Transepithelial versus epithelium‐off corneal crosslinking for progressive keratoconus
Abstract
Background
Keratoconus is the most common corneal dystrophy. It can cause loss of uncorrected and best‐corrected visual acuity through ectasia (thinning) of the central or paracentral cornea, irregular corneal scarring, or corneal perforation. Disease onset usually occurs in the second to fourth decade of life, periods of peak educational attainment or career development. The condition is lifelong and sight‐threatening.
Corneal collagen crosslinking (CXL) using ultraviolet A (UVA) light applied to the cornea is the only treatment that has been shown to slow progression of disease. The original, more widely known technique involves application of UVA light to de‐epithelialized cornea, to which a photosensitizer (riboflavin) is added topically throughout the irradiation process.
Transepithelial CXL is a recently advocated alternative to the standard CXL procedure, in that the epithelium is kept intact during CXL. Retention of the epithelium offers the putative advantages of faster healing, less patient discomfort, faster visual rehabilitation, and less risk of corneal haze.
Objectives
To assess the short‐ and long‐term effectiveness and safety of transepithelial CXL compared with epithelium‐off CXL for progressive keratoconus.
Search methods
To identify potentially eligible studies, we searched the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Trials Register) (2020, Issue 1); Ovid MEDLINE; Embase.com; PubMed; Latin American and Caribbean Health Sciences Literature database (LILACS); ClinicalTrials.gov; and World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP). We did not impose any date or language restrictions. We last searched the electronic databases on 15 January 2020.
Selection criteria
We included randomized controlled trials (RCTs) in which transepithelial CXL had been compared with epithelium‐off CXL in participants with progressive keratoconus.
Data collection and analysis
We used standard Cochrane methodology.
Main results
We included 13 studies with 661 eyes of 567 participants enrolled; 13 to 119 participants were enrolled per study. Seven studies were conducted in Europe, three in the Middle East, and one each in India, Russia, and Turkey. Seven studies were parallel‐group RCTs, one study was an RCT with a paired‐eyes design, and five studies were RCTs in which both eyes of some or all participants were assigned to the same intervention.
Eleven studies compared transepithelial CXL with epithelium‐off CXL in participants with progressive keratoconus. There was no evidence of an important difference between intervention groups in maximum keratometry (denoted 'maximum K' or 'Kmax'; also known as steepest keratometry measurement) at 12 months or later (mean difference (MD) 0.99 diopters (D), 95% CI −0.11 to 2.09; 5 studies; 177 eyes; I2 = 41%; very low certainty evidence). Few studies described other outcomes of interest. The evidence is very uncertain that epithelium‐off CXL may have a small (data from two studies were not pooled due to considerable heterogeneity (I2 = 92%)) or no effect on stabilization of progressive keratoconus compared with transepithelial CXL; comparison of the estimated proportions of eyes with decreases or increases of 2 or more diopters in maximum K at 12 months from one study with 61 eyes was RR 0.32 (95% CI 0.09 to 1.12) and RR (non‐event) 0.86 (95% CI 0.74 to 1.00), respectively (very low certainty). We did not estimate an overall effect on corrected‐distance visual acuity (CDVA) because substantial heterogeneity was detected (I2 = 70%). No study evaluated CDVA gain or loss of 10 or more letters on a logarithm of the minimum angle of resolution (logMAR) chart. Transepithelial CXL may result in little to no difference in CDVA at 12 months or beyond. Four studies reported that either no adverse events or no serious adverse events had been observed. Another study noted no change in endothelial cell count after either procedure. Moderate certainty evidence from 4 studies (221 eyes) found that epithelium‐off CXL resulted in a slight increase in corneal haze or scarring when compared to transepithelial CXL (RR (non‐event) 1.07, 95% CI 1.01 to 1.14).
Three studies, one of which had three arms, compared outcomes among participants assigned to transepithelial CXL using iontophoresis versus those assigned to epithelium‐off CXL. No conclusive evidence was found for either keratometry or visual acuity outcomes at 12 months or later after surgery. Low certainty evidence suggests that transepithelial CXL using iontophoresis results in no difference in logMAR CDVA (MD 0.00 letter, 95% CI −0.04 to 0.04; 2 studies; 51 eyes). Only one study examined gain or loss of 10 or more logMAR letters. In terms of adverse events, one case of subepithelial infiltrate was reported after transepithelial CXL with iontophoresis, whereas two cases of faint corneal scars and four cases of permanent haze were observed after epithelium‐off CXL. Vogt's striae were found in one eye after each intervention. The certainty of the evidence was low or very low for the outcomes in this comparison due to imprecision of estimates for all outcomes and risk of bias in the studies from which data have been reported.
Authors' conclusions
Because of lack of precision, frequent indeterminate risk of bias due to inadequate reporting, and inconsistency in outcomes measured and reported among studies in this systematic review, it remains unknown whether transepithelial CXL, or any other approach, may confer an advantage over epithelium‐off CXL for patients with progressive keratoconus with respect to further progression of keratoconus, visual acuity outcomes, and patient‐reported outcomes (PROs). Arrest of the progression of keratoconus should be the primary outcome of interest in future trials of CXL, particularly when comparing the effectiveness of different approaches to CXL. Furthermore, methods of assessing and defining progressive keratoconus should be standardized. Trials with longer follow‐up are required in order to assure that outcomes are measured after corneal wound‐healing and stabilization of keratoconus. In addition, perioperative, intraoperative, and postoperative care should be standardized to permit meaningful comparisons of CXL methods. Methods to increase penetration of riboflavin through intact epithelium as well as delivery of increased dose of UVA may be needed to improve outcomes. PROs should be measured and reported. The visual significance of adverse outcomes, such as corneal haze, should be assessed and correlated with other outcomes, including PROs.
PICOs
Plain language summary
What surgical procedure works best to slow the progression of keratoconus (an eye disease)?
Why is this question important?
Keratoconus is a disease that affects the thin, clear outer layer of the eye, known as the cornea. Normally, the cornea is dome‐shaped. In people with keratoconus, the cornea slowly thins, and a cone‐shaped bulge develops in the center of the cornea. The disease usually begins between the ages of teens and 40, and persists throughout life. It causes blurry or distorted vision that may not be improved by wearing glasses and may result in perforation of the cornea and other visual problems.
Treatments such as glasses and contact lenses can be used to improve the vision of people with keratoconus. However, these do not slow the progression of the disease. The only treatment known to slow disease progression is ‘corneal collagen crosslinking’ (CXL).
CXL is a surgical procedure that aims to strengthen the cornea and prevent further thinning. It involves shining ultraviolet A (invisible) light rays onto eyes that have been treated with eye drops containing riboflavin (a vitamin). When the light rays meet the riboflavin, new links form between the fibers that make up the cornea.
There are two types of CXL. One type requires the removal of the cells on surface of the cornea, to make it easier for the riboflavin to reach the cornea. This procedure is called ‘epithelium‐off CXL’. The other type does not require the removal of these cells. This procedure is called ‘transepithelial CXL’. Surgeons who carry out this procedure can use chemicals to help riboflavin penetrate the cells on the surface of the cornea. They can also deliver riboflavin to the cornea using a small electrical current (iontophoresis).
Epithelium‐off CXL is the more commonly used procedure. However, transepithelial CXL could have advantages, such as faster healing and less patient discomfort. We reviewed the evidence to find out which of these two procedures is more beneficial and less risky for people with keratoconus.
How did we identify and evaluate the evidence?
We searched the medical literature for studies that compared epithelium‐off CXL against transepithelial CXL. Then we compared the results and summarized the evidence from all the studies. We rated our confidence in the evidence, based on factors such as study methods and sizes, and the consistency of findings across studies.
What did we find?
We found 13 studies with a total of 567 people. The studies took place in Europe, the Middle East, India, Russia, and Turkey. The shortest studies lasted six months, and the longest study lasted more than three years. Eleven studies compared transepithelial CXL without iontophoresis against epithelium‐off CXL. Three studies compared transepithelial CXL with iontophoresis against epithelium‐off CXL.
Transepithelial CXL without iontophoresis compared to epithelium‐off CXL
We do not know if one procedure is better than the other for preventing progression of keratoconus or visual loss because too few robust studies have compared the effects of these two CXL methods.
Evidence from four studies suggests that corneal hazing (clouding of the cornea) or scarring are probably more common with epithelium‐off CXL.
Transepithelial CXL with iontophoresis compared to epithelium‐off CXL
Evidence from two studies suggests that there may be little to no difference between the two procedures in changes to vision clarity. We do not know if one procedure is better than the other to prevent progression of keratoconus because two few robust studies have compared the two methods.
The evidence does not suggest that one procedure leads to more unwanted events than the other. However, our confidence in this evidence is low, because it is based on three studies that did not use robust methods.
What does this mean?
Due to a lack of robust evidence, we do not know if epithelium‐off CXL or transepithelial CXL is better for slowing keratoconus progression.
Adverse events such as corneal hazing or scarring are probably more common with epithelium‐off CXL than with transepithelial CXL without iontophoresis.
We need more and larger studies to strengthen the evidence. These should compare the benefits and the risks of different CXL procedures. Studies should aim to follow patients for more than 12 months, so that long‐term effects can be compared as it can take at least that much time for corneal tissue to heal from any procedure.
How‐up‐to date is this review?
The evidence in this Cochrane Review is current to January 2020.
