Keratoconus is a bilateral progressive ectatic corneal disease characterized by localized conical protrusion and corneal thinning. Epithelial thickening occurs in response to stromal thinning, reducing corneal astigmatism. Scanning high-frequency ultrasound revealed the corneal epithelium has a doughnut-like profile with localized central thinning surrounded by an annulus of thick epithelium to minimize local topographic irregularities and restore the normal curvature of the cornea as far as possible.1 Three-dimensional corneal epithelial mapping in vivo by anterior segment optical coherence tomography (AS-OCT) has recently become available in clinical practice, facilitating the capture of optical images and high-speed measurements of epithelial thickness.2 A large-scale study of healthy individuals provided the normative values for epithelial thickness.3
The epithelial profile seems to depend on the severity of keratoconus and can be used for the monitoring of disease progression with scanning high-frequency ultrasound.4 Such monitoring of the thickness distribution of the corneal epithelium is known to be useful for the clinical diagnosis of keratoconus and assessing its progression.5–7 Epithelial thickness compensates for stromal irregularities and is strongly correlated with stromal thickness, which decreases with the progression of keratoconus. Moreover, measurements of epithelial thickness in the thinnest zone of the cornea and the location of this zone on OCT epithelial mapping may facilitate the early diagnosis of forme fruste keratoconus.7,8
Corneal cross-linking (CXL) with ultraviolet-A (UV-A) and riboflavin is a surgical treatment used to increase corneal strength and stabilize the ectatic cornea.9,10 Standard CXL (S-CXL) has been shown to be effective and safe in several studies.11–14 Removal of the epithelium allows riboflavin to penetrate the stroma more easily,15 but may also be associated with major “epithelium-off” CXL complications, such as pain, temporary loss of visual acuity, and possible infectious keratitis.16 Various transepithelial protocols have been proposed to limit the occurrence of these complications.17,18 Unfortunately, these protocols were found to be ineffective for halting keratoconus progression.19 The most recently developed transepithelial protocol, iontophoresis-assisted CXL (I-CXL), uses a small electric current to enhance the penetration of riboflavin into the corneal stroma across an intact epithelium. This protocol was less effective at reducing maximum keratometry (Kmax) after 2 years than the standard protocol and the observed corneal demarcation line was shallower,20–23 but I-CXL remains a potentially useful technique for thin corneas. The efficacy of CXL is routinely evaluated by monitoring topographic parameters. Changes in epithelial thickness are correlated with keratoconus progression. Therefore, it is useful to evaluate the changes to the epithelium after CXL.
Some studies mapping the corneal epithelium after CXL have shown that significant epithelial remodeling occurs after S-CXL, with a decrease in peripheral epithelial thickness, resulting in a more regular thickness profile on AS-OCT24 and Artemis very high-frequency ultrasound scanning.25,26 Reinstein et al.25 suggested that the measurement of epithelial thickness profiles might detect changes earlier than corneal topography, making such measurements a useful adjunct to topography for patient monitoring after S-CXL.
We analyzed regional epithelial corneal remodeling after CXL to compare two different protocols: S-CXL and I-CXL.
Patients and Methods
This prospective, observational, non-randomized clinical study was performed at the Quinze-Vingts National Ophthalmology Hospital in Paris, France. Informed consent was obtained from each patient before inclusion in the study, in accordance with the tenets of the Declaration of Helsinki, and the study was approved by the Ethics Committee of the French Society of Ophthalmology (Institutional Review Board 00008855).
Patients with progressive keratoconus undergoing CXL between January 2015 and June 2016 were consecutively included in this study, in accordance with the inclusion/exclusion criteria, and were treated according to the protocol available at the time of inclusion. Keratoconus was diagnosed on the basis of corneal topography data (Orbscan IIz; Bausch & Lomb Surgical, Rochester, NY) and stromal thinning on AS-OCT.27,28 The inclusion criteria were as follows: patient older than 18 years, with progressive keratoconus, Kmax less than 60 diopters (D), and central corneal thickness (CCT) greater than 400 μm on spectral-domain AS-OCT (RTVue; Optovue, Inc., Fremont, CA). The exclusion criteria were as follows: patients with a history of eye surgery, corneal scarring, ocular surface problems, or other ocular diseases. Progression was defined as a decrease of at least 30 μm in corneal thickness measured with AS-OCT and a 1.00 D increase in Kmax measured with the Orbscan IIz during the past 6 months.
Eye drops containing 1% tetracaine and 1% pilocarpine were instilled for local anesthesia before the procedure. CXL was performed according to the equipment manufacturer's protocol, as follows (Table A, available in the online version of this article).
After epithelial debridement, one drop of 0.1% riboflavin ophthalmic solution in 20% dextran (Ricrolin; Sooft SPA, Montegiorgio, Italy) was applied topically to the cornea every 2 minutes, for 30 minutes. The central cornea was then irradiated for 30 minutes with a 3-mW/cm2 UV-A light (X-Vega; Sooft SPA) at a working distance of 5 cm (5.4 J/cm2 surface dose). Riboflavin eye drops were applied every 5 minutes during UV-A irradiation. A soft bandage contact lens was placed over the cornea at the end of surgery, and was maintained in position until reepithelialization occurred.
