Journal of Refractive Surgery

Original Article Supplemental Data

Accelerated Epithelium-off Corneal Cross-linking With High Ultraviolet Energy Dose (7.2 J/cm2) for Progressive Keratoconus: 2-Year Results in a Chinese Population

Yanwei Kang, MD; Shaowei Li, MD, PhD; Chang Liu, MD; Man Xu, MD; Shuai Shi, MD; Yanbo Liu, MD

Abstract

PURPOSE:

To evaluate the results of epithelium-off continuous light accelerated corneal cross-linking (CXL) with a total dose of 7.2 J/cm2 for treating progressive keratoconus in a Chinese population during 24 months of follow-up.

METHODS:

In this retrospective, interventional case series, 45 eyes of 31 consecutive patients with progressive keratoconus were evaluated. All patients underwent accelerated CXL with settings of 30 mW/cm2 for 4 minutes, corresponding to a total dose of 7.2 J/cm2. Visual acuity, manifest refraction, epithelial thickness, topography, tomography, aberrometry, endothelial cell count, and intraocular pressure were evaluated at baseline and at 1, 3, 6, 12, 18, and 24 months postoperatively.

RESULTS:

Progressive keratoconus was stabilized in 91.11% and 93.33% of the patients at 12 and 24 months, respectively. The improvement in corrected distance visual acuity was significant throughout the postoperative follow-up period (P < .05), excluding month 1. A significant decrease in the maximum keratometric values (0.67 ± 1.68, 0.92 ± 1.78, and 0.97 ± 1.73 D) was observed at months 12, 18, and 24, respectively (P < .05 for all). Corneal irregularity improved, particularly total root mean square and higher order aberrations at 12 to 24 months after CXL. In bilateral CXL, the progression of the first eye was highly predictive of the outcome of the second eye.

CONCLUSIONS:

CXL with a total dose of 7.2 J/cm2 maintains long-term results in halting the progression of keratoconus, with significant improvement in the corrected distance visual acuity and stability of keratometric values. Further clinical studies with longer follow-up periods and larger samples are necessary to confirm these results.

[J Refract Surg. 2020;36(11):731–739.]

Abstract

PURPOSE:

To evaluate the results of epithelium-off continuous light accelerated corneal cross-linking (CXL) with a total dose of 7.2 J/cm2 for treating progressive keratoconus in a Chinese population during 24 months of follow-up.

METHODS:

In this retrospective, interventional case series, 45 eyes of 31 consecutive patients with progressive keratoconus were evaluated. All patients underwent accelerated CXL with settings of 30 mW/cm2 for 4 minutes, corresponding to a total dose of 7.2 J/cm2. Visual acuity, manifest refraction, epithelial thickness, topography, tomography, aberrometry, endothelial cell count, and intraocular pressure were evaluated at baseline and at 1, 3, 6, 12, 18, and 24 months postoperatively.

RESULTS:

Progressive keratoconus was stabilized in 91.11% and 93.33% of the patients at 12 and 24 months, respectively. The improvement in corrected distance visual acuity was significant throughout the postoperative follow-up period (P < .05), excluding month 1. A significant decrease in the maximum keratometric values (0.67 ± 1.68, 0.92 ± 1.78, and 0.97 ± 1.73 D) was observed at months 12, 18, and 24, respectively (P < .05 for all). Corneal irregularity improved, particularly total root mean square and higher order aberrations at 12 to 24 months after CXL. In bilateral CXL, the progression of the first eye was highly predictive of the outcome of the second eye.

CONCLUSIONS:

CXL with a total dose of 7.2 J/cm2 maintains long-term results in halting the progression of keratoconus, with significant improvement in the corrected distance visual acuity and stability of keratometric values. Further clinical studies with longer follow-up periods and larger samples are necessary to confirm these results.

[J Refract Surg. 2020;36(11):731–739.]

Keratoconus is a corneal ectasia characterized by progressive corneal thinning and irregular corneal astigmatism, which may lead to irreversible visual loss and the need for keratoplasty. The etiology of keratoconus remains uncertain and the ectasia progression may be related to the reduced biomechanical strength of the stroma.1 As the only conservative treatment, corneal cross-linking (CXL) with riboflavin and ultraviolet-A radiation stabilizes the disease by simulating age-related CXL in the cornea.2 The efficacy and safety of the standard CXL procedure (Dresden protocol, 3 mW/cm2 ultraviolet radiation for 30 minutes, 5.4 J/cm2 energy dose) in the treatment of progressive keratoconus has been demonstrated in numerous studies.3,4 However, the standard CXL technique is time-consuming and excessive corneal dehydration and thinning may occur during the lengthy exposure period of 30 minutes. Accelerated protocols purportedly shorten the treatment duration via the application of a higher ultraviolet-A irradiance. Multiple variations have been reported but a unified protocol for accelerated CXL has not been established. Most accelerated treatment protocols maintain a total energy dose of 5.4 J/cm2 based on the Bunsen-Roscoe law of reciprocity, which states that the same photochemical reaction is achieved with greater ultraviolet-A (UVA) irradiance intensity with a corresponding lower total exposure time. However, experimental and clinical studies suggest that the efficiency of accelerated CXL is reduced relative to standard CXL5–7 and additional alternative modifications need to be considered. Although a higher treatment dose of 7.2 J/cm2 has been proposed to compensate for the reduced efficiency of accelerated CXL, limited long-term clinical data are available, primarily from Middle Eastern patients.8,9

The current study aimed to evaluate the clinical outcomes of a continuous accelerated CXL protocol with a total dose of 7.2 J/cm2 in a Chinese population with a 2-year follow-up.

Patients and Methods

Study Design

This retrospective, non-randomized, single-center, interventional case series included 45 eyes of 31 patients with keratoconus who underwent accelerated CXL between January 2015 and January 2017 at Beijing Aier-Intech Eye Hospital, Beijing, China. The study was conducted according to the tenets of the Declaration of Helsinki and approved by the local ethics committee of Beijing Aier-Intech Eye Hospital. Written informed consent was obtained.

The inclusion criteria were the presence of keratoconus classified as first, second, or third stage according to the Amsler-Krumeich classification; documented ectasia progression; and central corneal thickness of 400 µm or greater. Ectasia progression was defined as an increase in the maximum keratometry (Kmax) value of 1.00 diopters (D) or greater and a corresponding change (1.00 D of greater) in the subjective refraction or a decrease in the thinnest corneal thickness of greater than 5% in the prior 6 months. The exclusion criteria included a central corneal thickness of less than 400 µm, previous ocular surgery, corneal opacity, corneal inflammation, ocular or systemic autoimmune disorders, pregnancy, or nursing mothers.

At the preoperative and postoperative follow-up (at 1, 3, 6, 12, 18, and 24 months) examinations, all patients underwent assessment of uncorrected (UDVA) and corrected (CDVA) distance visual acuity, manifest refraction, non-contact tonometry, slit-lamp biomicroscopy, and endothelial cell density using non-contact specular microscopy (CEM-530; Nidek Co, Ltd), central epithelial thickness (2-mm diameter) measured by spectral-domain optical coherence tomography (RTVue XR; Optovue), and central pachymetry and optical topography and aberrometry data analyzed with Pentacam (Oculus Optikgeräte GmbH). The maximum curvature of the anterior corneal surface was the Kmax reading (on anterior sagittal curvature maps). At 1 and 2 years after CXL, overall progression was classified as improvement (Kmax decrease of greater than 1.00 D), stabilization (Kmax change of 1.00 D or less), or worsening (Kmax increase of greater than 1.00 D).10

CXL Procedure

Riboflavin UVA–induced corneal CXL was performed under sterile conditions. The surgical procedure was conducted under topical anesthesia with oxybuprocaine hydrochloride eye drops (0.4%, 20 mL:80 mg, Santen Seiyaku). Additionally, 30 minutes before the procedure, 2% pilocarpine drops were instilled into the conjunctival sac to narrow the pupil, and the corneal epithelium was abraded mechanically with a crescent blunt blade in the central 9-mm diameter area.

A photosensitizing solution of riboflavin 0.1% and HPMC 1% (VibeX Rapid; Avedro, Inc) was applied onto the cornea every 1.5 minutes for 10 minutes until the aqueous was stained yellow, which was verified by slit-lamp examination under blue light. Following adequate penetration of the riboflavin, the solution was washed off with balanced salt solution. Continuous UVA irradiation with a wavelength of 365 nm was then initiated with an irradiance of 30 mW/cm2 (KXL System; Avedro, Inc) for 4 minutes with a beam aperture diameter of 9 mm, for a total surface dose of 7.2 J/cm2. During UVA exposure, riboflavin solution was reapplied every 1.5 minutes to maintain corneal hydration and riboflavin saturation (Table 1). A silicone hydrogel therapeutic contact lens (Pure Vision; Bausch & Lomb) was applied until corneal reepithelialization was confirmed, usually on postoperative days 4 to 7.

