Corneal Cross Linking: Protocols and literature review

Corneal Cross Linking
Protocols and literature
review
Dr. Tukezban Huseynova

v Corneal cross-linking (CXL) is an FDA approved minimally invasive intervention that
utilises ultraviolet (UVA) and riboflavin (vitamin B2)
Definition
v The goal of CXL is the artificial increasing of the degree of cross-links in the corneal
stroma for sufficient mechanical stability
It‘s determined by the
- chemical composition,
- the structure
- organisation of the extracellular matrix
(collagen fibers and ground substance)
2. Wu D., Lim DK., Lim BX., et al. Corneal Cross-Linking: The evolution of treatment for corneal diseases, Front. Pharmacol., 2021
1. Corneal Cross Linking, Drs. Farhad Hafezi and J. Bradley Randleman, 2017

History of CXL
v In the early 1980’s keratoconus was identified as a weak cornea from a biomechanical point of view
v In December 2005, the first commercially available CXL device and riboflavin were delivered by
Peschke and the 1 st International corneal cross linking congress took place in Zurich
v Edmund, Andreassen and Nash performed biomechanical measurements, and they confirmed a lower
Young’s modulus and lower viscoelastic properties in this disease
v It has been assumed that these results are related to the collagen and the proteoglycans
v In 2003 Wolensak et al. introduced CXL as a minimally invasive procedure to halt the
progression of keratoconus
3. Edmund C. Corneal elasticity and ocular rigidity in normal and keratoconic eyes. Acta Ophthalmol (Copenh) 1988;66:134-140.
4. Andreassen TT, Simonsen AH, Oxlund H. Biomechanical properties of keratoconus and normal corneas. Exp Eye Res 1980;31:435-441.
5. Nash IS, Greene PR, Foster CS. Comparison of mechanical properties of keratoconus and normal corneas. Exp Eye Res 1982;35:413-424.
6. Wollensak G, Spoerl E, Seiler T. Riboflavin/ultraviolet – a – induced collagen crosslinking for the treatment of keratoconus. Am. J Ophthalmol 2003;135:620-7

Principles of CXL

Principles of CXL
v CXL (riboflavin + UVA) significantly increases corneal tensile strength and
biomechanical resistance to collagenase digestion
v CXL has multiple effects in the anterior cornea:
- biomechanical stiffening
- increased resistance to proteolysis
- thermostability
- reduced corneal permeability
- anti – hydration effect
- anti – infectious effect
UVA + RF
Photodynamic effect, PDT
v Main components of PDT
- Photosensitizer (RF)
- Light
- Oxygen

The role of Oxygen in CXL
- The decrease the irradiation time
- Epithelium –on treatment
Note: thin corneas have higher oxygen availability, which might reduce the
required amount of UV fluence in advanced KC corneas
v Oxygen is important to induce biomechanical stiffening with CXL
reduces the available tissue
oxygen concentration during CXL
decreases the
therapeutic effect
v The clinical impact will be dependet on the stage and progression of KC

Riboflavin (RF)
2. Spoerl E, Mrochen M, Sliney D, Trokel S, Seiler T. Safety of UVA-riboflavin cross-linking of the cornea. Cornea 2007;26:385-389
v Riboflavin is a photoactivated chromophore that
plays an integral role in facilitating CXL
v Types of riboflavin:
- Hypoosmolar formulation is being used to artificially thicken thin corneas
prior to CXL
- Hyperosmolar formulation is being used to reduce corneal oedema when
treating bullous keratopathy
v RF has a buffer function (riboflavin schielding) against UV – A: absorbs UVA,
thereby reducing the risk of damage to posteriorly located structures
(endothelium, lens and retina)

Riboflavin
Note:
- During Riboflavin/UVA treatment keratocyte apoptosis occured up
to depths ranging from 270 to 350 μm
- This damage appears to be transient as repopulation of
keratocytes with a normal keratocyte dencity within the entire
corneal stroma is being observed at 6 months

