|Year : 2017 | Volume
| Issue : 2 | Page : 39-48
Epithelium-off versus epithelium-on corneal collagen cross-linking with accelerated UV − a protocol for treatment of keratoconus
Mohamed El-Kateb1, Magdi M Mostafa2, Kamel A Soliman2, Samir Y Saleh2
1 Department of Ophthalmology, Alexandria University, Alexandria, Egypt
2 Department of Ophthalmology, Assiut University, Assiut, Egypt
|Date of Web Publication||1-Aug-2018|
Magdi M Mostafa
Department of Ophthalmology, Assiut University, Assiut, 71621
Source of Support: None, Conflict of Interest: None
Purpose Our purpose was to compare the efficacy of ‘epithelium-off’ and ‘epithelium-on’ cross-linking (CXL) in treatment of progressive keratoconus.
Patients and methods This study included 48 eyes of 26 patients who met our inclusion criteria. The Epi-Off CXL group included 32 eyes of 17 patients, and the Epi-On CXL group included 16 eyes of nine patients. Preoperative assessments of uncorrected and best-corrected visual acuities, refractive errors, keratometry, and corneal tomography including pachymetry, were compared with the postoperative values.
Results Preoperatively, there was a statistically nonsignificant difference between the two groups in all studied variables except for the pachymetry at thinnest location. In the Epi-Off group, there was a significant improvement of uncorrected visual acuity, best-corrected visual acuity, Kmax, and inferior–superior value at the 12-month visit. There was late significant worsening of the back elevation and spherical equivalent at the 12-month visit and also significant thinning of pachymetry at thinnest location associated with significant worsening of the average thickness increase. All other variables showed nonsignificant change (stabilization) at both postoperative visits. In the Epi-On group, there was significant thinning of pachymetry at thinnest location and stabilization of uncorrected corrected visual acuity, best-corrected visual acuity, K1, Kmax, (inferior–superior), Y-coordinate, and front elevation at both postoperative visits, and early stabilization with late worsening of all of other variables.
Conclusion The Epi-Off CXL was found to be more superior to Epi-On CXL in terms of stabilization of progressive keratoconus but was inevitably associated with complications related to epithelial debridement.
Keywords: cross-linking, Epi-Off cross-linking, Epi-On cross-linking, keratoconus
|How to cite this article:|
El-Kateb M, Mostafa MM, Soliman KA, Saleh SY. Epithelium-off versus epithelium-on corneal collagen cross-linking with accelerated UV − a protocol for treatment of keratoconus. Egypt J Cataract Refract Surg 2017;23:39-48
|How to cite this URL:|
El-Kateb M, Mostafa MM, Soliman KA, Saleh SY. Epithelium-off versus epithelium-on corneal collagen cross-linking with accelerated UV − a protocol for treatment of keratoconus. Egypt J Cataract Refract Surg [serial online] 2017 [cited 2019 Mar 19];23:39-48. Available from: http://www.jcrs.eg.net/text.asp?2017/23/2/39/238369
| Introduction|| |
Keratoconus (KC) is a degenerative corneal disease characterized by being a progressive, noninflammatory, bilateral, but asymmetrical disorder that affects the stromal biomechanical stability resulting in forward protrusion of the cornea ,. KC has a very high effect on the quality of life of patients, owing to either the disease itself or the treatments that were available before the advent of corneal collagen cross-linking (CXL) .
CXL is the first treatment that targets the basis of progression of KC, the biomechanical weakness, through stiffening the cornea and arresting the progression of KC .
The standard procedure of CXL, described in 2003 , involved the removal of central 8–9 mm of corneal epithelium to allow the passage of the hydrophilic macromolecule of riboflavin into the stroma . However, corneal de-epithelialization was found to be related to some postoperative complications such as postoperative pain, temporary visual diminution, healing problems of the epithelium, anterior stromal haze, corneal infection, herpes virus reactivation, and even corneal melting ,.
Leaving the epithelium intact, during the CXL procedure, has the advantage of avoiding the aforementioned postoperative complications related to epithelial removal . Moreover, thinner corneas, which are only 400 μm (with epithelium), may be safer to be treated by the Epi-On rather than the Epi-Off CXL, as the endothelium is better protected by Ultrviolet-A (UVA)-filtering effect of the intact epithelium . However, leaving the epithelium intact has been related to particular drawbacks that can decrease the efficacy of Epi-On CXL; these drawbacks include preventing riboflavin penetration and homogenous saturation of the stroma , reducing oxygen diffusion into the stroma and, on the contrary, it consumes 10 times more oxygen than stromal layer of comparable thickness ,, and finally, blocking the UVA penetration into the stroma .
