Corneal Collagen Cross-Linking in the Stabilization of Keratoconus
Background: Keratoconus is a slowly progressive ectatic deformity of the cornea with a prevalence of 200 to 400 cases per 100 000 persons. The cornea is thinner than normal and irregularly warped; irregular astigmatism and myopia result. Riboflavin-UVA crosslinking (collagen cross-linking) makes corneal tissue more rigid through a photochemical effect and can stop the progression of the disease.
Methods: This review is based on relevant publications retrieved by a selective search in Medline, as well as on meta-analyses, Cochrane Reviews, and reports of national and international health care institutions.
Results: Pertinent randomized controlled trials (RCTs) have shown that cross-linking prevents the progression of keratoconus to a statistically significant extent, as determined by measurement of topographic parameters. In the largest RCT to date (follow-up of 100 eyes for three years), the maximal corneal refractive power increased by 1.75 ± 0.38 diopters in the control group and decreased by −1.03 ± 0.19 diopters in the cross-linking group (p <0.001). This was also the only trial in which data were reported on the patient-relevant endpoint of uncorrected visual acuity, which mildly improved in the cross-linking group (−0.15 ± 0.06 logMAR, p = 0.009). Serious complications of cross-linking are known to date only from a few reports of individual cases. Cohort studies with follow-up times of up to ten years have shown that the condition can continue to progress after cross-linking, especially in younger patients.
Conclusion: Cross-linking is the first available treatment for keratoconus that can improve the natural course of the disease.
Keratoconus is a corneal disorder involving progressive deformation and thinning of the cornea due to hitherto unknown causes. The disorder often begins in the second decade of life and always affects both eyes, albeit sometimes to highly varying degrees. The disease incidence is approximately 13 cases/100 000 inhabitants per year, with the prevalence lying between 200 and 400 affected individuals/100 000 inhabitants (1). Children and adolescents with, e.g., atopic dermatitis, a positive family history, or trisomy 21 are at greater risk. Rahi et al. found atopy in 35% of individuals affected by keratoconus, whereas this was the case in only 12% of control subjects (2). However, frequent vigorous eye rubbing among atopic individuals might explain the correlation with keratoconus, since after a multivariate risk factor analysis only eye rubbing but not atopy remained a significant predictor of keratoconus (3). Therefore, early indications of keratoconus can also be identified by the dermatologist or pediatrician; patients who develop visual difficulties should be referred to an ophthalmologist.
Since the cornea with its refractive power plays an important role in the optical system of the eye, progressive corneal deformation results in an increase in refractive power and subsequent myopic shift, as well as in an (increasingly irregular) curvature of the cornea (astigmatism). Affected individuals first notice a non-specific deterioration in vision, which prompts a visit to the ophthalmologist, who often initially diagnoses moderate short-sightedness—and possibly astigmatism. The cone-shaped protrusion is typically displaced in a downwards direction, explaining the progressive irregularity of corneal refractive power. Ultimately, this leads to a situation in which visual function can no longer be adequately corrected with glasses, resulting in the suspected diagnosis of keratoconus. The older the affected individual, the slower the disease progresses (4). Whether a complete halt in disease progression can occur has not been conclusively established as yet, since there are no studies involving lifelong follow-up.
At early stages, the disease is generally not diagnosed in the context of routine ophthalmological examinations, since there are virtually no morphological changes. Computer-assisted measurement of the cornea (corneal topography or corneal tomography) can help to confirm or exclude the suspected diagnosis of keratoconus. Typical topo-/tomographic findings, such as increased paracentral corneal refractive power, protrusion of the anterior and/or posterior corneal surfaces, as well as paracentral corneal thinning, are seen in the case of keratoconus. In the case of progression, all these findings increase at varying degrees and speeds over the disease course and can be quantified by means of repeated topo-/tomographic examinations (Figure 1). When interpreting examination results, one must bear in mind that examinations performed on different systems cannot be compared with one another (5) and that each method has system-specific measurement fluctuations (6, 7). Morphological findings that are visible to the ophthalmologist generally do not occur until later stages of the disease.
