Corneal Collagen Cross Linking with Riboflavin

Hi, I am glad you reached this page so that we can partner with you in the fight against Keratoconus Eye Disease. You have, like thousands of our patients suffered from poor eye disease. To add salt to injury, very few people including Doctors may have been able to understand your visual problems.

What is Corneal Collagen Cross Linking with Riboflavin or CXL?

Corneal Collagen Cross Linking with Riboflavin is a relatively newer method to strengthen the weak cornea in Keratoconus eye disease. The Avedro epithelium off (epi-off) method was recently approved by FDA. Some surgeons have abbreviated Corneal Collagen Cross Linking with Riboflavin  to C3R. It’s important to remember, though there are many manufacturers of Riboflavin and UV dispensing machines, only Avedro (now Glaukos) has FDA approval based on safety, efficacy and good manufacturing practices (GMP).

Epithelium on (epi-on), where top layer is not removed, is NOT FDA approved. This method has not been shown to be safe or as effective as FDA approved epi-off, which allows 30 minutes of soaking with Riboflavin.

In fact, the FDA approved method, also called Dresden protocol, which is named after the city where it originated, is considered the gold standard of treatment among Keratoconus doctors from around the world. That is the treatment we offer here at Khanna Vision Institute, as we believe in only the best.

Corneal collagen cross linking is an important intervention in the treatment of Keratoconus. The distorted cornea causes various aberrations leading to poor functional vision. In many cases, the cornea can rupture. The only rehabilitation in such cases can be performed with corneal transplants once the cornea has ruptured. The goal of a Keratoconus doctor is to prevent this major procedure. This can be achieved by corneal collagen cross linking by riboflavin, making the cornea stronger to stop the further progression of Keratoconus. The strength of the cornea is measured by Young’s modulus, which is defined as stress/strain. Experiments showed that it took more force or strain to stretch a cornea which had been strengthened by cross linking. 

How does Corneal Collagen Cross Linking with Riboflavin (CXL or C3R) work?

We will illustrate the problems of Keratoconus eye disease and its cure using CXL with a few simple examples. Imagine there is a room filled with water with a wooden door that is strong and able to hold back the water. Now imagine the door has been replaced with a plastic sheet. Plastic is not as strong as wood. What is likely to happen? The outward pressure from the water is going to push on the plastic sheet, causing it to bulge outward and gravity is going to pull this bulge downward. If we want to reverse this trend and strengthen the plastic door we can polymerize the plastic door by adding chemicals and activating them with ultraviolet radiation.

This is exactly what transpires in Keratoconus eye disease and CXL. The collagen fibers in the cornea are shorter and stubby and get pushed to the periphery. This make the center of the cornea thin and the fluids inside the eye exert outward pressure on this weakened area of the cornea, making it bulge. Pressure is equal to force divided by the area. As the fibers are pushed to the periphery, the pressure is more severe on the central, thinner area. This trend is paused and reversed by cornea cross linking. CXL forms linkages between the fibers, preventing them from moving away and instead bringing them closer.This is the difference between breaking a single twig versus many twigs tied together. It is easy to break a single twig, but it becomes nearly impossible to break many of them together.

Another fun way to look at it to visualize beautiful colorful butterflies flying around. There are only strings hanging from the ceiling but no wall. Outside there are birds waiting to devour them. If we tied horizontal strings to the vertical ones it would form a net and hold the butterflies back. Likewise, crosslinking keratoconic eyes’ cornea holds back the eye fluids.

 

Effects of CXL by increasing crosslinks

Effects of CXL by increasing crosslinks

Procedure and the steps in corneal collagen cross linking with Riboflavin

The top most layer of the clear part of the cornea is termed the epithelium. It prevents fluids and bugs from entering the cornea. This has to be removed to allow the Riboflavin to penetrate the cornea. The two main stars of the procedure are Riboflavin (Vitamin B2) and ultraviolet A irradiation (UVA). Riboflavin is the photosensitizer in the photopolymerization chemical reaction.  UVA irradiation excites free radicals to form intrafibrillar and interfibrillar carbonyl-based collagen covalent bonds. Riboflavin is applied and is left to soak for 30 minutes. It is then activated by UVA radiation for 30 minutes.

