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The Role of Collagen Crosslinking in the Treatment of keratoconus and Ectasia


Collagen crosslinking with riboflavin (C3R) is a relatively new procedure that has been developed to increase corneal rigidity through increased crosslinks.1-4 The procedure has been shown to increase corneal rigidity in both porcine and human corneas in experimental studies3 and has been used in the treatment of keratoconus,s>6 arresting collagen melts in corneal ulcers7 and in ectasia following LASIK.s


How does it work?


Riboflavin, or vitamin B2, acts as a photomediator and is absorbed by ultraviolet light at 370 nm. Free radicals are created, which cause a change at the Amino group of amino acids in collagen. This change results in an increase in covalent bonds in corneal collagen, leading to thickening of colla-gen fibrils and an increase in tensile strength of the cornea.


UVA light 370nm


The maximal effect of crosslinking is confined to the anterior 300 microns of the cornea.


How is it performed?


The goal is to ensure that riboflavin penetrates the cornea, but as riboflavin is a large molecule, penetration through the corneal epithelium is difficult without either removing or creating breaks in the epithelium or by breaking the tight junctions between epithelial cells through use of agents such as tetracaine. There are champions of both. Riboflavin is instilled and although advised to be used every 5



minutes for 30 minutes, it is absorbed into the cornea with less frequent drops as long as the eyes are kept closed and patient is kept supine. To ensure adequate absorption, the eye is checked at the slitlamp to ensure the cornea is stained yel¬low and the presence of riboflavin is confirmed in the anterior chamber. Riboflavin with dextran is used in corneas that are 400 microns or more in thickness to avoid potential endothe¬lial damage. In thinner corneas, an alternative preparation of riboflavin without dextran is used. The solution is hypotonic and fluid is absorbed into the cornea, inducing some thicken¬ing. This is checked using pachymetry to ensure that the cornea has thickened to 400 microns before commencing UV radiation. A speculum is inserted and topical anesthetic is applied periodically. Ultraviolet light exposure is then carried out using the Peschke UVX device (Peschke Meditrade GmbH, Germany), which is calibrated to deliver UV light at 370 nm with an irradiance of 3mW/cm2 (see Figure 4). A con¬tact lens is then placed on the eye as a bandage and to ensure comfort, and ciprofloxacin is instilled. Patients are instructed to use ciprofloxacin four times daily and return the following 24 to 48 hours to have the contact lens removed. Within a few days an anterior haze is noted, and this disappears over time, usually within a few weeks.


Role in Ectasia


The procedure has been used with some success in kerato¬conus and ectasia following LASIK. Crosslinking involves the anterior 300 microns, and whether ectasia has occurred because of treatment on form fruste keratoconus or through the inadvertent creation of a thick flap is not completely rele¬vant, as both the overlying flap and stromal bed undergo crosslinking. The authors have treated seven eyes with post¬LASIK ectasia. Data is hard to interpret based on small num¬bers and short follow-up; however, a small improvement in subjective visual acuity has been observed and patients have reported a decrease in fluctuation. Of a little concern is a demonstrable decrease in central corneal thickness. This might be expected because of collagen fibril thickening and consequent shortening as well as transient loss of keratocytes. Although there have been reports of improvements in ker¬atometry, this has not been the author's observation. Overall, the impression is that the corneas do stabilize, or at least the rate of progression slows considerably.


Collagen cross linking (CXL)

  • Collagen cross-linking in the cornea using riboflavin (B2) - UVA treatment leads to a significant increase in mechanical stiffness of the corneal Spörl et al Opthalmologe 1997

  • Increased rigidity by more than 300%

  • Young’s modulus increased by 4.5 x

Principle of action CXL UVA-X

  • Increase in intra- and inter-fibrillar covalent bonds by photosensitized oxidation

  • Penetration of approx. 300 µm

  • Epithelium scraped off after anesthetic

  • Photosensitizer riboflavin B2 0.1% in 20% Dextran

  • UVA 370 nm

  • Irradiance 3 mW/cm2 for 30 min

  • Dose of 5.4 J/cm2

  • CL and antibiotic eye-drops

Side effects

  • Keratocyte damage

  • Endothelium damage

  • Safety depth of 400 µm established


  • Diseases where a biomechanical stabilization of the cornea is sought:

  • Keratoconus (KC)

  • Corneal melting

  • Iatrogenic keratectasia

Keratoconus (KC)

  • Noninflammatory ectasia of the cornea

  • (Para)central corneal thinning

  • Irregular astigmatism

  • Bilateral (asymmetric) and progressive

  • 1:2000 in general population

  • Onset at puberty, 20% progress to PKP


  • Spectacles (early stages)

  • GP CL

  • Epikeratoplasty

  • Intracorneal rings

  • PKP


  • CXL stopped the process

  • 23 eyes, follow up average of 2 years

  • BSCVA better by 1.26 lines in 65%

  • SEQ reduced by 1.14 D

  • Max K post-op progressed in 1 pt (0.28 D)

  • Pre-op progression of 1.42 D in 52 %


  • Regression!

  • anterior part of the cornea responsible for the curvature

  • Max K reduced by 2 D in 70 %

  • Fellow eyes progression by 1.5 D in 22%

Other degenerations

  • Marginal pellucid degeneration

  • Keratoglobus

  • Alcali burns

  • Collagenase secretion from the perilimbal conjunctiva in the recovery phase

  • Melting occurs at a later phase

  • Collagen diseases (SLE, RA, Polyarteritis nodosa, Wegener’s

  • granulomatosis, polychondritis…)

  • Severe persistent peripheral infiltration

  • Ulceration, thinning and melting

  • Scleral thinning

Mooren’s ulcer

  • Peripheral ulcerative keratitis caused by ischaemic necrosis from vasculitis of limbal vessels

  • Adjacent conjunctiva produces collagenases and proteglyconases

  • Limited form

  • Unilateral, elderly, less aggressive

  • Progressive form

  • Bilateral, younger, more agreesive

Other possibilities

  • Stabilizing cornea after other procedures

  • Intacs

  • CK

  • Ortho K

  • Post RK?

  • (Central island prevention by reducing differential stromal hydration)

CXL mechanically stabilizes cornea with KC, keratectasia or corneal melting

  • More rigid cornea is more resistant to collagenases

  • To stop KC progression at earlier stages

  • To prevent keratectasia (deeper ablation)

  • To combine with topo-PRK/EPI/LASEK in KC forme fruste?





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