Mechanism of Riboflavin action
UVA
Activated riboflavin
Oxidative Pathway Glycosylation Pathway
Type 1
(Non-oxygen mediated)
Type 2
(Oxygen mediated)
Riboflavin radicals Singlet oxygen species
Formation of covalent crosslinks and resultant strengthening of cornea
Advanced glycation end
products-mediated
mechanism

Note: CXL protocols were developed based on the principle:
1. to maximise treatment efficacy, safety and comfort
2. modifications have been made according:
- UVA irradiation
- Riboflavin’s route of administration
- Oxygen supplementation
- And to improve visual acuity

2. Wollensak G, Spoerl E, Reber F, at al. Corneal endothelial cytotoxicity of riboflavin/UVA treatment in vitro. Ophthalmic Res 2003;35:324-8
q Dresden Protocols (Conventional CXL)
Epithelial Debridement Soakage with Riboflavin
(0.1% riboflavin in 20%dextran)
UV radiation (370 nm) at
3 mW/cm² for 30 min
Surface dose achieved 5.4 J/ cm²
Note: Recommended in eyes with corneal thickness of at least 400 microns after de-epithelization to prevent
endothelial toxicity
8-9 mm
Beam Diameter
Epithelium - Off
Oxygen Delivery: Room air
UV-A delivery: 3 mW/cm²; 30 min

CXL - Protocols
UVA - Irradiation

2. Schindl, A., Rosado-Schlosser, B., and Trautinger, F. (2001). Die Reziprozitätsregel in der Photobiologie. Der Hautarzt 52, 779–785
3. Peyman, A., Nouralishahi, A., Hafezi, F., et al., (2016). Stromal Demarcation Line in Pulsed Versus Continuous Light Accelerated Corneal Cross-Linking for Keratoconus. J. Refract Surg. 32, 206–208
4. Mazzotta, C., Raiskup, F., Hafezi, F., et al. (2021). Long Term Results of Accelerated 9 mW Corneal Crosslinking for Early Progressive Keratoconus: the Siena Eye-Cross Study 2. Eye Vis. 8, 16
q UV-A irradiation accelerated protocol
Variable:
- 30 mW/cm² for 3 min
- 18mW/cm² for 5 min
- 9 mW/cm² for 10 minutes
Surface dose achieved
5.4 J/ cm²
Epithelium - Off
based on Bunsen-Roscoe’s law
of photochemical reciprocity

CXL - Protocols
Based on improving Riboflavin delivery

q Riboflavin delivery Transepithelial (TE) protocol
TE-Protocol with:
1. Chemical enhancers
(benzalkonium chloride,
gentamicin, chlorobutanol,
and trometamol)
2. Iontophoresis
3. Femto – second laser TE
with phonophoresis
Challenges:
1. Riboflavin does not penetrate the
intact epithelium
2. An intact epithelium diminishes
oxygen diffusion
3. Demarcation line is approx. 200
micron
Epithelium - On
UV-A delivery: 3 mW/cm²; 30 min/variable
Wu D., Lim DK., Lim BX., et al. Corneal Cross-Linking: The evolution of treatment for corneal diseases, Front. Pharmacol., 2021

Modification of epithelial permability:
- BAC, EDTA, Vit E
- Iontophoresis
- Channel forming peptide
- Mechanical alterations
Modification of application:
- Increase of contact time
- wash away of riboflavin from
the epithelium before
irradiation
Modification of riboflavin solution:
- Without dextran
- Hypoosmolar
- Higher riboflavin concentration
Modification of UV dosage:
- 20% more UV dosage (absorbed
UV light in the epithelium must
be compensated)
Parameters for an effective TE - CXL

q Riboflavin delivery Transepithelial (TE) protocol
Epithelium - On
UV-A delivery: 3 mW/cm²; 30 min/variable
Conclusion: This study showed that although transepithelial CXL was a safe procedure
without epithelial healing problems, 23% of cases showed a continued keratoconus
progression after 1 year. Therefore, at this time, we do not recommend replacing epi-
off CXL by transepithelial CXL for treatment of progressive keratoconus
1. Soeters, N., Wisse, R. P. L., Godefrooij, et al. (2015). Transepithelial Versus Epithelium-Off Corneal Cross-Linking for the Treatment of Progressive Keratoconus: A Randomized
Controlled Trial. Am. J. Ophthalmol. 159, 821–828

