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• Vol. 36, No. 11, 2020 731
O R I G I N A L A R T I C L E
Keratoconus is a corneal ectasia characterized by progressive corneal thinning and irregular corneal astigmatism, which may lead to irre-
versible visual loss and the need for keratoplasty. The etiology of keratoconus remains uncertain and the ec-tasia progression may be related to the reduced bio-mechanical strength of the stroma.1 As the only con-servative 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 proce-dure (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 tech-nique is time-consuming and excessive corneal dehy-dration and thinning may occur during the lengthy exposure period of 30 minutes. Accelerated protocols purportedly shorten the treatment duration via the ap-plication of a higher ultraviolet-A irradiance. Multiple
ABSTRACT
PURPOSE: To evaluate the results of epithelium-off continu-ous 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 sig-nificant throughout the postoperative follow-up period (P < .05), excluding month 1. A significant decrease in the maxi-mum 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.]
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).
Submitted: December 10, 2019; Accepted: August 19, 2020
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.
Correspondence: Shaowei Li, MD, PhD, Aier School of Ophthalmology, Central South University, No. 198 Furongzhonglu Road, Changsha, China. Email: [email protected]
doi:10.3928/1081597X-20200820-01
Accelerated Epithelium-off Corneal Cross-linking With High Ultraviolet Energy Dose (7.2 J/cm2) for Progressive Keratoconus: 2-Year Results in a Chinese PopulationYanwei Kang, MD; Shaowei Li, MD, PhD; Chang Liu, MD; Man Xu, MD; Shuai Shi, MD; Yanbo Liu, MD
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variations have been reported but a unified protocol for accelerated CXL has not been established. Most acceler-ated treatment protocols maintain a total energy dose of 5.4 J/cm2 based on the Bunsen-Roscoe law of reciproc-ity, 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 sug-gest 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 com-pensate 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 METHODSStudy deSign
This retrospective, non-randomized, single-center, interventional case series included 45 eyes of 31 pa-tients with keratoconus who underwent accelerated CXL between January 2015 and January 2017 at Bei-jing 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 kerato-conus classified as first, second, or third stage accord-ing to the Amsler-Krumeich classification; document-ed 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 correspond-ing change (1.00 D of greater) in the subjective refrac-tion 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 pa-tients underwent assessment of uncorrected (UDVA) and corrected (CDVA) distance visual acuity, manifest refraction, non-contact tonometry, slit-lamp biomi-croscopy, and endothelial cell density using non-con-tact specular microscopy (CEM-530; Nidek Co, Ltd), central epithelial thickness (2-mm diameter) mea-
sured by spectral-domain optical coherence tomog-raphy (RTVue XR; Optovue), and central pachymetry and optical topography and aberrometry data analyzed with Pentacam (Oculus Optikgeräte GmbH). The max-imum 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 clas-sified 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 ProCedureRiboflavin UVA–induced corneal CXL was per-
formed under sterile conditions. The surgical proce-dure was conducted under topical anesthesia with oxy-buprocaine 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 ad-equate 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 Sys-tem; 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 reap-plied 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 con-firmed, usually on postoperative days 4 to 7.
Postoperatively, 0.5% levofloxacin eye drops (Cra-vit; Santen Pharmaceutical Company) were prescribed (four times daily for 1 week) along with 0.3% sodium hyaluronate eye drops (Hialid 0.3; Santen Pharmaceuti-cal Company) (four times daily for 4 weeks), and 0.1% fluorometholone eye drops (Flumetholon; Santen Phar-maceutical Company) were administered twice daily for 2 weeks after removal of the bandage contact lens.
StatiStiCaL anaLySiSStatistical analysis was performed using SPSS soft-
ware 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
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paired t test for the data that conformed to a normal dis-tribution, 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 ana-lyzed 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 evalu-
ated. 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 preop-erative and postoperative outcomes, Table A (avail-able in the online version of this article) indicates the differences between the overall cohort and each subgroup. Tables B-C (available in the online ver-sion of this article) show the changes in parameters at 2 years in each subgroup (stabilized, improved, or worsened).
ViSuaL aCuity and refraCtiVe outComeSThe UDVA did not significantly change, whereas
the CDVA exhibited significant improvement through-out the follow-up period, excluding 1 month. The manifest refractive spherical equivalent was signifi-cantly reduced at 12 and 24 months due to a signifi-cant sphere decrease. No significant cylinder changes were detected in these follow-up periods.
toPograPhiC reSuLtSFigures 1-2 illustrate the overall changing trend
of keratometric values. Significant flat (K1), steep (K2), mean (Kmean), and Kmax increases were ob-served at 1 month. After month 1, K1 values exhib-ited no significant improvement. The K2 changes were similar to the K1 changes, aside from a sig-nificant 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 post-operative 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).
tomograPhiC reSuLtSA significant decrease in corneal thickness was ob-
served 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 reSuLtSTotal root mean square, corneal higher order aber-
rations, and spherical aberration were improved be-tween 12 and 24 months postoperatively.
endotheLiaL reSuLtS and intraoCuLar PreSSureThere were no significant differences in the endo-
thelial cell density or intraocular pressure compared to baseline throughout the follow-up period.
ProgreSSionThe 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 pro-gression 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 sec-ond postoperative year. Therefore, at 2 years, disease progression was halted in 93.33% of cases and the 3
TABLE 1 CXL Methods
Parameter VariableTreatment target Progressive keratoconusFluence (total) (J/cm2) 7.2Soak time and interval (minutes)
10 (q1.5)
Intensity (mW) 30Treatment time (minutes) 4Epithelium status OffChromophore Riboflavin (Avedro, Inc)Chromophore carrier HPMCChromophore osmolarity Iso-osmolarChromophore concentration 0.1%Light source KXL System (Avedro, Inc)Irradiation mode (interval) ContinuousCXL = corneal cross-linking
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TABLE 2Preoperative and Postoperative Data After CXL (7.2 J/cm2) for Progressive Keratoconus
Parameter Baseline Month 1 Month 3 Month 6 Month 12 Month 18 Month 24
Number 45 45 45 45 45 45 45UDVA (logMAR) 0.63 ± 0.26 0.59 ± 0.25 0.58 ± 0.28 0.58 ± 0.26 0.59 ± 0.30 0.60 ± 0.27 0.59 ± 0.28P – .305 .095 .055 .311 .376 .168CDVA (logMAR) 0.17 ± 0.16 0.16 ± 0.15 0.12 ± 0.12 0.11 ± 0.10 0.10 ± 0.09 0.09 ± 0.08 0.06 ± 0.07P – .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 ± 3.01P – .391 .082 .095 .001a .144 .048a
K1 (D) 45.33 ± 3.22 45.84 ± 4.11 45.27 ± 3.83 45.25 ± 3.54 45.24 ± 3.42 45.08 ± 3.16 45.04 ± 3.37P – .006a .731 .475 .471 .060 .091K2 (D) 48.69 ± 4.68 49.25 ± 5.08 48.79 ± 4.80 48.59 ± 4.65 48.53 ± 4.53 48.36 ± 4.31 48.40 ± 4.37P – .001a .421 .415 .383 .032a .050Kmean (D) 46.91 ± 3.70 47.43 ± 4.35 46.94 ± 4.10 46.85 ± 3.85 46.81 ± 3.76 46.63 ± 3.53 46.64 ± 3.69P – .001a .836 .562 .461 .027a .048a
