Clinical Applications of Corneal Cross-linking

Review of visual physiology

The cornea is the clear protective outer layer of the eye. Along with the sclera (white of the eye), it serves as a barrier against dirt, germs, and other particles that can harm the eye’s delicate components. The cornea is also capable of filtering out some amounts of the sun’s ultraviolet light.

The cornea also plays a key role in the vision. As light enters the eye, it is refracted, or bent, by the outside shape of the cornea. The curvature of this outer layer helps determine how well the eye can focus on objects close-up and far away.

There are three main layers of the cornea:

  • Epithelium: The most superficial layer of the cornea, the epithelium stops outside matter from entering the eye. This layer of the cornea also absorbs oxygen and nutrients from tears.
  • Boman’s Membrane: Boman’s membrane lies just beneath the epithelium. Because this layer is very tough and difficult to penetrate, it protects the cornea from injury.
  • Stroma: The stroma is the largest layer of the cornea and is found behind the epithelium. It is made up mostly of water and proteins that give it an elastic but solid form.
  • Descemet’s Membrane: It is a membrane that lies between the stroma and the endothelium. The endothelium is just underneath Descemet’s and is only one cell layer thick. This layer pumps water from the cornea, keeping it clear. If damaged or disease, these cells will not regenerate.
  • Endothelium: It is a single layer of cells located between the stroma and the aqueous humor (the clear fluid found in the front and rear chambers of the eye). The endothelium works as a pump, expelling excess water as it is absorbed into the stroma. Without this specialized function, the stroma could become water logged, hazy and opaque in appearance, also reducing vision.
  • * Dua’s Layer: Recent Studies by university of Nottingam, UK suggest discover of a 6th corneal layer (very thin at 15 micron yet very strong layer) found between Stroma and Descents membrane. Further research is undertaken that could potentially re-write the clinical chapters and offer further insight to treatment.

Corneal Diseases & Disorders

The term “corneal disease” refers to a variety of conditions that affect mainly the cornea. These include infections, degenerations, and many other disorders of the cornea that may arise either as a result of heredity, imbalance of enzymes within the cornea, physical damage, or other post-operative implications. Below are some of the most common corneal disorders.


Definition: Keratoconus is regarded as the most common corneal disorder affecting on average 1 in 2000 people. It is a progressive eye disease in which the normally round cornea thins and begins to bulge into a cone-like shape. This cone shape deflects light as it enters the eye on its way to the light-sensitive retina by which it is significantly distorting vision. Keratoconus often occurs in both eyes and typically begins during a person’s teens or 20’s. Data from numerous research institutions suggests the weakening of the corneal tissue that leads to keratoconus may be due to an imbalance of enzymes within the cornea. This imbalance makes the cornea more susceptible to oxidative damage from compounds called free radicals, causing it to weaken and bulge forward. Risk factors for oxidative damage and weakening of the cornea include a genetic predisposition, explaining why keratoconus often affects more than one member of the same family. Keratoconus is also associated with overexposure to ultraviolet rays from the sun, excessive eye rubbing, a history of poorly fitted contact lenses and chronic eye irritation.

Diagnosis and Symptoms: Keratoconus can be difficult to detect, because it usually develops slowly. However, in some cases keratoconus may proceed rapidly. As the cornea becomes more irregular in shape, it causes progressive nearsightedness and irregular astigmatism creating additional problems with distorted and blurred vision as well as glare and light sensitivity problems. Often the keratoconus sufferers experience changes in their eyeglass prescription every time they visit their eye care practitioner. It’s not unusual to have a delayed diagnosis of keratoconus, if the practitioner is unfamiliar with the early-stage symptoms of the disease.