Authors' conclusions
Summary of findings
| Transepithelial CXL compared with epithelium‐off CXL for progressive keratoconus | ||||||
| Patient or population: participants with keratoconus Settings: tertiary care or university hospital Intervention: transepithelial CXL Comparison: epithelium‐off CXL | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No. of participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Assumed risk | Corresponding risk | |||||
| Epithelium‐off CXL | Transepithelial CXL | |||||
| Mean change in maximum K from baseline or final value—at 12 months or more (diopters) | The mean maximum K ranged across control groups from −1.5 to −0.92 (change from baseline), or | The mean maximum K in the intervention groups was −1 to 0.3 (change from baseline), or (95% CI −0.11 to 2.09). | ‐ | 177 eyes | ⊕⊝⊝⊝ | |
| Proportion of participants whose maximum K decreased by at least 2 diopters—at 12 months | 269 per 1000 | 86 per 1000 | RR 0.32 (0.09 to 1.12) | 61 participants | ⊕⊝⊝⊝ | |
| Proportion of participants whose maximum K increased by at least 2 diopters—at 12 months | 0 per 1000 | 143 per 1000 | RR (non‐event) 0.86 (0.74 to 1.00) | 61 participants | ⊕⊝⊝⊝ | |
| Proportion of participants whose keratoconus remained stable—at 12 months | 1000 per 1000 | 441 per 1000, or 800 per 1000 (data not pooled due to considerable heterogeneity (I2 = 92%)) | ‐ | 131 participants | ⊕⊝⊝⊝ | |
| Mean change in corrected distance visual acuity (logMAR) from baseline or final values—at 12 months or more | The mean corrected distance visual acuity ranged across control groups from −0.13 to −0.07 (change from baseline), or 0.05 (final value). | The mean corrected distance visual acuity in the intervention groups was −0.16 to −0.11 (change from baseline), or 0.02 (final value), and mean difference from −0.07 to 0.02 (data not pooled due to substantial heterogeneity (I2 = 70%)) | ‐ | 137 eyes | ⊕⊝⊝⊝ | |
| Proportion of participants who gained 10 or more logMAR letters from baseline | ‐ | ‐ | ‐ | ‐ | ‐ | No study reported gains of 10 or more logMAR letters. |
| Proportion of participants who lost 10 or more logMAR letters from baseline | ‐ | ‐ | ‐ | ‐ | ‐ | No study reported losses of 10 or more logMAR letters. |
| Adverse outcomes—corneal haze or scarring | 76 per 1000 | 0 per 1000 | RR (non‐event) 1.07 (1.01 to 1.14) | 221 eyes (4 studies) | ⊕⊕⊕⊝ | Herpetic keratitis, sterile infiltrate, and epithelial defect observed in 1 eye each in epithelium‐off group; Vogt's striae reported in 1 eye in each intervention group. |
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; CXL: corneal collagen crosslinking; logMAR: logarithm of the minimum angle of resolution;RR: risk ratio | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1Downgraded one level for study limitation due to high risk of performance and other biases among included studies. | ||||||
| Transepithelial CXL using iontophoresiscompared with epithelium‐off CXL for progressive keratoconus | |||||
| Patient or population: participants with progressive keratoconus Settings: tertiary care or university hospital Intervention: transepithelial CXL using iontophoresis Comparison: epithelium‐off CXL | |||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No. of participants | Certainty of the evidence | |
|---|---|---|---|---|---|
| Assumed risk | Corresponding risk | ||||
| Epithelium‐off CXL | Transepithelial CXL using iontophoresis | ||||
| Mean change in maximum K from baseline or final value—at 12 months or more (diopters) | The mean maximum K ranged across control groups −1.51 (change from baseline), or | The mean maximum K in the intervention groups was −1.05 (change from baseline), or | ‐ | 51 eyes | ⊕⊝⊝⊝ |
| Proportion of participants whose maximum K decreased by at least 2 diopters—at 24 months | 91 per 1000 | 0 per 1000 | RR (non‐event) 1.12 (0.89 to 1.40) | 31 eyes | ⊕⊝⊝⊝ |
| Proportion of participants whose maximum K increased by at least 2 diopters—at 24 months | 0 per 1000 | 0 per 1000 | RR (non‐event) 1.00 (0.87 to 1.15) | 31 eyes | ⊕⊝⊝⊝ |
| Proportion of participants whose keratoconus remained stable—at 24 months | 1000 per 1000 | 900 per 1000 | RR 0.92 (0.76 to 1.12) | 31 eyes | ⊕⊝⊝⊝ |
| Mean change in corrected distance visual acuity (logMAR) from baseline or final values at 12 months or more | The mean corrected distance visual acuity ranged across control groups −0.13 (change from baseline), or 0.03 (final value). | The mean corrected distance visual acuity in the intervention groups was −0.13 (change from baseline), or 0.04 (final value), and no mean difference (95% CI −0.04 to 0.04). | ‐ | 51 eyes | ⊕⊕⊝⊝ |
| Proportion of participants who gained 10 or more logMAR letters from baseline | 83 per 1000 | 227 per 1000 | RR 2.73 (0.36 to 20.74) | 34 eyes | ⊕⊝⊝⊝ |
| Proportion of participants who lost 10 or more logMAR letters from baseline | 0 per 1000 | 0 per 1000 | RR 1.00 (0.88 to 1.13) | 34 eyes | ⊕⊝⊝⊝ |
| Adverse outcomes | 1 subepithelial infiltrate in transepithelial CXL group; 2 faint corneal scars and 4 permanent haze in epithelium‐off CXL group; Vogt's striae observed in 1 eye in each intervention group. | ‐ | 203 eyes (3 studies) | ⊕⊕⊝⊝ | |
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; CXL: corneal collagen crosslinking; logMAR: logarithm of the minimum angle of resolution;RR: risk ratio | |||||
| GRADE Working Group grades of evidence | |||||
| 1Downgraded one level for study limitation due to high risk of performance and other biases among included studies. | |||||
Background
Description of the condition
Keratoconus is a corneal condition that can cause loss of uncorrected and best‐corrected visual acuity through ectasia (thinning) of the central or paracentral cornea, irregular corneal scarring, or corneal perforation. It is most commonly described as a corneal dystrophy, but is influenced by environmental factors. The condition is bilateral but often asymmetric in severity (Rabinowitz 1998). Keratoconus is the most common corneal dystrophy; the prevalence in the Netherlands was recently estimated to be 1:375 (265 cases per 100,000, 95% confidence interval (CI) 260 to 270) (Godefrooij 2017a), which is six times higher than the previous estimate of 1:2000 (Kennedy 1986). Analysis of data from 4.4 million individuals enrolled in the Netherlands' largest national health insurance provider showed an annual incidence of keratoconus of 1:7500 in the relevant age category (13.3 cases per 100 000, 95% CI 11.6 to 15.2), which was also five to 10 times higher than previous population studies reported (Godefrooij 2017a). The reason for this increase is likely improved detection using corneal imaging.
Since the 1980s, when anterior corneal imaging devices became available, studies have reported keratoconus to be more prevalent among men than women, although earlier studies based on clinical examination did not show gender association. In the study from the Netherlands, 60.6% of diagnosed patients were male, and the mean age at diagnosis was 28.3 years. Disease onset usually occurs in the second to fourth decade of life, which are periods of peak educational attainment or career development in most middle‐income and high‐income countries. The condition is lifelong and sight‐threatening. Keratoconus therefore imposes a high economic burden on patients and caregivers (Rebenitsch 2011).
Studies from the United Kingdom have found that individuals with Indian, Pakistani, and Bangladeshi ethnicity have a higher prevalence of keratoconus compared with those from Northern Europe (Cozma 2005; Georgiou 2004; Pearson 2000). The differential disease burden surrounding gender, race, and ethnicity may arise from different diagnostic testing capabilities and different diagnostic criteria used in different populations over time.
Keratoconus is most commonly an isolated sporadic disorder. It has been reported to be associated with Down syndrome (Alio 2018; Rados 1948) and Leber congenital amaurosis (Elder 1994; Godel 1978), but is more often associated with atopy, wearing hard contact lenses, eye rubbing, and a positive family history of the disorder; in 13.5% of cases there is a family history of the disease (Zadnik 1998). The inheritance in these cases is believed to exhibit variable penetrance (Rabinowitz 1990). Consequently, both genetic and environmental factors probably contribute to the development of keratoconus.
Treatments such as spectacles, contact lenses, intrastromal corneal ring segments, and corneal transplantation serve to improve vision but do not slow the progression of disease, which corneal collagen crosslinking (CXL) purports to do.
Diagnosis
Aside from retinoscopic or slit‐lamp biomicroscopic findings in longer‐standing keratoconus (e.g. corneal iron ring, Vogt’s striae, Munson's sign, evidence of previous corneal hydrops), earlier stages of keratoconus are evident using modern corneal imaging. These devices include computer‐assisted videophotokeratoscopy or Scheimpflug imaging, which detects subtle abnormalities in topography of the anterior and posterior corneal surface, allowing detailed qualitative and quantitative analysis of corneal shape of the front and back surfaces. Placido‐disc‐based corneal topography provides tangential and axial dioptric power maps of the anterior corneal surface. Based on these maps, various topographic indices have been proposed for the diagnosis of preclinical (forme fruste) and clinical keratoconus and the grading of disease severity. These image‐based indices include asymmetry in dioptric power between inferior and superior hemispheres of the cornea, bow‐tie asymmetry, and skewed astigmatic axes.
Newer Scheimpflug‐based corneal tomography helps the clinician to distinguish subclinical keratoconus and keratoconus from normal corneas by examination of anterior elevation and posterior elevation at the thinnest point, change in anterior elevation, change in posterior elevation, corneal thickness at the thinnest point, location of the thinnest point, pachymetric progression, and maximum keratometry (denoted 'maximum K' or 'Kmax'; also known as the steepest keratometry measurement, maximum cone apex curvature, maximum curvature power of the whole anterior surface of the cornea, or power of the steepest point) (Cavas‐Martínez 2016).
There is no universal method to diagnose keratoconus, especially forme fruste keratoconus. The best and safest method is to collect and analyze data using different modalities and to use established clinical parameters.
Pathogenesis
Corneal collagen fibrils are organized into bundles known as lamellae, of which there are about 300 in the central cornea and 500 in the peripheral cornea. Lamellae account for the biomechanical characteristics and strength of the normal cornea. Proteoglycans are an important component of the corneal stroma matrix. Biochemical and immunohistochemical studies of these proteoglycans show differences between normal and keratoconic corneas (Meek 2005; Raiskup‐Wolf 2008). Corneal ectasia can develop in many different ways (e.g. fewer collagen lamellae than normal, fewer collagen fibrils per lamella, closer packing of collagen fibrils, or any combination of these). These conditions may arise from defects in the proteoglycans forming the extracellular matrix, destruction of previously formed components, an increased distensibility of corneal tissue causing sliding of collagen fibers or lamellae, or a combination of these mechanisms (Akhtar 2008; Hayes 2008).
Disease progression
Just as there are no definitive criteria for the diagnosis of keratoconus, there are no definitive criteria for its progression. Corneal changes apparent on slit‐lamp biomicroscopic examination in overt cases of keratoconus are not always present to demonstrate evidence of progression, therefore one cannot rely on clinical criteria alone. Increase in maximum keratometry (K) reading by 1 diopter (D) or more remains the most frequently reported index of disease progression (Caporossi 2010; Hersh 2011; Raiskup‐Wolf 2008; Wittig‐Silva 2008).
Other parameters used to identify or monitor disease progression include worsening of refractive or corneal astigmatism (a result of corneal ectasia that is progressing); change in uncorrected or corrected distance visual acuity, or both (O'Brart 2015; Poli 2015); and worsening of corneal topographical indices other than maximum K. These indices include simulated keratometry (Sim K) or mean keratometry (mean K). In their review of data submitted for approval of CXL, the US Food and Drug Administration (FDA) defined keratoconus progression as exhibiting one or more of the following changes over 24 months: an increase of 1.00 D or greater in the 'steepest keratometry measurement' (i.e. Kmax; not to be confused with steepest central simulated keratometry, known as steep K or K2), an increase of 1.00 D or greater in manifest cylinder, and an increase of 0.50 D or greater in manifest refraction spherical equivalent. Others have defined progression as change occurring over the 6‐ to 24‐month period.
Consequently, the definition of progressive keratoconus varies in the parameters examined, the amount of change in the parameters, and the length of time over which change is observed to document an indication for CXL, ranging from 6 to 24 months. Terminology also varies: 'maximum keratometry,' 'apical keratometry,' 'cone apex keratometry,' 'steepest keratometry,' or 'maximum cone apex curvature' have been used interchangeably.
Description of the intervention
In earlier decades corneal transplantation (keratoplasty) was performed in 10% to 20% of patients with keratoconus (Gordon 2006; Rabinowitz 1998; Tuft 1994). Although rare, keratoconus has been reported to recur in transplanted corneas (Abelson 1980). Recent studies strongly suggest that the introduction of CXL has reduced the need for corneal transplantation. In the three‐year period after the introduction of CXL in the Netherlands (2012 to 2014), 25% fewer corneal transplants were performed than in the three‐year period before its introduction (2005 to 2007) (Godefrooij 2016). At an institution in Norway, the frequency of keratoplasty was more than halved during 2013 to 2014 relative to 2005 to 2006, a decline attributed to the introduction of CXL (Sandvik 2015). Consequently, by halting or decreasing the progression of keratoconus through corneal stiffening (Wollensak 2003a), CXL has the potential to decrease the number of keratoconus patients who undergo invasive procedures (lamellar or penetrating keratoplasties), with their attendant risks of rejection, endophthalmitis, and other infections.
