ORIGINAL ARTICLE
Accelerated versus conventional corneal collagen crosslinking Minoru Tomita, MD, PhD, Mariko Mita, MD, PhD, Tukezban Huseynova, MD
PURPOSE: To compare the outcomes of accelerated corneal collagen crosslinking (CXL) and conventional corneal CXL. SETTINGS: Private practice, Tokyo, Japan. DESIGN: Comparative study. METHODS: Eyes with keratoconus had accelerated CXL (KXL system; 15 minutes riboflavin [Vibex Rapid] presoak; 3 minutes 30 mW/cm2 ultraviolet-A [UVA] light) or conventional CXL (CCL-365 Vario system; 30 minutes riboflavin [Vibex] presoak; 30 minutes 3 mW/cm2 UVA light). The postoperative changes in visual acuity, keratometry readings, morphologic changes in the cornea, demarcation line existence, and corneal biomechanical responses with accelerated CXL and conventional CXL were compared. The follow-up was 1 year. RESULTS: The study enrolled 48 eyes of 39 patients; 30 eyes had accelerated CXL, and 18 eyes had conventional CXL. There were no statistically significant differences in postoperative changes in uncorrected or corrected distance visual acuity or in the manifest refraction spherical equivalent between the 2 procedures. There were also no statistically significant differences in the postoperative changes in the keratometric readings from the Pentacam Scheimpflug device or the corneal biomechanical responses from a dynamic bidirectional applanation device (Ocular Response Analyzer) or a dynamic Scheimpflug analyzer (Corvis ST) between the procedures. Similar morphologic changes and a pronounced demarcation line were apparent in eyes in both groups postoperatively. CONCLUSIONS: Accelerated CXL and conventional CXL were both safe and effective. Accelerated CXL, being a fast procedure, appears to be more beneficial for patients and surgeons. Financial Disclosure(s): No author has a financial or proprietary interest in any material or method mentioned. J Cataract Refract Surg 2014; 40:1013–1020 Q 2014 ASCRS and ESCRS
Keratoconus is a degenerative disorder of the eye in which structural changes in the cornea cause it to thin and develop a more conical shape than the normal gradual curve.1 Degraded normal collagen or synthesis of abnormal collagen might play a role in the pathogenesis of keratoconus. Keratoconus evolves as a result of increased levels of lysosomal and proteolytic enzymes2–4 and a decreased concentration of protease inhibitors,3,5 which results in corneal thinning and an altered configuration of corneal collagen lamellae.6,7 The only treatment that aims to stop or decrease the progression of keratoconus is collagen crosslinking (CXL) with ultraviolet-A (UVA) light and riboflavin. The treatment increases corneal rigidity8 and stiffens the anterior corneal stroma.9 The treatment, also known as CCR, CCL, and KXL,A is based on significant stiffening of the corneal stroma Q 2014 ASCRS and ESCRS Published by Elsevier Inc.
due to photochemical crosslinking of the individual collagen fibers. The treatment was first performed in the 1990s at Dresden University, Germany.10,11 In this study, we compared the outcomes of 2 CXL techniques; that is, conventional CXL and accelerated CXL. Both use the same dose of UVA irradiation but differ in the time of irradiation, the riboflavin solution used, and the soak time. PATIENTS AND METHODS This study comprised eyes with keratoconus that had conventional CXL or accelerated CXL. All patients signed informed consent forms, which explained the surgical procedure, possible risks, and patients' rights. All patients had a rigorous preoperative assessment and were determined to be suitable candidates for accelerated CXL or conventional CXL. 0886-3350/$ - see front matter http://dx.doi.org/10.1016/j.jcrs.2013.12.012
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Table 1. Differences between the 2 CXL procedures. Parameter Riboflavin Trade name* Ingredients Soak time (min) UVA System* Wavelength (nm) UVA irradiation (mW/cm2) Irradiation time (min) Total dose intensity (J/cm2)
Accelerated CXL
Conventional CXL
Vibex Rapid Isotonic 0.1% riboflavin with HPMC 15
Vibex Isotonic 0.1% riboflavin with 20.0% dextran T500 30
KXL 365 30 3 5.4
CCL-365 Vario 365 3 30 5.4
CXL Z collagen crosslinking; HPMC Z hydroxypropyl methylcellulose; UVA Z ultraviolet A *VibeX Rapid, VibeX, and the KXL system are by Avedro, Inc. The CCL-365 Vario system is by Peschke Meditrade GmbH.
Key inclusion criteria were age between 20 years and 45 years, progression of keratoconus, keratoconus classified as first or second stage according to the Amsler-Krumeich classification,12 central corneal thickness (CCT) greater than 400 mm, and endothelial cell density (ECD) greater than 2000 cell/cm2. Patients with ocular, corneal, or immune system disorders and those who were pregnant or breastfeeding were excluded from the study. Visual acuity before and after treatment was recorded using a logMAR chart. The following indices provided by the Pentacam conventional Scheimpflug system (Oculus Optikger€ate GmbH) were recorded: CCT, front average keratometry (Kmean) values, and maximum K (Kmax) value. The same Scheimpflug system was also used for tomographic evaluation, including sagittal curvature and anterior elevation maps, before and after treatment. The corneal biomechanical parameters were tested with a dynamic bidirectional applanation device (Ocular Response Analyzer, Reichert Ophthalmic Instruments) and a dynamic Scheimpflug analyzer (Corvis ST, Oculus Optikger€ate GmbH). Morphologic changes in the cornea were evaluated using confocal microscopy (Heidelberg Retinal Tomograph II Cornea Module, Rostock) preoperatively and postoperatively. The follow-up was 1 year.