The corneal epithelium was left in place. Riboflavin penetration across the cornea was facilitated by iontophoresis (with an I-ON CXL device; Iacer, Veneto, Italy). The passive electrode (PROTENS ELITE 4848LE; Bio Protech, Inc., Gangwon-do, Korea) was applied to the forehead and the active electrode (Iontofor CXL; Sooft SPA) was placed on the open eye and filled with riboflavin (Ricrolin±; Sooft SPA). The current intensity was initially set to 0.2 mA and was gradually increased to 1.0 mA over a period of 5 minutes. The central cornea was then irradiated for 9 minutes with UV-A light (X-Vega) to achieve an intended irradiance of 10 mW/cm2 (5.4 J/cm2 surface dose) at a working distance of 5 cm.
All procedures were monitored by the surgeon (particularly during centering for irradiation: the patients were asked to look straight at the light). Topical antibiotics (0.3% tobramycin, four times/day) were applied on treated eyes for 7 days, together with topical dexamethasone four times daily and hyaluronate eye drops for 1 month. Patients also took analgesics if necessary.
Patients were examined at baseline and at 1, 3, and 6 months after the procedure. The examinations performed included tests of corrected distance visual acuity (CDVA) (Snellen chart) and slit-lamp examinations. The AS-OCT pachymetry map and additional corneal power software (RTVue corneal adaptor module software, version 5.5) automatically processed the OCT scans to provide 6-mm scan diameter pachymetry and epithelial mapping, together with the thinnest corneal and epithelium thicknesses. For each eye, we performed measurements and statistical analyses for the central 6-mm zone; the thinnest central corneal and epithelial thicknesses and 16 peripheral measurements on the corneal vertex (horizontal, vertical, and skew meridians) were obtained. Stromal thicknesses were calculated for each point by determining the difference between pachymetry measurements and epithelial thickness. Orbscan IIz (Bausch & Lomb Surgical, Rochester, NY) acquisitions were performed to study Kmax in the 3-mm zone at the center of the cornea. Demarcation line depth was measured by AS-OCT centrally and 2 mm nasally and temporally from the center 1 month after the CXL procedure.
Results are presented as mean ± standard deviation for continuous variables and as proportions (%) for categorical variables. Paired Student's t tests were used for statistical comparisons of preoperative and postoperative continuous data. For binary outcomes, stratified Cochran chi-square tests were used to compare proportions between groups. The Snellen CDVA was converted into logarithm of the minimum angle of resolution (logMAR) units for analysis. Corrected P values less than .05 were considered statistically significant. Statistical analysis was performed with SPSS for Windows software (version 20.0; SPSS, Inc., Chicago, IL).
Sixty eyes from 60 patients were included in this study. The patients in the two treatment groups were comparable in terms of the baseline characteristics (Table 1). The mean age was 25.4 ± 6.44 years in the S-CXL group and 29.1 ± 7.3 years in the I-CXL group. No intraoperative or postoperative complications were observed in any of the patients.
Patient Demographics and Ocular Characteristics at Inclusion
Results comparing both protocols are shown in Figures 1–2 and Figure A and Table B, available in the online verstion of this article.
Mean change in epithelial thickness distribution 6 months after surgery, within the central 6-mm area (n = 30), after (A) standard corneal cross-linking (S-CXL) and (B) iontophoresis-assisted CXL (I-CXL). Values in blue indicate a significant change after surgery (P < .05). S = superior; I = inferior; T = temporal; N = nasal
Epithelial thickness across the central 6 mm of the corneal vertex in the horizontal and vertical meridians before surgery (M0) and 6 months after (M6) (A–B) standard corneal cross-linking (S-CXL) or (C–D) iontophoresis-assisted CXL (I-CXL). *P < .05. S = superior; I = inferior; T = temporal; N = nasal
Representative result of epithelial thickness mapping by spectral-domain optical coherence tomography (SD-OCT) for one eye before surgery and 6 months after (A–B) standard corneal cross-linking (S-CXL) or (C–D) iontophoresis-assisted CXL (I-CXL).
Change in Epithelial Pachymetry (μm) at 3 and 6 mm After CXL
Mean preoperative central epithelial thickness was 49.1 ± 5.4 μm. At 6 months postoperatively, statistically non-significant central epithelium thinning was recorded (48.1 ± 5.8μm) (P = .25). At 1 month postoperatively, no significant difference in epithelial thickness profile was observed at any location. At 3 months postoperatively, the epithelium was significantly thinner at 3 and 6 mm in the nasal (P = .013 and .003, respectively) and superior (P = .026 and .035, respectively) areas, and at 6 mm in the inferior area (P = .007). At 6 months postoperatively, it was significantly thinner at 3 mm in the superior (P = .026), inferior (P = .034), inferonasal (P = .024), and nasal (P = .035) areas. It was significantly thinner at 6 mm in the superior (P = .039), nasal (P = .043), and inferior (P = .01) areas. No significant difference in stromal thickness profile was observed at any location.
