Corneal Collagen Cross-Linking with Riboflavin also abbreviated as C3R is a non-invasive corneal treatment shown to slow the progression of keratoconus. It does so by increasing the strength of corneal tissue. It can also help those that cannot wear contact lenses to more easily fit into them. Corneal Collagen Cross-linking with Riboflavin C3R has been demonstrated in Europe to strengthen a weakened corneal structure. This simple, well-tolerated procedure begins with the application of riboflavin vitamin B2 drops on the cornea which are then activated with a mild UV Ultraviolet light.

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Corneal collagen cross-linking CXL with riboflavin and ultraviolet-A UVA is a new technique of corneal tissue strengthening by using riboflavin as a photosensitizer and UVA to increase the formation of intra and interfibrillar covalent bonds by photosensitized oxidation.

Keratocyte apoptosis in the anterior segment of the corneal stroma all the way down to a depth of about microns has been described and a demarcation line between the treated and untreated cornea has been clearly shown. It is important to ensure that the cytotoxic threshold for the endothelium has not been exceeded by strictly respecting the minimal corneal thickness. Confocal microscopy studies show that repopulation of keratocytes is already visible 1 month after the treatment, reaching its pre-operative quantity and quality in terms of functional morphology within 6 months after the treatment.

The major indication for the use of CXL is to inhibit the progression of corneal ectasias, such as keratoconus and pellucid marginal degeneration. CXL may also be effective in the treatment and prophylaxis of iatrogenic keratectasia, resulting from excessively aggressive photoablation.

This treatment has also been used to treat infectious corneal ulcers with apparent favorable results. Combination with other treatments, such as intracorneal ring segment implantation, limited topography-guided photoablation and conductive keratoplasty have been used with different levels of success.

Corneal CXL, or C3R, is certainly a topic that has raised a significant interest since its first application more than 10 years ago.

In alone, there were 49 publications related to this topic compared to a mere six publications in Corneal CXL with riboflavin and UVA is a new technique of corneal tissue strengthening using riboflavin as a photosensitizer and UVA to increase the formation of intra-and interfibrillar covalent bonds by photosensitized oxidation.

By comparison, the same UVA irradiance at the corneal surface as used in the aforementioned studies can be measured at noon during an average sunny summer day in the tropics 23 of latitude and m above sea level. Despite the expected reduction of irradiance from the corneal surface toward the deeper layers of corneal stroma, the irradiation levels still exceed the threshold down to a depth of approximately microns.

Therefore, keratocyte apoptosis in the anterior stromal layer has been described and a demarcation line between the treated and untreated cornea has been clearly shown in both in vitro and in vivo studies.

Using a wavelength of — nm with an accumulated irradiance of 5. Therefore, for clinical use, a uniformly emitting irradiance source is required, and must be continuously evaluated. Therefore, there is an UV absorption coefficient that shields the more posterior structures such as the endothelium, the crystalline lens and the retina.

Confocal microscopy shows the repopulation of keratocytes by 1 month after treatment, reaching their pre-operative quantity and quality in terms of functional morphology within 6 months after treatment. Kymionis et al. Whether repeat treatment may be necessary due to corneal collagen turnover remains unanswered.

The treatment procedure should be performed under sterile conditions in an operating theater. The currently accepted treatment protocol includes deepithelialization for efficient penetration of riboflavin due to the incomplete absorption of riboflavin by the epithelium because of tight junctions.

This method has been successfully used for the treatment of progressive keratoconus and pellucid marginal degeneration since and for iatrogenic keratectasia since Published and peer-reviewed data on the safety and efficacy of these parameters for cross-linking are available from numerous research groups, with long-term results out to 6 years.

Abrasion of the corneal epithelium out to 7 mm is performed under topical anesthesia. Riboflavin solution, 0. The saturation of the cornea with riboflavin and its presence in the anterior chamber is monitored closely by slitlamp inspection prior to treatment.

