International Journal of Keratoconus and Ectatic Corneal Diseases
Volume 10 | Issue 1-2 | Year 2023

Two-year Outcomes of Transepithelial Customized Cross-linking for Mild to Moderate Keratoconus

Miltos Balidis1, Spyridon Koronis2, Penelope Burle de Politis3https://orcid.org/0000-0001-7839-8897, Georgios Sidiropoulos4, Achilleas Rasoglou5

1–5Cornea Service, Ophthalmica Eye Institute, Thessaloniki, Greece

Corresponding Author: Spyridon Koronis, Cornea Service, Ophthalmica Eye Institute, Thessaloniki, Greece, Phone: +30 6979236654, e-mail: spyridonkoronis@gmail.com

How to cite this article: Balidis M, Koronis S, de Politis PB, et al. Two-year Outcomes of Transepithelial Customized Cross-linking for Mild to Moderate Keratoconus. Int J Kerat Ect Cor Dis 2023;10(1–2)26–31.

Source of support: Nil

Conflict of interest: Dr Militos Balidis is associated as the Editorial Board member of this journal and this manuscript was subjected to this journal’s standard review procedures, with this peer review handled independently of this editorial board member and his research group.

Received on: 19 September 2023; Accepted on: 29 November 2023; Published on: 23 April 2024


Background/Aim: Corneal cross-linking remains the only treatment option capable of halting keratoconus progression. Customized cross-linking is a new topographically-guided protocol consisting of irradiating different corneal treatment zones with variable energy beam profiles. In this study cohort, customized cross-linking was combined with sustained oxygen delivery and high-energy pulsed UV-A irradiation at the apex of the cone, without epithelial debridement. This paper presents outcomes through 24 months postoperatively in keratoconus patients treated with this tailored cross-linking procedure.

Materials and methods: This study involves 54 eyes of 43 patients with keratoconus. Visual acuity and corneal topography were recorded preoperatively. Every patient was examined at 1, 6, 12, and 24 months postoperatively and corneal topography and anterior optical coherence tomography were performed. Corrected distance visual acuity (CDVA), Kmax values, anterior and posterior elevation, and demarcation line depth were recorded.

Results: Median CDVA improved from 0.14 to 0.01 logMAR (p < 0.001) at the 24-month visit. Kmax was successfully reduced from 53.2 ± 8.2 D to 51.5 ± 9.0 D (p < 0.001). Median anterior elevation decreased from 16 to 15 μm (p = 0.01), while median posterior elevation remained stable at 40 μm (p = 0.35), at 12 months. In the first postoperative month, the mean demarcation line depth was 344.6 ± 62.8 μm, equating to 72.7 ± 10.9% of corneal thickness.

Conclusion: Customized corneal cross-linking is a safe and effective procedure for the management of keratoconus, customized and less invasive than cross-linking with epithelial removal. Our encouraging results and minimal complication rates point to a very promising technique that may change the standards for cross-linking.

What is already known on this topic

What this study adds

How this study might affect research, practice, or policy

Keywords: Corneal collagen cross-linking, Keratoconus, Transepithelial cross-linking.


Keratoconus is a progressive ectatic disorder of the cornea, leading to potentially severe visual impairment. The disease typically manifests during late puberty or early adulthood and may progress at variable rates.1 If left untreated, it can progress to the point of requiring corneal transplant, which was estimated to occur in up to 27% of keratoconus patients prior to the introduction of cross-linking.2

Halting keratoconus progression is mainly achieved through corneal collagen cross-linking. The original Dresden protocol for cross-linking consists of debriding the corneal epithelium (standard epithelium-off or “epi-off” technique), saturating the stroma with 0.1% riboflavin solution and applying UV-A radiation.3 Alternatively, the procedure can be performed transepithelially without epithelium removal (epithelium-on or “epi-on” technique). The transepithelial approach reduces the risk of complications associated with de-epithelialization, such as corneal haze and infectious keratitis. It also minimizes discomfort and accelerates rehabilitation.4,5

Another proposed procedural modification to improve patient experience during cross-linking was to reduce the overall treatment time. In order to shorten treatment time, the amount of UV irradiance and total UV energy dose used has been increased. The Bunsen–Roscoe law theorizes that irradiation time and UV intensity can be altered without changing the ultimate photochemical effects, provided that the total energy received by the cornea is the same.6 However, the increased treatment energy also accelerates stromal oxygen consumption, and the depletion of stromal oxygen during a cross-linking treatment may negatively reduce its therapeutic effects.

