Long-term Effects and Prognostic Factors of Accelerated Cross-Linking with Retention Ring-assisted Riboflavin Application on Keratoconus Progression

Article information

Korean J Ophthalmol. 2025;39(2):145-156

Publication date (electronic) : 2025 February 26

doi : https://doi.org/10.3341/kjo.2025.0001

Seonghwan Kim ¹^,²^,³, Won Jong Choi ¹^,⁴, Chang Ho Yoon ³^,⁴^,⁵, Mee Kum Kim ¹^,³^,⁴^,⁵

¹Department of Ophthalmology, Seoul National University College of Medicine, Seoul, Korea

²Department of Ophthalmology, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul, Korea

³Laboratory of Ocular Regenerative Medicine and Immunology, Biomedical Research Institute, Seoul National University Hospital, Seoul, Korea

⁴Department of Ophthalmology, Seoul National University Hospital, Seoul, Korea

⁵Transplantation Research Institute, Seoul National University Medical Research Center, Seoul, Korea

Corresponding Author: Mee Kum Kim, MD, PhD. Department of Ophthalmology, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul 03080, Korea. Tel: 82-2-2072-2665, Fax: 82-2-741-3187, Email: kmk9@snu.ac.kr

Received 2025 January 3; Revised 2025 February 7; Accepted 2025 February 10.

Abstract

Purpose

To evaluate the long-term efficacy, safety, and prognostic factors of pulsed-light accelerated corneal collagen cross-linking (A-CXL) with continuous riboflavin application to halt keratoconus progression

Methods

A-CXL with retention ring-assisted continuous riboflavin application for either 10 or 5 minutes was performed in 37 eyes of 33 patients with progressive keratoconus between 2016 and 2020. Successful halting rates and prognostic factors of time-dependent changes in keratometric values, visual acuity, refractive errors, topographic indices, central corneal thickness, thinnest corneal thickness, irregularity at 3- and 5-mm zone, and endothelial cell density were evaluated.

Results

Survival analysis showed successful halting rates of 71% and 89% in A-CXL with 5- and 10- minute–applied riboflavin, respectively. Best-corrected visual acuity significantly improved after A-CXL in both groups. Maximum keratometry decreased significantly from 52.52 to 50.39 diopters (p < 0.001) in the 10-minute group, while there was no significant decrease in the 5-minute group (52.77–51.80 diopters, p = 0.146). irregularity in 3- and 5-mm zone decreased significantly in the 10-minute group, while there was no difference in 5-minute group. Central corneal thickness and thinnest corneal thickness did not differ, and endothelial cell density changes were within acceptable ranges in both groups before and after the surgery. Among keratometric values, keratometric astigmatism was significantly related to posttreatment corneal flattening effect in multivariate regression analysis.

Conclusions

A-CXL with continuous riboflavin application for 10 minutes is an effective and safe treatment for preventing keratoconus progression. In addition, higher corneal astigmatism showed greater posttreatment corneal flattening effect in successfully treated patients.

Keywords: Accelerated cross-linking; Continuous application; Keratoconus; Prognostic; Riboflavin

Keratoconus is a corneal ectatic disorder characterized by progressive protrusion and thinning of the corneal stroma, resulting in irregular astigmatism and visual disturbance [1,2]. Collagen cross-linking (CXL) with ultraviolet A (UV-A) light and riboflavin (vitamin B2) halts the progression of keratoconus and has the benefit of delaying corneal transplantation [1–4]. Overall, the 10-year data suggest that CXL is a valid treatment option for keratoconus [5–8].

Since the introduction of the conventional Dresden protocol for CXL [4], new treatment options have been widely investigated, such as energy delivery, riboflavin instillation, and riboflavin penetration-facilitating methods [2,9,10]. In addition, accelerated CXL (A-CXL) has been developed to shorten surgical time [11,12]; however, its efficacy compared with that of conventional protocols has long been debated [13–25]. Recently, a study reported that A-CXL using a retention ring for 10-minute continuous application of 0.1% isotonic riboflavin showed comparable efficacy to that of the conventional protocol in 1 year [9].