Surgical Technique Corneal CXL was performed at Shinagawa LASIK Center under sterile conditions. The ocular surface was anesthetized several times with topical lidocaine hydrochloride 2.0%
Submitted: June 20, 2013. Final revision submitted: December 15, 2013. Accepted: December 20, 2013. From Shinagawa LASIK Center (Tomita, Mita, Huseynova), Tokyo, Japan; the Department of Ophthalmology (Tomita), Wenzhou Medical College, Wenzhou, China.
eyedrops (Xylocaine). To loosen the epithelium from the stroma, the retention ring was filled with an alcohol 20% solution and a 30-second soak was performed. The loosened epithelium was then removed from the 9.0 mm treatment zone using a smooth spatula. Table 1 shows the differences in the accelerated CXL and conventional CXL procedures. In both methods, after the administration of riboflavin, the corneal surface was rinsed thoroughly with a sterile solution. Ultrasound (US) pachymetry was then performed. If the cornea was thinner than 400 mm, distilled water was administered, after which US pachymetry was performed again to confirm that the stroma had swollen to more than 400 mm. This was repeated until adequate corneal thickness was obtained. Next, the cornea was exposed to UVA. At the end of the procedure, a soft contact lens bandage was placed on the eye. Postoperatively, moxifloxacin hydrochloride 0.5% (Vigamox), dexamethasone metasulfobenzoate sodium 0.1% (DEX), and hyaluronate sodium 0.3% (Hyalein mini) were administered every hour on the day of surgery. After 1 day, the medication dose was reduced to 5 times a day. The moxifloxacin hydrochloride 0.5% was continued for 1 week. The soft contact lens bandage was removed after 1 week. Fluorometholone 0.1% and sodium hyaluronate 0.3% were administered 5 times a day from 1 week to 1 month postoperatively. After 1 month, no medication was used.
Statistical Analysis The results are expressed as the mean G SD. The normality of the data was tested with the Shapiro-Wilk test. A paired t test was performed to analyze the postoperative changes. If the data were not distributed normally, the Wilcoxon rank-sum test was performed using JMP statistical software (version 9, SAS Institute, Inc.). The difference in outcomes between the 2 methods was assessed using an unpaired t test; if the distribution of the data was not distributed normally, the Mann-Whitney U test was performed. The level for statistical significance was set at P!.05.
Yuko Yoshida and Megumi Fujiwara provided editorial assistance. Corresponding author: Minoru Tomita, MD, PhD, Shinagawa LASIK Center, Yurakucho ITOCiA 14F, 2-7-1 Yurakucho, Chiyoda-ku, Tokyo 100-0006, Japan. E-mail: [email protected].
RESULTS The study enrolled 48 eyes of 39 patients. Table 2 shows the patients' demographics.
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Table 2. Preoperative patient demographic data. Parameter Eyes/patients (n) Age (y) Mean G SD Range Corneal astigmatism (D) Mean G SD Range MRSE (D) Mean G SD Range Mean K (D) G SD Mean Kmax G SD Mean Kmean G SD Mean CCT (mm) G SD Mean ECD (cells/cm2) G SD
Accelerated CXL Conventional CXL 30/21 31.17 G 5.5 21, 45
18/18 30.83 G 5.2 21, 39
2.43 G 1.62 0.25, 6.00
1.99 G 1.85 0.25, 7.50
5.37 G 3.07 0.38, 13.38
5.27 G 3.89 0.50, 15.13
50.45 G 5.28 45.51 G 2.30 515 G 28.68 2710 G 261.19
48.82 G 4.56 44.86 G 2.33 522 G 34.72 2843 G 310.87
CCT Z central corneal thickness; CXL Z collagen crosslinking; ECD Z endothelial cell density; K Z keratometry; Kmax Z maximum keratometry; Kmean Z front average keratometry; MRSE Z manifest refraction spherical equivalent
There were no statistically significant differences in postoperative uncorrected (UDVA) or corrected (CDVA) distance visual acuity between the
Figure 1. The UDVA and CDVA before and after accelerated CXL and conventional CXL (ACXL Z accelerated collagen crosslinking; CDVA Z corrected distance visual acuity; CXL Z conventional collagen crosslinking; UDVA Z uncorrected distance visual acuity).
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accelerated CXL group and the conventional CXL group (Figure 1). Figure 2 shows the mean K readings from the conventional Scheimpflug system preoperatively and during the 1-year follow-up. There was a statistically significant increase in the Kmax value 3 months after accelerated CXL (PZ.001). After conventional CXL, there was a statistically significant decrease in the Kmax value 1 year after treatment (PZ.0001). The decrease in the Kmean value was statistically significant 3, 6, and 12 months after conventional CXL and 6 and 12 months after accelerated CXL (both P!.05). Table 3 shows the mean values of the changes and the P values of the comparison between accelerated CXL and conventional CXL. There was a regression in the Kmax value obtained with the conventional Scheimpflug differential analysis system 1 year after both procedures (Figure 3). Table 4 shows the mean values of the biomechanical responses from the dynamic bidirectional applanation device and the dynamic Scheimpflug analyzer preoperatively and 1 year postoperatively. Figure 4 shows box plots of the distribution of the mean corneal biomechanical responses in terms of the preoperative changes and postoperative changes by method. Table 5 shows a between-group comparison of the mean change in corneal biomechanical responses 1
Figure 2. Kmax and Kmean values before and after accelerated CXL and conventional CXL (* Z statistically significant difference between time points; ACXL Z accelerated collagen crosslinking; CXL Z conventional collagen crosslinking; Kmax Z maximum keratometry; Kmean Z front average keratometry).
