Corneal collagen cross-linking [CXL]

For the treatment of melting corneal ulcers, and bullous keratopathy.

Background:

Corneal collagen cross-linking [CXL] was developed for the treatment of primary and secondary corneal ectatic disease in humans including keratoconus. Between 2003 and 2007 additional indications for CXL were introduced: bullous keratopathy, early Fuch’s dystrophy and the treatment of infectious and non-infectious corneal melting ulcers. The first publication in the veterinary literature was in 2014 when Spiess et al published a paper in the journal “Veterinary Ophthalmology”.1

CXL is a technique that creates intrafibrillar covalent bonds in the collagen fibres of the corneal stroma via the photoactivation of riboflavin by ultraviolet A [UV–A] light.2

Corneal ulcers are a very common problem in dogs, cats and horses and can lead to various degrees of visual impairment including blindness. Corneal melting is caused by the release of both exogenous and endogenous collagenolytic matrix metalloprotease [MMP] enzymes and an imbalance between these proteolytic enzymes and proteinase inhibitors present in the precorneal tear film [PTF] and cornea. Currently, the treatment for melting corneal ulcers involves very aggressive treatment with topical antimicrobials to fight a potential infection as well as anti-collagenase to directly counter the collagenolysis. The inability of clients to medicate frequently enough, patient non-compliance and antimicrobial drug resistance can lead to progressive ulceration and even globe perforation. This may require tectonic surgery leading to extensive corneal scarring or even enucleation.6

Besides the treatment of melting corneal ulcers, CXL has also been used for the treatment of bullous keratopathy.5 A number of conditions can lead to bullous keratopathy including breed related endothelial dystrophy, iris to cornea persistent pupillary membranes, trauma, uveitis, glaucoma and age related endothelial degeneration. The traditional treatment for bullous keratopathy is frequent applications of 5% NaCl drops, this, however, does not lead to significant decrease in stromal oedema and corneal opacification.  Other more invasive treatments include 360-degree conjunctival graft and thermokeratoplasty. Both of these treatments reduce corneal transparency even more. CXL decreases corneal oedema and increases visual acuity in humans.5 A case report by Pot et al describes four dogs suffering from persistent corneal erosions due to bullous keratopathy treated with CXL. The corneal erosions healed within 7 days in all four dogs after treatment and remained so for the follow up period that was 17 months in one patient.5

CXL is induced by introducing riboflavin to the cornea. The riboflavin acts as a photosensitiser when exposed to UV–A light.6 Riboflavin absorbs the UV–A producing reactive oxygen species [ROS]. These free radicals introduce new crosslinks between collagen fibres increasing the biomechanical stability of the cornea.4,6  The free radicals also directly damage and destroy micro-organisms and lead to apoptosis of cells in the irradiated area. 6

CXL

There are however certain risks to the eye from the exposure to UV–A, namely damage to corneal cells including endothelial cells as well as intraocular structures. Riboflavin limits the risks of direct damage, as it limits radiant transmission to deeper ocular structures by absorbing UV–A light.4 In human, porcine and lago corneas damage occurs to a depth of 300ųm with surface irradiation of 3mW/cm2. It is therefore recommended that CXL is only done in corneas thicker than 400ųm as this will prevent damage to the corneal endothelial cells and intraocular structures.6

Method

In dogs and cats, the procedure is done under general anaesthesia. The ulcer is cleaned and the surrounding 2–3 mm of epithelial cells are removed with a scalpel or diamond polisher. 0.1 % Riboflavin solution is applied, 1 drop every 2 minutes for 30 minutes. Penetration of the Riboflavin is then confirmed by visualising the fluorescence of Riboflavin in the anterior chamber with slitlamp biomicroscopy using a cobalt blue light. The cornea is then rinsed and the cornea is irradiated. Various different protocols have been described varying from 3 mW/cm2 for 30 minutes to 30 mW/cm2 for 3 minutes.1,6 The Peschke unit used at the Johannesburg and Cape Animal Eye Hospitals allows irradiation at 45 mW/cm2 for 2 minutes.

Postradiation treatment consists of Tobramycin for 7 days and Atropine drops for 3 days. Post-operative check-up examinations are recommended: 1 day – 3 days – 1 week – 1 month – 3 months.

Horses are treated sedated in a standing position using an auriculopalpebral nerve block as well as intravenous sedation. The remaining CXL protocol remains the same as in small animals.

Postradiation treatment in horses consists of Tobramycin for 7 days, Atropine for 3 days as well as oral Flunixin for 7 – 10 days. Postop re-examinations are similar to small animals.

Contraindications

CXL can lead to Herpesvirus exacerbation in humans.2 In a report by F. Famose, CXL did not lead to any reactivation in two FHV positive cats but there were no signs of active disease at the time of CXL treatment. CXL should not be used in feline patients with active FHV keratitis. CXL is also contra-indicated in corneas thinner than 400ųm as this may lead to endothelial damage or damage to intraocular structures.

Conclusion

CXL offers an alternative treatment for melting ulcerative keratitis, as well as bullous keratopathy. It is non-invasive, requires less frequent and shorter postoperative care and leads to substantially less opacities in the cornea compared to tectonic surgical procedures. This remains a relatively new procedure and more indications and/or other indications or contra-indications may still be discovered.

 

References:

1.  Famose F. Evaluation of accelerated collagen cross-linking for the treatment of melting keratitis in eight dogs. Veterinary Ophthalmology 2014; 17: 358 – 367.

2.  Famose F. Evaluation of accelerated collagen cross-linking for the treatment of melting keratitis in ten cats Veterinary Ophthalmology 2015; 18: 95 – 104.

3.  Gallhoefer S, Spiess BM, Guscetti F et al.  Penetration depth of corneal cross-linking with riboflavin and UV–A [CXL] in horses and rabbits. Veterinary Ophthalmology 2016; 19:275 – 284.

4.  Hellander–Edman et al. Corneal cross-linking in 9 horses with ulcerative keratitis http://biomedicalcentral.com/1746-6148/9/128

5.  Pot SA, Gallhoefer NS, Walser–Reinhardt L et al. Treatment of bullous keratopathy with corneal cross-linking in two dogs. Veterinary Ophthalmology 2015; 18: 168 173.

6.  Spiess BM, Pot SA, Hafezi F. Corneal collagen cross-linking [CXL] for the treatment of melting keratitis in cats and dogs: a pilot study. Veterinary Ophthalmology 2014; 17 1–11.