The purpose of this study was to summarize key findings from a systematic review of the effectiveness and safety of transepithelial corneal crosslinking (CXL) compared with epithelium-off CXL for progressive keratoconus.
Cochrane systematic review.
We included in our review only randomized controlled trials (RCTs) in which transepithelial and epithelium-off CXL had been compared among participants with progressive keratoconus. The primary outcome was keratoconus stabilization based on post-operative maximum keratometry (Kmax). We adhered to Cochrane methods for trial selection, data extraction, risk of bias evaluation, and data synthesis.
Thirteen RCTs with 567 participants (661 eyes) were included; 11 studies compared non-iontophoresis-assisted transepithelial with epithelium-off CXL. Keratoconus stabilization was described as an outcome in 2 studies. The estimated difference in Kmax means (ie, the “mean difference,” MD) from meta-analysis of 177 eyes in 5 RCTs indicated that there were no differences between intervention groups in Kmax at 12 months or later (MD: 0.99 diopter [D]; 95% confidence interval: −0.11 to 2.09). Meta-analysis of keratometry and visual acuity outcomes at 12 months or longer after surgery from 2 studies that had compared transepithelial CXL using iontophoresis provided no conclusive evidence of an advantage over epithelium-off CXL.
Lack of precision due to small sample sizes, indeterminate risk of bias due to inadequate reporting, and inconsistency in how outcomes were measured and reported among studies make it difficult to state with confidence whether transepithelial CXL confers an advantage over epithelium-off CXL for patients with progressive keratoconus with respect to stabilization of keratoconus, visual acuity, or patient-reported outcomes based on available data.
K eratoconus can cause loss of uncorrected and best-corrected distance visual acuity (uncorrected distance visual acuity [UDVA] and corrected distance visual acuity [CDVA]) through corneal perforation, ectasia of the central or paracentral cornea, or corneal scarring, all of which can lead to irregular astigmatism. Keratoconus is bilateral but often asymmetric in severity. The condition may be influenced by environmental factors but is often described as the most common corneal dystrophy. The prevalence in the Netherlands was recently estimated to be 1:375 (265 cases per 100,000 population; 95% confidence interval [CI]: 260-270), which is 6 times higher than the previous estimate of 1:2,000 from a 48-year clinical and epidemiological study of keratoconus in residents of Olmsted County, Minnesota. The annual incidence of keratoconus of 1:7,500 (13.3 cases per 100,000 population; 95% CI: 11.6-15.2) also was 5-10 times higher than previous population studies reported. The reason for increased prevalence and incidence is likely improved detection with increased use of corneal imaging.
Multiple topographic and tomographic imaging modalities and diagnostic indices exist. There is, however, no universal method to diagnose keratoconus, nor are there standardized criteria to judge progressive keratoconus. Newer Scheimpflug-based tomography helps distinguish subclinical keratoconus from normal corneas by interpretation and display of change in either anterior and posterior elevations; location of and corneal pachymetry at the thinnest point; pachymetric progression; and maximum keratometry (Kmax for “maximum K” to denote the maximum curvature power of the whole anterior corneal surface, also known as maximum cone apex curvature). Increase in Kmax by 1 or more diopters (D) remains the most frequently reported index of disease progression, more so than worsening of refractive or corneal astigmatism or change in UDVA or CDVA , or worsening of corneal topographical indices other than Kmax.
Corneal collagen crosslinking (CXL) using ultraviolet A (UVA) radiation applied to the cornea is the only treatment shown to slow progression of keratoconus. Theoretically CXL slows keratoconus progression by strengthening and stabilizing the collagen lamellae, resulting in corneal mechanical stiffening. CXL may improve refractive error by reducing the irregular astigmatism caused by corneal biochemical instability and preventing further corneal steepening. The original technique involves application of UVA radiation to de-epithelialized cornea to which riboflavin, a photosensitizer, is added topically before and during irradiation. Transepithelial CXL is a newer alternative with many variants in which the epithelium is not denuded, offering the putative advantages of faster healing, less patient discomfort, faster visual rehabilitation, and less risk of corneal haze. An increasing number of studies comparing transepithelial and epithelium-off CXL are being undertaken to determine which technique better achieves the stated goal of CXL, which is to halt or slow progression of keratoconus.