Recent studies have demonstrated the pivotal role of oxygen in the development of more stable bonds between collagen fibers, leading to increased corneal strength.7 Moreover, pulsed-light exposure decreases oxygen consumption rate, keeping oxygen concentration on the corneal surface almost stable during irradiation.8,9 Another important tool to serve this purpose is the specially designed oxygen delivery system, Boost Goggles (Glaukos Corp., USA), which provides a high-oxygen environment over the cornea throughout the procedure.6,9

Sinha Roy and Dupps proposed that a non-uniform treatment might strengthen the apex of the cone to a greater extent than the surrounding areas of the cornea, thus reducing shape change disparity. Such a technique, termed topography-guided customized cross-linking, would involve a topography-guided treatment plan where a higher UV dose is targeted toward the cone area and the remaining corneal areas within the treatment zone would be irradiated with lower treatment doses.10 Mazzotta et al. subsequently demonstrated that epithelium-off topography-guided customized cross-linking had a stronger flattening effect when compared to standard cross-linking.11

In the present study, we assess a relatively novel approach that combined epithelium-on cross-linking with oxygen supplementation and customized irradiation with UV-A light on a targeted area of the ectatic cornea. Such a targeted approach has been shown to be more efficacious than either epithelium-on or epithelium-off cross-linking using a standard approach.12


The study was conducted at the Ophthalmica Eye Institute in Thessaloniki, Greece. It was a prospective interventional case series involving 54 eyes of 43 patients with keratoconus who underwent oxygen-supplemented, epithelium-on customized corneal cross-linking from February 2018 to January 2021. All patients provided written consent prior to surgery and the tenets of the Declaration of Helsinki were fully respected.

Inclusion criteria were defined as age between 12 and 55 years and topographic evidence of keratoconus; maximum corneal curvature (Kmax) ≥ 47.00 D; localized steepening on topographic maps; and localized elevation in the anterior and posterior corneal surfaces. Corneal topography and tomography were obtained with Pentacam® (Oculus Inc., Germany). Contact lens wearers were instructed to remove their contact lenses 1 week prior to preoperative screening and agreed to abstain from using them until the 12-month visit.

Exclusion criteria were defined as hypersensitivity to riboflavin, corneal pachymetry lower than 380 μm at the thinnest location, history of corneal surgery, corneal scarring, aphakia, pseudophakia, any other visually significant ocular condition that could confound outcomes, and history of previous corneal cross-linking.

Patients underwent a full preoperative examination including corrected distance visual acuity (CDVA), refraction, slit-lamp biomicroscopy, and Scheimpflug corneal tomography (Pentacam). Postoperatively, they were examined at 1 week and 1, 6, 12, and 24 months.

The efficacy parameters included change in CDVA; spherical equivalent; and demarcation line depth at 1 month postoperatively, measured on anterior segment optical coherence tomography scans (SPECTRALIS® Heidelberg Engineering, Germany), at a point corresponding to the thinnest pachymetry. In addition, changes in the following Pentacam readings were recorded: Κmax; thinnest corneal pachymetry; maximum anterior and posterior elevation, as indicated by the Belin-Ambrosio enhanced ectasia display; Fourier analysis-calculated maximum decentration; and regularization index (RI), as proposed by Seiler et al., using the maximum flattening and steepening in the central 6 mm of the comparison maps.13


After the instillation of a topical anesthetic (tetracaine 1%) and insertion of a lid speculum, a Weck-Cel® sponge soaked with 0.25% riboflavin ophthalmic solution (ParaCel™ Part 1, Glaukos Corp., USA) was used to remove the mucin layer of the tear film from the corneal surface by swiping the horizontal and vertical meridians. Two drops of ParaCel Part 1 were instilled every 60 seconds for 4 minutes, followed by two drops of 0.22% riboflavin ophthalmic solution (ParaCel Part 2) every 30 seconds for 6 minutes.