CXL was first approved in Europe. The first individuals with keratoconus to receive crosslinking were treated in Dresden, Germany; the CXL protocol developed by Seiler and colleagues in 1997 and used in clinical trials in Germany by 1998 is named the 'Dresden protocol' (Spoerl 1998; Spoerl 1999; Wollensak 2003a). It is an epithelium‐off procedure and is the current standard worldwide, although some investigators are altering the length of time of the treatment and treatment protocols (Haberman 2018; Kymionis 2014; Kymionis 2017; Medeiros 2016; Price 2018b; Spadea 2018; Toker 2017).
The National Institute for Health and Care Excellence (NICE) in the UK produced interventional procedures guidance (IPG) for keratoconus in 2009, updating it in 2013 to encompass keratectasia as well as keratoconus (NICE 2019). The FDA approved the Dresden protocol in 2016 for use in the USA. It involves first de‐epithelializing the central cornea (approximately 9 mm) and applying a solution of riboflavin‐dextran (0.1% riboflavin‐5‐phosphate and 20% dextran T‐500) as a photosensitizer to pre‐treat the cornea, and then repeating the application every five minutes for the duration of the 30‐minute treatment with ultraviolet A (UVA) 1 cm away from the cornea, using 370 nm UVA with an irradiance of 3 mW/cm2. The NICE IPG acknowledges that “precise timings and treatment protocols vary.” It also states: "Postoperatively, topical antibiotics and anti‐inflammatory drops are normally prescribed, with topical steroids if necessary." The original Dresden protocol did not utilize postoperative topical steroids (Wollensak 2003a); postoperative steroids were used for two weeks in the FDA trial (Hersh 2017). In some cases, a bandage contact lens may also be used for a few days. The procedure is done on one eye at a time and may be repeated when needed.
All of the seminal publications on CXL have described epithelium‐off procedures. Transepithelial CXL is a recent alternative to the standard CXL procedure where the epithelium is kept intact during CXL. This technique is theoretically associated with avoidance of issues associated with removal of corneal epithelium such as delayed re‐epithelialization and risk of microbial keratitis, reduction of pain, reduction of corneal haze, reduction of transient corneal edema, reduction of glare, and avoidance of corneal dehydration and thinning during epithelium‐off CXL, thus allowing treatment of very thin, ectatic corneas (Caporossi 2012; Greenstein 2010; Hayes 2008; Hersh 2018; Mazzotta 2007; Wollensak 2009). Because the epithelium is a barrier to diffusion of riboflavin—a large molecule—into the corneal stroma, newer studies have described methods by which to circumvent this limitation through either iontophoresis (Bikbova 2016; Buzzonetti 2015) or chemical permeability enhancers such as topical anesthetics and benzalkonium chloride, which Wollensak and colleagues were the first to describe (Koppen 2012; Vinciguerra 2016; Wollensak 2009).
How the intervention might work
Since Wollensak's publication of CXL in human trials in 2003, studies have supported the efficacy of epithelium‐off corneal collagen crosslinking (O'Brart 2013; Poli 2015; Raiskup 2015; Wittig‐Silva 2014). Natural crosslinking occurs in the cornea with age (Knox Cartwright 2011); therapeutic CXL offers a much higher level of crosslinking beyond that which occurs with age. Seiler and colleagues found significant increases in stromal stress‐strain measurements (i.e. corneal rigidity) in animal models following CXL treatment, which have been replicated in human trials (Wollensak 2003b). These trials have also shown an increase in the diameter of corneal collagen fibers, which likely contributes to decreased progression of ectasia. The resultant effect of CXL is increased resistance to both enzymatic digestion and thermal damage (Spoerl 2004a; Spoerl 2004b; Wollensak 2003b).
In short, it is theorized that CXL has an impact on keratoconus progression by strengthening and stabilizing the collagen lamellae, resulting in mechanical stiffening of the cornea. CXL may improve the patient's refractive error by reducing the irregular astigmatism caused by the biochemical instability of the cornea (Hersh 2017), and preventing the progression of corneal steepening. However, improvement of refractive error is neither guaranteed nor significant in many patients. The improvement in vision has been found to be greater when CXL is combined with intracorneal ring segments than when using the segments alone (Chan 2007).
Transepithelial CXL differs from the standard CXL procedure in that the epithelium is kept intact during CXL. The reason the corneal epithelium is removed prior to standard CXL is to facilitate stromal absorption of riboflavin, a large molecule. Retention of the epithelium in CXL offers the putative advantages of faster healing, less patient discomfort, faster visual rehabilitation, and less risk of corneal haze (Caporossi 2012; Greenstein 2010; Hayes 2008; Hersh 2018; Mazzotta 2007; Wollensak 2009). Haze seen with epithelium‐off CXL generally does not occur in transepithelial CXL. Haze is the result of keratocyte apoptosis and repopulation by myofibroblasts, leading to decreased corneal transparency and a clinically visible line demarcating the depth of the actual crosslinking effect (Kuo 1997; Mazzotta 2007; Seiler 2006; Wollensak 2007). In fact, some clinician researchers believe that aside from the main goal of stabilization of keratoconus, indicators of CXL effect are a visible demarcation line (that can appear as 'haze'), flattened keratometry, and reduced pachymetry (Doors 2009; Seiler 2006). In addition, transepithelial CXL may decrease the amount of corneal thinning that occurs during crosslinking (which can be substantial), thus allowing treatment of very thin, ectatic corneas, for which CXL may otherwise be precluded for fear of UVA damage to intraocular structures (Filippello 2012; Khairy 2014; Rosenblat 2016; Spadea 2012).
Why it is important to do this review
The question remains as to which method of CXL is more effective and safe. Although epithelium‐off CXL is more established than the transepithelial technique, an increasing number of studies of transepithelial CXL and epithelium‐off CXL are being undertaken to evaluate their comparative effectiveness. It is unclear which technique better achieves the stated goal of CXL, which is to halt or slow progression of keratoconus (as defined in various ways). Furthermore, controversy surrounds the clinical effects of transepithelial CXL compared with epithelium‐off corneal crosslinking for keratoconus (Al Fayez 2015; Kocak 2014; Leccisotti 2010; Magli 2013; Rossi 2015; Wen 2018). Research on rabbit eyes suggests that corneal biomechanical rigidity after transepithelial CXL is one‐fifth of that after epithelium‐off procedures (Wollensak 2009). In addition, the progression of keratoconus is not linear over time. Periods of stability can be interrupted by periods of progression. Because estimation of the rate of turnover of collagen and the extracellular matrix of the corneal stroma may be years or decades, long‐term follow‐up after CXL is essential to determine the longevity of effects and to identify long‐term complications (Caporossi 2013; O'Brart 2015; Poli 2015; Raiskup‐Wolf 2008; Shalchi 2015; Soeters 2015).
There are also uncertainties regarding patient satisfaction, quality of life, and cost‐effectiveness of the two interventions. By a median of 3.5 years after CXL, 89% of approximately 500 CXL patients in one center who responded to a survey reported that they believed CXL had halted their disease progression (Price 2018a). Treatment at a younger age and at a mild stage of keratoconus was associated with higher satisfaction and perceived efficacy (Price 2018a), although objectively more patients with worse disease had improvement in visual acuity and corneal flattening (Greenstein 2013). The expectations of patients with advanced stages of keratoconus may exceed what CXL can deliver, leading to lower perceived efficacy (Price 2016). Researchers calculated that CXL for progressive keratoconus is cost‐effective at a willingness‐to‐pay threshold of three times the gross domestic product (GDP) per capita. Cost‐effectiveness was strongly influenced by the assumption that CXL is effective for 10 years in the base‐case scenario. The treatment would be extremely cost‐effective if the effects last 15 years or longer (Godefrooij 2017b; Leung 2017).
Objectives
To assess the short‐ and long‐term effectiveness and safety of transepithelial CXL compared with epithelium‐off CXL for progressive keratoconus.
Methods
Criteria for considering studies for this review
Types of studies
We included data only from randomized controlled trials (RCTs) comparing transepithelial CXL with epithelium‐off CXL. Although we were primarily interested in studies in which participants had been followed for 24 months or longer, we also included studies with shorter follow‐up times. We planned to accept quasi‐randomized controlled trials (i.e. trials using quasi‐random methods to allocate participants, such as alternation, date of birth, or case record number) if no RCTs were identified. We did not include quasi‐randomized controlled trials in this review because we identified RCTs.
Types of participants
We included studies of participants with progressive keratoconus. We recorded participant characteristics (age, gender, age at onset), location of the cone, preoperative severity of disease (when described in terms other than 'progressive keratoconus'), and any comorbid conditions (e.g. Down syndrome) when this information was available. We excluded studies of participants with corneal ectasia due to other reasons (e.g. ectasia status post laser in‐situ keratomileusis). We excluded studies that enrolled participants under the age of 14 (FDA approval is for individuals 14 years of age and older).
In most publications, progressive keratoconus is defined as one or more of the following: an increase of at least 1.00 D of Kmax, not to be confused with steepest central simulated keratometry, known as steep K or K2); an increase of at least 1.00 D in manifest cylinder; or an increase of 0.5 D or more in manifest refraction spherical equivalent (MRSE) over the previous 6‐ to 24‐month period. The FDA utilized these criteria when reviewing data for CXL submitted for approval, but defined progression as change occurring over the previous 24‐month period, which is much longer than most studies. Other criteria to be considered for progressive keratoconus are 1.00 D or more increase in mean keratometry or in steepest central simulated keratometry (steep K or K2) in the previous 6‐ to 24‐month period (Sinhab 2014).
Examples of less conservative definitions of progressive keratoconus are as follows:
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an increase of at least 1.00 D in maximum K or central corneal astigmatism over a six‐month period (Çerman 2015);
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an increase of at least 0.5 D in maximum K, in steepest central simulated keratometry values (steep K or K2), in mean keratometry (the mean of steepest and flattest central simulated keratometry), and/or in topographic cylinder value over the previous 6 to 12 months (Soeters 2015);
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reduced uncorrected distance visual acuity (UDVA) or corrected distance visual acuity (CDVA) by more than 1 logarithm of the minimum angle of resolution (logMAR) line and/or worsening of refractive or corneal astigmatism, Sim K, or Kmax by 0.75 D over the 12 to 24 months prior to CXL (O'Brart 2015).
Types of interventions
We included studies in which transepithelial CXL was compared with epithelium‐off CXL. We included studies in which different adjunctive therapy was used in both treatment arms. Riboflavin is a photosensitizer used in both methods of CXL. Chemical enhancers such as benzalkonium chloride or topical anesthetic (proparacaine as well as iontophoresis) may be used to improve transepithelial stromal absorption of riboflavin.
Types of outcome measures
Critical outcomes
The critical outcome for this review is keratometry (K), a measurement of corneal curvature that is used to assess keratoconus progression. Because K may be quantified in various ways in individual studies (e.g. maximum K versus mean K), we examined K both as a continuous outcome (change in maximum K from baseline) and as a dichotomous outcome (proportion of participants whose maximum K decreased by at least 2 D, indicating arrest or slowing of disease progression), proportion of eyes whose maximum K increased by at least 2 D from baseline, and proportion of eyes whose maximum K remained stable (Asri 2011). Our time points of interest were 12 and 24 months after corneal CXL. We extracted the available data closest to these time points.
