 1-year follow up. The study was approved by local Ethics Committee. As a standard protocol, patients older than 18 years who had stable corneal topography and refraction for at least 1 year and estimated residual bed thickness >350 μm were offered this procedure. All surgeries were performed by one surgeon after obtaining appropriate written consent.

The diagnosis of subclinical keratoconus was made using Pentacam (Pentacam; Oculus, Inc, Wetzlar, Germany) based on the Belin-Ambrósio Enhanced Ectasia Display which evaluates elevation data (anterior and posterior), pachymetric distribution, and keratometry. It provides an overall map reading called the final D, which is based on the regression analysis against a standard database of normal and keratoconic corneas.[8],[9],[10],[11],[12] The final D represents a value normalized to its mean and is reported as standard deviations (SD) from the mean. For keratoconus suspect cases, the parameter is coded with “yellow” color by the software based on the variation from the normal (≥1.6 SD and <2.6 SD).[8],[9],[10],[11],[12]

Surgical technique

Under topical anesthesia, the central 9 mm epithelium was removed using ethanol 20% and Weck-Cel sponge. All topography-guided PRK procedures were performed using excimer laser (NIDEK EC-5000 CXIII, Nidek Co. Ltd., Gamagori, Japan) with a 6 mm optical zone and a transition zone of 2 mm in all eyes. Topography-guided PRK procedures were followed by accelerated CXL with the corneal cross-linking system (The KXL ® System, Avedro Inc., Waltham, MA). As previously reported,[13],[14] eyes with myopic spherical equivalent >4.0 D were applied mitomycin C 0.4 mg/ml (0.02%) for 25 s and washed with 40 ml of balanced salt solution (BSS) (Alcon Laboratories, Fort Worth, TX, USA). Accelerated CXL was performed by soaking the exposed stroma with 0.22% isotonic riboflavin (Vibex Xtra, Avedro Inc., Waltham, MA) for 90 s. After completely rinsing the corneal bed with BSS, UVA continuous light treatment was initiated at 30 mW/cm 2 for 90 s delivering a total energy of 2.7 J/cm 2 to the cornea. During UVA treatment, stroma was rinsed with BSS as needed. Bandage soft contact lens was placed. The contact lens was removed after the epithelial defect had closed (3–5 days postoperatively). All patients were treated postoperatively with topical moxifloxacin 0.5% (Vigamox ®, Alcon Laboratories, Fort Worth, TX, USA) eye drops four times a day or qua'ter in di'e daily for 1 week and prednisolone acetate 1% (Pred Forte, Allergan Pharmaceuticals Ltd., Ireland) for 1 month.

Outcome measures

The 1-year follow up data were available for 140 eyes (75 patients) and were included in this study analysis. Study parameters included uncorrected distance visual acuity (UDVA), corrected distance visual acuity (CDVA), manifest and cycloplegic refraction, scotopic pupillometry, central ultrasound pachymetry, slit-lamp examination of the anterior and posterior segments of the eye, and keratometry (flat and steep) measured at baseline and postoperatively at 1, 3, 6, and 12 months. As a standard protocol, contact lens wearers were instructed to discontinue use for a minimum of 2 weeks before the preoperative eye examination for soft contact lenses and 1 month for hard contact lenses. Visual acuity was recorded using Snellen's chart and converted to logMAR values for analysis. The flat and steep K values were measured by OPD-Scan (NIDEK Co Ltd, Gamagori, Japan). Corneal haze was documented at each postoperative visit and graded on a scale of 0–4 (0 = clear cornea; 1 = mild haze; 2 = moderate haze; 3 = severe haze; 4 = reticular haze obstructing iris anatomy).

Statistical analysis

Statistical analysis was performed using SPSS software (version 17.0; IBM Corp, Somers, NY, USA). Repeated-measures ANOVA with Bonferroni corrected post hoc testing and descriptive statistics were used to analyze the change from baseline (preprocedure levels) to 1, 3, 6, and 12 months' values as well as other successive time intervals, i.e., 1–3, 3–6, and 6–12 months. A statistically significant difference was based on the level α = 0.05.