Treatment: In early stage of keratoconus, eyeglasses or soft contact lenses are normally the first treatment, however as the disease continues to progress and the cornea thins and becomes increasingly more irregular in shape, glasses and soft contacts no longer provide adequate vision correction. Presently the treatments for moderate and advanced keratoconus disorders (excluding

Corneal Collagen Cross-Linking include:

Gas & Rigid Contact Lenses (GP or RGP): If eye glasses or soft contact lenses can no longer control keratoconus, then rigid gas permeable contact lenses are usually the next modality of treatment. Their rigid lens material enables GP lenses to vault over the cornea, replacing its irregular shape with a smooth, uniform refracting surface to improve vision. RGP contact lenses can be less comfortable to wear than soft contacts whilst fitting the contact lenses on a keratoconic cornea is very challenging and time-consuming where the patients expect frequent return visits to refine fit and the prescription as keratoconus continues to progress.

Piggyback System: This is a two lens system: an RGP lens is worn on top of a soft lens. The RGP lens provides crisp vision and the soft lens acts as a support base for the RGP.

Hybrid Contact Lenses: The Hybrid lenses combining a highly oxygen-permeable rigid centre with a soft peripheral skirt have been designed specifically for keratoconus and vaults above the eye’s cone shape for increased comfort. Although the hybrid lenses are available in a wide variety of parameters to provide a fit that conforms well to the irregular shape of a keratoconic eye it is still important to consider that as keratoconus progresses they provide an interim option only.

Scleral and Semi-scleral Lenses: Scleral lenses cover a larger portion of the sclera, whereas semi-scleral lenses cover a smaller area. Because the centre vaults over the irregularly shaped cornea, this lens doesn’t apply pressure to the eye’s cone-shaped surface and feels more comfortable. These types of lenses also are more stable than conventional contact lenses, which move with each blink because they only partially cover the cornea. This cone-shaped device resembles a large contact lens and works partly by maintaining a “pool” of fluid on the eye’s surface through which light rays pass and are bent to achieve proper focus. The BSLPD also fills in a highly irregular eye surface with fluid to help achieve proper focus. Although this lens is proving as the most comfortable of all lenses it is important to consider that it too remains as a temporary solution whilst the price of the lens and fitting procedure is in excess of US $6,000 per eye.

Intacs (Corneal Inserts): Intacts are tiny plastic inserts which are placed just under the eye’s surface in the periphery of the cornea and help re-shape the cornea for clearer vision. Intacs have been used in cases when keratoconus patients can no longer obtain functional vision with contact lenses or eyeglasses. The implants also have the advantage of being removable and exchangeable. Studies have shown that Intacs can improve the visual acuity of a keratoconic eye by an average of two lines on a standard eye chart However intacs might only delay but can’t prevent a corneal transplant as keratoconus continues to progress.

Corneal Transplant (Corneal Graft or Penetrating Keratoplasty): It is an invasive surgery which involves the removal of the central portion of the diseased cornea and replacing it with a matched cornea from donor. Corneal transplant has up until now been unavoidable and the final means of treatment of keratoconus once all previous possibilities the have been exhausted. The procedure carries significant pre and post operative risks, and considerably affects the quality of life of those who have undergone the corneal transplant surgery forcing them to take medication for the rest of their life and limits their physical activities. Despite the transplant procedure, the Graft rejection still occurs in 12% to 20% of the patients (Kirkness et al 1990; Troutman and Lawless 1987) whilst despite the risky and invasive nature of the procedure, the corneal graft will typically last for up to 10 years, upon which additional corneal transplant may be required.

Pellucid Marginal Degeneration (PMD)

Definition: Pellucid marginal degeneration (PMD) – is a rare condition whereby the lower cornea becomes thinner and the optic surface of the cornea becomes irregular and the vision becomes blurry. The resulting shape of the cornea is similar to a pregnant belly whereby the lower portion of the cornea protruding forward.

PMD is often misdiagnosed as Keratoconus, although similar, the resulting cornea shape can be quite different. PMD often has cornea sizes similar to that of a regular eye but a very steep curve in the bottom of the cornea. PMD has been observed in families giving it an inherited trait and on occasion it has been observed unilaterally in one eye only. Typically it is bilateral affecting both eyes.

