Three‑year clinical observation of the outcomes of transepithelial and epithelial‑off accelerated corneal collagen crosslinking treatment for different types of progressive keratoconus
- Authors:
- Published online on: May 12, 2020 https://doi.org/10.3892/etm.2020.8741
- Pages: 786-795
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Copyright: © Huang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Abstract
Introduction
Keratoconus, also known as corneal ectasia or corneal dilatation, is a non-inflammatory dilating disease of the eyes that affects the cornea; the clinical manifestations are progressive corneal thinning and protrusion leading to progressive myopia, irregular astigmatism and corneal scarring (1). Keratoconus is a disease in which the biomechanical properties of the cornea are gradually weakened by changes in corneal collagen fiber structure and extracellular matrix, as well as apoptosis of corneal cells (2). A recently developed technique known as riboflavin/ultraviolet (UV) corneal collagen cross-linking (CXL) may alleviate these pathological changes associated with keratoconus, thereby effectively preventing the development of secondary corneal dilation after keratoconus or refractive surgery (3); however, the standard early treatment plan is time-consuming. For patients with a thin cornea, there is also a risk of damaging corneal endothelial cells; thus, epithelial-off CXL should only be used in patients with a thick cornea.
Accelerated transepithelial CXL (ATE-CXL) is a novel and minimally invasive technique in which the use of high-irradiation pulsed UV light significantly reduces the treatment duration. In the present study, a pre- and post-control study design was used to evaluate changes in clinical characteristics after ATE-CXL, assess the safety and effectiveness of this treatment and analyze the reproducibility and stability of the long-term effects on keratoconus progression.
Materials and methods
Subjects and grouping
Patients diagnosed with advanced keratoconus who underwent monocular or binocular ATE-CXL were enrolled between January 2014 and December 2017 in the present prospective, non-randomized, controlled clinical study. The inclusion criteria were as follows: i) Primary keratoconus, corneal topography indicating progressive enlargement of keratoconus lesions, maximal curvature increased by ≥1 D or optometry astigmatism increased by ≥1 D, or equivalent spherical degree increased by ≥0.5 D; ii) vision loss or corrected visual acuity (VA) <20/20; iii) at least one of the following positive signs on slit lamp examination: Thinning of the corneal stroma, tapered forward bulging, Fleischer ring, Vogt line, or epithelial or subepithelial scar; iv) central diopter of the corneal surface >47 D, difference between 3 mm below the corneal center and the upper 3 diopters >3 D, and difference between the central anterior surface of the cornea >1 D determined on corneal topographic examination. The exclusion criteria were as follows: Thinnest corneal thickness (TCT) <340 µm; endothelial cell density (ECD) <2,000/mm2; post-elastic membrane rupture matrix edema; acute keratoconus; corneal trauma or secondary corneal ectasia after surgery; ocular diseases other than keratoconus and refractive error; systemic diseases affecting the eye, including collagen disease; and pregnancy. Ultimately, 70 cases with 96 eyes (48 males and 22 females; age range, 13-30 years) with the time from disease onset ranging from 0.52 to 120 months were included in the study. The follow-up time was 3 years. According to the Amsier-Krumeich grading standard and corneal thickness (4), different keratoconus types were divided into the following four groups according to the surgical method that was used: Group A, ATE-CXL central; group B, accelerated epithelial-off (A)-CXL central; group C, ATE-CXL peripheral; and group D, A-CXL peripheral. The treatment procedures were as follows: Group A, ATE-CXL for central keratoconus [maximum corneal curvature (Kmax)] <3 mm from the cornea; 340 µm <TCT<400 µm; n=22 cases, 34 eyes); group B, A-CXL for central keratoconus (Kmax <3 mm from the cornea; TCT >400 µm; n=17 cases, 26 eyes); group C, ATE-CXL for peripheral keratoconus (Kmax in the central 3 mm of the cornea, 340 µm <TCT <400 µm; n=16 cases, 18 eyes; and group D, A-CXL for peripheral keratoconus (Kmax outside the 3 mm corneal area, TCT >400 µm; n=15 cases of 18 eyes).
