Corneal cross-linking (CXL) for keratoglobus

Keratoglobus is a special corneal thinning disease that differs from keratoconus in one important way: instead of a single point of thinning of the cornea (which results in a bulging and the development of a cone), the cornea in people with keratoglobus is thin everywhere in topography.1

The causes of keratoglobus are still unclear. Treatment options for keratoglobus were limited until recently: corneal transplant surgery is a good option in patients with advanced keratoconus, but it is riskier to perform in patients with keratoglobus. Full-thickness corneal transplants result in problems placing the corneal sutures (into a thinner, less stable region of the existing cornea increasing the risk of failure) and partial-thickness (“lamellar”) transplants often have problems with small perforations and issues where the transplant meets the patient’s cornea, loss of immune privilege (meaning that the patient will require to take immune suppressing eyedrops for the rest of your life), and these procedures can fail and can require multiple surgeries to successfully treat the patient.2,3

If corneal cross-linking (CXL) can treat keratoconus and reduce the number of corneal transplants, can it also do the same in keratoglobus?

Cross-linking thin corneas

The first hurdle to be cleared is the fact that keratoglobus corneas are extremely thin – often far thinner than in keratoconus. However, the problem of cross-linking thin corneas in keratoconus has been tackled in a number of ways: artificially swelling the cornea with hypotonic riboflavin before cross-linking to make it thick enough to safely cross-link;4 placing a riboflavin-soaked contact lens,5 or instead of removing the epithelial cells at the top of the cornea before soaking the layer underneath (the stroma), the surgeon instead leaves an island of epithelium cells above the thinnest point. However, the first approach can lead to unpredictable swelling, the second results in around a 30% lower strengthening effect (oxygen is required during the cross-linking reaction, and the contact lens acts as a barrier to oxygen entry),6 and the epithelium island approach can result in unpredictable stiffening effects.

Alter the irradiation, not the thickness

Rather than modifying thickness, the alternative approach is to modify the total UV energy delivered to the cornea, so the cornea is cross-linked, but still leaves a 70 µm un-cross-linked safety margin at the bottom of the cornea to protect the endothelial cells underneath. Our research group has previously characterized the diffusion of both riboflavin and oxygen into the cornea, the effect of UV light intensity, and correlated it all to the depth of the cross-linking effect.7 In essence, the algorithm we developed means we can measure the thickness of a cornea before cross-linking and use the algorithm to determine the duration of UV irradiation required to generate the desired cross-linking depth, individualized to each patient’s cornea. This approach, called the “sub400 protocol”8 has now been tested in a monocentric study, and the one-year results in nearly 50 eyes with keratoconus, with the thinnest cornea being 214 µm, have now been published in the American Journal of Ophthalmology, with a success rate of nearly 90%.

First successful CXL in keratoglobus

Recently, we reported the first case of CXL, using the sub400 protocol, in a cornea with keratoglobus that, at its thinnest point, had a pre-irradiation (post-abrasion/ riboflavin saturation) thickness of 231 µm.9 The UV irradiation duration was 2 minutes, according to the sub400 protocol algorithm. The treatment was a success: the epithelial cells had completely repopulated after 8 days, and the patient’s keratometry (corneal shape) remained stable at his most recent check-up, 32 months after the procedure, and with scleral contact lenses, the patient can achieve 20/20 vision when spectacles are worn. Based on this treatment success, CXL using the individualized sub400 protocol could become a more widespread treatment option for the eyes of patients with keratoglobus.

References

  1. Wallang BS, Das S. Keratoglobus. Eye (Lond). 2013; 27(9):1004–1012.
  2. Rathi VM, Murthy SI, Bagga B, Taneja M, Chaurasia S, Sangwan VS. Keratoglobus: an experience at a tertiary eye care center in India. Indian J Ophthalmol. 2015; 63(3):233–238.
  3. Karimian F, Baradaran-Rafii A, Faramarzi A, Akbari M. Limbal stem cell-sparing lamellar keratoplasty for the management of advanced keratoglobus. Cornea. 2014; 33(1):105–108.
  4. 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.
  5. 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.
  6. 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.
  7. Kling S, Hafezi F. An algorithm to predict the biomechanical stiffening effect in corneal cross-linking. J Refract Surg. 2017;33(2):128-136.
  8. 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.
  9. Hafezi F, Torres-Netto EA, Randleman JB, et al. Corneal cross-linking for keratoglobus using individualized fluence. Journal of Refractive Surgery Case Reports. 2021;1(1).

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