Symptoms: Unlike keratoconus, pain is not normally present, and aside from the visual deterioration, no symptoms accompany the condition. Normally, PMD does not present with vascularisation of the cornea, scarring, or any deposits of the lipid.

Diagnosis: The patient exhibits normal corneal thickness in the centre, with an intact central epithelium, but the inferior cornea exhibits a peripheral band of thinning. Proper diagnosis of PMD can be accomplished with the use of corneal topography (cornea surface shape) and cornea pachymetry (cornea thickness) mapping.

Treatment: Visual acuity cannot usually be corrected with the use of corrected lenses, but success has been shown with the use of rigid contact lenses combined with over-refraction. Patients wearing contacts report increased problems with glare and contrast sensitivity, but it is not clear if this is due to the corneal disease, or the contact lenses themselves. Due to the progressive nature of this disorder further treatment modalities are the same as in cases of keratoconus. The following diagram represents a graphical representation of the cornea with PMD.

Post-lasik Iatrogenic Ectasia

Definition: The development of Iatrogenic corneal ectasia is a well-recognised complication following ablative refractive surgery that is induced accidentally by the refractive surgeon. It is an insidious process and may be seen months after an originally uncomplicated refractive procedure.

These two well-known factors causing iatrogenic keratectasia after LASIK are the removal of excessive amount of tissue from the posterior stromal layers and LASIK done in a previously undiagnosed forme fruste keratoconus.

The progression into frank ectasia is hastened by ablating the central corneal tissue in forme fruste keratoconus and, hence, this is a definite contraindication to LASIK. The following image below on the left is a photo of a patient who had LASIK in 1997. He developed corneal ectasia (bulging) and started losing his vision several years later. The image below on the right shows the protrusion of a cornea which developed post-LASIK ectasia. The abnormal corneal curvature results in severe visual distortion which is not correctable with glasses or soft contact lenses.

Symptoms: The patient with ectasia may experience progressive myopia; effects similar to irregular astigmatism such as ghosting and other distortions; and fluctuating vision.

Diagnosis: Ectasia is diagnosed with corneal topography. It can also be seen in confocal microscopy or Artemis VHF digital ultrasound. Detection of a mild keratectasia requires knowledge about the posterior curvature of the cornea. Posterior corneal surface topographic changes after LASIK are known. Increased negative keratometric dioptres and oblate a sphericity of the PCC, which correlate significantly with the intended correction, are common after LASIK, leading to mild keratectasia.

Treatment: Different techniques have been suggested for the treatment of iatrogenic keratectasia without satisfactory outcomes either biomechanically or visually. In many cases, [corneal transplant] is eventually performed to manage this complication

Bullous Keratopathy

Definition: Bullous keratopathy is most common in older people. Occasionally, bullous keratopathy occurs after eye surgery, such as cataract removal or after placement of a poorly designed or mal-positioned intraocular lens implant, leading to bullous keratopathy. The swelling leads to the formation of fluid-filled blisters on the surface of the cornea. The blisters can rupture causing pain, often with the sensation of a foreign object trapped in the eye, and can impair vision.

Corneal edema is another reason for Bullous Keratopathy, it characterized by the formation of large subepithelial bullae that cause intense pain when they rupture and expose corneal nerves.

Symptoms: Pain associated with bullous keratopathy can be due to swelling of the epithelium with resultant stretching of corneal nerves or rupture of bullae with exposure of corneal nerve endings to an often noxious environment. As the edema progresses, bullae rupture results in pain, photophobia, and epiphora. Subsequent epithelial defects predispose the cornea to infection and can contribute to the development of anterior uveitis.

Diagnosis: The diagnosis of Bullous Keratopathy is based on the typical appearance of a swollen, cloudy cornea with blisters on the surface.