There are two phases of the process, an early aerobic phase and later anaerobic. In the oxygen dependent aerobic phase, molecules of riboflavin are excited to a single or triplet state and reactive free oxygen radicals are liberated. These interact with collagen in the later anaerobic phase, when oxygen is depleted. As a result of this murky process, corneal rigidity is increased and collagen fiber becomes thicker and more resistant to enzymatic degradation. There is decreased permeability and swelling of the cornea, especially in the anterior stroma.

Who is a good candidate for corneal collagen cross linking?

Every young person should be treated with the corneal collagen cross linking with Riboflavin procedure at the time Keratoconus is diagnosed. However, not everyone can be fortunate enough to undergo this process and halt Keratoconus. The thickness of the central cornea has to be above four hundred microns. The shape of the cornea is another determining factor. The effect is best observed when the curvature of the cornea is between 52 and 57 diopters, but it can be performed if the curvature is less than 52. The central cornea should also be free of scars and folds.

Avedro epi off cornea cross linking Procedural
Keratoconus surgeon Dr.Khanna performing CXL

Keratoconus surgeon Dr.Khanna performing CXL

Dr.Khanna adjusting KXL system for UV Radiation

Is the CXL surgery painful?

Your eyelids offer the cornea protection. In order to see the world, the cornea has to be uncovered. It is exposed to the elements of nature, meaning there is potential for a lot of damage. The cornea is supplied with a lot of nerve endings and these corneal nerves can be activated before any permanent damage occurs.The nerve endings lie below the top layer (epithelium) of the cornea. This area has the highest nerve endings per millimetre in the entire body.

When we perform corneal cross linking, we have to push riboflavin and UV radiation below the epithelium. We have to traumatize, and even remove this layer. This stimulates the corneal nerves and that can cause pain.

How to decrease pain with corneal collagen cross linking for Keratoconus

The unknown is the basis of fear. Knowledge and awareness decreases fear. At our Keratoconus center, we invest time in explaining each step of the procedure. We also diligently go over risks, benefits and consent forms, which allows most doubts and fears to be removed. We offer communication with previous patients who underwent collagen cross linking for Keratoconus. This can done by either reading written accounts, watching videos or personal interaction with the patients.

A multitude of methods are used to make the procedure as an enjoyable experience as possible. We play music of your choice to relax you and further relaxation is achieved with yogic deep breathing. The staff talks with you, explaining each step of the procedure before it happens and instills pain free drops.

After corneal collagen cross linking is done

A contact lens bandage is placed on the cornea. This prevents the eyelid from irritating the surface of the cornea. Dark glasses and protective shields are also given for your comfort. Specially formulated drops that prevent pain are dispensed to take home. Medication to decrease pain, or analgesics, may be prescribed. We also keep in close communication after you go home. We will call later that same day to see how you are feeling and make sure you don’t have any questions/concerns. You also get the doctor’s cell phone number in case you do need to reach him.

Each Keratoconus center can be different. We want to make sure your experience is pain free and pleasant. Contact us and set up a consultation to meet our Keratoconus expert!

Corneal Cross Linking Recovery

Epithelium off recovery requires the epithelium to regenerate. It takes 48 to 72 hours for the epithelium to grow back and cover the area from which it had been removed. During this time there can be pain and photophobia. This is overcome by employing various painkilling drops. As the cornea in Keratoconus patients is not “normal”, the healing process can be delayed. It is important the doctor keeps a close watch on the healing eye. There is a possibility of contracting infection. Vision can be blurry for a few days to weeks. Therefore it is wise only to do one eye at a time.

Epithelium on CXL is not as effective as epi-off. Some Keratoconus surgeons prefer this method as the healing is quicker, however there is a higher risk of complications. The agitated epithelium may die and fall off leading to corneal abrasion which may cause pain and blurry vision.

Planning the recovery from corneal cross linking

Corneal cross linkage is an important procedure to preserve sight. It is better to allocate time to recover from this vision preserving procedure. It is best to do while on vacation or over a holiday break. Avoid undergoing this treatment during schools finals/exams or around important meetings or deadlines at work..

You will have a bandage contact lens on your treated eye for between 4 to 7 days. You will also be wearing dark sunglasses. During this time you can expect a foreign body feeling of irritation and watering of the eye. The vision may be blurred with some discomfort and rarely, sharp pain may occur. Increased mucoid discharge and severe pain may indicate infection. That is why you will be instilling antibiotic drops.

