Overview of Collagen Cross Linking for Keratoconus
Keratoconus (KC) is a fairly common eye condition that affects the clear, dome-shaped tissue at the front of the eye called the cornea. The condition causes the cornea to thin and bulge out in the center. This distortion of the cornea is due to changes in the structure of a protein called collagen found within the eye. This can alter vision, often causing short-sightedness and irregular eye shape. KC usually starts affecting people in their teens or twenties, and typically involves both eyes, though one may be affected earlier than the other.
We’re not entirely sure what causes keratoconus but we know it can be linked to a range of other conditions, including some types of blindness at birth, allergic conditions, Down’s syndrome, and certain disorders that affect the connective tissues in the body like Ehlers-Danlos and Marfan syndromes.
There are specific clues doctors look for to diagnose KC. One sign is when the lower eyelid bulges out in a V shape when you look downwards (this is called Munson’s sign). Another hint for doctors can come from an examination using a slit-lamp microscope which can reveal faint, vertical stress lines in the eye’s tissue and a ring of iron near the edge of the cornea (called Vogt striae and a Fleischer ring, respectively). Some doctors use a light and a small, handheld lens to inspect your retina – revealing a ‘scissor’ type reflex, or an ‘oil-drop’ effect.
Advanced techniques like Placido-disc topography, Scheimpflug imaging, and Optical Coherence Tomography can provide more precise details about your cornea. The Amsler-Krumeich system is a commonly used grading system for KC based on multiple factors like the severity of the refractive error, central corneal curvature and thickness, and scarring. There are also several other indices proposed to detect early KC subtler than what can be detected in routine clinical examination.
Early stages of KC can usually be treated with glasses, and as the condition worsens, patients might need to use hard, gas-permeable contact lenses. A small number of patients may reach a point where they need corneal transplant surgery. However, newer treatments like lamellar surgery and cross-linking therapy with Ultraviolet A (UV-A) light and riboflavin (Vitamin B2) have shown promise in delaying more invasive treatments and slowing down the disease progression.
The latter treatment—UV-A and riboflavin cross-linking therapy—has been used since the late 1990s. The technique uses riboflavin as a kind of ‘light-activator’, and when exposed to longer wavelength UV-A light, it triggers a chemical reaction within the collagen molecules in the eye. This reaction forms stronger bonds between the collagen fibers increasing the overall strength and rigidity of the cornea, thus preventing it from becoming thinner and more distorted.
Anatomy and Physiology of Collagen Cross Linking for Keratoconus
The cornea, the clear front surface of the eye, is made up of multiple layers with different properties. Each layer is composed of distinct substances that have differences in density. A healthy cornea can transmit about 80% of visible light. Layer by layer, these are what makes up the cornea:
1. Tear Film: This is the outermost layer of the cornea, composed of lipids (fats) and water. A layer of protein about 3 micrometers thick helps lubricate and protect the cornea, and maintains a smooth surface for incoming light.
2. Epithelial Layer: Underneath the tear film, this layer does not have a continuous protein structure.
3. Basement Membrane: Just below the epithelial layer, this layer is just barely 0.3 micrometers thick and made of collagen (a protein) and laminin (a substance that helps cells stick together).
4. Bowman’s layer: This is an 17 micrometer, acellular layer made of randomly arranged collagen fibers.
5. Stroma: The bulk of the cornea is composed of this layer, which can differ in thickness between individuals. It contains densely arranged collagen fibrils that are organized into lamella, which run parallel to the cornea’s surface.
6. Dua’s or Pre-Descemet’s layer: Similar to stroma tissue, has a different proteoglycan arrangement due to more lamella and space between the collagen fibrils.
7. Endothelial layer: This layer, formed by endothelial cells, is just 3 micrometers thick.
8. Endothelial cells: These form a monolayer and don’t have a continuous protein network.
The manner in which these different fibers and proteins are packed is crucial to maintaining clear vision. Proteoglycans (proteins that have chained sugars called GAG attached to them) help maintain the necessary spacing between these components.
These layers have different materials like collagen, laminin, fibers, and fibronectin that form strong fibers and a solid network. There are also elastin, which helps the cornea tolerate strain without permanent deformation.