The aim of this article is to critically present and discuss—in an evidence-based manner and using the currently available literature—the efficacy of cross-linking to halt the progression of keratoconus.
Disease course and treatment options to date
Early on in the disease, when affected individuals experience the first symptoms, changes in corneal refractive power can generally be corrected with glasses. As astigmatism becomes increasingly irregular, special dimensionally rigid contact lenses mostly need to be used. If, eventually, contact lenses can no longer be fitted, corneal transplantation may become necessary for the purposes of visual rehabilitation.
An observational study on 2363 patients found that approximately 22% required keratoplasty for visual rehabilitation (8). The prognosis for the majority of keratoconus patients following keratoplasty is excellent (9, 10), although one must anticipate that, in the often young patients, a second transplant may be necessary in the further course. Atopic patients have a somewhat poorer prognosis (11) since, due to chronic blepharokeratoconjunctivitis, they frequently experience inflammatory flare ups on the ocular surface and associated corneal vascularization, which increase the risk of transplant rejection following corneal transplantation.
It would be beneficial to all those affected if disease progression could be stopped or slowed down, thereby precluding the need for corneal transplantation. Early indirect evidence in the literature (12, 13) suggests that in recent years, since the introduction of cross-linking, ever fewer keratoconus patients require keratoplasty.
Progression of keratoconus
As a rule, progression of the disease differs considerably from individual to individual. The younger the affected individuals are, the higher their risk for (rapid and pronounced) progression (4). Progression may be stimulated by vigorous and frequent eye rubbing (14). There are currently no standardized guidelines for the definition of disease progression. Numerous clinical studies have used different parameters to this end. The most important parameters include (15):
- An increase in maximum corneal refractive power (Kmax) by more that 1 dpt within 1 year
- An increase in (corneal) myopia by more than 3 dpt or astigmatism by more than 1.5 dpt within 12 months
- An increase in mean corneal refractive power by more than 1.5 dpt within 12 months
- A reduction in minimal corneal thickness of more that 5% within 12 months.
A decline in visual acuity appears to be a less suitable parameter to determine progression, since keratoconus patients often report variable vision (16) and objective findings do not always correspond to subjective perception (17). In addition, eyeglass lenses can hamper the determination of refraction, or contact lens correction can compensate for altered values of corneal refractive power, meaning that no deterioration in vision can be determined despite altered corneal refractive power.
Regular topo-/tomographic examinations are required to identify disease progression. The measurement fluctuations for the respective parameters need to be taken into consideration in the diagnosis. Therefore, suspected progression should always be repeatedly confirmed in the further disease course. With regard to examination intervals, the individual risk profiles of affected individuals need to be taken into consideration (risk factors: eye rubbing, young patient age, steep corneal curvature gradient, high astigmatism, marked loss of vision, confirmed progression in the fellow eye, ocular allergies, atopic dermatitis, or trisomy 21). Therefore, it is recommended that young patients under the age of 25 years be monitored more frequently (e.g., every 3–6 months) and older patients less frequently (e.g., every 6–12 months).
Cross-linking in keratoconus
Much like the stiffening of heterologous heart valve transplants (18), the principle of riboflavin-UVA cross-linking is based on a photochemical effect that was first presented by Spoerl et al. in 1998 (19). Cross-linking was first used in patients at the end of the 1990s, while the first clinical results were published in 2003 (20).
Following removal of the corneal epithelium, the riboflavin applied via eye drops penetrates to the deep corneal layers. There it absorbs the UVA light (370 nm wavelength, 3 mW/cm² irradiation) with which the cornea is irradiated for 30 min. This produces free oxygen radicals that lead to the creation of covalent bonds between the collagen fibrils in the corneal stroma (Figure 2). Riboflavin also has a protective effect, since only when the stroma is saturated with riboflavin, will the high-energy UVA light be sufficiently absorbed in the cornea, thus preventing damage to intraocular structures.