One hundred and forty eyes of 75 patients (35 females and 40 males), with a mean age of 25.7 ± 5.2 years (range: 19–39 years) were included in this study. All refractive and keratometric parameters demonstrated a statistically significant improvement from baseline to postoperative 12 months. At the last follow-up visit (12 months), MRSE was −0.32 ± 0.59 D (vs. −2.64 ± 1.26 D preoperatively), steep K was 42.25 ± 2.09 D (vs. 45.31 ± 1.67 D preoperatively), flat K was 41.53 ± 2.04 D (vs. 44.05 ± 1.74 D preoperatively), and average K was 41.89 ± 2.06 D (vs. 44.68 ± 1.63 D preoperatively). Of the visual outcomes, UDVA demonstrated a statistically significant improvement at postoperative 12 months with 0.03 ± 0.11 logMAR compared to 0.73 ± 0.35 logMAR preoperatively. The CDVA was 0.03 ± 0.11 logMAR at postoperative 12 months compared to 0 ± 0 logMAR at baseline (P > 0.05) [Table 1].{Table 1}


At postoperative 12 months, 90.7% (127/140) eyes achieved 20/20 or better UDVA and 96.4% (135/140) eyes achieved UDVA of 20/40 or better as compared to 100% eyes with 20/20 or better CDVA preoperatively [Figure 1].{Figure 1}


At postoperative 12 months, 94.3% (132/140) eyes were within ± 1.00 D of attempted refractive correction and 79.3% (111/140) eyes were within ± 0.5 D of attempted refractive correction [Figure 2]. [Figure 3] illustrates scatterplot of 12 months attempted versus achieved MRSE. Comparison of preoperative and 12-month postoperative astigmatism is shown in [Figure 4]. At 12 months, 82.9% (116/140) eyes had ≤0.25 D astigmatism as compared to only 22.9% (32/140) eyes preoperatively [Figure 4].{Figure 2}{Figure 3}{Figure 4}


Change in MRSE from preoperative state to 1, 3, 6, and 12 months' follow-up is shown in stability chart [Figure 5]. A statistically significant improvement in MRSE was observed at postoperative 1 month. At postoperative 3-month follow-up, there was a slight increase in MRSE, which, however, was statistically not significant. The improvement in MRSE was observed at postoperative 6 and 12 months; the improvement, however, was statistically significant for the comparison between 1 and 12 months.{Figure 5}


Analysis of change in lines of CDVA revealed that 90.7% (127/140) eyes maintained their preoperative CDVA, 2.1% (3/140) eyes lost 1 line, 3.6% (5/140) eyes lost 2 lines, and 3.6% (5/140) eyes lost 3 or more lines of CDVA [Figure 6].{Figure 6}


Corneal haze (Grade 1) was observed in 7.14% (10/140) eyes and corneal ectasia developed in 1 eye (0.7%) postoperatively.


Laser refractive surgeries are the most commonly used method for vision correction due to high efficacy, predictability, stability, and safety outcomes. Combined PRK and CXL procedure has been recognized to provide good clinical improvement and corneal stabilization in eyes with manifest keratoconus and post-LASIK ectasia.[4],[5],[15],[16] The evidence of successful outcomes in keratoconus eyes after combined procedure of CXL and laser ablation led to the thought of evaluating this combined procedure in eyes with subclinical keratoconus. With recent advances in ultraviolet light sources and CXL techniques, accelerated or high-fluence protocols have been developed that use UVA light sources of greater irradiance to deliver the cumulative dose of 5.4 J/cm 2 over a shorter period.[17] Within the shorter follow-up available, there is evidence to support that the results of accelerated CXL are comparable with standard CXL in halting the progression of keratoconus with shorter exposure time.[17],[18],[19] In laser refractive settings, the combination of laser ablation and accelerated CXL may prove beneficial due to significantly reduced exposure time and lesser interruption in the flow of the procedure. Therefore, in the current study, we evaluated the outcomes of accelerated CXL in conjunction with topography-guided PRK in eyes with subclinical keratoconus and found that the UDVA, MRSE, and average K demonstrated a statistically significant improvement from baseline to postoperative 1, 3, 6, and 12 months. In the present study, due to the much lower severity of ectasia in eyes with subclinical keratoconus, a total energy of 2.7 J/cm 2 was used.

