sub400: cross-linking extremely thin corneas

Several strategies have been developed to treat very thin corneas over the years. ELZA’s Medical Director, Farhad Hafezi, has helped to clinically and experimentally verify the effectiveness if these techniques (see below), including swelling the thin cornea to a safe thickness for cross-linking (as described above) (1) contact lens-assisted CXL (CACXL) (2) and the Epithelial Island technique (3) where an island of epithelial cells are left above the thinnest point of the cornea.

Which technique is chosen must be carefully considered on a case-by-case basis. Swelling the cornea can be unpredictable, as each patient’s cornea swells to a different extent. CACXL reduces the strengthening effect by 30%, and epithelial islands result in unpredictable stiffening effects.

ELZA’s clinicians and researchers, led by Professor Hafezi, have developed a new technique for cross-linking thin corneas, that is tailored to each patient’s individual corneal thickness (4). Instead of modifying the cornea, we customise the dose of light delivered to deliver safe and effective cross-linking, even in ultra-thin corneas. 

Our researchers discovered the essential role oxygen plays in cross-linking (5) and modelled how riboflavin, UV light, and oxygen interact in the cornea to cross-link it over time. This resulted in an algorithm, which is fully clinically validated (6), that predicts the depth of cross-linking, and means that surgeons can customise the duration of UV irradiation to achieve a safe depth of cross-linking, even in corneas as thin as 220 µm.

This protocol, named sub400, enables the ELZA Institute to treat ultra-thin corneas, without resorting to methods like artificially thickening the cornea through swelling, leaving epithelial islands or needing a contact lens, helpfully avoiding the drawbacks that have been associated with these methods (i.e. unpredictable effects and sub-optimal corneal strengthening).

In 2021, the sub400 protocol was published in the American Journal of Ophthalmology (4) and has a success rate of nearly 90%.

References

1. Hafezi F, Mrochen M, Iseli HP, Seiler T. Collagen crosslinking with ultraviolet-A and hypoosmolar riboflavin solution in thin corneas. J Cataract Refract Surg. 2009;35(4):621-624.
2. Jacob S, Kumar DA, Agarwal A, Basu S, Sinha P, Agarwal A. Contact lens-assisted collagen cross-linking (CACXL): A new technique for cross-linking thin corneas. J Refract Surg. 2014;30(6):366-372.
3. Mazzotta C, Ramovecchi V. Customized epithelial debridement for thin ectatic corneas undergoing corneal cross-linking: epithelial island cross-linking technique. Clin Ophthalmol. 2014;8:1337-1343.
4. Hafezi F, Kling S, Gilardoni F et al. Individualized corneal cross-linking with riboflavin and UV-A in ultra-thin corneas: the sub400 protocol. Am J Ophthalmol. 2021; 224:133–142.
5. Kling S, Richoz O, Hammer A, et al. Increased biomechanical efficacy of corneal cross-linking in thin corneas due to higher oxygen availability. J Refract Surg. 2015;31(12):840-846.
6. Kling S, Hafezi F. An algorithm to predict the biomechanical stiffening effect in corneal cross-linking. J Refract Surg. 2017;33(2):128-136.