The term cross-linking has recently secured a prominent place on the ophthalmic radar screen of new technologies with the advent of corneal cross-linking for keratoconus. Cross-linking has existed for a long time in the field of synthetic polymers and also in the biologic domain of natural polymers, such as proteins. A cross-link is a bond that links or connects one polymer chain to another polymer chain. Cross-linking bestows added strength to biological proteins to make them mechanically stable, and some naturally occurring examples include skin, hair and cartilage.
Collagen cross-linking was first used in 2004 for keratoconus management utilizing ultraviolet A (UVA) light irradiation combined with corneal riboflavin (vitamin B2) application. UVA activation of riboflavin, which is a photosensitizer, results in free radicals of oxygen, and this facilitates physical collagen cross-linking that results in increased formation of intrafibrillar and interfibrillar covalent bonds by this photosensitized oxidation process. A significant factor is the rate and depth of riboflavin penetration into the deeper cornea, and epithelial removal was embraced to facilitate the penetration. However, in recent times, “epi-on” vs. “epi-off” for corneal collagen cross-linking continues to be a subject of debate and controversy.
In April, Avedro received FDA approval for the company’s collagen cross-linking system for the treatment of progressive keratoconus. It also included approval of Avedro’s riboflavin solutions, namely Photrexa Viscous and Photrexa. Surgeons choose a minimum corneal thickness of 400 µm in an effort to provide endothelial protection. Globally, collagen cross-linking has also been used to treat infectious keratitis and as a combined treatment with intracorneal rings and modified PRK. Potential side effects include corneal haze, diffuse lamellar keratitis and herpetic keratitis reactivation. Overall, collagen cross-linking appears to be safe and effective in controlling keratoconus progression.
In this column, Dr. Hersh describes the technique of corneal collagen cross-linking in a stepwise manner for the treatment of progressive keratoconus.
Thomas “TJ” John, MD
OSN Surgical Maneuvers Editor
Corneal collagen cross-linking is a treatment designed to decrease the progression of keratoconus. The biomechanical strength of the cornea depends upon the lamellar organization of the collagen fibers that comprise the corneal stroma, mediated by an interconnecting network of proteoglycans. While the pathogenesis of keratoconus remains unclear, it appears that a primary event leads to the loss and/or slippage of collagen fibrils and changes to the extracellular matrix in the corneal stroma. Collagen cross-linking aims to halt the keratoconus disease process by strengthening the cornea’s mechanical architecture. The treatment results in stiffening of the cornea, with the clinical goal being a consequent decrease in progression of the disease process. In vitro studies show that immediately after corneal collagen cross-linking, stress measurement increases in human corneas by more than 300%.
Figure 1. The central epithelium is removed over a 9 mm diameter performed per the surgeon’s preferred technique.
Figure 2. Epithelial defect stained with riboflavin solution.
Images: Hersh PS
Figure 4. Note the presence of a yellow/green flare in the anterior chamber, demonstrating adequate riboflavin uptake.
Figure 5. Administration of UVA. Patient gaze is at the fixation light of the instrument, and the surgeon maintains proper centration throughout the 30-minute UV phase of the procedure.
On April 15, the corneal collagen cross-linking procedure was approved in the U.S. by the FDA for the treatment of progressive keratoconus in patients older than 14 years of age. Approval was granted to Avedro specifically for collagen cross-linking using its riboflavin products Photrexa Viscous and Photrexa. Photrexa Viscous comprises riboflavin 5’-phosphate 0.146% in solution containing 20% dextran. It is used for riboflavin loading and during UV exposure. Photrexa is riboflavin 5’-phosphate 0.146% without dextran and is used for corneal swelling after the loading phase in corneas that have a thickness of less than 400 µm. The riboflavin drops are used in conjunction with the Avedro KXL System, which operates at 365 nm UVA at a power of 3 mW/cm2.
The approved procedure is similar to the method used internationally for many years:
1. The eye is prepped and draped in the usual fashion and a lid speculum is placed.
2. A 9 mm removal of the central epithelium is performed per the surgeon’s preference. Usually, either a spatula or 20% alcohol is used to remove the epithelium (Figure 1).
3. Lid speculum is removed.
4. Riboflavin (Photrexa Viscous) is applied topically every 2 minutes for 30 minutes. The patient is instructed to keep the eye closed between drops.
5. After 30 minutes, confirm adequate riboflavin uptake. The patient is examined at the slit lamp. Uptake is confirmed by a homogeneous green fluorescence throughout the corneal stroma (Figure 2) and by the presence of a yellow-green flare in the anterior chamber (Figure 3).
6. If uptake is not adequate, additional riboflavin is administered until flare is observed (Figure 4).
7. Perform ultrasound pachymetry. If the corneal thickness is less than 400 µm, instill two drops of Photrexa every 5 to 10 seconds until the corneal thickness increases to at least 400 µm. Typically, we apply the drops for 2-minute intervals and then recheck pachymetry. UV administration should not be performed until this 400 µm threshold is met.
8. Place the patient under the KXL System.
9. Place the lid speculum and use the controller to center the treatment in the x, y and z planes over the central cornea.
10. Irradiate the eye for 30 minutes, assuring that the patient maintains gaze and the treatment is centered (Figure 5).
11. During irradiation, continue topical instillation of Photrexa Viscous onto the eye every 2 minutes.
At the conclusion of the procedure, we typically instill an antibiotic and a corticosteroid drop and place a therapeutic contact lens (Figure 6). The contact lens is removed upon epithelial healing 3 to 5 days postoperatively.
FDA approval of cross-linking was based on the results of two randomized, controlled clinical trials sponsored by Avedro. The primary efficacy criterion was a difference in the change in maximum keratometry on corneal topography analysis between treatment and sham control groups (Figure 7). Maximum keratometry was chosen as a quantitative descriptor of keratoconus severity. Change in maximum keratometry can be thought of as an indicator for progression or stability of keratoconus. In study 1, average maximum keratometry improved (flattened) by 1.4 D at 1 year postoperatively; in study 2, average maximum keratometry improved by 1.7 D. This was compared with steepening of maximum keratometry, on average, in control eyes (Figure 8).
Proper patient selection and adherence to procedural protocol have shown corneal collagen cross-linking to be a safe and effective treatment of keratoconus. It represents our first available technique for stabilizing or slowing progression of topographic irregularity in keratoconus and is an invaluable new tool in our management of this progressive corneal disorder.
- Caruso C, et al. Cornea. 2016;doi:10.1097/ICO.0000000000000809.
- Hersh PS, et al. J Cataract Refract Surg. 2011;doi:10.1016/j.jcrs.2010.07.030.
- Shalchi Z, et al. Eye (Lond). 2015;doi:10.1038/eye.2014.230.
- Tabibian D, et al. Eye Vis (Lond). 2016;doi:10.1186/s40662-016-0042-x.
- Wollensak G, et al. Am J Ophthalmol. 2003;doi:10.1016/S0002-9394(02)02220-1.
- For more information:
- Peter S. Hersh, MD, FACS, can be reached at the Cornea and Laser Eye Institute – Hersh Vision Group, CLEI Center for Keratoconus, 300 Frank W. Burr Blvd., Suite 71, Teaneck, NJ 07666; email: firstname.lastname@example.org.
- Edited by Thomas “TJ” John, MD, a clinical associate professor at Loyola University at Chicago and in private practice in Oak Brook, Tinley Park and Oak Lawn, Ill. He can be reached at email: email@example.com.
Disclosures: Hersh reports he is the medical monitor for the U.S. multicenter clinical trials for Avedro. John reports no relevant financial disclosures.