CXL Methods

Table 1:

CXL Methods

Postoperatively, 0.5% levofloxacin eye drops (Cravit; Santen Pharmaceutical Company) were prescribed (four times daily for 1 week) along with 0.3% sodium hyaluronate eye drops (Hialid 0.3; Santen Pharmaceutical Company) (four times daily for 4 weeks), and 0.1% fluorometholone eye drops (Flumetholon; Santen Pharmaceutical Company) were administered twice daily for 2 weeks after removal of the bandage contact lens.

Statistical Analysis

Statistical analysis was performed using SPSS software version 18.0 (SPSS, Inc). Continuous variables are expressed as mean ± standard deviation. The normality of all data samples was tested using the Shapiro-Wilk test. The postoperative changes were assessed using a paired t test for the data that conformed to a normal distribution, and the Wilcoxon rank test for non-normally distributed data. Categorical data were evaluated using the chi-square test with continuity correction when necessary. Comparisons among subgroups were analyzed using one-way analysis of variance with post hoc Tukey's test. A P value of less than .05 was considered statistically significant.

Results

Forty-five eyes of 31 patients (20 men) were evaluated. The mean age was 21.61 ± 5.91 years (range: 18 to 35 years). Of these, 14 (45.16%) patients received bilateral CXL treatment. The overall progression analysis comprised the following: 23 (51.11%) eyes stabilized, 19 (42.22%) improved, and 3 (6.67%) worsened. Table 2 summarizes the primary preoperative and postoperative outcomes, Table A (available in the online version of this article) indicates the differences between the overall cohort and each subgroup. Tables BC (available in the online version of this article) show the changes in parameters at 2 years in each subgroup (stabilized, improved, or worsened).

Preoperative and Postoperative Data After CXL (7.2 J/cm2) for Progressive Keratoconus

Table 2:

Preoperative and Postoperative Data After CXL (7.2 J/cm2) for Progressive Keratoconus

Baseline Data of Subgroups Based on Overall Progression After CXL (7.2 J/cm2) for Progressive Keratoconus

Table A:

Baseline Data of Subgroups Based on Overall Progression After CXL (7.2 J/cm2) for Progressive Keratoconus

Postoperative Data of Subgroups Based on Overall Progression After CXL (7.2 J/cm2) for Progressive KeratoconusPostoperative Data of Subgroups Based on Overall Progression After CXL (7.2 J/cm2) for Progressive Keratoconus

Table B:

Postoperative Data of Subgroups Based on Overall Progression After CXL (7.2 J/cm2) for Progressive Keratoconus

Postoperative Aberrometry Data of Subgroups Based on Overall Progression After CXL (7.2 J/cm2) for Progressive Keratoconus

Table C:

Postoperative Aberrometry Data of Subgroups Based on Overall Progression After CXL (7.2 J/cm2) for Progressive Keratoconus

VisuaL Acuity and Refractive Outcomes

The UDVA did not significantly change, whereas the CDVA exhibited significant improvement throughout the follow-up period, excluding 1 month. The manifest refractive spherical equivalent was significantly reduced at 12 and 24 months due to a significant sphere decrease. No significant cylinder changes were detected in these follow-up periods.

Topographic Results

Figures 12 illustrate the overall changing trend of keratometric values. Significant flat (K1), steep (K2), mean (Kmean), and Kmax increases were observed at 1 month. After month 1, K1 values exhibited no significant improvement. The K2 changes were similar to the K1 changes, aside from a significant improvement at 18 months. A significant reduction in the Kmean values was observed after 18 and 24 months. The Kmax values demonstrated significant improvement after 12, 18, and 24 postoperative months. The decreases in Kmax values were 0.67 ± 1.68 D, 0.92 ± 1.78 D, and 0.97 ± 1.73 D at months 12, 18, and 24, respectively. Significant changes were observed between 12 and 18 months (P = .018), with no significant reduction between 18 and 24 months (P = .675). The y coordinate of Kmax was significantly different at 3 and 12 months (P = .036 and .034, respectively).

Preoperative and postoperative flat (K1), steep (K2), and mean (Kmean) keratometric values with error bars indicate standard error. D = diopters

Figure 1.

Preoperative and postoperative flat (K1), steep (K2), and mean (Kmean) keratometric values with error bars indicate standard error. D = diopters

Preoperative and postoperative maximum keratometry (Kmax) values with error bars indicate standard error. D = diopters

Figure 2.

Preoperative and postoperative maximum keratometry (Kmax) values with error bars indicate standard error. D = diopters

Tomographic Results

A significant decrease in corneal thickness was observed at 1 to 6 months postoperatively, which returned to baseline by 12 months, and remained stable until 24 months. Although fluctuated, center epithelial thickness did not significantly change at any follow-up times.

Aberrometry Results

Total root mean square, corneal higher order aberrations, and spherical aberration were improved between 12 and 24 months postoperatively.

Endothelial Results and Intraocular Pressure

There were no significant differences in the endothelial cell density or intraocular pressure compared to baseline throughout the follow-up period.

Progression

The overall progression analysis demonstrated the following (Figure 3): 1 year after CXL, 28 (62.22%) eyes were stabilized, 13 (28.89%) improved, and 4 (8.89%) worsened. Two years after CXL, 23 (51.11%) eyes were stabilized, 19 (42.22%) improved, and 3 (6.67%) worsened. Of the 13 improved eyes at 1 year, 1 eye resumed preoperative corneal steepening at 2 years, 1 eye exhibited increased Kmax and underwent progression in the second year, and the other 11 eyes did not change. Ten eyes that did not improve within the first year (8 stable eyes and 2 worsened eyes) exhibited Kmax flattening of 1.00 D or greater during the second postoperative year. Therefore, at 2 years, disease progression was halted in 93.33% of cases and the 3 worsened eyes (6.67%) in 3 patients were recorded as progression. In these 3 progressive eyes, by 24 months, the Kmax value had increased from 47.10 to 48.10 D, 47.40 to 51.50 D, and 75.10 to 78.10 D, respectively.

Maximum keratometry (Kmax) values change percentage. D = diopters

Figure 3.

Maximum keratometry (Kmax) values change percentage. D = diopters

Fourteen of the 31 patients underwent bilateral CXL. In these patients, the Kmax was stabilized in 14 of 28 eyes (50%), whereas the remaining 14 (50%) improved and none worsened. Bilateral stabilization occurred in 5 of 14 cases (35.71%) and bilateral improvement was observed in 5 of 14 cases (35.71%). Stabilization in 1 eye and improvement in the second eye was observed in 4 patients (28.57%).

Complications

No serious adverse events were noted. Eye pain associated with the epithelial debridement was common in the early postoperative period. In 1 patient, bilateral sterile infiltrates were present at the first week postoperatively and resolved with the use of topical steroids within 2 weeks.

Discussion

Prior studies of accelerated CXL with 5.4 J/cm2 have reported the use of different levels of UVA irradiance and illumination times (9 mW/cm2 for 10 minutes, 10 mW/cm2 for 9 minutes, 18 mW/cm2 for 5 minutes, and 30 mW/cm2 for 3 minutes). Ex vivo studies of accelerated CXL in porcine corneas have yielded mixed results, demonstrating equivalent stiffness compared to standard CXL in one study,11 whereas another study of multiple irradiation settings demonstrated decreased biomechanical effects.5 Clinical studies have reported similar conflicting results for accelerated CXL treatment. Two independent studies12,13 reported less reduction in Kmax in the high-intensity protocol than in conventional CXL. Moreover, Brittingham et al14 observed increased Kmax with accelerated CXL. Hashemi et al6 and Chow et al7 evaluated a study on high fluence treatments and no significant differences were found. They concluded that accelerated CXL was not as effective as conventional CXL. Webb et al15 suggested the decreased stiffening in the central and posterior cornea accounted for the reduced strengthening in accelerated CXL.

Complex photochemical mechanisms may contribute to the differences in these results.16 This complex reaction is still not fully understood at this time. The validity of the photochemical reaction following the Bunsen-Roscoe law was approximately 95% in biology and greater than 80% in medicine.11 Further, CXL photochemistry with high-power settings had been deduced in inanimate physical systems such as darkroom photography. It remains to be accurately determined whether the higher-power settings are applicable to proportionally shorten the treatment duration. An ex vivo study indicated that the increase of cross-link bonds in the CXL process can be achieved through optimizing the critical element, such as riboflavin composition, oxygen level, and UVA radiation.17 So it is possible that further modifications with both increased irradiance and a higher energy dose are needed to maintain the same effect. Subsequent studies employing the higher cumulative dose are limited. The stabilization of keratoconus with a flattening of the steep keratometry value was reported by Kanellopoulos18 in the accelerated protocol (6.3 J/cm2, 7 mW/cm2 for 15 minutes). Sherif19 observed a significant reduction in the average keratometry at 1 year after accelerated CXL with settings of 30 mW/cm2 for 4 minutes and 20 seconds, which corresponded to a total dose of 7.8 J/cm2.