Central epithelial thickness before surgery was 48.9 ± 5.6 μm. Six months postoperatively, statistically non-significant central epithelium thinning was recorded (48.8 ± 4.8 μm) (P = .70). At 1 and 3 months postoperatively, no significant difference in epithelial thickness profile was observed at any location. At 6 months postoperatively, significant thinning was observed at 3 (P = .04) and 6 (P = .01) mm in the inferior area. No significant differences in stromal thickness profile were observed at any location.
The corneal demarcation line was visible on AS-OCT 1 month after surgery in 40% of cases at a mean depth of 221 ± 23 μm after I-CXL and 100% of cases at a mean depth of 301 ± 62 μm after S-CXL. The demarcation line was significantly more visible, at a deeper location, for S-CXL than for I-CXL (P = .02 and .005, respectively). Six months postoperatively, Kmax, CCT, and minimum corneal pachymetry were stable in both groups. At 6 months postoperatively, CDVA had improved in the I-CXL group (P = .003) and stabilized in the S-CXL group (Table 2).
Changes in CDVA, Kmax, CCT, and Minimal Corneal Pachymetry (μm) 6 Months After CXL
To our knowledge, the current study is the first to compare the regional epithelial remodeling after I-CXL and S-CXL with AS-OCT. We found that more significant epithelial remodeling occurred shortly after S-CXL than I-CXL, with a greater decrease in peripheral epithelial thickness and a smaller decrease in the regional variation of epithelial thickness.
In normal eyes, the corneal epithelium is thinner toward the center and superior zones than it is in the peripheral and inferior areas.2,29 Reinstein et al.1 described epithelial thickness profiles measured by ultrasound (Artemis very high-frequency) in patients with keratoconus. They were the first to find that the epithelium had a doughnut-like profile, with localized central epithelial thinning in the center of the cone surrounded by an annulus of thick epithelium. These features were explained by the known mechanism of epithelial compensation: the epithelium appears to undergo remodeling to reduce the bulging of the anterior stromal surface and render the anterior corneal surface more regular by thinning over the cone and thickening around it. These authors also showed that monitoring the distribution of corneal epithelial thickness with ultrasound was a useful way of evaluating the progression of keratoconus.1,4 These findings led to interest in epithelial mapping in subsequent studies. However, only results for S-CXL have been published.24–26 Using ultrasound, Reinstein et al.25 detected lower levels of peripheral epithelial thickening and significant differences between the thinnest and thickest parts of the epithelium following the treatment of two eyes by S-CXL for ectasia after LASIK, these differences persisting up to 2 years later. Kanellopoulos et al.26 also measured epithelial thickness by ultrasound and found thickening of the epithelium near the center, with a thinner epithelium in the temporal inferior periphery in eyes with keratoconus. Moreover, they first demonstrated that epithelium thickness distributions were more similar to the control group in eyes with keratoconus treated by S-CXL. Thus, keratoconic eyes treated by S-CXL have an epithelial thickness profile that is less erratic than untreated keratoconic eyes and a more homogenous profile. A recent study based on SD-OCT in 17 keratoconic eyes and 14 eyes with postoperative ectasia showed a thinning of the peripheral epithelium and a lower level of regional variation 3 months after S-CXL.24 Significant epithelial remodeling was observed, with localized thinning at 3 months in the vertical (superior and inferior) and horizontal (nasal and temporal) meridian areas of the cornea. The authors also concluded that S-CXL effectively halted the progression of corneal ectasia, stabilizing Kmax, CCT, and minimum stromal thicknesses. They suggested that epithelium remodeling after S-CXL minimized local topographic irregularities and restored the curvature of the cornea to values as normal as possible. These findings may account for the significant decrease in Kmax and minimum corneal pachymetry some years later.30 Our results for S-CXL are consistent with these findings.
In another studied “epithelium-off” protocol, Kanellopoulos and Asimellis31 found that AS-OCT indicated a thinner and more homogeneous remodeled epithelium in the keratoconic eyes treated using the Athens protocol. More recently, Haberman et al.32 found that significant epithelial remodeling occurred after accelerated CXL in eyes with progressive keratoconus, with improved regularity across the central 6 mm by 12 months after treatment. When comparing the significantly thinner sectors, there was no significant difference between the 6- and 12-month time points, indicating that the remodeling might plateau sometime between 3 and 6 months.
By contrast, some epithelial remodeling occurred after I-CXL, but it was much milder than that observed after S-CXL, with significant epithelial thinning observed only after 6 months at 3 and 6 mm in the inferior area. We do not believe that these differences are due to deepithelialization because reepithelialization is generally complete 4 to 5 days after surgery, whereas central and minimum epithelial thicknesses remained stable at 1 month. We hypothesized that these differences were instead due to a difference in mechanism of action between the two techniques: I-CXL is an epithelium-on protocol, in which the riboflavin penetrates less deeply into the stroma and has a more superficial effect.