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Table 3. Between-group comparison of the mean change in outcomes 1 year postoperatively. Mean G SD Change Corneal astigmatism (D) MRSE (D) Keratometry (D) Kmax Kmean ECD (cells/cm2)
Accelerated CXL
Conventional CXL
P Value
0.42 G 1.11 0.64 G 1.84
0.15 G 1.64 0.39 G 0.88*
.59 .60
0.62 G 1.46 0.39 G 0.80* 106.66 G 254.74
1.77 G 2.65* 1.03 G 1.03* 365.06 G 976.19
.21 .06 .03
CXL Z collagen crosslinking; ECD Z endothelial cell density; Kmax Z maximum keratometry; Kmean Z front average keratometry; MRSE Z manifest refraction spherical equivalent *Statistically significantly decreased after treatment
year postoperatively. No statistically significant differences in the changes in corneal biomechanical response were found between the 2 methods. Figure 5 shows confocal images of the changes after accelerated CXL and conventional CXL at an anterior corneal depth of 150 mm. Elimination of stromal keratocytes, increased tissue reflectivity, and honeycomblike patterns were more pronounced 1 month after accelerated CXL (Figure 5, A). At 3 months, some keratocyte repopulation was evident with both types of CXL, and the honeycomb structures were still apparent (Figure 5, A and B). At 6 months, the honeycomb-like patterns were still visible in the conventional CXL eyes but were no longer visible in the
accelerated CXL eyes (Figure 5, B); however, at the 1-year follow-up, some honeycomb patterns were observable in both treatments groups. Figure 6 shows optical coherence tomography (OCT) images 1 month after treatment. The stromal demarcation line was at a depth of approximately 350 mm in the accelerated CXL eyes (Figure 6, A) and approximately 380 mm in the conventional CXL eyes (Figure 6, B). The mean demarcation line depth was 294.38 mm G 60.57 (SD) (range 197 to 402 mm) for accelerated CXL and 380.78 G 54.99 mm (range 280 to 466 mm) for conventional CXL; there was no statistically significant difference in the demarcation line depth between the 2 treatment groups (PO.05).
Figure 3. Scheimpflug differential analysis comparing 1-month postoperative with results accelerated CXL (A) and conventional CXL (B) (Kmax Z maximum keratometry).
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Table 4. Mean corneal biomechanical response outcomes. Mean G SD Accelerated CXL Device/Parameter Dynamic bidirectional applanation CH (mm Hg) CFR (mm Hg) Dynamic Scheimpflug analyzer DA (mm) Dist (mm) RadCurv (mm)
Conventional CXL
Preop
1 Y Postop
Preop
1 Y Postop
8.73 G 1.41 7.50 G 2.02
8.49 G 1.33 7.89 G 1.39
8.71 G 1.15 7.17 G 1.63
8.57 G 1.75 7.48 G 1.95
1.22 G 0.12 3.86 G 1.30 5.88 G 0.87
1.26 G 0.10 5.01 G 0.83 6.05 G 0.83
1.29 G 0.13 4.34 G 1.36 5.65 G 1.46
1.27 G 0.11 4.76 G 1.19 5.75 G 1.35
CH Z corneal hysteresis; CRF Z corneal resistance factor; CXL Z collagen crosslinking; DA Z deformation amplitude; Dist Z distance between corneal bending points; RadCurv Z radius of curvature
DISCUSSION Corneal CXL stabilizes the cornea in cases of keratoconus13 and ectasia.14,15 Collagen crosslinking provides a potential means for stiffening the cornea by increasing the molecular bonds, which increases the mechanical strength of the tissue. In vivo experiments have shown that a combination of UVA radiation and riboflavin is the most effective and least harmful procedure for inducing CXL in the human cornea. Wollensak et al.13 describe the most commonly used procedure for CXL, which is considered to be the conventional method. The UVA illumination associated with conventional CXL uses an irradiance of 3 mW/cm2 and a 365 nm source illuminating the riboflavin-treated eye for 30 minutes (cumulative dose 5.4 J/cm2).
In this study, we performed 2 methods of CXL: conventional and accelerated. The device used for accelerated CXL significantly reduces exposure time while maintaining the same treatment dose; hence, the description “accelerated.” After a riboflavin 0.1% solution is applied to the corneal surface, the system delivers UVA light (365 nm wavelength) in a uniform circular pattern to the cornea. The wavelength of 365 nm has been reported to achieve maximum absorption of the riboflavin while remaining below harmful DNA and retinal radiation levels.16 The UVA exposure in our study was performed for 3 minutes at a power of 30 mW/cm2 (total dose 5.4 J/cm2). The diffusion process of riboflavin 0.1% in dextran 20% in the corneal stroma has been modeled using a
Figure 4. Mean postoperative biomechanical responses changes (D Z change; ACXL Z accelerated collagen crosslinking; CH Z corneal hysteresis; CRF Z corneal resistance factor; CXL Z conventional collagen crosslinking; DA Z deformation amplitude; Dist Z distance between corneal bending points; RadCurv Z radius of curvature). J CATARACT REFRACT SURG - VOL 40, JUNE 2014
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Table 5. Between-group comparison of the mean change in corneal biomechanical responses 1 year postoperatively. Mean G SD Device/Change Dynamic bidirectional applanation CH (mm Hg) CFR (mm Hg) Dynamic Scheimpflug DA (mm) Dist (mm) RadCurv (mm)
Accelerated CXL
Conventional CXL
P Value
0.24 G 1.71 0.28 G 2.04
0.03 G 1.46 0.13 G 1.36
.72 .76
0.03 G 0.10 1.44 G 1.37* 0.01 G 0.86
0.00 G 0.11 0.45 G 1.53 0.18 G 2.26
.41 .14 .90
CH Z corneal hysteresis; CRF Z corneal resistance factor; CXL Z collagen crosslinking; DA Z deformation amplitude; Dist Z distance between corneal bending points; RadCurv Z radius of curvature *Statistically significant change
finite element model.B This model describes the transport of riboflavin in dextran 20% using the Fick second law of diffusion and of riboflavin UVA absorption in the corneal stroma using the BeerLambert law. The model showed that a riboflavin concentration gradient similar to that obtained with the classic Dresden protocol was obtained in the anterior cornea with a shortened soaking time and with less riboflavin present in the posterior cornea. Ultraviolet light is absorbed by riboflavin linearly according to the Beer-Lambert law. The model showed that similar doses of UVA absorbed by riboflavin in the anterior cornea theoretically provide CXL comparable to that in the classic protocol. A lower UVA dose absorbed by the significantly lower concentration of
riboflavin in the posterior cornea during accelerated CXL theoretically makes the shorter total procedure time safer for the endothelium. Based on this information, we chose a soak time of 15 minutes for our study in the accelerated CXL group to ensure safety to the endothelium. Corneal CXL leads to a marked increase in corneal biomechanical stability.17 This biochemical effect contributes to the increased resistance of the crosslinked corneas. One study17 concluded that when using the conventional UVA–riboflavin technique, a minimum preoperative corneal thickness of 400 mm after removal of the epithelium is mandatory to avoid damage to the corneal endothelium. Spoerl et al.15 showed that the UVA intensity (total 5.4 J/cm2)
Figure 5. Corneal morphological changes during after accelerated CXL (A) and conventional CXL (B) (CXL Z conventional collagen crosslinking). J CATARACT REFRACT SURG - VOL 40, JUNE 2014
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In addition, it is known that the turnover of corneal collagen is very slow.23 Therefore, prospective studies of accelerated CXL and conventional CXL outcomes with a follow-up of at least 8 to 10 years are necessary. WHAT WAS KNOWN Both accelerated CXL and conventional CXL are effective methods to treat eyes with keratoconus. WHAT THIS PAPER ADDS There were no significant differences in the outcomes between the 2 CXL methods. Figure 6. Optical coherence tomography images of the cornea 1 month after accelerated CXL (A) and conventional CXL (B).