However, only a few studies have reported the long-term results of A-CXL in adult keratoconus patients [26,27]. Herein, we investigated the long-term effects of A-CXL with 10-minute riboflavin application on halting the progression of keratoconus. In addition, we investigated whether prognostic corneal parameters suggested a greater corneal flattening effect after treatment in 10 minutes of riboflavin applied A-CXL. Finally, we compared the effects of A-CXL according to the continuous riboflavin application time (10 minutes vs. 5 minutes).

Materials and Methods

Ethics statement

This study was approved by the Institutional Review Board of Seoul National University Hospital (No. 2012-180-1186), with a waiver of informed consent. The study adhered to the tenets of the Declaration of Helsinki.

Patients

The medical records of patients who underwent CXL procedures were retrospectively reviewed. A total of 37 eyes of 33 patients who were diagnosed with progressive keratoconus and underwent retention ring-assisted A-CXL with the application of riboflavin between 2016 and 2020 were included. Patients treated between 2016 and 2018 underwent A-CXL with continuous riboflavin application for 10 minutes (10-minute group), while those treated between 2018 and 2020 received A-CXL with continuous riboflavin application for 5 minutes (5-minute group). A total of 18 eyes from 16 patients were included in the 10-minute group, and 19 eyes from 17 patients were included in the 5-minute group. Progression was defined as an increase in maximum keratometry (K_max) of more than 1.5 diopters (D) per year in serial topography [9]. Patients with a preoperative K_max >60 D or thinnest corneal thickness <400 μm were excluded from the indication for A-CXL.

Surgical procedures

The patients underwent A-CXL following the same procedures as in the previous study [9], except for riboflavin application time (10 or 5 minutes). After removal of the corneal epithelium, 8.0-mm retention ring (Frimen Inc) was applied on the epi-off corneal surface, and 0.1% isotonic riboflavin (Vibex Rapid, Avedro Inc) with dextran-free hydroxypropyl methylcellulose (Vibex Rapid, Avedro Inc) was continuously applied for either 10 or 5 minutes. UV-A (Avedro Inc) was applied for 8 minutes at an intensity of 30 mW/cm² with pulsation (1 second on/off), resulting in a cumulative dose of 7.2 J/cm². Postoperatively, all patients in the 10- and 5-minute groups were administered topical 0.5% moxifloxacin and 1% prednisolone four times daily for 1 week. After 1 week, following complete epithelial healing, 0.02% ocumetholone was applied four times daily for 4 weeks.

Clinical outcomes and prognostic factor analysis

Preoperative and postoperative examinations included best-corrected visual acuity (BCVA) as a logarithm of the minimum angle of resolution (logMAR), refractive errors measured using an Auto Kerato-Refractometer (KR-8900, Topcon), keratometric values, including maximum (K_max), minimum (K_min), and average (K_avg) values, and 3- and 5-mm irregularity indices calculated using topography (ORBSCAN IIz, Technolas Perfect Vision GmbH). Corneal thickness was measured using anterior segment optical coherence tomography (Visante OCT, Carl Zeiss Meditec). Endothelial cell density (ECD) was measured using noncontact specular microscopy (SP-8800, Konan). Preoperative parameters were compared with postoperative measurements at 6, 12, 24, and 36 months in the 10- and 5-minute groups. Failure to halt the progression of keratoconus was defined as more than 1.5 D progression of K_max postoperatively compared with baseline K_max. Progression-free survival and final success rates were compared between the 10- and 5-minute groups.

To identify the prognostic factors that may be associated with greater postoperative corneal flattening, various corneal parameters were analyzed using univariate and multivariate regression methods in eyes with successfully halted progression for 3 years in the 10-minute group (n = 16). ΔK_max was used as the main outcome measure and was defined as follows: ΔK_max = (3-year postoperative K_max) – (preoperative K_max) [28]. A negative ΔK_max value indicated a decrease in corneal power. The more negative the ΔK_max, the more favorable the outcome after CXL.

