- Email: [email protected]
Epithelium-on corneal collagen crosslinking for management of advanced keratoconus
ARTICLE
Epithelium-on corneal collagen crosslinking for management of advanced keratoconus Shihao Chen, MD, OD, MSc, Tommy C.Y. Chan, FRCS, Jia Zhang, MD, MSc, Ping Ding, MD, Jason C.K. Chan, MB BS, Marco C.Y. Yu, PhD, Yini Li, MD, PhD, Vishal Jhanji, MD, FRCOphth, Qinmei Wang, MD
PURPOSE: To report the 1-year visual and keratometric results of epithelium-on corneal collagen crosslinking (CXL) for advanced keratoconus (median maximum keratometry [K] R58.0 diopters [D]). SETTING: School of Ophthalmology and Optometry and Eye Hospital of Wenzhou Medical College, Wenzhou, China. DESIGN: Prospective case series. METHODS: Patients with bilateral progressive keratoconus had tetracaine-enhanced epithelium-on CXL. The worse eye had CXL, and the fellow eye was not treated. Results were reported 1, 3, 6, and 12 months postoperatively. The outcomes were compared with those in the fellow untreated eyes. RESULTS: Twenty-one eyes of 21 patients with a median age of 20.4 years (interquartile range [IQR], 9.5 years) were treated. A significant improvement in postoperative uncorrected distance visual acuity was observed at 12 months (P Z .002). Postoperative corrected distance visual acuity improved at 6 months and 12 months (P % .009) compared with baseline values. The maximum K decreased by 1.63 D from the median preoperative maximum K of 62.7 D (IQR, 12.9 D) at 12 months (P < .001). The reduction in maximum K was higher after CXL than in untreated eyes at the end of 12 months (P Z .001). Correlation analysis between the preoperative maximum K values and the change over 6 to 12 months between different studies showed a significant correlation (r Z 0.764, P < .001; Spearman correlation). CONCLUSIONS: Epithelium-on CXL was an effective treatment for patients with advanced keratoconus. A higher preoperative maximum K value correlated with greater corneal flattening after CXL. Financial Disclosure: None of the authors has a financial or proprietary interest in any material or method mentioned. J Cataract Refract Surg 2016; 42:738–749 Q 2016 ASCRS and ESCRS
Keratoconus is associated with progressive corneal thinning and bulging.1 The development of irregular astigmatism and stromal scarring often has a significant negative impact on the quality of life of affected patients.2 Corneal collagen crosslinking (CXL) has been shown to stabilize progression of keratectasia and prevent visual loss.3 The conventional CXL technique necessitates the removal of corneal epithelium to facilitate penetration of riboflavin into the corneal stroma.4 The clinical and topographic outcomes of conventional CXL are established.5–7 However, epithelial removal can be associated with potential 738
Q 2016 ASCRS and ESCRS Published by Elsevier Inc.
complications, including severe pain,8 corneal haze,9 corneal infiltrates,10 and infectious keratitis.11 Epithelium-on CXL was introduced to avoid epithelial removal and its associated complications. Various techniques have been used to enhance the penetration of riboflavin through intact corneal epithelium, including the use of topical tetracaine,12 benzalkonium chloride (BAC),13,14 trometamol, and ethylenediaminetetraacetic acid.15–18 In some studies, mechanical microabrasions or punctures were induced over the corneal epithelium to further enhance the penetration of riboflavin, with good clinical results.18,19 Clinical http://dx.doi.org/10.1016/j.jcrs.2016.02.041 0886-3350
EPITHELIUM-ON CXL FOR ADVANCED KERATOCONUS
results with epithelium-on CXL were not as promising as with epithelium-off CXL.20,21 The corneal epithelium is a significant barrier to riboflavin absorption into the stroma.22 Gore et al.23 found that the existing commercial epithelium-on CXL protocols achieve relatively low riboflavin concentrations in the anterior corneal stroma compared with that achieved with established epithelium-off instillation. A reduced stromal riboflavin concentration could compromise the efficacy of riboflavin and ultraviolet-A (UVA) corneal CXL. Hypotonic riboflavin 0.1% solution without dextran has been used to increase the penetration of riboflavin into the corneal stroma.24 Recent studies25–27 showed that conventional CXL has a more pronounced flattening effect in cases with advanced keratoconus. The current study presents 1-year visual and keratometric results of tetracaine-assisted epithelium-on CXL for advanced keratoconus (median maximum keratometry [K] R58.0 diopters [D]). PATIENTS AND METHODS Patients This prospective contralateral-eye control study was performed at the School of Ophthalmology and Optometry and the Eye Hospital of Wenzhou Medical College, Wenzhou, China. The study was performed in accordance with the tenets of the Declaration of Helsinki. The hospital's ethics committee approved the study protocol. Informed consent was obtained from all patients before participation. Patients who were diagnosed with bilateral keratoconus were recruited between January 2010 and March 2013. Patients with progressive keratoconus, defined as an increase in maximum K and/or in manifest cylinder of 1.0 D or more over the past 12 months, were included. Patients with a corneal thickness of less than 400 mm, endothelial cell density less than 2000 cell/mm2, severe corneal scarring or ocular surface disease, autoimmune disease, or pregnancy
739
were excluded. The worse eye of each patient received CXL; the fellow eye was left untreated.
Ocular Examination All patients had an uncorrected distance visual acuity (UDVA) and corrected distance visual acuity (CDVA) measurement, slitlamp examination, refraction (RT-2100, Nidek Co. Ltd.), and Scheimpflug corneal topography (Pentacam, Oculus Optikger€ ate GmbH) before and at 1, 3, 6, and 12 months after epithelium-on CXL. The mean K, flat K, steep K, maximum K, central corneal thickness (CCT), thinnest corneal thickness, anterior elevation, and posterior elevation were evaluated. A fixed best-fit sphere of 8.0 mm was used for all measurements. All patients were asked to discontinue contact lens wear 2 weeks before the preoperative and postoperative evaluations.
Surgical Technique The CXL was performed without epithelial debridement. During the riboflavin imbibition period, patients were allowed to blink normally. Tetracaine 1.0% without BAC was applied every minute for 15 minutes. Subsequently, hypotonic riboflavin 0.5% solution without dextran (China Resources Double-Crane Pharmaceutical Co. Ltd.) was applied every minute for 30 minutes. The corneal thickness was measured with ultrasonic pachymetry (SP-3000, Tomey, Ltd.) before UVA illumination. In cases in which the corneal thickness was less than 400 mm before UVA illumination, the corneal stroma was hydrated with distilled water until a corneal thickness of 400 mm or more was achieved. A blepharostat was inserted. Using a circular spot diameter of 9.0 mm, 365 nm UVA with irradiance of 3mW/cm2 (UV-X, IROC Innocross AG) was applied over the cornea for 30 minutes. During UVA illumination, tetracaine was instilled 2 to 3 times for anesthesia. After completion of treatment, the residual riboflavin solution was rinsed out with a balanced salt solution. One drop each of tobramycin and dexamethasone was applied, and a bandage contact lens was inserted. The bandage contact lens was removed on the first postoperative day. A mixture of topical tobramycin and dexamethasone was started 4 times a day for 1 week. Artificial teardrops were used 6 times a day for 1 month postoperatively.
Statistical Analysis
Submitted: November 5, 2015. Final revision submitted: January 29, 2016. Accepted: February 1, 2016. From the Department of Ophthalmology (Chen, Zhang, Ding, Li, Wang), Affiliated Eye Hospital of Wenzhou Medical College, Wenzhou, Zhejiang, the Department of Ophthalmology and Visual Sciences (T.C.Y. Chan, Jhanji), Chinese University of Hong Kong, and Hong Kong Eye Hospital (T.C.Y. Chan, J.C.K. Chan, Jhanji), Mongkok, Kowloon, and the Department of Mathematics and Statistics (Yu), Hang Seng Management College, Hong Kong, China. Supported by the Wenzhou Key Scientific and Technological Innovation Team Project and the Wenzhou City Technology Bureau Project. Corresponding author: Vishal Jhanji, MD, FRCOphth, Department of Ophthalmology and Visual Sciences, Chinese University of Hong Kong, Hong Kong, China. E-mail: [email protected].
Statistical analysis was performed using R 2.15.3 (R Foundation for Statistical ComputingA). Comparisons of UDVA, CDVA, spherical equivalent (SE), K, corneal thickness, anterior elevation, and posterior elevation measurements between different timepoints were performed using Wilcoxon signed-rank tests. A P value less than 0.05 was considered statistically significant. Comparisons of these parameters between treated eyes and fellow untreated eyes were performed using Friedman tests. Bonferroni adjustments were considered for multiple testing in pairwise comparisons between different timepoints.
RESULTS Data for comparison was available from 21 treated eyes and 16 fellow untreated eyes at the end of 12 months. The median age of the patients was 20.4 years (interquartile range [IQR], 9.5 years).