Pre-operative examination
Follow-up examination included evaluation of uncorrected distant (UD)VA, best-corrected distant (BD)VA, apparent optometry, compensated intraocular pressure (IOPcc), Kmax, mean corneal curvature (Km), TCT, corneal astigmatism (CA), anterior corneal elevation (ACE) and corneal ECD.
TCT was measured by optical coherence tomography (Heidelberg Engineering Ltd.) using an Scheimpflug imaging corneal topographer (Pentacam HR software v.6.07r12; Oculus Optikgeräte GmbH). Corneal topography (Fig. 1) and corneal ECD were measured using a corneal endothelial cell counter (SP-2000P; Topcon Corporation).
ATE-CXL
The septum was opened and surface anesthetic was applied to the cornea, which was infiltrated with ParaCel solution (Avedro, Inc.) every 90 sec for a total induction time of 4 min. The corneal surface was rinsed and then infiltrated with VibeXXtra solution (0.25% riboflavin isotonic saline solution; Avedro, Inc.) every 90 sec for a total induction time of 6-10 min. After washing with balanced salt solution (BSS), the cornea was subjected to ATE-CXL with UV radiation cross-linking reinforcement. The irradiation intensity was 45 mW/cm2, the irradiation spot diameter was 9 mm and a pulse irradiation mode was used (interval: 1 sec on/1 sec off). The total irradiation time was 320 sec and the total irradiation energy was 7.2 J/cm2. During irradiation, 5% keratin solution (Shanghai Xianding Biotechnology Co., Ltd.) was applied to keep the corneal surface moist. The cornea was rinsed with BSS and eye drops were applied once. A sterile corneal bandage lens and an eye mask were applied to complete the procedure. There was no difference between the peripheral and central keratoconus operations and the eye position was not adjusted.
A-CXL
The septum was opened and after soaking the cornea with 20% alcohol for 15 sec under topical anesthesia, a 9-mm diameter corneal epithelial ring saw was used to remove the epithelium in the central region of the cornea. The cornea was covered with 0.1% riboflavin solution and the process was repeated every 90 sec for 10 min. The cornea was rinsed with BSS and A-CXL was performed by UVA radiation cross-linking reinforcement using an Avedro corneal remodeling platform (Avedro, Inc.) with the following settings: Spot diameter, 9 mm; pulse irradiation mode with pulse irradiation interval of 1 sec on/1 sec off; total energy, 7.2 J/cm2; power intensity, 30 mW/cm2; induction time, 10 min, UV pulse time, 8 min; and actual action time, 4 min. During irradiation, keratin solution was used to keep the corneal surface moist and afterwards, the cornea was rinsed with BSS. Eye drops were applied, followed by a sterile soft corneal bandage lens along with an eye mask. There was no difference between the peripheral and central keratoconus operations and the eye position was not adjusted.
Post-operative treatment and examination
At 1 day after surgery, antibiotics [levofloxacin (Clonidine) eye drops] were applied 4 times a day, 1 drop each time along with artificial tears (polyvinyl alcohol eye drops; Ruizhu PVA 20; Hubei Yuanda Tiantianming Pharmaceutical Co., Ltd.) once daily, 1 drop each time. When the epithelium had completely healed, the contact lens was removed and tobramycin dexamethasone eye drops were applied 4 times a day for 1 week. Timolol eye drops (Wuhan Wujing Pharmaceutical Co., Ltd) were applied twice per day and tobramycin dexamethasone eye drops (Hangzhou Minsheng Pharmaceutical Co., Ltd) were used once a week for 4 weeks until inflammation of the ocular surface subsided. During this period, patients were regularly examined and the cornea and IOP were closely monitored. UDVA, BDVA, apparent optometry, IOPcc, Kmax, Km, CA, TCT, ACE and ECD were recorded 3 years after the procedure.
