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ARTICLE

Efficacy of different accelerated corneal crosslinking protocols for progressive keratoconus € € Ebru Toker, MD, Eren C¸ erman, MD, FEBOphth, Deniz Ozarslan Ozcan, MD, € Ozge Beg€ um Seferog lu, MD

Purpose: To evaluate the efficacy of different accelerated corneal crosslinking (CXL) treatment protocols in patients with progressive keratoconus. Setting: Marmara University School of Medicine, Istanbul, Turkey. Design: Retrospective case series. Methods: Patients with progressive keratoconus had 9 mW accelerated CXL (10 minutes; 9 mW/cm2), 30 mW continuouslight accelerated CXL (4 minutes; 30 mW/cm2), or 30 mW pulsed-light accelerated CXL (8 minutes [1 second on/1 second off]; 30 mW/cm2). Results: Of 134 eyes, 34 eyes had conventional CXL, 45 had 9 mW accelerated CXL, 28 had 30 mW continuous-light accelerated CXL (4 minutes, 30 mW/cm2), and 27 eyes had 30 mW pulsed-light accelerated CXL. The uncorrected (UDVA) (P < .001 both) and corrected (CDVA) distance visual acuities increased in with

K

eratoconus is a progressive noninflammatory ectatic disease of the cornea characterized by irregular astigmatism and related vision loss. The past decade has seen a radical transformation of management options for keratoconus. One is the development and widespread acceptance of corneal crosslinking (CXL). Crosslinking is a process in which a combination of riboflavin, ultraviolet (UV) light, and a photochemical reaction induces free radicals, leading to development of chemical bonds between the collagen fibrils and thereby increasing the mechanical strength and biochemical stability of the corneal stromal tissue.1,2 The conventional CXL procedure consists of 30 minutes of irradiation with ultraviolet-A (UVA) light after instillation of riboflavin 0.1% in the deepithelialized cornea.3 Clinical success of the treatment has been shown in numerous clinical

conventional CXL and 9 mW accelerated CXL (P Z .001 and P Z .002, respectively). With 30 mW continuous accelerated CXL, only CDVA improved (P Z .019). With 30 mW pulsed accelerated CXL, UDVA and CDVA did not change significantly (P > .05). With conventional CXL and 9 mW accelerated CXL, all keratometric (K) readings (K1, K2, mean K, maximum K) improved significantly (conventional CXL: P Z .014, P Z .002, P Z .008, and P < .001, respectively; 9 mW accelerated CXL: all P < .001). With 30 mW, no K values changed significantly compared with baseline (all groups P > .05).

Conclusion: Although 30 mW accelerated CXL treatment modalities appeared to be effective in stabilizing keratoconus progression, they seemed less effective in achieving topographic improvement. J Cataract Refract Surg 2017; 43:1089–1099 Q 2017 ASCRS and ESCRS

Supplemental material available at www.jcrsjournal.org.

studies, and CXL has become one of the main preferred treatment modalities to halt keratoconus progression.4–6 One of its most important drawbacks is the long duration of the treatment. A major modification in recent years is accelerated CXL. This approach is based on the Bunsen-Roscoe law of reciprocity.7–9 Keeping the energy dose constant would theoretically achieve the same biological effect with higher irradiances and shorter exposure. However, this assumption is valid within a certain limit only; that is, illumination intensities up to 50 mW/cm2 and illumination times longer than 2 minutes.7 Studies9–11 have found that although fluences of 9 mW/cm2 and 10 mW/cm2 have a similar biomechanical effect compared with the 3 mW/cm2 standard irradiance, 18 mW has no stiffening effect. The failure of biomechanical stiffening might be related to the

Submitted: February 9, 2017 | Final revision submitted: May 30, 2017 | Accepted: May 31, 2017 From the Department of Ophthalmology, Marmara University School of Medicine, Istanbul, Turkey. Drs. Toker and C¸erman contributed equally to this work. itim Aras¸tırma Hastanesi, Go €z Hastalıkları Anabilim Dalı, Pendik, Istanbul, Turkey. E-mail: dretoker@ Corresponding author: Ebru Toker, MD, Marmara Universitesi Eg gmail.com. Q 2017 ASCRS and ESCRS Published by Elsevier Inc.