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Table 1. Visual and topographic characteristics before and after transepithelial CXL for progressive keratoconus. P Value* Parameter UDVA (logMAR) Baseline 1 month 3 months 6 months 12 months CDVA (logMAR) Baseline 1 month 3 months 6 months 12 months SE (D) Baseline 1 month 3 months 6 months 12 months Ksteep (D) Baseline 1 month 3 months 6 months 12 months Kflat (D) Baseline 1 month 3 months 6 months 12 months Km (D) Baseline 1 month 3 months 6 months 12 months Kmax (D) Baseline 1 month 3 months 6 months 12 months CCT (mm) Baseline 1 month 3 months 6 months 12 months TCT (mm) Baseline 1 month 3 months
Mean
SD
Vs Baseline
Vs 1 Mo
Vs 3 Mo
Vs 6 Mo
0.97 0.85 0.85 0.80 0.79
0.36 0.30 0.27 0.32 0.26
d .092 .040 .029 .002
d d .445 .238 .089
d d d .678 .343
d d d d .636
0.34 0.30 0.31 0.28 0.25
0.19 0.18 0.18 0.18 0.17
d .167 .070 .009 !.001
d d .397 .021 .001
d d d .171 .006
d d d d .007
7.63 6.88 6.87 5.91 5.70
4.68 4.98 4.97 4.74 4.50
d !.001 .003 !.001 !.001
d d .848 .004 .022
d d d .026 .010
d d d d .100
55.26 54.57 54.76 54.28 54.51
6.25 5.36 6.41 6.35 6.28
d .153 !.001 .003 .002
d d !.001 .004 .001
d d d .670 .322
d d d d .737
50.32 49.91 50.30 49.83 50.16
5.60 5.02 5.47 5.68 5.82
d .026 .741 .554 .523
d d .007 .012 .008
d d d .911 .466
d d d d .721
52.64 52.12 52.43 51.93 52.24
5.81 5.05 5.84 5.89 5.97
d .036 .088 .020 .054
d d .002 .002 .001
d d d .709 .848
d d d d .594
63.95 63.18 62.75 61.88 62.32
9.60 9.31 9.08 8.84 8.97
d .781 .001 .006 !.001
d d .002 .018 .001
d d d .872 .173
d d d d .010
456.24 447.47 442.65 449.04 453.20
43.16 40.29 49.18 53.13 50.09
d !.001 .008 .023 .264
d d .717 .028 .004
d d d .025 .004
d d d d .036
443.24 435.19 433.04
42.22 39.11 50.72
d .001 .019
d d .643
d d d
d d d (continued on next page)
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Table 1. (Cont.) P Value* Parameter
Mean
SD
Vs Baseline
6 months 12 months AE (mm) Baseline 1 month 3 months 6 months 12 months PE (mm) Baseline 1 month 3 months 6 months 12 months
438.43 439.64
53.68 45.55
.037 .183
40.48 39.90 36.65 36.39 37.76
16.27 17.08 14.32 14.41 15.52
83.40 79.33 81.08 78.60 78.64
34.18 26.76 37.74 33.60 31.21
Vs 1 Mo
Vs 3 Mo
Vs 6 Mo
.038 .014
.062 .032
d .241
d .361 .006 .017 .003
d d .001 .003 .001
d d d .102 .431
d d d d .731
d .837 .478 .454 .216
d d .316 .779 .150
d d d .741 .135
d d d d .062
AE Z anterior elevation; CCT Z central corneal thickness; CDVA Z corrected distance visual acuity; Kflat Z keratometry at flat axis; Kmax Z maximal keratometry; Kmean Z mean keratometry; Ksteep Z keratometry at steep axis; PE Z posterior elevation; SE Z spherical equivalent; TCT Z thinnest corneal thickness; UDVA Z uncorrected distance visual acuity *Wilcoxon signed-rank tests were considered significant at a 5% level with Bonferroni adjustments for multiple testing between different timepoints (ie, P ! .005).
Table 1 shows the treatement results. A significant improvement in UDVA was observed at 12 months compared with baseline values. The postoperative CDVA was better at 6 months and 12 months than at baseline. The SE dropped significantly after surgery. The SE changed by 1.93 D by the end of 12 months. The mean K remained stable throughout the 1-year follow-up period. Maximum K decreased significantly 12 months postoperatively. The change in maximum K, steep K, flat K, and mean K values was 1.63 D, 0.75 D, 0.16 D, and 0.40 D, respectively, at the end of 12 months postoperatively. The median preoperative maximum K was 62.7 D (IQR, 12.9 D). One year postoperatively, 11 eyes had a decrease in maximum K of 1.0 D or more; no eye had an increase in maximum K of more than 1.0 D. The anterior elevation remained fairly stable up to 6 months. Overall, there was a statistically significant decrease in anterior elevation between baseline and 12-month anterior elevation values. There was no significant change in posterior elevation at any follow-up timepoint (Table 1). The CCT dropped significantly 1 month and 3 months postoperatively; this was followed by an increase over the subsequent 9 months. As a consequence, there was no statistically significant difference between the baseline CCT and 12-month CCT. Similarly, the thinnest corneal thickness decreased during the 3 months postoperatively; this was followed by a slow increase thereafter. The overall change in corneal thickness was less than 5 mm over the 12-month follow-up (Table 1).
Sixteen patients completed visual and topographic examinations of both eyes at the end of 12 months. The changes in UDVA and CDVA were significantly greater after CXL than in the fellow untreated eyes. The reduction in maximum K was also higher after CXL, with more change in anterior elevation but not in posterior elevation compared with the change in the fellow eyes, there was no difference in the change in corneal thickness between the treated eyes and untreated eyes (Table 2). No intraoperative or postoperative complications occurred. Transient corneal haze was observed in all eyes during the first postoperative week. DISCUSSION The data in the current study suggest that epitheliumon CXL can halt keratoconus progression over 1 year of follow-up. Previous studies of the efficacy of epithelium-on CXL13–21,28–34 had variable results, mainly because of the different surgical protocols shown in Table 3. Furthermore, studies25–27,35 have also shown that CXL is more effective in stabilizing eyes with keratoconus and a high maximum K. This trend was also observed in studies evaluating epithelium-on CXL. Studies of eyes with a high preoperative maximum K showed flattening of maximum K,14,16,18,30 whereas studies of eyes with low to moderate preoperative maximum K showed stabilizing or even worsening of maximum K.13,15,17,20,31,33 Indeed, in other studies13–19,21,28–33 as well as ours,
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Table 2. Comparison of visual and topographic outcomes in eyes after transepithelial CXL for progressive keratoconus and the contralateral control eyes. CXL Parameter UDVA (logMAR) 3 months preop 6 months – preop 12 months – preop CDVA (logMAR) 3 months preop 6 months – preop 12 months – preop SEQ (D) 3 months preop 6 months – preop 12 months – preop Ksteep (D) 3 months preop 6 months – preop 12 months – preop Kflat (D) 3 months preop 6 months – preop 12 months – preop Km (D) 3 months preop 6 months – preop 12 months – preop Kmax (D) 3 months preop 6 months – preop 12 months – preop CCT (mm) 3 months preop 6 months – preop 12 months – preop TCT (mm) 3 months preop 6 months – preop 12 months – preop AE (mm) 3 months preop 6 months – preop 12 months – preop PE (mm) 3 months preop 6 months – preop 12 months – preop
Mean
Control SD
Mean
SD
P Value*
0.141 0.335 0.147 0.364 0.171 0.320
0.057 0.045 0.123
0.175 0.237 0.204
.157 .034 .001
0.053 0.209 0.056 0.200 0.094 0.218
0.013 0.012 0.002
0.043 0.046 0.042
.008 .096 .001
0.365 4.767 1.634 4.460 1.773 4.749
0.135 0.241 0.172
0.367 0.997 1.164
.366 .033 .134
0.657 6.532 0.900 6.268 0.969 6.486
0.071 0.133 0.150
0.312 0.430 0.528
.001 .001 .003
0.057 5.528 0.400 5.381 0.188 5.492
0.071 0.153 0.012
0.350 .782 0.393 .796 0.606 1.000
0.300 5.902 0.620 5.694 0.506 5.863
0.021 0.013 0.063
0.294 0.307 0.541
.593 .109 .046
1.386 10.166 1.740 10.451 2.107 10.451
0.086 0.207 0.207
0.293 0.505 0.505
.033 .020 .001
14.857 62.492 32.071 126.423 7.667 47.658 28.933 119.570 2.125 61.516 28.500 114.444
.033 .071 .617
13.143 48.079 4.733 47.363 3.500 47.571
1.214 10.793 0.200 11.797 1.938 13.051
.013 .071 .617
4.143 18.826 4.067 18.828 4.813 18.855
0.143 0.200 1.063
1.956 1.971 3.605
.002 .002 .001
1.929 35.331 5.933 35.716 13.875 35.658
0.500 0.067 0.000
4.553 1.000 9.588 .796 6.186 .052
AE Z anterior elevation; CCT Z central corneal thickness; CDVA Z corrected distance visual acuity; Kflat Z keratometry at flat axis; Kmax Z maximal keratometry; Kmean Z mean keratometry; Ksteep Z keratometry at steep axis; PE Z posterior elevation; SEQ Z spherical equivalent; TCT Z thinnest corneal thickness; UDVA Z uncorrected distance visual acuity *Friedman tests were considered statistically significant at a 5% level with Bonferroni adjustments for multiple testing between different timepoints (ie, P ! .017)
correlation analysis of the change in maximum K between preoperative values and values over 6 to 12 months postoperatively showed a significant correlation (r Z 0.764, P ! .001; Spearman correlation) (Figure 1). Reasons for more pronounced flattening of maximum K after epithelium-on CXL in advanced keratoconus are not fully understood. We hypothesize that this could be partly attributed to a relatively deeper penetration of crosslinking in eyes with advanced keratoconus. Epithelium-on CXL is reported in the peer-reviewed literature,29 with results showing a significantly weaker biomechanical effect than epithelium-off CXL.15 Gore et al.23 reported reduced stromal riboflavin concentration using commercially available riboflavin formulations during epithelium-on CXL compared with during conventional epithelium-off CXL. The authors noted that peak stromal riboflavin concentrations for MedioCross TE (Avedro), RicrolinC (Sooft italia S.p.A.), Paracel/Xtra (Avedro), and Ribocross TE (Servimed Srl) were 0.054%, 0.031%, 0.021%, and 0.015%, respectively. The stromal concentration at a depth of 300 mm in epithelium-off corneas was 0.075%, whereas at the same depth, MedioCross TE and RicrolinC achieved 0.018% and 0.016%, respectively.23 Another issue that affects epithelium-on CXL relates to UVA absorption and filtering by the intact epithelium.36,37 Results in a study by Baiocchi et al.4 suggest that absorption by the epithelium is approximately one third, leading to less energy reaching the riboflavin-saturated stroma. This might be partially attributed to reduced riboflavin permeability through the intact epithelium, mainly because of its large molecular weight.4 It remains to be seen whether increased UVA irradiance is necessary for better epithelium-on CXL results.37 The biomechanical efficacy of epithelium-on CXL has also been shown to be less than that of conventional CXL in rabbit corneas.22 Tetracaine administration alone was not sufficient to permit riboflavin penetration into the corneal stroma in an animal model.38 The stromal demarcation line was shallower, less distinct, or even absent after epithelium-on CXL.16,21,39 In the current study, chemical disruption of the epithelial tight junctions was attempted by application of tetracaine. A hypotonic riboflavin solution was used without dextran to increase the permeability of the corneal epithelium. We used riboflavin 0.5% to enhance its penetration and achieve higher UVA absorption. The absorption coefficient of riboflavin has been found to linearly correlate with concentrations up to 0.5%.40 Postoperatively, we noted a significant decrease in anterior elevation but not in posterior elevation after epithelium-on CXL, suggesting that the flattening effect was mainly over the