Kmax (D) 54.04 ± 9.50 55.03 ± 10.03 54.14 ± 9.76 53.76 ± 9.78 53.37 ± 9.57 53.12 ± 9.25 53.07 ± 9.31P – < .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 .584Kmax 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 .810Astigmatism (D) 3.36 ± 2.76 3.42 ± 2.80 3.52 ± 2.51 3.33 ± 2.68 3.29 ± 2.52 3.30 ± 2.36 3.34 ± 2.22P – .702 .241 .719 .620 .625 .934CET (µm) 50.93 ± 3.80 49.89 ± 3.85 51.62 ± 4.31 51.51 ± 4.09 51.22 ± 4.31 51.91 ± 5.35 51.29 ± 4.08P – .006a .130 .136 .476 .086 .408CCT (µm) 487.60 ± 42.53 466.64 ± 41.62 474.87 ± 44.21 480.33 ± 44.12 485.24 ± 44.47 486.71 ± 43.81 487.93 ± 44.29P – < .001a < .001a < .001a .161 .612 .864TCT (µm) 480.04 ± 42.60 457.82 ± 43.91 466.33 ± 45.96 471.56 ± 46.68 476.51 ± 45.82 478.27 ± 45.59 479.18 ± 46.21P – < .001a < .001a < .001a .092 .362 .675IOP (mm Hg) 12.42 ± 2.82 12.83 ± 3.14 12.13 ± 2.97 12.38 ± 2.65 12.18 ± 3.08 12.07 ± 3.09 12.29 ± 2.71P – .307 .425 .893 .507 .360 .656ECD (cells/mm2) 3,126.42 ± 366.87 3,143.11 ± 372.82 3,178.02 ± 325.66 3,133.87 ± 387.32 3,123.27 ± 303.39 3,100.89 ± 343.76 3,089.96 ± 390.04P – .733 .241 .820 .918 .271 .178Total-RMS 8.65 ± 8.03 9.64 ± 8.01 8.77 ± 7.63 8.46 ± 7.73 7.98 ± 7.76 7.75 ± 7.89 7.46 ± 7.63P – < .001a .573 .336 .010a .008a .001a
HOA-RMS 1.95 ± 1.76 2.28 ± 1.87 2.02 ± 1.79 1.94 ± 1.78 1.79 ± 1.73 1.78 ± 1.80 1.74 ± 1.71P – < .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 .921Z3
-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 ± 1.55P – .001a .406 .441 .287 .415 .274Z3
-3 (vertical trefoil) -0.05 ± 0.32 0.07 ± 0.40 0.08 ± 0.42 0.09 ± 0.64 0.05 ± 0.21 0.05 ± 0.40 0.00 ± 0.29P – .021a .019a .108 .032a .078 .372Z4
0 (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 ± 0.25 0.00 ± 0.27 -0.01 ± 0.23 -0.07 ± 0.49 -0.05 ± 0.35 -0.01 ± 0.19
P – .523 .599 .928 .447 .501 .851CXL = corneal cross-linking; UDVA = uncorrected distance visual acuity; CDVA = corrected distance visual acuity; SE = spherical equivalent; D = diopters; K1 = flattest keratometric reading; K2 = steepest keratometric reading; Kmean = mean keratometry; Kmax = maximum keratometry; Kmax coordinate-x = x coordinate of maxi-mum keratometry; Kmax coordinate-y = y coordinate of maximum keratometry; CET = center epithelial thickness; CCT = central corneal thickness; TCT = thinnest corneal thickness; IOP = intraocular pressure; ECD = endothelial cell density; RMS = root mean square; HOA = higher order aberrations aStatistically significant (P < .05).
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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.
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 im-provement 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%).
ComPLiCationSNo serious adverse events were noted. Eye pain associ-
ated with the epithelial debridement was common in the early postoperative period. In 1 patient, bilateral sterile in-filtrates were present at the first week postoperatively and resolved with the use of topical steroids within 2 weeks.
DISCUSSIONPrior 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 acceler-ated CXL in porcine corneas have yielded mixed re-sults, 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 treat-ment. Two independent studies12,13 reported less re-duction in Kmax in the high-intensity protocol than in conventional CXL. Moreover, Brittingham et al14 ob-served increased Kmax with accelerated CXL. Hash-emi 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 suggest-ed the decreased stiffening in the central and posterior cornea accounted for the reduced strengthening in ac-celerated CXL.
Complex photochemical mechanisms may contrib-ute 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 bi-ology 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 ap-plicable to proportionally shorten the treatment dura-tion. 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 ri-boflavin composition, oxygen level, and UVA radia-tion.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 stud-ies employing the higher cumulative dose are limited.
Figure 1. Preoperative and postoperative flat (K1), steep (K2), and mean (Kmean) keratometric 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
Figure 3. Maximum keratometry (Kmax) values change percentage. D = diopters
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The stabilization of keratoconus with a flattening of the steep keratometry value was reported by Kanello-poulos18 in the accelerated protocol (6.3 J/cm2, 7 mW/cm2 for 15 minutes). Sherif19 observed a significant re-duction in the average keratometry at 1 year after ac-celerated CXL with settings of 30 mW/cm2 for 4 min-utes 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 ac-celerated CXL with a total dose of 7.2 J/cm2 (30 mW/cm2 for 4 minutes). The mean CDVA improved sig-nificantly from postoperative months 3 to 24, whereas the changes in the mean UDVA and corneal astig-matism 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 signifi-cant improvement or stabilization in the mean K1, K2, Kmean, and Kmax values, aside from the first postop-erative month, when worsening of these values was observed. This initial increase may be attributed to the treatment-related deepithelialization with more sig-nificant stromal irregularity exposed in the CXL treat-ment21 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 proto-col (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, al-though 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 min-utes), 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 with-in 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 im-proved, 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 to-ward normal configuration.
After 24 months of follow-up, keratoconus progres-sion 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, where-as 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 treat-ment 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 signif-icant 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 treat-ment protocol at 12 months. In other studies of this treatment protocol, Ozgurhan et al9 and Bozkurt et al8 observed significant UDVA, CDVA, Ksteep, Kflat, Ka-verage, and Kapex improvements in cohorts of 44 and 47 eyes, respectively, with a 100% success rate of halt-ing disease progression over 24 months. Such a high success rate and more keratoconus index improve-ments 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
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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 ef-ficiency of CXL in patients with keratoconus warrants clarification in further studies.
With regard to the 14 cases of bilateral CXL, the change in the first eye was predictive of the contralat-eral 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 prop-erly in terms of outcome evolution after CXL.
The corneal pachymetry outcomes were reduced at 1 month postoperatively and then returned to near base-line 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 dif-ferent, 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 re-modeling duration was similar to that of transepithelial photorefractive keratectomy and was later than recov-ery 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 re-sults confirmed that there was no damage to the cor-neal endothelium, which is consistent with the find-ings of Mazzotta et al.31 Intraocular pressure analysis revealed no significant differences after treatment, and no late change in intraocular pressure has been report-ed 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 in-
clude the small sample size, retrospective design, ab-sence of evaluation of the demarcation line, and lack of a control group. However, the postoperative change in visual acuity and topography provide valuable in-formation on the 2-year efficacy and safety of the high-er 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.