Riboflavin saturation ensures the formation of free radicals whereas riboflavin shielding ensures the protection of deeper ocular structures such as the corneal endothelium. UVA irradiation is performed using an optical system Koehler type illumination consisting of an array of seven UVA diodes with a potentiometer in series to allow for regulation of voltage UV-X, Peschkemed, Huenenberg, Switzerland.

During the procedure, riboflavin solution and topical anesthetic oxybuprocaine 0. Treatment in progress with the cornea soaked with riboflavin and irradiated by the ultraviolet lamp. After the treatment, one drop of topical ofloxacin 0.

The patients are instructed to instill topical ofloxacin 0. In most cases, the contact lens is removed on the third day after treatment. The patient is then instructed to instill topical dexamethasone phosphate 0. A cross-linking procedure without epithelial removal would likely be less painful than one with the large diameter epithelial removal described above and would be ideal if it efficiently stabilized keratectasia. Several substances have been used to loosen the tight junctions of the epithelial layer and thus increase the penetration of riboflavin.

One is a riboflavin solution containing benzalkonium chloride BAK , the most commonly used preservative in ophthalmic medications. BAK is also a tensioactive substance, surfactant or an active surface agent that changes the surface tension value, and hence would facilitate the penetration of substances through the epithelium. Currently, there are no peer-reviewed studies that present data on this approach. However, in a comparative in vitro study, Samaras et al.

Mild regression that occurs may be explained as an effect of the rearrangement of corneal lamellae and the surrounding matrix. This process produces a rearrangement of corneal lamellae and a relocation of the surrounding matrix, which, in turn, results in the reduction of the central corneal curvature. The first in vivo controlled clinical study by Wollensak et al.

Results from a study by Coscunseven et al. A study by Jankov et al. Agrawal found similar results in 37 eyes of Indian subjects 1 year after treatment. Corneal cross-linking has also been used successfully in stopping the advancement of iatrogenic ectasia after excimer laser ablation.

In a recently published study, CXL was performed in 10 patients with previously undiagnosed forme fruste keratoconus or pellucid marginal corneal degeneration that underwent LASIK for myopic astigmatism and subsequently developed iatrogenic keratectasia.

The CXL is a promising technique for treating corneal melts or infectious keratitis because cross-linking would strengthen a collagenolytic cornea while UVA irradiation eliminates the infectious agent. CXL of the cornea has been shown to have an anti-edematous effect in the cornea. Wollensak et al. Corneal thickness was reduced by The bullous changes of the epithelium were markedly improved, with the patients reporting no pain or discomfort after CXL.

In such cases, CXL is primarily suited for patients with pain symptoms, restricted visual prognosis or to extend the time interval for an upcoming corneal transplantation. Other studies with alternative treatment methods for keratoconus, such as implantation of intracorneal rings, have reported more than a two-line increase in BSCVA.

These observations lead us to the following hypothesis: If the treatment with CXL stops or slows the progression of keratoconus, while other methods can reshape the cornea, a logical solution would be to combine the two treatment methods in order to synergize their effects. In this combined method, a pre-treatment with an alternative method would significantly reshape the cornea by flattening and regularizing corneal shape, which would be followed by CXL to stabilize the cornea. Alternatively, the CXL procedure could be performed first, followed by a reshaping procedure.

Kamburoglu et al. Mean keratometry pre-operatively was Following bilateral Intacs SK implantation, CXL was performed the following day in the left eye and after 1 month in the right eye. In , Chan et al. We have previously conducted a prospective, comparative study that comprised 48 eyes of 43 patients with progressive keratoconus. Therefore, CXL treatment showed a similar effect when applied over the cornea with ICR already in place as it had on with CXL-only treatments, having a similar modest improvement in all corneal parameters.

Compared to the modest reduction in spherical equivalent, cylinder and max K after CXL only, other treatment methods for keratoconus, such as intracorneal rings, show greater improvement of corneal parameters.

Miranda et al. Therefore, ICR implantation showed a greater effect when applied over an intact cornea rather than on a cornea already treated with CXL, although showing improvement in all the corneal parameters in either treatment sequence. These findings suggest that although each of the treatment steps demonstrates the improving effect on the cornea, a stiffer cornea already treated by CXL somewhat inhibits the flattening forces of ICR, thus restricting their effect and decreasing the maximal flattening potential.

