You are here

Article Text

Article menu

Download PDFPDF

Clinical science
Accelerated transepithelial corneal cross-linking for progressive keratoconus: a prospective study of 12 months
  1. Wei Aixinjueluo1,
  2. Tomohiko Usui1,
  3. Takashi Miyai1,
  4. Tetsuya Toyono1,
  5. Toshihiro Sakisaka1,
  6. Satoru Yamagami2
  1. 1 Department of Ophthalmology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
  2. 2 Division of Ophthalmology, Department of Visual Sciences, Nihon University, Chiyoda-ku, Japan
  1. Correspondence to Dr Wei Aixinjueluo, Department of Ophthalmology, Graduate School of Medicine, The University of Tokyo, Japan, 7-3-1 Hongo Bunkyo-ku, Tokyo 113-8655, Japan; waixinjueluo{at}yahoo.co.jp

Abstract

Background/aims To evaluate the clinical results of accelerated transepithelial corneal cross-linking (CXL) in Japanese patients with progressive keratoconus (KCN).

Methods Thirty eyes of 19 patients (16 male, 3 female patients) with progressive KCN were included. The mean age was 24.9±7.0 (range 16–38) years. All patients received ultraviolet A radiation for 3 min at an irradiance of 30 mW/cm2. Patients were followed up on the first day, at 1 week and 2 weeks, and at 1 month, 3 months, 6 months and 12 months postoperatively. Clinical examinations included measures of uncorrected visual acuity, best corrected visual acuity (BCVA), average keratometry (AveK), maximum keratometry (Kmax), central corneal thickness, thinnest corneal thickness (TCT), endothelial cell density, intraocular pressure and non-mydriatic indirect fundus examination. Patients were asked to report any pain or discomfort at each visit.

Results There were no intraoperative or postoperative complications. All 30 eyes finished the follow-up. After 12 months, there was a significant decrease in Kmax (p<0.0001), AveK (p=0.003) and TCT (p=0.002), and a significant improvement in BCVA (p=0.001). There were no other significant changes. Pain or foreign-body sensation following CXL appeared in the first 2 days, but lasted no more than 1 week in all cases.

Conclusions There were no complications associated with accelerated transepithelial corneal CXL, and the clinical outcomes were appraisable in a 12-month follow-up.

Trial registration number UMIN000009372.

  • Cornea
  • Optics and Refraction
  • Treatment Surgery

https://doi.org/10.1136/bjophthalmol-2016-309775

Statistics from Altmetric.com

    Request Permissions

    If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

    Introduction

    Keratoconus (KCN) is a bilateral, non-inflammatory, corneal ectatic disorder with classic histopathological features including progressive stromal thinning, iron deposition in the epithelial basement membrane and breaks in the Bowman's layer.1 It was reported that the keratocytes had an irregular structure, and there was a lack of obliquely oriented anterior-to-posterior lamellae crossing or interweaving the stress-bearing lamellae in the anterior stroma of KCN corneas.2 Moreover, the restricted distribution and decreased activity of the cross-linking enzyme lysyl oxidase in KCN corneas was suggested to be a potential reason for the inadequate collagen cross-linking that is a hallmark of this disease.3

    Since Wollensak et al 4 published the procedure of corneal cross-linking (CXL) in 2003, it has become an established therapy for KCN, post-laser in-situ keratomileusis ectasia and pellucid marginal degeneration to arrest the disease progression and to defer the timing of corneal transplantation.5 CXL is a procedure whereby riboflavin sensitisation with ultraviolet A (UVA) radiation induces the photopolymerisation of collagen fibrils in the corneal stroma. The standard treatment protocol of CXL, commonly referred to as the ‘Dresden protocol’, includes central removal of the epithelium, application of photosensitising riboflavin drops for 30 min and exposure to UVA (370 nm, 3 mW/cm2) radiation at a 1-cm distance for a duration of 30 min with a total energy of 5.4 J/cm2.4 CXL has been proven to increase corneal stiffness by up to 328.9%, based on a number of basic and clinical studies performed internationally over a period of over 10 years. Moreover, after CXL, many patients show flattening and regularisation of the corneal curvature, which can in turn cause a reduction of myopia and astigmatism.6–8 A transepithelial CXL (epithelium-on CXL, epi-on CXL) procedure was proposed in 2010 by Leccisotti and Islam9 with the aim to reduce the postoperative complications of epithelium-off CXL (epi-off CXL), such as infections, corneal haze, corneal oedema, sterile infiltrates and intense pain. The transepithelial penetration of riboflavin has been improved by using riboflavin solutions containing enhancers, such as benzalkonium chloride (BAC), tetracaine, surfactants, EDTA and trometamol.10 Transepithelial CXL is especially appealing for use in patients who are sensitive to the possible effects of epithelial debridement and patients with a central corneal thickness (CCT) of less than 400 μm, for whom the epi-off CXL procedure cannot be applied without serious risks to the endothelium.