After the contact lens is removed you will start putting in steroid drops. The foggy vision may take a few weeks to clear up. It may be a good idea to put lubricating drops in during this phase of healing.

Close supervision by the Keratoconus surgeon will help quicken the recovery and avoid any pitfalls. The doctor can tell the best time to return to wearing your old contacts, or prescribe new ones if need be.


"I was diagnosed with Keratoconus several years ago and was told my only option was hard contact lenses.  I knew that I would never be able to comfortably wear those, so I found Dr. Khanna online and went to meet him in person for a consultation.  By the time I left the office, I had other options and I knew I could trust him with my vision.  I had surgery last year to have Intacs implanted and this year I'm going back to have cataract surgery.  Dr. Khanna is a skilled surgeon and is always up on the latest research, so you know you're going to get what's best for you.  I live in Vegas and it's worth the trip knowing I'm in good hands.  I would definitely recommend a visit to Dr. Khanna if you're looking for a professional and reputable eye surgeon."




"I was diagnosed with Keratoconus when I was 19 years old.  I had spotty vision since I was 11, but was able to correct it with contacts and glasses. With the Keratoconus, I was unable to wear any kind of contacts because they were very uncomfortable.  I stuck to glasses and just dealt with my bad vision, which got progressively worse.

In 2008, I decided that I had to do something about my Keratoconus.  I was browsing the web and found Dr. Khanna and a procedure called Intacs.  Within a month (maybe less!) I was having the procedure done.
When one of my Intacs came out a few months later, I was taken care of immediately, and had a replacement Intac put in a few months after that.

Dr. Khanna and his staff are very helpful and knowledgeable.  I am always greeted with smiles from the entire staff and Dr Khanna when I go for my follow-up appointments.  They're always so friendly and I actually look forward to my appointments.

Getting Intacs was the best thing I have ever done for my vision!  I went from "counting fingers" to not needing any contacts or glasses!  Heck, the vision in my right eye is 20/20 and my left eye is steadily improving!  If you have Keratoconus and want to get Intacs, go to Dr. Khanna.  When you're in the waiting room, watching their video, look out for me -- I'm the girl in the red tank top having the Intacs procedure done." 😉



"Hi my name is Juan, I am 25 years old, and I am from Westminster, CA. Four weeks ago I tried to have Lasik surgery in Newport Beach. I was diagnosed with Keratoconus on my right eye. They told me that if I didn't do anything about it, I would lose my vision. They referred me to a specialist that was extremely expensive. I was even considering giving up the chance of saving my eye. As a last hope, I started calling specialists that I found on the web. Thank God that I found Dr. Khanna. About a week ago, he performed the surgery on my right eye to stop the Keratoconus and it was done at a very affordable price. It was so affordable that I also had Lasik surgery on my left eye. I feel very happy because Dr. Khanna saved my vision. The surgery itself lasted between 5 to 10 minutes, and it was painless, plus I found Dr. Khanna very confident and experienced. Before the surgery, I could not read even big letters with my right eye. Now that I have the Intacts implants that lift my cornea to the position where it belongs -- I'm very impressed with the results. It is amazing how much my vision improved with the surgery. If you are looking for a Lasik surgeon, Dr. Khanna is the perfect doctor to trust your eyes with. Visit www.khannainstitute.com  for more info about Dr. Khanna. I am sure you will be satisfied too!"


Corneal Cross Linking on a Thin Cornea

We know that with Keratoconus the corneal collagen fibers are decreased in number and volume. This decreases the tensile strength of the cornea to hold back the internal pressure of the eye. We can increase the Young’s modulus, or the rigidity, of the cornea with corneal cross linking. This intervention is more challenging in extremely thin corneas. We need to protect the inner cornea and the inside of the eye from the UV radiation we apply. If the cornea is thinner than 400 microns we need to develop a different strategy. When doing epi-off corneal cross linking we remove the top 5o microns when we discard the epithelium. This is why the cornea has to be more than 450 microns to start safely. It is common knowledge among Keratoconus surgeons that epi-off corneal cross linking is more effective than epi-on corneal cross linking. In thin corneas, epi-on CXL may be used because the 50 microns of epithelium adds a barrier to the UV light.

What about extremely thin corneas, where even the epithelium protection is not enough? A novel strategy has been devised – contact lens assisted CXL. A 300 micron contact lens is soaked in riboflavin and then placed over the bare cornea. It helps the cornea to swell, as well as prevents UVA radiation from penetrating deeper.