This difference was confirmed by the depth of the demarcation line, one of the indirect clinical outcomes for CXL efficacy. This line represents the transition zone between the treated and untreated stroma.33–35 It can be detected by confocal microscopy and AS-OCT, and is most clearly visible 1 month after treatment.35 The mean demarcation line was more superficial in I-CXL and was less frequently visible with this technique (221 μm, visible in 40% of cases) than with S-CXL (301 μm, visible in all cases), as reported in other recent studies, suggesting that I-CXL may be less efficient than S-CXL.20,22,23 In our study, keratoconus remained stable in both groups. By contrast, Jouve et al.22 showed that I-CXL halted the progression of keratoconus less efficiently than S-CXL after 2 years of follow-up: the failure rate of I-CXL was 20%, whereas that of S-CXL was 7.5%. S-CXL may also be considered more effective than I-CXL because more epithelial remodeling occurred after S-CXL than after I-CXL. Indeed, the epithelium over the cone became thinner due to a decrease in the need to compensate for stromal irregularities, demonstrating an increase in the regularity of the corneal surface after surgery.36 We suggest that epithelial mapping after CXL, with the monitoring of peripheral thinning and an attenuation of the doughnut shape, may be useful for assessing the early efficacy of CXL because the epithelium tends to compensate for irregularities of the stromal surface.1
Kanellopoulos et al.26 showed that corneas that are less rigid and thus biomechanically unstable (keratoconus and ectasia after LASIK), but have a thicker epithelium than normal corneas. The epithelial layer seems to be thicker because these elastic corneas are more sensitive to mechanical variations, such as intraocular pressure, rubbing of the ocular surface, and blinking. The increase in corneal rigidity after CXL may, therefore, account for the thinning of the epithelium. Our results are consistent with this hypothesis. The higher efficacy of S-CXL resulted in greater epithelial remodeling after S-CXL than after I-CXL.
Some studies have shown that Kmax may increase soon after CXL.10,37 However, we observed a stabilization at 1, 3, and 6 months, as in other studies.22,23 These discrepancies between studies may be accounted for by early variations of epithelial thickness masking differences in keratometry after CXL.25 However, the discrepancies between studies could also be inherent to the nature of the keratoconic cornea. The calculation of Kmax might be approximate in the keratoconic eyes.
Six months after surgery, CDVA was stable for S-CXL and had improved for I-CXL. These findings confirm the results of other studies.21,22 With S-CXL, this improvement first appeared 1 year after surgery. There are several possible reasons for the long-term improvement in CDVA after CXL21,22,25: a decrease in high-level aberration, the myopic spherical equivalent, and Kmax. These changes could be explained by epithelial remodeling, which minimizes local topographic irregularities, potentially leading to a gradual improvement in the shape of the anterior stromal surface many months after CXL,25 and a gradual improvement of the CVDA. By inducing epithelial remodeling in the presence of the epithelium, I-CXL may result in less corneal haze and, therefore, a more rapid recovery of vision than S-CXL. Indeed, it is vital to understand the natural time course of CDVA change after CXL, which is probably related to the remodeling of both epithelium and stroma over the time frame of 1 year.11 Consistent with these structural and physiological responses, the corneal haze after S-CXL peaks at 1 month, reaches a plateau at 3 months, and then gradually returns to baseline values over the next 9 months.38 This may explain the faster recovery after I-CXL than after S-CXL.
Despite the lower efficacy of I-CXL than of S-CXL, transepithelial approaches remain of interest and are useful, particularly in cases of thin corneas. We believe that further optimization of the approach described here would improve its results. First, we could increase the total density of the UV-A energy delivered to the cornea by 20% (ie, to 6.5 J/cm2) to obtain CXL levels in the cornea during I-CXL similar to those achieved during S-CXL.23 Indeed, approximately 15% to 20% of UV-A light is absorbed by the epithelium during an epithelium-on procedure.39 Second, the current and/or the duration of iontophoresis could be increased to increase riboflavin penetration,40 although in vivo studies would be required beforehand to ensure that such procedures are safe for the endothelium. Bilgihan et al.41 described a new protocol involving the use of 10% alcohol solution as an enhancer, 0.2% riboflavin, and 9 mW/cm2 power for 13 minutes, with a total dose of 7.2 J/cm2. They hypothesized that the problem of the barrier function of the epithelium could be overcome by using dilute alcohol solution (10% ethanol for 10 minutes) to separate hemidesmosomal attachments and increase epithelial permeability. They found no significant difference between the mean depth and visibility of the demarcation line between this protocol (n = 46 eyes) and S-CXL (n = 47 eyes). All patients were stable after 12 months.
As already described previously,24–26 significant epithelial remodeling is evident 6 months after S-CXL, with localized peripheral thinning and a regular, even thickness of the epithelium at the center and in the periphery. Remodeling does occur after I-CXL, but in fewer corneal areas than after S-CXL. As after S-CXL, corneal epithelial thickness distribution has a more homogenous profile than after I-CXL and the S-CXL protocol appears more effective to stop ectatic progression in keratoconic eyes than the I-CXL protocol. The measurement of epithelial thickness profiles after CXL could be used as a new adjunctive follow-up tool for monitoring the efficacy of CXL and the progression of keratoconus. This approach may be more sensitive than topography for detecting changes in the surface of the stroma induced by CXL. Comparisons of long-term changes in Kmax with the epithelial modeling observed following S-CXL and I-CXL might make it possible to establish a relationship between epithelial remodeling and CXL success.