0886-3350/$ - see frontmatter http://dx.doi.org/10.1016/j.jcrs.2017.05.036

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reduced oxygen availability during accelerated procedures. Oxygen and its role in the generation of reactive oxygen radicals during type II reactions play a central role in initiating and driving the CXL process. The biomechanical effect of CXL is dependent on oxygen availability.12 A model of the photochemical kinetics of CXL showed that illumination with UVA irradiation (3 mW/cm2) causes a rapid (10- to 15-second) depletion of oxygen and that oxygen concentration gradually begins to increase after 10 minutes. Oxygen is more rapidly depleted at high irradiation intensities (30 mW/cm2) within 5 seconds, and turning off the UV light leads to faster replenishment of oxygen to its original level within 3 to 4 minutes.13 Based on this finding, the method of pulsing the UVA light was recently introduced. The off phase of the light allows for more oxygen diffusion, which in turn might enhance oxygen availability and generate more crosslinking effects. Over the past 2 years, studies of the clinical efficacy of different accelerated CXL protocols started to appear in the literature. In general, they generally report favorable outcomes, with stabilization or slight to moderate improvements in topographic indices and visual acuity.14–25 In this study, we analyzed the 12-month results of 3 protocols of accelerated CXLd9 mW/cm2, 30 mW/cm2 continuous-light, and 30 mW/cm2 pulsed-lightdand compared the results with those achieved with conventional (3 mW/cm2) CXL. We also defined a best-fit curve, which fits to data in the literature (including our cases) to show the relationship between CXL efficacy, duration, and irradiation intensity. PATIENTS AND METHODS Eyes of patients with a diagnosis of progressive keratoconus who had conventional CXL (3 mW/cm2 for 30 minutes), accelerated CXL (9 mW/cm2 for 10 minutes), continuous-light accelerated CXL (30 mW/cm2 for 4 minutes), or pulsed-light accelerated CXL (30 mW/cm2 [1 second on, 1 second off] for 8 minutes) at Marmara University Training and Research Hospital, Istanbul, Turkey, between November 2012 and August 2015, were enrolled in this comparative study. The study was performed in accordance with the tenets of the Declaration of Helsinki. Ethics approval was obtained from the local ethics committee. All patients or their parents provided informed consent before enrollment. Because irradiance is the power:area ratio and light intensity is the transmitted energy/area, the term irradiance is used in all instances to describe the unit mW/cm2. For descriptive purposes, groups were defined as conventional CXL, 9 mW accelerated CXL, 30 mW continuous accelerated CXL, and 30 mW pulsed accelerated CXL. In a slight deviation from the standard Dresden protocol, patients with a thinnest preoperative corneal thickness of more than 350 mm were included in the study only if pre-UVA pachymetry of 400 mm could be achieved with hypotonic riboflavin solution. The exclusion criteria included second-eye surgery, apical corneal scarring, a history of corneal surgery, delayed epithelial healing or severe dry eye, continuous ocular infections, connective tissue diseases, pregnancy, or lactation during the study period. The diagnosis of progressive keratoconus was made based on topographic parameters and was defined as 1 or more of the following changes at 2 consecutive control visits: (1) a more than 1.00 diopter (D) increase in the maximum curvature of the cornea (maximum keratometry [K]) within 12 months, (2) a 2% Volume 43 Issue 8 August 2017

decrease in central corneal thickness, or (3) a 0.50 D increase in the spherical equivalent (SE), which is similar to the criteria used in earlier studies.26 All patients had a full ophthalmic examination before treatment. Measurements of uncorrected (UDVA) and corrected (CDVA) distance visual acuities, SE, and cylinder as well as corneal topography, pachymetry, aberrometry (Pentacam, Oculus Optikger€ate GmbH), anterior segment optical coherence tomography (RTVue, Optovue Inc.), and specular microscopy (SP-02, Costruzione Strumenti Oftalmici) were performed at baseline and at the 12-month follow-up. Postoperative stabilization of keratoconus was defined as a change in maximum K of no more than G1.00 D.27 Surgical Technique The CXL was performed under sterile conditions. Proxymetacaine hydrochloride 0.5% eyedrops were applied for topical anesthesia. The central 9.00 mm epithelium was removed via mechanical debridement with a hockey knife. Riboflavin 0.1% in a hydroxypropyl methylcellulose solution was administered topically every 2 to 3 minutes for a total of 20 minutes. Riboflavin administration was continued during UV illumination with the same intervals. Ultrasound pachymetry was performed before UVA irradiation; if the corneal thickness was less than 400 mm, hypotonic riboflavin solution was administered every 15 seconds with the eyelid speculum off the eye until a corneal thickness of 400 mm was obtained. The cornea was exposed to UVA 365 nm light as described above using the CCL-Vario system (Peschke Meditrade GmbH) or the KXL system (Avedro, Inc.). A therapeutic soft contact lens (Purevision, Bausch & Lomb, Inc.) was placed on the treated cornea. Topical loteprednol etabonate ophthalmic suspension 0.5% (Lotemax) and moxifloxacin hydrochloride ophthalmic solution (Vigamox) were administered postoperatively. Statistical Analysis The chi-square test, 1-way analysis of variance (ANOVA), KruskalWallis test, and their post hoc tests were performed with Instat statistical software (Graphpad Software, Inc.). Other analyses were performed with SPSS software (version 16.0, SPSS, Inc.). For comparison of preoperative variables and postoperative variables (within-group comparisons), the paired t test was used for normal distributions and the Wilcoxon signed-rank test for non-normal distributions. Between-group comparisons of normally distributed data were performed using 1-way ANOVA with the post hoc Tukey test and non-normal data were analyzed with the Kruskal-Wallis test with the post hoc Dunn test. All keratometric and pachymetric variables were distributed normally; the other data were not normally distributed. A P value less than 0.05 was considered statistically significant. The minimum detectable difference value was calculated by comparing K values without significant differences. For the minimum detectable difference calculation, Stata software (version 14, 2014, Statacorp LLC) was used by group sample size and the mean G SD. The minimum detectable difference was given in diopters. A literature review was performed via a PubMed search of the medical literature on accelerated CXL using the following keywords in various combinations: cornea, collagen, crosslinking, accelerated, high-intensity, irradiance, mW/cm2, pulsed, and continuous. Reference lists from the selected articles were used to obtain further articles. Articles were appraised critically, and pertinent information was included in the review and cited accordingly. For analysis of the data in the literature, visual acuity given in Snellen notation was converted to logarithm of the minimum angle of resolution (logMAR) values. When analyzing the correlations of the variables between various studies, the mean of variables and the sample size of that study were multiplied. The best-fit 3-dimensional (3-D) surface was analyzed with Tablecurve 3-D software (Systat Software, Inc.). A macro that was

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ACCELERATED CXL IN PROGRESSIVE KERATOCONUS

written with Excel software (Office 2013, Microsoft Corp.) to calculate from the input’s irradiation intensity and procedure duration the output demarcation line depth according to the best-fit line for the data in the literature and in the present study (Supplement 1, available at www.jcrsjournal.org).