Statistical analysis
Data were analyzed using SPSS v.20.0 software (IBM Corp.) and values are expressed as the mean ± standard deviation. Pre- and post-operative changes in the same group were analyzed with the paired-samples t-test, while one-way analysis of variance and Student-Newman-Keuls were was used for inter-group comparisons. The sex ratio was compared by χ2 analysis, and t-test and binary logistic regression analysis were used to evaluate associations between UDVA, BDVA, Kmax, CA, ACE, TCT and ECD. P<0.05 was considered to indicate statistical significance.
Results
Comparative analysis of general data between groups A and B and groups C and D
Regarding the clinical data, there were no statistically significant differences in terms of age, sex, onset, Kmax position or corneal thickness between groups A and B and between groups C and D (P>0.05; Table I).
Post-operative outcomes of ATE-CXL and A-CXL for patients with central keratoconus
In group A, UDVA and BDVA differed significantly pre- vs. post-surgery (P<0.05; Table II); however, there were no significant changes in Kmax, CA, TCT, ECD, IOP and ACE values (P>0.05). In group B, UDVA and BDVA differed significantly pre- vs. post-surgery surgery (P<0.05), but there were no changes in the values of Kmax, CA, ACE, TCT or ECD (P>0.05; Table II). On the other hand, there was a significant correlation between the change in IOP and changes in BDVA and TCT after surgery as compared to the pre-operative values in group B. IOP was not significantly different between the post- and pre-operative stages in groups A and B (Fig. 2A and B).
Groups A and B did not differ in terms of change in UDVA value (post- vs. pre-operative; P>0.05); the changes in Kmax in groups A and B were -5.4±8.0 and -4.4±7.0 D, respectively, and there was no significant difference between the two groups (P>0.05). Similarly, the two groups exhibited no difference in terms of the change in CA (-1.4±2.0 and -1.5±1.0 D, respectively; P>0.05). The change in ACE in groups A and B was -4.2±1.6 and -6.3±2.8 µm, respectively, and there was no statistically significant difference between the two groups either for ACE (P>0.05) or TCT (P=0.20) (Table II and Fig. 1).
Table II indicates that there was no statistical difference between group A and group B before treatment. After treatment, there was remission in both groups, but group A had a statistically significant improvement in BDVA (P=0.032) when compared with group B.
Post-operative outcomes of ATE-CXL and A-CXL in patients with peripheral keratoconus
The differences in UDVA, Kmax and ACE prior to vs. after surgery in group C were statistically significant (P<0.01); however, there were no significant differences in BDVA, CA, TCT or ECD (P>0.05; Table II and Fig. 3). There was a significant correlation between changes in IOP and Kmax after as compared to prior to treatment in group C (Fig. 2).
The differences between pre- and post-surgery UDVA, Kmax and ACE in group D were significant (P<0.05); however, there was no significant difference in BDVA (P>0.05; Fig. 3 and Table II). Post-operative Kmax, TCT and ECD values differed significantly from those prior to surgery (P<0.05; Fig. 3; Table II).
The change in UDVA (post- vs. pre-operative) was similar between groups C and D (P>0.05); however, changes in Kmax differed significantly, with values of -2.5±1.8 and -3.2±2.8 D, respectively (P=0.01). The changes in CA values were also significant at -0.2±0.6 and -0.2±0.8 D, respectively (P<0.05). There were no differences in the changes in TCT, ACE and ECD between groups C and D (P=0.20; Table II).
Table III indicates that there was no statistical difference between group C and group D before treatment. After treatment, there was remission in both groups, but group D had a statistically significant improvement in BDVA (P=0.047), CA (P=0.045) and ACE (P=0.012) compared with group C.
The intergroup comparison shows that ATE-CXL achieved better control of central keratoconus UDVA, Kmax and CA as compared with A-CXL (P<0.05).
Discussion
The histopathologic changes observed in keratoconus are linked to the structural changes in corneal collagen fibers and biomechanical weakening caused by corneal cell apoptosis. The UV-riboflavin CXL procedure was developed by a research team at the University of Dresden, Germany for the treatment of keratoconus and has been indicated to increase the mechanical strength of collagen fiber and their capacity for resisting corneal expansion (4,5). In addition to increasing corneal hardness, cross-linking surgery may reduce resource utilization and thus alleviate the economic burden on patients (6). Since its first application to the treatment of progressive keratoconus in 2003, corneal collagen cross-linking has been expanded to include a variety of corneal diseases (7). The increased tensile strength of the corneal matrix after cross-linking increases corneal resistance to degradation by proteolytic enzymes, including matrix metalloproteinase and thermal damage (8-10). One study suggested that corneal topography and wavefront aberration values were stable at 7 years after cross-linking (11).