CXL - Protocols
Improving oxygen diffusion

2. Gore, D. M., Leucci, M. T., Koay, et al. (2021). Accelerated Pulsed High-Fluence Corneal Cross-Linking for Progressive Keratoconus. Am. J. Ophthalmol. 221, 9–16
- Corneas with thickness <375 μm were excluded
- High-fluence, pulsed UV-A was delivered at 30 mW/cm2
for 4 minutes with a 1.5 s on/off cycle
- The total energy delivered was 7.2 J/cm2
- At 6 and 12 months, modest corneal flattening with
keratometric stabilisation in 98.3% of eyes was noted
- No changes in central keratometry were noted
- Moreover, mean corrected distance visual acuity,
manifest refraction and endothelial cell density did not
change
CXL - Protocols
q Pulsed UV -A
Epithelium – Off/variable

2. Moramarco, A., Iovieno, A., Sartori, A., et al. (2015). Corneal Stromal Demarcation Line after Accelerated Crosslinking Using Continuous and Pulsed Light. J. Cataract Refract. Surg. 41, 2546–2551
- The study compared accelerated CXL using continuous
UVA exposure at 30 mW/cm2 for 4 minutes with
accelerated CXL using pulsed UVA with 8 minutes (1
second on: 1 second off) of UVA exposure at 30 mW/cm2
- Stromal demarcation line was significantly deeper in the
Pulsed UV-A group (213 ± 47.38 μm) compared to
continuous group (149 ± 36.03 μm)
CXL - Protocols
q Pulsed UV -A
Epithelium – Off/variable

2. Mazzotta, C., Bagaglia, S. A., Sgheri, Aet al. (2020a). Iontophoresis Corneal Cross-Linking with Enhanced Fluence and Pulsed UV-A Light: 3-Year Clinical Results. J. Refract Surg. 36, 286–292
- Patients underwent iontophoresis-assisted cross-linking
with riboflavin solution and received UVA irradiation of
18 mW/cm2 of pulsed-light on-off exposure
- At 3 years, the average uncorrected distance visual acuity
improved from 0.50 ± 0.10 to 0.36 ± 0.08 logMAR
- Anterior segment optical coherence tomography showed
that the demarcation lines were situated at an average
depth of 285.8 ± 20.2 µm in more than 80% of patients at
1 month postoperatively
CXL - Protocols
q Pulsed UV -A
Epithelium – On with iontophoresis
q Enhanced – fluence pulsed light Iontophoresis CXL

2. Aydın, E., and Aslan, M. G. (2021). The Efficiency and Safety of Oxygen-Supplemented Accelerated Transepithelial Corneal Cross-Linking. Int. Ophthalmol.
CXL - Protocols
q Pulsed UV -A
Epithelium – On protocol
q Periocular oxygen supplementation
- A randomised, age-sex-matched study
- 0.25% riboflavin was used, 10 J/cm2 (1s: 1s, pulsed)
- Accelerated epithelium-on protocol had a larger
decrease in maximum keratometry values
(p-value = 0.019)
- A significantly deeper demarcation line (320 ±
17 µm) when compared to the control group (269 ±
19 µm)
Oxygen Delivery: Hyperoxic

CXL - Protocols
q Pulsed UV -A
Epithelium – On protocol
q Periocular oxygen supplementation
Oxygen Delivery: Hyperoxic
CONCLUSION:
- Supplementary oxygen increases the oxygen availability during corneal cross-linking.
- At higher irradiances, supplementary oxygen is beneficial and eliminates the bottleneck
of oxygen allowing a potentially more efficient cross-linking.
- The calibrated numerical model can quantify the spatial oxygen concentration related
to different scenarios such as irradiance or environmental oxygen concentration.