Corneal collagen cross linking combined with PTK and PRK

Cretan protocol plus can improve refractive errors, like astigmatism, on patients with Keratoconus. This will also allow us do the CXL procedure combined with PTK and PRK.  This is based on our experience and a study paper published in the Journal of Cataract and Refractive surgery by Dr. Grentzelos from Crete, Greece.

Corneal collagen cross linking, as you may know by now, was invented by Dr. Wollensack. It can halt the progression of Keratoconus. In United States, the FDA has approved the Avedro KXL/Photrexa system to prevent progression in post Lasik ectasia and progressive Keratoconus patients. The major drawback has been that patients are still left with refractive errors, especially astigmatism, and the vision is not optimal in these teens and young adults. Keratoconus surgeons had been hesitant to apply laser energy to the Keratoconus cornea, for fear that additional tissue removal may further weaken the cornea.

Precautions

Corneal collagen cross linking, combined with PTK and PRK, can only be done for minor corrections where the total corneal tissue ablated is less than 50 microns, with at least 350 microns left. Judicial judgment by an experienced Keratoconus and laser surgeon is very important. We usually have restricted to treat astigmatism in the central 6 mm zone, especially when tissue ablated is away from the thinnest zone.

Advantages

Vision can be improved. This combination allows for rapid improvement of vision, avoiding contact lenses. Bonus, there is no additional pain! If the two procedures are done separately, there is discomfort and healing time for each. Another advantage of using the PTK mode for removal of epithelium is it flattens the cone, decreasing higher order aberrations.

Caution

As with any advancement, we have to be careful of potential side effects. PTK can weaken the thinnest, bulging part of the cornea. This may destabilize the cornea. Please consult with your Keratoconus expert to find out if this is a good choice for you.

Basic principles, science and research of corneal collagen cross linking

The main aim of corneal cross linking is to halt the increase in the bulging of the cornea and make the cornea stronger and resistant to the internal pressure of the eye. The secondary aim is to flatten the cornea and improve the vision.

Science research results

Even with our modern technology it is difficult to demonstrate the exact working and effect of cross linking on the human cornea. We do have indirect evidence of the success of CXL. Young’s modulus, or stress/strain ratio, is increased with CXL and is the hallmark to demonstrate the effectiveness in the lab. The strengthening is increased if there is a higher content of collagen present . 

Corneas develop more collagen fiber thickness after CXL. This treatment makes the cornea more resistant to degradation processes mediated by pepsin, trypsin and collagenase with increase in collagen turnaround time.

Standard procedure of collagen corneal cross linking

The procedure for corneal cross linking is simple. First the epithelium or the top layer is modulated. It may be totally removed for a circumference of 9 mm. The epithelium may be removed by a variety of methods. Diluted ethyl alcohol is usually employed. Laser epithelium removal is another choice. It may also help in flattening the cone. These methods where epithelium or the top layer of the cornea is totally removed is called epithelium off CXL, or epi-off CXL. If the epithelium is only agitated, but not removed, then it is called epithelium on CXL, or epi-on CXL. The standard Dresden protocol, also called conventional collagen corneal cross linking, was described by Wollensask. It requires epithelial removal (epi-off), the instillation of 0.1 % Riboflavin solution for 30 minutes, followed by 30 minutes of UVA irradiation, with a wavelength of 370 nm and power of 3 mW/cm2 (5.4 J/cm2). 

Gold standard of corneal collagen cross linking for Keratoconus

The inventors of corneal collagen cross linking tried various combinations in the lab and in clinical practice. They found the most effective treatment for the cure of Keratoconus was epithelium off corneal collagen cross linking with riboflavin. This is the current gold standard against which all other methods and variations have to be tested.

Indications for collagen corneal cross linking

  1. Progressive Keratoconus
  2. Lasik ectasia getting worse
  3. Pellucid marginal degeneration

An important point we have to consider is what the term “progression” actually means. Various researchers, clinicians and surgeons may define it differently. It may also vary by the machines used for topography or OCT. A Pentacam may show numbers differently than an Atlas topography. This is where the surgeon’s experience becomes important. It may be better to err on the side of caution.