- Reinstein DZ, Archer TJ, Gobbe M. Corneal epithelial thickness profile in the diagnosis of keratoconus. J Refract Surg. 2009;25:604–610.
- Rocha KM, Perez-Straziota CE, Perez-Straziota E, Stulting RD, Randleman JB. SD-OCT analysis of regional epithelial thickness profiles in keratoconus, postoperative corneal ectasia, and normal eyes. J Refract Surg. 2013;29:173–179. doi:10.3928/1081597X-20130129-08 [CrossRef]
- Kanellopoulos AJ, Asimellis G. In vivo three- dimensional corneal epithelium imaging in normal eyes by anterior-segment optical coherence tomography: a clinical reference study. Cornea. 2013;32:1493–1498. doi:10.1097/ICO.0b013e3182a15cee [CrossRef]
- Reinstein DZ, Gobbe M, Archer TJ, Silverman RH, Coleman DJ. Epithelial, stromal, and corneal thickness in keratoconus: three-dimensional display with Artemis very high-frequency digital ultrasound. J Refract Surg. 2010;26:259–271. doi:10.3928/1081597X-20100218-01 [CrossRef]
- Sandali O, El Sanharawi M, Temstet C, et al. Fourier-domain optical coherence tomography imaging in keratoconus: a corneal structural classification. Ophthalmology. 2013;120:2403–2412. doi:10.1016/j.ophtha.2013.05.027 [CrossRef]
- Tang M, Li Y, Chamberlain W, Louie DJ, Schallhorn JM, Huang D. Differentiating keratoconus and corneal warpage by analyzing focal change patterns in corneal topography, pachymetry, and epithelial thickness maps. Invest Ophthalmol Vis Sci. 2016;57:OCT544–OCT549. doi:10.1167/iovs.15-18938 [CrossRef]
- Kanellopoulos AJ, Asimellis G. Anterior segment optical coherence tomography: assisted topographic corneal epithelial thickness distribution imaging of a keratoconus patient. Case Rep Ophthalmol. 2013;4:74–78. doi:10.1159/000350630 [CrossRef]
- Temstet C, Sandali O, Bouheraoua N, et al. Corneal epithelial thickness mapping using Fourier-domain optical coherence tomography for detection of forme fruste keratoconus. J Cataract Refract Surg. 2015;41:812–820. doi:10.1016/j.jcrs.2014.06.043 [CrossRef]
- Spoerl E, Wollensak G, Seiler T. Increased resistance of cross-linked cornea against enzymatic digestion. Curr Eye Res. 2004;29:35–40. doi:10.1080/02713680490513182 [CrossRef]
- Wollensak G, Spoerl E, Seiler T. Riboflavin/ultraviolet-a-induced collagen crosslinking for the treatment of keratoconus. Am J Ophthalmol. 2003;135:620–627. doi:10.1016/S0002-9394(02)02220-1 [CrossRef]
- Hersh PS, Stulting RD, Muller D, Durrie DS, Rajpal RKUnited States Crosslinking Study Group. United States Multicenter Clinical Trial of Corneal Collagen Crosslinking for Keratoconus Treatment. Ophthalmology. 2017;124:1259–1270. doi:10.1016/j.ophtha.2017.03.052 [CrossRef]
- Caporossi A, Mazzotta C, Baiocchi S, Caporossi T. Long-term results of riboflavin ultraviolet A corneal collagen cross-linking for keratoconus in Italy: The Siena Eye Cross Study. Am J Ophthalmol. 2010;149:585–593. doi:10.1016/j.ajo.2009.10.021 [CrossRef]
- Vinciguerra R, Romano MR, 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;120:908–916. doi:10.1016/j.ophtha.2012.10.023 [CrossRef]
- Padmanabhan P, Rachapalle Reddi S, Rajagopal R, et al. Corneal collagen cross-linking for keratoconus in pediatric patients-long-term results. Cornea. 2017;36:138–143. doi:10.1097/ICO.0000000000001102 [CrossRef]
- Wollensak G, Iomdina E. Biomechanical and histological changes after corneal crosslinking with and without epithelial debridement. J Cataract Refract Surg. 2009;35:540–546. doi:10.1016/j.jcrs.2008.11.036 [CrossRef]