AUTHOR CONTRIBUTIONSStudy 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)
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TABLE ABaseline Data of Subgroups Based on Overall Progression After CXL (7.2 J/cm2) for Progressive Keratoconus
Parameter All Patients Improvement Stabilization WorseningP (Subgroup Differences)
Number 45 (100%) 19 (42.22%) 23 (51.11%) 3 (6.67%)UDVA (logMAR) 0.63 ± 0.26 0.52 ± 0.23 0.69 ± 0.26 0.81 ± 0.20P – .120 .327 .248 .218CDVA (logMAR) 0.17 ± 0.16 0.23 ± 0.12 0.12 ± 0.17 0.17 ± 0.21P – .162 .265 .960 .408SE (D) -6.24 ± 3.19 -6.30 ± 3.48 -6.29 ± 2.97 -5.58 ± 4.05P – .952 .959 .733 .936K1 (D) 45.33 ± 3.22 46.55 ± 3.88 44.40 ± 2.07 44.63 ± 4.55P – .196 .218 .726 .09K2 (D) 48.69 ± 4.68 50.61 ± 4.88 47.37 ± 4.17 46.67 ± 3.94P – .144 .258 .469 .058Kmean (D) 46.91 ± 3.70 48.46 ± 4.23 45.80 ± 2.73 45.63 ± 4.26P – .147 .207 .568 .052Kmax (D) 54.04 ± 9.50 57.56 ± 9.90 50.80 ± 7.35 56.53 ± 16.08P – .185 .158 .674 .061Kmax coordinate-x (mm) -0.07 ± 0.45 -0.08 ± 0.37 -0.08 ± 0.52 0.01 ± 0.31P – .409 .438 .762 .924Kmax coordinate-y (mm) -0.81 ± 1.13 -0.64 ± 0.75 -0.85 ± 1.41 -1.51 ± 0.18P – .099 .156 .162 .332CET (µm) 50.93 ± 3.80 50.26 ± 3.21 51.22 ± 3.94 53.00 ± 6.56P – .156 .566 .230 .459CCT (µm) 487.60 ± 42.53 472.37 ± 39.02 495.87 ± 41.39 520.67 ± 51.16P – .185 .447 .203 .074TCT (µm) 480.04 ± 42.60 465.26 ± 40.11 488.43 ± 42.04 509.33 ± 42.74P – .202 .443 .255 .098IOP (mm Hg) 12.42 ± 2.82 12.16 ± 2.71 12.48 ± 2.87 13.67 ± 3.79P – .730 .939 .470 .693ECD (cells/mm2) 3,126.42 ± 366.87 3,064.11 ± 380.46 3,202.35 ± 355.51 2,939.00 ± 334.90P – .541 .418 .394 .321Age (y) 21.61 ± 5.91 21.73 ± 6.94 22.10 ± 5.18 17.00 ± 2.03P – .940 .735 .189 .252Sex ratio (M:F) 1.37 (26:19) 1.38 (11:8) 1.30 (13:10) 2.00 (2:1)P – .993 .921 1.000 .945Total-RMS 8.65 ± 8.03 10.81 ± 8.62 6.30 ± 5.79 13.02 ± 15.65P – .977 .237 .066 .120HOA-RMS 1.95 ± 1.76 2.28 ± 1.65 1.55 ± 1.57 2.88 ± 3.50P – .717 .471 .056 .268Z3
1 (horizontal coma) -0.10 ± 0.81 -0.21 ± 0.95 -0.09 ± 0.72 0.48 ± 0.34P – .612 .610 .426 .404Z3
-1 (vertical coma) -1.19 ± 1.61 -1.38 ± 1.35 -0.89 ± 1.55 -2.35 ± 3.33P – .878 .557 .045 .274Z3
-3 (vertical trefoil) -0.05 ± 0.32 -0.06 ± 0.32 -0.02 ± 0.34 -0.15 ± 0.29P – .818 .873 .664 .800Z4
0 (primary spherical) -0.42 ± 0.98 -0.76 ± 1.22 -0.12 ± 0.59 -0.59 ± 1.23P – .629 .172 .474 .101Z4
-4 (vertical quadrafoil) -0.02 ± 0.27 0.00 ± 0.27 -0.07 ± 0.22 0.33 ± 0.46P – .884 .555 .209 .050CXL = corneal cross-linking; UDVA = uncorrected distance visual acuity; CDVA = corrected distance visual acuity; SE = spherical equivalent; D = diopters; K1 = flattest keratometric reading; K2 = steepest keratometric reading; Kmean = mean keratometry; Kmax = maximum keratometry; Kmax coordinate-x = x coordinate of maxi-mum keratometry; Kmax coordinate-y = y coordinate of maximum keratometry; CET = center epithelial thickness; CCT = central corneal thickness; TCT = thinnest corneal thickness; IOP = intraocular pressure; ECD = endothelial cell density; RMS = root mean square; HOA = higher order aberrations
TABL
E B
Post
oper
ativ
e Da
ta o
f Sub
grou
ps B
ased
on
Over
all P
rogr
essi
on A
fter
CXL
(7.2
J/c
m2 ) f
or P
rogr
essi
ve K
erat
ocon
usPa
ram
eter
Base
line
Mon
th 1
Mon
th 3
Mon
th 6
Mon
th 1
2M
onth
18
Mon
th 2
4Im
prov
emen
t (42
.22%
, n =
19)
UDVA
(log
MAR
)0.
56 ±
0.2
30.
55 ±
0.1
90.
51 ±
0.2
50.
51 ±
0.2
70.
57 ±
0.3
40.
57 ±
0.2
90.
55 ±
0.2
7P
–.8
00.4
04.3
68.8
52.9
08.8
33CD
VA (l
ogM
AR)
0.21
± 0
.14
0.19
± 0
.12
0.14
± 0
.10
0.11
± 0
.08
0.12
± 0
.07
0.10
± 0
.07
0.08
± 0
.07
P.4
40.0
19a
.002
a.0
08a
.001
a<
.001
a
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.
78P
–.7
35.2
28.4
35.0
10a
.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.
02P
–.0
04a
.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.
71P
–<
.001
a.6
08.0
32a
.042
a.0
05a
.002
a
Kmea
n (D
)48
.46
± 4.
2349
.35
± 4.
7948
.43
± 4.
8148
.20
± 4.
5447
.94
± 4.
2847
.92
± 4.
2147
.93
± 4.
26P
–<
.001
a.8
93.1
32.0
44a
.036
a.0
30a
Kmax
(D)
57.5
6 ±
9.90
58.4
8 ±
10.0
857
.26
± 10
.30
56.6
8 ±
10.1
855
.85
± 10
.07
55.4
5 ±
9.76
55.2
2 ±
9.86
P–
.008
a.4
33.0
24a
.001
a<
.001
a<
.001
a
Kmax
coo
rdin
ate-
x (m
m)
-0.0
8 ±
0.37
-0.1
0 ±
0.40
-0.1
3 ±
0.37
-0.1
3 ±
0.44
-0.1
0 ±
0.41
-0.1
5 ±
0.36
-0.0
9 ±
0.37
P–
.690
.173
.353
.616
.086
.786
Kmax
coo
rdin
ate-
y (m
m)
-0.6
4 ±
0.75
-0.7
6 ±
0.47
-0.4
8 ±
0.91
-0.5
6 ±
0.87
-0.4
8 ±
0.88
-0.5
2 ±
0.89
-0.7
2 ±
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.
26P
–.0
76.2
95.6
77.8
56.1
63.8
61CC
T (µ
m)
472.
37 ±
39.
0245
5.00
± 4
0.71
458.
16 ±
43.
8046
4.16
± 4
4.04
467.
47 ±
44.
1747
1.42
± 4
4.43
471.
95 ±
45.
96P
–.0
01a
< .0
01a
.007
a.1
50.7
70.9
12TC
T (µ
m)
465.
26 ±
40.
1144
6.84
± 4
3.19
450.
05 ±
44.
5345
6.37
± 4
4.73
459.
47 ±
45.
6846
1.95
± 4
6.13
462.
16 ±
48.
10P
–.0
01a
< .0
01a
.009
a.1
26.3
44.4
48IO
P (m
m H
g)12
.16
± 2.