In a prospective study, Kanellpoulos included a total of eyes with keratoconus. In a similar prospective study, Kymionis et al. Therefore, the primary treatment target is cylinder in order to improve the irregular astigmatism and the secondary target is correcting some of the sphere. Most importantly, the eye may not require a corneal transplant.

Immediately after conductive keratoplasty, a significant corneal topographic improvement was observed. However, the effect of conductive keratoplasty regressed 3 months post-operatively and remained unchanged until the sixth post-operative month in both patients. Although CXL is a minimally invasive method, recent reports have indicated possible adverse effects.

In a recent retrospective study of eyes of patients with stage keratoconus, 8. Mazzotta and colleagues have also presented two cases of post-operative corneal haze among a cohort of 40 eyes of 39 keratoconus patients. Repeated examination of the pre-operative confocal studies of these patients revealed a reticular pattern of stromal microstriae that may imply advanced keratoconus.

Additional case reports describe diffuse lamellar keratitis 38 and a reactivation of herpetic keratitis 39 following CXL. In both cases, prompt diagnosis and treatment resulted in favorable resolution. In another report, Koppen et al. Corneal CXL mediated by riboflavin and UVA appears to be a safe and efficacious procedure in halting the progression of keratoconus and iatrogenic ectasia.

CXL reduces the corneal curvature, spherical equivalent refraction and refractive cylinder in eyes with corneal instability and progressive irregular astigmatism due to keratoconus and ectasia. The CXL technique is promising in treating corneal melting conditions or infectious keratitis because cross-linking would strengthen a collagenolytic cornea while UVA irradiation eliminates the infectious agent.

Combination of ICR implantation with CXL seems to have a synergistic effect for reverting the progressive irregular astigmatism due to keratoconus or iatrogenic ectasia. A sequential or simultaneous combination of limited topography-guided PRK and CXL, whose goal is normalizing the cornea as much as possible, shows promising results.

Source of Support: Nil. Conflict of Interest: None declared. National Center for Biotechnology Information , U.

Middle East Afr J Ophthalmol. Mirko R. Lake , 2 Georgos Kymionis , 3 and Efekan Coskunseven 4. Jankov II. Jonathan C. Author information Copyright and License information Disclaimer. Laser Focus-Centre for Eye Microsurgery. Corresponding Author: Dr. E-mail: moc.


Corneal Collagen Cross-Linking (C3R) with Riboflavin

Shroff Eye has stood for excellence in eye care since A firm commitment to quality is at the heart of all services provided at our centers at Bandra W and Marine Drive, Mumbai. With current methods using rigid contact lens or intra corneal ring segments, only the refractive error spectacle numbers can be corrected, but it has very little effect on the progression of keratoconus. A new non surgical, non invasive treatment, based on collagen cross linking with Ultraviolet A UVA, nm and riboflavin Vitamin B 2 , a photosensitizing agent is now available. This increase in corneal strength has shown to arrest the progression of keratoconus in numerous studies all over the world. The treatment is performed in our operation theatre under complete sterile conditions. Usually, only one eye is treated in one sitting.


Crosslinking Procedure

It is used in an attempt to make the cornea stronger. According to a Cochrane review, there is insufficient evidence to determine if it is useful in keratoconus. A Cochrane review found that the evidence on corneal collagen cross-linking was insufficient to determine if it is an effective procedure for the treatment of keratoconus. Among those with keratoconus who worsen CXL may be used. In this group the most common side effects are haziness of the cornea, punctate keratitis, corneal striae, corneal epithelium defect, and eye pain. In those who use it after post-LASIK ectasia , the most common side effects are haziness of the cornea, corneal epithelium defect, corneal striae, dry eye, eye pain, punctate keratitis, and sensitivity to bright lights. There are no long term studies about crosslinking effect on pregnancy and lactation.

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