Treatment: Bullous keratopathy is treated by reducing the amount of fluid in the cornea. Salty eye drops (hypertonic saline) can be used to draw the excess fluid from the cornea. Soft contact lenses can be used to decrease discomfort by acting as a bandage to the cornea. If vision is reduced or discomfort is significant and prolonged, corneal transplantation is often done.

Post Intra-stromal Corneal Ring

Definition: Intrastromal corneal rings, also known as intracorneal rings are two small, rainbow shaped pieces of plastic that are implanted in the eye to correct poor vision. Doctor will need to make a small incision in the cornea of the eye, and inserting two crescent or semi-circular shaped ring segments between the layers of the corneal stroma, one on each side of the pupil. The embedding of the rings in the cornea has the effect of flattening the cornea and changing the refraction of light passing through the cornea on its way into the eye.

Symptoms: Symptoms such as photophobia, visual discomfort, eyestrain, and itching diminish or disappear after surgery. Rubbing the eye after surgery can displace the segments and stimulate disease progression. Rubbing could also theoretically change the regularity of the corneal surface, leading to visual acuity loss.

Complications include localized incision-related epithelial defects, epithelial plug formation, wound dehiscence, superficial neovascularisation, surgically induced astigmatism, infiltrates in the channel, transient decreased corneal sensation, and delayed infectious keratitis. Other observations included haze and deposits around the intrastromal channel.

Treatment: Postoperatively, antibiotic-corticosteroid combination drops and/or ointment are typically used.

Corneal Ulcer (Corneal Melting)

Definition: The most common cause of corneal ulcers is germs, but most of them cannot invade a healthy cornea with adequate tears and a functioning eyelid. They gain access because injury has impaired these defence mechanisms. A direct injury from a foreign object inoculates germs directly through the outer layer of the cornea, just as it does to the skin. A caustic chemical can inflame the cornea by itself or so damage it that germs can invade. Improper use of contact lenses has become a common cause of corneal injury. Eyelid or tear function failure is the other way to make the eye vulnerable to infection.

Symptoms: The cornea is intensely sensitive, so corneal ulcers normally produce severe pain. If the corneal ulcer is centrally located, vision is impaired or completely absent. Tearing is present and the eye is red. It hurts to look at bright lights.

Diagnosis: The doctor will take a case history to try to determine the cause of the ulcer. This can include improper use of contact lenses; injury, such as a scratch from a twig; or severe dry eye. An instrument called a slit lamp will be used to examine the cornea. The slit lamp is a microscope with a light source that magnifies the cornea, allowing the extent of the ulcer to be seen. Fluorescein, a yellow dye, may be used to illuminate further detail. If a germ is responsible for the ulcer, identification may require scraping samples directly from the cornea, conjunctiva, and lids, and sending them to the laboratory.

Treatment: A corneal ulcer needs to be treated aggressively, as it can result in loss of vision. The first step is to eliminate infection. Broad spectrum antibiotics will be used before the lab results come back. Medications may then be changed to more specifically target the cause of the infection. A combination of medications may be necessary. Patients should return for their follow-up visits so that the doctor can monitor the healing process. The cornea can heal from many insults, but if it remains scarred, corneal transplantation may be necessary to restore vision. If the corneal ulcer is large, hospitalization may be necessary.

Infectious Keratitis

Definition: Keratitis means inflammation of the cornea. Causes include infection, dry eye syndrome, blepharitis, and autoimmune disorders. Infectious keratitis refers specifically to keratitis caused by a bacterial, viral, or fungal infection. People who wear contact lenses are especially prone to infectious keratitis, and their risk of infection increases as they wear their contact lenses for longer periods. Infectious keratitis can develop into a corneal ulcer if the infection becomes severe.

Symptoms: Patient may experience eye pain, redness, decreased vision, and sensitivity to light. The severity of symptoms may depend on which type of bacterium, virus, or fungus is causing the infection. Some infections may scar the cornea to limit vision. Others may result in perforation of the cornea, (an infection inside the eye), or even loss of the eye.