Corneal thickness also plays a crucial role here: this should not become thinner than 400 µm during irradiation, since intraocular structures, such as the corneal endothelium, would otherwise be at risk (21). It is important to bear in mind in relation to corneal thickness that thinning can occur during treatment. This can be compensated in the short term by the use of hypotonic riboflavin eye drops, which in turn, can reduce the effectiveness of the treatment (22).
The treatment method described above has now become established as the “Dresdner protocol.” The aim of cross-linking is to stabilize the corneal tissue in order to halt or at least slow down disease progression; however, a cure as such is not possible. Thus, no further changes in topo-/tomographic parameters consistent with progression are seen following cross-linking. In some cases, a reduction in corneal refractive power and regularization of the corneal surface is seen, which can be associated with an improvement in visual acuity (Figure 3). The investigation conducted by Wittig-Silva et al. found a reduction in maximum corneal refractive power by more than 2 dpt in 13% of participants in the cross-linking group (23).
Also, by halting disease progression, it was possible to prevent keratoconus from advancing to a point where corneal transplantation becomes necessary.
Details on possible side effects and complications, as well as on current variants such as transepithelial or accelerated cross-linking can be found in the eMethods section.
Target group and indication for cross-linking
Cross-linking should be performed at a stage of disease in which affected individuals still have adequately good visual acuity. Furthermore, primarily those patients in whom progression has previously been identified should be treated.
Since disease progression is more pronounced in young individuals than it is in older patients, cross-linking is of considerable relevance to young patients in particular. For example, study results suggest that the treatment effect in young people could be more pronounced than in older patients, whereby a mean reduction in maximum corneal refractive power of 1.27 dpt was observed within 2 years following cross-linking in patients under 18 years of age (24).
In addition, complications also appear to occur less frequently in younger patients. For instance, a complication rate of 1% was observed in under 35-year-olds compared to a complication rate of 3% when all age groups were considered (25). However, a decline in treatment effect and renewed progression appear to occur more frequently in young patients. Mazzotta et al. reported that keratoconus progressed within a follow-up period of 10 years in 24% of young patients aged 15 years or younger (26). Therefore, regular check-ups (depending on the risk profile, e.g., patient age) should be performed even after treatment, initially every 6 months and later annually or, in the case of subjective symptoms, in the interim.
In addition to countless case series and cohort studies, a number of randomized controlled trials have now also been conducted. Therefore, we performed a literature search in Medline using the terms “keratoconus (cross-link* or crosslink*) trial,” which yielded six relevant studies out of 131 hits (inclusion criteria: randomized, controlled, at least 12 months follow-up; see Table). Meta-analyses, Cochrane reviews, and reports compiled by national and international healthcare institutions were also taken into account.
Randomized controlled trials (evidence level Ib)
All studies identified and included on the basis of the literature search showed a statistically significantly positive effect for cross-linking on the change in maximum corneal refractive power (Kmax). Furthermore, some studies also found a positive effect on uncorrected or corrected visual acuity. Wittig-Silva et al. (23), who included and followed up 100 eyes with progressive keratoconus for 3 years, found an increase in maximum corneal refractive power of 1.75 ± 0.38 dpt in the control group, whereas a flattening of −1.03 ± 0.19 dpt was seen in the cross-linking group (p <0.001). Moreover, a deterioration in uncorrected visual acuity of + 0.1 ± 0.04 logMAR (logarithm of the minimum angle of resolution) was observed in the control group, while a mild improvement in uncorrected visual acuity of −0.15 ± 0.06 logMAR was seen in the cross-linking group (p = 0.009). However, all studies published to date (23, 27–31) have methodological weaknesses that need to be taken into account when interpreting their results. Overall, only very few complications and adverse effects were reported in the studies discussed here. Detailed information on the studies’ methods, effects, complications, and methodological deficiencies can be found in the Table.