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Table 3. Summary of studies using transepithelial corneal CXL with chemical enhancers. Corneal Thickness (mm)
Design
Eyes†
Enhancement
UDVA
CDVA
Keratometry (D)
Koppen13/2012
Prospective study Follow up: 12 months in 37 eyes 18 months in 21 eyes
53 eyes of 38 patients Mean age: 24.02 G 7.29 (12, 46)
Proparacaine with benzalkonium chloride, riboflavin 0.1% with dextran 20%
Not reported
Change from baseline 12 months: 0.06 P !.05 18 months: 0.05
Change from baseline 12 months: 8.06 P !.05 18 months: 10.31 P !.05
None reported
Lesniak14/2014
Prospective comparative study Follow up: 6 months
30 eyes from 25 patients 1-min group: 18 eyes 2-min group: 12 eyes Mean age: 31.8 (18, 58)
Proparacaine containing benzalkonium chloride, riboflavin 0.1% (hypotonic) without dextran 1-min or 2-min group: riboflavin added every 1 or 2 min during UVA
1-min group: 0.98 / 0.91 2-min group: 0.73 / 0.64 P Z .845 for changes after TE-CXL between both groups Overall: 0.88 / 0.80 P Z .114
Not reported
None reported
Leccisotti15/2010
Prospective comparative study Follow up: 12 months
51 out of 64 patients completed Fellow eye as control Mean age: 26.9 G 6.3 (18, 39)
Gentamicin, EDTA, benzalkonium chloride, oxybuprocaine, riboflavin 0.1% with dextran 20%
Not reported
1-min group: 0.28 / 0.22 2-min group: 0.36 / 0.25 P !.05 for 1-min group compared with baseline P Z .572 for changes after TECXL between groups Overall: 0.31 / 0.23 P Z .032 Control 0.081 / 0.120 P !.05 TE-CXL 0.111 / 0.075 P !.05 P !.05 between groups
Change from baseline Placido 12 months: 0.47 18 months: 0.65 Scheimpflug 12 months: 1.33 P !.05 18 months: 1.76 P !.05 1-min group: 56.60 / 56.14 2-min group: 61.82 / 60.36 P !.05 for 2-min group compared with baseline P Z .119 changes after TECXL between groups Overall: 58.69 / 57.83 P Z .010
Not reported
2 cases of TE-CXL showed transient subepithelial haze
Filippello16/2012
Prospective comparative study Follow up: 18 months
40 eyes from 20 patients Contralateral eye as control Mean age: 27 (12, 42)
Oxybuprocaine, riboflavin 0.1% with dextran 15% and trometamolEDTA Silicone ring
Control 0.84 / 0.98 TE-CXL 0.71 / 0.48 P !.05 between groups
Kapex Control 51.69 / 53.3 P O.05 TE-CXL 54.31 / 54.81 P O.05 P O.05 between groups Kapex Control 58.89 / 60.93 P O.05 TE-CXL 59.12 / 57.95 P !.05
Study*/Year
Transient hyperemia, foreign body sensation, photophobia after first few hours and days (continued on next page)
EPITHELIUM-ON CXL FOR ADVANCED KERATOCONUS
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Control 0.46 / 0.64 TE-CXL 0.35 / 0.24 P !.05 between groups
Complications
Control 423 / 398 P O.05 TE-CXL 412 / 408 P O.05
743
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Table 3. (Cont.) Study*/Year Caporossi17/2013
Rechichi18/2013
Corneal Thickness (mm)
Eyes†
Enhancement
UDVA
CDVA
Keratometry (D)
Prospective study Follow up: 24 months Prospective comparative study Follow up: 12 months
26 eyes of 26 patients Mean age: 22 (11, 26) 28 eyes of 28 patients Worst eye with highest average keratometry was treated, fellow eye as control Mean age: 28.8 (18, 41) 61 eyes of 53 patients Mean age: 32 G 10 (15, 52)
Riboflavin 0.1% with dextran 15% and trometamolEDTA Oxybuprocaine, riboflavin 0.1% with 15% dextran and trometamolEDTA Epithelial puncturing using corneal disruptor Silicone ring Proparacaine with benzalkonium chloride, microabrasion with Merocel sponge, riboflavin 0.5% (hypotonic) without dextran C-CXL Oxybuprocaine, riboflavin 0.1% with dextran 20% TE-CXL Tetracaine with benzalkonium chloride, riboflavin 0.1% without dextran
0.40 / 0.35 P Z .61
0.75 / 0.8 P Z .57
Kmax 48.59 / 50.14 P Z .05
461 / 429 P Z .04
5 patients retreated by C-CXL
Control 0.75 / 0.85 TE-CXL 0.73 / 0.48 P !.05
Control 0.29 / 0.37 TE-CXL 0.30 / 0.25 P !.05
Kapex Control 59.11 / 60.52 TE-CXL 59.21 / 56.18 P O.05
Control 442.38 / 427.50 TE-CXL 442.00 / 427.00 P O.05
None reported
20/133 / 20/67 PZ0
20/32 / 20/24 PZ0
Kmax 55.55 / 54.98 P Z .02
451 / 460 P Z .15
None reported
Change from baseline P Z .007 (12 months) P !.0001 (3 years) between groups
Change from baseline C-CXL 0.15 (12 months) 0.1 (3 years) TE-CXL 0.2 (12 months) 0.24 (3 years) P Z .30 (12 months) P Z .055 (3 years) between groups C-CXL 0.26 / 0.21 TE-CXL
Kmax C-CXL significantly decreased compared with baseline TE-CXL significantly increased compared with baseline P Z .0007 (12 months) P !.0001 (3 years) between groups
Not reported
C-CXL: Stromal haze, transient change in corneal thickness resolved in the first 6 months
C-CXL 57.8 / 56.8 TE-CXL
C-CXL 467 / 460 TE-CXL
4 eyes (15%) had complications
Stojanovic19/2012
Retrospective study Follow up: 12 months
Al Fayez20/2015
Prospective comparative study Follow up: 3 years
70 eyes of 70 patients C-CXL: 36 eyes TE-CXL: 34 eyes Mean age C-CXL: 24.1 G 5.3 TE-CXL: 24.8 G 4.2
Soeters21/2015
Prospective comparative study
61 eyes of 61 patients C-CXL: 26 eyes
C-CXL Riboflavin 0.1% (isotonic) with dextran 20%
C-CXL 1.07 / 0.97 TE-CXL
Complications
EPITHELIUM-ON CXL FOR ADVANCED KERATOCONUS
J CATARACT REFRACT SURG - VOL 42, MAY 2016
Design
J CATARACT REFRACT SURG - VOL 42, MAY 2016
Magli29/2013
Salman30/2013
TE-CXL: 35 eyes Median age C-CXL: 24 (18, 44) TE-CXL: 24 (18, 48)
Prospective study Follow up: 6 months in 16 eyes 12 months in 7 eyes Retrospective comparative study Follow up: 12 months
16 eyes of 16 patients Mean age: 34.4 G 11.9 (18, 61)
Prospective comparative study Follow up: 12 months
39 eyes of 30 patients C-CXL: 23 eyes of 19 patients TE-CXL: 16 eyes of 11 patients Mean age C-CXL: 14.75 G 2.1 TE-CXL: 15 G 2.1 44 eyes of 22 patients Right eye as TECXL while left eye as control Mean age: 15.7 G 2.1 (13, 18)
One eye received hypoosmolar riboflavin because of corneal thickness !400 mm after 30 min isotonic riboflavin TE-CXL Oxybuprocaine, riboflavin 0.1% with dextran 20% Silicone ring Oxybyprocaine with p-hydroxybenzoate, riboflavin 0.1% with trometamol and sodium EDTA C-CXL Riboflavin 0.1% with dextran 20% TE-CXL Riboflavin 0.1% with dextran 15% and trometamolEDTA Lidocaine Silicone ring
0.76 / 0.71 P Z .591 between groups
0.30 / 0.16 P Z .023 between groups
56.4 / 56.6 P Z .022 between groups
457 / 459 P !.001 between groups
after C-CXL versus none in TE-CXL 8 eyes (23%) showed an increase of Kmax O1 D in TE-CXL
0.95 / 0.61 (6 months) P Z .015 / 0.74 (12 months) P Z .295
0.37 / 0.33 (6 months) P Z.695 / 0.34 (12 months) P Z .817 C-CXL 0.36 / 0.36 P Z .8 TE-CXL 0.24 / 0.27 P Z .5 P O.05 between groups
Kapex 61.30 / 56.10 (6 months) P Z .027 / 58.21 (12 months) P Z .339
369.6 / 365.4 (6 months) P Z .579 / 367.7 (12 months) P Z .826
None reported
Kmax C-CXL 50.13 / 49.02 P Z .01 TE-CXL 49.27 / 48.13 P Z .02 P O.05 between groups
C-CXL 487.2 / 492 P Z .5 TE-CXL 490.2 / 488.0 P Z .6 P O.05 between groups
Proparacaine, riboflavin 0.1% with dextran 15% and trometamolEDTA
Control 0.84 / 0.94 P Z .324 TE-CXL 0.95 / 0.68 P Z .023
Control 0.42 / 0.51 P Z .543 TE-CXL 0.51 / 0.49 P Z .189
Kapex Control 61.30 / 64.20 P Z .044 TE-CXL 60.30 / 58.10 P Z .027
Control 482.6 / 477.7 P Z .579 TE-CXL 469.6 / 467.7 P Z .679
C-CXL Transient corneal edema Persistent cornea edema in 2 eyes TE-CXL Transient hyperemia, foreign body sensation and photophobia Epithelial defect, transient hyperemia and foreign body sensation
C-CXL 0.68 / 0.67 P Z .1 TE-CXL 0.55 / 0.54 P Z .3 P O.05 between groups
EPITHELIUM-ON CXL FOR ADVANCED KERATOCONUS
Spadea28/2012
Follow up: 12 months
(continued on next page)
745
746
Table 3. (Cont.)
Kmax 55.43 / 55.48 P Z .88
467.5 / 459.8 P Z .07
None reported
Kmax C-CXL 57.46 / 55.15 P !.001 TE-CXL 60.12 / 60.0 P O.05 C-CXL had greater reduction than TECXL P !.001 Kmax 48.90 / 52.90 P !.05
C-CXL 462 / 440.1 P !.05 TE-CXL 425.3 / 419.4 P !.001 C-CXL showed greater reduction than TE-CXL P Z .004
None reported
445 / 449 P O.05
None reported
Flat keratometry, 42.1 / 42.2 Steep keratometry, 44.4 / 43.7
503 / 528
None reported
Enhancement
UDVA
CDVA
Keratometry (D)
Prospective study Follow up: 6 months Retrospective comparative study Follow up: 18 months
36 eyes of 36 patients Mean age 24.5 G 5 (12, 33) 60 eyes of 43 patients C-CXL: 30 eyes of 20 patients TE-CXL: 30 eyes of 23 patients Mean age C-CXL: 23.7 G 3.9 TE-CXL: 22.8 G 4.7
Oxybuprocaine, riboflavin 0.1% with dextran 20% Silicone ring C-CXL Proparacaine, riboflavin 0.1% with 20% dextran TE-CXL Proparacaine, riboflavin 0.1% with dextran 20%
Not reported
0.72 / 0.89 P !.01
C-CXL 0.61 / 0.49 P !.001 TE-CXL 0.71 / 0.59 P !.001 P O.05 between groups
C-CXL 0.35 / 0.22 P !.001 TE-CXL 0.42 / 0.31 P !.001 P O.05 between groups
Buzzonetti33/2012
Prospective study Follow up: 18 months
0.19 / 0.1 P !.05
Case report Follow up: 6 months
Oxybuprocaine, riboflavin 0.1% with trometamol and sodium EDTA Riboflavin 0.25% with benzalkonium chloride 0.02%, followed by isotonic riboflavin 0.25% in saline Topographic custom UVA
Not reported
Kanellopoulos34/ 2014
13 eyes of 13 patients Mean age 14.4 G 3.7 (8, 18) 1 eye Age: 37
20/40 / 20/25
Not reported
C ¸ erman32/2015
C-CXL Z conventional collagen crosslinking; CDVA Z corrected distance visual acuity; EDTA Z ethylenediaminetetraacetic acid; Kapex Z apical keratometry; Kmax Z maximum keratometry; TE-CXL Z transepithelial collagen crosslinking; UDVA Z uncorrected distance visual acuity; UVA Z ultraviolet-A *First author † Some means are GSD; values in parentheses are ranges.