(P O .05). Spherical and trefoil aberrations and the index of height decentration (IHD) in the 9 mW accelerated CXL group were statistically significantly higher than in the conventional CXL group (P Z .026, P !. 001, and P !. 001, respectively).

RESULTS Preoperative Parameters

Postoperative Visual Acuity and Refraction

This study evaluated 134 eyes of 134 patients with a mean age of 24.1 G 5.86 years (range 13 to 34 years). Of 134 eyes, 34 eyes had conventional CXL, 45 had 9 mW accelerated CXL, 28 had 30 mW continuous-light accelerated CXL (4 minutes, 30 mW/cm2), and 27 eyes had 30 mW pulsedlight accelerated CXL. There was no statistically significant difference in age, preoperative K, astigmatism, or pachymetry between the groups (P O .05). The 9 mW accelerated CXL group had statistically significantly worse preoperative UDVA and CDVA than the other groups and significantly higher SE values than the 30 mW continuous accelerated CXL group (Table 1). Preoperatively, there were no statistically significant between-group differences in the index of surface variance (ISV), index of vertical asymmetry (IVA), keratoconus index (KI), center keratoconus index (CKI), index of height asymmetry (IHA), minimum radius of curvature (Rmin), root mean square (RMS), or coma aberration values

Table 2 shows the mean change in UDVA and CDVA at 12 months. Within-group analysis showed that the conventional CXL group and 9 mW accelerated CXL group had a statistically significant improvement in UDVA (both P ! .001) and CDVA (P Z .001 and P Z .002, respectively). The 30 mW continuous accelerated CXL group had a statistically significant improvement in CDVA (P Z .019) but no significant change in UDVA (P O .05). The 30 mW pulsed accelerated CXL group did not have a statistically significant change in UDVA or CDVA (both P O .05) (Figures 1 and 2). The betweengroups analysis found no statistically significant difference between groups in the change in UDVA or CDVA between baseline and 12 months postoperatively (both P O .05, Kruskal-Wallis test). In the within-groups analysis of refractive errors, only the conventional CXL group and 9 mW accelerated CXL group had a statistically significant improvement in SE (P Z .006

Table 1. Baseline demographic, clinical, and topographic parameters in conventional and accelerated CXL groups. Parameter Age (y) Mean G SD Range K1 (D) Mean G SD Range K2 (D) Mean G SD Range Kmean (D) Mean G SD Range Kmax (D) Mean G SD Range UDVA (logMAR) Mean G SD Range CDVA (logMAR) Mean G SD Range SE (D) Mean G SD Range Astigmatism (D) Mean G SD Range Pachymetry (mm) Mean G SD Range

Conventional CXL (n Z 34)

9 mW ACXL (n Z 45)

30 mW cACXL (n Z 28)

30 mW pACXL (n Z 27)

21.1 G 5.4 13, 30

22.4 G 5.0 14, 33

24.1 G 4.9 15, 34

22.4 G 5.0 13, 34

47.3 G 3.4 41.6, 54.4

48.0 G 3.5 41.4, 57.9

46.4 G 3.5 41.6, 57.9

46.8 G 2.8 41.4, 52.1

50.8 G 3.0 45.7, 57.6

52.4 G 4.0 45.1, 63.2

50.4 G 4.2 43.2, 63.0

50.8 G 4.1 43.0, 62.1

49.0 G 3.1 43.7, 55.9

50.1 G 3.6 43.5, 60.4

48.4 G 3.7 42.4, 60.4

48.8 G 3.3 42.2, 56.7

58.0 G 5.4 49.3, 68.9

59.4 G 4.7 51.2, 75.5

56.1 G 6.1 47.7, 75.0

56.8 G 6.1 46.5, 77.1

0.55 G .034 0.02, 1.30

0.81 G 0.36* 0.22, 1.50

0.51 G 0.38 0.00, 1.30

0.48 G 0.28 0.10, 1.30

0.31 G 0.22 0.00, 1.00

0.47 G 0.26† 0.00, 1.00

0.32 G 0.26 0.00, 1.30

0.27 G 0.22 0.00, 0.80


6.33 G 4.33
18.7, 5.50


7.43 G 4.20z
18.35, 1.25


5.13 G 4.14
21.0,
1.00


5.10 G 2.88
11.50,
0.50


4.43 G 2.75
10.75,
0.25


4.37 G 2.23
11.50,
1.00


4.75 G 2.72
11.50,
1.25


4.60 G 3.27
12.50,
0.50

462.1 G 20.1 423, 514

448.7 G 37.1 354, 523

467.6 G 20.0 432, 498

462.7 G 20.2 429, 496

ACXL Z accelerated corneal crosslinking; cACXL Z continuous accelerated corneal crosslinking; CDVA Z corrected distance visual acuity; CXL Z corneal crosslinking; K1 Z flat keratometry; K2 Z steep keratometry; Kmax Z maximum keratometry; Kmean Z mean keratometry; logMAR Z logarithm of the minimum angle of resolution; pACXL Z pulsed-light accelerated corneal crosslinking; SE Z spherical equivalent; UDVA Z uncorrected distance visual acuity *Significantly different than other groups (Kruskal-Wallis test) † Significantly different from conventional and 30 mW pACXL groups (Kruskal-Wallis test with Dunn post hoc test) z Significantly different from 30 mW cACXL group (Kruskal-Wallis test with Dunn post hoc test)