- Snibson GR. Collagen cross-linking: a new treatment paradigm in corneal disease: a review. Clin Experiment Ophthalmol. 2010;38:141–153. doi:10.1111/j.1442-9071.2010.02228.x [CrossRef]
- 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. doi:10.1016/j.jcrs.2013.03.026 [CrossRef]
- Çerman E, Toker E, Ozarslan Ozcan D. Transepithelial versus epithelium-off crosslinking in adults with progressive keratoconus. J Cataract Refract Surg. 2015;41:1416–1425. doi:10.1016/j.jcrs.2014.10.041 [CrossRef]
- Li W, Wang B. Efficacy and safety of transepithelial corneal collagen crosslinking surgery versus standard corneal collagen crosslinking surgery for keratoconus: a meta-analysis of randomized controlled trials. BMC Ophthalmol. 2017;17:262. doi:10.1186/s12886-017-0657-2 [CrossRef]
- Bikbova G, Bikbov M. Standard corneal collagen crosslinking versus transepithelial iontophoresis-assisted corneal crosslinking, 24 months follow-up: randomized control trial. Acta Ophthalmol. 2016;94:e600–e606. doi:10.1111/aos.13032 [CrossRef]
- Lombardo M, Giannini D, Lombardo G, Serrao S. Randomized controlled trial comparing transepithelial corneal cross-linking using iontophoresis with the Dresden protocol in progressive keratoconus. Ophthalmology. 2017;124:804–812. doi:10.1016/j.ophtha.2017.01.040 [CrossRef]
- Jouve L, Borderie V, Sandali O, et al. Conventional and iontophoresis corneal cross-linking for keratoconus: efficacy and assessment by optical coherence tomography and confocal microscopy. Cornea. 2017;36:153–162. doi:10.1097/ICO.0000000000001062 [CrossRef]
- Bouheraoua N, Jouve L, El Sanharawi M, et al. Optical coherence tomography and confocal microscopy following three different protocols of corneal collagen-crosslinking in keratoconus. Invest Ophthalmol Vis Sci. 2014;55:7601–7609. doi:10.1167/iovs.14-15662 [CrossRef]
- Rocha KM, Perez-Straziota CE, Stulting RD, Randleman JB. Epithelial and stromal remodeling after corneal collagen cross-linking evaluated by spectral-domain OCT. J Refract Surg. 2014;30:122–127. Erratum: J Refract Surg. 2014;30:171. doi:10.3928/1081597X-20140120-08 [CrossRef]
- Reinstein DZ, Gobbe M, Archer TJ, Couch D. Epithelial thickness profile as a method to evaluate the effectiveness of collagen cross-linking treatment after corneal ectasia. J Refract Surg. 2011;27:356–363. doi:10.3928/1081597X-20100930-01 [CrossRef]
- Kanellopoulos AJ, Aslanides IM, Asimellis G. Correlation between epithelial thickness in normal corneas, untreated ectatic corneas, and ectatic corneas previously treated with CXL: is overall epithelial thickness a very early ectasia prognostic factor?Clin Ophthalmol. 2012;6:789–800. doi:10.2147/OPTH.S31524 [CrossRef]
- Jonuscheit S, Doughty MJ, Button NF. On the use of Orbscan II to assess the peripheral corneal thickness in humans: a comparison with ultrasound pachymetry measures. Ophthalmic Physiol Opt. 2007;27:179–189. doi:10.1111/j.1475-1313.2006.00459.x [CrossRef]
- Hashemi H, Roshani M, Mehravaran S, Parsafar H, Yazdani K. Effect of corneal thickness on the agreement between ultrasound and Orbscan II pachymetry. J Cataract Refract Surg. 2007;33:1694–1700. doi:10.1016/j.jcrs.2007.05.036 [CrossRef]
- Reinstein DZ, Archer TJ, Gobbe M, Silverman RH, Coleman DJ. Epithelial thickness in the normal cornea: three-dimensional display with Artemis very high-frequency digital ultrasound. J Refract Surg. 2008;24:571–581.
- Raiskup F, Theuring A, Pillunat LE, Spoerl E. Corneal collagen crosslinking with riboflavin and ultraviolet-A light in progressive keratoconus: ten-year results. J Cataract Refract Surg. 2015;41:41–46.