This article presents the outcomes of 45 eyes of 31 patients with progressive keratoconus treated with accelerated CXL with a total dose of 7.2 J/cm2 (30 mW/cm2 for 4 minutes). The mean CDVA improved significantly from postoperative months 3 to 24, whereas the changes in the mean UDVA and corneal astigmatism were not significant at any observation time point. The visual acuity outcomes were in agreement with the findings of Woo et al.20 The improvement of CDVA may be attributed to the improved refractive error, keratometric values, and corneal aberrations, as Ozgurhan et al9 demonstrated in their study. The absence of significant improvement in UDVA may be due to higher baseline refractive error.

The topographic results analysis revealed significant improvement or stabilization in the mean K1, K2, Kmean, and Kmax values, aside from the first postoperative month, when worsening of these values was observed. This initial increase may be attributed to the treatment-related deepithelialization with more significant stromal irregularity exposed in the CXL treatment21 or UVA exposure induced stromal dehydration followed by rehydration after a short-term lag.22 Kmax decreased significantly at 12 months, followed by a relatively flat downward trend, with a mean decrease of 0.97 ± 1.73 D at 24 months compared to baseline. This flattening effect is consistent with the findings of prior clinical studies of the same treatment protocol (30 mW/cm2 for 4 minutes), which found Kmax reductions of 1.009 and 0.878 D after CXL. This change is comparable to previously reported Kmax decreases of 1.30,23 1.27,24 and 0.6025 D after standard CXL, although less than 2.00 D was reported by Wollensak et al.2 In the accelerated CXL setting using 5.4 J/cm2, Miraftab et al26 reviewed 23 studies and found that the average Kmax reductions at 1 year were 0.18 ± 1.44 D (30 mW/cm2 for 3 minutes), 0.35 ± 1.03 D (18 mW/cm2 for 5 minutes), 0.46 ± 1.23 D (9 mW/cm2 for 10 minutes), and 0.95 ± 1.36 D (3 mW/cm2 for 30 minutes). In two other retrospective comparative studies, Lang et al27 reported Kmax values reduced 1.53 ± 2.10 D (3 mW/cm2 for 30 minutes), 0.71 ± 1.30 D (9 mW/cm2 for 10 minutes), 0.70 ± 2.30 D (30 mW/cm2 for 4 minutes) at 12 months after treatment, whereas Toker et al28 showed different results: Kmax values improved by 2.15 ± 2.60 D (3 mW/cm2 for 30 minutes), 1.64 ± 1.97 D (9 mW/cm2 for 10 minutes), 0.01 ± 0.98 D (30 mW/cm2 for 8 minutes, pulsed-light accelerated CXL), and increased 0.01 ± 0.82 D (30 mW/cm2 for 4 minutes) by 12 months. It is also of note that Kmax decreases continued through month 18 postoperatively and then plateaued through the remaining 6-month follow-up. This differed from the findings of Kuechler et al,29 who demonstrated that Kmax improvement occurred within the first 12 months after surgery.

Further, cornea irregularity correction was observed during the postoperative follow-up. The y coordinate of Kmax tended to return to the center. Total root mean square and corneal higher order aberrations were improved, particularly the vertical coma and spherical aberration in the improvement group. These results are similar to the findings of Naderan and Jahanrad,30 who concluded that CXL arranged keratoconic eyes toward normal configuration.

After 24 months of follow-up, keratoconus progression was arrested or improved in 93.33% of cases. The Kmax values decreased by greater than 1.00 D in 19 eyes (42.2%) and increased by 1.00 D or greater in 3 eyes (6.67%) at 24 months after CXL. The progression of 1.00 D may be regarded as treatment failure, whereas the increase was not statistically significant in the worsened eyes. It remains uncertain whether the rate of progression in these 3 eyes slowed or whether it continued its natural evolution.

There are limited studies applying the same treatment energy (30 mW/cm2 for 4 minutes) (Table D, available in the online version of this article). Woo et al20 treated 47 eyes and demonstrated stability in UDVA and topographic parameters (K1, K2, and Kmean), with significant CDVA improvement at 6 and 12 months postoperatively. Lang et al27 reported significant CDVA, Kmax, and Kmean improvements within 12 months. Toker et al28 observed significant CDVA improvements at 12 months. Conversely, Mazzotta et al31 did not find any significant changes in the UDVA, CDVA, Kaverage, and Kapical with the same treatment protocol at 12 months. In other studies of this treatment protocol, Ozgurhan et al9 and Bozkurt et al8 observed significant UDVA, CDVA, Ksteep, Kflat, Kaverage, and Kapex improvements in cohorts of 44 and 47 eyes, respectively, with a 100% success rate of halting disease progression over 24 months. Such a high success rate and more keratoconus index improvements may be because eyes with greater keratoconus severity were included in their study, because corneas with a preoperative Kmax of 55.00 D or greater have a greater likelihood of topographic Kmax flattening than flatter corneas.32 The baseline Kmax of 57.10 ± 5.50 D in the study by Ozgurhan et al and 56.40 ± 4.55 D in the study by Bozkurt et al were obviously steeper than the 54.04 ± 9.50 D Kmax reported in our study. Ethnic differences may be another explanatory factor. The site of both studies (Beyoglu) is located within the Middle Eastern region. Although a recent systematic review and metaanalysis implied that Middle Eastern patients demonstrated a greater prevalence, incidence, and severity of keratoconus than European and East Asian patients,33 whether ethnicity influences the efficiency of CXL in patients with keratoconus warrants clarification in further studies.

Clinical Studies of Epithelium-off Accelerated CXL With High Energy Dose for Progressive KeratoconusClinical Studies of Epithelium-off Accelerated CXL With High Energy Dose for Progressive KeratoconusClinical Studies of Epithelium-off Accelerated CXL With High Energy Dose for Progressive Keratoconus

Table D:

Clinical Studies of Epithelium-off Accelerated CXL With High Energy Dose for Progressive Keratoconus

With regard to the 14 cases of bilateral CXL, the change in the first eye was predictive of the contralateral eye's outcome. These results were similar to those reported by Poli et al.34

Moreover, among the treated 45 eyes, 12 improved during the first postoperative year and remained stable through year 2, and 10 exhibited Kmax flattening that began after the first year and continued through the second year, indicating a persistent effect of CXL in these patients. When corneas react to CXL or how long this reaction will persist is not fully understood, and therefore it is important to counsel the patient properly in terms of outcome evolution after CXL.

The corneal pachymetry outcomes were reduced at 1 month postoperatively and then returned to near baseline levels by 12 months. Most studies have reported similar dynamic changes.35,36 The evolution may be related to the corneal collagen compaction initially followed by subsequent enlargement of the corneal collagen fiber diameter.36 Although not statistically different, the early decrease of central epithelial thickness with thickening in the next 3 months may be clinically meaningful. The remodeling indicated the epithelial ability to compensate for optical irregularities and may relate to subepithelial nerve regeneration.21,37 The remodeling duration was similar to that of transepithelial photorefractive keratectomy and was later than recovery times in the transepithelial CXL protocol.37,38

The total surface dose of 7.2 J/cm2 UVA exposure theoretically delivers 0.43 J/cm2 energy at 400 µm depth.39 This dose is below the previously reported endothelial damage threshold of 0.65 J/cm2.40 Our results confirmed that there was no damage to the corneal endothelium, which is consistent with the findings of Mazzotta et al.31 Intraocular pressure analysis revealed no significant differences after treatment, and no late change in intraocular pressure has been reported after CXL to date.

The strengths of this study were the evaluation of the accelerated higher UVA dose (7.2 J/cm2) and a long follow-up period of 24 months. Study limitations include the small sample size, retrospective design, absence of evaluation of the demarcation line, and lack of a control group. However, the postoperative change in visual acuity and topography provide valuable information on the 2-year efficacy and safety of the higher dose accelerated CXL procedure.

The current study demonstrates that accelerated epithelium-off CXL treatment with a higher UVA dose stabilized or improved progressive keratoconus over 2 years. In addition to reducing disease progression, the procedure also elicited beneficial visual effects and corneal flattening. The promising outcomes of this study warrant further evaluation in large, prospective, randomized cohorts with longer follow-up.