7112
.26
± 2.
7011
.42
± 2.
7111
.63
± 2.
3412
.12
± 2.
4511
.84
± 2.
1711
.63
± 2.
95P
–.8
75.1
30.2
49.7
38.1
44.3
26St
abili
zatio
n (5
1.11
%, n
= 2
3)UD
VA (l
ogM
AR)
0.66
± 0
.28
0.62
± 0
.31
0.62
± 0
.31
0.61
± 0
.26
0.59
± 0
.28
0.61
± 0
.27
0.59
± 0
.29
P–
.439
.268
.047
a.0
15a
.066
.037
a
CDVA
(log
MAR
)0.
14 ±
0.1
70.
14 ±
0.1
70.
12 ±
0.1
40.
10 ±
0.1
20.
09 ±
0.1
00.
08 ±
0.0
90.
04 ±
0.0
5P
–.9
34.2
09.0
25a
.054
.014
a.0
03a
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.
94P
–.7
22.3
60.1
33.0
68.1
66.1
71K1
(D)
44.4
0 ±
2.07
44.4
7 ±
2.28
44.5
1 ±
2.32
44.3
2 ±
2.07
44.4
5 ±
2.23
44.2
8 ±
2.16
44.3
5 ±
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.
18P
–.1
33.2
52.6
01.1
67.8
98.9
22Km
ean
(D)
45.8
0 ±
2.73
45.9
6 ±
3.05
45.9
6 ±
2.97
45.7
4 ±
2.66
45.8
3 ±
2.75
45.8
0 ±
2.84
45.8
0 ±
2.79
P–
.297
1.00
0.9
40.1
71.5
45.6
78Km
ax (D
)50
.80
± 7.
3551
.76
± 8.
3150
.81
± 7.
7750
.61
± 7.
4350
.50
± 7.
3151
.18
± 7.
6250
.86
± 7.
69P
–.0
08a
.050
.733
.977
.171
.006
a
Kmax
coo
rdin
ate-
x (m
m)
-0.0
8 ±
0.52
-0.0
8 ±
0.55
-0.1
4 ±
0.68
-0.2
2 ±
0.63
-0.1
3 ±
0.51
-0.1
1 ±
0.48
-0.1
0 ±
0.69
P–
.946
.498
.137
.322
.611
.770
TABL
E B
Post
oper
ativ
e Da
ta o
f Sub
grou
ps B
ased
on
Over
all P
rogr
essi
on A
fter
CXL
(7.2
J/c
m2 ) f
or P
rogr
essi
ve K
erat
ocon
usPa
ram
eter
Base
line
Mon
th 1
Mon
th 3
Mon
th 6
Mon
th 1
2M
onth
18
Mon
th 2
4
Kmax
coo
rdin
ate-
y (m
m)
-0.8
5 ±
1.41
-0.8
1 ±
1.28
-0.7
0 ±
1.49
-0.7
4 ±
1.45
-0.6
3 ±
1.15
-0.6
7 ±
1.02
-0.7
5 ±
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.
45P
–.1
55.1
06.0
32a
.313
.173
.097
CCT
(µm
)49
5.87
± 4
1.39
473.
13 ±
37.
8849
6.78
± 3
9.69
496.
52 ±
39.
1249
7.74
± 3
8.63
486.
22 ±
39.
2949
0.96
± 3
9.45
P–
< .0
01a
< .0
01a
.003
a.5
45.7
35.3
80TC
T (µ
m)
488.
43 ±
42.
0446
4.43
± 3
9.88
488.
70 ±
39.
9848
9.17
± 4
0.16
489.
70 ±
40.
0347
8.22
± 4
1.05
482.
04 ±
44.
15P
–<
.001
a<
.001
a.0
12a
.865
.703
.550
IOP
(mm
Hg)
12.4
8 ±
2.87
12.9
8 ±
3.43
12.5
2 ±
3.40
12.9
6 ±
3.51
12.5
7 ±
2.45
12.7
4 ±
2.61
12.7
8 ±
2.71
P–
.369
.620
.553
.944
.336
.820
Wor
seni
ng (6
.67%
, n =
3)
UDVA
(log
MAR
)0.
81 ±
0.2
00.
67 ±
0.0
60.
67 ±
0.0
60.
74 ±
0.0
70.
74 ±
0.0
70.
74 ±
0.0
70.
80 ±
0.1
7P
–.3
71.2
50.6
35.6
35.6
35.9
68CD
VA (l
ogM
AR)
0.17
± 0
.21
0.16
± 0
.06
0.07
± 0
.13
0.12
± 0
.11
0.12
± 0
.11
0.12
± 0
.11
0.12
± 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.
09P
.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.
86P
–.6
04.8
75.4
31.4
87.5
46.2
52K2
(D)
46.6
7 ±
3.94
47.7
0 ±
6.32
47.5
7 ±
5.92
47.4
7 ±
4.62
47.1
0 ±
4.68
46.6
3 ±
3.04
47.2
0 ±
5.14
P–
.595
.603
.469
.684
.978
.717
Kmea
n (D
)45
.63
± 4.
2646
.63
± 6.
8246
.20
± 6.
0646
.30
± 5.
0346
.13
± 5.
2645
.20
± 2.
9444
.70
± 4.
97P
–.6
01.7
05.4
27.5
88.6
82.5
50Km
ax (D
)56
.53
± 16
.08
58.2
7 ±
16.9
257
.07
± 17
.24
57.5
0 ±
17.9
157
.33
± 16
.78
57.6
7 ±
16.2
859
.23
± 16
.43
P–
.404
.735
.606
.678
.627
.097
Kmax
coo
rdin
ate-
x (m
m)
0.01
± 0
.31
0.14
± 0
.13
0.22
± 0
.18
0.06
± 0
.41
-0.0
5 ±
0.37
0.26
± 0
.09
-0.1
4 ±
0.41
P–
.598
.530
.663
.537
.295
.173
Kmax
coo
rdin
ate-
y (m
m)
-1.5
1 ±
0.18
-0.1
6 ±
1.76
-0.1
2 ±
1.70
-1.3
7 ±
0.15
-1.4
6 ±
0.43
-1.5
2 ±
0.28
-1.3
7 ±
0.17
P–
.341
.319
.040
a.8
08.9
31.1
99CE
T (µ
m)
53.0
0 ±
6.56
50.0
0 ±
4.58
50.6
7 ±
5.51
51.3
3 ±
6.11
52.0
0 ±
7.00
51.6
7 ±
7.23
51.0
0 ±
7.00
P–
.122
.073
.300
.667
.625
.423
CCT
(µm
)52
0.67
± 5
1.16
490.
67 ±
69.
0449
3.67
± 6
3.96
501.
33 ±
61.
7850
9.33
± 5
6.80
508.
33 ±
60.
0551
4.00
± 5
6.29
P–
.122
.070
.116
.079
.179
.275
TCT
(µm
)50
9.33
± 4
2.74
476.
67 ±
77.
1147
8.33
± 7
5.66
487.
33 ±
68.
2549
1.00
± 7
1.04
498.
00 ±
65.