Because estimation of the rate of turnover of collagen and the extracellular matrix of the corneal stroma may require years or decades, long-term follow-up after CXL is essential to determine longevity of effects and to identify long-term complications. , , , The main objective of this summary of the authors’ Cochrane systematic review is to report the comparative safety and effectiveness of transepithelial CXL compared with epithelium-off CXL, based on the best currently available evidence.
Adhering to the methods in the Cochrane Handbook for Systematic Reviews of Interventions (Supplemental Materials), we included randomized controlled trials (RCTs) in our review. Methods are summarized below; details are given in the full Cochrane systematic review. Eligible trials compared transepithelial CXL with epithelium-off CXL for treatment of progressive keratoconus. We excluded studies of participants with corneal ectasia of other types (eg, status post laser in situ keratomileusis). We excluded studies that enrolled participants under age 14 (US Food and Drug Administration approval for epithelium-off CXL is for patients 14 years of age and older). Trials that included adjunctive therapy or modification of either technique (such as iontophoresis or chemical enhancers to improve stromal absorption of riboflavin) were eligible. Although the irradiance in standard epithelium-off CXL has been 3 mW/cm 2 for 30 minutes, trials that used all irradiance levels and duration were included.
To identify RCTs potentially eligible for this review (and also controlled clinical trials in case we found no or few RCTs), we searched CENTRAL (which contains the Cochrane Eyes and Vision Trials Register); Ovid MEDLINE; OvidMEDLINE In-Process and Other Non-Indexed Citations; Ovid MEDLINE Daily; Ovid OLDMEDLINE; EMBASE; PubMed; Latin American and Caribbean Health Sciences Literature Database (LILACS); the metaRegister of Controlled Trials (mRCT) ( www.controlledtrials.com ); ClinicalTrials.gov ( www.clinicaltrials.gov ); and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) ( www.who.int/ictrp/search/en ). We did not impose any date or language restrictions in the electronic search for trials. We also used the Science Citation Index Expanded database to identify additional studies that had cited trials included in this review. We last searched the electronic databases on January 15, 2020. The Cochrane systematic review provides our detailed search strategies for the electronic databases. We also searched the references cited by included studies for trials not identified by any automated search.
Pairs of authors independently reviewed titles and abstracts resulting from the search to identify citations referring to trials that definitely or possibly were eligible based on our inclusion criteria. The final eligibility decision was based on independent review by 2 authors of the full text of articles; disagreements were resolved by discussion. After ascertaining that more than 1 RCT was eligible for inclusion, we elected to include only RCTs in this review.
OUTCOMES OF INTEREST
The primary outcome for this review was stabilization of keratoconus progression as indicated by Kmax, a measurement of corneal curvature used to assess keratoconus progression. The outcome time points of primary interest were 12 and 24 months after corneal CXL; however, participants in included trials rarely had been followed for one year or longer. Therefore, we also considered outcomes after shorter follow-up periods. We analyzed Kmax both as a continuous outcome (change in Kmax from baseline) and as a dichotomous outcome (proportion of participants whose Kmax decreased by at least 2 D (indicating arrest or slowing of disease progression), proportion of eyes whose Kmax increased by at least 2 D from baseline, and proportion of eyes whose Kmax remained stable versus those that increased by >1 D, used to denote progression. We considered the following secondary outcomes at 12 months or more after CXL, based on measurements made at the longest follow-up time: the mean change in CDVA from baseline recorded and analyzed as the number of letters read correctly on a chart with a logarithm of the minimum angle of resolution (logMAR) scale ; the proportion of participants who gained 10 or more logMAR letters from baseline, equivalent to 2 lines (0.2) on a logMAR scale; the proportion who lost 10 or more logMAR letters from baseline; vision-related quality of life as assessed by a validated questionnaire (eg, the National Eye Institute Visual Function Questionnaire); the proportion who experienced adverse events; and direct and indirect costs of either type of surgery.
