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Corneal cross-linking considerations


Young male patient receiving CXL treatment

CPD hours

Optometrists: This activity may qualify for 25min of your required CPD hours (dependent upon your personal learning plan).

GPs: This activity may qualify as a self-recorded learning activity (2 CPD points per hour).

Note: The estimated completion time includes time spent reading this article and completing the reflection questions.

Corneal collagen cross-linking (CXL) is an established and important treatment option for the management of patients with keratoconus (KC). Although not curative, it has been shown to effectively halt KC progression. The original Dresden protocol sets out specific criteria when administering CXL, including removal of the epithelium and a minimum corneal thickness of 400 µm.

But what happens when you have a patient that doesn’t match the Dresden criteria exactly? And is epi-off the only acceptable CXL technique? Vision Eye Institute’s Dr Uday Bhatt, Dr Alex Ioannidis, Dr Abi Tenen and Prof Rasik Vajpayee share their thoughts.

Consideration: How do you manage a patient with signs of KC progression and thin corneas?

Drs Bhatt, Ioannidis, Tenen and Vajpayee

This type of patient can be managed with a two-prong strategy:

  1. Offering CXL to stiffen the cornea, which is proven to stop/reduce the progression of KC
  2. Minimise rubbing of the eyes by educating the patient about potential consequences and also treating any underlying condition(s) that cause ocular pruritis.

The Dresden protocol allows CXL to be performed safely when the post-debridement corneal thickness is 400 μm or greater. This is to minimise the risk of irradiation damage to the corneal endothelium with UVA illumination. However, the cornea may be thinner than this cut-off in advanced cases of KC.

There are various methods to perform CXL in thinner corneas:

  • Hypo-osmolar riboflavin – this specific formulation of vitamin B2 causes the cornea to absorb water and swell to the safety level of >400 μm
  • Contact lens-assisted CXL – a soft contact lens is used to increase the corneal thickness artificially
  • Epithelial islands technique – islands of epithelium are left intact where the cornea is extremely thin
  • UV modification – customising the total amount of UV energy applied to the cornea, based on each patient’s corneal thickness
  • Transepithelial CXL – the epithelium is left intact to keep the cornea at its maximum pachymetry.

Additionally, improved awareness and screening protocols for KC may facilitate earlier disease detection in patients before the cornea reaches a sub-400 μm thickness.

Consideration: How do you manage a 13-year-old patient with progression in only one eye?

Drs Bhatt, Ioannidis, Tenen and Vajpayee

Younger KC patients generally exhibit faster disease progression. In such cases, there is no doubt that the main objectives are to halt the progression, prevent visual loss and ultimately avoid corneal transplantation (if possible). Currently, CXL is the only known treatment that has been proven to prevent progression.

CXL performed in children has shown similar initial efficacy as adults in terms of improvement of visual and topographic outcomes.

However, long-term outcomes are more variable. In addition, there is a much higher prevalence of allergic eye disease in children with KC and that also needs to be aggressively managed.

Consideration: Epi-on vs epi-off CXL?

The main objective of CXL is to halt the progression of KC.  Although a number of different CXL techniques have been described in the literature, it is the original Dresden Protocol that remains the most widely studied to date and whose efficacy and safety has been clearly demonstrated. First described by Wollensak, this method involves removal of the corneal epithelium before UVA is delivered to the stroma at a standardised fluence of 5.4 J/cm2.

Drs Bhatt, Ioannidis and Vajpayee

While we understand the desire to improve the tolerability, safety and ease of delivery of conventional CXL (e.g. reducing postoperative pain, risk of infection and wound-related complications), epi-on techniques DO NOT yet meet the gold standard. Corneal biomechanical rigidity has been shown to be significantly higher (approximately 70%) following epi-off CXL compared to when the epithelium remains intact.

This can be attributed to the following concepts:

1. The riboflavin-epithelium penetration process

An intact corneal epithelium cannot be penetrated by riboflavin because it is a large, hydrophilic molecule. Additionally, up to a third of the UVA light is absorbed by the epithelium and Bowman’s layer, meaning a suboptimal dose is delivered to the underlying stroma.

2. Posterior stromal origin of corneal ectasia

The posterior layers of the cornea represent the weakest portion of the stroma and it is here that the ectatic process in KC begins, ultimately leading to anterior deformation. Therefore, deeper CXL penetration is important to help strengthen the stroma and stop KC progression. However, we are yet to see the necessary penetration with epi-on techniques, even those that make use of enhanced riboflavin solutions. Sufficient treatment penetration to at least 250–300 µm of stromal depth (and the desired stromal stiffening) remains a feature of only conventional epi-on CXL.