- Kanellopoulos AJ, Asimellis G. Epithelial remodeling after partial topography-guided normalization and high-fluence short-duration crosslinking (Athens protocol): results up to 1 year. J Cataract Refract Surg. 2014;40:1597–1602. doi:10.1016/j.jcrs.2014.02.036 [CrossRef]
- Haberman ID, Lang PZ, Broncano AF, Kim SW, Hafezi F, Randleman JB. Epithelial remodeling after corneal crosslinking using higher fluence and accelerated treatment time. J Cataract Refract Surg. 2018;44:306–312. doi:10.1016/j.jcrs.2017.12.021 [CrossRef]
- Seiler T, Hafezi F. Corneal cross-linking-induced stromal demarcation line. Cornea. 2006;25:1057–1059. doi:10.1097/01.ico.0000225720.38748.58 [CrossRef]
- Mazzotta C, Traversi C, Baiocchi S, et al. 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. doi:10.1016/j.ajo.2008.05.042 [CrossRef]
- Doors M, Tahzib NG, Eggink FA, Berendschot TT, Webers CA, Nuijts RM. Use of anterior segment optical coherence tomography to study corneal changes after collagen cross-linking. Am J Ophthalmol. 2009;148:844–851. doi:10.1016/j.ajo.2009.06.031 [CrossRef]
- Chen X, Stojanovic A, Wang X, Liang J, Hu D, Utheim TP. Epithelial thickness profile change after combined topography-guided transepithelial photorefractive keratectomy and corneal cross-linking in treatment of keratoconus. J Refract Surg. 2016;32:626–634. doi:10.3928/1081597X-20160531-02 [CrossRef]
- Greenstein SA, Fry KL, Hersh PS. Corneal topography indices after corneal collagen crosslinking for keratoconus and corneal ectasia: one-year results. J Cataract Refract Surg. 2011;37:1282–1290. doi:10.1016/j.jcrs.2011.01.029 [CrossRef]
- Greenstein SA, Fry KL, Bhatt J, Hersh PS. Natural history of stromal haze after corneal collagen crosslinking for keratoconus and corneal ectasia: Scheimpflug and biomicroscopic analysis. J Cataract Refract Surg. 2010;35:2105–2114. doi:10.1016/j.jcrs.2010.06.067 [CrossRef]
- Lombardo M, Pucci G, Barberi R, Lombardo G. Interaction of ultraviolet light with the cornea: clinical implications for corneal crosslinking. J Cataract Refract Surg. 2015;41:446–459. doi:10.1016/j.jcrs.2014.12.013 [CrossRef]
- Gore DM, O'Brart DP, French P, Dunsby C, Allan BD. A comparison of different corneal iontophoresis protocols for promoting transepithelial riboflavin penetration. Invest Ophthalmol Vis Sci. 2015;56:7908–7914. doi:10.1167/iovs.15-17569 [CrossRef]
- Bilgihan K, Yesilirmak N, Altay Y, Yuvarlak A, Ozdemir HB. Conventional corneal collagen cross-linking versus transepithelial diluted alcohol and iontophoresis-assisted corneal cross-linking in progressive keratoconus. Cornea. 2017;36:1492–1497. doi:10.1097/ICO.0000000000001383 [CrossRef]
Patient Demographics and Ocular Characteristics at Inclusiona
|Parameter||S-CXL (n = 30)||I-CXL (n = 30)||All Patients (N = 60)||P|
|Age (y)||25 ± 6.44||29 ± 7.36||27 ± 7.10||.07b|
|Amsler keratoconus stage||2.1 ± 0.66||2.3 ± 0.90||2.2 ± 0.80||.81b|
|CDVA (logMAR)||0.19 ± 0.23||0.27 ± 0.22||0.23 ± 0.22||.45b|
|Kmax (D)||49.90 ± 6.30||50.80 ± 5.20||50.40 ± 5.70||.32b|
|CCT (μm)||467 ± 35.9||464 ± 34||466 ± 34.6||.87b|
|Central epithelial thickness (μm)||49.1 ± 5.4||48.9 ± 5.6||49.0 ± 5.5||.80b|
Changes in CDVA, Kmax, CCT, and Minimal Corneal Pachymetry (μm) 6 Months After CXLa
| S-CXL||0.19 ± 0.23||0.18 ± 0.20||.34|
| I-CXL||0.27 ± 0.22||0.20 ± 0.2||.003|
| S-CXL||49.90 ± 6.30||50.10 ± 6.40||.17|
| I-CXL||50.80 ± 5.20||50.90 ± 5.00||.79|
|Central corneal thickness (μm)|