DATA COLLECTION AND ASSESSMENT OF TRIALS FOR RISK OF BIAS
Two review authors (S.N., I.C.K.) independently assessed the included studies for potential sources of bias according to Cochrane guidelines. The same authors independently extracted data from the included studies regarding trial characteristics, methods, participants, interventions, outcomes, and funding sources and recorded data on standard forms. One author (S.N.) entered the data using Review Manager software (RevMan; Cochrane, Ontario, Canada), and another author (I.C.K.) verified the data entered. Participant and surgery characteristics were compared among the trials to judge clinical and methodologic heterogeneity.
Included studies were evaluated for risk of selection, performance, outcome detection, attrition, selective reporting of outcomes, and other biases based on the Cochrane Risk of Bias tool (Cochrane). We judged each study to have been at “low risk,” high risk,” or “unclear risk” (whenever the information provided was insufficient to make an assessment) of bias of each type. Reasons were documented for these assessments; discrepancies were resolved through discussion. We attempted to contact study investigators by electronic mail when information in publications was insufficient for us to assess bias or when information required for data extraction was not reported clearly.
DATA SYNTHESIS AND ANALYSIS
Data synthesis and analysis were performed following Cochrane methods. We determined whether the design of each included trial specified intervention on 1 or both eyes from each participant and whether investigators randomized at the participant or at the eye level. We excluded studies with a paired-eyes design from our sensitivity analysis because of possible intrapersonal correlation of outcomes in the 2 eyes of a participant. We used the difference in means (“mean difference”) to compare interventions with respect to continuous outcomes, including change in Kmax, change in CDVA, and change in participant questionnaire responses regarding subjective visual function parameters. We separately analyzed studies by length of follow-up (<12 months and ≧12 months).
We calculated summary risk ratios (RRs) with 95% confidence intervals (CIs) to compare interventions with respect to dichotomous outcomes for which sufficient data were available from the included trials. Such outcomes included the proportion of eyes whose Kmax gained or lost 2 D, the proportion of eyes whose Kmax remained stable, the proportion of eyes that gained or lost 10 or more logMAR letters, and the proportion of eyes with adverse outcomes.
We calculated the I 2 statistic (percentage) to determine the proportion of variation in outcomes due to heterogeneity; we considered a value above 60% to suggest substantial statistical heterogeneity. We performed separate analyses by methods of outcome assessment to investigate observed heterogeneity.
We classified studies based on techniques within transepithelial CXL, and we compared epithelium-off CXL with transepithelial CXL separately with and without use of iontophoresis (ie, transepithelial CXL versus epithelium-off CXL, and transepithelial CXL using iontophoresis vs. epithelium-off CXL). We performed meta-analysis when clinical and methodological heterogeneity was minimal. To combine the outcome data from included trials in a meta-analysis to estimate the overall effect of epithelium-off CXL relative to transepithelial CXL, we used a random effects model; when fewer than 3 studies were included in an analysis, we used a fixed effect model. We explored comparisons between transepithelial and epithelium-off CXL techniques within subgroups to explain observed heterogeneity whenever sufficient data were available. Whenever the quality of the available data from a study prevented meaningful analysis, we omitted the study from quantitative analyses and reported the data in a narrative format when appropriate.
We assessed the certainty of evidence for each outcome according to the GRADE approach. We began our assessment by judging the randomized design of each included study to confer a high certainty of evidence and downgraded certainty to moderate, low, or very low when there was evidence of high risk of bias, inconsistency, indirectness, or imprecision.
The electronic searches yielded 3,364 records, of which 2,785 were screened after removing duplicates ( Figure 1 ). The full-text reports of 57 citations that were potentially relevant were obtained and screened. Thirteen RCTs, published in 22 reports, were included in this review. Searches of other sources did not identify any other potentially eligible trials. Seven studies were parallel group RCTs in which 1 eye of each participant was treated, 5 studies were RCTs in which both eyes of some or all participants were assigned to the same intervention, and 1 study was an RCT with a paired-eyes design. , In the trial with paired-eyes design, both eyes of participants had progressive keratoconus; 1 eye was randomly assigned to transepithelial CXL, and the other eye was assigned to epithelium-off CXL. We analyzed data from the studies that had assessed outcomes in both eyes separately without taking into account intra-person correlation.