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Table 2. Postoperative change in K readings, visual acuity, and refractive error. Mean ± SD Parameter

Conventional CXL

9 mW ACXL

30 mW cACXL

30 mW pACXL


0.10 G 0.16*
0.11 G 0.15* 0.96 G 1.50* 0.28 G 1.14
0.56 G 1.55*
0.74 G 1.28*
0.65 G 1.32*
2.15 G 2.60*
18.1 G 22.6*


0.21 G 0.30*
0.12 G 0.23* 0.49 G 1.29* 0.09 G 0.70
0.94 G 1.20*
0.94 G 1.39*
0.83 G 1.22*
1.64 G 1.97*
9.2 G 19.6*


0.05 G 0.17
0.10 G 0.20* 0.09 G 1.38 0.35 G 0.89 0.16 G 0.54x 0.14 G 0.70x 0.15 G 0.52x 0.01 G 0.82x
7.6 G 11.7*

0.02 G 0.25
0.06 G 0.17 0.09 G 1.21 0.61 G 1.33
0.04 G 0.89z
0.11 G 0.63z
0.08 G 0.59
0.01 G 0.98x 0.6 G 12.4†

DUDVA (logMAR) DCDVA (logMAR) DSE (D) DAstigmatism (D) DK1 (D) DK2 (D) DKmean (D) DKmax (D) DPachymetry (mm)

D Z postoperative change from baseline values at 12 months; ACXL Z accelerated corneal crosslinking; cACXL Z continuous accelerated corneal crosslinking; cACXL Z continuous accelerated corneal crosslinking; CDVA Z corrected distance visual acuity; CXL Z corneal crosslinking; CXL Z corneal crosslinking; K1 Z flat keratometry; K2 Z steep keratometry; Kmax Z maximum keratometry; Kmean Z mean keratometry; logMAR Z logarithm of the minimum angle of resolution; pACXL Z pulsed-light accelerated corneal crosslinking; SE Z spherical equivalent; UDVA Z uncorrected distance visual acuity *Significantly different compared with baseline measurement (Wilcoxon paired t test) † Significantly different from conventional CXL group (Kruskal-Wallis test with Dunn post hoc test) z Significantly different from 9 mW cACXL group (Kruskal-Wallis test with Dunn post hoc test) x Significantly different from conventional CXL and 9 mW cACXL groups (Kruskal-Wallis test with Dunn post hoc test)

and P Z .007, respectively). The between-group comparison found no difference in the postoperative change in astigmatism or SE between baseline and 12 months postoperatively (both P O .05, Kruskal-Wallis test). Table 2 also shows the mean change in K1, K2, mean K, and maximum K at 12 months. Within-groups analysis showed statistically significant improvement in all K readings in the conventional CXL group (K1, P Z .014; K2, P Z .002; mean K, P Z .008; maximum K, P ! .001) and 9 mW accelerated CXL group (all P ! .001). In the 30 mW groups,

none of the indices (K1, K2, mean K, maximum K) significantly improved (all P O .05) (Figure 3). The study was not powered enough to differentiate between the postoperative change in K readings in the conventional and 9 mW groups (P O .05; 95% confidence interval [CI] of difference,
1.51 to 0.50; minimum detectable difference, 1.46 D for maximum K and 0.68 D for mean K). The 30 mW continuous accelerated CXL group had statistically significantly less reduction in K1, K2, mean K, and maximum K values; all values were statistically significantly different from those in the conventional CXL group and 9 mW accelerated CXL group (both P ! .01). The 30 mW

Figure 1. Distribution of the preoperative and postoperative UDVA by group (* Z significantly different from baseline [Wilcoxon paired t test]; ACXL Z accelerated corneal crosslinking; cACXL Z continuous accelerated corneal crosslinking; CXL Z corneal crosslinking; logMAR Z logarithm of the minimum angle of resolution; pACXL Z pulsed-light accelerated corneal crosslinking).

Figure 2. Distribution of the preoperative and postoperative CDVA by group (* Z significantly different from baseline [Wilcoxon paired t test]; ACXL Z accelerated corneal crosslinking; cACXL Z continuous accelerated corneal crosslinking; CXL Z corneal crosslinking; logMAR Z logarithm of the minimum angle of resolution; pACXL Z pulsed-light accelerated corneal crosslinking).

Postoperative Keratometry

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Table 3. Percentage of regression (>1.0 D decrease in 1 year), stabilization (no change more than 1.0 D), and progression (>1.0 D increase in 12 months) in Kmax by group. Number (%) Group Conventional CXL 9 mW ACXL 30 mW cACXL 30 mW pACXL

Regression

Stabilization

Progression

20 (59) 22 (56) 3 (11)* 3 (11)*

12 (35) 20 (38) 22 (79) 21 (78)

2 (6) 3 (7) 3 (11) 3 (11)

ACXL Z accelerated corneal crosslinking; cACXL Z continuous accelerated corneal crosslinking; CXL Z corneal crosslinking; Kmax Z maximum keratometry; pACXL Z pulsed-light accelerated corneal crosslinking *Significantly different than expected compared with conventional CXL group (chi-square test)

