Corneal Cross-Linking (CXL)

A method aimed at halting the progression of keratoconus — suitability is assessed with Dr. Nejmi Öztürk, ophthalmologist and eye surgeon, at HG Hospital in Kahramanmaraş, Türkiye

What is cross-linking?

Cross-linking (corneal cross-linking, CXL) is the bonding of the corneal fibers to one another, and thereby the stiffening of the cornea (the clear front layer of the eye), by applying riboflavin (vitamin B2) drops to the cornea followed by controlled UV-A light. In this way the corneal tissue weakened by keratoconus becomes more resistant, and an attempt is made to halt the progression of the steepening.

The aim of the method is to halt progression; it does not aim to correct vision. After cross-linking the cornea may flatten by 1–2 diopters in some patients and vision may improve somewhat, but this is a possible side effect rather than a goal. The need for glasses or contact lenses continues after the procedure.

Long-term studies show that progression stops in the great majority of patients; in a small proportion it may continue, and the procedure can be repeated. For the disease as a whole, see the keratoconus treatment page.

Who is cross-linking suitable for?

Cross-linking is suitable for patients with keratoconus whose progression has been documented. Progression is shown by an increase in steepness on corneal measurements taken at intervals, thinning of the cornea or a marked change in the glasses prescription. Because the disease progresses quickly in young people, the procedure is planned without delay.

• Patients with keratoconus in whom progression has been shown on corneal measurements within 6–12 months
• Adolescent and young adult patients; in children, progression may be assumed at the time of diagnosis and an early decision made
• Patients with sufficient corneal thickness (usually at least 400 microns for the standard protocol)
• Patients with corneal weakening (ectasia) that has developed after refractive laser surgery

Who is it not suitable for?

Cross-linking is not suitable for patients whose cornea is very thin, who have a permanent central scar or whose disease is not progressing.

• Thin cornea: In the standard protocol, UV-A light can damage the inner layer of a cornea thinner than 400 microns. In these patients special protocols (corneal swelling drops, lens-assisted application, light duration adjusted to the thickness) are considered.
• Central corneal scar: If there is a scar that blocks vision, the benefit is limited.
• Non-progressive disease: In patients over 35–40 whose measurements have not changed for years, the procedure may not be necessary.
• Active infection, severe dry eye, previous herpes keratitis: UV-A light can reactivate the virus; the decision requires a special assessment.
• Pregnancy and breastfeeding: The procedure is usually postponed until after this period.
• Diseases that impair wound healing: In some rheumatic and immune diseases the balance of risk and benefit is assessed separately.

Which examinations and tests are done before the procedure?

For the cross-linking decision, corneal topography and tomography, corneal thickness measurement (pachymetry) and a full eye examination are done. Because comparison with previous measurements documents progression, it is important to bring your old printouts.

• Corneal topography and tomography: The point of greatest steepness and the front-to-back shape of the cornea are mapped.
• Pachymetry: The thickness at the thinnest point is measured; it determines the choice of protocol.
• Vision and glasses prescription measurement: Recorded for comparison after the procedure.
• Biomicroscope examination: Corneal scarring, dry eye and eyelid inflammation (blepharitis) are assessed; if there is eyelid inflammation, it is treated before the procedure.

How is cross-linking performed?

Cross-linking is performed with anesthetic drops, under operating-room conditions, in about 30–60 minutes; the patient is awake during the procedure and goes home the same day. The two eyes are usually planned in separate sessions.

1. Preparation: Anesthetic drops are applied to the eye; the eyelids are held open with a small device.
2. Removal of the epithelium (in the epi-off protocol): The epithelium, the thin outermost cell layer of the cornea, is gently removed in a central area of 8–9 mm. This allows the riboflavin to pass into the cornea.
3. Riboflavin application: Riboflavin drops are repeated every few minutes so that the cornea absorbs them; this stage takes 10–30 minutes depending on the protocol. The microscope is used to check that the cornea has reached yellow saturation.
4. Thickness check: The corneal thickness is measured again before the light; if necessary, corneal swelling drops are used.
5. UV-A light: The cornea is exposed to UV-A light of a set intensity for 3–30 minutes depending on the protocol. Riboflavin drops continue during this time.
6. Closing: Antibiotic drops are applied and a bandage contact lens is placed on the eye. This lens protects the surface until the epithelium heals.