used during CXL is far below the damage threshold for the corneal endothelium, iris, lens, and retina. The structures at greatest risk for damage from induced radicals are keratocytes and the corneal endothelium. After CXL, keratocytes show apoptosis to a stromal depth of 320 mm.15 In our study, the depth of effective treatment was evaluated using OCT images 1 month after treatment. The stromal demarcation line was at the depth of approximately 350 mm in the accelerated CXL group and approximately 380 mm in the conventional CXL group. As 1 study found,15 as long as the corneal stroma was 400 mm thick and the irradiance was 3 mW/cm2 or less, the endothelium was protected by the riboflavin concentration in the stroma. During accelerated CXL, the irradiance of UVA irradiation was increased to 30 mW/cm2; however, the time of irradiation was decreased to 3 minutes. No statistically significant difference in the preoperative to postoperative change in ECD was found between accelerated CXL and conventional CXL (PZ.68). We used corneal topography to monitor whether CXL was successful. In our study, we observed a regression of the Kmax values from the Pentacam Scheimpflug differential analysis system at 1 year after both treatments, which means that the corneas became flatter. According to the long-term follow-up presented by the Dresden group,18 on average, this flattening process can continue for years. The 3-month confocal microscopy results in our study are similar to those reported in the literature for conventional CXL19–21 and accelerated CXL.22 Reduced keratocyte density and stromal edema were observed in the anterior and intermediate stroma at 1 month. Three months postoperatively, keratocyte repopulation was noted in the central treated area, where the edema had partially disappeared.
Accelerated CXL is faster than the conventional CXL procedure, which makes it more beneficial than the conventional approach.
REFERENCES P, Malet F, Garra C, Gallois A, 1. Asri D, Touboul D, Fournie Malecaze F, Colin J. Corneal collagen crosslinking in progressive keratoconus: multicenter results from the French National Reference Center for Keratoconus. J Cataract Refract Surg 2011; 37:2137–2143 2. Rehany U, Lahav M, Shoshan S. Collagenolytic activity in keratoconus. Ann Ophthalmol 1982; 14:751–754 3. Kao WW, Vergnes JP, Ebert J, Sunder-Raj CV, Brown SI. Increased collagenase and gelatinase activities in keratoconus. Biochem Biophys Res Comm 1982; 107:929–936 4. Sawaguchi S, Yue BY, Sugar J, Gilboy JE. Lysosomal enzyme abnormalities in keratoconus. Arch Ophthalmol 1989; 107:1507–1510 5. Kenney MC, Nesburn AB, Burgeson RE, Butkowski RJ, Ljubimov AV. Abnormalities of the extracellular matrix in keratoconus corneas. Cornea 1997; 16:345–351 6. Daxer A, Fratzl P. Collagen fibril orientation in the human corneal stroma and its implication in keratoconus. Invest Ophthalmol Vis Sci 1997; 38:121–129. Available at: http://www.iovs.org/con tent/38/1/121.full.pdf. Accessed February 4, 2014 7. Meek KM, Tuft SJ, Huang Y, Gill PS, Hayes S, Newton RH, Bron AJ. Changes in collagen orientation and distribution in keratoconus corneas. Invest Ophthalmol Vis Sci 2005; 46:1948– 1956. Available at: http://www.iovs.org/content/46/6/1948.full. pdf. Accessed February 4, 2014 8. Wollensak G, Spoerl E, Seiler T. Stress-strain measurements of human and porcine corneas after riboflavin–ultraviolet-A-induced cross-linking. J Cataract Refract Surg 2003; 29:1780–1785 9. Kohlhaas M, Spoerl E, Schilde T, Unger G, Wittig C, Pillunat LE. Biomechanical evidence of the distribution of cross-links in corneas treated with riboflavin and ultraviolet A light. J Cataract Refract Surg 2006; 32:279–283 10. Spoerl E, Huhle M, Seiler T. Induction of cross-links in corneal tissue. Exp Eye Res 1998; 66:97–103 11. Spoerl E, Wollensak G, Seiler T. Increased resistance of crosslinked cornea against enzymatic digestion. Curr Eye Res 2004; 29:35–40 12. Krumeich JH, Daniel J. Lebend-Epikeratophakie und Tiefe € re Keratoplastik zur Stadiengerechten chirurgischen Lamella Behandlung des Keratokonus (KK) I-III [Live-epikeratophakia
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and deep lamellar keratoplasty for stage-related treatment of keratoconus]. Klin Monatsbl Augenheilkd 1997; 211:94–100 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://grmc. ca/assets/files/collagen_crosslinking_2003_wollensak.pdf. Accessed February 4, 2014 Hafezi F, Kanellopoulos J, Wiltfang R, Seiler T. Corneal collagen crosslinking with riboflavin and ultraviolet A to treat induced keratectasia after laser in situ keratomileusis. J Cataract Refract Surg 2007; 33:2035–2040 E, Trazza S. Corneal Vinciguerra P, Camesasca FI, Albe collagen cross-linking for ectasia after excimer laser refractive surgery: 1-year results. J Refract Surg 2010; 26:486–497 Spoerl E, Mrochen M, Sliney D, Trokel S, Seiler T. Safety of UVA– riboflavin cross-linking of the cornea. Cornea 2007; 26:385–389 €rl E, Reber F, Pillunat L, Funk R. Corneal Wollensak G, Spo endothelial cytotoxicity of riboflavin/UVA treatment in vitro. Ophthalmic Res 