Understanding the structure and substances that make up these layers helps doctors make predictions about its behavior, particularly during surgeries. For example, the tear film and cell layers are suspected of having little impact on the cornea’s strength, since they don’t have a regular protein structure. The stroma, an interwoven layer of corneal lamellas, contributes significantly to the cornea’s strength. It’s important for doctors to note that these properties can change with the depth of the cornea, which can impact surgical planning.
Why do People Need Collagen Cross Linking for Keratoconus
Keratoconus is a condition where the cornea, the clear front surface of the eye, thins out and bulges like a cone. This can affect vision and is one of the common reasons why people might be recommended for a treatment called corneal cross-linking (CXL). Other conditions that might also require CXL are pellucid marginal degeneration and Terrien marginal degeneration, or complications following eye surgeries like LASIK, PRK, or radial keratotomy.
When doctors consider whether CXL is necessary, they often look for signs that these conditions are getting worse, but this process can be a bit tricky because there’s no strict guidelines to follow. However, an influential group of experts, called the Global Delphi Panel of Keratoconus and Ectatic Diseases, advises to look for at least two of the following changes: more curving of the front or back layers of the cornea, or corneal thinning.
Based on previous research, other signs that might suggest conditions are progressing can include an increase in the steepest curvature of the cornea (Kmax value), increased nearsightedness or astigmatism, or a decrease in the mean central thickness of the cornea.
It’s important to remember that not everyone with keratoconus needs to undergo CXL. There are the simpler methods like using eyeglasses or rigid contact lenses, which forms the backbone of basic treatment. Also, CXL isn’t required for people who have keratoconus that isn’t getting any worse, especially for older folks whose corneas get naturally firmer with age.
When a Person Should Avoid Collagen Cross Linking for Keratoconus
Standard Corneal Cross-Linking (CXL) treatment, which is used to help with eye conditions, is not suitable for everyone. It might not be appropriate if the cornea (the clear, front surface of your eye) is thinner than 400 microns (this is super small, about 0.0016 inches) or if you had any past herpes related eye infections. In most cases, if your cornea is thinner than 400 microns, doctors would not perform the CXL treatment. However, there is a slightly different CXL procedure termed hypo osmolar CXL, which can be undertaken if your cornea thickness is somewhere between 370 to 400 microns.
Other reasons why you might not be able to get the CXL treatment can be if you presently have any other eye infection, severe scarring or opacity (cloudiness) in the cornea, neurotrophic keratitis (a condition where your cornea has problems feeling, leading to poor healing), severe dry eyes, history poor wound healing in the cornea, autoimmune disorders (where your body’s immune system mistakenly attacks your own body’s tissues), and pregnancy.
According to one study, they saw that sometimes eye infections specific to herpes simplex virus can occur after a person undergoes CXL treatment. For example, a woman got an infection in her cornea and an inflammation of the uvea (part of your eye that contains blood vessels) five days after her CXL treatment. Similarly, two more patients were found to have an infection in their corneas shortly after their CXL treatment. Because of such cases, eye doctors do not prefer to do CXL treatment if you had previous herpes infection of the eyes. They also found that infection caused by virus can occur even if you did not have a history of keratitis, which is inflammation of your cornea.
Equipment used for Collagen Cross Linking for Keratoconus
If your doctor has to perform a procedure called CXL, there are several types of specialized medical equipment they’ll need for it. Let’s break them down in simpler terms:
* Conjunctival forceps: Special tweezers to handle sensitive eye tissue.
* Diluted absolute alcohol: A liquid for sterilizing surfaces.
* Calliper: A precise measuring tool.
* Ink pen marker: For clearly marking areas of interest.
* Hockey stick blade: A type of small, curved knife.
* Crescent blade: Another type of small, curved surgical knife, different from the hockey stick blade.
* Riboflavin: A type of vitamin used in the procedure.
* Ultraviolet light: A special light wavelength often used in medical procedures.
* Hand-held slit lamp: A magnifying tool, allowing the doctor to see your eye more clearly.
* Normal saline: A type of saltwater solution often used in medical procedures.
* Saline cannula: A tube used to deliver saline solution to the eye.
