NICE Guidelines on CXL Photochemical corneal collagen cross-linkage using riboflavin and ultraviolet A for keratoconus and keratectasia Issued: September 2013 NICE interventional procedure guidance 466

1.1 Current evidence on the safety and efficacy of epithelium-off CXL for keratoconus and keratectasia is adequate in quality and quantity. Therefore, this procedure can be used provided that normal arrangements are in place for clinical governance, consent and audit. Recommendations

1.2 Current evidence on the safety and efficacy of epithelium-on (transepithelial CXL, and the combination (CXL-plus) procedures for keratoconus and keratectasia is inadequate in quantity and quality. Therefore, these procedures should only be used with special arrangements for clinical governance, consent and audit or research.

1.3 Clinicians wishing to undertake epithelium-on (transepithelial) CXL, or the combination (CXL-plus) procedures should take the following actions: A. Inform the clinical governance leads in their NHS trusts. B.Ensure that patients and their parents or carers understand the uncertainty about the efficacy and safety of the procedures in the long term and provide them with clear information. In addition, the use of NICE's information for the public is recommended. C.Audit and review clinical outcomes of all patients having these procedures for keratoconus and keratectasia.

1.4 Patient selection for these procedures should include assessment of corneal thickness and consideration of the likelihood of disease progression. 1.5 The procedures should only be carried out by ophthalmologists with expertise in managing corneal disease and specific training in the use of ultraviolet light or by appropriately trained staff under their supervision.

1.6 NICE encourages further research into CXL using riboflavin and UVA for keratoconus and keratectasia, especially epithelium-on (transepithelial) CXL and the combination (CXL-plus) procedures. Details of the techniques used should be clearly described. Reported outcomes should include visual acuity, corneal topography and quality of life. Data on long-term outcomes for all types of CXL using riboflavin and UVA for keratoconus and keratectasia would be useful – specifically data about prevention of progression to corneal transplantation and about repeat procedures and their efficacy.

The Procedures CXL was first developed in 1998 by Theo Seiler MD. Epithelium-off CXL Pre op drops, LA, Riboflavin A (0.1%) drops 1-5 min for min+/- BSS, AC Level, Lid speculum, Epithelium off, UVA ( um) at 1-5cm distance from corneal apex for 30 min BCL, Post op drops (Antibiotic +NSAIDs+/- Steroids) Epithelium-on (transepithelial) CXL CXL-plus Intracorneal ring segment (ICRS) implantation Photorefractive keratectomy (PRK) Phakic intraocular lens (PIOL) implantation

The aim of corneal crosslinking is to strengthen the cornea by increasing the number of "anchors" that bond collagen fibers together. (Diagram: Boxer Wachler Vision Institute) How does it work?

Corneal crosslinking strengthens bonds in the stroma of the cornea, which is the layer from which tissue is removed during LASIK surgery What does it do?

U.S. Olympic bobsledding champion Steve Holcomb overcame a heart breaking diagnosis of legal blindness that threatened to rob him forever of his lifelong dream of winning an Olympic gold medal 2007-Dr Brian Wachler did CXL-Plus for Steve who won Feb.2010, Vancouver Winter Olympic

Corneal collagen cross-linking eligibility criteria: Baseline data collection by Mr Philip Jaycock Please ensure that patients have Pentacam scans and refraction with contact lenses out for: i. RGP’s: minimum 2 weeks ii. Soft: minimum 1 week Patient Selection, Indications and Contraindications

Inclusion criteria (evidence of progression ): i. >1.00 D change in refractive astigmatism, OR ii. >1 line loss of corrected distance visual acuity, OR iii. >1.50 D increase in central steep anterior keratometry (Pentacam [K2] or other topography (eg. SimK), OR iv. >1.50 D increase in Kmax (Pentacam), OR v. >0.50 D increase in steep posterior K2 (Pentacam), OR vi. >13 microns decrease in central or minimum corneal thickness (Pentacam), OR vii. Previous LASIK with ectasia NB. Comparison should be with baseline (not simply previous visit). K2 = steep curvature in the central 3mm zone; there is no upper limit of Kmax (steepest point over the entire scanned anterior corneal surface).

Exclusion criteria:(Contraindications) i.Active ocular surface disease (e.g. Severe Dry Eye) ii. Pachymetry at thinnest location (epithelium on) < 375 microns iii.Significant corneal scarring iv.A history of previous herpes simplex keratitis is a relative contraindication. These patients may be given Acyclovir cover v.Poor epithelial wound healing vi.Autoimmune disorder For patients referred at 1st presentation please attach evidence of altered refraction or topographic changes indicating progression in line with the inclusion criteria above + baseline Pentacam scan.

Efficacy and Safety (Consent Info) Efficacy: (Outcomes) 1. Epithelium-off CXL: (meta-analysis data from systematic review) 1. Topography (maxK, meanK,minK) 2. CVA & UCVA 3. Astigmatism 4.SE 5.central corneal thickness 6. IOP 2. Epithelium-off CXL in combination with other interventions (CXL-plus): 1.CXL+ICRS & ICRS+CXL (48 eyes) 2.PRK+CXL (42) 3.CXL+PIOL (11) 3. Epithelium-on (transepithelial) CXL with or without additional interventions (CXL-plus): 1.Epi-on CXL (51) 2.Epi-on CXL+ICRS (14) 3.ICRS+Epi-on CXL (21)

Efficacy outcomes listed by specialist advisers: 1. Arrest of progression of keratoconus 2. Stabilization of corneal shape measured by; Topography, refraction and keratometry, refractive astigmatism, change in corneal thickness, cone apex power, quality of life and contact lens independence. Efficacy and Safety (Consent Info)

Safety: (Complication or Adverse Events) 1. Infections: 8- cases, 4-resloved,1-VA reduce, 3-unknown 2. Sterile Keratitis with scarring /loss of vision/needing keratoplasty in 3% (4/117): 2 patients reduced BCVA 3. Stromal Scar: 4-cases only 1 needed correction with lens 4. Corneal Oedema 24/12, Inflammation 2-3/52, Iris atrophy and pigment dispersion. 5. Corneal melting - 1 case, Perforation- 2 cases

6. Corneal burn and ulcer- 3 cases 7. Corneal haze with diffuse subepithelial opacification and paracentral thinning with scarring- 1 case 8. Stromal Haze- 10/10 cases ICRS+CXL on same day & ICRS+CXL after 6/12 (Temporary stromal oedema (70%), temporary haze (up to 100%), and permanent haze (10%) 9- Anecdotal AE: delayed epithelial healing, bilateral corneal infection, transient recurrent erosion syndrome, perforation after procedure- 1 case Efficacy and Safety (Consent Info)

6.1 The Committee noted that these procedures may be useful for some disabled people who have keratoconus or keratectasia and who would need to wear contact lenses, but are unable to do so. 6.2 The Committee noted that the primary aim of the procedures is to stabilise vision by halting progression of keratoconus or keratectasia but that many of the studies reported improvement of vision as a secondary outcome. Committee comments

6.3 The Committee noted that CXL techniques and precise treatment regimens are continuing to develop and evolve. 6.4 The Committee noted commentary from a patient group describing the serious impact that keratoconus or keratectasia can have on employment and quality of life. The Committee recognised the potential benefits that these procedures might offer, if further evidence supports their efficacy. Committee comments

Mr Muhammad Asalm Razzaq Locum Consultant Ophthalmologist, NDDH, Barnstaple. Questions? Thank You