EPITHELIUM-ON CXL FOR ADVANCED KERATOCONUS
Complications
Eyes†
De Bernardo31/ 2014
J CATARACT REFRACT SURG - VOL 42, MAY 2016
Corneal Thickness (mm)
Design
Study*/Year
EPITHELIUM-ON CXL FOR ADVANCED KERATOCONUS
Figure 1. Association between preoperative maximum K or apical K and its change over 6 to 12 months among studies in the literature (see Table 3).
anterior cornea. This suggests that epithelium-on CXL has a weaker strengthening effect than the conventional epithelium-off protocol. Indeed, the biomechanical stiffening effect of BAC-assisted epithelium-on CXL was only 20% of the standard protocol in an animal model.41 A recently published randomized control trial comparing epithelium-on CXL with epithelium-off CXL21 found fairly stable maximum K values and improvement in CDVA over 1 year after epitheliumon CXL. The trend in maximum K flattening over time was significantly different from that for epithelium-off CXL, which showed a flattening of maximum K beginning 3 months postoperatively. Surprisingly, epithelium-on CXL had a more favorable outcome between the 2 groups, and the authors believed this could be explained by the corneal haze formation at the first postoperative month in the epithelium-off CXL group.21 Raiskup et al.42 found permanent corneal haze leading to a loss of 2 lines or more of CDVA in 8.6% of patients after conventional CXL. We also found that most studies using epithelium-on CXL showed improvement or maintenance of visual acuity. A similar gain in CDVA between epithelium-off CXL and epithelium-on CXL regardless of a different topographic flattening effect has also been reported.32 This could be caused by the absence of corneal haze, which was found to be supported by a lesser extent of keratocyte apoptosis and inflammation after epithelium-on CXL.38,41 It is possible that epithelium-on CXL allows faster visual recovery than standard epithelium-off CXL, which
747
causes significant visual impairment and topographic worsening in the first few months after treatment.5–7 Another recent modification of epithelium-on CXL included the use of iontophoresis to increase riboflavin penetration through the epithelium. Studies43,44 have shown improvement in visual outcomes and topographic parameters after the treatment in pediatric and adult patients with keratoconus. Although the demarcation line in iontophoresis-assisted CXL was more superficial than that in conventional epitheliumoff CXL,45 it appeared to be more distinguishable and deeper than the chemical-enhanced epitheliumon CXL. Longitudinal studies comparing different chemical-enhanced protocols with iontophoresisassisted epithelium-on CXL are warranted in the future. The current study is limited by its small sample. We did not measure the demarcation line and degree of discomfort after the treatment. Variations in epithelium-on CXL protocols and patient preoperative states could affect efficacy. However, the results in our study suggest that epithelium-on CXL is a viable treatment for patients with advanced keratoconus. Sufficient topographic flattening was achieved, and the risk for corneal haze or scar formation was minimized. WHAT WAS KNOWN Epithelium-on corneal CXL is safe for treating progressive keratoconus. Variable corneal topographic flattening effects have been associated with the procedure. WHAT THIS PAPER ADDS Epithelium-on corneal CXL could improve corneal flattening in eyes with advanced keratoconus. A higher preoperative keratometry was associated with greater corneal flattening after epithelium-on CXL.
REFERENCES 1. Jhanji V, Sharma N, Vajpayee RB. Management of keratoconus: current scenario. Br J Ophthalmol 2011; 95:1044–1050 2. Kymes SM, Walline JJ, Zadnik K, Gordon MO; and the Collaborative Longitudinal Evaluation of Keratoconus (CLEK) Study Group. Quality of life in keratoconus. Am J Ophthalmol 2004; 138:527–535. Available at: https://vrcc.wustl.edu/clekarchive/ pdf/22%20Kymes%20-%20Quality%20of%20Life.pdf. Accessed March 5, 2016 3. Wollensak G, Spoerl E, Seiler T. Riboflavin/ultraviolet-A– induced collagen crosslinking for the treatment of keratoconus. Am J Ophthalmol 2003; 135:620–627. Available at: http:// iogen.fi/files/2011/10/Wollensak_et_al_Keratoconus_2003.pdf. Accessed March 5, 2016 4. Baiocchi S, Mazzotta C, Cerretani D, Caporossi T, Caporossi A. Corneal crosslinking: riboflavin concentration in corneal stroma exposed with and without epithelium. J Cataract Refract Surg 2009; 35:893–899
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5. Hashemi H, Seyedian MA, Miraftab M, Fotouhi A, Asgari S. Corneal collagen cross-linking with riboflavin and ultraviolet A irradiation for keratoconus; long-term results. Ophthalmology 2013; 120:1515–1520. Available at: http://www.aaojournal.org/ article/S0161-6420(13)00014-6/pdf. Accessed March 5, 2016 6. Vinciguerra R, Romano MR, Camesasca FI, Azzolini C, Trazza S, Morenghi E, Vinciguerra P. Corneal cross-linking as a treatment for keratoconus; four-year morphologic and clinical outcomes with respect to patient age. Ophthalmology 2013; 120:908–916 7. Wittig-Silva C, Chan E, Islam FMA, Wu T, Whiting M, Snibson GR. A randomized, controlled trial of corneal collagen cross-linking in progressive keratoconus; three-year results. Ophthalmology 2014; 121:812–821. Available at: http://www.aaojournal.org/ article/S0161-6420(13)01004-X/pdf. Accessed March 5, 2016 8. Ghanem VC, Ghanem RC, de Oliveira R. Postoperative pain after corneal collagen cross-linking. Cornea 2013; 32:20–24 9. Greenstein SA, Fry KL, Bhatt J, Hersh PS. Natural history of corneal haze after collagen crosslinking for keratoconus and corneal ectasia: Scheimpflug and biomicroscopic analysis. J Cataract Refract Surg 2010; 36:2105–2114. Available at: http://www.vision-institute.com/UserFiles/File/CXL%20Haze% 20Published.pdf. Accessed March 5, 2016 10. Mangioris GF, Papadopoulou DN, Balidis MO, Poulas JL, Papadopoulos NT, Seiler T. Corneal infiltrates after corneal collagen cross-linking. J Refract Surg 2010; 26:609–611 11. Gautam, Jhanji V, Satpathy G, Khokhar S, Agarwal T. Microsporidial keratitis after collagen cross-linking [letter]. Ocul Immunol Inflamm 2013; 21:495–497 12. Chan CCK, Sharma M, Boxer Wachler BS. Effect of inferiorsegment Intacs with and without C3-R on keratoconus. J Cataract Refract Surg 2007; 33:75–80 13. Koppen C, Wouters K, Mathysen D, Rozema J, Tassignon M-J. Refractive and topographic results of benzalkonium chlorideassisted transepithelial crosslinking. J Cataract Refract Surg 2012; 38:1000–1005 14. Lesniak SP, Hersh PS. Transepithelial corneal collagen crosslinking for keratoconus: six-month results. J Cataract Refract Surg 2014; 40:1971–1979 15. Leccisotti A, Islam T. Transepithelial corneal collagen crosslinking in keratoconus. J Refract Surg 2010; 26:942–948 16. Filippello M, Stagni E, O’Brart D. Transepithelial corneal collagen crosslinking: bilateral study. J Cataract Refract Surg 2012; 38:283–291; erratum, 1515 17. Caporossi A, Mazzotta C, Paradiso AL, Baiocchi S, Marigliani D, Caporossi T. Transepithelial corneal collagen crosslinking for progressive keratoconus: 24-month clinical results. J Cataract Refract Surg 2013; 39:1157–1163 18. Rechichi M, Daya S, Scorcia V, Meduri A, Scorcia G. Epithelialdisruption collagen crosslinking for keratoconus: one-year results. J Cataract Refract Surg 2013; 39:1171–1178 19. Stojanovic A, Chen X, Jin N, Zhang T, Stojanovic F, Raeder S, Utheim TP. Safety and efficacy of epithelium-on corneal collagen cross-linking using a multifactorial approach to achieve proper stromal riboflavin saturation. J Ophthalmol 2012:498435 Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC341 3959/pdf/JOP2012-498435.pdf. Accessed March 5, 2016 20. Al Fayez MF, Alfayez S, Alfayez Y. Transepithelial versus epithelium-off corneal collagen cross-linking for progressive keratoconus: a prospective randomized controlled trial. Cornea 2015; 34(suppl 10):S53–S56 21. Soeters N, Wisse RPL, Godefrooij DA, Imhof SM, Tahzib NG. Transepithelial versus epithelium-off corneal cross-linking for the treatment of progressive keratoconus: a randomized controlled trial. Am J Ophthalmol 2015; 159:821–828.e3
22. Tao X, Yu H, Zhang Y, Li Z, Jhanji V, Ni S, Wang Y, Mu G. Role of corneal epithelium in riboflavin/ultraviolet-A mediated corneal cross-linking treatment in rabbit eyes. Biomed Res Int 2013:624563. Available at: http://www.ncbi.nlm.nih.gov/pmc/ articles/PMC3712226/pdf/BMRI2013-624563.pdf. Accessed March 5, 2016 23. Gore DM, O’Brart D, French P, Dunsby C, Allan BD. Transepithelial riboflavin absorption in an ex vivo rabbit corneal model. Invest Ophthalmol Vis Sci 2015; 56:5006–5011. Available at: http://iovs.arvojournals.org/article.aspx?articleidZ2422882. Accessed March 5, 2016 24. Raiskup F, Pinelli R, Spoerl E. Riboflavin osmolar modification for transepithelial corneal cross-linking. Curr Eye Res 2012; 37:234–238 25. Chan TCY, Chow VWS, Jhanji V, Wong VWY. Different topographic response between mild to moderate and advanced keratoconus after accelerated collagen cross-linking. Cornea 2015; 34:922–927 26. Chow VWS, Chan TCY, Yu M, Wong VWY, Jhanji V. One-year outcomes of conventional and accelerated collagen crosslinking in progressive keratoconus. Sci Rep 2015; 5:14425. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4585888/pdf/ srep14425.pdf. Accessed March 5, 2016 27. Sloot F, Soeters N, van der Valk R, Tahzib NG. Effective corneal collagen crosslinking in advanced cases of progressive keratoconus. J Cataract Refract Surg 2013; 39:1141–1145 28. Spadea L, Mencucci R. Transepithelial corneal collagen crosslinking in ultrathin keratoconic corneas. Clin Ophthalmol 2012; 6:1785–1792. Available at: http://www.ncbi.nlm.nih.gov/pmc/ articles/PMC3497455/pdf/opth-6-1785.pdf. Accessed March 5, 2016 29. Magli A, Forte R, Tortori A, Capasso L, Marsico G, Piozzi E. Epithelium-off corneal collagen cross-linking versus transepithelial cross-linking for pediatric keratoconus. Cornea 2013; 32:597–601 30. Salman AG. Transepithelial corneal collagen crosslinking for progressive keratoconus in a pediatric age group. J Cataract Refract Surg 2013; 39:1164–1170 31. De Bernardo M, Capasso L, Tortori A, Lanza M, Caliendo L, Rosa N. Trans epithelial corneal collagen crosslinking for progressive keratoconus: 6 months follow up. Cont Lens Anterior Eye 2014; 37:438–441 32. C‚erman E, Toker E, Ozarslan Ozcan D. Transepithelial versus epithelium-off crosslinking in adults with progressive keratoconus. J Cataract Refract Surg 2015; 41:1416–1425 33. Buzzonetti L, Petrocelli G. Transepithelial corneal cross-linking in pediatric patients: early results. J Refract Surg 2012; 28: 763–767 34. Kanellopoulos AJ, Dupps WJ, Seven I, Asimellis G. Toric topographically customized transepithelial, pulsed, very highfluence, higher energy and higher riboflavin concentration collagen cross-linking in keratoconus. Case Rep Ophthalmol 2014; 5:172–180. Available at: http://www.ncbi.nlm.nih.gov/ pmc/articles/PMC4105951/pdf/cop-0005-0172.pdf. Accessed March 5, 2016 35. Greenstein SA, Hersh PS. Characteristics influencing outcomes of corneal collagen crosslinking for keratoconus and ectasia: implications for patient selection. J Cataract Refract Surg 2013; 39:1133–1140 36. Podskochy A. Protective role of corneal epithelium against ultraviolet radiation damage. Acta Ophthalmol Scand 2004; 82:714–717. Available at: http://onlinelibrary.wiley.com/doi/10. 1111/j.1600-0420.2004.00369.x/pdf. Accessed March 5, 2016 37. Kanellopoulos AJ, Asimellis G, Salvador-Culla B, Chodosh J, Ciolino JB. High-irradiance CXL combined with myopic LASIK:
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38.