Other important outcomes
We considered the following important outcomes at 12 months or more after CXL. When there were multiple measurements after 12 months, we extracted the measurement made at the longest follow‐up time point.
1. Visual acuity (visual acuity recorded and analyzed as the number of letters read on a chart with a logMAR scale (ETDRS 1985).
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Mean change in CDVA from baseline
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Proportion of participants who gained 10 or more letters from baseline (equivalent to 2 lines; 0.2 on a logMAR scale)
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Proportion of participants who lost 10 or more letters (2 lines, 0.2 logMAR) from baseline
2. Patient questionnaire responses regarding subjective visual function parameters (e.g. photophobia, difficulty driving at night, difficult reading, diplopia, fluctuation in vision, glare, haloes, starbursts, dryness, pain, foreign body sensation), preferably as change from baseline.
3. Costs of the interventions as reported from the individual studies.
Adverse outcomes
We reported the following adverse outcomes at the longest follow‐up time point when presented in the included studies: proportion of participants who had central corneal opacity or haze or scar; corneal sterile infiltrate; herpetic keratitis; non‐healing or other epithelial defect lasting more than one week; eye pain or irritation; dry eye; photophobia; punctate keratitis; corneal inflammation; endothelial cell damage as indicated by decrease in endothelial cell density. Corneal stromolysis ('melt') has been described in the setting of CXL complicated by microbial infection or combined with excimer laser, but not CXL alone to date.
Search methods for identification of studies
Electronic searches
The Cochrane Eyes and Vision Information Specialist searched the following electronic databases for RCTs and controlled clinical trials. There were no restrictions to language or year of publication. The electronic databases were last searched on 15 January 2020.
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Cochrane Central Register of Controlled Trials (CENTRAL; 2020, Issue 1) (which contains the Cochrane Eyes and Vision Trials Register) in the Cochrane Library (searched 15 January 2020) (Appendix 1)
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MEDLINE Ovid (1946 to 15 January 2020) (Appendix 2)
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Embase.com (1947 to 15 January 2020) (Appendix 3)
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PubMed (1946 to 15 January 2020) (Appendix 4)
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LILACS (Latin American and Caribbean Health Science Information database) (1982 to 15 January 2020) (Appendix 5)
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US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov (www.clinicaltrials.gov; searched 15 January 2020) (Appendix 6)
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World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp; searched 15 January 2020) (Appendix 7)
Searching other resources
We searched the reference lists of reports from included trials to look for additional trials. We did not search conference abstracts for the purposes of this review, as many eyes and vision conference abstracts are routinely included in Embase.com, which we searched as part of the electronic searches.
Data collection and analysis
Selection of studies
After duplicates were removed from the merged search results, two review authors (two of IK, KL, MR) independently used Covidence to screen titles and abstracts of all records identified by the search (Covidence). The review authors classified each record as either relevant or not relevant for full‐text review. Two review authors (two of IK, KL, MR) independently assessed the full‐text copies of all records identified as relevant during title and abstract screening to determine eligibility for inclusion. All discrepancies between review authors were resolved by discussion at each stage of the screening process. We identified and grouped reports from the same study to avoid extracting data from the same study for the same outcomes more than once. We contacted the authors of trial reports (and waited two weeks for a response) in an attempt to clarify any details needed to permit a complete assessment of eligibility. We documented the reasons for exclusion for each study judged as not eligible after review of the full‐text reports. All full‐text reports were published in English. For future updates, we will first attempt to screen reports published in languages other than English for relevancy using Google Translate (translate.google.com). Whenever a clear decision cannot be made based on a translated version, we will consult colleagues who are fluent in the language to determine eligibility and, in the case the study is eligible for inclusion, to assist with data extraction.
Data extraction and management
Two review authors (two of IK, MR, SN) independently used Covidence to extract the data from included trials as proposed in the protocol (Kuo 2020). Two review authors (IK and SN) compared the extracted data and resolved any discrepancies by discussion. One review author exported data from Covidence into Review Manager 5 (Review Manager 2020), and a second review author verified the exported data.
Assessment of risk of bias in included studies
We attempted to contact the authors of reports via email if information to permit a judgement was insufficient. We assessed risk of bias using the available information when we did not receive the response within two weeks. Two review authors (two of IK, MR, SN) independently assessed the risk of bias in each included study, following the guidance in Chapter 8 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2017). Specific items for consideration included random sequence generation and allocation concealment before randomization (selection bias), masking of participants and study personnel (performance bias), masking of outcome assessors (detection bias), missing data and intention‐to‐treat analysis (attrition bias), selective outcome reporting (reporting bias), and other potential sources of bias. We assigned each study for each domain as having 'low risk of bias,' 'high risk of bias,' or, when the information provided was insufficient to make an assessment, 'unclear risk of bias.' We documented the reasons for our assessments and resolved any discrepancies through discussion. Our assessments, for individual studies and overall, are provided in the 'Risk of bias' summary figures.
Measures of treatment effect
We used mean difference to compare interventions with respect to continuous outcomes, including change in maximum K, change in CDVA, and change in patient questionnaire responses regarding subjective visual function parameters. We did not analyze the cost of the interventions because no included study examined this outcome.
We used risk ratios to compare interventions for dichotomous outcomes, including proportion of participants whose maximum K decreased by at least 2 D or increased by at least 2 D, proportion of participants whose maximum K remained stable, proportion of participants who gained 10 or more logMAR letters, proportion who lost 10 or more logMAR letters, and proportion of participants who experienced adverse events.
Unit of analysis issues
We determined whether the design of each included study specified intervention on one or both eyes from each participant and whether study investigators randomized at the participant level or at the eye level. In four of the 13 included studies, both eyes of all or some participants were included (Bikbova 2016; Cifariello 2018; Lombardo 2016; Razmjoo 2014), and in one study a paired‐eyes design was employed (Stojanovic 2014). None of these studies considered intraperson correlation of outcomes in the analysis. We analyzed these data as reported. This approach was conservative, as confidence intervals were wider than they would have been if the potential within‐person correlation was accounted for. Only one eye per participant was included in the remaining eight studies.
Because certain medical treatments have the potential to influence the outcome in the contralateral eye, we excluded studies that adopted a paired design in our sensitivity analysis. In addition, keratoconus tends to have asymmetrical presentation, which would complicate interpretation of findings from studies with a paired‐eyes design. In future updates, we will extract estimates that properly account for the intraperson correlation of two eyes of a participant when both eyes have been treated whenever the required data are available.
Dealing with missing data
Where data on included studies were unclear or incomplete, we contacted the authors of reports via email. We received responses and information from several authors (Lombardo 2016; Nawaz 2015; Razmjoo 2014; Rossi 2015; Rossi 2018; Soeters 2015). When there was no response within two weeks, we analyzed the data using the available information. We did not impute missing data. 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.
Assessment of heterogeneity
We assessed clinical and methodological heterogeneity by examining participant characteristics and outcomes, carefully reviewing the study report(s), and taking into consideration potential risk of bias. We examined forest plots and the I2 values and compared effect estimates and confidence intervals among studies. We considered an I2 value greater than 60% as indicative of substantial heterogeneity and suggesting that a meta‐analysis to estimate an overall intervention effect may not be appropriate.
We anticipated that heterogeneity would be significant, arising from baseline patient characteristics, different definitions of 'progressive keratoconus,' techniques used for transepithelial and epithelium‐off CXL, and various outcome measures. Substantial heterogeneity may affect the overall strength of the evidence. We explored comparisons between transepithelial and epithelium‐off CXL techniques within subgroups to explain observed heterogeneity whenever sufficient data were available.
Assessment of reporting biases
We did not use funnel plots to assess small‐study effects, which could be due to publication bias, because fewer than 10 trials contributed data to any meta‐analysis. We judged selective reporting as part of the 'Risk of bias' assessment for each individual study.
Data synthesis
We followed the guidelines in Chapter 9 of the Cochrane Handbook for Systematic Reviews of Interventions for data synthesis and analysis (Deeks 2017). The results for each prespecified outcome are reported in summary of findings Table 1; summary of findings Table 2. We analyzed studies separately by length of follow‐up (< 12 months and ≧ 12 months). We used a random‐effects model for quantitative syntheses when three or more studies reported data for the same outcome.
Subgroup analysis and investigation of heterogeneity
We classified studies based on techniques within transepithelial CXL, and compared epithelium‐off CXL with transepithelial CXL separately with and without use of iontophoresis (i.e. transepithelial CXL versus epithelium‐off CXL, and transepithelial CXL using iontophoresis versus epithelium‐off CXL). We also performed subgroup analyses by methods of outcome reporting to investigate observed heterogeneity. We planned to perform other subgroup analysis to account for differences in types of participants, type of riboflavin used, method of administration, how riboflavin saturation was assessed, and power and timing of UV light exposure; however, lack of data from included studies precluded these subgroup analyses.
As stated above, we excluded trials that enrolled patients with corneal ectasia that was not keratoconus and that did not report outcomes separately for participants with keratoconus.
Sensitivity analysis
We conducted sensitivity analysis to determine the impact on effect estimates of a paired‐eyes design of one included trial and any post hoc decisions made during the review process. We have reported the results of any sensitivity analysis performed and discussed our interpretation of the effects on the overall findings of the review.
Summary of findings and assessment of the certainty of the evidence
We have presented 'Summary of findings' tables for the two comparisons: 1) transepithelial CXL versus epithelium‐off CXL; and 2) transepithelial CXL using iontophoresis versus epithelium‐off CXL (summary of findings Table 1; summary of findings Table 2). The 'Summary of findings' tables include the following seven outcomes, assessed at 12 months after CXL whenever sufficient data were available.
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Mean change in maximum K from baseline
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Proportion of participants whose maximum K decreased or increased by at least 2 D from baseline
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Proportion of participants whose maximum K remained stable
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Mean change in CDVA from baseline
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Proportion of participants who gained 10 or more logMAR letters from baseline
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Proportion of participants who lost 10 or more logMAR letters from baseline
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Adverse outcomes
We used the GRADE approach to assess the overall certainty of evidence for each outcome. We began our assessment by judging the randomized design of each included study to confer a high certainty of evidence for each outcome, downgrading certainty to moderate, low, or very low when there was evidence of high risk of bias, inconsistency, indirectness, or imprecision. We will consider publication bias in updates to the review that include more trials in individual meta‐analyses.
Results
Description of studies
Results of the search
Our searches of the electronic databases in January 2020 yielded 3364 records. After removal of duplicates, 2785 titles and abstracts were screened. We retrieved 57 full‐text reports for further review. After full‐text screening, we included 13 studies (22 records), identified two ongoing studies (two records), listed one study (one record) as awaiting classification, and excluded 32 studies (32 records) with reasons. We contacted the investigator of one study to clarify study eligibility, but did not receive a response (ChiCTR1900021768). Two ongoing studies were reported to start in 2019 and estimated to complete in 2021 (NCT03990506) and 2024 (NCT03858036). A study selection flow diagram is shown in Figure 1.
Study flow diagram.
Included studies
See: Characteristics of included studies
We included 13 studies in the review. Seven studies were parallel‐group RCTs; one study was an RCT with a paired‐eyes design (Stojanovic 2014); five studies were RCTs in which both eyes of some or all participants were assigned to the same intervention, and data from each eye were analyzed separately without taking into account intraperson correlation.
