Corneal Cross-Linking

Corneal collagen cross-linking with Riboflavin (Vitamin B2) and long-wave UltraViolet A (UV-A) is a surgical treatment for corneal ectasia. Cross-linking (also called C3-R, CXL, CCL, and KXL) is performed to make the cornea more rigid. 

The most common corneal ectasia is keratoconus. Keratoconus has the following characteristics:

See the list below:

• generally believed to be non-inflammatory, although there are numerous recent papers published suggesting that there may be an inflammatory component;
• progressive corneal ectasia;
• increasing irregular astigmatism;
• loss of best corrected visual acuity (BCVA) and may lead to surgery;
• possible scaring and hydrops (acute disruption of Descemet's membrane in the setting of corneal ectasia);
• genetic and environmental causes;
• no curative treatment.

The main benefit of corneal cross-linking is to halt the progression of corneal ectasia (also known as 'kerectasia' or 'keratectasia'). 

The currently accepted medical indications for corneal cross-linking are:

See the list below:

• individuals with keratoconus, with documented progression of corneal ectasia,
• children with keratoconus, who are eye rubbers, and
• individuals with LASIK-induced corneal ectasia.

In post-refractive surgery (LASIK or Radial Keratotomy) ectasia, there are currently no definitive criteria for progression. Parameters which are considered include changes in refraction, uncorrected and best corrected visual acuity, and corneal shape.

Other indications for corneal cross-linking include:

See the list below:

• Pellucid Marginal Degeneration
• Terrien Marginal Degeneration
• Corneal Infection

There are numerous contraindications to corneal cross-linking:

See the list below:

• Corneal thickness of less than 400 microns (may cause irreversible damage to the corneal endothelium)
• Prior herpetic infection (may result in viral reactivation)
• Concurrent infection (although there are now more scientific papers attesting to the efficacy of cross-linking in sterilizing bacterial and fungal corneal ulcers)
• Severe corneal scarring or opacification (the results are uneven and unpredictable)
• History of poor epithelial wound healing
• Severe ocular surface disease (ex. dry eye)
• Autoimmune disorders

Poorer results are noted in the following:

See the list below:

• > 35 years old (the cornea is naturally cross-linked by the UVA from sunlight)
• < 400 micron cornea (possible irreversible endothelial damage)
• Keratoconus Stage III or IV (scarring and opacification)
• Keratometry > 57 D

The most consistent results of observational and randomized controlled studies has been that corneal cross-linking induces a small decrease in keratometry values that appears to be maintained over at least a year. This is a significant finding, inasmuch as progressive keratoconus keratometry typically increases over time. Important corneal cross-linking studies are listed below:

• C.G. Carus University Hospital, Dresden, Germany Study  ^[11]
• Siena Eye Cross Study  ^[12]
• Australian Study  ^[13]
• US FDA Phase III Trials  ^[20]

Complications of corneal collagen cross-linking include:

See the list below:

• temporary stromal edema (< =70%) ^[14]
• temporary haze (< =100%) ^[14]
• permanent haze (< =10%) ^[14]
• corneal scarring ^{[14, 17]}
• sterile infiltrates ^{[14, 17]}
• infectious keratitis: Bacterial/protozoan/herpetic ^{[15, 18, 19]}
• diffuse lamellar keratitis (DLK) ^[16]

Epithelium Off or On?

Should we do transepithelial crosslinking or not?

• Shallower demarcation
• Reduced efficacy

Is it good for children?

Higher UV fluence is better?

Shorter operation time may be achieved by means of UV-fluences between 10 to 15 mW/cm2 and riboflavin in HPMC solution.

Shorter operation time results in a shallower demarcation line.

A standard patient education web and video (animation) session is completed. A corneal cross-linking surgery consent form is read to and signed by the patient and the surgeon.