Figure 3. Postoperative change in flat K (K1), steep K (K2), mean K (Kmean), and maximum K (Kmax) values (* Z significantly different from baseline [Wilcoxon paired t test]; ACXL Z accelerated corneal crosslinking; cACXL Z continuous accelerated corneal crosslinking; CXL Z corneal crosslinking; pACXL Z pulsed-light accelerated corneal crosslinking).

pulsed accelerated CXL group had statistically significantly less improvement in K1 and K2 than the 9 mW accelerated CXL group (P Z .044 and P ! .03, respectively) and in maximum K than the conventional CXL group and 9 mW accelerated CXL group (both P ! .001). Table 3 shows the percentage of regression, stabilization, and progression in maximum K at the end of 12 months. The chi-square test showed that the distribution of regression, stabilization, and progression was statistically significantly associated with the CXL protocol (P ! .001). When arranged as a 4 box chi-square test, results showed that patients in the conventional CXL or 9 mW accelerated CXL group had a statistically significantly increased chance

of a regression in maximum K (P ! .001). However, patients in both 30 mW accelerated CXL groups did not have a significantly increased risk for progression. Postoperative Pachymetry

Table 2 shows the changes in pachymetry between baseline and 12 months after CXL. Within-groups analysis showed no change in the 30 mW pulsed accelerated CXL group and a significant reduction in all other groups (P ! .001). Between-group analysis found that the 30 mW pulsed accelerated CXL group had statistically significantly less thinning in pachymetry than the conventional CXL group (P ! .001). Postoperative Topographic Indices

Table 4 shows the postoperative change in the topographic indices. There was no significant change in the IHA in any group (P O .05). The change in all other variables was statistically significant in the conventional CXL group in the paired analysis (CKI, P Z .027; trefoil aberration, P Z .006; spherical aberration, P Z .024; all other variables, P ! .001).

Table 4. Mean change in topographic data in the CXL groups. Mean ± SD Parameter DISV DIVA DKI DCKI DIHA DIHD DRmin DRMS DAberration (mm) Spherical Coma Trefoil

Conventional CXL

9 mW ACXL

30 mW cACXL

30 mW pACXL


9.53 G 9.14*
0.11 G 0.13*
0.03 G 0.03*
0.01 G 0.03*
9.90 G 26.52 0.02 G 0.02* 0.15 G 0.27*
1.62 G 2.33*


3.67 G 17.54*
0.03 G 0.16 0.00 G 0.06*
0.02 G 0.03*
7.09 G 30.14
0.01 G 0.03*,† 0.16 G 0.20*
0.91 G 10.90*


2.25 G 4.87*,†
0.06 G 0.09*
0.01 G 0.03z 0.00 G 0.01z 6.51 G 24.04 0.02 G 0.03*,z
0.02 G 0.13x
0.52 G 0.99*

2.07 G 0.16x
0.01 G 0.15† 0.04 G 0.02z 0.00 G 0.20z
1.67 G 26.82 0.00 G 0.02†
0.05 G 0.13x 0.14 G .1.55†


0.20 G 0.47*
0.29 G 0.41* 0.18 G 0.34*


0.31 G 0.39*
0.09 G 0.47 0.10 G 0.39*

0.04 G 0.17z
0.13 G 0.26* 0.15 G 0.25*

0.02 G 0.15z 0.01 G 0.28 .04 G .20

D Z postoperative change from baseline values at 12 months; ACXL Z accelerated corneal crosslinking; cACXL Z continuous-light corneal crosslinking; CKI Z center keratoconus index; CXL Z corneal crosslinking; IHA Z index of height asymmetry; IHD Z index of height decentration; ISV Z index of surface variance; IVA Z index of vertical asymmetry; KI Z keratoconus index; pACXL Z pulsed-light corneal crosslinking; Rmin Z minimum sagittal curvature; RMS Z root mean square *Significantly different compared with baseline measurement (Wilcoxon paired t test) † Significantly different from conventional CXL group (Kruskal-Wallis test with Dunn post hoc test) z Significantly different from 9 mW cACXL group (Kruskal-Wallis test with Dunn post hoc test) x Significantly different from conventional CXL and 9 mW cACXL groups (Kruskal-Wallis test with Dunn post hoc test)

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acuity. There was a significant moderate correlation between the demarcation line depth and flattening in the K1, K2, mean K, and maximum K (increase in negative values) and improvement in UDVA and CDVA (increase in negative logMAR values). The postoperative improvement in the UDVA and CDVA negatively correlated with the preoperative visual acuity. The stepwise multiple linear regression analysis showed that the most important factor predicting the change in maximum K was the type of CXL (P ! .001; b Z 0.573; 95% CI,
4.78 to
2.48; r2 Z 22.4) and the preoperative maximum K (P Z .006; b Z
0.273; 95% CI,
1.72 to
0.30, r2 Z 29.5).

Table 5. Mean depth of the demarcation line by group. Demarcation Line Depth (mm) Group Conventional CXL 9 mW ACXL 30 mW cACXL 30 mW pACXL

Mean ± SD

Min, Max

266 G 40 273 G 31 173 G 20 166 G 22

210, 310 200, 343 135, 210 130, 207

cACXL Z continuous accelerated corneal crosslinking; CXL Z corneal crosslinking; pACXL Z pulsed-light accelerated corneal crosslinking

The 9 mW accelerated CXL group had a significantly significant change in all variables except for IHA and coma aberrations (ISV, P Z .002; KI, P Z .033; IHD, P Z .006; RMS, P Z .004; trefoil aberration, P Z .019; all other variables, P ! .001). In the 30 mW continuous accelerated CXL group, the changes in the ISV, IVA, IHD, RMS, coma, and trefoil aberration values were statistically significant (ISV, P Z .029; RMS, P Z .017; coma aberration, P Z .009; trefoil aberration, P Z .003; all other variables, P ! .001). In the 30 mW pulsed accelerated CXL group, no variable changed significantly from baseline to 12 months postoperatively.