Pain is not expected during the procedure; a sensation of light, pressure and wetness is normal. Once the drops wear off, particularly in the first 1–3 days, stinging and burning can be marked; pain relief and a drop schedule are given for this.

What is the difference between the standard and accelerated protocols?

In the standard protocol, low-intensity UV-A light is applied for 30 minutes; in accelerated protocols, higher-intensity light is applied for 3–10 minutes. The total light energy delivered to the cornea is kept the same in both approaches. Long-term results are reported to be close to those of the standard protocol; which protocol is used is decided according to the corneal thickness and the physician’s assessment.

Feature	Standard protocol	Accelerated protocol
Riboflavin time	About 30 minutes	About 10–20 minutes
UV-A time	30 minutes, low intensity	3–10 minutes, high intensity
Total procedure time	About 60 minutes	About 30 minutes
Body of evidence	Data with the longest follow-up	Medium- to long-term data are increasing
Suitable situations	Most patients	Patients who cannot stay still for long, children, scheduling considerations

Approaches with (epi-off) and without (epi-on) removal of the epithelium

In the epi-off approach the outer cell layer of the cornea is removed; the riboflavin penetrates the tissue better, and the evidence for halting progression is strongest with this method. In the epi-on (transepithelial) approach the epithelium is left in place; the risk of stinging and infection is lower and healing is faster, but because riboflavin penetration is limited, its effect has been found to be smaller. Newer-generation epi-on protocols are being developed to reduce this difference. Epi-on may be considered for very thin corneas and some pediatric patients; the decision is made together with the physician.

Cross-linking step by step

Forming new bonds between the fibers of the cornea with riboflavin and UV-A, shown schematically on a corneal cross-section.

1. Removing the epitheliumSo that riboflavin can enter the cornea, the outermost layer, the epithelium, is removed in most applications (epi-off). Anesthetic drops are given.
2. Applying riboflavinRiboflavin (vitamin B2) drops are applied at set intervals until they have soaked into the corneal tissue. This stage takes about 20–30 minutes.
3. Applying UV-A lightControlled UV-A light activates the riboflavin. In accelerated protocols the time is shorter while the total energy is kept the same.
4. Bandage lensAt the end of the procedure a protective bandage lens is placed. The epithelium closes within a few days; stinging and watering in the first days are expected.

What is recovery like after cross-linking?

The first 3–5 days after cross-linking pass with stinging, watering and light sensitivity; vision stays blurred for a few weeks, and the cornea becomes stable over months. The timeline below is for the epi-off protocol; with epi-on the first days are more comfortable.

• Day 1: Stinging, burning and watering are marked; the bandage lens is in place. The eye is not rubbed; a dim room and sunglasses bring relief. The surface and the lens are assessed at the check-up.
• Days 3–5: The epithelium heals over; the bandage lens is removed by the physician. The antibiotic drops are stopped; the steroid (cortisone) drops and artificial tears continue.
• Week 1: The stinging largely passes; vision is still blurred. Return to desk work is usually possible.
• Month 1: Vision approaches the level before the procedure. Slight haziness inside the cornea (haze) may be seen; the drops are continued at a reduced dose. Patients who wear rigid lenses usually return to their lenses after this check-up.
• Months 3–6: Vision and the glasses prescription begin to settle; new glasses or lenses are prescribed in this period.
• Month 12: The corneal map is compared with the one before the procedure; whether progression has stopped is assessed with this measurement. Later check-ups are planned yearly.

For patients coming from Elbistan, Afşin, Göksun and the surrounding districts, the day 1 check-up and the bandage-lens removal check-up are planned close to the day of the procedure; for the later check-ups, the travel days are set in advance.

During the first month, swimming pools and the sea, eye make-up, dusty environments and eye rubbing are avoided. Allergy treatment is continued after the procedure; rubbing must be given up.