Statistical analysis

Statistical analyses were performed using IBM SPSS ver. 27.0 (IBM Corp) and GraphPad Prism ver. 10.4.1 (GraphPad Software Inc). Chi-square test and independent t-test were used to compare baseline parameters in the 10- and 5-minute groups. Mixed-effects analysis was used to compare preoperative and postoperative BCVA, refractive errors, topographic indices, central corneal thickness (CCT), thinnest corneal thickness (TCT), irregularity (IR) at 3 and 5 mm, and ECD. Survival curves were generated using the Kaplan-Meier method, and the difference in survival after A-CXL between the 10- and 5-minute groups was compared using the log-rank test. In addition, the prognostic factors for a higher corneal flattening effect were evaluated. The effect of preoperative variables (age, BCVA, K_max, K_avg, keratometric astigmatism [K_astig], spherical equivalent [SE], IR at 3 and 5 mm, CCT, and TCT) on ΔK_max was evaluated using univariate linear regression analysis and multivariate analysis with stepwise linear regression analysis. The data are presented as mean ± standard deviation, and statistical significance was set at p < 0.05.

Results

The demographic and baseline characteristics of the study groups are shown in Table 1. The mean age was 27.2 ± 7.6 years in the 10-minute group and 26.9 ± 5.0 years in the 5-minute group. The majority of participants in both groups were men, with 77.8% (14 out of 18) in the 10-minute group and 78.9% (15 out of 19) in the 5-minute group. There were no significant differences in the baseline measurements between the two groups.

Table 1

Baseline demographic characteristics of patients who underwent accelerated cross-linking with 10- or 5-minute riboflavin application

In the 10-minute group, BCVA improved significantly at 3-year postoperative from preoperative 0.43 to 0.21 log-MAR (mixed-effects analysis, p = 0.021) (Fig. 1A), and SE showed a significant decrease in myopia from preoperative −10.84 to −9.06 D at 3 years after surgery (mixed-effects analysis, p = 0.036) (Fig. 1B). There was no significant difference between preoperative and postoperative astigmatism in refraction (Fig. 1C).

Fig. 1

Changes in visual acuity and refractive errors following accelerated pulsed cross-linking with 10-minute riboflavin application. (A) Best-corrected visual acuity (BCVA), as a logarithm of the minimum angle of resolution (logMAR). BCVA significantly improved at 3-year postoperative comparing with preoperative data (0.43 to 0.21 logMAR; mixed-effects analysis, p = 0.021). (B) Spherical equivalent (SE) in diopters (D). SE showed a significant decrease in myopia from −10.84 D preoperatively to −9.06 D at 3-year postoperative (mixed-effects analysis, p = 0.036). (C) Cylindrical refractive errors. No significant difference was found between preoperative and postoperative astigmatism in refraction. ^*p < 0.05.

Long-term changes in topographic indices showed a significant decrease in K_max and K_avg at 3-year postoperative (from 52.52 to 50.39 D and from 49.64 to 48.04 D, respectively) (Fig. 2A, 2B). K_astig showed a significant decrease at 12 and 24 months postoperatively (4.45 and 4.58 D, respectively) but did not show a significant difference at postoperative 36 months (4.69 D) compared with preoperative K_astig (5.76 D) (Fig. 2C). IR at 3 and 5 mm showed statistically significant decreases from 5.76 to 5.63 (mixed-effects analysis, p < 0.001) and 6.65 to 5.72 (mixed-effects analysis, p = 0.004), respectively, at 3 years after surgery (Fig. 2D, 2E). CCT, TCT, and ECD showed no statistically significant differences before and after surgery (Fig. 3A–3C).