Best-Fit Curve of Demarcation Line Depth in Relation Irradiation Duration and Intensity

The demarcation line was significantly deeper in the conventional CXL group and 9 mW accelerated CXL groups. There was a moderate correlation between the depth of the demarcation line and the flattening observed in keratometry and improvements in visual acuity; the demarcation line depth indicated that accelerated CXL might provide less effective treatment if the irradiance is higher than 9 mW/cm2. Figure 4 shows a 3-D surface-fit model created using the data in the literature showing the relationship between irradiance, the duration of the CXL procedure, and the demarcation line depth. There was a relatively linear relationship between duration and demarcation line depth on the y–z planes (Figure 4, A [arrow]). On the other hand, the model showed a saturation graph in the x–z planes (Figure 4, B [arrow]). The following equation was used in the model:
Demarcation line depth Z ð
831Þ þ
6138e
Irradiance

Postoperative Demarcation Line Depth and Endothelial Cell Count

The demarcation line was significantly shallower in the 30 mW groups than in the conventional CXL group (both P ! .001) (Table 5). The demarcation line depth in the 9 mW accelerated CXL group was not statistically significantly different than that in the conventional CXL group (P O .05). The postoperative endothelial cell count did not change significantly from baseline (P O .05). In all groups, no patient lost more than 2 Snellen lines of CDVA. One 1 patient (9 mw accelerated CXL group) lost 1 Snellen line. Three patients had peripheral sterile infiltrates; all resolved without an effect on the CDVA.

þ 960eCXL

duration 79

where e is the Euler’s number. This equation had an r2 value of 70.4 and a standard deviation of G30.3 mm. The equation is a simplified version of the real formula used in the Excel macro, which is given in Supplement 1 (available at www.jcrsjournal.org). The numbers in the equation were rounded to whole numbers, but the result is fairly close to that of the macro in Supplement 1.

Correlations

Table 6 shows the results of the correlation analysis of the demarcation line depth, preoperative K values, and preoperative visual acuity with the change in K values and visual

Table 6. Pearson correlation coefficient (r) and P values for statistically significant correlations between various variables. DK1

DK2

DKmean

DKmax

DUDVA

DCDVA

Parameter

r Value

P Value

r Value

P Value

r Value

P Value

r Value

P Value

r Value

P Value

r Value

P Value

Demarcation line depth Preop K1 Preop K2 Preop Kmean Preop Kmax Preop UDVA Preop CDVA


0.464*

!.001


0.482*

!.001


0.462*

!.001


0.472*

!.001


0.360*

!.001


0.464*

!.001

d d d d d d

d d d d d d

d d d d d d

d d d d d d

d d d d d d

d d d d d d

d d d
0.274 d d

d d d .001 d d

d d d
0.198
0.439*
0.329*

d d d .022 !.001 !.001

d
0.227
.0198
0.223
0.257
0.474*

d .008 .022 .010 .003 !.001

D Z postoperative change from baseline values at 12 months; CDVA Z corrected distance visual acuity; K1 Z keratometry in the flat meridian; K2 Z keratometry in the steep meridian; Kmax Z maximum keratometry; Kmean Z mean keratometry; UDVA Z uncorrected distance visual acuity *Moderate significant correlation with Pearson correlation test

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ACCELERATED CXL IN PROGRESSIVE KERATOCONUS

Figure 4. Three-dimensional representation of the possible relationship between irradiance, procedure duration, and demarcation line depth in CXL obtained through the review of the data from the literature and the cohort in present study (r2 Z 70.4; SD Z G30.3).

DISCUSSION In this study, the postoperative flattening of the cornea was greater with conventional CXL and 9 mW accelerated CXL than with the 30 mW accelerated CXL treatments. The conventional CXL and 9 mW accelerated CXL groups had greater improvement in UDVA and CDVA than both 30 mW accelerated CXL groups. The SE was significantly improved in the conventional CXL and 9 mW accelerated CXL groups but not in the 30 mW groups. Although the postoperative keratoconus progression rate in the 30 mW accelerated CXL groups was comparable to that of the 9 mW and conventional CXL groups (11% versus 6% and 7%), a significantly lower percentage of patients in the 30 mW groups had topographic improvement (regression in K values O1.0 D) at the 12-month follow-up (11% versus 56% and 59%, respectively). A significantly shallower demarcation line was observed in the 30 mW accelerated CXL groups. These findings suggest a reduced treatment effect with 30 mW accelerated CXL than with conventional CXL and 9 mW accelerated CXL. It is possible there was improper acceptance of the null hypothesis when comparing the conventional group and 9 mW group. Although there was an insignificant difference in the change in maximum K and mean K, the minimum detectable difference in K readings for our sample size was greater than the detected mean difference. Schumacher et al.9 and Beshtawi et al.10 did not find any differences in the biomechanical effects of 3 mW/cm2 and 9 or 10 mW/cm2 procedures. Hammer et al.11 showed a stiffening effect of the 9 mW/cm2 procedure compared with non-crosslinked controls; however, this effect was significantly lower than with the conventional 3 mW/cm2 treatment. Moreover, the 18 mW/cm2 treatment appeared to be ineffective in increasing the rigidity of the cornea. Wernli et al.,7 in their ex vivo study on porcine corneas, found that the Bunsen-Roscoe reciprocity law was valid for irradiance values up to approximately 40 to 45 mW/cm2