Once the cornea was loaded with riboflavin, residual ParaCel™ was washed out with a balanced salt solution (BSS). The oxygen delivery system (Boost Goggles™) was positioned, and oxygen flow was set at a rate of 2.5 L/min. The eye was then aligned under the UV-A system (Mosaic™ System, Glaukos Corp., USA), which delivered 365 nm UV-A of 30 mW/cm2 pulsed irradiation (1 sec on/1 sec off).

The customized treatment zones were designed as concentric circles based on the topographic image. The outer zone was a circle covering the extent of anterior elevation. This zone received total energy equal to 7.2 J in the span of 8 minutes.

The transition zone was an intermediate circle, its radius being the average between the inner and the outer zones. This zone received total energy equal to 10.4 J in the span of 11 minutes and 6 seconds. The inner zone was a circle centered at the apex of posterior elevation, its radius varying with the extent of the posterior elevation. This zone received a total energy equal to 15 J in the span of 16 minutes and 40 seconds.

Following the procedure, a bandage contact lens was applied. Topical antibiotics and nonsteroidal anti-inflammatory drops were prescribed, respectively for 2 and 5 days postoperatively. The contact lens was removed 2 days postoperatively.

Statistical Analysis

Statistical analysis was conducted with RStudio version 1.1.463 (RStudio Inc., USA). All data were tested for normality of distribution using the Shapiro–Wilk test. Parametric data was analyzed with the paired t-test, while the Wilcoxon rank sum test was performed for non-parametric data. p-values < 0.05 were considered statistically significant.


Study Population

Customized corneal cross-linking was performed on 54 eyes of 43 Caucasian patients, 31 men and 12 women, starting in February 2018 and ending in January 2021. Age ranged from 13 to 41 (mean 24.4 ± 6.9 years).


Corrected Distance Visual Acuity

Median preoperative CDVA was 0.14 logMAR. Postoperatively, median CDVA was stable in the first month at 0.15 logMAR (p = 0.26, 95% CI from −0.12 to 0.03 logMAR), then improved by the 6-month visit to a median value of 0.03 logMAR (p < 0.001, 95% CI from −0.12 to −0.04 logMAR). By the 24-month visit, CDVA improved to a median of 0.01 logMAR (interquartile range—IQR: −0.15). There was a significant median change of −0.1 logMAR (IQR 0.14) (p < 0.001, 95% CI from −0.25 to −0.11). Corrected distance visual acuity change during follow-up is depicted in Figure 1A.

Figs 1A and B: Box plot graphs of CDVA and Kmax at baseline and 1, 6, and 12 postoperative months


Kmax was reduced from 53.2 ± 8.2 D to 51.5 ± 9.0 D, at 24 postoperative months (p < 0.001, 95% CI from −1.9 to −0.7). Kmax decline started as early as 1 month after treatment to 52.8 ± 8.6 D (p < 0.001, 95% CI from −2.1 to −0.8), then Kmax values were relatively stable by month 6 (51.7 ± 7.7 D; p < 0.001, 95% CI from −1.9 to −0.7). Changes in Kmax are demonstrated in Figure 1B.

Regularization index: Mean RI was 4.4 ± 2.9 D at 1 month and remained stable until the end of follow-up. At 24 months, the median RI was 5.4 ± 3.0 D (range, 1.8–12.4 D).

Corneal Pachymetry

Thinnest corneal pachymetry decreased from 472.9 ± 38.1 preoperatively to 454.5 ± 38.4 μm at 6 months postoperatively, before starting to increase and stabilize at the 12th postoperative month. The thinnest corneal pachymetry was 465.4 ± 39.7 μm at 12 months (95% CI from –11.5 to 1.0 μm; p = 0.11 vs preoperative) and 460.3 ± 39.4 μm at 24 months (95% CI from −13 to −2.5 μm; p = 0.003 vs preoperative).

Anterior and Posterior Elevation

Median anterior elevation decreased from 16 to 15 μm at 24 months (p = 0.01, 95% CI from −5.5 to −1.0). Posterior elevation increased significantly until the 12th postoperative month, from 40 to 44.5 μm (p < 0.001, 95% CI from 1.5 to 7.5 μm). At the 24th month, the change was no longer statistically significant compared to baseline, with a median value of 40 μm (p = 0.35, 95% CI from −1.5 to 5 μm).