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flap and residual stroma biomechanical properties studied ex-vivo. Br J Ophthalmol 2015; 99:870–874 Hayes S, O’Brart DP, Lamdin LS, Doutch J, Samaras K, Marshall J, Meek KM. Effect of complete epithelial debridement before riboflavin–ultraviolet-A corneal collagen crosslinking therapy. J Cataract Refract Surg 2008; 34:657–661 Mastropasqua L, Nubile M, Lanzini M, Calienno R, Mastropasqua R, Agnifili L, Toto L. Morphological modification of the cornea after standard and transepithelial corneal crosslinking as imaged by anterior segment optical coherence tomography and laser scanning in vivo confocal microscopy. Cornea 2013; 32:855–861 Schumacher S, Mrochen M, Spoerl E. Absorption of UV-light by riboflavin solutions with different concentration [letter]. J Refract Surg 2012; 28:91–92. Available at: http://www.healio.com/ ophthalmology/journals/jrs/2012-2-28-2/%7Bdb668b4d-4a5f4164-a2fd-50fdf3f8e70b%7D/absorption-of-uv-light-by-riboflavinsolutions-with-different-concentration. Accessed March 5, 2016 Wollensak G, Iomdina E. Biomechanical and histological changes after corneal crosslinking with and without epithelial debridement. J Cataract Refract Surg 2009; 35: 540–546
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42. Raiskup F, Hoyer A, Spoerl E. Permanent corneal haze after riboflavin-UVA-induced cross-linking in keratoconus. J Refract Surg 2009; 25:S824–S828 43. Vinciguerra P, Randleman JB, Romano V, Legrottaglie EF, Rosetta P, Camesasca FI, Piscopo R, Azzolini C, Vinciguerra R. Transepithelial iontophoresis corneal collagen cross-linking for progressive keratoconus: initial clinical outcomes. J Refract Surg 2014; 30:746–753 44. Buzzonetti L, Petrocelli G, Valente P, Iarossi G, Ardia R, Petroni S. Iontophoretic transepithelial corneal cross-linking to halt keratoconus in pediatric cases: 15-month follow-up. Cornea 2015; 34:512–515 45. Bonnel S, Berguiga M, De Rivoyre B, Bedubourg G, Sendon D, Froussart-Maille F, Rigal-Sastourne J-C. Demarcation line evaluation of iontophoresis-assisted transepithelial corneal collagen cross-linking for keratoconus. J Refract Surg 2015; 31:36–40
OTHER CITED MATERIAL A. R Development Core Team. The R Project for Statistical Computing. Vienna, Austria, R Foundation for Statistical Computing. Available at: http://cran.r-project.org/doc/manuals/ refman.pdf. Accessed March 5, 2016
J CATARACT REFRACT SURG - VOL 42, MAY 2016
Epithelium-on corneal collagen crosslinking for management of advanced keratoconus Shihao Chen, MD, OD, MSc, Tommy C.Y. Chan, FRCS, Jia Zhang, MD, MSc, Ping Ding, MD, Jason C.K. Chan, MB BS, Marco C.Y. Yu, PhD, Yini Li, MD, PhD, Vishal Jhanji, MD, FRCOphth, Qinmei Wang, MD
PURPOSE: To report the 1-year visual and keratometric results of epithelium-on corneal collagen crosslinking (CXL) for advanced keratoconus (median maximum keratometry [K] R58.0 diopters [D]). SETTING: School of Ophthalmology and Optometry and Eye Hospital of Wenzhou Medical College, Wenzhou, China. DESIGN: Prospective case series. METHODS: Patients with bilateral progressive keratoconus had tetracaine-enhanced epithelium-on CXL. The worse eye had CXL, and the fellow eye was not treated. Results were reported 1, 3, 6, and 12 months postoperatively. The outcomes were compared with those in the fellow untreated eyes. RESULTS: Twenty-one eyes of 21 patients with a median age of 20.4 years (interquartile range [IQR], 9.5 years) were treated. A significant improvement in postoperative uncorrected distance visual acuity was observed at 12 months (P Z .002). Postoperative corrected distance visual acuity improved at 6 months and 12 months (P % .009) compared with baseline values. The maximum K decreased by 1.63 D from the median preoperative maximum K of 62.7 D (IQR, 12.9 D) at 12 months (P < .001). The reduction in maximum K was higher after CXL than in untreated eyes at the end of 12 months (P Z .001). Correlation analysis between the preoperative maximum K values and the change over 6 to 12 months between different studies showed a significant correlation (r Z 0.764, P < .001; Spearman correlation). CONCLUSIONS: Epithelium-on CXL was an effective treatment for patients with advanced keratoconus. A higher preoperative maximum K value correlated with greater corneal flattening after CXL. Financial Disclosure: None of the authors has a financial or proprietary interest in any material or method mentioned. J Cataract Refract Surg 2016; 42:738–749 Q 2016 ASCRS and ESCRS
Keratoconus is associated with progressive corneal thinning and bulging.1 The development of irregular astigmatism and stromal scarring often has a significant negative impact on the quality of life of affected patients.2 Corneal collagen crosslinking (CXL) has been shown to stabilize progression of keratectasia and prevent visual loss.3 The conventional CXL technique necessitates the removal of corneal epithelium to facilitate penetration of riboflavin into the corneal stroma.4 The clinical and topographic outcomes of conventional CXL are established.5–7 However, epithelial removal can be associated with potential 738
Q 2016 ASCRS and ESCRS Published by Elsevier Inc.
complications, including severe pain,8 corneal haze,9 corneal infiltrates,10 and infectious keratitis.11 Epithelium-on CXL was introduced to avoid epithelial removal and its associated complications. Various techniques have been used to enhance the penetration of riboflavin through intact corneal epithelium, including the use of topical tetracaine,12 benzalkonium chloride (BAC),13,14 trometamol, and ethylenediaminetetraacetic acid.15–18 In some studies, mechanical microabrasions or punctures were induced over the corneal epithelium to further enhance the penetration of riboflavin, with good clinical results.18,19 Clinical http://dx.doi.org/10.1016/j.jcrs.2016.02.041 0886-3350
EPITHELIUM-ON CXL FOR ADVANCED KERATOCONUS
results with epithelium-on CXL were not as promising as with epithelium-off CXL.20,21 The corneal epithelium is a significant barrier to riboflavin absorption into the stroma.22 Gore et al.23 found that the existing commercial epithelium-on CXL protocols achieve relatively low riboflavin concentrations in the anterior corneal stroma compared with that achieved with established epithelium-off instillation. A reduced stromal riboflavin concentration could compromise the efficacy of riboflavin and ultraviolet-A (UVA) corneal CXL. Hypotonic riboflavin 0.1% solution without dextran has been used to increase the penetration of riboflavin into the corneal stroma.24 Recent studies25–27 showed that conventional CXL has a more pronounced flattening effect in cases with advanced keratoconus. The current study presents 1-year visual and keratometric results of tetracaine-assisted epithelium-on CXL for advanced keratoconus (median maximum keratometry [K] R58.0 diopters [D]). PATIENTS AND METHODS Patients This prospective contralateral-eye control study was performed at the School of Ophthalmology and Optometry and the Eye Hospital of Wenzhou Medical College, Wenzhou, China. The study was performed in accordance with the tenets of the Declaration of Helsinki. The hospital's ethics committee approved the study protocol. Informed consent was obtained from all patients before participation. Patients who were diagnosed with bilateral keratoconus were recruited between January 2010 and March 2013. Patients with progressive keratoconus, defined as an increase in maximum K and/or in manifest cylinder of 1.0 D or more over the past 12 months, were included. Patients with a corneal thickness of less than 400 mm, endothelial cell density less than 2000 cell/mm2, severe corneal scarring or ocular surface disease, autoimmune disease, or pregnancy
739
were excluded. The worse eye of each patient received CXL; the fellow eye was left untreated.