Now, there’s also a quicker version of the CXL procedure known as ‘accelerated CXL’. For this faster procedure, they’ll need an additional piece of equipment known as an ‘accelerated CXL machine’.[21]
Who is needed to perform Collagen Cross Linking for Keratoconus?
Carrying out CXL, which is a type of eye surgery, requires the joint effort of a team of eye surgeons, a supportive OT nurse, mid-level eye care staff, and a committed counselor. The eye surgeon is the one who does the surgical procedure. The OT nurse assists by getting the patient ready for surgery and providing the necessary tools. The mid-level eye care staff assists with moving the patient. Before and after the operation, the counselor is there to guide the patient and provide necessary information.
How is Collagen Cross Linking for Keratoconus performed
The Dresden protocol is a standard procedure used to treat a certain eye condition called keratoconus. It is named for the University of Dresden in Germany, where it was originally developed. This common and effective procedure involves removing the center part of the epithelium (the thin layer covering the front of the eye), followed by applying a solution of riboflavin (a type of vitamin B) and then exposing the eye to a certain type of ultraviolet light called UVA.
This procedure has been found to have very positive results that last for a number of years. But it’s not suitable for everyone. For example, people with thinner corneas may be at risk of damage to the inner layer of the eye, called the endothelium. In these cases, other versions of the protocol can be used to offer additional protection, such as leaving the epithelium in place or using a type of riboflavin solution that increases the thickness of the cornea.
Another variation of the Dresden protocol involves applying a semi-rigid contact lens to the eye, then applying riboflavin beneath it using a procedure involving a thin tube known as a cannula. The UV light exposure time is increased in this case because the contact lens absorbs some of the light. This technique results in a flattening effect on the cornea.
There’s another method where the procedure is performed without removing the epithelium – this is known as “epithelial-on” procedure. This can reduce the risk of certain complications, like inflammation of the cornea (known as keratitis) and postoperative pain, but can also reduce the effectiveness of the treatment.
There are also accelerated protocols which shorten the time of the procedure and reduce exposure of the cornea to infection. These work by increasing the intensity of the UV irradiation, reducing it from 30 minutes to around 3 minutes, with similar results and potentially safer for thin corneas.
The use of iontophoresis, which uses a low electric current to facilitate riboflavin penetration into the cornea is also under study. This shortens both the penetration time for riboflavin and the duration of ultraviolet light exposure. However, comprehensive long-term comparative studies against conventional protocols are not yet available.
Possible Complications of Collagen Cross Linking for Keratoconus
After undergoing a certain type of eye surgery, patients may experience some complications. These can include a temporary clouding of the cornea (the clear front surface of the eye), which may affect 10% to 90% of patients. Other possible issues include delayed healing of the outer layer of the eye, sterile infiltrates (small areas of inflammation), and central stromal scars. From previous studies and reports, we know that postoperative bacterial, herpetic (related to herpes virus), protozoal (single-celled organisms), and fungal infections of the cornea can occur.
The clouding of the cornea, also known as stromal haze, is usually temporary. It’s thought to be caused by increased swelling and activation of corneal cells and typically happens three to six months after surgery.
While they are less common, more severe side effects can happen. These include corneal melts (a serious condition where the cornea thins and can lead to a hole) and endothelial failure (a condition where the inner layer of the cornea fails, causing vision problems). Another possible complication is treatment failure, which is defined as the condition getting worse with certain changes in the measures of the cornea’s curvature and thickness six months after surgery. This may happen in up to 10% of patients.
What Else Should I Know About Collagen Cross Linking for Keratoconus?
Corneal Cross-Linking (CXL) is a safe and effective way to stop the progression of abnormal shapes (ectasias) in your cornea, which is the clear layer that covers the front of your eyes. This means that it helps prevent the need for more intense treatment down the line. There are several modifications to the original CXL method, although some of these have shown mixed results and we’re still waiting on long-term data.
CXL is also being used more frequently as a treatment for microbial keratitis, which is an infection of the cornea, and also to address low nearsightedness. However, more research is needed in these areas.
CXL has become more and more popular in the past decade. Most patients receiving this treatment are in their first or second decade of life, which highlights how important it is to catch and treat this issue early on. This can help prevent permanent vision loss. There are also treatment possibilities for those with thinner corneas, and in most cases, vision can be preserved.