We also need to come up with a standard for defining progression among Keratoconus doctors.  Progression in various studies is considered when:

  1. There is an increase in K-max of 1 diopter (D) in 1 year.
  2. Increase in nearsightedness and/or astigmatism ≥3 D in 6 months.
  3. A mean central K-reading change of ≥1.5 D observed in three consecutive topographies in 6 months.
  4. If there is a decrease ≥5 % in mean central corneal thickness in three consecutive tomographies in the last 6 months.

Contraindications to undergoing standard CXL treatment:

  1. Corneal thickness of less than 400 microns.
  2. Previous herpetic infection.
  3. Immunological disease.
  4. Severe scarring or haziness of the cornea.
  5. Epithelial wound healing problems.
  6. Severe dry eye or eye surface disorders.
  7. Pregnancy and breast-feeding. 

The classification below of corneal cross linking procedure is based on, and similar to, the one proposed by Dr. Hafezi, Dr. Randelmann et al.    

Cross linking with Riboflavin (C3R)         Cross linking with Rose Bengal (C3RB)

EPITHELIUM STATUS

  • EPITHELIUM OFF
  • EPITHELIUM ON
  • CORNEA CHANNEL

This is the classic method described by Wollensack et al. Traditionally, the epithelium is removed by a chemical, either tetracaine or ethyl alcohol. Laser epithelium removal (PTK) is a new variant.

CHROMOPHORE (RIBOFLAVIN) SOAKING TIME

  • 30 MIN
  •  10 MIN
  • OTHER

For epi-on cornea cross linking procedures, a longer soaking time may be needed, up to 60 minutes, and on a rare case it could be longer. The end point is flare in the anterior chamber.

UV RADIATION TIME

  • 30 MIN
  • 10 MIN
  • 6 MIN

This is the gold standard time with 3 mw/cm2 power. This combination gives the best cross linking effect.

MODIFIERS

  • OXYGEN
  • IONTOPHORESIS
  • PULSED

Oxygen gets depleted during the cross linking process in the cornea. Adding oxygen may increase the speed and effectiveness of the procedure.

Learn more about corneal collagen cross linking costs and insurance coverage. We offer FDA approved, Avedro epi-off, classic Dresden protocol conventional corneal cross linking.

Portrait of a happy paramedica carrying a portable oxygen unit

"I was a paramedic for over 20 years before my Keratoconus got so bad I had to give it up. It is not right for me to put my patients at risk because I can not see their charts, medication or test results correctly."


Limits and complications of collagen corneal cross linking (CXL)

  1. In around 8.1–33.3 % of patients CXL may not be beneficial. The central cornea continues to steepen more than 1 D in a year, or vision deteriorates further. The great news is research papers with follow ups ranging from 6 months to 6 years all showed stabilization of Keratoconus, with flattening of the central cornea. There is also documentation of improvement of vision with epic off collagen corneal cross linking.
  2. Infection remains the main problem. Bacteria, fungus, herpes and acantamoeba can all invade the denuded cornea. Clinicians and patient have to be vigilant against this threat.

  3. Corneal haze is quite common. It occurs three weeks to three months later, but the good news is that it resolves on its own. It may be related to keratocyte activation.

  4. Corneal edema may occur.

  5. Watering, tearing, and pain are the most common complications but they do resolve quickly.
 

Considering cross corneal linking or CXL? Here are a list of questions to ask your eye doctor:

How is Keratoconus treated?

What are my treatment options, and which do you recommend?

What treatment options are covered by insurance?

Is the procedure that you are recommending FDA approved or investigatory?

If the procedure you are recommending is not FDA approved, am I being enrolled in a clinical study?

Is it true some malpractice insurance are not covering doctors performing corneal cross linking?

Are you a Board Certified Ophthalmologist?

Have you been fellowship trained in cornea refractive procedures?

How long have you been performing cornea cross linking with Riboflavin?

Do you have experience in combined Intacs insertion and corneal collagen cross linking?

Are you considered a Keratoconus expert?

Have you had to manage any complications? If so, how did you manage them?

Will I need contacts or eyeglasses after the procedure?

 

 

COMMON ABBREVIATIONS USED

BCVA: Best-corrected visual acuity

CXL: Corneal cross linking

D: Diopter

DALK: Deep anterior lamellar keratoplasty

ICRS: Intracorneal ring segments

PRK: Photorefractive keratectomy 

SE:Spherical equivalent

UVA: Ultraviolet A irradiation

UCVA: Uncorrected visual acuity

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