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  26. Miraftab M, Hashemi H, Abdollahi M, Nikfar S, Asgari S. The efficacy of standard versus accelerated epi-off corneal cross-linking protocols: a systematic review and subgroup analysis. Int Ophthalmol. 2019;39(11):2675–2683. doi:10.1007/s10792-019-01091-y [CrossRef]
  27. Lang PZ, Hafezi NL, Khandelwal SS, Torres-Netto EA, Hafezi F, Randleman JB. Comparative functional outcomes after corneal crosslinking using standard, accelerated, and accelerated with higher total fluence protocols. Cornea. 2019;38(4):433–441. doi:10.1097/ICO.0000000000001878 [CrossRef]
  28. Toker E, Çerman E, Özcan DO, Seferoglu OB. Efficacy of different accelerated corneal crosslinking protocols for progressive keratoconus. J Cataract Refract Surg. 2017;43(8):1089–1099. doi:10.1016/j.jcrs.2017.05.036 [CrossRef]
  29. Kuechler SJ, Tappeiner C, Epstein D, Frueh BE. Keratoconus progression after corneal cross-linking in eyes with preoperative maximum keratometry values of 58 diopters and steeper. Cornea. 2018;37(11):1444–1448. doi:10.1097/ICO.0000000000001736 [CrossRef]
  30. Naderan M, Jahanrad A. Higher-order aberration 4 years after corneal collagen cross-linking. Indian J Ophthalmol. 2017;65(9):808–812. doi:10.4103/ijo.IJO_21_17 [CrossRef]
  31. Mazzotta C, Traversi C, Paradiso AL, Latronico ME, Rechichi M. Pulsed light accelerated crosslinking versus continuous light accelerated crosslinking: one-year results. J Ophthalmol. 2014;2014:604731. doi:10.1155/2014/604731 [CrossRef]
  32. Greenstein SA, Hersh PS. Characteristics influencing outcomes of corneal collagen crosslinking for keratoconus and ectasia: implications for patient selection. J Cataract Refract Surg. 2013;39(8):1133–1140. doi:10.1016/j.jcrs.2013.06.007 [CrossRef]
  33. Ferdi AC, Nguyen V, Gore DM, Allan BD, Rozema JJ, Watson SL. Keratoconus natural progression: a systematic review and meta-analysis of 11,529 eyes. Ophthalmology. 2019;126(7):935–945. doi:10.1016/j.ophtha.2019.02.029 [CrossRef]
  34. Poli M, Lefevre A, Auxenfans C, Burillon C. Corneal collagen cross-linking for the treatment of progressive corneal ectasia: 6-year prospective outcome in a French population. Am J Ophthalmol. 2015;160(4):654–662.e1. doi:10.1016/j.ajo.2015.06.027 [CrossRef]
  35. Greenstein SA, Shah VP, Fry KL, Hersh PS. Corneal thickness changes after corneal collagen crosslinking for keratoconus and corneal ectasia: one-year results. J Cataract Refract Surg. 2011;37(4):691–700. doi:10.1016/j.jcrs.2010.10.052 [CrossRef]
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  37. Hou J, Wang Y, Lei Y, Zheng X, Zhang Y. Corneal epithelial remodeling and its effect on corneal asphericity after transepithelial photorefractive keratectomy for myopia. J Ophthalmol. 2016;2016:8582362. doi:10.1155/2016/8582362 [CrossRef]
  38. Zhang X, Sun L, Chen Y, Li M, Tian M, Zhou X. One-year outcomes of pachymetry and epithelium thicknesses after accelerated (45 mW/cm2) transepithelial corneal collagen cross-linking for keratoconus patients. Sci Rep. 2016;6(1):32692. doi:10.1038/srep32692 [CrossRef]
  39. Spoerl E, Mrochen M, Sliney D, Trokel S, Seiler T. Safety of UVA-riboflavin cross-linking of the cornea. Cornea. 2007;26(4):385–389. doi:10.1097/ICO.0b013e3180334f78 [CrossRef]
  40. Wollensak G, Spoerl E, Wilsch M, Seiler T. Endothelial cell damage after riboflavin-ultraviolet-A treatment in the rabbit. J Cataract Refract Surg. 2003;29(9):1786–1790. doi:10.1016/S0886-3350(03)00343-2 [CrossRef]
  41. Choi M, Kim J, Kim EK, Seo KY, Kim TI. Comparison of the conventional Dresden protocol and accelerated protocol with higher ultraviolet intensity in corneal collagen cross-linking for keratoconus. Cornea. 2017;36(5):523–529. doi:10.1097/ICO.0000000000001165 [CrossRef]
  42. Jiang LZ, Jiang W, Qiu SY. Conventional vs. pulsed-light accelerated corneal collagen cross-linking for the treatment of progressive keratoconus: 12-month results from a prospective study. Exp Ther Med. 2017;14(5):4238–4244. doi:10.3892/etm.2017.5031 [CrossRef]
  43. Moineau N, Sauvan L, Benichou J, Ho Wang Yin G, Hoffart L. [High-irradiance accelerated corneal collagen crosslinking for the treatment of keratoconus: a retrospective study]. J Fr Ophtalmol. 2017;40(4):319–328. doi:10.1016/j.jfo.2016.11.014 [CrossRef]
  44. Yildirim Y, Olcucu O, Gunaydin ZK, et al. Comparison of accelerated corneal collagen cross-linking types for treating keratoconus. Curr Eye Res. 2017;42(7):971–975. doi:10.1080/02713683.2017.1284241 [CrossRef]
  45. Iqbal M, Elmassry A, Saad H, et al. Standard cross-linking protocol versus accelerated and transepithelial cross-linking protocols for treatment of paediatric keratoconus: a 2-year comparative study. Acta Ophthalmol. 2020;98(3):e352–e362. doi:10.1111/aos.14275 [CrossRef]
  46. Dervenis N, Dervenis P, Dragoumis N, Papandroudis A, Zachariadis Z, Balidis M. Accelerated, pulsed collagen cross-linking versus the Dresden protocol in keratoconus: a case series. Med Princ Pract. 2020;29(4):332–337. doi:10.1159/000505598 [CrossRef]
  47. Omar IAN, Zein HA. Accelerated epithelium-off corneal collagen cross-linking for keratoconus: 12-month results. Clin Ophthalmol. 2019;13:2385–2394. doi:10.2147/OPTH.S232118 [CrossRef]
  48. Ziaei M, Gokul A, Vellara H, Patel D, McGhee CNJ. Prospective two year study of changes in corneal density following transepithelial pulsed, epithelium-off continuous and epithelium-off pulsed, corneal crosslinking for keratoconus. Cont Lens Anterior Eye. 2020;S1367-0484(20)30047-3. doi:10.1016/j.clae.2020.03.004 [CrossRef]

CXL Methods

ParameterVariable
Treatment targetProgressive keratoconus
Fluence (total) (J/cm2)7.2
Soak time and interval (minutes)10 (q1.5)
Intensity (mW)30
Treatment time (minutes)4
Epithelium statusOff
ChromophoreRiboflavin (Avedro, Inc)
Chromophore carrierHPMC
Chromophore osmolarityIso-osmolar
Chromophore concentration0.1%
Light sourceKXL System (Avedro, Inc)
Irradiation mode (interval)Continuous

Preoperative and Postoperative Data After CXL (7.2 J/cm2) for Progressive Keratoconus