Spherical Equivalent

Spherical equivalent showed non-significant changes throughout the follow-up, from a median value of −2.6 D preoperatively to −2.3 D at 24 months (p = 0.45, 95% CI from −0.61 to 0.44 D).

Demarcation Line Depth

The mean demarcation line depth at 1 month postoperatively was 344.6 ± 62.8 μm, equating to 72.7 ± 10.9% of corneal thickness at the time of the scan. The demarcation line depth of each patient is depicted in Figure 2. Figure 3 demonstrates a deep demarcation line in one of our patients.

Fig. 2: Histogram of demarcation line depth at the thinnest location

Fig. 3: Anterior segment optical coherence tomography showing demarcation line depth and respective treatment zones at 1 month postoperatively (inner zone 455 μm, transition zone 452 μm, outer zone 315 μm)

Correlation Analyses

Results were evaluated for potential correlations through Kendall’s τ. In brief, CDVA at 12 months correlated significantly with preoperative CDVA (τ = 0.57; p < 0.001), preoperative thinnest pachymetry (τ = −0.34, p = 0.028), preoperative Kmax (τ = 0.35, p = 0.022), postoperative Kmax (τ = 0.33, p = 0.034) and postoperative thinnest pachymetry (Kendall’s τ = −0.34, p = 0.025). The change in CDVA from baseline to 12 months correlated significantly with preoperative CDVA (τ = −0.38, p = 0.014) and demarcation line depth at 1 month (Kendall’s τ = −0.4; p = 0.007; Fig. 4). The RI correlated with demarcation line depth at 1 month postoperatively (τ = 0.31; p = 0.037).

Fig. 4: Correlation between demarcation line depth and CDVA


One patient presented with postoperative corneal haze (4.2%), most evident and vision-impacting at 1 month postoperatively and waning between 3 and 6 months. After resolution at 6 months, CDVA was better than baseline values (0.15 logMAR vs 0.3 logMAR, preoperatively). There were no other adverse events.


In this prospective non-comparative interventional case series, we study outcomes through 24 months following a novel epithelium-on procedure combining customized cross-linking, oxygen supplementation, and high-energy UV pulsing. Results in this 54-eye cohort with keratoconus showed efficacy in halting keratoconus progression and improving CDVA, while safety outcomes were favorable.

Several techniques have been proposed to optimize transepithelial cross-linking. The main drawback in most epithelium-on protocols has been the limited riboflavin penetration through the intact corneal epithelium. To overcome this downside, chemically-enhanced riboflavin preparations have been proposed, but have proven less effective when compared to the Dresden standard epi-off protocol, with a high rate of treatment failure.14 Alternatively, 0.5% hypotonic and EDTA-enhanced riboflavin solutions have been used in epithelium-on cross-linking procedures.12,13 For example, in the randomized controlled trial (RCT) using hypotonic riboflavin by Stojanovic et al., CDVA improved by −0.15 logMAR at 12 months, a similar gain to the Dresden protocol group.15 Another proposed transepithelial technique to penetrate the corneal epithelium uses an iontophoresis device to create an electrical gradient that allows for the inward molecular movement of 0.1% hypotonic riboflavin solution through an intact epithelial barrier. Results of the associated RCT by Bikbova and Bikbov suggest that iontophoresis cross-linking can successfully halt keratoconus progression, but with no clear benefits when compared to the standard epi-off protocol.16

Our results show significant improvement in CDVA which was documented at 6 months postoperatively and throughout the 2-year follow-up. The median CDVA change at 24 months (−0.08 logMAR) is comparable to that reported with the standard epi-off protocol, which trials have demonstrated to range from 0 to −0.14 logMAR.1619 Notably, median CDVA change was stable at 1 month postoperatively in our study, whereas Dresden protocol-based studies report worse CDVA 1 month after treatment, with a shift from +0.02 to +0.08 logMAR.1820 Even at 3 months postoperatively, CDVA change in the Dresden protocol is expected to be minor (from −0.01 to +0.02, as reported in RCTs).1719 In contrast, in the present study, we demonstrate an early and sustained improvement in visual function and corneal curvature after the combined epi-on, oxygen-boosted, UV-pulsed, customized cross-linking procedure, with earlier onset than in the reports for the standard epi-off protocol.