    Recently, accelerated CXL has been established to shorten the duration of the standard CXL procedure by increasing illumination intensity. This protocol was based on the photochemical law of reciprocity (Bunsen-Roscoe law), which states that if the products of the intensity of illumination and the time of exposure are equal, the quantities of chemical material undergoing change will also be equal. The ex vivo results of CXL performed in porcine corneas show that the Bunsen-Roscoe reciprocity law is valid for illumination intensities up to 45 mW/cm2 and illumination times of more than 2 min.11 Several devices have been introduced for accelerated CXL, such as the UV-X 2000 (IROC AG, Zurich, Switzerland), CCL-VARIO (PESCHKE GmbH, Huenen-berg, Switzerland) and KXL (Avedro, Waltham, Massachusetts, USA), by which the operation time can be shortened from 1 hour to several minutes.

    Here we report our clinical results of accelerated transepithelial corneal CXL performed in patients with progressive KCN during a 12-month follow-up.

    Methods and materials

    Patients

    The study included 30 eyes of 19 patients (16 male and 3 female patients, age >14 years) with progressive KCN. The mean age was 24.9±7.0 (range 16–38) years. Two patients (4 eyes) were younger than 18 years and 17 patients (26 eyes) were aged between 19 years and 38 years. Eleven eyes were in stage I, 9 eyes were in stage II and 10 eyes were in stage III on the Amsler-Krumeich scale. Patients were recruited from among the outpatients of the Department of Ophthalmology, The University of Tokyo Hospital, between October 2012 and January 2015. All patients received an explanation of the study protocol and provided written informed consent.

    Inclusion and exclusion criteria

    To be eligible for inclusion, patients had to be over 14 years of age, diagnosed clinically with KCN, have clinical evidence of progression, and with thinnest corneal thickness (TCT) measuring >380 μm which is recommend by the transepithelial CXL protocol. Evidence of progressive KCN included an increase in maximum keratometry (Kmax) of greater than 1.00 dioptre (D), an increase in mean spherical refractive equivalent to 1.00 D, an increase in astigmatism of 1.00 D, or a decrease in base curve of hard contact lens of more than 0.1 mm over the previous 24 months. Patients had to have at least one of the parameters listed above to be included in the study.

    Patients were excluded from the study if they had a history of Descemet's membrane rupture, glaucoma, uveitis, severe dry eye, concurrent corneal infections, pseudophakic eyes or systemic disease that could affect corneal healing, such as diabetes. In addition, pregnant or lactating women were excluded from the study.

    Surgical procedure

    All patients were treated by accelerated transepithelial corneal CXL (KXL, Avedro). After topical anaesthesia (4% lidocaine), the corneal surface was treated by the application of 0.25% riboflavin solution supplemented with BAC, EDTA, trometamol, hydroxypropyl-methylcellulose (ParaCell, Avedro) for 4 min, and 0.25% riboflavin solution (VibeX Extra, Avedro) for 6 min. An additional drop was applied every 90 s during the soak time.

    The TCT was measured with a handheld ultrasound pachymeter (Handy Pachymeter, SP-100, TOMEY, Japan). If the TCT was thinner than 380 μm, distilled water was applied until the thickness condition was satisfied.