A detailed history and comprehensive eye examination is performed on each patient. Best potential visual acuity is taken. Ancillary diagnostic eye tests to determine corneal curvature, astigmatism and thickness are performed. The examination includes:

See the list below:

• Detailed medical and ophthalmic history, including weight, allergies, sleep patterns, medical conditions, eye rubbing, eye trauma, contact lens use, prior eye surgeries, changes in visual acuity, changes in prescription eyeglasses.
• Detailed family eye history, heritable disease
• Assessment of ability to lay still flat-on-back for an hour, while staring at a focusing light.
• Uncorrected visual acuity for both distance and near, including pinhole testing.
• Best corrected visual acuity (with current eyeglasses, current contact lenses, manifest refraction) for both distance and near, including pinhole testing.
• External eye examination
• Ocular alignment and motility
• Pupillary function
• Intraocular pressure (IOP) measurement using a Goldmann Applanation Tonometer
• Slit lamp biomicroscopy of the anterior segment (conjunctiva cornea, anterior chamber, iris, lens)
• Dilated eye examination of the posterior segment (lens, vitreous, retina, macula, optic nerve)
• Refraction
• Keratometry
• Corneal Topography
• Optical Coherence Tomography (anterior segment, macula, optic nerve)
• Specular microscopy
• Ultrasonic pachymetry
• Higher order aberrometry

Ultraviolet Light Source

There are numerous ultraviolet light source providers, ranging from the very basic to the highly customizable advanced versions. Here is a list of popular devices:

See list below:

• Avedro  http://avedro.com/medical-professionals/products/mosaic/
• IROC  http://avedro.com/medical-professionals/products/iroc-innocross/uv-x-2000/
• Peschke  http://www.peschketrade.com/products/peschke-cxl/

Riboflavin solutions

There are countless Riboflavin preparations by different manufacturers. Here is a list of the most common preparations by Peschke http://www.skymed.co.il/upload/document/crosslinking/Ribo%20Fact%20Sheet_new.pdf:

See list below:

• Standard Riboflavin Solution with Dextran for epithelium-off procedure: The Dresden Original preparation; 0.1% Riboflavin (Vitamin B2), 20% dextran 500
• Standard Riboflavin Solution without Dextran for epithelium-off procedure: doesn't reduce corneal thickness; 0.1% Riboflavin (Vitamin B2), 1.1% HPMC
• Hypotonic Riboflavin Solution for corneal swelling: to swell thin corneas (< 400 μm) by means of osmotic effect; 0.1% Riboflavin (Vitamin B2)
• Transepithelial Solution for epithelium-on procedure: no removal of the corneal epithelium necessary; significant reduction of pain and danger of postoperative infections; 0.25% Riboflavin (Vitamin B2), 1.2% HPMC, 0.01% Benzalkoniumcloride
• Riboflavin Solution for use with LASIK procedures: for use in connection with LASIK procedures on thin corneas; recommended usage after flap preparation and excimer treatment put 3-5 drops on stroma, put flap back, wait for 3-4 minutes, open flap and rinse off Riboflavin, put flap back and radiate with 1/2 of the recommended energy (1/2 of the time); >=0.23% Riboflavin (Vitamin B2)

Following corneal cross-linking, patients need to be followed to complete visual rehabilitation.

Since we do Epi-Off procedures exclusively, we follow up all patients on:

• Day 1 | to check if the bandage contact lens is still on
• Day 5 to 7 | to remove the bandage contact lens (patient is requested to return to the clinic, when ocular discomfort is at a minimum)
• Months 1, 3, 6 | fluctuating visual acuity is initially large, loss in best corrected visual acuity of 2-3 lines
• Months 9, 12 | best corrected visual acuity returns to pre-corneal cross-linking levels, and may improve to 2-3 lines, may return to rigid gas permeable lenses
• Months 15, 18, 21, 24 | maximum flattening is achieved at 24 months, may have new rigid gas permeable lenses

The procedure is usually done in a clean room, such as a refractive surgery suite. It may also be performed in a sterile room, like an operating theater. Preoperative medications are given in the peri-operative room. Facial and eyelash scrubs for antisepsis using an aseptic technique is completed. The patient is assisted into the operating suite and lies down supine on an operating table. Topical ophthalmic anesthesia, usually proparacaine, is given to the patient. Sterile drapes are placed to keep the eyelashes away from the operative field. A self-retaining bladed eyelid retractor is applied to keep the eyelid open during the entire procedure. BSS is used to wash debris from the conjunctiva. Ultrasonic pachymetry is performed on specific areas of the cornea.