2003; 35:324–328 Raiskup-Wolf F, Hoyer A, Spoerl E, Pillunat LE. Collagen crosslinking with riboflavin and ultraviolet-A light in keratoconus: longterm results. J Cataract Refract Surg 2008; 34:796–801 Mazzotta C, Traversi C, Baiocchi S, Caporossi O, Bovone C, Sparano MC, Balestrazzi A, Caporossi A. Corneal healing after riboflavin ultraviolet-A collagen cross-linking determined by confocal laser scanning microscopy in vivo: early and late modifications. Am J Ophthalmol 2008; 146:527–533. Available at: http://www.bon.de/index.php/fileuploader/download/download/ ?dZ1&fileZcustom%2Fupload%2FFile-1389100729.pdf. Accessed February 14, 2014 Mazzotta C, Balestrazzi A, Baiocchi S, Traversi C, Caporossi A. Stromal haze after combined riboflavin-UVA corneal collagen cross-linking in keratoconus: in vivo confocal microscopic evaluation [letter]. Clin Exp Ophthalmol 2007; 35:580–582
21. Mazzotta C, Caporossi T, Denaro R, Bovone C, Sparano C, Paradiso A, Baiocchi S, Caporossi A. Morphological and functional correlations in riboflavin UV A corneal collagen crosslinking for keratoconus. Acta Ophthalmol 2012; 90:259–265. Available at: http://onlinelibrary.wiley.com/doi/10.1111/j.17553768.2010.01890.x/pdf. Accessed February 4, 2014 22. Touboul D, Efron N, Smadja D, Praud D, Malet F, Colin J. Corneal confocal microscopy following conventional, transepithelial, and accelerated corneal collagen cross-linking procedures for keratoconus. J Refract Surg 2012; 28:769–776 €ki T, Pelliniemi LJ, Vuorio E. Collagens and collagen23. Ihanama related matrix components in the human and mouse eye. Prog Retin Eye Res 2004; 23:403–434
OTHER CITED MATERIAL A. National Keratoconus Foundation. Keraflex Clinical Trial Starts in the US. August 2012. Available at: http://www.nkcf.org/kera flex-kxl. Accessed February 4, 2014 B. Pertaub R, Friedman MD, Eddington WA, Muller D. Computer modeling study of corneal cross-linking with riboflavin. IOVS 2012; 53:ARVO E-Abstract 6814. Available at: http://abstracts. iovs.org//cgi/content/abstract/53/6/6814?sidZ11d960e6-4563470a-adc6-1961df482911. Accessed February 4, 2014
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First author: Minoru Tomita, MD, PhD Private practice, Tokyo, Japan
Accelerated versus conventional corneal collagen crosslinking Minoru Tomita, MD, PhD, Mariko Mita, MD, PhD, Tukezban Huseynova, MD
PURPOSE: To compare the outcomes of accelerated corneal collagen crosslinking (CXL) and conventional corneal CXL. SETTINGS: Private practice, Tokyo, Japan. DESIGN: Comparative study. METHODS: Eyes with keratoconus had accelerated CXL (KXL system; 15 minutes riboflavin [Vibex Rapid] presoak; 3 minutes 30 mW/cm2 ultraviolet-A [UVA] light) or conventional CXL (CCL-365 Vario system; 30 minutes riboflavin [Vibex] presoak; 30 minutes 3 mW/cm2 UVA light). The postoperative changes in visual acuity, keratometry readings, morphologic changes in the cornea, demarcation line existence, and corneal biomechanical responses with accelerated CXL and conventional CXL were compared. The follow-up was 1 year. RESULTS: The study enrolled 48 eyes of 39 patients; 30 eyes had accelerated CXL, and 18 eyes had conventional CXL. There were no statistically significant differences in postoperative changes in uncorrected or corrected distance visual acuity or in the manifest refraction spherical equivalent between the 2 procedures. There were also no statistically significant differences in the postoperative changes in the keratometric readings from the Pentacam Scheimpflug device or the corneal biomechanical responses from a dynamic bidirectional applanation device (Ocular Response Analyzer) or a dynamic Scheimpflug analyzer (Corvis ST) between the procedures. Similar morphologic changes and a pronounced demarcation line were apparent in eyes in both groups postoperatively. CONCLUSIONS: Accelerated CXL and conventional CXL were both safe and effective. Accelerated CXL, being a fast procedure, appears to be more beneficial for patients and surgeons. Financial Disclosure(s): No author has a financial or proprietary interest in any material or method mentioned. J Cataract Refract Surg 2014; 40:1013–1020 Q 2014 ASCRS and ESCRS
Keratoconus is a degenerative disorder of the eye in which structural changes in the cornea cause it to thin and develop a more conical shape than the normal gradual curve.1 Degraded normal collagen or synthesis of abnormal collagen might play a role in the pathogenesis of keratoconus. Keratoconus evolves as a result of increased levels of lysosomal and proteolytic enzymes2–4 and a decreased concentration of protease inhibitors,3,5 which results in corneal thinning and an altered configuration of corneal collagen lamellae.6,7 The only treatment that aims to stop or decrease the progression of keratoconus is collagen crosslinking (CXL) with ultraviolet-A (UVA) light and riboflavin. The treatment increases corneal rigidity8 and stiffens the anterior corneal stroma.9 The treatment, also known as CCR, CCL, and KXL,A is based on significant stiffening of the corneal stroma Q 2014 ASCRS and ESCRS Published by Elsevier Inc.