    UVA treatment at a 370 nm wavelength was performed with continued application of 0.25% riboflavin solution (VibeX Extra) at an irradiance of 30 mW/cm2 for 3 min, delivering a dose of 5.4 J/cm2 without corneal epithelial debridement. One drop of VibeX Extra was applied every 90 s during irradiation.

    After the irradiation, optical antibiotic ointment (0.3% ofloxacin) was instilled and an eye bandage was applied for 1 day. An antibiotic and corticosteroid (1.5% levofloxacin, 0.1% fluorometholone) were topically applied for 1 week. No more corticosteroid was used after the first week postoperatively.

    Patients were followed up clinically on the first day, and then at 1 week, 2 weeks, 1 month, 3 months, 6 months and 12 months postoperatively. Preoperative and postoperative examinations included uncorrected visual acuities (UCVAs), best corrected visual acuities (BCVAs), average keratometry (AveK), Kmax, CCT, TCT evaluated by anterior segment optical coherence tomography (Casia SS-1000, TOMEY, Japan), endothelial cell density (ECD) by specular microscopy (FA-3809, KONAN Medical, Japan), intraocular pressure (IOP) by applanation tonometry (Goldmann, Haag-Streit AG, Koeniz, Switzerland) and non-mydriatic indirect fundus examination with +20 D Volk lens (Volk Optical, Mentor, Ohio, USA). Patients were also asked to report any pain or discomfort during the procedure at each visit.

    Statistical analysis

    Results were analysed using the Wilcoxon test. Measurements at each follow-up were compared with the baseline values. Statistical analysis was performed using the JMP-12 software (JMP, Buckinghamshire, UK). p Values <0.05 were considered statistically significant.

    Results

    All surgeries were performed uneventfully, without intraoperative complications. All of the 30 eyes finished the 12-month follow-up postoperatively. The changes in the various measurements over the follow-up period are graphically represented using medians and IQR in figures 1 ⇓–3. In particular, there was a constant, significant improvement in log10 Minimum Angular Resolution BCVA scores over the follow-up period, from 0.18±0.32 at 1 month (p=0.02) to 0.13±0.24 at 12 months (p=0.001), in Kmax from 59.45±9.34 D at 3 months (p<0.0001) to 58.11±9.40 D at 12 months (p<0.0001) and in AveK from 52.17±7.76 D at 3 months (p=0.034) to 51.38±7.32 D at 12 months (p=0.003). In four eyes of two patients younger than 18 years, the Kmax, AveK, UCVA and BCVA showed no deterioration at 12 months. ECD showed no significant change throughout the 12-month follow-up period (2857.4±246.2; p=0.922).

    Figure 1
    Figure 1

    The log10 Minimum Angular Resolution (LogMAR) uncorrected visual acuities (UCVAs) and LogMAR best corrected visual acuities (BCVAs) after corneal cross-linking (CXL). There was no significant change in LogMAR BCVA at 1 week (0.96±0.57; p=0.841) and the trend lasted to the 12th month (0.91±0.52; p=0.398). The BCVA showed no significant change until 2 weeks (0.27±0.39; p=0.495), but improved from the 1st month (0.18±0.32; p=0.02) to the 12th month (0.13±0.24; p=0.001) *p<0.05, **p<0.01, ***p<0.001.

    Figure 2
    Figure 2

    The maximum keratometry (Kmax) and average keratometry (AveK) after corneal cross-linking (CXL). There was no significant change in Kmax from the 1st week (61.43±9.95 D; p=0.622) to the 1st month (60.91±9.73 D; p=0.170) but a statistically significant improvement from the 3rd month (59.45±9.34 D; p<0.0001) to the 12th month (58.11±9.40 D; p<0.0001) postoperatively. There was no significant change in AveK until 3 months, when the measured value improved to 52.17±7.76 D (p=0.034). The improvement continued to the 12th month (51.38±7.32 D; p=0.003) postoperatively. *p<0.05, **p<0.01, ***p<0.001.