CXL - Protocols
Optimising visual acuity

2. Mazzotta, C., Sgheri, A., Bagaglia, etal. (2020b). Customized Corneal Crosslinking for Treatment of Progressive Keratoconus: Clinical and OCT Outcomes Using a Transepithelial Approach
with Supplemental Oxygen. J. Cataract Refract. Surg. 46, 1582–1587
CXL - Protocols
Epithelium – off/Epithelium – on with oxygen supplementation
Oxygen Delivery: Room air/Hyperoxic
q Customized protocol (CurV)
- A total of 27 eyes were included in this study
- Significant improvement in corrected distance visual acuity
with flattening of steep keratometry at their follow-up 6
months after the procedure
- Two demarcation lines were observed at mean depths of
218.23 ± 43.32 µm and 325.71 ± 39.70 µm
- Notably, these demarcation lines were approximately 30%
deeper in this series than previously reported by studies
which utilised epithelium-off CurV protocols
- This suggests the possibility of conducting CurV without the
need for de-epithelisation
UV-A delivery customised according to corneal topography

2. Seiler, T. G., Fischinger, I., Koller, T., Zapp, D., Frueh, B. E., and Seiler, T. (2016). Customized Corneal Cross-Linking: One-Year Results. Am. J. Ophthalmol. 166, 14–21
CXL - Protocols
Epithelium – off/Epithelium – on with oxygen supplementation
Oxygen Delivery: Room air/Hyperoxic
q Customized protocol (CurV)
- One year results showed greater changes in maximum
keratometry values (−1.7 ± 2.0 diopter vs. −0.9 ± 1.3 diopter)
- superior epithelial healing time (2.56 ± 0.50 days vs. 3.19 ±
0.73 days) than patients treated with an epithelium-off
protocol
UV-A delivery customised according to corneal topography

2. Kymionis, G. D., Kontadakis, G. A., Kounis, G. A., et al. (2009). Simultaneous Topography-Guided PRK Followed by Corneal Collagen Cross-Linking for Keratoconus. J. Refract Surg. 25, S807–S811
CXL - Protocols
Topo. – guided transepithelial PRK
folowed by CXL
q Athen’s protocol
UV-A delivery: 10 min; 6mW/cm2

2. Grentzelos, M. A., et al.(2019). Long-term Comparison of Combined T-PTK and CXL (Cretan Protocol) Versus CXL with Mechanical Epithelial Debridement for Keratoconus. J. Refract Surg. 35, 650–655
CXL - Protocols
Transepithelial PRK (tPRK) with CXL
q Cretan protocol
UV-A delivery: 3 mW/cm2 ; 30 min
- A 3 year prospective comparative study of 30
eyes showed visual improvement and
reduction in corneal astigmatism
- Patients who underwent routine epithelium-
off CXL did not experience improvements in
visual acuity or corneal astigmatism

2. Singal, N.,et al. (2020). Comparison of Accelerated CXL Alone, Accelerated CXL-ICRS, and Accelerated CXL-TG-PRK in Progressive Keratoconus and Other Corneal Ectasias. J. Cataract Refract. Surg. 46, 276–286.
CXL - Protocols
Intracorneal Ring segment implantation (ICRS) with CXL
q ICRS with CXL

CXL - Protocols
Anti – Infective application
Photoactivated chromophore for infectious keratitis (PACK)– CXL