Types of participants
Seven of the 13 included studies were conducted in Europe (five in Italy, one each in the Netherlands and Norway), three in the Middle East (one each in Iran, Jordan, and Saudi Arabia), and one each in India, Russia, and Turkey. In total, 567 participants (661 eyes) with progressive keratoconus were enrolled; 13 to 119 participants were enrolled per study. The mean age of participants ranged from 23 to 30, with a median of 28 years. The composition of study populations by gender ranged from 15% to 73% women, with a median of 31%. The mean maximum K ranged from 47 to 58 D, with a median of 54 D. The mean logMAR best‐corrected distance visual acuity at baseline was 0.10 to 0.34, with a median of 0.29.
Types of interventions
Three trials described transepithelial CXL using iontophoresis (Bikbova 2016; Lombardo 2016; Rossi 2018), but only two trials provided quantifiable data for meta‐analysis (Lombardo 2016; Rossi 2018). Eleven trials described non‐iontophoresis‐assisted transepithelial CXL, including one trial that compared three arms: iontophoresis‐assisted transepithelial, transepithelial, and epithelium‐off crosslinking (Rossi 2018). Pre‐irradiation riboflavin 0.10% with dextran 15% to 20% was instilled in all eyes in trials except one (Stojanovic 2014), which used riboflavin 0.5% without dextran. Stojanovic and colleagues utilized a Merocel sponge to produce microabrasions of the superficial epithelial layers caused by friction upon blinking by the patient. These microabrasions enhance riboflavin penetration through the otherwise intact corneal epithelium (Stojanovic 2012). In addition to the use of topical anesthetic drops (which can also enhance penetration of riboflavin and were used in both transepithelial and epithelium‐off trials), two studies utilized agents to enhance penetration. These agents were benzalkonium chloride 0.02% for 30 minutes (Al Fayez 2015), and proparacaine 0.5% and gentamicin 0.3% both preserved with benzalkonium chloride 0.005% every minute for the first 5 minutes before saturation with riboflavin along with the same preserved proparacaine 0.5% every 30 seconds until saturation was confirmed at the slit lamp (Stojanovic 2014). Several trials utilized a combination drug formulated specifically for transepithelial procedures consisting of riboflavin 0.1% plus dextran 15% enhanced with amino acid TRIS (trometamol) and EDTA (ethylenediaminetetraacetic acid) prior to irradiation; others used riboflavin 0.1% alone or riboflavin 0.1% with dextran 15% to 20%. Both iontophoresis‐assisted transepithelial studies utilized riboflavin 0.1% with trometamol and EDTA, without dextran.
One trial described transepithelial CXL of the central 3 mm of the cornea, leaving the epithelium intact in the 3‐millimeter ring surrounding this central zone (Razmjoo 2014). Corneas were constantly bathed in riboflavin during irradiation in iontophoresis‐assisted transepithelial procedures. Riboflavin was not instilled during irradiation in transepithelial procedures in two trials (Al Fayez 2015; Stojanovic 2014).
Investigators of transepithelial trials without iontophoresis irradiated corneas for 30 minutes; iontophoresis‐assisted trials described irradiation for 9 minutes(Lombardo 2016) or 10 minutes( Rossi 2018). When utilized, postoperative topical steroid drops were instilled for one to four weeks after surgery; steroid drop regimens included dexamethasone 0.1%, fluorometholone 0.1%, prednisolone acetate 1%, and betamethasone. Participants in one trial did not receive any steroid drop after transepithelial CXL (Cifariello 2018). In short, investigators described different mechanisms to promote riboflavin as well as UV light absorption, and variability in the time, power (10 mW/cm2 in both trials of transepithelial CXL with iontophoresis, in contrast to 3 mW/cm2 in transepithelial CXL trials without iontophoresis), and distance between irradiation source and cornea (1 cm to 5 cm).
The epithelium‐off procedures were more uniform. Most investigators used the Dresden protocol, which employs UVA‐light diodes (370 nm) at a 1‐centimeter distance for 30 minutes using 3 mW/cm2 irradiance, which corresponds to a dose of 5.4 J/cm2. As with the transepithelial studies, the cross‐linking devices were manufactured by different companies. Pre‐irradiation riboflavin 0.1% and dextran 20% were instilled in all eyes undergoing epithelium‐off procedures, except for one trial that used 0.5% riboflavin without dextran (Stojanovic 2014). Intraoperative riboflavin was instilled every 2 to 5 minutes during irradiation in all trials. Concentration of the riboflavin was 0.1%, except for one trial that used 0.025% (Lombardo 2016). Postoperative topical steroid drop regimens varied (e.g. fluorometholone 0.1%, betamethasone, dexamethasone 0.1%, prednisolone acetate 1%) and ranged in length from one to four weeks.
Two studies did not investigate clinical parameters (Acar 2014; Mastropasqua 2013), but instead compared morphological corneal changes after epithelium‐off CXL and after transepithelial CXL without iontophoresis using in vivo confocal microscopy and/or anterior segment optical coherence tomography. One group studied whether prolonged riboflavin pre‐treatment of eyes undergoing transepithelial CXL could facilitate penetration of riboflavin through intact corneal epithelium (Acar 2014). By instilling riboflavin 0.1% along with dextran 20% and chemical enhancers every 10 minutes for 2 hours prior to transepithelial CXL, their goal was to approximate a similar depth of effect as epithelium‐off procedures. Neither study described postoperative topical steroid drop regimens (Acar 2014; Mastropasqua 2013).
Types of outcomes
Critical outcomes
All studies except for two (Acar 2014; Mastropasqua 2013) measured keratometry outcomes. However, summary data were reported from some studies without indicators of precision (e.g. standard deviation) or denominators or estimates by intervention were compared using only P values or were reported only in figures. Eight studies reported keratometry outcomes when follow‐up examinations ended at 6 months (Nawaz 2015; Razmjoo 2014), 12 months (Rossi 2015; Rossi 2018; Soeters 2015; Stojanovic 2014), or 24 months (Cifariello 2018; Lombardo 2016); data from these studies were included in the meta‐analyses.
Other important outcomes
1. Visual acuity
All studies except for two (Acar 2014; Mastropasqua 2013)assessed visual acuity, but only six studies provided data for CDVA in a form suitable for inclusion in meta‐analysis at 6 months (Nawaz 2015), 12 months (Rossi 2015; Rossi 2018; Soeters 2015; Stojanovic 2014), and 24 months (Lombardo 2016). Only one study reported the proportion of participants who gained or lost 10 or more logMAR letters from baseline (Lombardo 2016).
2. Subjective visual function
One study measured subjective symptoms among participants using the Ocular Surface Disease Index and reported scores at one month (Cifariello 2018).
3. Costs of the interventions as reported from individual studies
None of the included studies reported or evaluated the costs of the interventions compared.
Adverse outcomes
All studies except one (Mastropasqua 2013) reported intraoperative or postoperative complications.
Excluded studies
We excluded 32 studies after full‐text review and provided the reasons of exclusion in the Characteristics of excluded studies table. In summary, we excluded 20 studies that were not RCTs, six studies with the wrong participants (not participants with progressive keratoconus, or not adult participants), and two studies evaluating the wrong interventions. We excluded three studies because they were preliminary reports. We excluded one RCT because it was terminated early due to few participants.
Risk of bias in included studies
Our assessment of the risk of bias for each of 13 studies is described in the Characteristics of included studies table. A summary of 'Risk of bias' assessments is shown in Figure 2.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Allocation
Five studies reported employing an adequate method for random sequence generation by using a computer‐generated random number table (Al Fayez 2015; Lombardo 2016; Razmjoo 2014; Rossi 2015; Rossi 2018). We judged these studies as at low risk of bias for this domain. The remaining eight studies did not specify the method for allocation sequence generation and were therefore judged to be at unclear risk of bias. Of the eight studies, reports from two studies stated that the investigators had used "odd‐even number method (randomized control trial)"(Al Zubi 2019; Nawaz 2015). We attempted to contact the study investigators by email to clarify this statement, but did not receive a reply.
We judged two studies as having a low risk of bias based on the reported use of adequate procedures for allocation concealment before assignment (Al Fayez 2015; Lombardo 2016). The remaining 11 studies provided insufficient information to permit a judgement on allocation concealment and were judged as having an unclear risk of bias for this domain.
Blinding
Given the nature of the interventions, masking the surgeons in the trials included in this review would have been challenging. Eight studies reported that participants and personnel were aware of the allocation; we judged these studies to be at high risk of performance bias (Al Fayez 2015; Cifariello 2018; Lombardo 2016; Razmjoo 2014; Rossi 2015; Rossi 2018; Soeters 2015; Stojanovic 2014). The remaining five trials provided insufficient information to permit a judgement and were judged as having an unclear risk of bias.
Incomplete outcome data
We judged seven studies in which all participants had been examined for the primary outcome (Acar 2014; Razmjoo 2014; Rossi 2015; Rossi 2018; Stojanovic 2014) or an intention‐to‐treat analysis was performed (Lombardo 2016; Soeters 2015), as having a low risk of attrition bias. The numbers of participants who were excluded or lost to follow‐up were not explicitly reported for the other six studies; in the absence of this information, we judged the risk of attrition bias for these studies as unclear (Al Fayez 2015; Al Zubi 2019; Bikbova 2016; Cifariello 2018; Mastropasqua 2013; Nawaz 2015).
Selective reporting
Three studies reported all outcomes specified in the clinical trial registries and were thus judged to be at low risk of reporting bias (Lombardo 2016; Razmjoo 2014; Stojanovic 2014). Protocols or trial registry records were not publicly available for the other 10 studies. We designated four studies as having a high risk of selective outcome reporting because either not all outcomes specified in the methods were described in the results sections, or the study failed to report key outcomes that the investigators would have been expected to measure and report for such a study, or outcomes were incompletely reported, so as to reduce precision (Al Fayez 2015; Al Zubi 2019; Bikbova 2016; Nawaz 2015). We judged the remaining six trials to have an unclear risk of reporting bias.
Other potential sources of bias
We judged three studies to have a high risk of other bias due to a baseline imbalance between intervention groups (Cifariello 2018; Rossi 2015; Soeters 2015). One study received medical devices from industry and was assessed as at high risk of bias for this domain (Lombardo 2016). We judged six studies to be at low risk of other bias (Acar 2014; Al Fayez 2015; Mastropasqua 2013; Nawaz 2015; Razmjoo 2014; Rossi 2018), and the remaining two studies as at unclear risk of bias for this domain because insufficient information was provided to permit a judgement.
Effects of interventions
See: Summary of findings 1 Transepithelial CXL compared with epithelium‐off CXL for progressive keratoconus; Summary of findings 2 Transepithelial CXL using iontophoresis compared with epithelium‐off CXL for progressive keratoconus
Because of implicit heterogeneity, we assigned trials into two comparison groups: the three trials in which transepithelial CXL was used with iontophoresis assistance (Bikbova 2016; Lombardo 2016; Rossi 2018); and the 11 trials without iontophoresis assistance (Acar 2014; Al Fayez 2015; Al Zubi 2019; Cifariello 2018; Mastropasqua 2013; Nawaz 2015; Razmjoo 2014; Rossi 2015; Rossi 2018; Soeters 2015; Stojanovic 2014).