    Figure 3
    Figure 3

    The central corneal thickness (CCT) and thinnest corneal thickness (TCT) after corneal cross-linking (CXL). CCT showed no significant change from the 1st week (438.4±47.5 μm; p=0.685) until the 12th month (432.4±48.9 μm; p=0.106), except at the 6-month follow-up (430.2±51.0 μm; p=0.025). There was no significant change in TCT up to the 3rd month (405.2±50.8 μm; p=0.329), but a statistically significant decrease from the 6th month (398.7±55.2 μm; p=0.008) to the 12th month (398.6±52.1 μm; p=0.002) postoperatively. *p<0.05, **p<0.01, ***p<0.001.

    In correlation analysis of the change in Kmax between preoperative values and 12-month values postoperatively showed a slight correlation (r=−0.394, p=0.032; Spearman's correlation) (figure 4).

    Figure 4
    Figure 4

    Correlation analysis of the change in Kmax between preoperative values and 12-month values postoperatively (Spearman's correlation). Change in Kmax between preoperative values and 12-month values postoperatively showed a slight correlation (r=−0.394, p=0.032).

    The corneal stromal demarcation line was determined by anterior segment optical coherence tomography (Casia SS-1000) at a depth of approximately 150–200 μm in 9 eyes (30% of the total number) (figure 5). Qualitatively, the demarcation is not as clear as can be observed with the standard procedure. There was no significant difference in the response to CXL between the eyes with and without the demarcation line.

    Figure 5
    Figure 5

    The corneal stromal demarcation line after corneal cross-linking (CXL). The corneal stromal demarcation line was determined by anterior segment optical coherence tomography (Casia SS-1000) at a depth of approximately 150–200 μm in nine eyes.

    There was no postoperative corneal haze, corneal oedema, sterile infiltrates or infection in any of the patients. The IOP and fundus showed no significant change. Pain or foreign body sensation following CXL was reported, especially in the first 2 days, but lasted no more than 1 week in all cases.

    Discussion

    This is the first report of the clinical results of accelerated transepithelial corneal CXL for progressive KCN in an Asian population, as far as we know. The only report of accelerated transepithelial CXL (45 mW/cm2 for 2 min 40 s) was published recently and showed no significant changes in spherical equivalent, corrected distance visual acuity (CDVA) and topographical indices, but did show a significant increase in TCT at 1-year and 2-year follow-ups, compared with preoperative measurements in 48 eyes.12 In our study, we analysed the UCVA, BCVA, AveK, Kmax, CCT, TCT and ECD data regularly from 1 week to 12 months postoperatively.

    A series for the Asian population that included 48 eyes with progressive KCN, with 30 eyes undergoing accelerated CXL (30 mW/cm2 for 3 min) and 18 eyes undergoing standard CXL, reported no significant change in uncorrected distance visual acuity (UDVA) and CDVA in both groups during the 12-month follow-up. Kmax showed a significant decrease 1 year after standard CXL and 3 months after accelerated CXL. Kmean showed a significant decrease 3 months, 6 months and 12 months after standard CXL and 6 months and 12 months after accelerated CXL.13 After accelerated transepithelial corneal CXL, we found statistically significant improvements in Kmax and AveK from the 3rd month to the 12th month postoperatively. BCVA showed significant improvements from the 1st month to the 12th month postoperatively while UCVA showed no significant change during the follow-up period. These clinical outcomes were comparable to those of accelerated CXL or standard CXL in an Asian population described above. There was almost no significant change in CCT, but there was a significant decrease in TCT from the 6th month to the 12th month. There was no postoperative corneal haze, corneal oedema, sterile infiltrates, infection or significant endothelial damage throughout the follow-up period. Pain or foreign body sensation following CXL appeared, especially in the first 2 days, but lasted no more than 1 week in all cases.