Thus, Epi-On CXL mandates a special type of riboflavin that can penetrate through intact epithelium . It should contain enhancers such as EDTA, benzalkonium chloride (BAC), and trometamol and the topical anesthetic tetracaine 1% which is reported to loosen epithelial tight junctions and facilitate epithelial permeability ,,. Despite this, the epithelium is still a major barrier for riboflavin penetration even with the prolonged application of a cationic surfactant such as BAC .
The standard procedure is time consuming and troublesome for both the patient and the surgeon. The reduction of CXL procedure duration can be achieved through either a shorter riboflavin administration time with improved corneal penetration, e.g. iontophoresis, or through the application of higher ultraviolet ray (UV) doses . The theoretical background of the latter modification is based on the photochemical reciprocity law (Bunsen–Roscoe law), which states that, the effect of a photochemical or photobiological reaction is directly proportional to the total irradiation dose, irrespective of the time span over which the dose is delivered ,.
| Patients and methods|| |
A nonrandomized, noncontrol, comparative interventional prospective study was conducted.
This study included 48 eyes of 26 patients, who met our inclusion criteria and were of stage I–II according to Amsler–Krumeich classification ,. The study was carried out from July 2014 to December 2016. The patients were divided into two groups: the Epi-Off CXL group that underwent epithelial removal before riboflavin instillation (32 eyes of 17 patients) and the Epi-On CXL group, where epithelium was not removed (16 eyes of nine patients). This division was not randomized and depended mainly on the corneal thickness if it allowed or not the epithelial removal with a minimum residual corneal thickness of 400 μm. In both groups, the accelerated UVA treatment protocol was used.
The study was approved by the Institutional Review Board/Ethics Committee of the Faculty of Medicine at Assiut University and was conducted in accordance with the Declaration of Helsinki. Every patient was informed about his or her condition, the nature of the procedure, and its possible consequences, and a written consent was obtained from each patient or from the parents, if the patient was younger than 18 years.
The study was carried out in three private eye centers (Alnoor, Teba, and Alforsan centers) in Assiut where the equipments are available, after approval from administration of each center.
The following inclusion criteria were applied:
- Progressive KC with a maximum corneal power (Kmax) less than 60 D.
- Progressive KC was identified when one or more of the following characteristics were found during a period of 6–12 months before treatment: loss of two or more lines of the corrected distant visual acuity on Snellen chart in 1 year , an increase in the cylinder magnitude on manifest refraction by greater than or equal to 1.00 D in 1 year , an increase in the manifest refraction spherical equivalent (MRSE) by greater than or equal to 1.00 D in 1 year , an increase in the mean K (Km)  or maximum K (Kmax) by greater than or equal to 1.00 D in 1 year , or a decrease in central corneal thickness by more than or equal to 5% in 6 months .
- Corneal thickness without epithelium greater than or equal to 400 μm (in the Epi-Off CXL group). The cornea was eligible for Epi-On CXL if the corneal thickness with epithelium greater than or equal to 400 μm.
- Age of patient between 14 and 40 years.
The following exclusion criteria were applied:
- Corneal scarring.
- Epithelial healing disorders, e.g.:
- Recurrent corneal erosion syndrome or.
- History of diseases that may delay corneal healing or predispose the eye to future complications (e.g. rheumatic disorders, glaucoma, uveitis, chemical burn, and corneal dystrophy).
- History suggestive of herpetic keratitis because the UVR can activate herpes virus.
- History of previous corneal surgery or iatrogenic ectasia.
- Pregnancy and breast-feeding.
Preoperative evaluation included full history taking and ophthalmological examination in addition to topographical evaluation using the Pentacam Comprehensive Eye Scanner (Oculus Optikgera, Wetzlar, Germany).
Early postoperative follow-up
Follow-up was aimed at detecting and treating any postoperative complication. It was done at the slit-lamp on the first, third, and sixth postoperative days, and then at 2 weeks, 1 month, and 3 months.
Late postoperative follow-up
Follow-up of the patient at the sixth and 12th month postoperatively was aimed at evaluation of CXL visual, refractive, and topographical effects.
The UVA-emitting device used in the study was Vega CBM X-Linker (CSO, Italy) which emits at 370 nm to produce 10 mW/cm2, which when used for 9 min produces a total energy of 5.4 J/cm2.
Before treatment, the irradiance of the UV machine was calibrated using a UV light meter (Baush and Lomb, New York, USA) (YK-35UV). The radiant energy was acceptable when it was ±10% of the intended energy.
Patient preparation was carried out before the patient was brought to the operative room through administration of pilocarpine hydrochloride 2% (ocucarpine 2%; Alexandria Co. for Pharmaceuticals, Alexandria, Egypt) miotic eye drops every 10 min for three times to reduce the risk of UV exposure of retroiridal eye structures, prophylactic antibiotic drop of moxifloxacin hydrochloride 0.5% (Vigamox; Alcon, Fort Worth, Texas, United States) every 5 min for four times, and one drop of the topical anesthetic, benoxinate hydrochloride 0.4% (Benox; E.I.P.I. Co., Cairo, Egypt) every 5 min for four times.