due to photochemical crosslinking of the individual collagen fibers. The treatment was first performed in the 1990s at Dresden University, Germany.10,11 In this study, we compared the outcomes of 2 CXL techniques; that is, conventional CXL and accelerated CXL. Both use the same dose of UVA irradiation but differ in the time of irradiation, the riboflavin solution used, and the soak time. PATIENTS AND METHODS This study comprised eyes with keratoconus that had conventional CXL or accelerated CXL. All patients signed informed consent forms, which explained the surgical procedure, possible risks, and patients' rights. All patients had a rigorous preoperative assessment and were determined to be suitable candidates for accelerated CXL or conventional CXL. 0886-3350/$ - see front matter http://dx.doi.org/10.1016/j.jcrs.2013.12.012
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Table 1. Differences between the 2 CXL procedures. Parameter Riboflavin Trade name* Ingredients Soak time (min) UVA System* Wavelength (nm) UVA irradiation (mW/cm2) Irradiation time (min) Total dose intensity (J/cm2)
Accelerated CXL
Conventional CXL
Vibex Rapid Isotonic 0.1% riboflavin with HPMC 15
Vibex Isotonic 0.1% riboflavin with 20.0% dextran T500 30
KXL 365 30 3 5.4
CCL-365 Vario 365 3 30 5.4
CXL Z collagen crosslinking; HPMC Z hydroxypropyl methylcellulose; UVA Z ultraviolet A *VibeX Rapid, VibeX, and the KXL system are by Avedro, Inc. The CCL-365 Vario system is by Peschke Meditrade GmbH.
Key inclusion criteria were age between 20 years and 45 years, progression of keratoconus, keratoconus classified as first or second stage according to the Amsler-Krumeich classification,12 central corneal thickness (CCT) greater than 400 mm, and endothelial cell density (ECD) greater than 2000 cell/cm2. Patients with ocular, corneal, or immune system disorders and those who were pregnant or breastfeeding were excluded from the study. Visual acuity before and after treatment was recorded using a logMAR chart. The following indices provided by the Pentacam conventional Scheimpflug system (Oculus Optikger€ate GmbH) were recorded: CCT, front average keratometry (Kmean) values, and maximum K (Kmax) value. The same Scheimpflug system was also used for tomographic evaluation, including sagittal curvature and anterior elevation maps, before and after treatment. The corneal biomechanical parameters were tested with a dynamic bidirectional applanation device (Ocular Response Analyzer, Reichert Ophthalmic Instruments) and a dynamic Scheimpflug analyzer (Corvis ST, Oculus Optikger€ate GmbH). Morphologic changes in the cornea were evaluated using confocal microscopy (Heidelberg Retinal Tomograph II Cornea Module, Rostock) preoperatively and postoperatively. The follow-up was 1 year.
Surgical Technique Corneal CXL was performed at Shinagawa LASIK Center under sterile conditions. The ocular surface was anesthetized several times with topical lidocaine hydrochloride 2.0%
Submitted: June 20, 2013. Final revision submitted: December 15, 2013. Accepted: December 20, 2013. From Shinagawa LASIK Center (Tomita, Mita, Huseynova), Tokyo, Japan; the Department of Ophthalmology (Tomita), Wenzhou Medical College, Wenzhou, China.
eyedrops (Xylocaine). To loosen the epithelium from the stroma, the retention ring was filled with an alcohol 20% solution and a 30-second soak was performed. The loosened epithelium was then removed from the 9.0 mm treatment zone using a smooth spatula. Table 1 shows the differences in the accelerated CXL and conventional CXL procedures. In both methods, after the administration of riboflavin, the corneal surface was rinsed thoroughly with a sterile solution. Ultrasound (US) pachymetry was then performed. If the cornea was thinner than 400 mm, distilled water was administered, after which US pachymetry was performed again to confirm that the stroma had swollen to more than 400 mm. This was repeated until adequate corneal thickness was obtained. Next, the cornea was exposed to UVA. At the end of the procedure, a soft contact lens bandage was placed on the eye. Postoperatively, moxifloxacin hydrochloride 0.5% (Vigamox), dexamethasone metasulfobenzoate sodium 0.1% (DEX), and hyaluronate sodium 0.3% (Hyalein mini) were administered every hour on the day of surgery. After 1 day, the medication dose was reduced to 5 times a day. The moxifloxacin hydrochloride 0.5% was continued for 1 week. The soft contact lens bandage was removed after 1 week. Fluorometholone 0.1% and sodium hyaluronate 0.3% were administered 5 times a day from 1 week to 1 month postoperatively. After 1 month, no medication was used.
Statistical Analysis The results are expressed as the mean G SD. The normality of the data was tested with the Shapiro-Wilk test. A paired t test was performed to analyze the postoperative changes. If the data were not distributed normally, the Wilcoxon rank-sum test was performed using JMP statistical software (version 9, SAS Institute, Inc.). The difference in outcomes between the 2 methods was assessed using an unpaired t test; if the distribution of the data was not distributed normally, the Mann-Whitney U test was performed. The level for statistical significance was set at P!.05.
Yuko Yoshida and Megumi Fujiwara provided editorial assistance. Corresponding author: Minoru Tomita, MD, PhD, Shinagawa LASIK Center, Yurakucho ITOCiA 14F, 2-7-1 Yurakucho, Chiyoda-ku, Tokyo 100-0006, Japan. E-mail: [email protected].
RESULTS The study enrolled 48 eyes of 39 patients. Table 2 shows the patients' demographics.