Fig. 2

Corneal topographic changes following pulsed-light accelerated cross-linking with 10-minute riboflavin application over time. (A) Maximum keratometry (K_max). (B) Average keratometry (K_avg). (C) Keratometric astigmatism (K_astig). (D) Irregularity (IR) at 3 mm. (E) IR at 5 mm. Significant decreases were found in K_max (52.52 to 50.39 diopters [D]), K_avg (49.64 to 48.04 D), and IR at 3 mm (5.76 to 5.63) and at 5 mm (6.65 to 5.72) at 3-year postoperative compared with preoperative data. K_astig significantly decreased at postoperative 12 months (4.45 D) and 24 months (4.58 D) compared with preoperative data (5.76 D) but did not show significant difference at postoperative 36 months (4.69 D). ^*p < 0.05; ^†p < 0.01; ^‡p < 0.001.

Fig. 3

Long-term changes following pulsed-light accelerated cross-linking with 10-minute continuous application of riboflavin. (A) Central corneal thickness (CCT). (B) Thinnest corneal thickness (TCT). (C) Endothelial cell density (ECD). No significant differences were found in CCT (493 μm preoperatively vs. 481 μm at 3 years postoperatively; mixed-effects analysis, p = 0.293), TCT (470 μm preoperatively vs. 448 μm at 3 years postoperatively; mixed-effects analysis, p = 0.752), and ECD (2,718 cells/mm² at preoperatively vs. 2,705 cells/mm² at 3 years postoperatively; mixed-effects analysis, p = 0.075) before and after surgery.

Fig. 4A–4J shows the efficacy and safety of A-CXL with 5-minute application of riboflavin (5-minute group). Although the 3-year postoperative BCVA (0.30 logMAR) was significantly better than the preoperative BCVA (0.51 log- MAR; mixed-effects analysis, p = 0.027), no statistically significant differences were observed in SE, astigmatism in refraction, K_max, K_avg, K_astig, IR at 3 and 5 mm, CCT, or TCT before and after surgery. ΔBCVA ([3-year postoperative BCVA] – [preoperative BCVA]) was compared between the 10-minute group and the 5-minute group and no significant difference was found between the two groups (independent t-test, p = 0.947).

Fig. 4

Changes in measurements over time following pulsed-light accelerated cross-linking with 5-minute riboflavin application. (A) Best-corrected visual acuity (BCVA), as a logarithm of the minimum angle of resolution (logMAR). (B) Spherical equivalent (SE) in diopters (D). (C) Cylindrical refractive errors. (D) Irregularity (IR) at 3 mm. (E) IR at 5 mm. (F) Maximum keratometry (K_max). (G) Average keratometry (K_avg). (H) Keratometric astigmatism (K_astig). (I) Central corneal thickness (CCT). (J) Thinnest corneal thickness (TCT). Only BCVA showed significant change at postoperative 3 years (0.30 logMAR) compared to preoperative data (0.51 logMAR) in the 5-minute group (mixed-effects analysis, p = 0.027).

Survival of the progression-free state in the 10- and 5-minute groups is shown in Fig. 5. Although there was no statistical difference in survival between the two groups, progression was observed in 2 of 18 eyes (11.1%) in the 10-minute group and in 5 of 19 eyes (26.3%) in the 5-minute group.

Fig. 5

Survival analysis following pulsed-light accelerated cross-linking with 10- or 5-minute continuous riboflavin application. During the follow-up period, 2 of 18 eyes (11.1%) in the 10-minute group and 5 of 19 eyes (26.3%) in the 5-minute group showed progression. No significant difference was found between the 10-minute group and 5-minute group (log-rank test, p = 0.120).

Finally, we evaluated the possible prognostic factors associated with ΔK_max. Table 2 shows the results of univariate and multivariate analyses between preoperative variables and ΔK_max in eyes with successful progression-halting in the 10-minute group. In the univariate analysis, K_max (β = −0.802), K_avg (β = −0.695), and K_astig (β = −0.814) were statistically significant factors, whereas in the multivariate analysis, only K_astig (β = −0.597) showed significant results. This suggests that the greater the preoperative K_astig is, the more flattened the postoperative K_max at 3 years after A-CXL will be. As an example, Fig. 6A, 6B shows the preoperative and 3-year postoperative topographic images of the patient with the most flattened K_max after A-CXL in the 10-minute group. K_max decreased from 59.6 to 51.4 D (a decrease of 8.2 D).