What does the procedure change in the cornea?

Before and after the procedure: the weakened fiber structure and the newly formed cross-links.

1. Before the procedureThe bonds between the corneal fibers are weak; the tissue is less resistant to outside forces, and the distortion of shape can progress.
2. After the procedureRiboflavin and UV-A form new cross-links between the fibers. The aim is to maintain the existing shape; the cornea does not return to its former state.

What are the risks and limitations?

Cross-linking is generally considered a safe procedure; however, like every interventional procedure it has risks, and the result varies from person to person.

• Temporary reduction in vision: In the first weeks vision may be worse than before the procedure; it usually recovers in 1–3 months.
• Corneal haze: Seen in some patients; it usually settles in 6–12 months and can rarely be permanent.
• Infection: There is a risk of corneal infection while the epithelium is open; it is rare but can be serious. Keeping to the drop schedule and not missing the check-ups reduce the risk.
• Delayed healing of the epithelium: More common in people with dry eye and eyelid inflammation.
• Corneal scarring and damage to the inner layer (endothelium): Rare; when the thickness requirement is respected, endothelial damage is very rare.
• Continued progression: In a small group of patients the disease continues to progress; the procedure can be repeated.

Limitations: Cross-linking does not reverse the existing steepness and irregularity; it does not remove the need for glasses and lenses. Additional methods such as lenses, combined laser or ring segments may be needed to correct vision.

What are the alternatives to cross-linking?

In progressive keratoconus, cross-linking is the method aimed at halting progression; the other methods are aimed at correcting vision and are usually planned together with cross-linking.

Method	Aim	Relationship to cross-linking	Details
Observation only	Monitoring in non-progressive patients	If progression is found, CXL follows	Keratoconus treatment
Contact lenses (RGP, hybrid, scleral)	To correct vision	Can be used from month 1 after CXL	Keratoconus treatment
Combined CXL + topography-guided laser	To reduce the irregularity while halting progression	A form of CXL applied in the same session	Combined CXL and laser
Intracorneal ring segments	To flatten the cone	Often together with CXL; not covered by SGK	Keratoconus treatment
Corneal transplant	To replace the tissue at an advanced stage	At advanced stages where CXL is too late	Corneal diseases

Assessment and planning in Kahramanmaraş

Your suitability for this method is assessed with the examination and measurements at HG Hospital in Kahramanmaraş, Türkiye; the method that suits you is planned together. The keratoconus examination, corneal measurements and progression follow-up are carried out at HG Hospital by Dr. Nejmi Öztürk, ophthalmologist and eye surgeon.

Cross-linking may be covered by SGK under certain conditions; the conditions of coverage (documented progression, age and thickness criteria) are clarified at the consultation. HG Hospital is a private hospital contracted with the Turkish social security institution (SGK); patients with valid SGK coverage may use it, although a private-hospital co-payment may apply. Patients without SGK coverage, such as international patients and visitors from abroad, pay privately or through their private or travel health insurance; the hospital checks coverage before treatment. Fee information is given by the hospital after the examination.

Patients from Elbistan, Afşin, Göksun, Ekinözü and Nurhak come to HG Hospital in the center of Kahramanmaraş for the assessment; Dr. Öztürk does not see patients in Elbistan. The examination and corneal measurements are completed on the same day as far as possible; for travel and planning information, see the Elbistan and the surrounding area page.

Frequently asked questions

Sources

• Turkish Ophthalmological Society — todnet.org
• American Academy of Ophthalmology (AAO) — aao.org
• European Society of Cataract and Refractive Surgeons (ESCRS) — escrs.org
• National Eye Institute (NEI) — nei.nih.gov

Related pages

• Keratoconus treatment
• Combined cross-linking and topography-guided laser
• Corneal diseases
• Information for patients from Elbistan and the surrounding area

This page is for information only; diagnosis and treatment decisions are made after an examination. The results of any surgical or interventional procedure may vary from person to person. You are advised to obtain detailed advice from your physician before any procedure.