    The clinical outcomes of standard CXL have been well described in several trials.4 ,7 ,8 ,14–16 In a 5-year study of epi-off CXL in 40 eyes with progressive KCN, the mean K, Kmax, UCVA and astigmatism showed no change during the 5 years.7 A prospective trial over a 3-year follow-up period included 152 patients aged 10–18 years with progressive KCN (the ‘Siena CXL Pediatrics’ trial) and showed that CXL was also effective and safe for the paediatric population.16

    Accelerated CXL has been reported to be as safe and effective as standard CXL for the treatment of progressive KCN.13 ,17–19 A bilateral study of 21 patients with progressive KCN treated with accelerated CXL (7 mW/cm2 for 15 min) in one eye and with conventional CXL in the fellow eye showed no disease progression in each group, with similar improvement in visual acuity and keratometric parameters over a mean follow-up period of 46 months.19

    The clinical results of transepithelial CXL have been reported in case series and comparative trials with variable outcomes.9 ,20–25 A bilateral study of 20 eyes treated by transepithelial CXL reported significant improvement in UCVA, BCVA and keratometry values with no apparent progression in the transepithelial CXL group after 18 months, compared with untreated fellow eyes.20 In another bilateral study of 51 patients with KCN with CCT less than 400 μm undergoing transepithelial CXL, there was significant improvement in CDVA, spherical equivalent refraction and simulated keratometry compared with the untreated fellow eyes after 1 year.21 In a recently published bilateral study of advanced KCN where the worse eye received transepithelial CXL, and the fellow eye was left untreated, there were significant improvements in UDVA, CDVA and Kmax, compared with baseline values and untreated eyes at 1 year.22 However, in a prospective randomised controlled trial of 3-year follow-up with 70 eyes of mild and moderate KCN, Kmax showed a decrease in the epi-off group (36 eyes) but an increase in the epi-on group (34 eyes).23 Another randomised controlled trial of 1 year found an increase in Kmax in 23% of the epi-on group of 34 eyes compared with none in the epi-off group of 26 eyes, but a significant favourable outcome in CDVA in the epi-on group.24 The variable outcomes of the transepithelial CXL studies may result from the difference in ages of the patients, stages of KCN, riboflavin products, CXL devices and surgical procedures.

    In our study, we demonstrated that accelerated transepithelial corneal CXL was safe and effective for progressive KCN over a 12-month follow-up period. We observed faster recovery, and a reduced rate of complications and operative and postoperative discomfort related to epithelial removal. Accelerated transepithelial corneal CXL was also suggested to be more effective in advanced KCN with high keratometry. Although the reason is not known clearly at present, we suppose that a comparatively higher percentage of the cross-linked cornea in thinner eyes of advanced KCN may contribute to the better outcomes. The limitations of our study were the small sample size, the short follow-up period and the lack of control group. We customarily explain the surgical procedures, advantages and disadvantages of all possible protocols of CXL to every patient before the operation and admit his or her request. Almost all of the patients preferred the accelerated transepithelial protocol as it offered a shorter operative time and fewer complications even accompanied by the potentiality of less effect. As a result, we only perform CXL by other protocols in limited numbers and the scale is too small to be used as control at present. A longer follow-up with a larger number of patients including a control group treated with different CXL protocols or a multi-institutional joint research are mandatory to assess the long-term results and indications of accelerated transepithelial corneal CXL.