The skin around the eyes was wiped with 10% povidone–iodine solution (Betadine 10%; El-Nile Co., Cairo, Egypt) and a sterile draping was applied. Another drop of topical anesthesia was instilled before the insertion of lid speculum.
Regarding the epithelium for the Epi-Off CXL group, the central 8–9 mm of corneal epithelium was marked with a caliber and removed by mechanical debridement using a blunt Hockey Stick Knife (Huaian Tisurg Medical Instruments Co.). For the Epi-On CXL group, the epithelium was not removed, but instead, its permeability to riboflavin was enhanced by the instillation of topical anesthetic eye drops in addition to the BAC preservative (0.01%) present in the eye drops as well as in the transepithelial riboflavin solution.
Regarding riboflavin instillation, before starting the riboflavin instillation, the room lights were decreased to avoid affecting the composition and efficacy of riboflavin, and also the syringe that contains the riboflavin was covered by a sterile towel to avoid exposure to light. Riboflavin must have been kept in the refrigerator at +4 to +8°C. For the Epi-off CXL group, MedioCROSS-M (Medio-Haus-Medizin Produkte GmbH) was used, whereas for the Epi-On CXL group, MedioCROSS-TE (Medio-Haus-Medizin Produkte GmbH) was used. Instillation of either type continued every 2 min for 30 min. At the end of the 30 min, stromal absorption of riboflavin was confirmed under the surgical microscopic of WaveLight Allegretto 200 Hz laser (Alcon Laboratories Inc.).
The UVA radiation was focused on the central 8 mm of corneal surface at the wavelength of 370 nm to give a total dose of 5.4 J/cm2 through the accelerated protocol (10 mW/cm2 for 9 min).
During the UVA treatment, protection of the surgeon eyes was done using protective goggles that block the wavelength of 370 nm (Ellex, Australia) in addition to the usual personal protective equipments including the gown, overhead, facemask and gloves; protection of the limbal area by accurate focusing; and meticulous centration of the UV circle. Riboflavin instillation was continued every 3 min during UVA treatment, and topical anesthesia was instilled whenever the patient complained from pain or burning sensation.
After UVA treatment was finished, washing of riboflavin solution from the corneal surface and conjunctival sac was done using balanced salt solution. Then, topical broad-spectrum antibiotic drops, e.g. moxifloxacin (Vigamox; Alcon), were instilled and a bandage contact lens (Bausch & Lomb PureVision; Baush and Lomb, New York, USA) was then fitted onto the cornea in both of Epi-Off and Epi-On CXL groups.
Postoperative treatment included preservative-free Moxifloxacin (Vigamox; Alcon) five times per day. Steroid/antibiotic combination eye drops, tobramycin 0.3% plus dexamethasone 0.1% (TobraDex; Alcon), were instilled twice per day until re-epithelization and removal of contact lens, then it was increased to five times per day for a week, and then two times per day for another 2 weeks in the Epi-Off group, whereas for the Epi-On group, it was given five times per day from the second postoperative day. Preservative-free tears substitute, carboxymethylcellulose sodium 0.5% (Refresh Plus; Allergan, Dublin, Republic of Ireland), five times per day, was used for 3–4 weeks. Oral analgesic was prescribed three times per day to relief pain until re-epithelialization, e.g. ibuprofene (Brufen; Abbott) 400 mg three times per day for adults or 200 mg three times per day for children below 18 years. The patient was advised to use sunglasses for 2 weeks.
Statistical analysis was done using the ‘statistical package for the social sciences’ (version 16.0; SPSS Inc., Chicago, Illinois, USA) for analysis. The uncorrected and best-corrected visual acuities (UCVA and BCVA) were measured in decimal notation, which was converted to logMAR notation because it is more suitable for statistical analysis, whereas the decimal notation was used for descriptive purposes because it is easier to understand than the logMAR.
The normality of data was checked using Kolmogorov–Smirnov (K-S) test which found that the data of each group were not normally distributed. Preoperative and postoperative parameters within each group were compared using the nonparametric Wilcoxon’s signed rank test. Postoperative parameters were compared between the two groups using the nonparametric Mann–Whitney test. P value of less than 0.05 was considered to be statistically significant.
| Results|| |
Our study included 48 eyes of 26 patients, 12 (46%) males and 14 (54%) females, whose age ranged from 14 to 38 years, with a mean age of 23.80±7.10 years. Those 48 eyes were divided into two groups: the Epi-Off CXL group included 32 eyes of 17 patients, and the Epi-On CXL group included 16 eyes of nine patients.
There was no statistically significant difference between the two groups at preoperative baseline except for the ‘Pachymetry at thinnest location’ that showed statistically significant difference, which was expected as it was much thinner in the Epi-On, see [Table 1].