Ocular Examination All patients had an uncorrected distance visual acuity (UDVA) and corrected distance visual acuity (CDVA) measurement, slitlamp examination, refraction (RT-2100, Nidek Co. Ltd.), and Scheimpflug corneal topography (Pentacam, Oculus Optikger€ ate GmbH) before and at 1, 3, 6, and 12 months after epithelium-on CXL. The mean K, flat K, steep K, maximum K, central corneal thickness (CCT), thinnest corneal thickness, anterior elevation, and posterior elevation were evaluated. A fixed best-fit sphere of 8.0 mm was used for all measurements. All patients were asked to discontinue contact lens wear 2 weeks before the preoperative and postoperative evaluations.
Surgical Technique The CXL was performed without epithelial debridement. During the riboflavin imbibition period, patients were allowed to blink normally. Tetracaine 1.0% without BAC was applied every minute for 15 minutes. Subsequently, hypotonic riboflavin 0.5% solution without dextran (China Resources Double-Crane Pharmaceutical Co. Ltd.) was applied every minute for 30 minutes. The corneal thickness was measured with ultrasonic pachymetry (SP-3000, Tomey, Ltd.) before UVA illumination. In cases in which the corneal thickness was less than 400 mm before UVA illumination, the corneal stroma was hydrated with distilled water until a corneal thickness of 400 mm or more was achieved. A blepharostat was inserted. Using a circular spot diameter of 9.0 mm, 365 nm UVA with irradiance of 3mW/cm2 (UV-X, IROC Innocross AG) was applied over the cornea for 30 minutes. During UVA illumination, tetracaine was instilled 2 to 3 times for anesthesia. After completion of treatment, the residual riboflavin solution was rinsed out with a balanced salt solution. One drop each of tobramycin and dexamethasone was applied, and a bandage contact lens was inserted. The bandage contact lens was removed on the first postoperative day. A mixture of topical tobramycin and dexamethasone was started 4 times a day for 1 week. Artificial teardrops were used 6 times a day for 1 month postoperatively.
Statistical Analysis
Submitted: November 5, 2015. Final revision submitted: January 29, 2016. Accepted: February 1, 2016. From the Department of Ophthalmology (Chen, Zhang, Ding, Li, Wang), Affiliated Eye Hospital of Wenzhou Medical College, Wenzhou, Zhejiang, the Department of Ophthalmology and Visual Sciences (T.C.Y. Chan, Jhanji), Chinese University of Hong Kong, and Hong Kong Eye Hospital (T.C.Y. Chan, J.C.K. Chan, Jhanji), Mongkok, Kowloon, and the Department of Mathematics and Statistics (Yu), Hang Seng Management College, Hong Kong, China. Supported by the Wenzhou Key Scientific and Technological Innovation Team Project and the Wenzhou City Technology Bureau Project. Corresponding author: Vishal Jhanji, MD, FRCOphth, Department of Ophthalmology and Visual Sciences, Chinese University of Hong Kong, Hong Kong, China. E-mail: [email protected].
Statistical analysis was performed using R 2.15.3 (R Foundation for Statistical ComputingA). Comparisons of UDVA, CDVA, spherical equivalent (SE), K, corneal thickness, anterior elevation, and posterior elevation measurements between different timepoints were performed using Wilcoxon signed-rank tests. A P value less than 0.05 was considered statistically significant. Comparisons of these parameters between treated eyes and fellow untreated eyes were performed using Friedman tests. Bonferroni adjustments were considered for multiple testing in pairwise comparisons between different timepoints.
RESULTS Data for comparison was available from 21 treated eyes and 16 fellow untreated eyes at the end of 12 months. The median age of the patients was 20.4 years (interquartile range [IQR], 9.5 years).
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Table 1. Visual and topographic characteristics before and after transepithelial CXL for progressive keratoconus. P Value* Parameter UDVA (logMAR) Baseline 1 month 3 months 6 months 12 months CDVA (logMAR) Baseline 1 month 3 months 6 months 12 months SE (D) Baseline 1 month 3 months 6 months 12 months Ksteep (D) Baseline 1 month 3 months 6 months 12 months Kflat (D) Baseline 1 month 3 months 6 months 12 months Km (D) Baseline 1 month 3 months 6 months 12 months Kmax (D) Baseline 1 month 3 months 6 months 12 months CCT (mm) Baseline 1 month 3 months 6 months 12 months TCT (mm) Baseline 1 month 3 months
Mean
SD
Vs Baseline
Vs 1 Mo
Vs 3 Mo
Vs 6 Mo
0.97 0.85 0.85 0.80 0.79
0.36 0.30 0.27 0.32 0.26
d .092 .040 .029 .002
d d .445 .238 .089
d d d .678 .343
d d d d .636
0.34 0.30 0.31 0.28 0.25
0.19 0.18 0.18 0.18 0.17
d .167 .070 .009 !.001
d d .397 .021 .001
d d d .171 .006
d d d d .007
7.63 6.88 6.87 5.91 5.70
4.68 4.98 4.97 4.74 4.50
d !.001 .003 !.001 !.001
d d .848 .004 .022
d d d .026 .010
d d d d .100
55.26 54.57 54.76 54.28 54.51
6.25 5.36 6.41 6.35 6.28
d .153 !.001 .003 .002
d d !.001 .004 .001
d d d .670 .322
d d d d .737
50.32 49.91 50.30 49.83 50.16
5.60 5.02 5.47 5.68 5.82
d .026 .741 .554 .523
d d .007 .012 .008
d d d .911 .466
d d d d .721
52.64 52.12 52.43 51.93 52.24
5.81 5.05 5.84 5.89 5.97
d .036 .088 .020 .054
d d .002 .002 .001
d d d .709 .848
d d d d .594
63.95 63.18 62.75 61.88 62.32
9.60 9.31 9.08 8.84 8.97
d .781 .001 .006 !.001
d d .002 .018 .001
d d d .872 .173
d d d d .010
456.24 447.47 442.65 449.04 453.20
43.16 40.29 49.18 53.13 50.09
d !.001 .008 .023 .264
d d .717 .028 .004
d d d .025 .004
d d d d .036
443.24 435.19 433.04
42.22 39.11 50.72
d .001 .019
d d .643
d d d
d d d (continued on next page)
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Table 1. (Cont.) P Value* Parameter
Mean
SD
Vs Baseline
6 months 12 months AE (mm) Baseline 1 month 3 months 6 months 12 months PE (mm) Baseline 1 month 3 months 6 months 12 months
438.43 439.64
53.68 45.55
.037 .183
40.48 39.90 36.65 36.39 37.76
16.27 17.08 14.32 14.41 15.52
83.40 79.33 81.08 78.60 78.64
34.18 26.76 37.74 33.60 31.21
Vs 1 Mo
Vs 3 Mo
Vs 6 Mo
.038 .014
.062 .032
d .241
d .361 .006 .017 .003
d d .001 .003 .001
d d d .102 .431
d d d d .731
d .837 .478 .454 .216
d d .316 .779 .150
d d d .741 .135
d d d d .062
AE Z anterior elevation; CCT Z central corneal thickness; CDVA Z corrected distance visual acuity; Kflat Z keratometry at flat axis; Kmax Z maximal keratometry; Kmean Z mean keratometry; Ksteep Z keratometry at steep axis; PE Z posterior elevation; SE Z spherical equivalent; TCT Z thinnest corneal thickness; UDVA Z uncorrected distance visual acuity *Wilcoxon signed-rank tests were considered significant at a 5% level with Bonferroni adjustments for multiple testing between different timepoints (ie, P ! .005).
Table 1 shows the treatement results. A significant improvement in UDVA was observed at 12 months compared with baseline values. The postoperative CDVA was better at 6 months and 12 months than at baseline. The SE dropped significantly after surgery. The SE changed by 1.93 D by the end of 12 months. The mean K remained stable throughout the 1-year follow-up period. Maximum K decreased significantly 12 months postoperatively. The change in maximum K, steep K, flat K, and mean K values was 1.63 D, 0.75 D, 0.16 D, and 0.40 D, respectively, at the end of 12 months postoperatively. The median preoperative maximum K was 62.7 D (IQR, 12.9 D). One year postoperatively, 11 eyes had a decrease in maximum K of 1.0 D or more; no eye had an increase in maximum K of more than 1.0 D. The anterior elevation remained fairly stable up to 6 months. Overall, there was a statistically significant decrease in anterior elevation between baseline and 12-month anterior elevation values. There was no significant change in posterior elevation at any follow-up timepoint (Table 1). The CCT dropped significantly 1 month and 3 months postoperatively; this was followed by an increase over the subsequent 9 months. As a consequence, there was no statistically significant difference between the baseline CCT and 12-month CCT. Similarly, the thinnest corneal thickness decreased during the 3 months postoperatively; this was followed by a slow increase thereafter. The overall change in corneal thickness was less than 5 mm over the 12-month follow-up (Table 1).
