Recent Updates In Corneal Collagen Crosslinking.

Dr. Amr Mounir.MDLecturer of OphthalmologySohag University Hospital

Introduction: Corneal collagen cross-linking is a technique

which uses UV light and a photosensitizer to strengthen chemical bonds in the cornea.

The goal of the treatment is to halt progressive and irregular changes in corneal shape known as ectasia.

Corneal collagen cross-linking techniques were developed in Europe by researchers at the University of Dresden in the late 1990's

  Now, CXL is considered as the main treatment option for patients with progressive Keratoconus and post Lasik ectasia

After practicing CXL for several years. Refinement becomes a must.

Recent advances and debates about CXL are needed to discussed

Epi-On Versus Epi-Off

Epithelium-Off vs. Epithelium-On CXL

One of the big questions is whether epithelium-on CXL can provide similar results to crosslinking procedures where the epithelium has been removed (Epi-off CXL)

Advantages of epithelium-on CXL include reduced risk of infection, less corneal haze and fewer delays in epithelial healing.

Due to Epi-off complications ….Epi-on still in mind

How to increase efficacy of Epi-on ??Iontophoresis

Enhanced Riboflavin solutions

Iontophoresis

Iontophoresis consists of the transfer of molecules, with an ionic charge, inside the tissues to treat, thanks to a low intensity electric field.

Iontophoresis increases the penetration power of special type of riboflavin into the underlying epithelium with increase efficacy of Epi-on CXL

The mid-term results (12-18 months) available in scientific literature (Bikbova et al., Acta Oftalmologica; Vinciguerra et al., JRS; Mastropasqua et al., EUCORNEA and ESCRS Congress 2014) show how iontophoresis is an efficacious technique in stabilizing progressive keratoconus (reduction of Kmax, no variation in corneal thickness in the follow-up period) with a moderate inflammatory activation and no cases of haze in the treated patients.

Enhanced Riboflavin solutions

Enhanced Riboflavin solutionsTo increase Riboflavin penetration to the corneal epithelium

Done by increase in riboflavin concentration or using substances increase epithelial disintegration

Customized Crosslinking

Customized Crosslinking to Reshape the CorneaConventional CXL achieves this effect by uniformly stiffening the central 9mm of the anterior stroma.

Customized UVA illumination patterns will allow surgeons to focally stiffen the weakest region of the cornea rather than the conventional approach of uniformly stiffening the entire central cornea.

The Finite Element Method (FEM)

Photorefractive intrastromal cross-linking (PiXL)The device delivers specific light patterns to the cornea based on a patient’s topographic data.

Used for refractive purposes. 

CXL at Slit lamp

The C-Eye device will allow for the treatment of corneal infections at the slit lamp.

Antimicrobial resistance

The graphic shows that by 2050, the WHO expects that more people will die due to antibiotic resistance than to cancer and diabetes combined.

PACK-CXL kills bacteria irrespective of their antibiotic resistance.

Corneal collagen cross-linking (CXL) in thin corneas

In the conventional CXL protocol,A minimum de-epithelialized corneal thickness of 400 μm is recommended to avoid potential irradiation damage to the corneal endothelium

The modified CXL protocolsIn advanced keratoconus, stromal thickness is often lower than 400 μm, which limits the application of CXL in that category So, modified CXL is needed.

SolutionsPower

Thickness

TimeRiboflavin concentration

The modified CXL protocols for thin corneaHypoosmolar riboflavin solution:- The deepithelialized cornea can swell to double its normal thickness when irrigated with a Hypoosmolar solution. - The 0.1 % dextran-free Hypoosmolar riboflavin was then administered until the corneal thickness at the thinnest point reached 400 μm, before the initiation of UVA irradiation.

The modified CXL protocols for thin corneaTransepithelial collagen cross-linking-  By adding the enhancers to help riboflavin penetrate to the

corneal stroma through the intact epithelium, CXL can be performed without epithelial debridement (Transepithelial CXL)

- Thinner corneas can be treated safer by Transepithelial compared to the conventional CXL, since the endothelium is better protected by UVA-filtering effect of the intact epithelium.

The modified CXL protocols for thin corneaCustom epithelial debridement technique- In this modified CXL approach, 8.0 mm diameter of corneal

epithelium was removed; leaving a small, localized area of corneal epithelium corresponding to the thinnest area over the apex of the cone.

- The ability of the epithelium to absorb the UVA radiation may lead to reduced CXL effect in the cone area and affect the efficacy of the whole procedure. Long-term efficacy of this modified CXL procedure with a larger number of patients needs to be assessed.

The modified CXL protocols for thin corneaContact lens-assisted collagen cross-linking

A Soflens daily disposable soft contact lens of 90 μm thickness immersed in isoosmolar riboflavin 0.1 % in dextran for 30 minutes, before it was applied onto the deepithelialized, riboflavin-saturated cornea. The riboflavin solution was instilled every 3 minutes. The pre-corneal riboflavin film with contact lens created an absorption medium in the pre-corneal space by artificially increasing the thickness of the “riboflavin-filter

PACK-CXL for Infectious Keratitis

Effects of PACK-CXL in infective keratitis Cornea :1- Increase the biomechanical strength of cornea2- Stabilize and increase response of cornea todigestive enzymes of pathogens.

Effects of PACK-CXL in infective keratitis Microorganism:

3- Interaction of the chromophore (riboflavin) with the nucleic acids of the pathogen and inhibition of replication.4. Damage to the pathogen’s cell walls caused by massive amounts of Reactive oxygen species (ROS)

Evidence based research:

My experience4 years old boy with infected corneal ulcer with severe AC reaction due to trauma

The patient received topical fortified eye drops and topical antifungal ( Voriconazole) but without response

The decision was to use PACK-cxl as a last option.

Result: No improvement

ConclusionTheoretically, PACK-CXL is effective in infective keratitis but need further evidence based research

Pediatric CXL

KERATOCONUS PROGRESSION Most frequent in younger patients (< 18 years)

Risk of acute KC development (< 16 years) More significant and faster refractive and pachymetric worsening in young patients

25 % progression with CXL

Pediatric Comorbidities

Vernal keratoconjunctivitis (VKC):- Continued surface inflammation and the tendency toward eye rubbing further accelerates keratoconus progression and may lead to advanced disease in young age.- Many eyes with VKC demonstrate partial limbal cell deficiency which may result in delayed epithelial healing after standard CXL treatment.

Advices in pediatric CXL

1- Don't wait for progression Once diagnosed must be crosslinked

2- Hit Hard TE CXL may be of limited

value especially in the pediatric age 

 Standard epithelium off CXL is recommended in pediatric eyes

TE CXL is needed in thin corneas

Epi-off ???? Take care endothelium and infection

3- Frequent screening25 % progression with CXL

4- In ocular allergyNo eye rubbing Don't do CXL in active VKC

Home Message Epi-On CXL is less effective than Epi-Off CXL But the Latter

has more complications. Trials has been mad to increase efficacy of Epi-On CXL by

Enhanced Riboflavin solutions and iontophoresis. Customized UVA illumination patterns will allow surgeons to

focally stiffen the weakest region of the cornea not all the cornea.

Theoretically, PACK-CXL is effective in infective keratitis but need further evidence based research.

Pediatric CXL should be aggressive , don't wait for progression and frequent screening is mandatory.

Thank you