ParameterBaselineMonth 1Month 3Month 6Month 12Month 18Month 24
Number45454545454545
UDVA (logMAR)0.63 ± 0.260.59 ± 0.250.58 ± 0.280.58 ± 0.260.59 ± 0.300.60 ± 0.270.59 ± 0.28
P.305.095.055.311.376.168
CDVA (logMAR)0.17 ± 0.160.16 ± 0.150.12 ± 0.120.11 ± 0.100.10 ± 0.090.09 ± 0.080.06 ± 0.07
P.576.003a< .001a.001a< .001a< .001a
SE (D)−6.24 ± 3.19−5.97 ± 3.09−5.74 ± 2.92−5.72 ± 3.00−5.25 ± 3.07−5.71 ± 3.11−5.48 ± 3.01
P.391.082.095.001a.144.048a
K1 (D)45.33 ± 3.2245.84 ± 4.1145.27 ± 3.8345.25 ± 3.5445.24 ± 3.4245.08 ± 3.1645.04 ± 3.37
P.006a.731.475.471.060.091
K2 (D)48.69 ± 4.6849.25 ± 5.0848.79 ± 4.8048.59 ± 4.6548.53 ± 4.5348.36 ± 4.3148.40 ± 4.37
P.001a.421.415.383.032a.050
Kmean (D)46.91 ± 3.7047.43 ± 4.3546.94 ± 4.1046.85 ± 3.8546.81 ± 3.7646.63 ± 3.5346.64 ± 3.69
P.001a.836.562.461.027a.048a
Kmax (D)54.04 ± 9.5055.03 ± 10.0354.14 ± 9.7653.76 ± 9.7853.37 ± 9.5753.12 ± 9.2553.07 ± 9.31
P< .001a.628.182.011a.001a.001a
Kmax coordinate-x (mm)−0.07 ± 0.45−0.07 ± 0.47−0.11 ± 0.54−0.16 ± 0.54−0.12 ± 0.45−0.10 ± 0.42−0.10 ± 0.55
P.979.447.094.217.491.584
Kmax coordinate-y (mm)−0.81 ± 1.13−0.75 ± 1.04−0.57 ± 1.27−0.71 ± 1.18−0.62 ± 1.02−0.66 ± 0.95−0.78 ± 0.83
P.624.036a.247.034a.186.810
Astigmatism (D)3.36 ± 2.763.42 ± 2.803.52 ± 2.513.33 ± 2.683.29 ± 2.523.30 ± 2.363.34 ± 2.22
P.702.241.719.620.625.934
CET (µm)50.93 ± 3.8049.89 ± 3.8551.62 ± 4.3151.51 ± 4.0951.22 ± 4.3151.91 ± 5.3551.29 ± 4.08
P.006a.130.136.476.086.408
CCT (µm)487.60 ± 42.53466.64 ± 41.62474.87 ± 44.21480.33 ± 44.12485.24 ± 44.47486.71 ± 43.81487.93 ± 44.29
P< .001a< .001a< .001a.161.612.864
TCT (µm)480.04 ± 42.60457.82 ± 43.91466.33 ± 45.96471.56 ± 46.68476.51 ± 45.82478.27 ± 45.59479.18 ± 46.21
P< .001a< .001a< .001a.092.362.675
IOP (mm Hg)12.42 ± 2.8212.83 ± 3.1412.13 ± 2.9712.38 ± 2.6512.18 ± 3.0812.07 ± 3.0912.29 ± 2.71
P.307.425.893.507.360.656
ECD (cells/mm2)3,126.42 ± 366.873,143.11 ± 372.823,178.02 ± 325.663,133.87 ± 387.323,123.27 ± 303.393,100.89 ± 343.763,089.96 ± 390.04
P.733.241.820.918.271.178
Total-RMS8.65 ± 8.039.64 ± 8.018.77 ± 7.638.46 ± 7.737.98 ± 7.767.75 ± 7.897.46 ± 7.63
P< .001a.573.336.010a.008a.001a
HOA-RMS1.95 ± 1.762.28 ± 1.872.02 ± 1.791.94 ± 1.781.79 ± 1.731.78 ± 1.801.74 ± 1.71
P< .001a.156.880.004a.020a.006a
Z31 (horizontal coma)−0.10 ± 0.81−0.11 ± 0.80−0.11 ± 0.75−0.09 ± 0.76−0.06 ± 0.70−0.08 ± 0.71−0.11 ± 0.64
P.721.778.723.416.635.921
Z3−1 (vertical coma)−1.19 ± 1.61−1.40 ± 1.70−1.23 ± 1.67−1.14 ± 1.57−1.14 ± 1.59−1.14 ± 1.65−1.13 ± 1.55
P.001a.406.441.287.415.274
Z3−3 (vertical trefoil)−0.05 ± 0.320.07 ± 0.400.08 ± 0.420.09 ± 0.640.05 ± 0.210.05 ± 0.400.00 ± 0.29
P.021a.019a.108.032a.078.372
Z40 (primary spherical)−0.42 ± 0.98−0.64 ± 1.14−0.42 ± 1.00−0.40 ± 0.97−0.35 ± 0.92−0.21 ± 0.86−0.16 ± 0.94
P< .001a.966.661.059.022a.010a
Z4−4 (vertical quadrafoil)−0.02 ± 0.27−0.03 ± 0.250.00 ± 0.27−0.01 ± 0.23−0.07 ± 0.49−0.05 ± 0.35−0.01 ± 0.19
P.523.599.928.447.501.851

Baseline Data of Subgroups Based on Overall Progression After CXL (7.2 J/cm2) for Progressive Keratoconus

ParameterAll PatientsImprovementStabilizationWorseningP (Subgroup Differences)
Number45 (100%)19 (42.22%)23 (51.11%)3 (6.67%)
UDVA (logMAR)0.63 ± 0.260.52 ± 0.230.69 ± 0.260.81 ± 0.20
P.120.327.248.218
CDVA (logMAR)0.17 ± 0.160.23 ± 0.120.12 ± 0.170.17 ± 0.21
P.162.265.960.408
SE (D)−6.24 ± 3.19−6.30 ± 3.48−6.29 ± 2.97−5.58 ± 4.05
P.952.959.733.936
K1 (D)45.33 ± 3.2246.55 ± 3.8844.40 ± 2.0744.63 ± 4.55
P.196.218.726.09
K2 (D)48.69 ± 4.6850.61 ± 4.8847.37 ± 4.1746.67 ± 3.94
P.144.258.469.058
Kmean (D)46.91 ± 3.7048.46 ± 4.2345.80 ± 2.7345.63 ± 4.26
P.147.207.568.052
Kmax (D)54.04 ± 9.5057.56 ± 9.9050.80 ± 7.3556.53 ± 16.08
P.185.158.674.061
Kmax coordinate-x (mm)−0.07 ± 0.45−0.08 ± 0.37−0.08 ± 0.520.01 ± 0.31
P.409.438.762.924
Kmax coordinate-y (mm)−0.81 ± 1.13−0.64 ± 0.75−0.85 ± 1.41−1.51 ± 0.18
P.099.156.162.332
CET (µm)50.93 ± 3.8050.26 ± 3.2151.22 ± 3.9453.00 ± 6.56
P.156.566.230.459
CCT (µm)487.60 ± 42.53472.37 ± 39.02495.87 ± 41.39520.67 ± 51.16
P.185.447.203.074
TCT (µm)480.04 ± 42.60465.26 ± 40.11488.43 ± 42.04509.33 ± 42.74
P.202.443.255.098
IOP (mm Hg)12.42 ± 2.8212.16 ± 2.7112.48 ± 2.8713.67 ± 3.79
P.730.939.470.693
ECD (cells/mm2)3,126.42 ± 366.873,064.11 ± 380.463,202.35 ± 355.512,939.00 ± 334.90
P.541.418.394.321
Age (y)21.61 ± 5.9121.73 ± 6.9422.10 ± 5.1817.00 ± 2.03
P.940.735.189.252
Sex ratio (M:F)1.37 (26:19)1.38 (11:8)1.30 (13:10)2.00 (2:1)
P.993.9211.000.945
Total-RMS8.65 ± 8.0310.81 ± 8.626.30 ± 5.7913.02 ± 15.65
P.977.237.066.120
HOA-RMS1.95 ± 1.762.28 ± 1.651.55 ± 1.572.88 ± 3.50
P.717.471.056.268
Z31 (horizontal coma)−0.10 ± 0.81−0.21 ± 0.95−0.09 ± 0.720.48 ± 0.34
P.612.610.426.404
Z3−1 (vertical coma)−1.19 ± 1.61−1.38 ± 1.35−0.89 ± 1.55−2.35 ± 3.33
P.878.557.045.274
Z3−3 (vertical trefoil)−0.05 ± 0.32−0.06 ± 0.32−0.02 ± 0.34−0.15 ± 0.29
P.818.873.664.800
Z40 (primary spherical)−0.42 ± 0.98−0.76 ± 1.22−0.12 ± 0.59−0.59 ± 1.23
P.629.172.474.101
Z4−4 (vertical quadrafoil)−0.02 ± 0.270.00 ± 0.27−0.07 ± 0.220.33 ± 0.46
P.884.555.209.050

Postoperative Data of Subgroups Based on Overall Progression After CXL (7.2 J/cm2) for Progressive Keratoconus