Different techniques of collagen cross linking may be performed.

• Standard Dresden Protocol (Epi-Off)
• Transepithelial cross-linking
• Pocket cross-linking
• Contact Lens-assisted cross-linking
• Accelerated cross-linking
• Athens Protocol (PRK + CXL)
• TG-PRK + CXL
• CXL + ICRS
• Lasik Xtra
• CXL + mini assymetric radial keratotomy
• Photorefractive Instrastromal corneal cross-linking

There are numerous different kinds of Riboflavin which are available for use:

• Riboflavin with Dextran solution is applied to the cornea for 30 minutes.
• Riboflavin with hydroxypropyl methylcellulose (HPMC) solution has better corneal penetration is applied to the cornea for 10 minutes.

At the end of the cross-linking procedure, a bandage contact lens is applied and removed after complete epithelialization. A topical treatment with artificial tears, steroids, and antibiotics is prescribed.

The standard protocol of corneal cross-linking is with epithelium removal. The corneal epithelial layer is removed to increase the penetration of riboflavin into the corneal stroma. Corneal collagen cross-linking involves a 30 minute application of riboflavin solution to the eye that is activated by illumination with UV-A light for approximately 30 or less minutes. The riboflavin causes new bonds to form across adjacent collagen strands in the stromal layer of the cornea, which recovers and preserves some of the cornea's mechanical strength. 

Dresden Protocol

Total treatment time = 60 minutes

Eight to 9 mm central epithelial debridement (Epi-Off technique) with a blunt metal spatula or a soft brush. Photosensitization with an isotonic 0.1% Riboflavin (vitamin B2) mixed with 20% dextran solution, usually for 30 minutes (pre-soak) before irradiation and then every 2 to 5 minutes during irradiation to maintain saturation of the cornea.

Hypotonic riboflavin is used in patients with thinnest pachymetry below 400 μm, with the cutoff level being 350 μm. Ultrasound pachymetry is repeatedly performed during the procedure, and hypotonic riboflavin is administered every 10 seconds during two minutes whenever pachymetry drops below 400 μm. This minimal corneal thickness is maintained throughout the procedure to avoid harmful endothelial side effects that would occur if oxygen radicals were created too deep. Uniform 365nm ultraviolet A (UVA) irradiation at 3 mW/cm2 for 30 minutes, accounting for a surface dose of 5.4 J/cm2. The light causes the riboflavin to fluoresce, leading to the formation of bonds between collagen molecules (collagen crosslinking). The masking of the limbus and/or the treatment zone diameter is carefully selected to protect the limbal stem cells from the toxic effects of oxygen radicals generated by the procedure.

Transepithelial cross-linking technique is also known as epithelium-on (Epi-On) cross-linking technique. The epithelium is left intact in this technique, and a special formalution of riboflavin, supplemented with epithelial penetration enhancers trishydroxymethyl aminomethane and sodium EDTA, is used to allow adequate corneal stroma penetration.

This is usually performed in conjunction with intrastromal corneal ring segment insertion procedures. The instrastromal corneal pocket is directly injected with riboflavin.

This is performed for patients with corneal stromal thickness between 350 µm to 400 µm after epithelial removal. In this method a pre-corneal riboflavin film, a riboflavin-soaked UV barrier-free soft contact lens (90 microns thick) of negligible power and a pre-contact lens riboflavin film are used to decrease UV irradiance to safe levels at the level of the endothelium.

Total treatment time = 14 minutes or less

Accelerated cross-linking: a higher irradiance was delivered to reduce exposure time (i.e., 9 mW/cm2 for 10 minutes or 30 mW/cm2 for 4 minutes instead of 3 mW/cm2 for 30 minutes).

Eight to 9 mm central epithelial debridement (Epi-Off technique) with a blunt metal spatula or a soft brush. Photosensitization with 0.1% Riboflavin (vitamin B2) mixed with saline and HPMC solution, usually for 10 minutes (pre-soak) before irradiation and then every 2 to 5 minutes during irradiation to maintain saturation of the cornea.