    References

    1. ↵
      2. Rabinowitz YS
      . Keratoconus. Surv Ophthalmol 1998;42:297–319. doi:10.1016/S0039-6257(97)00119-7
      OpenUrlCrossRefPubMedWeb of Science
    2. ↵
      2. Daxer A ,
      3. Fratzl P
      . Collagen fibril orientation in the human corneal stroma and its implication in keratoconus. Invest Ophthalmol Vis Sci 1997;38:121–9.
      OpenUrlAbstract/FREE Full Text
    3. ↵
      2. Dudakova L ,
      3. Liskova P ,
      4. Trojek T , et al
      . Changes in lysyl oxidase (LOX) distribution and its decreased activity in keratoconus corneas. Exp Eye Res 2012;104:74–81. doi:10.1016/j.exer.2012.09.005
      OpenUrlCrossRefPubMedWeb of Science
    4. ↵
      2. Wollensak G ,
      3. Spoerl E ,
      4. Seiler T
      . Riboflavin/ultraviolet-a-induced collagen crosslinking for the treatment of keratoconus. Am J Ophthalmol 2003;135:620–7. doi:10.1016/S0002-9394(02)02220-1
      OpenUrlCrossRefPubMedWeb of Science
    5. ↵
      2. Richoz O ,
      3. Mavrakanas N ,
      4. Pajic B , et al
      . Corneal collagen cross-linking for ectasia after LASIK and photorefractive keratectomy: long-term results. Ophthalmology 2013;120:1354–9. doi:10.1016/j.ophtha.2012.12.027
      OpenUrlCrossRefPubMedWeb of Science
    6. ↵
      2. Wittig-Silva C ,
      3. Whiting M ,
      4. Lamoureux E , et al
      . A randomized controlled trial of corneal collagen cross-linking in progressive keratoconus: preliminary results. J Refract Surg 2008;24:S720–725.
      OpenUrlPubMedWeb of Science
    7. ↵
      2. Hashemi H ,
      3. Seyedian MA ,
      4. Miraftab M , et al
      . Corneal collagen cross-linking with riboflavin and ultraviolet a irradiation for keratoconus: long-term results. Ophthalmology 2013;120:1515–20. doi:10.1016/j.ophtha.2013.01.012
      OpenUrlCrossRefPubMedWeb of Science
    8. ↵
      2. Caporossi A ,
      3. Mazzotta C ,
      4. Baiocchi S , et al
      . Long-term results of riboflavin ultraviolet a corneal collagen cross-linking for keratoconus in Italy: the Siena eye cross study. Am J Ophthalmol 2010;149:585–93. doi:10.1016/j.ajo.2009.10.021
      OpenUrlCrossRefPubMed
    9. ↵
      2. Leccisotti A ,
      3. Islam T
      . Transepithelial corneal collagen cross-linking in keratoconus. J Refract Surg 2010;26:942–8. doi:10.3928/1081597X-20100212-09
      OpenUrlCrossRefPubMed
    10. ↵
      2. Raiskup F ,
      3. Pinelli R ,
      4. Spoerl E
      . Riboflavin osmolar modification for transepithelial corneal cross-linking. Curr Eye Res 2012;37:234–8. doi:10.3109/02713683.2011.637656
      OpenUrlCrossRefPubMedWeb of Science
    11. ↵
      2. Wernli J ,
      3. Schumacher S ,
      4. Spoerl E , et al
      . The efficacy of corneal cross-linking shows a sudden decrease with very high intensity UV light and short treatment time. Invest Ophthalmol Vis Sci 2013;54:1176–80. doi:10.1167/iovs.12-11409
      OpenUrlAbstract/FREE Full Text
    12. ↵
      2. Kir MB ,
      3. Türkyılmaz K ,
      4. Oner V
      . Transepithelial High-Intensity Cross-Linking for the Treatment of Progressive Keratoconus: 2-year Outcomes. Curr Eye Res Epub ahead of print: 1 Jun 2016. doi:10.3109/02713683.2016.1148742 doi:10.3109/02713683.2016.1148742
    13. ↵
      2. Tomita M ,
      3. Mita M ,
      4. Huseynova T
      . Accelerated versus conventional corneal collagen crosslinking. J Cataract Refract Surg 2014;40:1013–20. doi:10.1016/j.jcrs.2013.12.012
      OpenUrlCrossRefPubMed
    14. ↵
      2. Poli M ,
      3. Lefevre A ,
      4. Auxenfans C , et al
      . Corneal collagen cross-linking for the treatment of progressive corneal ectasia: 6-year prospective outcome in a French population. Am J Ophthalmol 2015;160:654–62.e651. doi:10.1016/j.ajo.2015.06.027
      OpenUrl
    15. ↵
      2. Vinciguerra R ,
      3. Romano MR ,
      4. Camesasca FI , et al