DESCRIPTION OF INCLUDED STUDIES
The 13 included studies were conducted in Europe (7 studies), the Middle East (3 studies), India (1 study), Russia (1 study), and Turkey (1 study). The studies reported data from a total of 661 eyes of 567 participants with progressive keratoconus; 345 eyes underwent transepithelial CXL, and 316 underwent epithelium-off CXL. Of the eyes that underwent transepithelial CXL, 108 eyes underwent iontophoresis-assisted transepithelial CXL. Clinical and methodological heterogeneity based on participant characteristics, topographic/tomographic devices, and descriptions of surgical technique provided in the trials was significant ( Table 1). The definition of progressive keratoconus and methods by which to assess it at trial entry varied across trials.
|Study Year ref||Country||Number of Participants/Eyes||Definition of Progressive Keratoconus||Keratometric Device||Iontophoresis-Assisted||Baseline Equivalence||Concentration of Riboflavin Pretreatment Before Transepithelial CXL Until Saturation||Topical Instillation Of Riboflavin 0.1% Drops During Transepithelial Treatment||Postoperative Regimen After Either Type of CXL (Exception Noted)||Diameter for Epithelium-Off Treatment(mm)|
|Acar et al. 2014||Turkey||13/13 eyes||“[I]ncrease in the steepest keratometry of 1.0 D or more in a 1-year period, 0.50 D increase in manifest refraction spherical equivalent, 1.00 D increase in manifest cylinder, or need for new contact lens fitting more than once in 2 years”||Not reported||No||Not reported||Riboflavin 0.1% + |
+ dextran 15% + trometalol + EDTA
|Every 5 min||Only for epithelium-off CXL: contact lens and netilmicin antibiotic drops||7-9|
|Al Fayez et al. 2015||Saudi Arabia||70/70 eyes||“[I]ncrease in the maximum K value or manifest astigmatism ≥1 D within the previous year based on repeated corneal topography”||Scheimpflug (Pentacam)||No||Comparable||0.10%||No||“[F]luorometholone for 2 weeks,” started post re-epithelialization in epithelium-off arm||9|
|Al Zubi et al. 2019||Jordan||80/ 80 eyes||“[G]reater than 0.5D rise in six months or greater than 1 D rise in steep K/12 months”||Scheimpflug (Pentacam)||No||Unclear/contradictory between text and table||0.10%||Every 3 min||Fluorometholone 4 times per day and taper over 4 weeks||7|
|Bikbova and Bikbov 2016||Russia||119/149 eyes||“[I]ncrease in steepest keratometry |
value by ≥1.0 D or
manifest cylinder, or ≥ 0.5 D in manifest spherical
equivalent refraction by repeated keratotopography
|Placido disc (OPD Nidek)||Yes||Comparable||0.10%||Constant exposure for iontophoresis arm||“[C]orticosteroid drops for 2 weeks ||9|
|Cifariello et al. 2018||Italy||32/40 eyes||“Progression of keratoconus was documented |
through a clinical and instrumental (topographic, pachymetric,
or aberrometric) worsening in the previous 6 months
|Placido disc/Scheimpflug (CSO Eye-top) and Scheimpflug (Pentacam)||No||No differences in baseline ocular surface disease index; statistical comparisons between other preoperative outcomes were not reported; mean age was significantly greater in transepithelial CXL group||Riboflavin 0.1% + dextran 15% + trometalol + EDTA||Every 5 min||Transepithelial CXL arm: tobramycin use 4 times per day for 1 week; no steroid epithelium-off CXL: dexamethasone 0.1% 4 times per day for 2 weeks||9|
|Lombardo et al. 2016||Italy||25/34 eyes||“[I]f there was an increase of at least 1 D in the Kmax derived by computerized Placido disc corneal topography over the 12 months preceding the operation”||Placido disc (Visante)||yes||Comparable baseline age, Kmax, preoperative endothelial count, central corneal thickness||Riboflavin 0.1% + |