Table 2

Preoperative variables associated with K_max flattening in successful patients using regression analysis with ΔK_max

Fig. 6

An example of topography of the most flattened maximum keratometry (K_max) after accelerated cross-linking. (A) Preoperative topography. (B) Topography at 3-year postoperative. K_max decreased from 59.6 diopters (D) preoperatively to 51.4 D at 3-year postoperative (a decrease of 8.2 D).

Discussion

In this study, we demonstrated that pulsed-light A-CXL with retention ring-assisted continuous riboflavin application for 10 minutes is an effective and safe procedure for suppressing keratoconus progression, and that visual improvement is likely to be related to a decrease in irregular and regular astigmatism and flattening of the cornea. Also, 5-minute riboflavin application showed partial improvement in BCVA, but the corneal flattening effect and reduction of astigmatism seemed to be less evident than with 10-minute riboflavin application.

When comparing our results with those of the A-CXL effect in previous reports with a follow-up period of 24 months or more (Table 3) [23,26,29–33], the outcome of the 10-minute group of the present study shows comparable or more effective data demonstrating an average of 2.13 D of corneal flattening and BCVA improvement of 0.22 logMAR [23,26,29–33]. This may be related to deep CXL in the corneal stroma (demarcation line 279 μm), possibly due to the continuous application of riboflavin.

Table 3

Comparison of the long-term effect in accelerated epithelium-off cross-linking of previous studies and present study

We also analyzed the factors associated with a higher K_max flattening effect in successful patients in the 10-minute group at 3 years after surgery. Unsuccessful patients were defined as those in whom the cornea failed to halt the progression of keratoconus, and they were excluded from the analysis. Univariate analysis showed that preoperative K_max, K_avg, and K_astig were statistically significant factors. Patients with higher preoperative K_max, K_avg, or K_astig had a more flattened K_max after surgery. In the multivariate analysis, K_astig was the only significant factor suggesting that a highly astigmatic cornea may show a maximal flattening effect after CXL. Wajnsztajn et al. [28] reported that eyes with higher preoperative K_max, SE, and logMAR (BCVA) values had more successful results. However, that study included various types of CXL (epithelium-on/off, accelerated, and standard protocol) and consequently, the outcomes differed from those in our study. Higher K_astig may indicate greater biomechanical instability of the cornea, making it more responsive to the stiffening effects of A-CXL, thereby leading to a greater flattening effect. This hypothesis was also supported by two previous reports, presenting more effective in topographic flattening in advanced keratoconus but not as effective in less progressed keratoconus [34,35]. Additionally, the multivariate analysis did not show preoperative K_max as a statistically significant factor for greater K_max flattening. This may be due to the small sample size of the present study, which could have resulted in insufficient statistical power. Further studies with a larger number of patients and extended follow-up periods are needed.

In previous studies, conventional CXL showed long-term efficacy and safety in treating keratoconus. The present study showed comparable effects regarding K_max flattening and improved BCVA compared with other conventional studies (Table 4) [5,36–43].

Table 4

Comparison of the long-term effect in standard Dresden cross-linking of previous studies and present study

Regarding the progression of keratoconus, 11.1% (2 of 18) and 26.3% (5 of 19) showed progression in the 10- and 5-minute groups, respectively. Although the difference was not statistically significant, 10-minute riboflavin application in A-CXL showed more favorable outcomes in halting the progression of keratoconus; this is concordant with other results such as the flattening effect and improvement in visual acuity. A longer riboflavin application time allows for greater diffusion into the corneal stroma, resulting in a higher concentration and deeper penetration of riboflavin available for cross-linking. Furthermore, an increased riboflavin concentration enhances the absorption of UV-A light, thereby improving CXL efficacy. This may contribute to a more pronounced corneal flattening effect. Of the two eyes that showed progression of keratoconus in the 10-minute group, one showed progression at 1 year postoperatively, and the other eye at 3 years postoperatively. Therefore, long-term follow-up is required to monitor the progression of keratoconic progression after A-CXL.