Comparison 1: Transepithelial CXL versus epithelium‐off CXL
As noted above, 11 studies compared outcomes among participants assigned to transepithelial CXL versus epithelium‐off CXL with length of follow‐up of 6 months (Acar 2014; Nawaz 2015; Razmjoo 2014), and 12 months or beyond (Al Fayez 2015; Al Zubi 2019; Cifariello 2018; Mastropasqua 2013; Rossi 2015; Rossi 2018; Soeters 2015; Stojanovic 2014). In three studies, both eyes of all or some participants were included (Cifariello 2018; Mastropasqua 2013; Razmjoo 2014), and one study employed a paired‐eyes design (Stojanovic 2014). None of these studies considered intraperson correlation of outcomes in the analysis. We analyzed these data as reported. This approach was conservative; confidence intervals were wider than they would have been if the potential within‐person correlation could have been accounted for. The results are summarized in Summary of findings table 1.
Keratometry outcomes
Five RCTs reported keratometry data suitable for inclusion in meta‐analyses, either as mean change in maximum K from baseline ( Rossi 2015; Soeters 2015) or mean maximum K (Cifariello 2018; Rossi 2018; Stojanovic 2014) at 12 months or more after surgery. Mean changes in maximum K ranged from a decrease of 0.5 to an increase of 1.99 D and yielded an overall estimated mean difference between interventions of 0.99 D (95% confidence interval (CI) −0.11 to 2.09; 177 eyes; I2 = 41%; Analysis 1.1; Figure 3). Although the overall estimate of mean difference favored epithelium‐off CXL, the confidence interval was consistent with no difference between the two interventions for this outcome at 12 months or later. We performed sensitivity analysis in which we excluded the study with a paired‐eyes design (Stojanovic 2014), as proposed in the review protocol; from that analysis we calculated a mean difference of 1.14 (95% CI −0.06 to 2.33). Heterogeneity remained moderate (I2 = 49%), and the confidence interval on the estimate from the remaining studies remained consistent with no difference. Subgroup analysis by the methods of outcome reporting estimated a mean difference of 1.21 (95% CI −0.48 to 2.90; I2 = 0) from three RCTs that reported mean maximum K (Cifariello 2018; Rossi 2018; Stojanovic 2014); and a mean difference of 0.90 (95% CI −0.94 to 2.74; I2 = 81%) from two RCTs that had reported mean change in maximum K from baseline (Rossi 2015; Soeters 2015). Two additional trials reported mean maximum K measured six months postsurgery (Nawaz 2015; Razmjoo 2014). The estimated overall difference in maximum K at six months was −1.02 (95% CI −2.53 to 0.49; 84 eyes; Analysis 1.1; Figure 3). In these studies with different time points (i.e. < 12 months and ≧ 12 months), the confidence interval was consistent with no difference. One study measured maximum K, but due to lack of available data we did not include this study in the meta‐analysis (Al Fayez 2015). The investigators reported that maximum K was significantly lower in the epithelium‐off group than in the transepithelial group.
Forest plot of comparison: 1 Transepithelial corneal collagen crosslinking versus epithelium‐off corneal collagen crosslinking, outcome: 1.1 Mean change in maximum K from baseline or final value.
Only one study reported the numbers or proportions of eyes with decreases or increases of 2 or more diopters in maximum K (Soeters 2015). At 12 months after surgery, estimated risk ratios were consistent with no or only a trivial difference between epithelium‐off CXL and transepithelial CXL in their effects on these outcomes for participants with progressive keratoconus (proportion of participants whose maximum K decreased by at least 2 D: risk ratio 0.32, 95% CI 0.09 to 1.12; Analysis 1.2; proportion of participants whose maximum K increased by at least 2 D: risk ratio (non‐event) 0.86, 95% CI 0.74 to 1.00; Analysis 1.3).
Estimated effects of all keratometry outcomes are very low certainty due to risk of performance and other biases (−1), imprecision (−1), and inconsistency (−1) among studies.
Progression of keratoconus
Two studies reported data regarding the progression of keratoconus (Al Fayez 2015; Soeters 2015). We did not combine the data from these two studies because considerable heterogeneity was detected (I2 = 92%). In the Soeters 2015 study, 7 (20%) of 35 eyes experienced progression of keratoconus at 12 months or longer after surgery in the transepithelial CXL arm versus none of 26 eyes in the epithelium‐off arm. The estimated risk ratio for stable keratoconus (i.e. no progression) was 0.81 (95% CI 0.68 to 0.96; 61 eyes; Analysis 1.4). Nineteen (56%) of 34 eyes in the transepithelial CXL arm and none of 36 eyes in the epithelium‐off arm experienced progression of keratoconus at 36 months after surgery in another study (Al Fayez 2015) with the estimated risk ratio for stable keratoconus of 0.45 (95%CI 0.31 to 0.65; 70 eyes; Analysis 1.4). These two studies suggest that epithelium‐off CXL may have a small effect on this outcome compared to transepithelial CXL, but the evidence is very uncertain; the evidence for this estimate is of very low certainty due to high risk of performance and other biases (−1), imprecision (−1) and unexplained heterogeneity (−1).
Visual acuity outcomes
Four included studies reported change in corrected distance visual acuity (CDVA) from baseline to 12 months or a later final examination (Rossi 2015; Rossi 2018; Soeters 2015; Stojanovic 2014). The estimated overall mean change in CDVA was −0.07 to 0.03 among the four studies (Analysis 1.5; Figure 4). Statistical heterogeneity (I2 = 70%) indicated that calculation of an overall effect was inappropriate. In sensitivity analysis excluding the trial with a paired‐eyes design (Stojanovic 2014), heterogeneity remained substantial (I2 = 80%), leading us to conclude that the study with a paired‐eyes design did not explain the heterogeneity. One additional study reported change in CDVA from baseline to six months (Nawaz 2015): estimated mean difference was 0.01 (95% CI −0.03 to 0.05; 40 eyes; Analysis 1.5), corresponding to a few letters of a line of Snellen visual acuity. The difference between interventions for change in CDVA may be neither clinically nor statistically significant at either 6 months or 12 months or beyond. The same trend may be observed in two studies that measured CDVA but were not included in the meta‐analysis due to lack of data (Al Fayez 2015; Al Zubi 2019). The evidence for the overall estimates is of very low certainty due to high risk of performance and other biases (−1), imprecision (−1), and unexplained heterogeneity (−1).
Forest plot of comparison: 1 Transepithelial corneal collagen crosslinking versus epithelium‐off corneal collagen crosslinking, outcome: 1.5 Mean change in corrected distance visual acuity (logMAR) from baseline or final values.
No study reported gains or losses of 10 or more letters of CDVA.
Subjective visual function
Only the Cifariello 2018 study compared transepithelial CXL with epithelium‐off CXL and measured a subjective outcome based on participant responses to a standard questionnaire, the Ocular Surface Disease Index. Mean scores at one‐month postintervention favored transepithelial CXL: mean difference −2.30 (95% CI −3.62 to −0.98; n = 40; Analysis 1.6). The evidence for this estimate is of low certainty due to risk of bias (−1) and imprecision (−1).
Costs of the interventions
No study reported costs of either intervention.
Adverse outcomes
All eleven studies reported information about adverse outcomes. The investigators of four studies reported either no adverse events or no serious adverse events (Al Fayez 2015; Razmjoo 2014; Rossi 2015; Stojanovic 2014). One study noted no change in endothelial cell count after either procedure (Rossi 2015).
Eye pain among participants in the epithelium‐off CXL group early in the postoperative period was mentioned in reports from two studies (Nawaz 2015; Rossi 2018). Corneal haze or scarring was reported in four eyes from one study (Al Zubi 2019), two eyes from another study (Nawaz 2015), and one from each of two studies (Cifariello 2018; Soeters 2015); all eight eyes had been assigned to epithelium‐off CXL. Of the eight affected participants, one had deep stromal haze at six months (Soeters 2015). According to the summary estimate of four studies, eyes undergoing epithelium‐off CXL somewhat more often experienced corneal haze or scarring (risk ratio (non‐event) 1.07, 95% CI 1.01 to 1.14; 221 eyes; I2 = 0%; Analysis 1.7; Figure 5). Herpetic keratitis, sterile infiltrate, and an epithelial defect were observed in one eye each in the epithelium‐off group in one study (Soeters 2015). In Cifariello 2018, one eye in each intervention group developed Vogt's striae. We graded the certainty of evidence as moderate for adverse outcomes, downgrading by one level for high risk of bias (−1).
Forest plot of comparison: 1 Transepithelial corneal collagen crosslinking versus epithelium‐off corneal collagen crosslinking, outcome: 1.7 Adverse outcomes—corneal haze or scarring.
Comparison 2: Transepithelial CXL using iontophoresis versus epithelium‐off CXL
Three studies compared outcomes among participants assigned to transepithelial CXL using iontophoresis versus those assigned to epithelium‐off CXL at the end of follow‐up of 12 months (Rossi 2018), or 24 months (Bikbova 2016; Lombardo 2016). Two studies included both eyes of some participants (Bikbova 2016; Lombardo 2016). Neither trial considered the non‐independence of the eyes of bilaterally affected participants in the analysis; thus, the confidence interval is wider than it should be. The results are summarized in Summary of findings table 2.
Keratometry outcomes
Two studies reported analyzeable data for change in maximum K from baseline to 12 months or longer after surgery (Lombardo 2016; Rossi 2018). The estimates of the mean difference in change were inconsistent: the estimate from Lombardo 2016 favored epithelium‐off CXL, but the estimate from Rossi 2018 favored transepithelial CXL using iontophoresis (Analysis 2.1; Figure 6). We did not estimate an overall effect on this outcome because substantial heterogeneity was detected (I2 = 68%).
Forest plot of comparison: 2 Transepithelial corneal collagen crosslinking using iontophoresis versus epithelium‐off corneal collagen crosslinking, outcome: 2.1 Mean change in maximum K from baseline or final value at 12 months or more.
The certainty of the evidence for this outcome is thus very low due to imprecision of estimates for all outcomes (−1), unexpected heterogeneity (−1), and risk of bias (−1) in the studies from which data have been reported.
Progression of keratoconus
Only one study reported data for a decrease in maximum K by 2 or more diopters (Lombardo 2016). One eye (9%) of 11 eyes in the epithelium‐off CXL arm, and none of 20 eyes in the transepithelial CXL with iontophoresis arm, had experienced such a decrease by 24 months (risk ratio (non‐event) 1.12, 95% CI 0.89 to 1.40; 31 eyes; Analysis 2.2). At 24 months, no eye in either intervention group had an increase in maximum K by 2 or more diopters (risk ratio (non‐event) 1.00, 95% CI 0.87 to 1.15; 31 eyes; Analysis 2.3). This study was the only one to report progression of keratoconus for this comparison of interventions. Two eyes (10%) among 20 eyes in the transepithelial CXL with iontophoresis arm versus none of 11 eyes in the epithelium‐off arm experienced progression of keratoconus (risk ratio for stable keratoconus 0.92, 95% CI 0.76 to 1.12; 31 eyes; Analysis 2.4).
The evidence for this estimate is of very low certainty due to high risk of bias (−1) and imprecision (−2).
Visual acuity outcomes
Data for all three outcomes specified for CDVA were reported by Lombardo 2016; in addition, Rossi 2018 reported data for mean change in CDVA. The overall estimate for mean change in logMAR CDVA from baseline to 12 months or later was mean difference 0.00 (95% CI −0.04 to 0.04, 51 eyes; Analysis 2.5; Figure 7). The confidence interval is consistent with no or only a trivial difference (2 letters or fewer) between the two interventions. However, confidence in the estimate is low due to imprecision (−1) and high risk of performance and other bias (−1). One study measured CDVA at 24 months or beyond, but due to lack of data was not included in the synthesis (Bikbova 2016); the authors reported that the difference in mean CDVA between groups was statistically significant in favor of transepithelial CXL.