Sixteen patients completed visual and topographic examinations of both eyes at the end of 12 months. The changes in UDVA and CDVA were significantly greater after CXL than in the fellow untreated eyes. The reduction in maximum K was also higher after CXL, with more change in anterior elevation but not in posterior elevation compared with the change in the fellow eyes, there was no difference in the change in corneal thickness between the treated eyes and untreated eyes (Table 2). No intraoperative or postoperative complications occurred. Transient corneal haze was observed in all eyes during the first postoperative week. DISCUSSION The data in the current study suggest that epitheliumon CXL can halt keratoconus progression over 1 year of follow-up. Previous studies of the efficacy of epithelium-on CXL13–21,28–34 had variable results, mainly because of the different surgical protocols shown in Table 3. Furthermore, studies25–27,35 have also shown that CXL is more effective in stabilizing eyes with keratoconus and a high maximum K. This trend was also observed in studies evaluating epithelium-on CXL. Studies of eyes with a high preoperative maximum K showed flattening of maximum K,14,16,18,30 whereas studies of eyes with low to moderate preoperative maximum K showed stabilizing or even worsening of maximum K.13,15,17,20,31,33 Indeed, in other studies13–19,21,28–33 as well as ours,
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Table 2. Comparison of visual and topographic outcomes in eyes after transepithelial CXL for progressive keratoconus and the contralateral control eyes. CXL Parameter UDVA (logMAR) 3 months preop 6 months – preop 12 months – preop CDVA (logMAR) 3 months preop 6 months – preop 12 months – preop SEQ (D) 3 months preop 6 months – preop 12 months – preop Ksteep (D) 3 months preop 6 months – preop 12 months – preop Kflat (D) 3 months preop 6 months – preop 12 months – preop Km (D) 3 months preop 6 months – preop 12 months – preop Kmax (D) 3 months preop 6 months – preop 12 months – preop CCT (mm) 3 months preop 6 months – preop 12 months – preop TCT (mm) 3 months preop 6 months – preop 12 months – preop AE (mm) 3 months preop 6 months – preop 12 months – preop PE (mm) 3 months preop 6 months – preop 12 months – preop
Mean
Control SD
Mean
SD
P Value*
0.141 0.335 0.147 0.364 0.171 0.320
0.057 0.045 0.123
0.175 0.237 0.204
.157 .034 .001
0.053 0.209 0.056 0.200 0.094 0.218
0.013 0.012 0.002
0.043 0.046 0.042
.008 .096 .001
0.365 4.767 1.634 4.460 1.773 4.749
0.135 0.241 0.172
0.367 0.997 1.164
.366 .033 .134
0.657 6.532 0.900 6.268 0.969 6.486
0.071 0.133 0.150
0.312 0.430 0.528
.001 .001 .003
0.057 5.528 0.400 5.381 0.188 5.492
0.071 0.153 0.012
0.350 .782 0.393 .796 0.606 1.000
0.300 5.902 0.620 5.694 0.506 5.863
0.021 0.013 0.063
0.294 0.307 0.541
.593 .109 .046
1.386 10.166 1.740 10.451 2.107 10.451
0.086 0.207 0.207
0.293 0.505 0.505
.033 .020 .001
14.857 62.492 32.071 126.423 7.667 47.658 28.933 119.570 2.125 61.516 28.500 114.444
.033 .071 .617
13.143 48.079 4.733 47.363 3.500 47.571
1.214 10.793 0.200 11.797 1.938 13.051
.013 .071 .617
4.143 18.826 4.067 18.828 4.813 18.855
0.143 0.200 1.063
1.956 1.971 3.605
.002 .002 .001
1.929 35.331 5.933 35.716 13.875 35.658
0.500 0.067 0.000
4.553 1.000 9.588 .796 6.186 .052
AE Z anterior elevation; CCT Z central corneal thickness; CDVA Z corrected distance visual acuity; Kflat Z keratometry at flat axis; Kmax Z maximal keratometry; Kmean Z mean keratometry; Ksteep Z keratometry at steep axis; PE Z posterior elevation; SEQ Z spherical equivalent; TCT Z thinnest corneal thickness; UDVA Z uncorrected distance visual acuity *Friedman tests were considered statistically significant at a 5% level with Bonferroni adjustments for multiple testing between different timepoints (ie, P ! .017)
correlation analysis of the change in maximum K between preoperative values and values over 6 to 12 months postoperatively showed a significant correlation (r Z 0.764, P ! .001; Spearman correlation) (Figure 1). Reasons for more pronounced flattening of maximum K after epithelium-on CXL in advanced keratoconus are not fully understood. We hypothesize that this could be partly attributed to a relatively deeper penetration of crosslinking in eyes with advanced keratoconus. Epithelium-on CXL is reported in the peer-reviewed literature,29 with results showing a significantly weaker biomechanical effect than epithelium-off CXL.15 Gore et al.23 reported reduced stromal riboflavin concentration using commercially available riboflavin formulations during epithelium-on CXL compared with during conventional epithelium-off CXL. The authors noted that peak stromal riboflavin concentrations for MedioCross TE (Avedro), RicrolinC (Sooft italia S.p.A.), Paracel/Xtra (Avedro), and Ribocross TE (Servimed Srl) were 0.054%, 0.031%, 0.021%, and 0.015%, respectively. The stromal concentration at a depth of 300 mm in epithelium-off corneas was 0.075%, whereas at the same depth, MedioCross TE and RicrolinC achieved 0.018% and 0.016%, respectively.23 Another issue that affects epithelium-on CXL relates to UVA absorption and filtering by the intact epithelium.36,37 Results in a study by Baiocchi et al.4 suggest that absorption by the epithelium is approximately one third, leading to less energy reaching the riboflavin-saturated stroma. This might be partially attributed to reduced riboflavin permeability through the intact epithelium, mainly because of its large molecular weight.4 It remains to be seen whether increased UVA irradiance is necessary for better epithelium-on CXL results.37 The biomechanical efficacy of epithelium-on CXL has also been shown to be less than that of conventional CXL in rabbit corneas.22 Tetracaine administration alone was not sufficient to permit riboflavin penetration into the corneal stroma in an animal model.38 The stromal demarcation line was shallower, less distinct, or even absent after epithelium-on CXL.16,21,39 In the current study, chemical disruption of the epithelial tight junctions was attempted by application of tetracaine. A hypotonic riboflavin solution was used without dextran to increase the permeability of the corneal epithelium. We used riboflavin 0.5% to enhance its penetration and achieve higher UVA absorption. The absorption coefficient of riboflavin has been found to linearly correlate with concentrations up to 0.5%.40 Postoperatively, we noted a significant decrease in anterior elevation but not in posterior elevation after epithelium-on CXL, suggesting that the flattening effect was mainly over the
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Table 3. Summary of studies using transepithelial corneal CXL with chemical enhancers. Corneal Thickness (mm)
Design
Eyes†
Enhancement
UDVA
CDVA
Keratometry (D)
Koppen13/2012
Prospective study Follow up: 12 months in 37 eyes 18 months in 21 eyes
53 eyes of 38 patients Mean age: 24.02 G 7.29 (12, 46)
Proparacaine with benzalkonium chloride, riboflavin 0.1% with dextran 20%
Not reported
Change from baseline 12 months: 0.06 P !.05 18 months: 0.05
Change from baseline 12 months: 8.06 P !.05 18 months: 10.31 P !.05
None reported
Lesniak14/2014
Prospective comparative study Follow up: 6 months
30 eyes from 25 patients 1-min group: 18 eyes 2-min group: 12 eyes Mean age: 31.8 (18, 58)
Proparacaine containing benzalkonium chloride, riboflavin 0.1% (hypotonic) without dextran 1-min or 2-min group: riboflavin added every 1 or 2 min during UVA
1-min group: 0.98 / 0.91 2-min group: 0.73 / 0.64 P Z .845 for changes after TE-CXL between both groups Overall: 0.88 / 0.80 P Z .114
Not reported
None reported
Leccisotti15/2010
Prospective comparative study Follow up: 12 months
51 out of 64 patients completed Fellow eye as control Mean age: 26.9 G 6.3 (18, 39)
Gentamicin, EDTA, benzalkonium chloride, oxybuprocaine, riboflavin 0.1% with dextran 20%
Not reported
1-min group: 0.28 / 0.22 2-min group: 0.36 / 0.25 P !.05 for 1-min group compared with baseline P Z .572 for changes after TECXL between groups Overall: 0.31 / 0.23 P Z .032 Control 0.081 / 0.120 P !.05 TE-CXL 0.111 / 0.075 P !.05 P !.05 between groups
Change from baseline Placido 12 months: 0.47 18 months: 0.65 Scheimpflug 12 months: 1.33 P !.05 18 months: 1.76 P !.05 1-min group: 56.60 / 56.14 2-min group: 61.82 / 60.36 P !.05 for 2-min group compared with baseline P Z .119 changes after TECXL between groups Overall: 58.69 / 57.83 P Z .010
Not reported
2 cases of TE-CXL showed transient subepithelial haze
Filippello16/2012
Prospective comparative study Follow up: 18 months
40 eyes from 20 patients Contralateral eye as control Mean age: 27 (12, 42)
Oxybuprocaine, riboflavin 0.1% with dextran 15% and trometamolEDTA Silicone ring
Control 0.84 / 0.98 TE-CXL 0.71 / 0.48 P !.05 between groups
Kapex Control 51.69 / 53.3 P O.05 TE-CXL 54.31 / 54.81 P O.05 P O.05 between groups Kapex Control 58.89 / 60.93 P O.05 TE-CXL 59.12 / 57.95 P !.05
Study*/Year
Transient hyperemia, foreign body sensation, photophobia after first few hours and days (continued on next page)
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J CATARACT REFRACT SURG - VOL 42, MAY 2016
Control 0.46 / 0.64 TE-CXL 0.35 / 0.24 P !.05 between groups
Complications
Control 423 / 398 P O.05 TE-CXL 412 / 408 P O.05
743
744
Table 3. (Cont.) Study*/Year Caporossi17/2013
Rechichi18/2013
Corneal Thickness (mm)
Eyes†
Enhancement
UDVA
CDVA
Keratometry (D)
Prospective study Follow up: 24 months Prospective comparative study Follow up: 12 months
26 eyes of 26 patients Mean age: 22 (11, 26) 28 eyes of 28 patients Worst eye with highest average keratometry was treated, fellow eye as control Mean age: 28.8 (18, 41) 61 eyes of 53 patients Mean age: 32 G 10 (15, 52)
Riboflavin 0.1% with dextran 15% and trometamolEDTA Oxybuprocaine, riboflavin 0.1% with 15% dextran and trometamolEDTA Epithelial puncturing using corneal disruptor Silicone ring Proparacaine with benzalkonium chloride, microabrasion with Merocel sponge, riboflavin 0.5% (hypotonic) without dextran C-CXL Oxybuprocaine, riboflavin 0.1% with dextran 20% TE-CXL Tetracaine with benzalkonium chloride, riboflavin 0.1% without dextran
0.40 / 0.35 P Z .61
0.75 / 0.8 P Z .57
Kmax 48.59 / 50.14 P Z .05
461 / 429 P Z .04