CXL - Protocols
Epithelium off
q PACK-CXL
Bacterial Keratitis
Ø Tawfeek et al. 2020
- A higher proportion of patients in the group receiving combination treatment of antibiotics with
PACK-CXL experienced complete resolution of ulcers
- Additionally, the mean resolution period was shorter compared to patients treated with antibiotics alone
Ø Torres Netto et al. 2020
- PACK-CXL alone is as efficient as antimicrobial therapy in small ulcers up to 4 mm in size
2.Tawfeek, M., Ammar, K., Hosny, M., and Enany, H. (2020). “Photo-activated Chromophore for Keratitis (PACK-CXL) as Adjunctive Therapy for Infectious Keratitis: A Prospective Study,” in 38th
Congress of the European Society of Cataract and Refractive Surgeons.
3. Torres-Netto, E. A., Shetty, R., Knyazer, B., Chen, S., Hosny, M., Gilardoni, F., et al. (2020). “Corneal Cross-Linking for Treating Infectious Keratitis: Final Results of the Prospective Randomized
Controlled Multicenter Trial,” in 38th Congress of the ESCRS
4. Corneal Cross Linking, Drs. Farhad Hafezi and J. Bradley Randleman, 2017 (Chapter 34)
2 days after
PACK - CXL
Corneal Cross Linking, Drs. Farhad Hafezi and J. Bradley Randleman, 2017 (Chapter 34)

2. Ting, D. S. J., Henein, C., Said, D. G., and Dua, H. S. (2020). Re: Prajna et al.: Cross-Linking-Assisted Infection Reduction (CLAIR): A randomized clinical trial evaluating the effect
of adjuvant cross-linking on outcomes in fungal keratitis (Ophthalmology. 2020;127:159-166)
3 Hafezi, F., Torres-Netto, E. A., and Hillen, M. J. P. (2021b). Re: Prajna et al.: Cross-Linking-Assisted Infection Reduction: A Randomized Clinical Trial Evaluating the Effect of
Adjuvant Cross-linking on Outcomes in Fungal Keratitis (Ophthalmology. 2020;127:159-166).
4. Wei, A., Wang, K., Wang, Y., Gong, L., Xu, J., and Shao, T. (2019). Evaluation of Corneal Cross-Linking as Adjuvant Therapy for the Management of Fungal Keratitis. Graefes Arch. Clin. Exp.
CXL - Protocols
Epithelium off
q PACK-CXL
Fungal Keratitis
Ø Ting et al. 2020; Hafezi et al. 2021b
- The best spectacle-corrected visual acuity at 3 weeks and 3 months appeared to deteriorate in the
PACK-CXL group
Ø Wei et al. 2020
- They demonstrated that CXL in combination with antifungals accelerated the duration of ulcer healing,
reduced the frequency of administered medications, and significantly reduced the maximum ulcer depth after
treatment

2. Hafezi, F., Mrochen, M., Iseli, H. P., and Seiler, T. (2009). Collagen Crosslinking with Ultraviolet-A and Hypoosmolar Riboflavin Solution in Thin Corneas. J. Cataract Refract. Surg.
3. Stojanovic, A., Zhou, W., and Utheim, T. P. (2014). Corneal Collagen Cross-Linking with and without Epithelial Removal: A Contralateral Study with 0.5% Hypotonic Riboflavin Solution
CXL - Protocols
Thin corneas
Epithelium off (Dextran free riboflavin solution)
q Hypoosmolar Riboflavin
Ø Hafezi et al., 2009
- Corneal swelling occurs due to hydrophilic properties of stromal proteoglycans, which form
“collagen-free lakes” and increases corneal thickness
- Hypo-osmolar riboflavin results in large interindividual variations in corneal swelling duration and
range (swelling duration ranged from 3 to 20 minutes and extent of swelling ranged from 36 to 105 μm)
Ø Stojanovic et al. 2020
- The efficacy of hypo-osmolar riboflavin has been suggested to be less pronounced compared with
standard formulations
Thin Cornea
Hypo-osmolar riboflavin
Swollen Cornea Swollen Cornea
UVA - radiation