8950
6.33
± 5
8.32
P–
.247
.246
.287
.380
.490
.772
IOP
(mm
Hg)
13.6
7 ±
3.79
15.3
3 ±
3.06
12.0
0 ±
6.56
14.0
0 ±
3.61
15.0
0 ±
2.65
13.0
0 ±
2.65
14.3
3 ±
2.52
P –
.300
.525
.826
.456
.691
.529
CXL
= co
rnea
l cro
ss-li
nkin
g; U
DVA
= un
corr
ecte
d di
stan
ce v
isua
l acu
ity; C
DVA
= co
rrec
ted
dist
ance
vis
ual a
cuity
; SE
= sp
heric
al e
quiva
lent
; D =
dio
pter
s; K
1 =
flatte
st k
erat
omet
ric re
adin
g; K
2 =
stee
pest
ker
atom
etric
read
ing;
Km
ean
= m
ean
kera
tom
etry
; Km
ax =
max
imum
ker
atom
etry
; Km
ax c
oord
inat
e-x
= x
coor
dina
te o
f max
imum
ker
atom
etry
; Km
ax c
oord
inat
e-y
= y
coor
dina
te o
f max
imum
ker
atom
etry
; CET
= c
ente
r epi
thel
ial t
hick
ness
; CCT
=
cent
ral c
orne
al th
ickn
ess;
TCT
= th
inne
st c
orne
al th
ickn
ess;
IOP
= in
trao
cula
r pre
ssur
e
a Sta
tistic
ally
sign
ifica
nt (P
< .0
5).
(con
t’d)
TABL
E C
Post
oper
ativ
e Ab
erro
met
ry D
ata
of S
ubgr
oups
Bas
ed o
n Ov
eral
l Pro
gres
sion
Afte
r CXL
(7.2
J/c
m2 ) f
or P
rogr
essi
ve K
erat
ocon
usPa
ram
eter
Base
line
Mon
th 1
Mon
th 3
Mon
th 6
Mon
th 1
2M
onth
18
Mon
th 2
4Im
prov
emen
t (42
.22%
, n =
19)
Tota
l-RM
S10
.81
± 8.
6211
.55
± 8.
1810
.38
± 7.
8810
.12
± 7.
668.
98 ±
7.7
88.
42 ±
7.8
88.
22 ±
8.0
2P
–.0
39a
.283
.102
< .0
01a
< .0
01a
< .0
01a
HOA
-RM
S2.
28 ±
1.6
52.
54 ±
1.6
82.
25 ±
1.6
22.
15 ±
1.5
61.
88 ±
1.5
31.
80 ±
1.5
31.
81 ±
1.5
2P
–.0
02a
.789
.180
< .0
01a
< .0
01a
.001
a
Z 31 (H
oriz
onta
l com
a)-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.
61P
–.5
59.8
89.9
51.5
68.7
48.5
62Z 3-1
(Ver
tical
com
a)-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.
18P
–.0
20a
.685
.349
.010
a.0
08a
.020
a
Z 3-3 (V
ertic
al tr
efoi
l)-0
.06
± 0.
320.
02 ±
0.3
50.
08 ±
0.3
20.
07 ±
0.2
80.
07 ±
0.2
00.
03 ±
0.1
60.
02 ±
0.2
0P
–.4
20.0
45a
.055
.084
.220
.246
Z 40 (Pr
imar
y sp
heric
al)
-0.7
6 ±
1.22
-1.1
3 ±
1.34
-0.7
5 ±
1.23
-0.7
0 ±
1.19
-0.6
1 ±
1.15
-0.3
7 ±
1.19
-0.3
2 ±
1.19
P–
< .0
01a
.871
.217
.026
a.0
40a
.017
a
Z 4-4 (V
ertic
al q
uadr
afoi
l)0.
00 ±
0.2
7-0
.05
± 0.
230.
05 ±
0.3
00.
01 ±
0.2
6-0
.13
± 0.
73-0
.09
± 0.
500.
02 ±
0.1
8P
–.2
76.3
94.7
08.3
63.3
12.6
22St
abili
zatio
n (5
1.11
%, n
= 2
3)To
tal-
RMS
6.30
± 5
.79
7.38
± 6
.41
6.88
± 6
.14
6.35
± 5
.87
6.29
± 5
.97
6.12
± 5
.85
5.75
± 5
.00
P–
< .0
01a
.009
a.7
03.9
45.3
66.0
55H
OA-R
MS
1.55
± 1
.57
1.88
± 1
.71
1.68
± 1
.65
1.60
± 1
.67
1.51
± 1
.58
1.53
± 1
.62
1.45
± 1
.49
P–
< .0
01a
.030
a.3
14.3
13.5
34.0
10a
Z 31 (H
oriz
onta
l com
a)-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.
62P
–.5
23.2
83.9
66.8
94.8
32.1
43Z 3-1
(Ver
tical
com
a)-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.
39P
–.0
59.2
07.4
49.3
09.6
09.4
61Z 3-3
(Ver
tical
tref
oil)
-0.0
2 ±
0.34
0.13
± 0
.42
0.09
± 0
.51
0.13
± 0
.86
0.04
± 0
.23
0.11
± 0
.51
-0.0
3 ±
0.35
P–
.005
a.2
06.3
37.3
81.1
49.8
68Z 40 (
Prim
ary
sphe
rical
)-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 ±
0.6
7P
–.2
68.7
22.9
60.6
55.3
92.2
47Z 4-4
(Ver
tical
qua
draf
oil)
-0.0
7 ±
0.22
-0.0
5 ±
0.26
-0.0
6 ±
0.25
-0.0
7 ±
0.18
-0.0
3 ±
0.19
-0.0
4 ±
0.17
-0.0
2 ±
0.17
P–
.491
.698
.940
.095
.320
.248
Wor
seni
ng (6
.67%
, n =
3)
Tota
l-RM
S13
.02
± 15
.65
14.9
1 ±
14.8
512
.97
± 14
.70
14.1
2 ±
16.7
314
.69
± 16
.66
15.9
5 ±
17.2
515
.86
± 16
.78
P–
.282
.950
.305
.264
.183
.133
HOA
-RM
S2.
88 ±
3.5
03.
64 ±
3.7
93.
09 ±
3.6
93.
16 ±
3.6
23.
27 ±
3.6
83.
62 ±
3.9
53.
53 ±
3.6
9P
–.1
71.3
13.3
15.2
38.1
75.1
88Z 31 (
horiz
onta
l com
a)0.
48 ±
0.3
40.
73 ±
0.6
50.
54 ±
0.2
60.
67 ±
0.5
80.
71 ±
0.6
80.
66 ±
0.9
30.
67 ±
0.6
9P
–.3
01.4
22.3
32.3
67.6
52.4
48Z 3-1
(ver
tical
com
a)-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.
48P
–.2
07.2
03.0
09a
.015
a.1
21.0
91Z 3-3
(ver
tical
tref
oil)
-0.1
5 ±
0.29
-0.0
8 ±
0.51
0.02
± 0
.20
-0.0
9 ±
0.29
0.09
± 0
.14
-0.2
5 ±
0.42
0.04
± 0
.31
P–
.732
.568
.377
.181
.470
.636
Z 40 (pr
imar
y sp
heric
al)
-0.5
9 ±
1.23
-0.7
2 ±
1.37
-0.7
8 ±
1.35
-0.7
2 ±
1.15
-0.5
9 ±
1.06
-0.3
6 ±
0.60
-0.5
5 ±
0.90
P–
.417
.314
.405
.970
.684
.901
Z 4-4 (v
ertic
al q
uadr
afoi
l)0.
33 ±
0.4
60.
18 ±
0.1
40.
15 ±
0.0
70.
24 ±
0.2
00.
05 ±
0.1
50.
20 ±
0.2
0-0
.10
± 0.
43P
–.5
41.5
70.6
59.4
67.6
52.4
61CX
L =
corn
eal c
ross
-link
ing;
RM
S =
root
mea
n sq
uare
; HOA
= h
ighe
r ord
er a
berr
atio
ns
a Sta
tistic
ally
sign
ifica
nt (P
< .0
5).