ParameterBaselineMonth 1Month 3Month 6Month 12Month 18Month 24
Improvement (42.22%, n =19)
  UDVA (logMAR)0.56 ± 0.230.55 ± 0.190.51 ± 0.250.51 ± 0.270.57 ± 0.340.57 ± 0.290.55 ± 0.27
   P.800.404.368.852.908.833
  CDVA (logMAR)0.21 ± 0.140.19 ± 0.120.14 ± 0.100.11 ± 0.080.12 ± 0.070.10 ± 0.070.08 ± 0.07
   P.440.019a.002a.008a.001a< .001a
  SE (D)−6.30 ± 3.48−6.07 ± 3.16−5.55 ± 2.65−5.80 ± 2.99−4.69 ± 3.19−5.69 ± 3.20−5.36 ± 2.78
   P.735.228.435.010a.432.184
  K1 (D)46.55 ± 3.8847.53 ± 4.8746.55 ± 4.7846.36 ± 4.3846.13 ± 4.1146.19 ± 3.9946.17 ± 4.02
   P.004a.985.279.059.158.171
  K2 (D)50.61 ± 4.8851.40 ± 5.0250.53 ± 5.0750.16 ± 4.9549.90 ± 4.6949.81 ± 4.7149.86 ± 4.71
   P< .001a.608.032a.042a.005a.002a
  Kmean (D)48.46 ± 4.2349.35 ± 4.7948.43 ± 4.8148.20 ± 4.5447.94 ± 4.2847.92 ± 4.2147.93 ± 4.26
   P< .001a.893.132.044a.036a.030a
  Kmax (D)57.56 ± 9.9058.48 ± 10.0857.26 ± 10.3056.68 ± 10.1855.85 ± 10.0755.45 ± 9.7655.22 ± 9.86
   P.008a.433.024a.001a< .001a< .001a
  Kmax coordinate-x (mm)−0.08 ± 0.37−0.10 ± 0.40−0.13 ± 0.37−0.13 ± 0.44−0.10 ± 0.41−0.15 ± 0.36−0.09 ± 0.37
   P.690.173.353.616.086.786
  Kmax coordinate-y (mm)−0.64 ± 0.75−0.76 ± 0.47−0.48 ± 0.91−0.56 ± 0.87−0.48 ± 0.88−0.52 ± 0.89−0.72 ± 0.56
   P.341.276.616.299.427.636
  CET (µm)50.26 ± 3.2149.05 ± 3.7351.05 ± 4.0650.53 ± 3.6350.37 ± 4.0251.84 ± 6.6550.16 ± 4.26
   P.076.295.677.856.163.861
  CCT (µm)472.37 ± 39.02455.00 ± 40.71458.16 ± 43.80464.16 ± 44.04467.47 ± 44.17471.42 ± 44.43471.95 ± 45.96
   P.001a< .001a.007a.150.770.912
  TCT (µm)465.26 ± 40.11446.84 ± 43.19450.05 ± 44.53456.37 ± 44.73459.47 ± 45.68461.95 ± 46.13462.16 ± 48.10
   P.001a< .001a.009a.126.344.448
  IOP (mm Hg)12.16 ± 2.7112.26 ± 2.7011.42 ± 2.7111.63 ± 2.3412.12 ± 2.4511.84 ± 2.1711.63 ± 2.95
   P.875.130.249.738.144.326
Stabilization (51.11%, n = 23)
  UDVA (logMAR)0.66 ± 0.280.62 ± 0.310.62 ± 0.310.61 ± 0.260.59 ± 0.280.61 ± 0.270.59 ± 0.29
   P.439.268.047a.015a.066.037a
  CDVA (logMAR)0.14 ± 0.170.14 ± 0.170.12 ± 0.140.10 ± 0.120.09 ± 0.100.08 ± 0.090.04 ± 0.05
   P.934.209.025a.054.014a.003a
  SE (D)−6.29 ± 2.97−6.19 ± 3.09−5.78 ± 2.86−5.82 ± 2.79−5.60 ± 3.21−6.05 ± 3.00−5.77 ± 2.94
   P.722.360.133.068.166.171
  K1 (D)44.40 ± 2.0744.47 ± 2.2844.51 ± 2.3244.32 ± 2.0744.45 ± 2.2344.28 ± 2.1644.35 ± 2.20
   P.625.449.660.319.335.635
  K2 (D)47.37 ± 4.1747.67 ± 4.5347.59 ± 4.2847.39 ± 3.8847.36 ± 3.7947.52 ± 4.1747.43 ± 4.18
   P.133.252.601.167.898.922
  Kmean (D)45.80 ± 2.7345.96 ± 3.0545.96 ± 2.9745.74 ± 2.6645.83 ± 2.7545.80 ± 2.8445.80 ± 2.79
   P.2971.000.940.171.545.678
  Kmax (D)50.80 ± 7.3551.76 ± 8.3150.81 ± 7.7750.61 ± 7.4350.50 ± 7.3151.18 ± 7.6250.86 ± 7.69
   P.008a.050.733.977.171.006a
  Kmax coordinate-x (mm)−0.08 ± 0.52−0.08 ± 0.55−0.14 ± 0.68−0.22 ± 0.63−0.13 ± 0.51−0.11 ± 0.48−0.10 ± 0.69
   P.946.498.137.322.611.770
  Kmax coordinate-y (mm)−0.85 ± 1.41−0.81 ± 1.28−0.70 ± 1.49−0.74 ± 1.45−0.63 ± 1.15−0.67 ± 1.02−0.75 ± 1.03
   P.754.184.336.057.296.572
  CET (µm)51.22 ± 3.9450.57 ± 3.9152.22 ± 4.4852.35 ± 4.2151.83 ± 4.2952.00 ± 4.0252.26 ± 3.45
   P.155.106.032a.313.173.097
  CCT (µm)495.87 ± 41.39473.13 ± 37.88496.78 ± 39.69496.52 ± 39.12497.74 ± 38.63486.22 ± 39.29490.96 ± 39.45
   P< .001a< .001a.003a.545.735.380
  TCT (µm)488.43 ± 42.04464.43 ± 39.88488.70 ± 39.98489.17 ± 40.16489.70 ± 40.03478.22 ± 41.05482.04 ± 44.15
   P< .001a< .001a.012a.865.703.550
  IOP (mm Hg)12.48 ± 2.8712.98 ± 3.4312.52 ± 3.4012.96 ± 3.5112.57 ± 2.4512.74 ± 2.6112.78 ± 2.71
   P.369.620.553.944.336.820
Worsening (6.67%, n = 3)
  UDVA (logMAR)0.81 ± 0.200.67 ± 0.060.67 ± 0.060.74 ± 0.070.74 ± 0.070.74 ± 0.070.80 ± 0.17
   P.371.250.635.635.635.968
  CDVA (logMAR)0.17 ± 0.210.16 ± 0.060.07 ± 0.130.12 ± 0.110.12 ± 0.110.12 ± 0.110.12 ± 0.16
   P.948.215.598.598.729.225
  SE (D)−5.58 ± 4.05−3.58 ± 2.38−4.54 ± 4.66−4.75 ± 4.61−4.75 ± 4.49−5.00 ± 5.85−5.25 ± 4.09
   P.284.228.328.294.639.739
  K1 (D)44.63 ± 4.5545.60 ± 7.2044.83 ± 6.2145.17 ± 5.4445.23 ± 5.7243.93 ± 2.8742.47 ± 4.86
   P.604.875.431.487.546.252
  K2 (D)46.67 ± 3.9447.70 ± 6.3247.57 ± 5.9247.47 ± 4.6247.10 ± 4.6846.63 ± 3.0447.20 ± 5.14
   P.595.603.469.684.978.717
  Kmean (D)45.63 ± 4.2646.63 ± 6.8246.20 ± 6.0646.30 ± 5.0346.13 ± 5.2645.20 ± 2.9444.70 ± 4.97
   P.601.705.427.588.682.550
  Kmax (D)56.53 ± 16.0858.27 ± 16.9257.07 ± 17.2457.50 ± 17.9157.33 ± 16.7857.67 ± 16.2859.23 ± 16.43
   P.404.735.606.678.627.097
  Kmax coordinate-x (mm)0.01 ± 0.310.14 ± 0.130.22 ± 0.180.06 ± 0.41−0.05 ± 0.370.26 ± 0.09−0.14 ± 0.41
   P.598.530.663.537.295.173
  Kmax coordinate-y (mm)−1.51 ± 0.18−0.16 ± 1.76−0.12 ± 1.70−1.37 ± 0.15−1.46 ± 0.43−1.52 ± 0.28−1.37 ± 0.17
   P.341.319.040a.808.931.199
  CET (µm)53.00 ± 6.5650.00 ± 4.5850.67 ± 5.5151.33 ± 6.1152.00 ± 7.0051.67 ± 7.2351.00 ± 7.00
   P.122.073.300.667.625.423
  CCT (µm)520.67 ± 51.16490.67 ± 69.04493.67 ± 63.96501.33 ± 61.78509.33 ± 56.80508.33 ± 60.05514.00 ± 56.29
   P.122.070.116.079.179.275
  TCT (µm)509.33 ± 42.74476.67 ± 77.11478.33 ± 75.66487.33 ± 68.25491.00 ± 71.04498.00 ± 65.89506.33 ± 58.32
   P.247.246.287.380.490.772
  IOP (mm Hg)13.67 ± 3.7915.33 ± 3.0612.00 ± 6.5614.00 ± 3.6115.00 ± 2.6513.00 ± 2.6514.33 ± 2.52
   P.300.525.826.456.691.529

Postoperative Aberrometry Data of Subgroups Based on Overall Progression After CXL (7.2 J/cm2) for Progressive Keratoconus