1. Riboflavin (vitamin B2) drops are applied to the cornea (10 minute riboflavin pre-soak)
2. The cornea is exposed to ultra violet light (4 minute irradiation with 30mW/cm2365nm UVA)
3. The light causes the riboflavin to fluoresce, leading to the formation of bonds between collagen molecules or collagen cross-linking2

Corneal cross-linking may be combined with:

See the list below:

• photorefractive keratectomy (PRK) | Athens Protocol
• Topography-guided PRK
• LASIK | Lasik Xtra
• intrastromal corneal ring segments
• mini assymetric radial keratotomy

Athens Protocol

The management of keratoconus and post-LASIK ectasia by means of combined, same-day, topography-guided partial PRK and collagen cross-linking. The steps are listed below:

See the list below:

• 6.5 mm phototherapeutic keratectomy to remove 50 μm of epithelium
• topography-guided partial PRK
• mitomycin C (0.025 for 20 seconds)
• CXL procedure

Lasik Xtra

Corneal cross-linking performed in conjunction with LASIK, enhances corneal biomechanical integrity. This combined procedure neither lengthens the operative time of the LASIK procedure, nor does it increase patient discomfort. After the refractive correction has been made in a standard LASIK procedure, 0.22% Isotonic Riboflavin with saline is applied to the exposed stromal bed and the flap is replaced. UVA illumination at 45 mW/cm2 is then applied through the intact epithelium for little over a minute.

Avedro's Photorefractive Intrastromal Cross-Linking (PixL™) procedure provides non-laser low refractive correction with Accelerated Cross-Linking alone, while eliminating the risk of weakening the corneal structure and integrity. PiXL both strengthens the cornea and restores its biomechanical stability, using precise, patterned topography-guided Accelerated Cross-Linking with programmable, customizable illumination patterns.

Low myopic patients, as well as post-cataract patients with low residual refractive errors, may benefit from this procedure.

The goals of pharmacotherapy are to reduce morbidity and prevent complications.

Class Summary

Antimicrobial therapy must be comprehensive and cover all likely pathogens in the context of this clinical setting.

Moxifloxacin ophthalmic (Moxeza, Vigamox)

Moxifloxacin is indicated for treating bacterial conjunctivitis and surgical prophylaxis. It inhibits topoisomerase II (DNA gyrase) and IV enzymes. DNA gyrase is essential in bacterial DNA replication, transcription, and repair. Topoisomerase IV plays a key role in chromosomal DNA portioning during bacterial cell division.

Class Summary

Corticosteroids are used for pseudomembranes and decreased vision and/or glare due to subepithelial infiltrates. They have anti-inflammatory properties and cause profound and varied metabolic effects. In addition, these agents modify the body's immune response to diverse stimuli.

Fluorometholone (Flarex, FML, FML Forte, Flarex)

This agent is used to treat ocular inflammation. Suppresses the migration of polymorphonuclear leukocytes and reverses capillary permeability.

Class Summary

The inhibition of prostaglandin synthesis results in vasoconstriction, a decrease in vascular permeability, leukocytosis, and a decrease on intraocular pressure (IOP). However, these agents have no significant effect on IOP.

Ketorolac ophthalmic (Acular, Acular LS, Acuvail)

Ketorolac ophthalmic inhibits prostaglandin synthesis by decreasing the activity of the enzyme cyclooxygenase. This results in decreased formation of prostaglandin precursors, which, in turn, results in reduced inflammation.

Class Summary

These agents function as tissue lubricants and modulate the interaction between adjacent tissues.

Sodium hyaluronate (Amvisc, Amvisc Plus, Provisc)

Sodium hyaluronate (hyaluronic acid or hyaluronan) is a high molecular mass, biological polysaccharide present in the extracellular matrix of connective tissues and aqueous humor and the vitreous. Also coats the corneal endothelium. It forms a viscoelastic solution in water, which makes it suitable for aqueous and vitreous humor in ophthalmic surgery.