Meta-analyses (evidence level Ia)
Despite the methodological weaknesses described in the Table and differences in the randomized controlled trials published to date, a number of working groups have attempted to bring these studies together in meta-analyses. However, the results of these systematic reviews should be interpreted with caution, since it is difficult to statistically combine the respective studies due to their considerable heterogeneity. Kobashi et al. (who included five studies with altogether 289 eyes, ) reached the conclusion in their systematic review that cross-linking can effectively halt the progression of keratoconus, although the evidence for this is limited due to the heterogeneity and methodological weaknesses of the individual studies. Therefore, it was not possible to meta-analytically summarize the results on maximum corneal refractive power due to the high heterogeneity (I² = 81%). Li et al. (who included six studies with 261 eyes in total, ) also confirmed the efficacy of cross-linking to halt the progression of keratoconus (the weighted mean difference for maximum corneal refractive power was −2.05; 95% confidence interval: [−3.10;–1.00]; p <0.00001). However, it was not possible at the time of the study to estimate medium- and long-term effects, since most studies had short follow-up periods.
Cochrane Review and other reports
In a 2015 Cochrane Review, Sykakis et al. (34) concluded that there is still insufficient evidence to demonstrate the efficacy of cross-linking, despite almost 700 published studies. The National Institute for Health and Care Excellence (NICE) in Great Britain came to the conclusion that there is sufficient qualitative as well as quantitative evidence for the efficacy of cross-linking, on the basis of which approval was recommended (35). The procedure was also approved by the FDA in the US due to a lack of alternatives, despite the fact that the evidence is classified as weak (31, 36). In its report, the German Institute for Quality and Efficiency in Health Care (Deutsche Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen, IQWiG) came to the conclusion that there is an indication pointing to the efficacy of cross-linking with regard to uncorrected visual acuity (1). It must be borne in mind here that this report only took into consideration patient-relevant endpoints (visual acuity) in the randomized controlled trials, meaning that, once the raw data had been statistically processed, the results of only one single study (23) lead to this conclusion.
As already discussed in the section “Progression of keratoconus,” it seems reasonable from an ophthalmologist’s point of view, on the other hand, to consider not only visual acuity but also the change in corneal shape or refractive power when assessing disease course in keratoconus patients, since these changes generally precede a deterioration in vision. The German Federal Joint Committee (Gemeinsamer Bundesausschuss, G-BA) has now decided, on the basis of the current evidence, to include cross-linking in the catalog of procedures covered by statutory health insurance in Germany.
Summary and outlook
Randomized controlled trials have demonstrated in recent years that riboflavin-UVA cross-linking is successfully able to halt disease progression in keratoconus patients. What is of particular importance here is that keratoconus progression is reliably identified, before the indication for treatment is made. This standardized treatment procedure with a low side-effects profile has now become firmly established in Germany. There is also an increasing number of reports on further developments such as transepithelial or accelerated cross-linking, both of which promise benefits for patients, but whose efficacy compared to standard cross-linking has not yet been demonstrated.
Conflict of interest statement
The authors state that there are no conflicts of interest.
Manuscript submitted on 2 July 2018, revised version accepted on 1 February 2019.
Translated from the original German by Christine Schaefer-Tsorpatzidis.
Prof. Dr. med. Philip Maier
Klinik für Augenheilkunde, Universitätsklinikum Freiburg
Medizinische Fakultät der Albert-Ludwigs-Universität Freiburg
Killianstr. 5, 79106 Freiburg, Germany
For eReferences please refer to:
Prof. Dr. med. Philip Maier, Prof. Dr. med. Thomas Reinhard
Department of Ophthalmology, St. Johannes Hospital, Dortmund: Prof. Dr. med. Markus Kohlhaas
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