The preoperative baseline and the postoperative mean values for each variable in both groups are presented in [Table 2]. The significance of change from the preoperative mean value to the 6-month mean value was represented by P1, whereas the significance of change from the preoperative mean value to the 12-month mean value was represented by P2. The amount of change from the preoperative value to the 6-month value was compared between the two groups, Epi-Off and Epi-On groups; the significance of difference between both groups at 6 months was described by P3; and the difference between the two groups at 12 months was described by P4. Any P value of these four was considered statistically significant when it was less than or equal to 0.05. For P1 and P2 values, * indicates significant improvement and # indicates significant worsening. For P3 and P4 values, § indicates significant difference between the two groups.
The UCVA and BCVA significantly improved in the Epi-Off group but showed nonsignificant change with the Epi-On group, so the Epi-Off group had significantly better visual outcome than the Epi-On group at the 12-month follow-up, but at the 6-month follow-up, there was no significant difference.
The MRSE, the refractive cylinder, and the corneal astigmatism, all showed significant worsening at the 12-month follow-up in the Epi-On group, but only the MRSE showed significant worsening at the 12-month visit in the Epi-Off group, which showed significantly better outcome of MRSE, refractive cylinder, and corneal astigmatism than the Epi-On group at the 12-month follow-up and for refractive cylinder at the 6-month follow-up.
The K1 showed nonsignificant change at both postoperative visits for both groups and there was no significant difference when comparing the change of K1 at 6 and 12 months for the two groups.
For the K2, Km, and Q-value, the Epi-Off group showed nonsignificant change at both postoperative visits, whereas the Epi-On group showed significant worsening at the 12-month follow-up. When comparing the two groups, the Epi-Off group resulted in significantly better outcome at the 12-month visit.
The Kmax showed significant improvement at both postoperative visits with the Epi-Off group, unlike the Epi-On group which showed nonsignificant change. On comparing the two groups, the Epi-Off group was significantly better at the 12-month visit.
There was significant improvement of the inferior–superior (I-S) value at the 12-month visit in the Epi-Off group, whereas there was nonsignificant change at both visits in the Epi-On group, but there was nonsignificant difference between the two groups.
Pachymetry at the thinnest location showed significant thinning at both visits in the two groups; moreover, there was nonsignificant difference between the two groups.
The vertical displacement of the thinnest location (Y-coordinate) and the front elevation showed nonsignificant change at both visits in both groups, and there was nonsignificant difference between the two groups.
The back elevation showed significant worsening at the 12-month visit in both groups, and there was nonsignificant difference between the groups.
The average thickness increase showed significant worsening at both postoperative visits in the Epi-Off group, whereas the Epi-On group showed significant worsening of the average thickness increase at the 12-month visit. Despite that, there was nonsignificant difference between the two groups.
Delayed re-epithelialization beyond 5 days postoperatively was found in four (12.5%) eyes of the 32 eyes that underwent Epi-Off CXL. Three of the four eyes had spring catarrh with one eye had steroid-induced cataract, whereas the fourth eye was not associated with any history of systemic diseases. All of the four eyes that had delayed re-epithelialization have recovered, and the corneal abraded area was re-epithelialized by the 12th day, but all left behind an anterior stromal haze.
In the Epi-On group, immediate postoperative slit-lamp examination revealed epithelial edema and punctate epitheliopathy in all eyes, but no corneal abrasions were found. These findings disappeared completely by the third postoperative day.
Anterior stromal haze
It was the most common complication noticed during the postoperative period as it was seen in 19 of 48 (39.6%) eyes ([Table 3]).
All of the eyes that developed anterior stromal haze had a mild degree of clouding that was of grade 1 according to the scoring system modified by Greenstein et al. .
Anterior stromal haze decreased in density during the follow-up period of 1 year. The eye that developed stromal haze in the Epi-On group showed complete resolution by the third month. For the 18 eyes of the Epi-Off group, 14 eyes showed complete resolution of the haze by the sixth month, whereas in the remaining four eyes, which were associated with delayed re-epithelialization, the haze disappeared at the 12-month follow-up.
For the whole study population, in nine of 48 (18.7%) eyes, the CXL failed to prevent progression of KC ([Table 4]). Failure was identified by one of the criteria suggested by Shalchi et al.  and Poli et al. .
|Table 4 Success and failure rates of cross-linking in each group of treatment|
Click here to view
| Discussion|| |
Visual acuity (UCVA and BCVA) showed significant improvement at both postoperative visits in the Epi-Off group, which was similar to Badawi  and Chow et al. . However, this was unlike the results of Waszczykowska and Jurowski , Elbaz et al. , and Sadoughi et al. , who reported nonsignificant change of vision that can be attributed to their use of different riboflavin solution containing 20% dextran and doubtful corneal saturation because of not using lid speculum allowing the lid to blink and sweep the riboflavin solution off the cornea , or instillation of riboflavin every 5 min rather than every 2 min . Moreover, Helena et al stated usage of 50% alcohol in epithelial debridement  which can lead to substantial damage to the underlying stroma causing more keratocyte loss and more corneal edema and haze .