ParameterBaselineMonth 1Month 3Month 6Month 12Month 18Month 24
Improvement (42.22%, n =19)
  Total-RMS10.81 ± 8.6211.55 ± 8.1810.38 ± 7.8810.12 ± 7.668.98 ± 7.788.42 ± 7.888.22 ± 8.02
   P.039a.283.102< .001a< .001a< .001a
  HOA-RMS2.28 ± 1.652.54 ± 1.682.25 ± 1.622.15 ± 1.561.88 ± 1.531.80 ± 1.531.81 ± 1.52
   P.002a.789.180< .001a< .001a.001a
  Z31 (Horizontal coma)−0.21 ± 0.95−0.25 ± 0.86−0.19 ± 0.80−0.20 ± 0.73−0.15 ± 0.66−0.17 ± 0.60−0.14 ± 0.61
   P.559.889.951.568.748.562
  Z3−1 (Vertical coma)−1.38 ± 1.35−1.54 ± 1.27−1.35 ± 1.34−1.28 ± 1.31−1.12 ± 1.24−1.11 ± 1.18−1.16 ± 1.18
   P.020a.685.349.010a.008a.020a
  Z3−3 (Vertical trefoil)−0.06 ± 0.320.02 ± 0.350.08 ± 0.320.07 ± 0.280.07 ± 0.200.03 ± 0.160.02 ± 0.20
   P.420.045a.055.084.220.246
  Z40 (Primary spherical)−0.76 ± 1.22−1.13 ± 1.34−0.75 ± 1.23−0.70 ± 1.19−0.61 ± 1.15−0.37 ± 1.19−0.32 ± 1.19
   P< .001a.871.217.026a.040a.017a
  Z4−4 (Vertical quadrafoil)0.00 ± 0.27−0.05 ± 0.230.05 ± 0.300.01 ± 0.26−0.13 ± 0.73−0.09 ± 0.500.02 ± 0.18
   P.276.394.708.363.312.622
Stabilization (51.11%, n = 23)
  Total-RMS6.30 ± 5.797.38 ± 6.416.88 ± 6.146.35 ± 5.876.29 ± 5.976.12 ± 5.855.75 ± 5.00
   P< .001a.009a.703.945.366.055
  HOA-RMS1.55 ± 1.571.88 ± 1.711.68 ± 1.651.60 ± 1.671.51 ± 1.581.53 ± 1.621.45 ± 1.49
   P< .001a.030a.314.313.534.010a
  Z31 (Horizontal coma)−0.09 ± 0.72−0.11 ± 0.72−0.13 ± 0.74−0.09 ± 0.77−0.09 ± 0.69−0.09 ± 0.74−0.18 ± 0.62
   P.523.283.966.894.832.143
  Z3−1 (Vertical coma)−0.89 ± 1.55−1.07 ± 1.66−0.97 ± 1.64−0.81 ± 1.43−0.92 ± 1.51−0.91 ± 1.54−0.84 ± 1.39
   P.059.207.449.309.609.461
  Z3−3 (Vertical trefoil)−0.02 ± 0.340.13 ± 0.420.09 ± 0.510.13 ± 0.860.04 ± 0.230.11 ± 0.51−0.03 ± 0.35
   P.005a.206.337.381.149.868
  Z40 (Primary spherical)−0.12 ± 0.59−0.21 ± 0.73−0.10 ± 0.62−0.12 ± 0.64−0.10 ± 0.61−0.07 ± 0.500.03 ± 0.67
   P.268.722.960.655.392.247
  Z4−4 (Vertical quadrafoil)−0.07 ± 0.22−0.05 ± 0.26−0.06 ± 0.25−0.07 ± 0.18−0.03 ± 0.19−0.04 ± 0.17−0.02 ± 0.17
   P.491.698.940.095.320.248
Worsening (6.67%, n = 3)
  Total-RMS13.02 ± 15.6514.91 ± 14.8512.97 ± 14.7014.12 ± 16.7314.69 ± 16.6615.95 ± 17.2515.86 ± 16.78
   P.282.950.305.264.183.133
  HOA-RMS2.88 ± 3.503.64 ± 3.793.09 ± 3.693.16 ± 3.623.27 ± 3.683.62 ± 3.953.53 ± 3.69
   P.171.313.315.238.175.188
  Z31 (horizontal coma)0.48 ± 0.340.73 ± 0.650.54 ± 0.260.67 ± 0.580.71 ± 0.680.66 ± 0.930.67 ± 0.69
   P.301.422.332.367.652.448
  Z3−1 (vertical coma)−2.35 ± 3.33−3.03 ± 3.61−2.55 ± 3.45−2.77 ± 3.34−2.92 ± 3.39−3.14 ± 3.80−3.10 ± 3.48
   P.207.203.009a.015a.121.091
  Z3−3 (vertical trefoil)−0.15 ± 0.29−0.08 ± 0.510.02 ± 0.20−0.09 ± 0.290.09 ± 0.14−0.25 ± 0.420.04 ± 0.31
   P.732.568.377.181.470.636
  Z40 (primary spherical)−0.59 ± 1.23−0.72 ± 1.37−0.78 ± 1.35−0.72 ± 1.15−0.59 ± 1.06−0.36 ± 0.60−0.55 ± 0.90
   P.417.314.405.970.684.901
  Z4−4 (vertical quadrafoil)0.33 ± 0.460.18 ± 0.140.15 ± 0.070.24 ± 0.200.05 ± 0.150.20 ± 0.20−0.10 ± 0.43
   P.541.570.659.467.652.461

Clinical Studies of Epithelium-off Accelerated CXL With High Energy Dose for Progressive Keratoconus

Author (Year), CountryHigh Dose (J/cm2)DesignTopography Follow-up Point (Mo)OverallEyes (n)Protocol (mW/cm2/min)aUDVA/CDVA (logMAR); K (D)bOther Significant Findings/Other NC Parameters
Kanellopoulos18 (2012), USA6.3Prospective comparative randomized18 to 56No progression; similar results in both groups217/15Improved (20/60 to 20/38)/improved (20/30 to 20/25) (logMAR NA); Ksteep improved 3.40 (49.50 to 46.10)Improved SE, cylinder/NC (ECD)
213/30Improved (20/62 to 20/40)/improved (20/30 to 20/25) (logMAR NA); Ksteep improved 2.90 (NA)Improved SE, cylinder/NC (ECD)

Choi et al41 (2017), South Korea6.6Retrospective comparative6Smaller topographic flattening in 3/3 min 40 s group133/3 min 40 sNA/NC (0.32 ± 0.24 to 0.26 ± 0.25); Kapical NC (56.63 ± 8.25 to 56.27 ± 8.37)Improved cylinder/NC (sphere, SE, Kflat, Ksteep, Kmean, CTapex, keratoconus indices
153/30NA/improved (0.17 ± 0.16 to 0.08 ± 0.09); Kapical NC (53.43 ± 6.48 to 53.03 ± 7.15)Improved SE, Ksteep, Kmean; decreased CTapex/NC (sphere, cylinder, Kflat, astigmatism, keratoconus indices)

Sherif19 (2014), Egypt7.8Prospective comparative randomized6,12Comparable results in both groups1430/4 min 20 sNA/improved 0.13 (0.48 ± 0.17 to 0.61 ± 0.15) (decimal scale); Ksteep improved 1.09 (49.29 ± 1.73 to 48.20 ± 1.43)Decreased CCT/NC (Kflat, CH, CRF)
113/30NA/improved 0.15 (0.49 ± 0.19 to 0.64 ± 0.16) (decimal scale); Ksteep NC (51.40 ± 1.69 to 50.24 ± 2.00)NC (Kflat, CCT, CH, CRF)

Mazzotta et al31 (2014), Italy7.2Prospective comparative12Keratoconus stable in both groups, better functional outcomes and deeper stromal penetration in pulsed group1030/4NC (4.10 to 4.60)/NC (7.50 to 9.10) (Snellen); Kapical NC (56.84 to 56.99)NC (Kaverage, coma)
1030/8 pulsed (1:1)NC (3.20 to 4.10)/NC (8.00 to 9.80) (Snellen); Kapical improved 1.39 (55.40 to 54.01)Improved Kaverage/NC (coma)

Ozgurhan et al9 (2014), Turkey7.2Retrospective1, 6, 12, 24No progression; for Kapex, 18/44 improved, 26/44 stabilized4430/4Improved 0.13 (0.52 ± 0.36 to 0.39 ± 0.26)/improved 0.08 (0.38 ± 0.24 to 0.30 ± 0.20); Kapex improved 1.0 (57.10 ± 5.50 to 56.10 ± 5.10)Improved K1, K2, Kmean, KVf, total HOA, coma, astigmatism II/NC (sphere, cylinder, SE, astigmatism, CCT, TCT, ECD, other keratoconus indices and total WFE, trefoil, quadrafoil, spherical aberration)

Bozkurt et al8 (2017), Turkey7.2Retrospective1, 6, 12, 24No progression; for Kapex, 53.1% stabilized, 46.7% improved4730/4Improved 0.10 (0.56 ± 0.38 to 0.46 ± 0.29)/improved 0.09 (0.42 ± 0.26 to 0.33 ± 0.22); Kapex improved 0.87 (56.40 ± 4.55 to 55.53 ± 4.54)Improved Kflat, Ksteep, Kaverage, total HOA, coma/NC (sphere, cylinder, CCT, astigmatism, total WFE, trefoil, quadrafoil, astigmatism II, spherical aberration)