TABL
E D
Clin
ical
Stu
dies
of E
pith
eliu
m-o
ff A
ccel
erat
ed C
XL W
ith H
igh
Ener
gy D
ose
for
Prog
ress
ive
Kera
toco
nus
Auth
or (Y
ear)
, Co
untr
y
High
Do
se
(J/c
m2 )
Desi
gn
Topo
grap
hy
Follo
w-u
p Po
int (
Mo)
Over
all
Eyes
(n)
Prot
ocol
(mW
/cm
2 /min
)aUD
VA/C
DVA
(logM
AR);
K (D
)bOt
her S
igni
fican
t Fin
ding
s/Ot
her N
C Pa
ram
eter
s
Kane
llopo
ulos
18
(201
2), U
SA6.
3Pr
ospe
ctiv
e
com
para
tive
ra
ndom
ized
18 to
56
No
prog
ress
ion;
sim
ilar
resu
lts in
bot
h gr
oups
217/
15Im
prov
ed (2
0/60
to 2
0/38
)/im
prov
ed
(20/
30 to
20/
25) (
logM
AR N
A);
Kste
ep im
prov
ed 3
.40
(49.
50 to
46
.10)
Impr
oved
SE,
cyl
inde
r/N
C (E
CD)
213/
30Im
prov
ed (2
0/62
to 2
0/40
)/im
prov
ed
(20/
30 to
20/
25) (
logM
AR N
A);
Kste
ep im
prov
ed 2
.90
(NA)
Impr
oved
SE,
cyl
inde
r/N
C (E
CD)
Choi
et a
l41 (2
017)
, So
uth
Kore
a6.
6Re
tros
pect
ive
com
para
tive
6Sm
alle
r to
pogr
aphi
c fla
t-te
ning
in 3
/3 m
in 4
0 s
grou
p
133/
3 m
in 4
0 s
NA/
NC
(0.3
2 ±
0.24
to 0
.26
± 0.
25);
Kapi
cal N
C (5
6.63
± 8
.25
to 5
6.27
±
8.37
)
Impr
oved
cyl
inde
r/N
C (s
pher
e,
SE, K
flat,
Kste
ep, K
mea
n,
CTap
ex, k
erat
ocon
us in
dice
s15
3/30
NA/
impr
oved
(0.1
7 ±
0.16
to 0
.08
± 0.
09);
Kapi
cal N
C (5
3.43
± 6
.48
to
53.0
3 ±
7.15
)
Impr
oved
SE,
Kst
eep,
Km
ean;
de
crea
sed
CTap
ex/N
C (s
pher
e,
cylin
der,
Kfla
t, as
tigm
atis
m,
kera
toco
nus
indi
ces)
Sher
if19 (2
014)
, Eg
ypt
7.8
Pros
pect
ive
co
mpa
rativ
e
rand
omiz
ed
6,12
Com
para
ble
resu
lts in
bot
h gr
oups
1430
/4 m
in 2
0 s
NA/
impr
oved
0.1
3 (0
.48
± 0.
17 to
0.
61 ±
0.1
5) (d
ecim
al s
cale
); Ks
teep
im
prov
ed 1
.09
(49.
29 ±
1.7
3 to
48.
20
± 1.
43)
Decr
ease
d CC
T/N
C (K
flat,
CH,
CRF)
113/
30N
A/im
prov
ed 0
.15
(0.4
9 ±
0.19
to
0.64
± 0
.16)
(dec
imal
sca
le);
Kste
ep
NC
(51.
40 ±
1.6
9 to
50.
24 ±
2.0
0)
NC
(Kfla
t, CC
T, C
H, C
RF)
Maz
zotta
et a
l31
(201
4), I
taly
7.2
Pros
pect
ive
co
mpa
rativ
e12
Kera
toco
nus
stab
le in
bot
h gr
oups
, bet
ter
func
tiona
l ou
tcom
es a
nd d
eepe
r st
ro-
mal
pen
etra
tion
in p
ulse
d gr
oup
1030
/4N
C (4
.10
to 4
.60)
/NC
(7.5
0 to
9.1
0)
(Sne
llen)
; Kap
ical
NC
(56.
84 to
56
.99)
NC
(Kav
erag
e, c
oma)
1030
/8 p
ulse
d (1
:1)
NC
(3.2
0 to
4.1
0)/N
C (8
.00
to 9
.80)
(S
nelle
n); K
apic
al im
prov
ed 1
.39
(55.
40 to
54.
01)
Impr
oved
Kav
erag
e/N
C (c
oma)
Ozgu
rhan
et a
l9 (2
014)
, Tur
key
7.2
Retr
ospe
ctiv
e1,
6, 1
2, 2
4N
o pr
ogre
ssio
n; fo
r Ka
pex,
18
/44
impr
oved
, 26/
44
stab
ilize
d
4430
/4Im
prov
ed 0
.13
(0.5
2 ±
0.36
to 0
.39
± 0.
26)/i
mpr
oved
0.0
8 (0
.38
± 0.
24
to 0
.30
± 0.
20);
Kape
x im
prov
ed 1
.0
(57.
10 ±
5.5
0 to
56.
10 ±
5.1
0)
Impr
oved
K1,
K2,
Km
ean,
KVf
, to
tal H
OA, c
oma,
ast
igm
atis
m
II/N
C (s
pher
e, c
ylin
der,
SE,
astig
mat
ism
, CCT
, TCT
, ECD
, ot
her
kera
toco
nus
indi
ces
and
tota
l WFE
, tre
foil,
qua
draf
oil,
sphe
rical
abe
rrat
ion)
Bozk
urt e
t al8
(201
7), T
urke
y7.
2Re
tros
pect
ive
1, 6
, 12,
24
No
prog
ress
ion;
for
Kape
x,
53.1
% s
tabi
lized
, 46.
7%
impr
oved
4730
/4Im
prov
ed 0
.10
(0.5
6 ±
0.38
to 0
.46
± 0.
29)/i
mpr
oved
0.0
9 (0
.42
± 0.
26 to
0.
33 ±
0.2
2); K
apex
impr
oved
0.8
7 (5
6.40
± 4
.55
to 5
5.53
± 4
.54)
Impr
oved
Kfla
t, Ks
teep
, Ka
vera
ge, t
otal
HOA
, com
a/N
C (s
pher
e, c
ylin
der,
CCT,
as
tigm
atis
m, t
otal
WFE
, tre
foil,
qu
adra
foil,
ast
igm
atis
m II
, sp
heric
al a
berr
atio
n)
Jian
g et
al42
(201
7),
Chin
a7.
2Pr
ospe
ctiv
e
com
para
tive
1, 3
, 6, 1
2Ke
rato
conu
s st
able
in b
oth
grou
ps, m
ore
visu
al a
nd
topo
grap
hy im
prov
emen
t in
3/3
0 gr
oup;
flat
tene
d or
st
able
Km
ax w
as 8
8.89
%
in 3
0/8
puls
ed g
roup
and
94
.44%
in 3
/30
grou
p
3630
/8 p
ulse
d (1
:1)
Impr
oved
0.1
2 (0
.82
± 0.