Dextran can lead to stromal dehydration resulting in intraoperative corneal thinning . Moreover, dextran was found to inhibit the paracellular transport of riboflavin . Replacing dextran with hydroxypropyl methylcellulose not only avoids the thinning effect of dextran and but also can increase the corneal thickness during CXL ,.
The UCVA and BCVA in our Epi-On were stabilized with statistically nonsignificant change at both postoperative visits, which was similar to the results of Gatzioufas et al. . However, Zhang et al.  reported statistically significant improvement of UCVA at both postoperative visits but nonsignificant improvement of the BCVA at both postoperative visits.
The maximum keratometry (Kmax) showed significant improvement at both postoperative visits with the Epi-Off group, which is similar to the results reported by Badawi , and Ozgurhan et al. , but unlike the results reported by Elbaz et al.  and Sadoughi et al. , who found stabilization of Kmax with no significant change, which may also be attributed to their use of different riboflavin solution containing 20% dextran. The Epi-On group shown nonsignificant change of Kmax at both postoperative visits, which was consistent with the results of Gatzioufas et al.  and Zhang et al. .
The pachymetry at the thinnest location showed significant thinning at both postoperative visits in both groups which was consistent with many studies ,,,,. On the contrary, Ozgurhan et al.  found nonsignificant change of the central corneal thickness at both postoperative visits, which may be because they used a different machine that combines Placido and Scheimpflug technologies, because some authors claim that the Scheimpflug-derived Kmax and pachymetry can deteriorate whereas the Placido disc-derived features appear stable . However, it was suggested that there is no ‘real’ reduction in corneal thickness after CXL , and that CXL modifies the optical density of the corneal stroma, influencing all pachymetric systems to different degrees . This can explain why Zhang et al.  found nonsignificant change of the thinnest location at both of postoperative visits, as they did not detect any demarcation line through anterior segment optical coherence tomography which means that the optical density of the corneal stroma did not change, thus measuring with Pentacam will not give significant thinning ,.
The MRSE and the back elevation showed nonsignificant change at the 6-month visit and significant worsening at the 12-month visit in both groups. Same result was reported by Chan et al. , for the back elevation in the Epi-Off group. On the contrary, most studies found nonsignificant change of both MRSE and back elevation at both postoperative visits in both groups ,,,.
All other 10 variables studied in the Epi-Off group showed nonsignificant change at both postoperative visits, which means stabilization of these variables, except for the I-S value, which showed significant improvement at the 12-month visit, and for the average thickness increase, which showed significant worsening at both postoperative visits, which may be a reflection of the significant thinning of the cornea at both postoperative visits.
In the Epi-On group, four of these 10 variables showed nonsignificant change at both postoperative visits, which means stabilization of these variables, which include K1, I-S, Y-coordinate, and front elevation. The remaining six variables include the refractive cylinder, corneal astigmatism, K2, Km, Q-value, and average thickness increase. These six variables showed stabilization at the 6-month visit but significant worsening at the 12-month visit, which means stabilization effect has short duration at the first 6 months postoperatively. The published data about the efficacy of Epi-On CXL are generally disappointing, although there is general acceptance that it is a safe procedure ,,,,.
Delayed re-epithelialization beyond 5 days was seen in 12.5% of eyes in the Epi-Off group, and this is consistent with the rate of 17.4% reported by Wajnsztajn et al. . Three out of the four eyes that had delayed re-epithelialization in our study gave history of spring catarrh which can explain the delay in epithelial healing, meanwhile, the fourth eye had no history of atopic or autoimmune diseases. Other possibilities that may have led to the delayed epithelial healing are either limbal stem cell injury caused by inadvertent exposure to UVA , because we did not use the silicone ring or Merocel shield ring, or the neurotoxic effect of the CXL .
This finding was a common finding in Epi-On studies. The immediate postoperative epithelial edema and punctate epitheliopathy seen in all cases of the Epi-On group disappeared by the third postoperative day. This is consistent with other Epi-On studies which reported epithelial changes that ranged from simple punctate epitheliopathy , to even frank epithelial defect, as reported by Gatzioufas et al.  in 46% of eyes.
The anterior stromal haze is because of keratocyte apoptosis and subsequent repopulation , leading to a clinically visible demarcation line . Haze was seen in 56.3% of the eyes in the Epi-Off group, which is less than the rate reported by Sherif  who found anterior stromal haze in 71% of Epi-Off group. This can be explained by his use of sharp knife in epithelial removal that may have injured the Bowman’s layer. In the Epi-On group, the haze was noted in one of 16 (6.25%) eyes. Keratocyte apoptosis occurs to a lesser extent after Epi-On CXL ; this may be the reason why haze is less in Epi-On CXL.