The current treatment was done in the eyes with CDVA of 20/20; thus, the expectations from this treatment were similar to that of standard refractive treatment. Therefore, the author chose to compare the refractive and visual outcomes of this study with those reported for normal eyes. Efficacy outcomes in the current study were observed to be similar to the previous literature. In the current study, 90.7% eyes achieved UDVA of 20/20 or better and 96.4% eyes achieved UDVA of 20/40 or better [Figure 1]. These results are consistent with the previous literature of PRK with reports of 90%–98.5% eyes achieving UDVA of 20/20 or better and 96%–100% eyes achieving 20/40 or better.[13],[20],[21],[22] Hence, the efficacy outcomes of the combined procedure (topography-guided PRK + accelerated CXL) in eyes with subclinical keratoconus are similar to the PRK outcomes.

Topography-guided excimer laser ablation procedures may have poor refractive predictability. In the current study, refractive predictability within ±0.5 D was 79.3% [Figure 2]. A review of literature reveals that the predictability of the combined procedure was similar or better than most of the previous literature on PRK. Majority of authors have reported 45%–77% of eyes within ±0.5 D of the target 6 months after PRK;[20],[21],[23] however, there is one study that has reported 100% eyes within ±0.5 D of the target.[13] The scatter-plot between attempted and achieved refraction revealed that there was a tendency toward undercorrection in the achieved refractive outcomes [Figure 3]. Further, a review of previous literature of PRK reveals that at least some regression in the mean MRSE values is observed during the first postoperative year.[20],[24],[25] In the current study, the improvement in the myopic refraction was observed between 6 and 12 months postoperatively [Figure 5]. This improvement was potentially due to the gradual flattening of the cornea after initial steepening associated with CXL. This is also supported by findings of steep and flat keratometry [Table 1]. A review of literature documenting long-term PRK outcomes reveals that some regression in mean MRSE values can be observed after 1 year as well;[20],[24],[25] therefore, at longer follow-up visits, when the effect of gradual flattening of the cornea due to initial CXL-associated steepening abates, regression in the manifest refraction may be observed.

We observed a loss in CDVA lines in 9.3% (13/140) eyes [Figure 6] which is consistent with the literature reporting approximately 8.5%–15% of such eyes after PRK [13],[21],[26],[27] (although 0% loss of CDVA lines has also been reported in a few studies [20],[28]). The loss in CDVA was observed to be associated with corneal haze (10 eyes), development of postrefractive surgery ectasia (1 eye), and irregular astigmatism (2 eyes) in the current data, which are known complications related to standard PRK.[13],[29],[30] Regarding haze, the occurrence reported in the literature after combined topography-guided PRK and CXL for keratoconus with/without the use of MMC ranges from 2.8% to 50%.[31],[32],[33],[34] The incidence in the present study was 7.1%, which is toward the lower end of the range of occurrence of haze reported in the literature. The current study, however, is probably not directly comparable to these studies from literature because of the reasons such as use of MMC only in eyes with high amount of myopic spherical equivalent (>4.0 D), the study population included the eyes with subclinical keratoconus, and the CXL procedure is accelerated and not the conventional one.