5 patients retreated by C-CXL
Control 0.75 / 0.85 TE-CXL 0.73 / 0.48 P !.05
Control 0.29 / 0.37 TE-CXL 0.30 / 0.25 P !.05
Kapex Control 59.11 / 60.52 TE-CXL 59.21 / 56.18 P O.05
Control 442.38 / 427.50 TE-CXL 442.00 / 427.00 P O.05
None reported
20/133 / 20/67 PZ0
20/32 / 20/24 PZ0
Kmax 55.55 / 54.98 P Z .02
451 / 460 P Z .15
None reported
Change from baseline P Z .007 (12 months) P !.0001 (3 years) between groups
Change from baseline C-CXL 0.15 (12 months) 0.1 (3 years) TE-CXL 0.2 (12 months) 0.24 (3 years) P Z .30 (12 months) P Z .055 (3 years) between groups C-CXL 0.26 / 0.21 TE-CXL
Kmax C-CXL significantly decreased compared with baseline TE-CXL significantly increased compared with baseline P Z .0007 (12 months) P !.0001 (3 years) between groups
Not reported
C-CXL: Stromal haze, transient change in corneal thickness resolved in the first 6 months
C-CXL 57.8 / 56.8 TE-CXL
C-CXL 467 / 460 TE-CXL
4 eyes (15%) had complications
Stojanovic19/2012
Retrospective study Follow up: 12 months
Al Fayez20/2015
Prospective comparative study Follow up: 3 years
70 eyes of 70 patients C-CXL: 36 eyes TE-CXL: 34 eyes Mean age C-CXL: 24.1 G 5.3 TE-CXL: 24.8 G 4.2
Soeters21/2015
Prospective comparative study
61 eyes of 61 patients C-CXL: 26 eyes
C-CXL Riboflavin 0.1% (isotonic) with dextran 20%
C-CXL 1.07 / 0.97 TE-CXL
Complications
EPITHELIUM-ON CXL FOR ADVANCED KERATOCONUS
J CATARACT REFRACT SURG - VOL 42, MAY 2016
Design
J CATARACT REFRACT SURG - VOL 42, MAY 2016
Magli29/2013
Salman30/2013
TE-CXL: 35 eyes Median age C-CXL: 24 (18, 44) TE-CXL: 24 (18, 48)
Prospective study Follow up: 6 months in 16 eyes 12 months in 7 eyes Retrospective comparative study Follow up: 12 months
16 eyes of 16 patients Mean age: 34.4 G 11.9 (18, 61)
Prospective comparative study Follow up: 12 months
39 eyes of 30 patients C-CXL: 23 eyes of 19 patients TE-CXL: 16 eyes of 11 patients Mean age C-CXL: 14.75 G 2.1 TE-CXL: 15 G 2.1 44 eyes of 22 patients Right eye as TECXL while left eye as control Mean age: 15.7 G 2.1 (13, 18)
One eye received hypoosmolar riboflavin because of corneal thickness !400 mm after 30 min isotonic riboflavin TE-CXL Oxybuprocaine, riboflavin 0.1% with dextran 20% Silicone ring Oxybyprocaine with p-hydroxybenzoate, riboflavin 0.1% with trometamol and sodium EDTA C-CXL Riboflavin 0.1% with dextran 20% TE-CXL Riboflavin 0.1% with dextran 15% and trometamolEDTA Lidocaine Silicone ring
0.76 / 0.71 P Z .591 between groups
0.30 / 0.16 P Z .023 between groups
56.4 / 56.6 P Z .022 between groups
457 / 459 P !.001 between groups
after C-CXL versus none in TE-CXL 8 eyes (23%) showed an increase of Kmax O1 D in TE-CXL
0.95 / 0.61 (6 months) P Z .015 / 0.74 (12 months) P Z .295
0.37 / 0.33 (6 months) P Z.695 / 0.34 (12 months) P Z .817 C-CXL 0.36 / 0.36 P Z .8 TE-CXL 0.24 / 0.27 P Z .5 P O.05 between groups
Kapex 61.30 / 56.10 (6 months) P Z .027 / 58.21 (12 months) P Z .339
369.6 / 365.4 (6 months) P Z .579 / 367.7 (12 months) P Z .826
None reported
Kmax C-CXL 50.13 / 49.02 P Z .01 TE-CXL 49.27 / 48.13 P Z .02 P O.05 between groups
C-CXL 487.2 / 492 P Z .5 TE-CXL 490.2 / 488.0 P Z .6 P O.05 between groups
Proparacaine, riboflavin 0.1% with dextran 15% and trometamolEDTA
Control 0.84 / 0.94 P Z .324 TE-CXL 0.95 / 0.68 P Z .023
Control 0.42 / 0.51 P Z .543 TE-CXL 0.51 / 0.49 P Z .189
Kapex Control 61.30 / 64.20 P Z .044 TE-CXL 60.30 / 58.10 P Z .027
Control 482.6 / 477.7 P Z .579 TE-CXL 469.6 / 467.7 P Z .679
C-CXL Transient corneal edema Persistent cornea edema in 2 eyes TE-CXL Transient hyperemia, foreign body sensation and photophobia Epithelial defect, transient hyperemia and foreign body sensation
C-CXL 0.68 / 0.67 P Z .1 TE-CXL 0.55 / 0.54 P Z .3 P O.05 between groups
EPITHELIUM-ON CXL FOR ADVANCED KERATOCONUS
Spadea28/2012
Follow up: 12 months
(continued on next page)
745
746
Table 3. (Cont.)
Kmax 55.43 / 55.48 P Z .88
467.5 / 459.8 P Z .07
None reported
Kmax C-CXL 57.46 / 55.15 P !.001 TE-CXL 60.12 / 60.0 P O.05 C-CXL had greater reduction than TECXL P !.001 Kmax 48.90 / 52.90 P !.05
C-CXL 462 / 440.1 P !.05 TE-CXL 425.3 / 419.4 P !.001 C-CXL showed greater reduction than TE-CXL P Z .004
None reported
445 / 449 P O.05
None reported
Flat keratometry, 42.1 / 42.2 Steep keratometry, 44.4 / 43.7
503 / 528
None reported
Enhancement
UDVA
CDVA
Keratometry (D)
Prospective study Follow up: 6 months Retrospective comparative study Follow up: 18 months
36 eyes of 36 patients Mean age 24.5 G 5 (12, 33) 60 eyes of 43 patients C-CXL: 30 eyes of 20 patients TE-CXL: 30 eyes of 23 patients Mean age C-CXL: 23.7 G 3.9 TE-CXL: 22.8 G 4.7
Oxybuprocaine, riboflavin 0.1% with dextran 20% Silicone ring C-CXL Proparacaine, riboflavin 0.1% with 20% dextran TE-CXL Proparacaine, riboflavin 0.1% with dextran 20%
Not reported
0.72 / 0.89 P !.01
C-CXL 0.61 / 0.49 P !.001 TE-CXL 0.71 / 0.59 P !.001 P O.05 between groups
C-CXL 0.35 / 0.22 P !.001 TE-CXL 0.42 / 0.31 P !.001 P O.05 between groups
Buzzonetti33/2012
Prospective study Follow up: 18 months
0.19 / 0.1 P !.05
Case report Follow up: 6 months
Oxybuprocaine, riboflavin 0.1% with trometamol and sodium EDTA Riboflavin 0.25% with benzalkonium chloride 0.02%, followed by isotonic riboflavin 0.25% in saline Topographic custom UVA
Not reported
Kanellopoulos34/ 2014
13 eyes of 13 patients Mean age 14.4 G 3.7 (8, 18) 1 eye Age: 37
20/40 / 20/25
Not reported
C ¸ erman32/2015
C-CXL Z conventional collagen crosslinking; CDVA Z corrected distance visual acuity; EDTA Z ethylenediaminetetraacetic acid; Kapex Z apical keratometry; Kmax Z maximum keratometry; TE-CXL Z transepithelial collagen crosslinking; UDVA Z uncorrected distance visual acuity; UVA Z ultraviolet-A *First author † Some means are GSD; values in parentheses are ranges.
EPITHELIUM-ON CXL FOR ADVANCED KERATOCONUS
Complications
Eyes†
De Bernardo31/ 2014
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Corneal Thickness (mm)
Design
Study*/Year
EPITHELIUM-ON CXL FOR ADVANCED KERATOCONUS
Figure 1. Association between preoperative maximum K or apical K and its change over 6 to 12 months among studies in the literature (see Table 3).
anterior cornea. This suggests that epithelium-on CXL has a weaker strengthening effect than the conventional epithelium-off protocol. Indeed, the biomechanical stiffening effect of BAC-assisted epithelium-on CXL was only 20% of the standard protocol in an animal model.41 A recently published randomized control trial comparing epithelium-on CXL with epithelium-off CXL21 found fairly stable maximum K values and improvement in CDVA over 1 year after epitheliumon CXL. The trend in maximum K flattening over time was significantly different from that for epithelium-off CXL, which showed a flattening of maximum K beginning 3 months postoperatively. Surprisingly, epithelium-on CXL had a more favorable outcome between the 2 groups, and the authors believed this could be explained by the corneal haze formation at the first postoperative month in the epithelium-off CXL group.21 Raiskup et al.42 found permanent corneal haze leading to a loss of 2 lines or more of CDVA in 8.6% of patients after conventional CXL. We also found that most studies using epithelium-on CXL showed improvement or maintenance of visual acuity. A similar gain in CDVA between epithelium-off CXL and epithelium-on CXL regardless of a different topographic flattening effect has also been reported.32 This could be caused by the absence of corneal haze, which was found to be supported by a lesser extent of keratocyte apoptosis and inflammation after epithelium-on CXL.38,41 It is possible that epithelium-on CXL allows faster visual recovery than standard epithelium-off CXL, which
747
causes significant visual impairment and topographic worsening in the first few months after treatment.5–7 Another recent modification of epithelium-on CXL included the use of iontophoresis to increase riboflavin penetration through the epithelium. Studies43,44 have shown improvement in visual outcomes and topographic parameters after the treatment in pediatric and adult patients with keratoconus. Although the demarcation line in iontophoresis-assisted CXL was more superficial than that in conventional epitheliumoff CXL,45 it appeared to be more distinguishable and deeper than the chemical-enhanced epitheliumon CXL. Longitudinal studies comparing different chemical-enhanced protocols with iontophoresisassisted epithelium-on CXL are warranted in the future. The current study is limited by its small sample. We did not measure the demarcation line and degree of discomfort after the treatment. Variations in epithelium-on CXL protocols and patient preoperative states could affect efficacy. However, the results in our study suggest that epithelium-on CXL is a viable treatment for patients with advanced keratoconus. Sufficient topographic flattening was achieved, and the risk for corneal haze or scar formation was minimized. WHAT WAS KNOWN Epithelium-on corneal CXL is safe for treating progressive keratoconus. Variable corneal topographic flattening effects have been associated with the procedure. WHAT THIS PAPER ADDS Epithelium-on corneal CXL could improve corneal flattening in eyes with advanced keratoconus. A higher preoperative keratometry was associated with greater corneal flattening after epithelium-on CXL.
REFERENCES 1. Jhanji V, Sharma N, Vajpayee RB. Management of keratoconus: current scenario. Br J Ophthalmol 2011; 95:1044–1050 2. Kymes SM, Walline JJ, Zadnik K, Gordon MO; and the Collaborative Longitudinal Evaluation of Keratoconus (CLEK) Study Group. Quality of life in keratoconus. Am J Ophthalmol 2004; 138:527–535. Available at: https://vrcc.wustl.edu/clekarchive/ pdf/22%20Kymes%20-%20Quality%20of%20Life.pdf. Accessed March 5, 2016 3. Wollensak G, Spoerl E, Seiler T. Riboflavin/ultraviolet-A– induced collagen crosslinking for the treatment of keratoconus. Am J Ophthalmol 2003; 135:620–627. Available at: http:// iogen.fi/files/2011/10/Wollensak_et_al_Keratoconus_2003.pdf. Accessed March 5, 2016 4. Baiocchi S, Mazzotta C, Cerretani D, Caporossi T, Caporossi A. Corneal crosslinking: riboflavin concentration in corneal stroma exposed with and without epithelium. J Cataract Refract Surg 2009; 35:893–899
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