There are multiple methods of CXL. EDTA has been used in patients with keratoconus to enhance riboflavin penetration and TE-CXL; at the 12-month follow-up, safety indices, including average uncorrected VA, mean equivalent spherical reduction, mean simulated corneal curvature K-value and mean surface variance index were higher in the TE-CXL group compared with those in the control group (A-CXL) (12), indicating that TE-CXL effectively inhibits keratoconus progression.
The traditional CXL procedure includes removal of epithelial tissue with a central corneal diameter of 5-9 mm under topical anesthesia (13) to facilitate the entry of riboflavin into the corneal stroma. During the addition of riboflavin, the corneal surface temperature is constant and does not result in thermal burns to the corneal tissue (14). After irradiation, antibiotic eye ointment is applied and a contact lens soaked with 3 g/l ofloxacin is worn by the patient until the corneal epithelium has healed by 8% (15). The cross-linking therapy for keratoconus is relatively safe; the major post-operative complication is aseptic infiltration of the corneal stromal and scarring of the central cornea, which occur at estimated rates of 7.6 and 2.8%, respectively (16). For patients with a corneal thickness <400 µm, a hypotonic riboflavin preparation has been used to induce edema of the corneal stroma and thus increase the thickness to >400 µm, after which cross-linking therapy achieved good results (17). An occasional complication is haze, which reduces the efficacy of steroid eye drops without affecting best-corrected VA (18). One patient developed diffuse lamellar keratitis after surgery and another developed herpes simplex keratitis that healed after treatment (19). Histological sections revealed an obvious boundary at a depth of 300 µm in the stromal layer, suggesting that the extent of cross-linking was limited to only the superficial tissue (17). Thus, the efficacy of cross-linking therapy for the posterior corneal cone remains to be determined; this is particularly important in the light of the fact that changes in corneal hardness and biomechanics after cross-linking therapy may increase the IOP (20).
Riboflavin/UV (370 nm) CXL is the first treatment that was indicated to effectively suppress keratoconus progression (3). The efficacy has been demonstrated experimentally and the technique lacks numerous disadvantages of other cross-linking methods (21). The adhesion of collagen fibers between adjacent layers of the keratoconus that are weakened by CXL was demonstrated by X-ray (22). In patients with a corneal thickness of >400 µm, CXL did not cause any damage to corneal endothelial cells and is therefore considered to be safe (7,23). It was also reported that CXL is able to increase corneal stress and strain, reduce swelling and increase the shrinkage temperature, as well as the tolerance of corneal stromal tissue to digestive enzymes (24-26). After CXL, the diameter of collagen fibers within 300 µm of the pre-corneal stroma was increased and no corneal endothelial cell damage occurred (27).
The present study indicated that the reduction in ACE persisted 3 years after ATE-CXL or A-CXL surgery, suggesting that the hardness of the corneal matrix fibers and tensile strength were increased, whereas the curvature was decreased by the cross-linking. At 3 years after CXL, most patients in the ATE-CXL group had improved UDVA and BDVA and reduced Kmax, CA, and ACE; however, the differences in Kmax, CA and ACE were attenuated compared with those in the A-CXL group, indicating that the transepithelial treatment was less effective than the epithelial approach.
After the surgery, UDVA and BDVA were significantly increased in groups A and B. A superior curative effect was observed in group A, which was reflected in the Kmax value. On the other hand, group B exhibited greater improvements in CA and ACE, indicating that while ATE-CXL and A-CXL may be used to treat central keratoconus, the latter achieves superior results.