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and that there was no significant increase in rigidity at higher intensities. The authors pointed out that the Bunsen-Roscoe reciprocity law might not be applicable if the illumination time is shorter than a certain limit or if the irradiance is increased beyond a certain level. Our observation is compatible with this viewpoint; however, for human corneas, a lower threshold for irradiance could be the point at which the Bunsen-Roscoe reciprocity law becomes invalid. This might explain the relatively lower effect found with the accelerated CXL treatment of 30 mW/cm2 for 3 minutes in our study. Indeed, our metaanalysis of the literature on accelerated CXL, which included 520 cases, showed a moderate relationship between CXL duration and topographic flattening (mean K) (P ! .001, r Z .336) when all studies with a follow-up time of 12 months or more were taken into consideration. This suggests that there might be a reduced treatment effect with decreased operation times and at higher levels of irradiance (Table 714–16,18–25,28–39). To our knowledge, only 1 recent study has compared the different irradiance levels of accelerated CXL.20 Shetty et al.20 compared 3 accelerated CXL procedures (9 mW/cm2 for 10 minutes, 18 mW/cm2 for 5 minutes, and 30 mW/cm2 for 3 minutes) and pointed to a potentially reduced effect of accelerated CXL with increases in irradiance. Specifically, when the treatment effect between groups was compared at the end of 12 months, the 9 mW and 18 mW groups had a lower flattening effect than the conventional CXL group and no improvement was observed in the 30 mW group. A previous study28 found that the stromal demarcation line was correlated with the effectiveness of the CXL procedure. According to our best-fit curve analysis for the data in the literature, including the data in this study, the minimum threshold of duration was 9.5 minutes when the target CXL effect was a demarcation line deeper than 250 mm. This is not the only fit formula. A better formula could be created if there were more information on the demarcation line depth in various time–irradiance combinations. Some findings suggest that the reduced treatment effect of accelerated CXL is be associated with increased oxygen consumption at higher irradiances and with the physiologic limits of oxygen diffusion capacity in the stroma.11 As Kamaev et al.13 have shown, the depletion of oxygen is more rapid at higher irradiances; however, there are conflicting theories on the role of oxygen. The authors point out how excess oxygen might be detrimental to the CXL process. Clinically, only Mazzotta et al.17 compared the 1-year results of pulsed-light versus continuous-light accelerated CXL (30 mW/cm2 for 4 minutes; 30 mW/cm2 for 8 minutes on, 1 minute off). In their study, the 2 groups comprised 10 eyes of 10 patients each; neither CDVA nor UDVA improved significantly in either group.17 On the other hand, the average K and apical K values improved significantly in the pulsed-light accelerated CXL group only. Mazzotta et al.36 found a deeper demarcation line (w200 mm) in the pulsed-light accelerated CXL group than in the continuous-light accelerated CXL group (160 mm). Kymionis et al.28 proposed that accelerated CXL should be modified Volume 43 Issue 8 August 2017

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Table 7. Existing literature on accelerated CXL containing information about the change in keratometry readings, the change in visual acuity, or demarcation line depth. Accelerated CXL Study*/Year

2

Eyes (n)

Compared Group

Kanellopoulos14/2012 Waszczykowska18/2015

Regimen, mW/cm (Time) 7 6

(15 min) (15 min)

21 16

Conventional CXL NA

FU (Mo)

Elbaz15/2014

9

(10 min)

16 16

NA NA

Ng19/2015

9

(10 min)

14

Conventional CXL

Shetty20/2015 Kyminois28/2014 Kymionis29/2014 C¸ınar30/2014

9 9 9 9

(10 min) (10 min) (14 min) (10 min)

36 12 26 23

18 and 30 mW/cm2 ACXL Conventional CXL Conventional CXL N/A

12 3 1 6

C¸ınar31/2014

9

(10 min)

13

Conventional CXL

6

Kymionis32/2014

9

(10 min)

9

NA

3

Shetty33/2014

9

(10 min)

30

NA

24

Shetty20/2015 Alnawaiseh21/2015

18 18

(5 min) (5 min)

33 28

9 and 30 mW/cm2 ACXL NA

Chow22/2015

18

(5 min)

19

Conventional CXL

12

Hashemi23/2015

18

(5 min)

31

Conventional CXL

6

€34/2014 Cingu

18

(5 min)

36

NA

6

Gatzioufas35/2013

18

(5 min)

7

NA

6

Ozgurhan36/2014

18

(5 min)

34

NA

Tomita16/2014

30 30

(3–8 min) (3 min)

30

Conventional CXL

12

Shetty20/2015 Sherif24/2014 Ozgurhan25/2015 Mazotta37/2014

30 30 30 30

(3 min) (20 s) (5 min) (3 min)

33 14

9 and 18 mW/cm2 ACXL Conventional CXL

12 12

10

6

30

(8 min)†

10

Mita38/2014

30

(3 min)

39

30 mW/cm2 8 min 3 min 30 mW/cm2 NA

6

Hashemian39/2014

30

(3 min)