2. Jacob, S., Kumar, D. A., Agarwal, A., et al. (2014). Contact Lens-Assisted Collagen Cross-Linking (CACXL): A New Technique for Cross-Linking Thin Corneas. J. Refract Surg. 30, 366–372
2. Kling, S., et al.. (2017). Corneal Cross-Linking with Riboflavin and UV-A in the Mouse Cornea In Vivo: Morphological, Biochemical, and Physiological Analysis. Trans. Vis. Sci. Tech. 6, 7
3. Wollensak, G., Spörl, E., and Herbst, H. (2019). Biomechanical Efficacy of Contact Lens-Assisted Collagen Cross-Linking in Porcine Eyes. Acta Ophthalmol. 97, e84–e90
CXL - Protocols
Epithelium off (Iso-osmolar riboflavin 0.1%)
q Contact – lens assisted CXL (CACXL)
Ø Jacob et al., 2014
- The protocol involved placing an ultraviolet barrier-free soft contact lens (0.09-mm thickness,
14-mm diameter) soaked in iso-osmolar riboflavin 0.1% for 30 minutes on the cornea
- Once the corneal thickness (CT) was confirmed to be greater than 400 μm, UVA irradiation was combined
with administration of iso-osmolar riboflavin 0.1%
- Their study found that CACXL achieved a stromal demarcation line mean depth of 252.9 ± 40.8 μm, with
no significant endothelial loss secondary to UVA toxicity identified
Ø Kling et al. 2017; Wollensak et al., 2019
- The presence of a contact lens over the epithelium creates an artificial barrier that reduces oxygen
diffusion into the stroma, which reduces efficacy of riboflavin and UVA in inducing cross-linking
Thin Cornea
Iso-osmolar RF, 0.1 %
UVA – radiation
+
Iso –osmolar RF 0.1%
Contact Lens
Swollen Cornea
CT > 400 μm
Thin corneas

Decision making for CACXL and AccCXL
Pachymetry > 400 µm
Conventional CXL/Acc.CXL
CL and cornea are soaked in 0.1%
Riboflavin for 30 min
Srivatsa S., Jacob S., Agarwal A. Contact lens assisted corneal cross linking in thin ectatitc corneas – A review. Indian Journal of Opthalm. 2020
Measured Pachymetry
Pachymetry < 400 µm
Functional Pachymetry with CL re-assessed after 30 min
Pachymetry with CL < 400 µm
Pachymetry with CL > 400 µm
CACXL or Acc.CXL (10 mW/cm2 ; 9 min) Add 2 drops of distilled water to minimally swell the cornea
Functional Pachymetry > 400 µm when confirmed
CACXL or Acc.CXL (10 mW/cm2 ; 9 min)

Cagil, N., Sarac, O., Can, G. D., et. Al (2017). Outcomes of Corneal Collagen Crosslinking Using a Customized Epithelial Debridement Technique in Keratoconic Eyes with Thin
Corneas. Int. Ophthalmol. 37, 103–109
CXL - Protocols
Customised pachymetry guided epithelial debridement
q Epithelial Island CXL technique
- The study observed an improvement in uncorrected visual acuity,
best corrected visual acuity, flattest keratometry value and
steepest keratometry values 1 year postoperatively
- However, there was significant endothelial cell density loss
(2550 ± 324 vs 2030 ± 200 cells/mm2) 1 year postoperatively
What is epithelial island CXL?
- Epithelial debridement over areas of thicker cornea
- Undebrided epithelium (“Island”) over the thinner apical area
- Once Riboflavin is applied, the “island” protects the thin
cornea from UVA
Thin corneas