Treatment failure is defined as worsening of KC owing to continued progression, which is identified by one of the following criteria suggested by Shalchi et al.  and Poli et al. .
- An increase in maximum K (Kmax) readings of 1.0 D over the preoperative value. Kmax is arguably the most important parameter when considering KC progression, and hence, treatment failure .
- A decrease of more than 0.1 (one line) in logMAR uncorrected or BCVA .
- An increase of keratometric values (K1, K2, and Km) by greater than 0.75 D .
Failure of CXL was found in three out of 32 eyes treated in Epi-Off group giving a rate of 9.4% which was consistent with the failure rate in previous work by Shetty et al. , who reported three eyes out of 30 (10%) eyes. Ng et al.  and Waszczykowska and Jurowski  reported failure rate of 8.3 and 6.25%, respectively. The lower failure rate in the last two studies may be because they excluded patients younger than 18 years. The younger age group below 18 years old has more aggressive disease ,, and was associated with decreased stabilization of the disease .
In the Epi-On group, failure rate was 37.5%, whereas Gatzioufas et al.  reported a failure rate of approximately 46%.
| Summary|| |
Treatment of KC with Epi-Off/accelerated CXL resulted in stabilization of almost all topographic parameters, which included K1, K2, Km, corneal astigmatism, front elevation, anterior surface asphericity (Q-value), and the vertical displacement of thinnest location (Y-coordinate), and even resulted in significant improvement of the Kmax and early stabilization followed by late significant improvement of the I-S value.
All of the aforementioned parameters have been stabilized or improved during the 1-year follow-up period. All of them, except the Y-coordinate, are related to the anterior corneal surface which means that the anterior corneal surface has been stabilized with some improvement in some of its parameters.
This was reflected on the visual acuity, both the UCVA and the BCVA, which revealed significant improvement, despite the late worsening of the MRSE and the nonsignificant change of refractive cylinder, as the improvement of visual acuity does not depend solely on the refractive error. The stabilization and relative improvement of the anterior surface parameters may have resulted in regularization of the anterior corneal surface, which may have led to improvement of higher order aberrations .
The back elevation was stabilized during the first follow-up but increased significantly at the end of the first postoperative year. The increase in back elevation together with thinning at the thinnest location both were reflected on the ‘average thickness increase’ which significantly increased at both postoperative visits.
Thus, the end result of Epi-Off CXL is stabilization with some improvement of the anterior surface-related parameters associated with continuation of worsening of the parameters related to the posterior surface. This means that the effect of Epi-Off/accelerated CXL is limited to the anterior cornea. This anteriorly located effect stabilized the cornea during the first postoperative year but may require further follow-up.
Treatment of KC with the Epi-On/accelerated CXL resulted in stabilization of UCVA, BCVA, K1, Kmax, I-S, Y-coordinate, and front elevation.
It resulted in early stabilization with late worsening of most of the refractive and topographic parameters, which included MRSE, refractive cylinder, K2, Km, corneal astigmatism, Q-value, back elevation, and the average thickness increase.
So, this technique of treatment may have resulted in early (6-month) stabilization of all parameters except the pachymetry at the thinnest location. Six months later, there was significant worsening of half of the aforementioned parameters in addition to the pachymetry of the thinnest location.
Although the Kmax and visual acuities were stabilized, K2 and Km got worsened. Thus, longer follow-up period is mandatory to know if the worsening will continue and extend to other parameters or not.
Financial support and sponsorship
Conflicts of interests
There are no conflicts of interest.
| References|| |
Rabinowitz YS. Keratoconus. Surv Ophthalmol 1998; 42:297–319.
Andreassen TT, Simonsen AH, Oxlund H. Biomechanical properties of keratoconus and normal corneas. Exp Eye Res 1980; 31:435–441.
Kymes SM, Walline JJ, Zadnik K, Sterling J, Gordon MO, CLEK Study Group. Changes in the quality-of-life of people with keratoconus. Am J Ophthalmol 2008; 145:611–617.
Wollensak G, Spoerl E, Seiler T. Riboflavin/ultraviolet-a-induced collagen crosslinking for the treatment of keratoconus. Am J Ophthalmol 2003; 135:620–627.
Baiocchi S, Mazzotta C, Cerretani D, Caporossi T, Caporossi A. Corneal crosslinking: riboflavin concentration in corneal stroma exposed with and without epithelium. J Cataract Refract Surg 2009; 35:893–899.
Filippello M, Stagni E, O’Brart D. Transepithelial corneal collagen crosslinking: bilateral study. J Cataract Refract Surg 2012; 38:283–291.
O’Brart D. Complications of corneal collagen cross-linking. Chapter 20. In: Singh AD, editor. Keratoconus: recent advances in diagnosis and treatment. 1st ed. Part of the series: Essentials in Ophthalmology. Switzerland: Springer International Publishing; 2017. pp. 239–247.