Limitations of our study include a small sample size and the retrospective nature of the analysis. However, the efficacy of A-CXL with 10-minute riboflavin application is still noteworthy, along with the evidence that the application should be maintained for 10 minutes even if it is continuous.

In conclusion, retention ring-assisted continuous riboflavin application for 10 minutes in pulsed-light A-CXL is a comparably effective and safe treatment for halting keratoconus progression and showed comparable outcomes with those in the accelerated and conventional CXL protocols of previous studies. Higher preoperative K_astig may be related to a greater flattening effect of K_max after 3 years of A-CXL.

Notes

Conflicts of Interest

None.

Acknowledgements

None.

Funding

None.

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Characteristic	10-min group (n = 18)	5-min group (n = 19)	p-value
Sex			0.999*
Male	14 (77.8)	15 (78.9)
Female	4 (22.2)	4 (21.1)
Medical history			-
Systemic disease	0 (0)	0 (0)
Atopy	1 (5.6)	2 (10.5)
Age (yr)	27.2 ± 7.6	26.9 ± 5.0	0.897^†
BCVA (logMAR)	0.43 ± 0.43	0.51 ± 0.36	0.549^†
UCVA (logMAR)	0.91 ± 0.31	0.71 ± 0.32	0.115^†
Refractive error
Spherical (D)	−8.41 ± 2.24	−6.92 ± 3.94	0.213^†
Cylinder (D)	4.86 ± 1.45	4.79 ± 2.42	0.929^†
Spherical equivalent (D)	−10.84 ± 2.20	−9.31 ± 3.95	0.209^†
Topography
K_max (D)	52.52 ± 4.50	52.77 ± 4.70	0.866^†
K_min (D)	46.76 ± 2.17	47.51 ± 3.76	0.462^†
K_avg (D)	49.64 ± 3.10	50.14 ± 4.07	0.675^†
K_astig (D)	5.76 ± 3.36	5.26 ± 2.49	0.610^†
Irregularity
At 3 mm	5.76 ± 3.36	5.26 ± 2.49	0.690^†
At 5 mm	6.65 ± 2.07	7.34 ± 2.31	0.345^†
AS-OCT
Central corneal thickness (μm)	493 ± 41	469 ± 52	0.228^†
Thinnest corneal thickness (μm)	470 ± 38	437 ± 63	0.149^†
Endothelial cell density (cells/mm²)	2,718 ± 205	2,725 ± 302	0.938^†

Variable	Univariate analysis		Multivariate analysis

	Standardized β	p-value	Standardized β	p-value
Age (yr)	−0.298	0.262	−0.115	0.438
BCVA (logMAR)	0.415	0.110	0.027	0.879
K_max (D)	−0.802	<0.001	NA	NA
K_avg (D)	−0.695	0.003	−0.427	0.083
K_astig (D)	−0.814	<0.001	−0.597	0.016
Spherical equivalent (D)	−0.122	0.691	−0.196	0.246
Irregularity
At 3 mm	−0.392	0.134	NA	NA
At 5 mm	−0.462	0.072	NA	NA
Central corneal thickness (μm)	0.409	0.116	NA	NA
Thinnest corneal thickness (μm)	0.363	0.167	NA	NA