In the current series of 140 eyes, we observed one case (0.7%) of postrefractive surgery ectasia within 3 months after the combined procedure. There is strong evidence from the previous literature regarding safety of the combined procedure of topography-guided PRK and CXL. From the overall data of nearly 237 eyes with manifest keratoconus from the previous six studies, no case of keratoconus progression has been reported after combined topography-guided PRK and CXL with follow-up durations ranging from 3 months to 2 years.[5],[31],[32],[35],[36],[37] On the careful review of these studies in comparison to the current one, we observed that possible reasons for ectasia development could be the amount of ablation and/or energy used for the accelerated CXL procedure. In all these studies on manifest keratoconus (from literature), partial correction (that is, up to 50 μ ablation) was attempted.[5],[31],[32],[35],[36],[37] In the current study on subclinical keratoconus, we attempted full refractive correction in all eyes (approximately 56% of which underwent ablation of >50 μm; keeping the residual bed thickness >350 μm). The eye which developed corneal ectasia postoperatively had preoperative spherical equivalent refractive error of −3.75 D and pachymetry of 602 μm. In the current data set of 140 eyes, there were 30 eyes (21.4%) which had undergone a higher amount of ablation and 110 eyes (%) had lower stromal bed thickness yet did not develop corneal ectasia until the last follow-up at 12 months. As such, the development of corneal ectasia did not appear to correlate to the amount of ablation.

Regarding the energy used for the CXL procedure, a standard dose of 5.4 J/cm 2 has been used in previous studies with manifest keratoconus.[5],[31],[32],[35],[36],[37] In the current study, we have used a lower energy dose of 2.7 J/cm 2 for accelerated CXL procedure. The use of lower energy is based on the pretext that in LASIK XTRA procedures, lower energies ranging from 1.8 to 2.7 J/cm 2 have been used in myopic and hyperopic eyes.[38] Since in the current series, we were treating eyes with subclinical keratoconus (early stage or aborted disease), 2.7 J/cm 2 seemed appropriate to strengthen the cornea. Given the outcomes, i.e., occurrence of one case of ectasia seems to suggest that this much energy may not be sufficient. Instead, the high energy dose of 5.4 J/cm 2 which has been extensively studied to halt the progression of keratoconus/ectasia may be applied in such eyes. The author is currently evaluating the efficacy of 5.4 J/cm 2 energy in preventing the progression of ectasia in combined topography-guided PRK and accelerated CXL procedure in subclinical keratoconus eyes.

Nevertheless, repeat CXL procedure utilizing epi-off technique was performed on this eye. For this purpose, 20% alcohol was applied on the cornea for 30 s and epithelium was removed using cellulose spears. Accelerated CXL was performed by soaking the exposed stroma with riboflavin 0.1% solution (VibeX) for 20 min. After completely rinsing the corneal bed with BSS, ultraviolet-A with incident intensity of 30 mW/cm 2 was applied for the next 4 min (KXL ® System) in a continuous treatment mode. This cross-linking procedure delivered a total energy of 7.2 J/cm 2 to the cornea. After repeat CXL, no further progression was observed until the last follow-up visit at 1 year, supporting the well-documented potential of CXL to halt progression.

Corneal ectasia is a long-term complication that may appear even several years after the refractive surgery. While the good visual and refractive outcomes of combined topography-guided PRK and accelerated CXL procedure offering spectacle independence advocate the efficacy of the procedure, current study presents an evidence of compromised safety, i.e., one case (0.7%) of ectasia development during the 1-year follow-up. As such, the use of 2.7 J/cm 2 energy may not be adequate. The author is following up the current study cohort to ensure the safety of the study subjects and will report long-term outcomes in a subsequent paper. Future studies are needed to evaluate the efficacy of higher energy dose of 5.4 j/cm 2 along with the evaluation of higher-order aberrations and endothelial cell density changes to obtain more objective information.


Raman Bedi, MD, critically reviewed the manuscript. Writing, editing, and statistics assistance provided by IrisARC-Analytics, Research and Consulting (Chandigarh, India).

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.


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