Jiang et al42 (2017), China7.2Prospective comparative1, 3, 6, 12Keratoconus stable in both groups, more visual and topography improvement in 3/30 group; flattened or stable Kmax was 88.89% in 30/8 pulsed group and 94.44% in 3/30 group3630/8 pulsed (1:1)Improved 0.12 (0.82 ± 0.37 to NA)/improved 0.09 (0.28 ± 0.23 to NA); Kmax improved 1.31 (53.05 ± 4.80 to 51.94)NC (SE, astigmatism, TCT, ECD)
363/30Improved 0.14 (0.90 ± 0.34 to NA)/improved 0.12 (0.36 ± 0.25 to NA); Kmax improved 1.80 (54.38 ± 5.65 to 52.78)Deeper demarcation line depth/NC (SE, astigmatism, TCT, ECD)

Moineau et al43 (2017), France7.2Retrospective1, 3, 630/4 CXL was reliable and effective therapeutic alternative procedure11030/4NC (0.55 ± 0.36 to 0.45 ± 0.33)/improved 0.069 (0.18 ± 0.19 to 0.13 ± 0.13); Kmax NC (55.70 ± 6.20 to 55.60 ± 6.34)Decreased TCT/NC (Kmean, densitometry)

Toker et al28 (2017), Turkey7.2Retrospective comparative12Keratoconus stable in all groups, less topographic improvement in 30 mW group2830/4NC (0.51 ± 0.38 to NA)/improved 0.10 (0.32 ± 0.26 to NA); Kmax NC (56.10 ± 6.10 to NA)Improved ISV, IVA, IHD, RMS, coma, trefoil; decreased TCT/NC (SE, K1, K2, Kmean, astigmatism, KI, CKI, IHA, Rmin, spherical aberration)
2730/8 pulsed (1:1)NC (0.48 ± 0.28 to NA)/NC (0.27 ± 0.22 to NA); Kmax NC (56.80 ± 6.10 to NA)NC (SE, K1, K2, Kmean, astigmatism, TCT, keratoconus indices, aberrometry)
459/10Improved 0.21 (0.81 ± 0.36 to NA)/improved 0.12 (0.47 ± 0.26 to NA); Kmax improved 1.64 (59.40 ± 4.70 to NA)Improved SE, K1, K2, Kmean, astigmatism, keratoconus indices (except IVA, IHA), aberrometry(except coma); decreased TCT/NC (astigmatism, IVA, IHA, coma)
343/30Improved 0.10 (0.55 ± 0.34 to NA)/improved 0.11 (0.31 ± 0.22 to NA); Kmax improved 2.15 (58.0 ± 5.40 to NA)Improved SE, K1, K2, Kmean, keratoconus indices (except IHA); decreased TCT/NC (astigmatism, IHA)

Woo et al20 (2017), Singapore7.2Prospective comparative1, 3, 6, 12Comparable results in both groups, improved biomechanics in 30/4 group4730/4NC (0.80 ± 0.30 to NA)/improved 0.32 (0.40 ± 0.20 to 0.08); K2 NC (52.15 ± 5.30 to 52.54)Worsened cylinder; improved CH, CRF/NC (SE, K1, Kmean, ECD, CCT, TCT)
293/30NC (0.86 ± 0.40 to NA)/improved 0.11 (0.37 ± 0.30 to NA); K2 NC (52.29 ± 5.40 to 51.48)NC (SE, cylinder, K1, Kmean, ECD, CCT, TCT, CH, CRF)

Yildirim et al44 (2017), Turkey7.2Prospective comparative12Similar refractive and topographic outcomes in both groups7230/4NC (0.60 ± 0.33 to 0.54 ± 0.30)/NC (0.36 ± 0.33 to 0.32 ± 0.20); Kapex improved 2.1 (58.80 ± 5.30 to 56.70 ± 6.30)NC (sphere, cylinder, SE, K1, K2, Kmean, CCT)
7418/5NC (0.56 ± 0.45 to 0.51 ± 0.36)/NC (0.30 ± 0.32 to 0.27 ± 0.20); Kapex improved 2.3 (55.90 ± 6.70 to 53.50 ± 6.90)NC (sphere, cylinder, SE, K1, K2, Kmean, CCT)

Iqbal et al45 (2019), Egypt7.2Prospective comparative randomized (multicenter)6, 12, 24More effective and greater stability, and no progression in 3/30 group; marked improved in myopia and spherical equivalent and 5.4% progression in 30/8 pulsed group9230/8 pulsed (1:1)NC (0.97 ± 0.26 to 0.93 ± 0.28)/NC (0.41 ± 0.20 to 0.38 ± 0.28); Kmax NC (50.70 ± 3.51 to 50.47 ± 3.72)NC (sphere, cylinder, SE, TCT)
913/30Improved 0.26 (1.11 ± 0.43 to 0.85 ± 0.34)/improved 0.24 (0.47 ± 0.40 to 0.23 ± 0.25); Kmax improved 1.17 (50.78 ± 3.82 to 49.61 ± 3.67)Improved sphere, cylinder, SE; decreased TCT

Lang et al27 (2019), Egypt7.2Retrospective comparative12Improved Kmax, CDVA and other variables, with similar functional outcomes in all groups, greater improved keratoconus indices in 3/30 group2930/4NA/improved 0.183 (0.743 ± 0.30 to NA); Kmax improved 0.697 (59.60 ± 7.50 to NA)Improved Kmean, CKI; increased anterior elevation (5 mm); decreased TCT/NC (SE, keratoconus indices [except CKI], IS, posterior elevation, RMS HOA, coma)
299/10NA/improved 0.129 (0.331 ± 0.32 to NA); Kmax improved 0.707 (53.10 ± 6.80 to NA)Improved Kmean, CKI, SE; increased anterior elevation (5 mm); decreased TCT/NC (keratoconus indices [except CKI], IS, posterior elevation, RMS HOA, coma)
353/30NA/improved 0.183 (1.29 ± 0.27 to NA); Kmax improved 1.53 (56.30 ± 6.10 to NA)Improved Kmean, CKI, ISV, IVA, KI, IHD; decreased TCT/NC (SE, IHA, IS, anterior/posterior elevation, RMS HOA, coma)

Dervenis et al46 (2020), Greece7.2Retrospective comparative6.9Similar structural outcomes and efficacies in both groups4020/18, pulsed (1:2)NA/NC (0.93 to 0.90) (logMAR NA); Kmax changed NA (46.57 to 45.49)Kmin, Kmean, and TCT changed NA
193/30NA/NC (0.68 to 0.74) (logMAR NA); Kmax changed NA (46.39 to 46.67)Kmin, Kmean, and TCT changed NA

Omar and Zein47 (2020), Egypt7.2Prospective12Improved keratometric readings, keratoconus indices, and HOA in 45/5 min 20 s pulsed CXL4045/5 min 20 s, pulsed (1:1)Improved 0.06 (0.32 ± 0.06 to 0.38 ± 0.04)/improved 0.04 (0.77 ± 0.02 to 0.81 ± 0.02) (logMAR NA); Kmax improved 1.57 (56.04 ± 7.75 to 54.47 ± 8.38)Improved K1, K2, astigmatism, IVA, ISV, KI, spherical aberrations, coma, trefoil; decreased CTapex, TCT, corneal volume/NC(SE, IHA, IHD, total aberrations, HOA)

Ziaei et al48 (2020), New Zealand7.2Prospective comparative24Higher degree corneal haze at 1 month and greater flattening effect in 30/4 group4030/4NC (0.66 ± 0.41 to 0.67 ± 0.48)/improved (0.36 ± 0.22 to 0.26 ± 0.27); Kmax improved 1.75 (57.48 ± 5.84 to 55.73 ± 6.04)Improved SE/NC (Kmean, TCT, densitometry)
4030/8 pulsed (1:1)NC (0.69 ± 0.29 to 0.64 ± 0.38)/improved (0.30 ± 0.16 to 0.23 ± 0.17); Kmax NC (58.11 ± 5.60 to 57.72 ± 4.54)NC (SE, Kmean, TCT, densitometry)
Authors

From Aier School of Ophthalmology, Central South University, Changsha, Hunan, China (YK, SL); Aier Institute of Cornea, Beijing, China (SL); the Department of Ophthalmology, Beijing Aier Intech Eye Hospital, Beijing, China (SL, CL, SS); and the Department of Ophthalmology, Guiyang Aier Eye Hospital, Guiyang, Guizhou, China (YL).

Supported by the Capital Health Development Research Project (No. 20200187) and Science Research Foundation of Aier Eye Hospital Group (Nos. AR1904D1 and AR1904D3).

The authors have no financial or proprietary interest in the materials presented herein.

AUTHOR CONTRIBUTIONS

Study concept and design (SL); data collection (YK, CL, MX, SS, YL); analysis and interpretation of data (YK); writing the manuscript (YK); critical revision of the manuscript (YK, SL, CL, MX, SS, YL); statistical expertise (MX); administrative, technical, or material support (SS, YL)

Correspondence: Shaowei Li, MD, PhD, Aier School of Ophthalmology, Central South University, No. 198 Furongzhonglu Road, Changsha, China. Email: lishaowei@csu.edu.cn

Received: December 10, 2019
Accepted: August 19, 2020

10.3928/1081597X-20200820-01

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