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Table 2. Preoperative patient demographic data. Parameter Eyes/patients (n) Age (y) Mean G SD Range Corneal astigmatism (D) Mean G SD Range MRSE (D) Mean G SD Range Mean K (D) G SD Mean Kmax G SD Mean Kmean G SD Mean CCT (mm) G SD Mean ECD (cells/cm2) G SD
Accelerated CXL Conventional CXL 30/21 31.17 G 5.5 21, 45
18/18 30.83 G 5.2 21, 39
2.43 G 1.62 0.25, 6.00
1.99 G 1.85 0.25, 7.50
5.37 G 3.07 0.38, 13.38
5.27 G 3.89 0.50, 15.13
50.45 G 5.28 45.51 G 2.30 515 G 28.68 2710 G 261.19
48.82 G 4.56 44.86 G 2.33 522 G 34.72 2843 G 310.87
CCT Z central corneal thickness; CXL Z collagen crosslinking; ECD Z endothelial cell density; K Z keratometry; Kmax Z maximum keratometry; Kmean Z front average keratometry; MRSE Z manifest refraction spherical equivalent
There were no statistically significant differences in postoperative uncorrected (UDVA) or corrected (CDVA) distance visual acuity between the
Figure 1. The UDVA and CDVA before and after accelerated CXL and conventional CXL (ACXL Z accelerated collagen crosslinking; CDVA Z corrected distance visual acuity; CXL Z conventional collagen crosslinking; UDVA Z uncorrected distance visual acuity).
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accelerated CXL group and the conventional CXL group (Figure 1). Figure 2 shows the mean K readings from the conventional Scheimpflug system preoperatively and during the 1-year follow-up. There was a statistically significant increase in the Kmax value 3 months after accelerated CXL (PZ.001). After conventional CXL, there was a statistically significant decrease in the Kmax value 1 year after treatment (PZ.0001). The decrease in the Kmean value was statistically significant 3, 6, and 12 months after conventional CXL and 6 and 12 months after accelerated CXL (both P!.05). Table 3 shows the mean values of the changes and the P values of the comparison between accelerated CXL and conventional CXL. There was a regression in the Kmax value obtained with the conventional Scheimpflug differential analysis system 1 year after both procedures (Figure 3). Table 4 shows the mean values of the biomechanical responses from the dynamic bidirectional applanation device and the dynamic Scheimpflug analyzer preoperatively and 1 year postoperatively. Figure 4 shows box plots of the distribution of the mean corneal biomechanical responses in terms of the preoperative changes and postoperative changes by method. Table 5 shows a between-group comparison of the mean change in corneal biomechanical responses 1
Figure 2. Kmax and Kmean values before and after accelerated CXL and conventional CXL (* Z statistically significant difference between time points; ACXL Z accelerated collagen crosslinking; CXL Z conventional collagen crosslinking; Kmax Z maximum keratometry; Kmean Z front average keratometry).
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Table 3. Between-group comparison of the mean change in outcomes 1 year postoperatively. Mean G SD Change Corneal astigmatism (D) MRSE (D) Keratometry (D) Kmax Kmean ECD (cells/cm2)
Accelerated CXL
Conventional CXL
P Value
0.42 G 1.11 0.64 G 1.84
0.15 G 1.64 0.39 G 0.88*
.59 .60
0.62 G 1.46 0.39 G 0.80* 106.66 G 254.74
1.77 G 2.65* 1.03 G 1.03* 365.06 G 976.19
.21 .06 .03
CXL Z collagen crosslinking; ECD Z endothelial cell density; Kmax Z maximum keratometry; Kmean Z front average keratometry; MRSE Z manifest refraction spherical equivalent *Statistically significantly decreased after treatment
year postoperatively. No statistically significant differences in the changes in corneal biomechanical response were found between the 2 methods. Figure 5 shows confocal images of the changes after accelerated CXL and conventional CXL at an anterior corneal depth of 150 mm. Elimination of stromal keratocytes, increased tissue reflectivity, and honeycomblike patterns were more pronounced 1 month after accelerated CXL (Figure 5, A). At 3 months, some keratocyte repopulation was evident with both types of CXL, and the honeycomb structures were still apparent (Figure 5, A and B). At 6 months, the honeycomb-like patterns were still visible in the conventional CXL eyes but were no longer visible in the
accelerated CXL eyes (Figure 5, B); however, at the 1-year follow-up, some honeycomb patterns were observable in both treatments groups. Figure 6 shows optical coherence tomography (OCT) images 1 month after treatment. The stromal demarcation line was at a depth of approximately 350 mm in the accelerated CXL eyes (Figure 6, A) and approximately 380 mm in the conventional CXL eyes (Figure 6, B). The mean demarcation line depth was 294.38 mm G 60.57 (SD) (range 197 to 402 mm) for accelerated CXL and 380.78 G 54.99 mm (range 280 to 466 mm) for conventional CXL; there was no statistically significant difference in the demarcation line depth between the 2 treatment groups (PO.05).
Figure 3. Scheimpflug differential analysis comparing 1-month postoperative with results accelerated CXL (A) and conventional CXL (B) (Kmax Z maximum keratometry).
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Table 4. Mean corneal biomechanical response outcomes. Mean G SD Accelerated CXL Device/Parameter Dynamic bidirectional applanation CH (mm Hg) CFR (mm Hg) Dynamic Scheimpflug analyzer DA (mm) Dist (mm) RadCurv (mm)
Conventional CXL
Preop
1 Y Postop
Preop
1 Y Postop
8.73 G 1.41 7.50 G 2.02
8.49 G 1.33 7.89 G 1.39
8.71 G 1.15 7.17 G 1.63
8.57 G 1.75 7.48 G 1.95
1.22 G 0.12 3.86 G 1.30 5.88 G 0.87
1.26 G 0.10 5.01 G 0.83 6.05 G 0.83
1.29 G 0.13 4.34 G 1.36 5.65 G 1.46
1.27 G 0.11 4.76 G 1.19 5.75 G 1.35
CH Z corneal hysteresis; CRF Z corneal resistance factor; CXL Z collagen crosslinking; DA Z deformation amplitude; Dist Z distance between corneal bending points; RadCurv Z radius of curvature
DISCUSSION Corneal CXL stabilizes the cornea in cases of keratoconus13 and ectasia.14,15 Collagen crosslinking provides a potential means for stiffening the cornea by increasing the molecular bonds, which increases the mechanical strength of the tissue. In vivo experiments have shown that a combination of UVA radiation and riboflavin is the most effective and least harmful procedure for inducing CXL in the human cornea. Wollensak et al.13 describe the most commonly used procedure for CXL, which is considered to be the conventional method. The UVA illumination associated with conventional CXL uses an irradiance of 3 mW/cm2 and a 365 nm source illuminating the riboflavin-treated eye for 30 minutes (cumulative dose 5.4 J/cm2).