Pinelli R. Corneal collagen crosslinking: is it necessary to remove epithelium? J Intraocular Implant Refract Soc India 2008; 4:28–34.
Chen X, Stojanovic A, Eidet JR, Utheim TP. Corneal collagen cross-linking (CXL) in thin corneas. Eye Vis (Lond) 2015; 2:15.
Leccisotti A, Islam T. Transepithelial corneal collagen cross-linking in keratoconus. J Refract Surg 2010; 26:942–948.
Gatzioufas Z, Raiskup F, O’Brart D, Spoerl E, Panos GD, Hafezi F. Transepithelial corneal cross-linking using an enhanced riboflavin solution. J Refract Surg 2016; 32:372–377.
Chan CC, Squissato V. Keratoconus and crosslinking: pharmacokinetic considerations. Expert Opin Drug Metab Toxicol 2013; 9:1613–1624.
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.
Koppen C, Wouters K, Mathysen D, Rozema J, Tassignon MJ. Refractive and topographic results of benzalkonium chloride-assisted transepithelial crosslinking. J Cataract Refract Surg 2012; 38:1000–1005.
Nakamura T, Yamada M, Teshima M, Nakashima M, To H, Ichikawa N, Sasaki H. Electrophysiological characterization of tight junctional pathway of rabbit cornea treated with ophthalmic ingredients. Biol Pharm Bull 2007; 30:2360–2364.
Chang SW, Chi RF, Wu CC, Su MJ. Benzalkonium chloride and gentamicin cause a leak in corneal epithelial cell membrane. Exp Eye Res 2000; 71:3–10.
Waszczykowska A, Jurowski P. Two-year accelerated corneal cross-linking outcome in patients with progressive keratoconus. Biomed Res Int 2015; 2015:325157.
Bunsen RW, Roscoe HE. Photochemical researches, part V: on the measurement of the chemical action of direct and diffuse sunlight. Proc R Soc Lond 1862 12:306–312.
Schumacher S, Oeftiger L, Mrochen M. Equivalence of biomechanical changes induced by rapid and standard corneal cross-linking, using riboflavin and ultraviolet radiation. Invest Ophthalmol Vis Sci 2011; 52:9048–9052.
Krumeich JH, Daniel J. Live epikeratophakia and deep lamellar keratoplasty for I-III stage-specific surgical treatment of keratoconus. Klin Monbl Augenheilkd 1997; 211:94–100.
Krumeich JH, Daniel J, Knülle A. Live-epikeratophakia for keratoconus. J Cataract Refract Surg 1998; 24:456–463.
Sadoughi MM, Einollahi B, Baradaran-Rafii A, Roshandel D, Hasani H, Nazeri M. Accelerated versus conventional corneal collagen cross-linking in patients with keratoconus: an intrapatient comparative study. Int Ophthalmol 2016. doi: 10.1007/s10792-016-0423-0.
Wittig-Silva C, Chan E, Islam FM, Wu T, Whiting M, Snibson GR. A randomized, controlled trial of corneal collagen cross-linking in progressive keratoconus: three-year results. Ophthalmology 2014; 121:812–821.
Khairy HA, Marey HM, Ellakwa AF. Epithelium-on corneal cross-linking treatment of progressive keratoconus: a prospective, consecutive study. Clin Ophthalmol 2014; 8:819–823.
Raiskup-Wolf F, Hoyer A, Spoerl E, Pillunat LE. Collagen crosslinking with riboflavin and ultraviolet-A light in keratoconus: long-term results. J Cataract Refract Surg 2008; 34:796–801.
Greenstein SA, Fry KL, Bhatt J, Hersh PS. Natural history of corneal haze after collagen crosslinking for keratoconus and corneal ectasia: Scheimpflug and biomicroscopic analysis. J Cataract Refract Surg 2010; 36:2105–2114.
Shalchi Z, Wang X, Nanavaty MA. Safety and efficacy of epithelium removal and transepithelial corneal collagen crosslinking for keratoconus. Eye (Lond) 2015; 29:15–29.
Poli M, Lefevre A, Auxenfans C, Burillon C. Corneal collagen cross-linking for the treatment of progressive corneal ectasia: 6-year prospective outcome in a French population. Am J Ophthalmol 2015; 160:654–662.
Badawi AE. Accelerated corneal collagen cross-linking in pediatric keratoconus: one year study. Saudi J Ophthalmol 2017; 31:11–18.
Chow VW, Chan TC, Yu M, Wong VW, Jhanji V. One-year outcomes of conventional and accelerated collagen crosslinking in progressive keratoconus. Sci Rep 2015; 5:14425.
Elbaz U, Shen C, Lichtinger A, Zauberman NA, Goldich Y, Chan CC et al.
) corneal collagen crosslinking for keratoconus − a 1-year follow-up. Cornea 2014; 33:769–773.