In groups C and D, UDVA was increased, whereas Kmax and CA were decreased after CXL. VA of the naked eye was higher in group C than in group D but Kmax and CA were lower. This provides further evidence that the transepithelial method is the less effective of the two cross-linking methods, particularly in patients with peripheral keratoconus.
Intra-group correlation analysis revealed that the difference between pre- and post-operative IOP in group C decreased with increasing difference in BDVA, whereas that of BC increased with increasing difference in TCT. TCT, IOP and diopter are presumed to be associated, although this is debated. The corneal thickness is reduced in myopia (28) and it has been determined that for each 70-µm decrease, the IOP as measured with a tonometer is 3.5 mmHg lower than the baseline value (29); however, other studies have not indicated any correlation between diopter and IOP (30). By contrast, a larger diopter was suggested to be associated with higher IOP (31). In the present study, a correlation was observed between diopter and IOP (P<0.05) that may be linked to the decrease in corneal thickness caused by reduced IOP, which increases TCT and results in a superior curative effect. In group C, a larger change in IOP was correlated with a greater change in Kmax. The changes in intraocular pressure and BDVA in group B before and after operation were larger than those in group A, which indicated that treatment received by Group B patients was more effective. In group D, the differences between pre- and post-operative UDVA and ACE values were correlated, which may be attributed to alterations in corneal shape caused by post-operative changes in ACE; however, further experimental data are required to confirm this possibility.
As conical cornea is a progressive complication of corneal degeneration, it is unable to self-heal, and the incidence and progression rate of the two eyes in the same patient are different. The progression rate in different patients also varied. Therefore, a pre- and post-control study design was adopted in the present study. By acute observation, changes in patients with ATE-CXL (UVA parameters: 45 mW/cm2 x320 sec, 7.2 J/cm2) and A-CXL (UVA parameters: 30 mW/cm2 x480 sec, 7.2 J/cm2) were assessed, and observation and analysis of long-term effects and associated factors of ATE-CXL in advanced keratoconus treatment were performed to verify the long-term safety and effectiveness of the surgical treatment of progressive cone cornea. The predictiveness and stability of outcomes determined in the present study are expected to contribute to the guidance and provide a reference for the clinical treatment of pyramidal cornea.
Of note, the present study had certain limitations. The left and the right eyes of the patients were not distinguished at the time of sample collection, which may have affected the accuracy of the results. In future experiments, the left or right eye should be used consistently in order to improve the accuracy of the experimental results.
In conclusion, ATE-CXL and A-CXL are safe and effective treatment methods for inhibiting keratoconus progression after 3 years. Central (and to a lesser extent, peripheral) keratoconus may be effectively controlled by either approach, with disease stabilization 3 years later. ATE-CXL is associated with fewer adverse reactions and better patient compliance, which may reduce post-operative pain and complications caused by epithelialization. ATE-CXL is the most suitable treatment for keratoconus of <400 µm with a corneal thickness of >400 µm; however, A-CXL yields superior long-term outcomes. The relatively small sample size precluded observation of the outcomes of ATE-CXL in patients with secondary keratoconus after refractive surgery. Larger studies with longer follow-up are required to verify the effectiveness of ATE-CXL for controlling keratoconus.
Acknowledgements
The authors thank Dr Kang Yu (Department of Ophthalmology, The First Affiliated Hospital of Nanchang University, Nanchang, China) for assistance with the preparation/writing of this manuscript.
Funding
This study was supported by the National Natural Science Foundation of China (grant no. 81660158) and the Natural Science Key Project of Jiangxi Province (grant no. 20161ACB21017).
Availability of data and materials
The datasets generated and/or analyzed in this study are available from the corresponding author on reasonable request.
Authors' contributions
JRH and YS designed the study. CHW, LMG, LFH, HFL, BL and HJJ collected and analyzed the data. JRH wrote the manuscript. All authors read and approved the final manuscript.
Ethical approval and informed consent
The study protocol was approved by The Medical Research Ethics Committee of the Affiliated Eye Hospital of Nanchang University (Nanchang, China). The experiments were performed according to relevant guidelines and regulations. All study subjects were informed of the study purpose and design and provided written informed consent prior to their participation.
Patient consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
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