37 to
NA)
/im
prov
ed 0
.09
(0.2
8 ±
0.23
to N
A);
Kmax
impr
oved
1.3
1 (5
3.05
± 4
.80
to 5
1.94
)
NC
(SE,
ast
igm
atis
m, T
CT,
ECD)
TABL
E D
Clin
ical
Stu
dies
of E
pith
eliu
m-o
ff A
ccel
erat
ed C
XL W
ith H
igh
Ener
gy D
ose
for
Prog
ress
ive
Kera
toco
nus
Auth
or (Y
ear)
, Co
untr
y
High
Do
se
(J/
cm2 )
Desi
gn
Topo
grap
hy
Follo
w-u
p Po
int (
Mo)
Over
all
Eyes
(n)
Prot
ocol
(mW
/cm
2 /min
)aUD
VA/C
DVA
(logM
AR);
K (D
)bOt
her S
igni
fican
t Fin
ding
s/Ot
her N
C Pa
ram
eter
s
363/
30Im
prov
ed 0
.14
(0.9
0 ±
0.34
to N
A)/
impr
oved
0.1
2 (0
.36
± 0.
25 to
NA)
; Km
ax im
prov
ed 1
.80
(54.
38 ±
5.6
5 to
52.
78)
Deep
er d
emar
catio
n lin
e de
pth/
NC
(SE,
ast
igm
atis
m,
TCT,
ECD
)
Moi
neau
et a
l43
(201
7), F
ranc
e7.
2Re
tros
pect
ive
1, 3
, 630
/4 C
XL w
as re
liabl
e an
d ef
fect
ive
ther
apeu
tic a
lter-
nativ
e pr
oced
ure
110
30/4
NC
(0.5
5 ±
0.36
to 0
.45
± 0.
33)/
impr
oved
0.0
69 (0
.18
± 0.
19 to
0.1
3 ±
0.13
); Km
ax N
C (5
5.70
± 6
.20
to
55.6
0 ±
6.34
)
Decr
ease
d TC
T/N
C (K
mea
n,
dens
itom
etry
)
Toke
r et
al28
(201
7),
Turk
ey7.
2Re
tros
pect
ive
com
para
tive
12Ke
rato
conu
s st
able
in a
ll gr
oups
, les
s to
pogr
aphi
c im
prov
emen
t in
30 m
W
grou
p
2830
/4N
C (0
.51
± 0.
38 to
NA)
/impr
oved
0.
10 (0
.32
± 0.
26 to
NA)
; Km
ax N
C (5
6.10
± 6
.10
to N
A)
Impr
oved
ISV,
IVA,
IHD,
RM
S,
com
a, tr
efoi
l; de
crea
sed
TCT/
NC
(SE,
K1,
K2,
Km
ean,
ast
ig-
mat
ism
, KI,
CKI,
IHA,
Rm
in,
sphe
rical
abe
rrat
ion)
2730
/8 p
ulse
d (1
:1)
NC
(0.4
8 ±
0.28
to N
A)/N
C (0
.27
± 0.
22 to
NA)
; Km
ax N
C (5
6.80
± 6
.10
to N
A)
NC
(SE,
K1,
K2,
Km
ean,
ast
ig-
mat
ism
, TCT
, ker
atoc
onus
in
dice
s, a
berr
omet
ry)
459/
10Im
prov
ed 0
.21
(0.8
1 ±
0.36
to N
A)/
impr
oved
0.1
2 (0
.47
± 0.
26 to
NA)
; Km
ax im
prov
ed 1
.64
(59.
40 ±
4.7
0 to
NA)
Impr
oved
SE,
K1,
K2,
Km
ean,
as
tigm
atis
m, k
erat
ocon
us
indi
ces
(exc
ept I
VA, I
HA)
, ab
erro
met
ry(e
xcep
t com
a);
decr
ease
d TC
T/N
C (a
stig
ma-
tism
, IVA
, IH
A, c
oma)
34
3/30
Impr
oved
0.1
0 (0
.55
± 0.
34 to
NA)
/im
prov
ed 0
.11
(0.3
1 ±
0.22
to N
A);
Kmax
impr
oved
2.1
5 (5
8.0
± 5.
40
to N
A)
Impr
oved
SE,
K1,
K2,
Km
ean,
ke
rato
conu
s in
dice
s (e
xcep
t IH
A); d
ecre
ased
TCT
/NC
(ast
ig-
mat
ism
, IH
A)
Woo
et a
l20 (2
017)
, Si
ngap
ore
7.2
Pros
pect
ive
co
mpa
rativ
e1,
3, 6
, 12
Com
para
ble
resu
lts in
bot
h gr
oups
, im
prov
ed b
iom
e-ch
anic
s in
30/
4 gr
oup
4730
/4N
C (0
.80
± 0.
30 to
NA)
/impr
oved
0.
32 (0
.40
± 0.
20 to
0.0
8); K
2 N
C (5
2.15
± 5
.30
to 5
2.54
)
Wor
sene
d cy
linde
r; im
prov
ed
CH, C
RF/N
C (S
E, K
1, K
mea
n,
ECD,
CCT
, TCT
)29
3/30
NC
(0.8
6 ±
0.40
to N
A)/im
prov
ed
0.11
(0.3
7 ±
0.30
to N
A); K
2 N
C (5
2.29
± 5
.40
to 5
1.48
)
NC
(SE,
cyl
inde
r, K1
, Km
ean,
EC
D, C
CT, T
CT, C
H, C
RF)
Yild
irim
et a
l44
(201
7), T
urke
y7.
2Pr
ospe
ctiv
e
com
para
tive
12Si
mila
r re
frac
tive
and
topo
-gr
aphi
c ou
tcom
es in
bot
h gr
oups
7230
/4N
C (0
.60
± 0.
33 to
0.5
4 ±
0.30
)/NC
(0.3
6 ±
0.33
to 0
.32
± 0.
20);
Kape
x im
prov
ed 2
.1 (5
8.80
± 5
.30
to 5
6.70
±
6.30
)
NC
(sph
ere,
cyl
inde
r, SE
, K1,
K2
, Km
ean,
CCT
)
7418
/5N
C (0
.56
± 0.
45 to
0.5
1 ±
0.36
)/NC
(0.3
0 ±
0.32
to 0
.27
± 0
.20)
; Kap
ex
impr
oved
2.3
(55.
90 ±
6.7
0 to
53.
50
± 6.
90)
NC
(sph
ere,
cyl
inde
r, SE
, K1,
K2
, Km
ean,
CCT
)
Iqba
l et a
l45 (2
019)
, Eg
ypt
7.2
Pros
pect
ive
co
mpa
rativ
e
rand
omiz
ed
(mul
ticen
ter)
6, 1
2, 2
4M
ore
effe
ctiv
e an
d gr
eate
r st
abili
ty, a
nd n
o pr
ogre
s-si
on in
3/3
0 gr
oup;
mar
ked
impr
oved
in m
yopi
a an
d sp
heric
al e
quiv
alen
t and
5.
4% p
rogr
essi
on in
30/
8 pu
lsed
gro
up
9230
/8 p
ulse
d (1
:1)
NC
(0.9
7 ±
0.26
to 0
.93
± 0.
28)/N
C (0
.41
± 0.
20 to
0.3
8 ±
0.28
); Km
ax
NC
(50.
70 ±
3.5
1 to
50.
47 ±
3.7
2)
NC
(sph
ere,
cyl
inde
r, SE
, TCT
)
(con
t’d)
TABL
E D
Clin
ical
Stu
dies
of E
pith
eliu
m-o
ff A
ccel
erat
ed C
XL W
ith H
igh
Ener
gy D
ose
for
Prog
ress
ive
Kera
toco
nus
Auth
or (Y
ear)
, Co
untr
y
High
Do
se
(J/
cm2 )
Desi
gn
Topo
grap
hy
Follo
w-u
p Po
int (
Mo)
Over
all
Eyes
(n)
Prot
ocol
(mW
/cm
2 /min
)aUD
VA/C
DVA
(logM
AR);
K (D
)bOt
her S
igni
fican
t Fin
ding
s/Ot
her N
C Pa
ram
eter
s
913/
30Im
prov
ed 0
.26
(1.1
1 ±
0.43
to 0
.85
± 0.