Dr Tenen

Whilst epi-on or transepithelial CXL is not the gold standard, it is useful to consider in cases with:

  • thin corneae
  • immunosuppression whereby epithelial debridement may pose an increased risk of infection
  • very young patients who may not tolerate an epi-off approach.

Transepithelial CXL is quick and comfortable and studies have shown clinically significant effects with this technique. In my practice, I have used transepithelial CXL for many years in select cases with excellent results showing approximately 80% of the effect of the full protocol. Of course, patient selection here is key and most patients still receive the Dresden protocol approach.


CPD reflection

  • What did I learn from this CPD activity?
  • Did what I learn meet my learning goals?
  • Has what I learned improved my competence and kept me up to date or built on my knowledge? How?
  • Does what I learned suggest that I could change my practice to improve patient outcomes? How? If not, why?
  • How could/should I change my practice to improve patient outcomes?
  • What do I need to do to implement change in my practice?
  • Do I need to do any further learning to ensure that I am competent and up to date?

  1. Wollensak G. Crosslinking treatment of progressive keratoconus: new hope. Curr Opin Ophthalmol 2006;17(4):356–60. doi: 10.1097/01.icu.0000233954.86723.25.
  2. Wollensak G, Spörl E. Biomechanical efficacy of corneal cross-linking using hypoosmolar riboflavin solution. Eur J Ophthalmol 2019;29(5):474-481. doi: 10.1177/1120672118801130.
  3. Srivatsa S, Jacob S, Agarwal A. Contact lens assisted corneal cross linking in thin ectatic corneas – A review. Indian J Ophthalmol 2020;68(12):2773-2778. doi: 10.4103/ijo.IJO_2138_20.
  4. Mazzotta C, Ramovecchi V. Customized epithelial debridement for thin ectatic corneas undergoing corneal cross-linking: epithelial island cross-linking technique. Clin Ophthalmol 2014;8:1337-43. doi: 10.2147/OPTH.S66372.
  5. Vohra V, Tuteja S, Chawla H. Collagen Cross Linking For Keratoconus. 2021 Feb 15. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan–.
  6. Kohlhaas M, Spoerl E, Schilde T, Unger G, Wittig C, Pillunat LE. Biomechanical evidence of the distribution of cross-links in corneas treated with riboflavin and ultraviolet A light. J Cataract Refract Surg 2006;32(2):279-83. doi: 10.1016/j.jcrs.2005.12.092.
  7. Schumacher S, Mrochen M, Wernli J, Bueeler M, Seiler T. Optimization model for UV-riboflavin corneal cross-linking. Invest Ophthalmol Vis Sci 2012;53(2):762-9. doi: 10.1167/iovs.11-8059.
  8. Podskochy A. Protective role of corneal epithelium against ultraviolet radiation damage. Acta Ophthalmol Scand 2004;82(6):714-7. doi: 10.1111/j.1600-0420.2004.00369.x.
  9. Scarcelli G, Kling S, Quijano E, Pineda R, Marcos S, Yun SH. Brillouin microscopy of collagen crosslinking: noncontact depth-dependent analysis of corneal elastic modulus. Invest Ophthalmol Vis Sci 2013;54(2):1418-25. doi: 10.1167/iovs.12-11387.
  10. Aixinjueluo W, Usui T, Miyai T, Toyono T, Sakisaka T, Yamagami S. Accelerated transepithelial corneal cross-linking for progressive keratoconus: a prospective study of 12 months. Br J Ophthalmol 2017;101(9):1244-1249. doi: 10.1136/bjophthalmol-2016-309775.
  11. Mukhtar S, Ambati BK. Pediatric keratoconus: a review of the literature. Int Ophthalmol 2018;38(5):2257-2266. doi: 10.1007/s10792-017-0699-8.
  12. Ziaei M, Vellara H, Gokul A, Patel D, McGhee CNJ. Prospective 2-year study of accelerated pulsed transepithelial corneal crosslinking outcomes for Keratoconus. Eye (Lond) 2019;33(12):1897-1903. doi: 10.1038/s41433-019-0502-3.
  13. Tian M, Jian W, Zhang X, et al. Three-year follow-up of accelerated transepithelial corneal cross-linking for progressive paediatric keratoconus. British Journal of Ophthalmology 2020;104:1608–1612.

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