Forest plot of comparison: 2 Transepithelial corneal collagen crosslinking using iontophoresis versus epithelium‐off corneal collagen crosslinking, outcome: 2.5 Mean change in corrected distance visual acuity (logMAR) from baseline or final values at 12 months or more.
As reported in Lombardo 2016, 5 eyes of 22 in the transepithelial CXL with iontophoresis arm gained 10 or more logMAR letters (0.2 logMAR) from baseline versus 1 of 12 eyes in the epithelium‐off CXL arm (Analysis 2.6); no eye in either intervention arm suffered a loss of 10 logMAR letters from baseline (Analysis 2.7). We judged the certainty of evidence as very low, downgrading for high risk of bias (−1) and imprecision due to small sample size and wide confidence intervals (−2).
Subjective visual function
No study reported data for subjective visual function or quality of life after surgery.
Costs of the interventions
No study reported data regarding costs of either intervention.
Adverse outcomes
All three studies (203 eyes in total) in this comparison reported information about adverse outcomes. Bikbova 2016 reported that no eye had experienced epithelial damage or reduced epithelial cell density. Lombardo 2016 reported that Vogt's striae were observed in one eye in each arm, and subepithelial infiltrate was observed in one eye in the transepithelial CXL with iontophoresis arm. Rossi 2018 mentioned only early eye pain among some participants in the epithelium‐off CXL group. In the epithelium‐off CXL arm, two eyes with faint corneal scars (16.7%) were observed by three months in Lombardo 2016; four participants (5%) had “permanent haze” in Bikbova 2016. We judged the certainty of evidence as low, downgrading for high risk of bias (−1) and for imprecision due to small sample size and wide confidence intervals (−1).
Discussion
Summary of main results
In this review, we have reported outcome data from 13 RCTs that compared transepithelial CXL versus epithelium‐off CXL for progressive keratoconus. We separately compared transepithelial CXL using iontophoresis versus epithelium‐off CXL and transepithelial CXL without iontophoresis versus epithelium‐off CXL. We included eight studies in meta‐analyses performed to estimate the relative effect of these interventions on our primary outcome of mean change in maximum K from baseline or final value of maximum K. Based on two studies that ended at six months (both without iontophoresis), there was no evidence of difference between transepithelial CXL and epithelium‐off CXL. When we examined data from six studies that reported outcomes at 12 months or later, there was again no evidence of a difference in the effects of the interventions on outcomes. Furthermore, change in CDVA from baseline at 6 and 12 months or later was no different between the techniques. No study reported a loss of 10 or more letters (0.2 logMAR units) of CDVA. Regarding subjective visual function, in one trial unmasked personnel administered the Ocular Surface Disease Index one month after surgery, with scores favoring transepithelial CXL without iontophoresis; however, imprecision and risk of bias lowered the certainty of evidence for a difference. No study reported the costs of either intervention. Adverse events such as corneal haze and temporary postoperative pain were not reported for any eye in the transepithelial CXL group. Haze or scarring occurred in 14 of 191 eyes in the epithelium‐off CXL group; most resolved by 6 months, but 4 eyes had “permanent haze” (Bikbova 2016). It is not clear how significant this haze was to participants' quality of vision.
As the goal of CXL is absence of significant steepening, we also examined data from the included trials for decrease or increase in maximum K of at least 2 D and for stability of maximum K (no steepening, or steepening by no more than 1 D). Two studies that compared transepithelial CXL versus epithelium‐off CXL reported data regarding keratoconus progression (Al Fayez 2015; Soeters 2015). Of these three keratometric outcomes, the CI was consistent with a difference in effects only for keratoconus progression. There was a 19% (Soeters 2015) or 55% (Al Fayez 2015) lower risk of progression for epithelium‐off CXL compared with transepithelial CXL, but risk of bias, imprecision, and unexplained heterogeneity lessen the certainty of evidence for this outcome. For the comparison of transepithelial CXL with iontophoresis versus epithelium‐off CXL, there was no evidence of difference with respect to progression of keratoconus or increase or decrease in maximum K of at least 2 D.
Overall completeness and applicability of evidence
All of the included studies evaluated transepithelial CXL versus epithelium‐off CXL, but lack of precision, a high risk of bias for multiple 'Risk of bias' domains for several studies (indicative of lack of methodologic rigor), and substantial heterogeneity often precluded the estimation of an overall effect. We explored comparisons between transepithelial and epithelium‐off CXL techniques within subgroups in an attempt to explain observed heterogeneity whenever sufficient data were available.
At the most elementary methodologic level, the authors of study reports often did not define their methods for measuring and reporting outcomes. For example, the target outcome for CXL is to halt or slow progression of keratoconus; however, when this outcome was reported, the report authors often failed to provide a detailed definition of progressive keratoconus as used in their studies. The period of time prior to CXL during which progression was noted could be 6 months, 12 months, or not reported. Baseline characteristics of participants and eyes, when reported, varied among the studies, possibly in part due to differences in measurement devices. The same variability in devices was seen in mean maximum K (Figure 3). Baseline and final measurements were obtained using topography/tomography units based on different technologies: Placido disc (CSO and Visante used by Rossi 2015 and Rossi 2018, and Lombardo 2016, respectively), scanning‐slit (Orbscan II used by Nawaz 2015), and Scheimpflug (Pentacam used by Cifariello 2018; Razmjoo 2014; Soeters 2015). Consequently, lack of a standard definition of progressive keratoconus and different measurement devices, as well as diverse perioperative, intraoperative, and postoperative protocols, increased heterogeneity and limited the applicability of evidence.
Results of studies with 6 months of follow‐up or less may be less clinically relevant than results from studies with 12 or more months of follow‐up given the time needed for corneal remodeling after kerato‐refractive procedures. Longer follow‐up is also important because progression of keratoconus is not linear over time. Patients can show stable keratometry values at the one‐year follow‐up visit and progression two years after transepithelial CXL (Caporossi 2013). Because stability at one year may be part of the natural disease course and not related to CXL, studies with longer follow‐up may be essential to assess the efficacy of CXL.
One reason for modification of transepithelial CXL is that in some non‐RCTs, transepithelial CXL alone has been less effective than epithelium‐off CXL, which shows stability 6 to 10 years after CXL (O'Brart 2015; Poli 2015; Raiskup-Wolf 2008). To enhance penetration of riboflavin through intact epithelium, some investigators have used iontophoresis, riboflavin formulations with trometamol and EDTA (ethylenediaminetetraacetic acid), or benzalkonium chloride or created corneal microabrasions. The plethora of techniques for transepithelial CXL may explain the high level of statistical heterogeneity in the results of some analyses. When all transepithelial CXL (including studies with iontophoresis) study arms were compared with epithelium‐off CXL study arms for mean change in maximum K from baseline at 6 or 12 months or longer, statistical heterogeneity was 50%. This level of heterogeneity indicated that calculation of an overall effect may be inappropriate. However, despite performing subgroup analysis to examine mean change in maximum K in two studies of transepithelial CXL without iontophoresis versus epithelium‐off CXL with 12 months of follow‐up (Rossi 2015; Soeters 2015), statistical heterogeneity remained significant (I2 = 81%). The mean changes and standard deviations reported in these two studies suggest either very different magnitude of effect of CXL despite almost identical transepithelial and epithelium‐off CXL protocols or very different baseline characteristics of participants and eyes, or both.
More experience has been obtained internationally with epithelium‐off CXL (specifically, the original Dresden protocol) than with any transepithelial CXL technique, but transepithelial CXL protocols are evolving rapidly. As observed in this systematic review, corneal haze was reported as an adverse effect of epithelium‐off CXL that can be temporary (lasting three to four months for three participants), 'deep stromal' at six months, or 'permanent' (Bikbova 2016). Although this finding may be significant to study personnel, this haze may not be visually significant to the patient. This distinction, along with patient‐reported outcomes, should be investigated in future studies of CXL.
Quality of the evidence
Overall, we graded the certainty of evidence for all comparisons of interventions to be very low or low due to prevalent risk of bias and imprecision related to the small number of participants enrolled in most trials.
The included studies had limitations in study design and implementation. Eleven (85%) RCTs had at least one domain that was judged as having unclear (indeterminate) risk of bias because sufficient information was not provided to permit an informed judgement. Risk of bias was unclear or high for most domains for most studies. We judged eight (62%) studies as at high risk of performance and detection biases; the most common bias was performance bias. Given the nature of the interventions, it would have been difficult to mask study personnel and participants. It is likely participants (and study personnel) were able to tell which eyes underwent epithelium‐off CXL because of participants' postprocedural pain. In addition, study personnel would be able to distinguish epithelium‐off versus transepithelial CXL when assessing participants' eyes at the slit‐lamp. The second most common bias was reporting bias (selective reporting). All studies measured keratometry outcomes and visual acuity (both key outcomes for this systematic review), but few provided data in a format suitable for inclusion in meta‐analysis. Furthermore, 8 (62%) and 10 (77%) studies did not provide adequate information on the method of random sequence generation and allocation concealment, respectively.
We judged five studies (38%) as at high risk of reporting bias because not all outcomes specified in the study protocols or methods sections were summarized in the results sections of reports or the report authors failed to report key outcomes, or reported outcomes incompletely without indicators of precision such as standard deviations, or depicted them in figures only without stating numerical values. We contacted the study authors to seek clarification and additional data to ensure that the review was as complete as possible when outcomes of interest were reported inadequately. We received the information and data for several studies through personal communication (Al Fayez 2015; Lombardo 2016; Nawaz 2015; Razmjoo 2014; Rossi 2015; Rossi 2018; Soeters 2015).
A third issue was inappropriate methods of data analysis when both eyes of participants were included in a study. Reports from five RCTs in which both eyes of some or all participants were assigned to the same interventions and one RCT with a paired‐eyes design did not describe or refer to appropriate analytical methods to handle correlations between eyes. We chose to analyze these data as reported rather than exclude them from the review, which thus affected the estimates of confidence intervals for outcomes from those studies.
Potential biases in the review process
We used standard Cochrane Review methodology to minimize bias and followed Methodological Expectations of Cochrane Intervention Reviews (MECIR) standards for the reporting of new Cochrane Intervention Reviews (editorial-unit.cochrane.org/mecir) in conducting this review and reporting our findings. An Information Specialist performed a highly sensitive search to identify studies. None of the authors has any financial conflicts of interest.
Agreements and disagreements with other studies or reviews
Three groups of authors have reported meta‐analyses in which they examined the same question as in this review (Kobashi 2018; Li 2017; Wen 2018), none of which provided convincing evidence of the superiority of one of the three CXL methods with respect to maximum K or visual acuity. Transepithelial CXL techniques may be associated with less than 0.1 logMAR improvement in visual acuity (Kobashi 2018; Li 2017), corresponding to less than 1 line on a Snellen visual acuity chart. Compared with our review, the three meta‐analyses:
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included fewer studies, some of which are included in our systematic review, and others which were not RCTs (Wen 2018);
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did not separate transepithelial CXL without iontophoresis from transepithelial CXL with iontophoresis (Kobashi 2018; Li 2017; Wen 2018);
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included studies of eyes with all types of corneal ectasia, not just progressive keratoconus (Kobashi 2018); and
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included one study of CXL in a pediatric population (Wen 2018).
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Forest plot of comparison: 1 Transepithelial corneal collagen crosslinking versus epithelium‐off corneal collagen crosslinking, outcome: 1.1 Mean change in maximum K from baseline or final value.