Cagini, C., Riccitelli, F., Messina, M., Piccinelli, F., Torroni, G., Said, D., et al. (2020). Epi-off-lenticule-on Corneal Collagen Cross-Linking in Thin Keratoconic Corneas. Int. Ophthalmol. 40,
CXL - Protocols
Epithelium off
q Epi – off – lenticule - on CXL
What is Epi – off – lenticule – on CXL?
- Riboflavin was applied on a donor corneal lenticule instead
of being applied directly onto the debrided corneal
epithelium
Ø Cagini et al., 2020
- Visual acuity and endothelial cell density remained stable over a 12 month follow-up duration
- Demarcation line was seen in all patients by 6 months of follow-up
Thin corneas

Hafezi, F., Kling, S., Gilardoni, F., et al. (2021). Individualized Corneal Cross-Linking with Riboflavin and UV-A in Ultrathin Corneas: The Sub400 Protocol. Am. J. Ophthalmol. 224, 133–142.
CXL - Protocols
Epithelium - off
q Sub400 protocol
UV-A delivery: adjusted according to the corneal thickness
to achieve a safe depth of CXL 70 micron away from the
endothelium
Ø Hafezi et al., 2021
- There was a significant improvement in corneal maximum keratometry values (−2.06 ± 3.66 diopters)
- No changes in corrected distance visual acuity
Thin corneas

CXL - Protocols
Paediatric Cornea

CXL - Protocols
Pediatric Cornea
Ø KC in the pediatric population is often more aggressive than in older age groups
Ø Epi-off CXL seems to be efficient for the first 2 years after CXL, but there is a controversy
about the longevity of the effect
Ø TE – CXL, although less efficient, may be considered in selected cases
What is known:
Why may CXL not work in some patients?
Ø Genetic Influence
Ø The biomechanical behaviors may be altered
Ø Atopy
Ø Allergy
Ø Further progression of KC
Corneal collagen cross linking, Mazen M.Sinjab, Arthur B. Cummings, 2017

Other indications for CXL
q LASIK Xtra and SMILE Xtra
CXL - Protocols
q Hyper – osmolar riboflavin
1. Konstantopoulos, A., Liu, Y.-C., Teo, E. P., et. Al (2019). Corneal Stability of LASIK and SMILE When Combined with Collagen Cross-Linking. Trans. Vis. Sci. Tech.Vis. Sci. Technol. 8, 21.
2. Kohnen, T., et al. (2020). Comparison of Femto-LASIK with Combined Accelerated Cross-Linking to Femto-LASIK in High Myopic Eyes: A Prospective Randomized Trial. Am. J. Ophthalmol. 211, 42–55
3. Hafezi, F., Dejica, P., and Majo, F. (2010). Modified Corneal Collagen Crosslinking Reduces Corneal Oedema and Diurnal Visual Fluctuations in Fuchs Dystrophy. Br. J. Ophthalmol. 94, 660–661
- Variable short term results reported.
Longer termed and larger scale
studies required
- Reduction of central corneal
thickness and visual acuity observed
in patients with bullous keratopathy

Contraindications for CXL
v Pregnancy
v Breastfeeding patient
v Prior herpetic eye infection
v Active ocular inflamation
v Severe central or paracentral scars
v Autoimmune disorders
v History of poor epithelial wound healing
v Corneal thickness < 400 µm (is still relative contraindication)

Complications after CXL

v Transient corneal haze - is a secondary condition due to increased collagen fibre
diameter post – CXL
- This is not associated with visual disturbances and
often regresses after 12 months
v Persistent corneal haze - Lasts beyond 12 months
- Negatively impacts visual acuity
- Thought to be secondary to the ongoing keatectasia and
corneal remodeling
Risk factors
- KC with minimal CT < 400 µm
- Presence of preoperative
activated keratocytes in the
anterior stroma (confocal
microscopy)
Pre - Op
- Defocus of UVA source
- Lack of Riboflavin 0.1 % during
irradiation
- Excessive riboflavin dextran
20% solution (dehydration)
Intra - Op
- Non-compliance with topical
corticosteroid therapy
- Infective keratitis
- Therapeutic lens intolerance
- Presence of Langerhan cells after
CL removal
Post - Op
2. Kozobolis, V., et al. (2016). Effect of Riboflavin/UVA Collagen Cross-Linking on Central Cornea, Limbus and Intraocular Pressure. Experimental Study in Rabbit Eyes. Acta Med.
(Hradec Kralove, Czech Repub.) 59, 91–96