77

Conventional CXL

15

O18 24 24 12 13.9

12 21.7

6

ACXL Z accelerated corneal crosslinking; CDVA Z corrected distance visual acuity; CXL Z corneal crosslinking; ECD Z endothelial cell density; FU Z follow-up; K Z keratometry; K1 Z flat keratometry; K2 Z steep keratometry; Kmax Z maximum keratometry; Kmean Z mean keratometry; logMAR Z logarithm of the minimum angle of resolution; NA Z not applicable; SE Z spherical equivalent; UDVA Z uncorrected distance visual acuity *First author † 1 second on/1 second off z Difference calculated as significant

based on the fact that they achieved a treatment effect comparable to that of the Dresden protocol by increasing the time setting by 40% at an irradiance of 9 mW/cm2. Mazzotta et al.17 and our group have used 33% increased treatment duration with a total energy dose of 7.2 J/cm2 instead of 5.2 J/cm2. In the present study, when comparing continuous-light and pulsed-light accelerated CXL, we found

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that pulsing the UV light did not improve the clinical outcomes. There was no significant difference between groups in the postoperative change in topographic indices, visual acuity, or demarcation line depth. The data in the present study suggest that pulsing the UV light at a high irradiance (30 mW/cm2) might not provide a long enough duration for adequate oxygen diffusion into the stroma.

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Table 7. (Cont.)

Topogrpahic Change (D)

Mean CDVA Change (logMAR)


3.4 (Kmax)
0.65 (Kmax)
0.35 (Kmean)


0.79 0.0


0.06 (Kmax) C0.01 (Kmean)
0.3 (Kmax) 0.0 (Kmean) 0.35 (Kmean) NA NA
1.35z (Kmax)
0.42z (Kmean)
1.14z (Kmax)
0.65z (Kmean)
1.53 (Kmax)
0.33 (Kmean)
2.06z (Kmean)


0.01

0.17 (Kmean)
1.6z (Kmax) 0.0 (Kmean)
0.47 (Kmax) C0.35 (Kmax) C0.05 (Kmean)
0.40z (Kmax)
0.05 (Kmean)
2.7 (Kmax)
0.9 (Kmean)

Demarcation Line (mm) 282

Remarks No significant difference in parameters between groups d d No significant change in K1, K2, Kmean, Kmax, and CDVA; only improved UDVA.

0.02

209

Significantly lower reduction in Kmax and Kmean; shallower demarcation line in ACXL.

NA NA NA
0.15z

292 223 322 d

d Corneal stroma demarcation line significantly deeper in conventional procedure No significantly different demarcation line depth. Significantly improved UDVA, CDVA, K1, K2, Kmean, Kmax, and mean SE


0.19z

d

No significant difference in UDVA, CDVA, Kmean, and Kmax values between groups


0.09

d

No significant visual gain; significant decrease in mean steep K; no ECD change


0.12z

All patients !14 years old

N/A
0.05

d d 203 d


0.14

d


0.01

d

Similar postoperative UDVA and CDVA, reduction in SE, and more effective topographic flattening with conventional CXL Similar UDVA and CDVA, decrease in Kmax and Kmean


0.12z

d

After ACXL, transient changes in the corneal endothelium

C0.17

d 208–249 d d

d d No significant change in the Kmean but significant reduction in Kmax

d 20-min vs 30-min riboflavin application compared; demarcation line deeper with 30-min riboflavin application


0.62 (Kmax)
0.39 (Kmean)
0.03 (Kmean)
1.09 (Kmax)

C0.13

NA

NA

208 160

NA

NA

200


0.76z (Kmax)
0.35 (Kmean)
1.85 (Kmax)


0.02

d

Functional results better in pulsed-light treatment, indicating optimized intraop oxygen availability in pulsed CXL UDVA significant improvement


0.16

d

No significant difference in any parameter between similar postop K readings

0

201

Similar postoperative K readings d K reading decreased in a similar manner; CDVA and UDVA significantly improved All patients !18 years; ACXL halted keratoconus progression d

As we40 and others41–45 have previously suggested that better therapeutic effects might be achieved in eyes with a worse preoperative CDVA and initially steeper corneas. The relatively greater treatment effect observed with 9 mW/cm2 continuous accelerated CXL in this study might be partly explained by the significantly worse preoperative UDVA and CDVA in this group. Even so, there was no significant difference in the preoperative K readings. This study is limited by its retrospective design, different group sample sizes, and some preoperative parameters in

the groups (ie, UDVA, CDVA, and SE). Another limitation is that despite using the same beam profile (top hat), 2 different UVA devices were used during the study. In conclusion, although the 3 mW/cm2, 9 mW/cm2, and 30 mW/cm2 protocols appeared to be equally effective in stopping the progression of corneal ectasia, the 3 mW/cm2 and 9 mW/cm2 treatments seemed to be more effective in achieving topographic, refractive, and visual improvements. After evaluating our mathematic model, which was created by reviewing the data in this and previous studies, we support the opinion that the duration of the

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procedure might be the rate-limiting step in the therapeutic effect of CXL. 13.

WHAT WAS KNOWN  Accelerated CXL is believed to have a therapeutic effect similar to that of conventional CXL.

14.

WHAT THIS PAPER ADDS  The 3 mW/cm2 and 9 mW/cm2 treatments seemed more effective in achieving topographic, refractive, and visual improvements.  The 3 mW/cm2, 9 mW/cm2, and 30 mW/cm2 protocols seemed to be equally effective in stopping the progression of corneal ectasia.

15.

16. 17.

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Disclosure: None of the authors has a financial or proprietary interest in any material or method mentioned.

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