Treatment: Treatment depends on the cause of the keratitis. Infectious keratitis generally requires antibacterial, antifungal, or antiviral therapy to treat the infection. This treatment can involve prescription eye drops, pills, or even intravenous therapy.

Central Island Prevention

Definition: Central Island is another source of reduction of vision–ghost images or other visual disturbances after LASIK. This is the result of a small raised area in the treatment zone that receives less laser energy and does not obtain full ablation compared to the surrounding tissue. Often, central islands disappear spontaneously after several months, but some require an enhancement procedure where the flap is lifted and a small amount of excimer laser energy is delivered to treat the raised area.

Symptoms: Visual symptoms with central islands are typically monocular diplopia or distortion.

Diagnosis: The diagnosis of a central island is made with the corneal topographer, which produces a digitized contour map of the corneal surface. A colour-coded topographical map can usually identify the raised central island.

Treatment: The first and least invasive technique for central island resolution is the use of contact lenses. If the central island is shallow, soft contacts may do the trick. If the islands are significantly elevated, a Rigid Gas Permeable (RGP) contact lens may be the better choice. This type of lens will “smash down” the island and make a more uniform surface. A technique that may be appropriate to resolve central islands is called CLAPIKS. This is an advanced use of contact lenses and topical eye drops to reshape the cornea.

Extended PRK/EPI/Lasek

Definition: PRK, or photorefractive keratectomy is a laser technique that treats the middle layers of the cornea to correct hyperopia (farsightedness), myopia (nearsightedness) and astigmatism. The purpose of PRK is to reshape the cornea to help the eye to focus at far distances, reducing, or in some cases eliminating, the need for glasses or contact lenses. PRK postoperative possible complications are:

  • Over/under correction
  • Visual acuity fluctuation
  • Halo around light sources
  • Starbursts around light sources
  • Decentred ablation
  • Corneal Haze
  • Epithelium erosion

EPI-LASEK, or laser epithelial keratomileusis, (not a misspelling of LASIK) is simply a modified PRK procedure. Epi-LASEK and PRK are similar; the only difference is that in PRK, the epithelium is removed completely whereas in epi-LASEK the patient’s epithelium serves as its own bandage following the procedure. EPI-LASEK possible complications are:

  • Same as PRK plus
  • Loss of epithelial flap

Treatment: Postoperative infections or inflammation can usually be treated with antibiotics or steroids. Sometimes haze or shifts in refraction may require the use of steroids.


Definition: Keratoglobus is a degenerative non-inflammatory disorder of the eye in which structural changes within the corneacause it to become extremely thin and change to a more globular shape than its normal gradual curve. It causes corneal thinning, primarily at the margins, resulting in a spherical, slightly enlarged eye. It is sometimes equated with “megalocornea.

Symptoms: Vision is characteristically quite poor from the induced myopic astigmatism. As with all irregular astigmatism, glare is a significant problem.

Diagnosis: The corneal diameter may be increased and the cornea is thinned throughout. Unlike Keratoconus, maximal thinning is usually in the mid-periphery. There may be scattered deep stromal opacities and unlike keratoconus. The interior chamber is characteristically very deep, occasionally being up to 5mm deep centrally. As with the other ecstatic dystrophies, hydrops can occur.

Treatment: Keratoglobus continues to be a somewhat mysterious disease, but it can be successfully managed with a variety of clinical and surgical techniques. Large diameter rigid lenses with a reverse geometry or aspheric design are usually required. Unfortunately, due to the whole of the cornea being affected, the fitting of even sclera lenses is more difficult.

Further progression of the disease usually leads to a need for surgery because of extreme thinning of the cornea. Clear lens extraction and implementation of an intraocular lens of very low or even negative power may be useful in reducing the high degree of induced myopia from the increased central corneal curvature. However, this does not address the induced corneal irregular astigmatism.

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