In this study, we performed 2 methods of CXL: conventional and accelerated. The device used for accelerated CXL significantly reduces exposure time while maintaining the same treatment dose; hence, the description “accelerated.” After a riboflavin 0.1% solution is applied to the corneal surface, the system delivers UVA light (365 nm wavelength) in a uniform circular pattern to the cornea. The wavelength of 365 nm has been reported to achieve maximum absorption of the riboflavin while remaining below harmful DNA and retinal radiation levels.16 The UVA exposure in our study was performed for 3 minutes at a power of 30 mW/cm2 (total dose 5.4 J/cm2). The diffusion process of riboflavin 0.1% in dextran 20% in the corneal stroma has been modeled using a
Figure 4. Mean postoperative biomechanical responses changes (D Z change; ACXL Z accelerated collagen crosslinking; CH Z corneal hysteresis; CRF Z corneal resistance factor; CXL Z conventional collagen crosslinking; DA Z deformation amplitude; Dist Z distance between corneal bending points; RadCurv Z radius of curvature). J CATARACT REFRACT SURG - VOL 40, JUNE 2014
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Table 5. Between-group comparison of the mean change in corneal biomechanical responses 1 year postoperatively. Mean G SD Device/Change Dynamic bidirectional applanation CH (mm Hg) CFR (mm Hg) Dynamic Scheimpflug DA (mm) Dist (mm) RadCurv (mm)
Accelerated CXL
Conventional CXL
P Value
0.24 G 1.71 0.28 G 2.04
0.03 G 1.46 0.13 G 1.36
.72 .76
0.03 G 0.10 1.44 G 1.37* 0.01 G 0.86
0.00 G 0.11 0.45 G 1.53 0.18 G 2.26
.41 .14 .90
CH Z corneal hysteresis; CRF Z corneal resistance factor; CXL Z collagen crosslinking; DA Z deformation amplitude; Dist Z distance between corneal bending points; RadCurv Z radius of curvature *Statistically significant change
finite element model.B This model describes the transport of riboflavin in dextran 20% using the Fick second law of diffusion and of riboflavin UVA absorption in the corneal stroma using the BeerLambert law. The model showed that a riboflavin concentration gradient similar to that obtained with the classic Dresden protocol was obtained in the anterior cornea with a shortened soaking time and with less riboflavin present in the posterior cornea. Ultraviolet light is absorbed by riboflavin linearly according to the Beer-Lambert law. The model showed that similar doses of UVA absorbed by riboflavin in the anterior cornea theoretically provide CXL comparable to that in the classic protocol. A lower UVA dose absorbed by the significantly lower concentration of
riboflavin in the posterior cornea during accelerated CXL theoretically makes the shorter total procedure time safer for the endothelium. Based on this information, we chose a soak time of 15 minutes for our study in the accelerated CXL group to ensure safety to the endothelium. Corneal CXL leads to a marked increase in corneal biomechanical stability.17 This biochemical effect contributes to the increased resistance of the crosslinked corneas. One study17 concluded that when using the conventional UVA–riboflavin technique, a minimum preoperative corneal thickness of 400 mm after removal of the epithelium is mandatory to avoid damage to the corneal endothelium. Spoerl et al.15 showed that the UVA intensity (total 5.4 J/cm2)
Figure 5. Corneal morphological changes during after accelerated CXL (A) and conventional CXL (B) (CXL Z conventional collagen crosslinking). J CATARACT REFRACT SURG - VOL 40, JUNE 2014
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In addition, it is known that the turnover of corneal collagen is very slow.23 Therefore, prospective studies of accelerated CXL and conventional CXL outcomes with a follow-up of at least 8 to 10 years are necessary. WHAT WAS KNOWN Both accelerated CXL and conventional CXL are effective methods to treat eyes with keratoconus. WHAT THIS PAPER ADDS There were no significant differences in the outcomes between the 2 CXL methods. Figure 6. Optical coherence tomography images of the cornea 1 month after accelerated CXL (A) and conventional CXL (B).
used during CXL is far below the damage threshold for the corneal endothelium, iris, lens, and retina. The structures at greatest risk for damage from induced radicals are keratocytes and the corneal endothelium. After CXL, keratocytes show apoptosis to a stromal depth of 320 mm.15 In our study, the depth of effective treatment was evaluated using OCT images 1 month after treatment. The stromal demarcation line was at the depth of approximately 350 mm in the accelerated CXL group and approximately 380 mm in the conventional CXL group. As 1 study found,15 as long as the corneal stroma was 400 mm thick and the irradiance was 3 mW/cm2 or less, the endothelium was protected by the riboflavin concentration in the stroma. During accelerated CXL, the irradiance of UVA irradiation was increased to 30 mW/cm2; however, the time of irradiation was decreased to 3 minutes. No statistically significant difference in the preoperative to postoperative change in ECD was found between accelerated CXL and conventional CXL (PZ.68). We used corneal topography to monitor whether CXL was successful. In our study, we observed a regression of the Kmax values from the Pentacam Scheimpflug differential analysis system at 1 year after both treatments, which means that the corneas became flatter. According to the long-term follow-up presented by the Dresden group,18 on average, this flattening process can continue for years. The 3-month confocal microscopy results in our study are similar to those reported in the literature for conventional CXL19–21 and accelerated CXL.22 Reduced keratocyte density and stromal edema were observed in the anterior and intermediate stroma at 1 month. Three months postoperatively, keratocyte repopulation was noted in the central treated area, where the edema had partially disappeared.
Accelerated CXL is faster than the conventional CXL procedure, which makes it more beneficial than the conventional approach.
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First author: Minoru Tomita, MD, PhD Private practice, Tokyo, Japan