Forest plot of comparison: 1 Transepithelial corneal collagen crosslinking versus epithelium‐off corneal collagen crosslinking, outcome: 1.5 Mean change in corrected distance visual acuity (logMAR) from baseline or final values.
Forest plot of comparison: 1 Transepithelial corneal collagen crosslinking versus epithelium‐off corneal collagen crosslinking, outcome: 1.7 Adverse outcomes—corneal haze or scarring.
Forest plot of comparison: 2 Transepithelial corneal collagen crosslinking using iontophoresis versus epithelium‐off corneal collagen crosslinking, outcome: 2.1 Mean change in maximum K from baseline or final value at 12 months or more.
Forest plot of comparison: 2 Transepithelial corneal collagen crosslinking using iontophoresis versus epithelium‐off corneal collagen crosslinking, outcome: 2.5 Mean change in corrected distance visual acuity (logMAR) from baseline or final values at 12 months or more.
Comparison 1: Transepithelial corneal collagen crosslinking versus epithelium‐off corneal collagen crosslinking, Outcome 1: Mean change in maximum K from baseline or final value
Comparison 1: Transepithelial corneal collagen crosslinking versus epithelium‐off corneal collagen crosslinking, Outcome 2: Proportion of participants whose maximum K decreased by at least 2 diopters
Comparison 1: Transepithelial corneal collagen crosslinking versus epithelium‐off corneal collagen crosslinking, Outcome 3: Proportion of participants whose maximum K increased by at least 2 diopters
Comparison 1: Transepithelial corneal collagen crosslinking versus epithelium‐off corneal collagen crosslinking, Outcome 4: Proportion of participants whose keratoconus remained stable
Comparison 1: Transepithelial corneal collagen crosslinking versus epithelium‐off corneal collagen crosslinking, Outcome 5: Mean change in corrected distance visual acuity (logMAR) from baseline or final values
Comparison 1: Transepithelial corneal collagen crosslinking versus epithelium‐off corneal collagen crosslinking, Outcome 6: Patient questionnaire of subjective visual function parameters (Ocular Surface Disease Index) at 1 month
Comparison 1: Transepithelial corneal collagen crosslinking versus epithelium‐off corneal collagen crosslinking, Outcome 7: Adverse outcomes—corneal haze or scarring
Comparison 2: Transepithelial corneal collagen crosslinking using iontophoresis versus epithelium‐off corneal collagen crosslinking, Outcome 1: Mean change in maximum K from baseline or final value at 12 months or more
Comparison 2: Transepithelial corneal collagen crosslinking using iontophoresis versus epithelium‐off corneal collagen crosslinking, Outcome 2: Proportion of participants whose maximum K decreased by at least 2 diopters
Comparison 2: Transepithelial corneal collagen crosslinking using iontophoresis versus epithelium‐off corneal collagen crosslinking, Outcome 3: Proportion of participants whose maximum K increased by at least 2 diopters
Comparison 2: Transepithelial corneal collagen crosslinking using iontophoresis versus epithelium‐off corneal collagen crosslinking, Outcome 4: Proportion of participants whose keratoconus remained stable
Comparison 2: Transepithelial corneal collagen crosslinking using iontophoresis versus epithelium‐off corneal collagen crosslinking, Outcome 5: Mean change in corrected distance visual acuity (logMAR) from baseline or final values at 12 months or more
Comparison 2: Transepithelial corneal collagen crosslinking using iontophoresis versus epithelium‐off corneal collagen crosslinking, Outcome 6: Proportion of participants who gained 10 or more logMAR letters from baseline
Comparison 2: Transepithelial corneal collagen crosslinking using iontophoresis versus epithelium‐off corneal collagen crosslinking, Outcome 7: Proportion of participants who lost 10 or more logMAR letters from baseline
| Transepithelial CXL compared with epithelium‐off CXL for progressive keratoconus | ||||||
| Patient or population: participants with keratoconus Settings: tertiary care or university hospital Intervention: transepithelial CXL Comparison: epithelium‐off CXL | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No. of participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Assumed risk | Corresponding risk | |||||
| Epithelium‐off CXL | Transepithelial CXL | |||||
| Mean change in maximum K from baseline or final value—at 12 months or more (diopters) | The mean maximum K ranged across control groups from −1.5 to −0.92 (change from baseline), or | The mean maximum K in the intervention groups was −1 to 0.3 (change from baseline), or (95% CI −0.11 to 2.09). | ‐ | 177 eyes | ⊕⊝⊝⊝ | |
| Proportion of participants whose maximum K decreased by at least 2 diopters—at 12 months | 269 per 1000 | 86 per 1000 | RR 0.32 (0.09 to 1.12) | 61 participants | ⊕⊝⊝⊝ | |
| Proportion of participants whose maximum K increased by at least 2 diopters—at 12 months | 0 per 1000 | 143 per 1000 | RR (non‐event) 0.86 (0.74 to 1.00) | 61 participants | ⊕⊝⊝⊝ | |
| Proportion of participants whose keratoconus remained stable—at 12 months | 1000 per 1000 | 441 per 1000, or 800 per 1000 (data not pooled due to considerable heterogeneity (I2 = 92%)) | ‐ | 131 participants | ⊕⊝⊝⊝ | |
| Mean change in corrected distance visual acuity (logMAR) from baseline or final values—at 12 months or more | The mean corrected distance visual acuity ranged across control groups from −0.13 to −0.07 (change from baseline), or 0.05 (final value). | The mean corrected distance visual acuity in the intervention groups was −0.16 to −0.11 (change from baseline), or 0.02 (final value), and mean difference from −0.07 to 0.02 (data not pooled due to substantial heterogeneity (I2 = 70%)) | ‐ | 137 eyes | ⊕⊝⊝⊝ | |
| Proportion of participants who gained 10 or more logMAR letters from baseline | ‐ | ‐ | ‐ | ‐ | ‐ | No study reported gains of 10 or more logMAR letters. |
| Proportion of participants who lost 10 or more logMAR letters from baseline | ‐ | ‐ | ‐ | ‐ | ‐ | No study reported losses of 10 or more logMAR letters. |
| Adverse outcomes—corneal haze or scarring | 76 per 1000 | 0 per 1000 | RR (non‐event) 1.07 (1.01 to 1.14) | 221 eyes (4 studies) | ⊕⊕⊕⊝ | Herpetic keratitis, sterile infiltrate, and epithelial defect observed in 1 eye each in epithelium‐off group; Vogt's striae reported in 1 eye in each intervention group. |
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; CXL: corneal collagen crosslinking; logMAR: logarithm of the minimum angle of resolution;RR: risk ratio | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1Downgraded one level for study limitation due to high risk of performance and other biases among included studies. | ||||||
| Transepithelial CXL using iontophoresiscompared with epithelium‐off CXL for progressive keratoconus | |||||
| Patient or population: participants with progressive keratoconus Settings: tertiary care or university hospital Intervention: transepithelial CXL using iontophoresis Comparison: epithelium‐off CXL | |||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No. of participants | Certainty of the evidence | |
|---|---|---|---|---|---|
| Assumed risk | Corresponding risk | ||||
| Epithelium‐off CXL | Transepithelial CXL using iontophoresis | ||||
| Mean change in maximum K from baseline or final value—at 12 months or more (diopters) | The mean maximum K ranged across control groups −1.51 (change from baseline), or | The mean maximum K in the intervention groups was −1.05 (change from baseline), or | ‐ | 51 eyes | ⊕⊝⊝⊝ |
| Proportion of participants whose maximum K decreased by at least 2 diopters—at 24 months | 91 per 1000 | 0 per 1000 | RR (non‐event) 1.12 (0.89 to 1.40) | 31 eyes | ⊕⊝⊝⊝ |
| Proportion of participants whose maximum K increased by at least 2 diopters—at 24 months | 0 per 1000 | 0 per 1000 | RR (non‐event) 1.00 (0.87 to 1.15) | 31 eyes | ⊕⊝⊝⊝ |
| Proportion of participants whose keratoconus remained stable—at 24 months | 1000 per 1000 | 900 per 1000 | RR 0.92 (0.76 to 1.12) | 31 eyes | ⊕⊝⊝⊝ |
| Mean change in corrected distance visual acuity (logMAR) from baseline or final values at 12 months or more | The mean corrected distance visual acuity ranged across control groups −0.13 (change from baseline), or 0.03 (final value). | The mean corrected distance visual acuity in the intervention groups was −0.13 (change from baseline), or 0.04 (final value), and no mean difference (95% CI −0.04 to 0.04). | ‐ | 51 eyes | ⊕⊕⊝⊝ |
| Proportion of participants who gained 10 or more logMAR letters from baseline | 83 per 1000 | 227 per 1000 | RR 2.73 (0.36 to 20.74) | 34 eyes | ⊕⊝⊝⊝ |
| Proportion of participants who lost 10 or more logMAR letters from baseline | 0 per 1000 | 0 per 1000 | RR 1.00 (0.88 to 1.13) | 34 eyes | ⊕⊝⊝⊝ |
| Adverse outcomes | 1 subepithelial infiltrate in transepithelial CXL group; 2 faint corneal scars and 4 permanent haze in epithelium‐off CXL group; Vogt's striae observed in 1 eye in each intervention group. | ‐ | 203 eyes (3 studies) | ⊕⊕⊝⊝ | |
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; CXL: corneal collagen crosslinking; logMAR: logarithm of the minimum angle of resolution;RR: risk ratio | |||||
| GRADE Working Group grades of evidence | |||||
| 1Downgraded one level for study limitation due to high risk of performance and other biases among included studies. | |||||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1.1 Mean change in maximum K from baseline or final value Show forest plot | 7 | Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| 1.1.1 at 6 months | 2 | 84 | Mean Difference (IV, Random, 95% CI) | ‐1.02 [‐2.53, 0.49] |
| 1.1.2 at 12 months or more | 5 | 177 | Mean Difference (IV, Random, 95% CI) | 0.99 [‐0.11, 2.09] |
| 1.2 Proportion of participants whose maximum K decreased by at least 2 diopters Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 1.3 Proportion of participants whose maximum K increased by at least 2 diopters Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 1.4 Proportion of participants whose keratoconus remained stable Show forest plot | 2 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 1.5 Mean change in corrected distance visual acuity (logMAR) from baseline or final values Show forest plot | 5 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| 1.5.1 at 6 months | 1 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| 1.5.2 at 12 months or more | 4 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| 1.6 Patient questionnaire of subjective visual function parameters (Ocular Surface Disease Index) at 1 month Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 1.7 Adverse outcomes—corneal haze or scarring Show forest plot | 4 | 221 | Risk Ratio (M‐H, Random, 95% CI) | 1.07 [1.01, 1.14] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 2.1 Mean change in maximum K from baseline or final value at 12 months or more Show forest plot | 2 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 2.2 Proportion of participants whose maximum K decreased by at least 2 diopters Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 2.3 Proportion of participants whose maximum K increased by at least 2 diopters Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 2.4 Proportion of participants whose keratoconus remained stable Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 2.5 Mean change in corrected distance visual acuity (logMAR) from baseline or final values at 12 months or more Show forest plot | 2 | 51 | Mean Difference (IV, Fixed, 95% CI) | 0.00 [‐0.04, 0.04] |
| 2.6 Proportion of participants who gained 10 or more logMAR letters from baseline Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 2.7 Proportion of participants who lost 10 or more logMAR letters from baseline Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