| S-CXL||467 ± 35.9||466 ± 41.9||.75|
| I-CXL||464 ± 34||460 ± 34||.48|
|Minimum corneal pachymetry (μm)|
| S-CXL||440 ± 33.5||438 ± 35.3||.64|
| I-CXL||433 ± 34||429 ± 32.9||.54|
|Fluence (total) (J/cm2)||5.4||5.4|
|Soak time and interval (min)||30(q2)||5|
|Treatment time (min)||30||9|
|Chromophore||Riboflavin (Ricrolin; Sooft SPA)||Riboflavin (Ricrolin±, Sooft SPA)|
|Chromophore carrier||Dextran 20%||Dextran 20%|
|Light source||UV-A light (X-Vega, Sooft SPA)||UV-A light (X-Vega, Sooft SPA)|
|Irradiation mode (interval)||Continuous||Continuous|
Change in Epithelial Pachymetry (μm) at 3 and 6 mm After CXLa
| Central||49.1 ± 5.4||50.1 ± 3.5 (P = .09)||50.2 ± 4.8 (P = .45)||48.1 ± 5.8 (P = .25)||–||–||–||–|
| S||56.3 ± 3.9||55.7 ± 6.1 (P = .40)||54.3 ± 4.7 (P = .026)||54.3 ± 5.5 (P = .026)||54.3 ± 4.2||53.4 ± 5.8 (P = .22)||52.8 ± 5.5 (P = .035)||52.5 ± 4.8 (P = .039)|
| SN||57.5 ± 5.1||56.0 ± 5.4 (P = .090)||55.7 ± 4.3 (P = .078)||55.8 ± 5.3 (P = .085)||56.0 ± 4.3||55.2 ± 4.9 (P = .41)||54.4 ± 4.7 (P = .12)||54.5 ± 4.7 (P = .15)|
| N||56.7 ± 5.8||54.9 ± 3.2 (P = .057)||53.2 ± 3.8 (P = .013)||54.2 ± 5.3 (P = .035)||57.5 ± 5.4||55.8 ± 5.1 (P = .062)||54.9 ± 4.6 (P = .003)||55.2 ± 6.1 (P = .043)|
| IN||54.9 ± 6.5||52.6 ± 5.0 (P = .063)||52.5 ± 5.2 (P = .57)||51.5 ± 4.4 (P = .024)||58.1 ± 6.6||56.8 ± 5.1 (P = .083)||56.6 ± 5.4 (P = .67)||56.4 ± 5.2 (P = .053)|
| I||51.2 ± 5.5||50.4 ± 5.6 (P = .32)||49.9 ± 3.6 (P = .29)||48.8 ± 4.2 (P = .034)||57.6 ± 6.0||55.7 ± 6.3 (P = .057)||54.3 ± 3.7 (P = .007)||54.3 ± 4.6 (P = .01)|
| IT||46.4 ± 4.3||47.8 ± 5.9 (P = .45)||48.6 ± 7.1 (P = .32)||46.6 ± 4.8 (P = .85)||51.7 ± 6.3||50.9 ± 5.8 (P = .063)||50.8 ± 7.8 (P = .070)||50.6 ± 5.3 (P = .062)|
| T||48.2 ± 4.4||48.6 ± 3.6 (P = .69)||48.0 ± 5.6 (P = .88)||48.9 ± 5.6 (P = .57)||53.2 ± 4.8||51.2 ± 4.3 (P = .16)||51.4 ± 6.4 (P = .28)||52.6 ± 4.9 (P = .59)|
| ST||54.2 ± 4.5||54.6 ± 6.2 (P = .88)||53.1 ± 4.0 (P = .28)||53.5 ± 5.8 (P = .58)||55.3 ± 4.9||54.9 ± 7.0 (P = .79)||53.9 ± 6.0 (P = .14)||54.1 ± 6.0 (P = .24)|
| Central||48.9 ± 5.6||49.2 ± 3.9 (P = .28||49.1 ± 4.6 (P = .32||48.8 ± 4.8 (P = .70)||–||–||–||–|
| S||57.8 ± 4.4||57.9 ± 4.2 (P = .84)||57.3 ± 5.0 (P = .43)||57.2 ± 4.1 (P = .14)||54.5 ± 4.1||52.2 ± 4.6 (P = .056)||52.5 ± 5.4 (P = .077)||53.0 ± 3.7 (P = .094)|
| SN||59.0 ± 4.7||57.4 ± 4.4 (P = .061)||57.8 ± 5.7 (P = .070)||58.2 ± 5.8 (P = .11)||55.6 ± 4.6||53.4 ± 4.3 (P = .052)||53.9 ± 4.8 (P = .69)||54.3 ± 4.6 (P = .86)|
| N||57.0 ± 6.1||58.3 ± 5.2 (P = .29)||56.5 ± 7.1 (P = .38)||56.1 ± 7.0 (P = .14)||56.4 ± 5.9||56.1 ± 4.2 (P = .13)||55.3 ± 6.3 (P = .095)||54.4 ± 8.0 (P = .051)|
| IN||52.8 ± 6.6||53.3 ± 3.7 (P = .23)||52.4 ± 4.9 (P = .41)||51.5 ± 6.3 (P = .096)||55.7 ± 8.1||57.1 ± 4.2 (P = .87)||55.2 ± 5.8 (P = .48)||55.0 ± 7.4 (P = .13)|
| I||50.3 ± 5.0||48.6 ± 3.6 (P = .064)||48.5 ± 4.2 (P = .061)||48.3 ± 4.5 (P = .04)||55.7 ± 5.0||54.9 ± 4.2 (P = .11)||54.5 ± 5.1 (P = .81)||53.2 ± 6.2 (P = .01)|
| IT||47.8 ± 4.6||47.3 ± 3.1 (P = .38)||47.1 ± 5.3 (P = .36)||46.4 ± 3.9 (P = .07)||53.6 ± 5.9||52.4 ± 2.9 (P = .11)||53.0 ± 6.0 (P = .33)||52.3 ± 4.9 (P = .07)|
| T||49.7 ± 6.9||48.9 ± 4.7 (P = .24)||50.3 ± 5.8 (P = .30)||50.5 ± 6.7 (P = .27)||54.6 ± 6.9||54.6 ± 4.5 (P = .87)||54.5 ± 4.6 (P = .73)||54.8 ± 5.5 (P = .52)|
| ST||55.4 ± 5.8||54.3 ± 4.5 (P = .094)||56.1 ± 3.4 (P = .27)||56.6 ± 4.2 (P = .17)||56.1 ± 5.7||54.4 ± 3.6 (P = .14)||55.2 ± 4.4 (P = .46)||55.8 ± 3.8 (P = .74)|