      . Corneal cross-linking as a treatment for keratoconus: four-year morphologic and clinical outcomes with respect to patient age. Ophthalmology 2013;120:908–16. doi:10.1016/j.ophtha.2012.10.023
      OpenUrl
    16. ↵
      2. Caporossi A ,
      3. Mazzotta C ,
      4. Baiocchi S , et al
      . Riboflavin-UVA-induced corneal collagen cross-linking in pediatric patients. Cornea 2012;31:227–31. doi:10.1097/ICO.0b013e31822159f6
      OpenUrlCrossRefPubMedWeb of Science
    17. ↵
      2. Cinar Y ,
      3. Cingü AK ,
      4. Türkcü FM , et al
      . Comparison of accelerated and conventional corneal collagen cross-linking for progressive keratoconus. Cutan Ocul Toxicol 2014;33:218–22. doi:10.3109/15569527.2013.834497
      OpenUrlCrossRefPubMed
    18. ↵
      2. Elbaz U ,
      3. Shen C ,
      4. Lichtinger A , et al
      . Accelerated (9-mW/cm2) corneal collagen crosslinking for keratoconus-A 1-year follow-up. Cornea 2014;33:769–73. doi:10.1097/ICO.0000000000000154
      OpenUrlCrossRefPubMedWeb of Science
    19. ↵
      2. Kanellopoulos AJ
      . Long term results of a prospective randomized bilateral eye comparison trial of higher fluence, shorter duration ultraviolet A radiation, and riboflavin collagen cross linking for progressive keratoconus. Clin Ophthalmol 2012;6:97–101. doi:10.2147/OPTH.S27170
      OpenUrlPubMed
    20. ↵
      2. Filippello M ,
      3. Stagni E ,
      4. O'Brart D
      . Transepithelial corneal collagen crosslinking: bilateral study. J Cataract Refract Surg 2012;38:283–91. doi:10.1016/j.jcrs.2011.08.030
      OpenUrlCrossRefPubMed
    21. ↵
      2. Leccisotti A
      . Transepithelial crosslinking. J Cataract Refract Surg 2012;38: 1706. doi:10.1016/j.jcrs.2012.07.011
      OpenUrlPubMed
    22. ↵
      2. Chen S ,
      3. Chan TC ,
      4. Zhang J , et al
      . Epithelium-on corneal collagen crosslinking for management of advanced keratoconus. J Cataract Refract Surg 2016;42: 738–49. doi:10.1016/j.jcrs.2016.02.041
      OpenUrl
    23. ↵
      2. Al Fayez MF ,
      3. Alfayez S ,
      4. Alfayez Y
      . Transepithelial Versus Epithelium-Off Corneal Collagen Cross-Linking for Progressive Keratoconus: A Prospective Randomized Controlled Trial. Cornea 2015;34(Suppl 10):S53–6. doi:10.1097/ICO.0000000000000547
      OpenUrl
    24. ↵
      2. Soeters N ,
      3. Wisse RP ,
      4. Godefrooij DA , et al
      . Transepithelial versus epithelium-off corneal cross-linking for the treatment of progressive keratoconus: a randomized controlled trial. Am J Ophthalmol 2015;159:821–8.e823. doi:10.1016/j.ajo.2015.02.005
      OpenUrl
    25. ↵
      2. Caporossi A ,
      3. Mazzotta C ,
      4. Baiocchi S , et al
      . Transepithelial corneal collagen crosslinking for keratoconus: qualitative investigation by in vivo HRT II confocal analysis. Eur J Ophthalmol 2012;22(Suppl 7):S81–8. doi:10.5301/ejo.5000125
      OpenUrlCrossRefPubMed

    Footnotes

    • Contributors All persons who meet authorship criteria are listed as authors, and all authors certify that they have participated sufficiently in the work to take public responsibility for the content, including participation in the concept, design, analysis, writing or revision of the manuscript. Furthermore, each author certifies that this material or similar material has not been and will not be submitted to or published in any other publication before its appearance in British Journal of Ophthalmology.

    • Competing interests None declared.

    • Patient consent Obtained.

    • Ethics approval Institutional Review Board of The University of Tokyo Hospital.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    Linked Articles

    • At a glance
      Highlights from this issue
      Keith Barton James Chodosh Jost B Jonas
      British Journal of Ophthalmology 2017; 101 i-ii Published Online First: 23 Aug 2017. doi: 10.1136/bjophthalmol-2017-311100