Other complications for CXL
v Sterile Infiltrate
v Infectious keratitis
v Persistent epithelial defect
v Stromal scaring
v Corneal melt
v Corneal endothelial decompensation
v Damage to the lens or retina
v Late onset of peripheral keratitis
1. Tzamalis, et al. (2019). Bandage Contact Lens and Topical Steroids Are Risk Factors for the Development of Microbial Keratitis After Epithelium-Off CXL. BMJ Open Ophth 4
2. Wollensak, G., Spoerl, E., and Seiler, T. (2003a). Riboflavin/ultraviolet-a-induced Collagen Crosslinking for the Treatment of Keratoconus. Am. J. Ophthalmol. 135, 620–627
3. Chanbour, W., Mokdad, I., Mouhajer, A., and Jarade, E. (2019). Late-Onset Sterile Peripheral Ulcerative Keratitis Post-Corneal Collagen Crosslinking. Cornea 38, 338–343

Sterile infiltrate 1 day after CXL
Corneal Cross Linking, Drs. Farhad Hafezi and J. Bradley Randleman, 2017 (Chapter 21)
Stromal scar after CXL
Non-healing epithelial defect

Future of CXL
q Dose - response
Riboflavin
UVA
Oxygen
Understanding the relationship between UVA, riboflavin and oxygen
q Diagnostic Tools
Ø Clear understanding of corneal epithelial mapping
Ø To develop machine learning algorithms which identify subclinical KC
Ø More research on genes and predisposing factors
Ø Standardized guidelines and protocols for treatment
Wu D., Lim DK., Lim BX., et al. Corneal Cross-Linking: The evolution of treatment for corneal diseases, Front. Pharmacol., 2021

v Rose Bengal (RB)
q Alternative Agents
Future of CXL
- Light activated RB can be used to seal wounds in cornea
- To bond amniotic membrane to the corneal surface, and for applications in many
other tissues
- CXL was evaluated by RB + green light (RGX)
- RGX initiated CXL did not decrease keratocyte viability
1. Gu C, Ni T, Verter EE, Redmond RW, Kochevar IE, Yao M. Photochemical tissue bonding: a potential strategy for treating limbal stem cell deficiency. Lasers Surg Med. 2011;43(5):433–42.
2. Tsao S, Yao M, Tsao H, Henry F, Zhao Y, Kochevar J, et al. Light-activated tissue bonding for excisional wound closure: a split-lesion clinical trial. Br J Dermatol. 2012;166(3):555–63.
3. Verter EE, Gisel TE, Yang P, Johnson AJ, Redmond RW, Kochevar IE. Light-initiated bonding of amniotic membrane to cornea. Invest Ophthalmol Vis Sci. 2011;52(13):9470–7.
4. O’Neill AC, Winograd JM, Zeballos JL, Johnson TS, Randolph MA, Bujold KE, et al. Microvascular anastomosis using a photochemical tissue bonding technique. Lasers Surg Med. 2007;39(9):716–22.

Thank you
Eye_dr_tuti
Eye_dr_tuti

Corneal Cross Linking: Protocols and literature review

Recommended

Recommended

More Related Content

What's hot

What's hot (20)

Similar to Corneal Cross Linking: Protocols and literature review

Similar to Corneal Cross Linking: Protocols and literature review (20)

More from Tukezban Huseynova, MD

More from Tukezban Huseynova, MD (16)

Recently uploaded

Recently uploaded (20)

Corneal Cross Linking: Protocols and literature review