Study	Irradiation	Mean total dose (J/cm²)	Riboflavin application time (frequency before irradiation)	Mean FU (mon)	No. of patients	Mean ΔBCVA* (logMAR)	Mean ΔK_max^† (D)	Mean ΔCCT^‡ (μm)	Mean ΔECD^§ (cells/cm²)	Mean DDL (μm)
Current study	30 mW/cm² for 8 min (1 sec on/off)	7.2	10 min (continuous)	36	18	−0.22	−2.13	−11.81	−13	279
	30 mW/cm² for 8 min (1 sec on/off)	7.2	5 min (continuous)	36	19	−0.21	−1.34	−27.74	−34	244
Mazzotta et al. [29] (2017)	15 mW/cm² for 12 min (1 sec on/off)	5.4	10 min (every 1 min)	24	132	−0.14	−0.42	5.03	NR	280
Ziaei et al. [31] (2019)	30 mW/cm² for 8 min (1 sec on/off)	7.2	10 min (continuous)	24	40	−0.03	−0.39	NR	NR	NR
	30 mW/cm² for 4 min (continuous)	7.2	10 min (continuous)	24	40	−0.10	−1.75	NR	NR	NR
Ting et al. [30] (2019)	9 mW/cm² for 10 min (continuous)	5.4	30 min (every 3 min)	24	52	−0.05	−1.68	NR	NR	NR
Moramarco et al. [26] (2020)	30 mW/cm² for 4 min (continuous)	7.2	15 min (every 2 min)	60	29	−0.04	−0.70	−1.69	58	NR
Marafon et al. [23] (2020)	30 mW/cm² for 8 min (1 sec on/off)	7.2	10 min (every 30 sec)	34	46	−0.11	−0.90	NR	−61	NR
Kang et al. [33] (2020)	30 mW/cm² for 4 min (continuous)	7.2	10 min (every 1.5 min)	24	45	−0.11	−0.97	0.33	−36	NR
Belviranli and Oltulu [32] (2020)	30 mW/cm² for 6 min (1 sec on/off)	5.4	10 min (every 2 min)	24	30	−0.17	−0.75	−5.8	NR	NR

Study	Irradiation	Mean total dose (J/cm²)	Riboflavin application		Mean FU (mon)	No. of patients	Mean ΔBCVA* (logMAR)	Mean ΔK_max^† (D)	Mean ΔCCT^‡ (μm)	Mean ΔECD^§ (cells/cm²)	Mean DDL (μm)

			Before irradiation	During irradiation
Current study	30 mW/cm² for 8 min (1 sec on/off)	7.2	10 min (continuous)	Not applied	36	18	−0.22	−2.13	−11.81	−13	279
Hashemi et al. [36] (2013)	3 mW/cm² for 30 min (continuous)	5.4	Every 3 min for 30 min	Every 3 min	60	39	−0.12	−0.24	2.08	NR	NR
Kymionis et al. [37] (2014)	3 mW/cm² for 30 min (continuous)	5.4	Every 3 min for 30 min	Every 5 min	60	13	−0.08	−2.53	−9	−115	280
Raiskup et al. [39] (2015)	3 mW/cm² for 30 min (continuous)	5.4	For 20 min	Every 4–5 min	120	34	−0.14	−3.64	NR	NR	NR
O’Brart et al. [38] (2015)	3 mW/cm² for 30 min (continuous)	5.4	Every 5 min for 10 min	Every 3–5 min	84	36	−0.05	−0.91	−4	NR	NR
Iqbal et al. [40] (2019)	3 mW/cm² for 30 min (continuous)	5.4	Every 3 min for 30 min	NR	60	40	−0.24	−1.77	NR	NR	NR
Vinciguerra et al. [5] (2020)	3 mW/cm² for 30 min (continuous)	5.4	Every 3 min for 30 min	Every 2 min	132	27	−0.03	−2.42	NR	NR	NR
Seifert et al. [42] (2022)	3 mW/cm² for 30 min (continuous)	5.4	Every 3 min for 30 min	Every 5 min	120	131	−0.08	−0.85	NR	NR	NR
Salman et al. [41] (2022)	3 mW/cm² for 30 min (continuous)	5.4	Every 3 min for 30 min	Every 3 min	120	45	−0.05	−1.11	NR	NR	NR
Enders et al. [43] (2023)	3 mW/cm² for 30 min (continuous)	5.4	For 30 min	NR	156	9	−0.08	−3.54	NR	NR	NR