+ trometalol + EDTA
|Constant exposure for iontophoresis arm||Fluorometholone twice per day starting 1 week after procedure for 3 weeks||10|
|Mastropasqua et al. 2013||Italy||35/40 eyes||“[M]ean central K-reading change of ≥1.5 diopters observed in 3 consecutive topographies during the preceding 6 months, or a mean central corneal thickness decrease of ≥5% in 3 consecutive examinations performed in the previous 6 months”||Scheimpflug (Pentacam)||No||Not reported||Riboflavin 0.1% + + dextran 15% + trometalol + EDTA||0.1% every 3 min||Not reported||Not reported|
|Nawaz et al. 2015||India||40/40 eyes||“[D]ocumented keratoconus progression on topography over at least 1-year follow-up”||Scanning slit (Orbscan II)||No||Comparable baseline age, gender, Kmax, preoperative endothelial cell count, visual acuity, kerato-metric astigmatism||0.10%||Riboflavin 0.10% + dextran 20%, with proparacaine, every 5 min||Prednisolone acetate 1% 4 times per day and taper over 4 weeks||7|
|Razmjoo et al. 2014||Iran||22/44 eyes||[I]n past 12 months, an increase in Kmax of 1.00 D, an increase of refractive astigmatism of 1 D of or increase of refractive error of 0.5 D”||Scheimpflug (Pentacam)||No||Comparable best corrected visual acuity topographic indices, and corneal density||0.10%||Every 2-3 min||Betamethasone every 3 h for 4 weeks||9|
|Rossi et al. 2015||Italy||20 /20 patients||“[P]rogressive keratoconus with a documented clinical and instrumental (topographic, pachymetric, or aberrometric) worsening in the previous 6 months of observation”||Scheimpflug (Pentacam)||No||UDVA and CDVA were higher in the epithelium-off CXL group; |
No significant differences in age, pachymetry, and keratometry
|Riboflavin 0.1% + dextran 15% + trometalol + EDTA||Dexamethasone 4 times per day and taper over 2 weeks||9|
|Rossi et al. 2018||Italy||30 /30 eyes||“[D]ocumented clinical and instrumental (topographic, pachymetric, or aberrometric) worsening in the prior 6 months”||Placido disc/Scheimpflug (CSO Eye-top)||Yes (1 of 3 arms)||“[H]omogeneous for sex and age”||Riboflavin 0.1% + trometalol + EDTA for iontophoresis arm; |
Riboflavin 0.1% + dextran 15% + EDTA for non-iontophoresis arm
|Constant exposure for iontophoresis arm||Dexamethasone 4 times per day and taper over 2 weeks||9|
|Soeters et al. 2015||the Nether-lands||61/61 eyes||“[I]ncrease in Kmax, Ksteep, mean keratometry, and/r topographic cylinder value by ≥0.5 D over the previous 6-12 months”||Scheimpflug (Pentacam)||No||Comparable except for “lower spherical equivalent and logMAR UCDA in the transepithelial group”||Riboflavin 0.1% + dextran 15% + EDTA||Fluorometholone twice per day for 2 weeks starting 1 week after procedure||9|
|Stojanovic et al. 2014||Norway||20/40 eyes||“[I]ncrease of astigmatism or myopia by 1 D or increase in average Sim K by 1.50 D.”||Placido disc (OPD-II, Nidek)||No||Unclear but no difference at any follow up through 12 months in topographic features, visual acuity, refraction, Kmax||0.50%||No||Dexamethasone 0.1% 4 times per day for 1 week||8|
|CXL = corneal crosslinking; D = diopter; EDTA = ethylene-diamine-tetraacetic acid; Kmax = steepest keratometry (ie, maximum keratometry, apical keratometry, maximum cone apex curvature); Ksteep = steep simulated keratometry (ie, steepest central simulated keratometry; K2); |
UCDA = uncorrected distance acuity; UDVA = uncorrected distance visual acuity.