Parallel to these changes, there was a significant reduction in Kmax, with a mean value of 1 D (Fig. 5). The benefit was noticeable already from the first month of follow-up. This contrasts with standard epi-off protocol-based studies, in which Kmax tends to increase in the first month, postoperatively (0.48–1.28 D), before decreasing from −0.78 to −1.77 after 12 months.18,19

Fig. 5: Corneal tomography comparison maps highlighting the change in anterior tangential curvature 6 months postoperatively (left map) and preoperatively (middle map); note the marked flattening of the cone in the difference map (right map)

Despite overall Kmax decrease in this study, five eyes (of five individual patients) yielded higher Kmax values at 24 months compared to their respective baseline, with differences ranging from 0.2 to 0.8 D. However, due to the limited repeatability of Pentacam® Kmax readings, especially in advanced keratoconus, it was not possible to establish disease progression.20 These patients remain under close monitoring, with no current plans for retreatment.

Anterior elevation showed a significant decrease until the end of follow-up, while posterior elevation significantly increased until the 12th month before exhibiting no significant difference by 24 months. This may be due to the remodeling effect of customized cross-linking, which can promote the regularization of the anterior and posterior cornea. Alternatively, automated changes in the best-fit sphere among examinations may have affected the results of anterior and posterior elevation readings.

To better characterize the remodeling effect of customized cross-linking, we calculated the RI as described by Seiler et al. Our results were similar: 5.4 ± 3.0 D at the end of follow-up compared to 5.2 ± 2.7 D of Seiler et al.13

The demarcation line depth, with a mean value of 344.6 μm in our study, compares favorably with the range typically reported in epithelium-off cross-linking trials using the Dresden protocol (from 280 to 380.8 μm),2123 thereby highlighting the effectiveness of the oxygen-supplemented, UV-pulsed, transepithelial customized cross-linking procedure. Additionally, since our study showed statistically significant (albeit weak) correlations between demarcation line depth with RI value and baseline-to-12-month CDVA change, the relatively deep demarcation line after customized cross-linking is particularly promising. Nonetheless, larger studies will be needed to confirm this result.

This transepithelial customized cross-linking procedure showed favorably safety. Although the total energy of 15 J/cm2 used in our protocol may have been considered high according to the initial guidelines published by Spoerl et al.,24 even those authors acknowledged that limited riboflavin absorption could affect the results and therefore might necessitate modifications. The subsequent theoretical model by Schumacher et al. in 2012 indeed showed that effective and safe modifications could be made to the UV profile of the standard protocol.25 In addition, Seiler et al. published a model demonstrating lower tissue concentration of riboflavin in the posterior stroma and corneal endothelium (as low as 0.015%, for a 0.1% riboflavin solution applied to the anterior cornea) than what was previously estimated by the Dresden study group, so it is possible that a higher energy dose than previously proposed can be safely administered without producing endothelial toxicity.3

Although clinical data on cross-linking with energy as high as 15 J/cm are still limited, it generally has shown a favorable safety profile. Sachdev et al. published encouraging results with transepithelial cross-linking in the correction of low myopia, with no reported complications, such as endothelial loss.26 In a similar prospective case series by El Hout et al., corneal haze was present in the majority of eyes (16 eyes or 84.2%) at 1 month but had resolved without sequelae by 6 months.27 Meanwhile, in our cohort, we had a single case of haze at 1 month postoperative that resolved between the 3rd and 6th months. Additionally, the intact epithelium after this transepithelial procedure ensured the absence of infectious keratitis.

To our knowledge, this prospective study with 2-year follow-up is, to-date, the longest-running trial yet published on this novel epi-on procedure combining customized cross-linking, oxygen supplementation, and high-energy UV pulsing. Due to its non-comparative nature, conclusions on efficacy compared to the Dresden protocol can only be indirect, and thus future prospective randomized trials may be needed to provide direct means of comparison. Nevertheless, oxygen-boosted epithelium-on customized cross-linking seems to be an effective and safe procedure, less invasive than epithelium-off cross-linking. Our encouraging results and minimal complication rate point to a promising technique that may change the standards for cross-linking, allowing for optimization of current guidelines and promotion of a new age in the treatment and stabilization of keratoconus.


Penelope Burle de Politis https://orcid.org/0000-0001-7839-8897


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