34)/i
mpr
oved
0.2
4 (0
.47
± 0.
40 to
0.
23 ±
0.2
5); K
max
impr
oved
1.1
7 (5
0.78
± 3
.82
to 4
9.61
± 3
.67)
Impr
oved
sph
ere,
cyl
inde
r, SE
; de
crea
sed
TCT
Lang
et a
l27 (2
019)
, Eg
ypt
7.2
Retr
ospe
ctiv
e co
mpa
rativ
e12
Impr
oved
Km
ax, C
DVA
and
othe
r va
riabl
es, w
ith s
imi-
lar
func
tiona
l out
com
es
in a
ll gr
oups
, gre
ater
im
prov
ed k
erat
ocon
us in
di-
ces
in 3
/30
grou
p
2930
/4N
A/im
prov
ed 0
.183
(0.7
43 ±
0.3
0 to
N
A); K
max
impr
oved
0.6
97 (5
9.60
±
7.50
to N
A)
Impr
oved
Km
ean,
CKI
; in
crea
sed
ante
rior
elev
atio
n (5
m
m);
decr
ease
d TC
T/N
C (S
E,
kera
toco
nus
indi
ces
[exc
ept
CKI],
IS, p
oste
rior
elev
atio
n,
RMS
HOA
, com
a)29
9/10
NA/
impr
oved
0.1
29 (0
.331
± 0
.32
to
NA)
; Km
ax im
prov
ed 0
.707
(53.
10 ±
6.
80 to
NA)
Impr
oved
Km
ean,
CKI
, SE;
in
crea
sed
ante
rior
elev
atio
n (5
m
m);
decr
ease
d TC
T/N
C (k
era-
toco
nus
indi
ces
[exc
ept C
KI],
IS, p
oste
rior
elev
atio
n, R
MS
HOA
, com
a)
353/
30N
A/im
prov
ed 0
.183
(1.2
9 ±
0.27
to
NA)
; Km
ax im
prov
ed 1
.53
(56.
30 ±
6.
10 to
NA)
Impr
oved
Km
ean,
CKI
, ISV
, IVA
, KI
, IH
D; d
ecre
ased
TCT
/NC
(SE,
IHA,
IS, a
nter
ior/
post
erio
r el
evat
ion,
RM
S H
OA, c
oma)
Derv
enis
et a
l46
(202
0), G
reec
e7.
2Re
tros
pect
ive
com
para
tive
6.9
Sim
ilar
stru
ctur
al o
ut-
com
es a
nd e
ffica
cies
in
both
gro
ups
4020
/18,
pul
sed
(1:2
)N
A/N
C (0
.93
to 0
.90)
(log
MAR
NA)
; Km
ax c
hang
ed N
A (4
6.57
to 4
5.49
)Km
in, K
mea
n, a
nd T
CT
chan
ged
NA
193/
30N
A/N
C (0
.68
to 0
.74)
(log
MAR
NA)
; Km
ax c
hang
ed N
A (4
6.39
to 4
6.67
)Km
in, K
mea
n, a
nd T
CT
chan
ged
NA
Omar
and
Zei
n47
(202
0), E
gypt
7.2
Pros
pect
ive
12Im
prov
ed k
erat
omet
ric
read
ings
, ker
atoc
onus
indi
-ce
s, a
nd H
OA in
45/
5 m
in
20 s
pul
sed
CXL
4045
/5 m
in 2
0 s,
pu
lsed
(1:1
)Im
prov
ed 0
.06
(0.3
2 ±
0.06
to 0
.38
± 0.
04)/i
mpr
oved
0.0
4 (0
.77
± 0.
02
to 0
.81
± 0.
02) (
logM
AR N
A); K
max
im
prov
ed 1
.57
(56.
04 ±
7.7
5 to
54.
47
± 8.
38)
Impr
oved
K1,
K2,
ast
igm
atis
m,
IVA,
ISV,
KI,
sphe
rical
abe
rra-
tions
, com
a, tr
efoi
l; de
crea
sed
CTap
ex, T
CT, c
orne
al v
olum
e/N
C(SE
, IH
A, IH
D, to
tal a
berr
a-tio
ns, H
OA)
Ziae
i et a
l48 (2
020)
, N
ew Z
eala
nd7.
2Pr
ospe
ctiv
e
com
para
tive
24H
ighe
r de
gree
cor
neal
ha
ze a
t 1 m
onth
and
gre
at-
er fl
atte
ning
effe
ct in
30/
4 gr
oup
4030
/4N
C (0
.66
± 0.
41 to
0.6
7 ±
0.48
)/im
prov
ed (0
.36
± 0.
22 to
0.2
6 ±
0.27
); Km
ax im
prov
ed 1
.75
(57.
48 ±
5.
84 to
55.
73 ±
6.0
4)
Impr
oved
SE/
NC
(Km
ean,
TCT
, de
nsito
met
ry)
4030
/8 p
ulse
d (1
:1)
NC
(0.6
9 ±
0.29
to 0
.64
± 0.
38)/
impr
oved
(0.3
0 ±
0.16
to 0
.23
± 0.
17);
Kmax
NC
(58.
11 ±
5.6
0 to
57
.72
± 4.
54)
NC
(SE,
Km
ean,
TCT
, den
si-
tom
etry
)
CXL
= co
rnea
l cro
ss-li
nkin
g; U
DVA
= un
corr
ecte
d di
stan
ce v
isua
l acu
ity; C
DVA
= co
rrec
ted
dist
ance
vis
ual a
cuity
; K =
ker
atom
etry
; D =
dio
pter
s; N
C =
nons
igni
fican
t cha
nge;
NA
= no
t ava
ilabl
e; K
stee
p =
stee
p ke
rato
met
ry; S
E =
sphe
rical
equ
ivale
nt; E
CD =
end
othe
lial c
ell d
ensi
ty; K
apic
al =
api
cal k
erat
omet
ry; K
flat =
flat
ker
atom
etry
; K m
ean
= m
ean
kera
tom
etry
; CTa
pex
= co
rnea
l thi
ckne
ss a
t the
ape
x; C
CT =
cen
tral
co
rnea
l thi
ckne
ss; C
H =
corn
eal h
yste
resi
s; C
RF =
cor
neal
resi
stan
ce fa
ctor
; Kav
erag
e =
aver
age
kera
tom
etry
; Kap
ex =
ape
x ke
rato
met
ry; K
Vf =
= k
erat
ocon
us v
erte
x fro
nt; H
OA =
hig
her o
rder
abe
rrat
ions
; TCT
=
thin
nest
cor
neal
thic
knes
s; W
FE =
wav
efro
nt e
rror
; Km
ax =
max
imum
ker
atom
etry
; ISV
= in
dex
of s
urfa
ce v
aria
nce;
IVA
= in
dex
of v
ertic
al a
sym
met
ry; I
HD =
inde
x of
hei
ght d
ecen
trat
ion;
RM
S =
root
mea
n sq
uare
; K1
= fla
ttest
ker
atom
etric
read
ing;
K2
= st
eepe
st k
erat
omet
ric re
adin
g; K
I = k
erat
ocon
us in
dex;
CKI
= c
ente
r ker
atoc
onus
inde
x; IH
A =
inde
x of
hei
ght a
sym
met
ry; R
min
= m
inim
um ra
dius
of c
urva
ture
; IS
= in
ferio
r–su
perio
r val
ue
a Pul
sed
= 1
seco
nd o
n/X
seco
nd o
ff.
b Pre
oper
ative
to p
osto
pera
tive.
(con
t’d)