Helena MC, Filatov VV, Johnston WT, Vidaurri-Leal J, Wilson SE, Talamo JH. Effects of 50% ethanol and mechanical epithelial debridement on corneal structure before and after excimer photorefractive keratectomy. Cornea 1997; 16:571–579.
Kymionis GD, Kounis GA, Portaliou DM, Grentzelos MA, Karavitaki AE, Coskunseven E et al.
Intraoperative pachymetric measurements during corneal collagen cross-linking with riboflavin and ultraviolet A irradiation. Ophthalmology 2009; 116:2336–2339.
Raiskup F, Pinelli R, Spoerl E. Riboflavin osmolar modification for transepithelial corneal cross-linking. Curr Eye Res 2012; 37:234–238.
Mark T, Ngounou F, Tamon J, Marx-Gross S, Preussner PR. Modulatory effect of different riboflavin compositions on the central corneal thickness of African keratoconus corneas during collagen crosslinking. Middle East Afr J Ophthalmol 2014; 21:66–71.
] [Full text]
Oltulu R, Şatirtav G, Donbaloğlu M, Kerimoğlu H, Özkağnici A, Karaibrahimoğlu A. Intraoperative corneal thickness monitoring during corneal collagen cross-linking with isotonic riboflavin solution with and without dextran. Cornea 2014; 33:1164–1167.
Zhang X, Sun L, Chen Y, Li M, Tian M, Zhou X. One-year outcomes of pachymetry and epithelium thicknesses after accelerated (45 mW/cm2
) transepithelial corneal collagen cross-linking for keratoconus patients. Sci Rep 2016; 6:32692.
Ozgurhan EB, Kara N, Cankaya KI, Kurt T, Demirok A. Accelerated corneal cross-linking in pediatric patients with keratoconus: 24-month outcomes. J Refract Surg 2014; 30:843–849.
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.
Mazzotta C, Traversi C, Baiocchi S, Caporossi O, Bovone C, Sparano MC 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.
Chan TC, Chow VW, Jhanji V, Wong VW. Different topographic response between mild to moderate and advanced keratoconus after accelerated collagen cross-linking. Cornea 2015; 34:922–927.
Kocak I, Aydin A, Kaya F, Koc H. Comparison of transepithelial corneal collagen crosslinking with epithelium-off crosslinking in progressive keratoconus. J Fr Ophtalmol 2014; 37:371–376.
Soeters N, Wisse RP, Godefrooij DA, Imhof SM, Tahzib NG. Transepithelial versus epithelium-off corneal cross-linking for the treatment of progressive keratoconus: a randomized controlled trial. Am J Ophthalmol 2015; 159:821–828.
Wajnsztajn D, Frenkel S, Frucht-Pery J. Early Complications after crosslinking for keratoconus. Poster presented at the joint meeting of the American Academy of Ophthalmology and Asia-Pacific Academy of Ophthalmology. Chicago, Illinois, USA: American Academy of Ophthalmology and Asia-Pacific Academy of Ophthalmology. November 2012.
Seiler TG, Schmidinger G, Fischinger I, Koller T, Seiler T. Complications of corneal cross-linking. Ophthalmologe 2013; 110:639–644.
Knappe S, Stachs O, Zhivov A, Hovakimyan M, Guthoff R. Results of confocal microscopy examinations after collagen cross-linking with riboflavin and UVA light in patients with progressive keratoconus. Ophthalmologica 2011; 225:95–104.
Wollensak G, Iomdina E, Dittert DD, Herbst H. Wound healing in the rabbit cornea after corneal collagen cross-linking with riboflavin and UVA. Cornea 2007; 26:600–605.
Seiler T, Hafezi F. Corneal cross-linking-induced stromal demarcation line. Cornea 2006; 25:1057–1059.
Sherif AM. Accelerated versus conventional corneal collagen cross-linking in the treatment of mild keratoconus: a comparative study. Clin Ophthalmol 2014; 8:1435–1440.
Wollensak G, Iomdina E. Biomechanical and histological changes after corneal crosslinking with and without epithelial debridement. J Cataract Refract Surg 2009; 35:540–546.
Shetty R, Nagaraja H, Jayadev C, Pahuja NK, Kurian Kummelil M, Nuijts RM. Accelerated corneal collagen cross-linking in pediatric patients: two-year follow-up results. Biomed Res Int 2014; 2014:894095.
Ng AL, Chan TC, Cheng AC. Conventional versus accelerated corneal collagen cross-linking in the treatment of keratoconus. Clin Exp Ophthalmol 2016; 44:8–14.
Li X, Yang H, Rabinowitz YS. Longitudinal study of keratoconus progression. Exp Eye Res 2007; 85:502–507.
Ertan A, Muftuoglu O. Keratoconus clinical findings according to different age and gender groups. Cornea 2008; 27:1109–1113.
[Table 1], [Table 2], [Table 3], [Table 4]