Answering Your Questions about Crosslinking

Answering Your Questions about Crosslinking

These are many common questions about corneal crosslinking (CXL). If you have questions that are not answered here, contact us

If you click on a question, the answer will reveal itself.

Crosslinking (CXL) is a treatment that stiffens the cornea through a photochemical reaction to slow or stop the progression of keratoconus (KC). In healthy corneas, natural bonds between the collagen fibers that make up a large part of the corneal structure help to hold it in a round, spherical shape. For those with KC, the collagen binding process is not fully effective, leading to changes in corneal strength, thickness and its overall shape. The cornea may start to exhibit a characteristic bulge or ‘cone’, and individuals may experience blurred or distorted vision that cannot be fully corrected by glasses.

A combination of ultraviolet light, oxygen, and riboflavin (vitamin B2) eyedrops create new collagen bonds. CXL improves the biomechanical strength of the cornea by forming additional collagen crosslinks and stops or slows KC from getting worse. In most cases, the treatment is completed in a single hour-long procedure.

Crosslinking (CXL) was first performed in the late 1990s. The first scientific article on keratoconus patients was published in 2003 in the American Journal of Ophthalmology by researchers in Dresden, Germany. The “Dresden” protocol described the results of 22 patients with progressive keratoconus who were treated with . Since that report, CXL has been performed internationally and doctors continue to look to the Dresden protocol as the standard of care while researching new and improved techniques.
The FDA-approved epithelium-off crosslinking (CXL) protocol takes about an hour to complete.

Your doctor will probably ask you not to wear your contacts for a few days or weeks prior to the procedure. That will give your eye the opportunity to rest and ‘reset’ before the treatment.

You are awake during the procedure, but because of anesthetic eyedrops, the level of discomfort to the treated eye is minimal. After the numbing eyedrops are applied, the outer layer of the cornea (epithelium) is gently removed. Riboflavin (vitamin B2) eyedrops are given every two minutes for at least 30 minutes, then the doctor will measure the saturation of the drops and the thickness of your cornea. Your doctor will then ask you to focus on an ultraviolet (UV) light for about 30 minutes while additional eyedrops are applied.

After the treatment, any remaining riboflavin eyedrops are rinsed off, antibiotic drops are given, a temporary bandage contact lens is applied, and the procedure is complete. This temporary contact lens is left in place for a few days while the epithelium heals. It is especially important to avoid eye rubbing after CXL.

The current FDA-approved crosslinking (CXL) treatment calls for the combination of oxygen, ultraviolet (UV) light, and riboflavin eyedrops. The riboflavin molecule is large and cannot freely penetrate cornea. Removing the thin outermost portion of the cornea (epithelium) facilitates the saturation of the riboflavin drops, the diffusion of UV light and oxygen, and the likelihood of success for the photochemical reaction. The procedure is sometimes referred to as [‘epi(thelium)-off’]. The success rate for epi-off CXL is extremely high, around 95% according to published data.

A CXL treatment that leaves the epithelium intact [‘epi(thelium)-on’] would be advantageous for patient comfort and a quicker return to contact lenses, provided it had a level of success similar to epi-off CXL. Some doctors have developed their own epi-on CXL techniques by modifying the riboflavin solution or altering the duration or intensity of the UV light exposure. The success rates of these epi-on procedures is not verified and varies greatly. None have been subjected to an FDA-type review.

Both treatments have advantages and disadvantages. The epi-off protocol has been vetted and approved by the FDA. Given the abundance of clinical data in medical literature for epi-off CXL, the success rate is known and exceeds that of any epi-on treatment. However, patients experience a longer recovery period and may experience early post-operative pain and risk of complication as the epithelium heals. The epi-off protocol is a covered benefit in most insurance plans.

As there is no drug or device approved for use in the U.S. for epi-on CXL, the procedure does not yet have a standardized protocol and the exact treatment and the likelihood of success is unknown. You may be more likely to need a repeat procedure for disease progression if you are treated with an epi-on procedure. Epi-on CXL likely means a shorter recovery time, with less discomfort or risk of complication. Because epi-on is considered investigational, these treatments are not covered by insurance and you should expect to pay out-of-pocket for the procedure.

It is important to discuss with your doctors which CXL treatment methods they offer and why they are recommending this procedure for you.

Clinical trials are an important scientific method to test both the safety and efficacy of new drugs and devices. They can be time consuming and expensive: the average cost to bring a new drug through the clinical trial process to approval by the FDA (U.S. Food and Drug Administration) exceeds $20 million and takes several years.

Glaukos (formerly Avedro), a pharmaceutical and medical device company organized a multi-center clinical trial for 205 eyes with progressive keratoconus using the epi-off crosslinking (CXL) protocol. The doctors involved were responsible for documenting changes in vision, corneal shape and other study parameters including any adverse events. Treated patients were monitored by their doctors for at least one year after treatment. All study data and results were submitted to obtain FDA approval for the CXL device and the riboflavin solution, called Photrexa or Photrexa Viscous, which was granted by the FDA in April 2016.

Individual doctors and physician groups have developed their own CXL protocols, using equipment that may have been developed for other purposes and eyedrops of their own creation. Most of these investigational protocols utilize an epi-on procedure, which may or may not be effective. Without a tightly controlled, randomized clinical trial and without the scrutiny of an independent regulatory body like the FDA, it is difficult to determine the actual success rate and possible complications. That is why these epi-on procedures are not covered by insurance.

There may be very good reasons to choose an experimental treatment, but patients should be aware there is an FDA-approved epi-off CXL option.

No. There is no cure for keratoconus, but most of the time it can be successfully managed. If you have crosslinking that leads to keratoconus stabilization, you may no longer experience vision changes and some of the other signs of keratoconus. You will still need to visit your doctor regularly to monitor your condition, ocular health, and maintain your glasses or contact lenses.
While some patients report little or no pain with the standard epi-off crosslinking (CXL) procedure, others describe discomfort for the first few days. Some describe a burning or gritty sensation (like sand in the eye) and others complain of light sensitivity and find wearing sunglasses helpful. Your doctor will give you numbing drops before the procedure begins and will send you home with post-operative instructions for pain management. Your doctor may recommend an over-the-counter product like Tylenol® or may prescribe some other pain medication. Your doctor may also suggest artificial tears or lubricating drops. Absolutely avoid all eye rubbing, even if it provides temporary relief. Any discomfort you experience should subside within a week or sooner after treatment.
If you have been diagnosed with keratoconus and your vision is fluctuating, or if the structure and thickness of your cornea is changing, your doctor will likely recommend corneal crosslinking (CXL). For patients with very mild disease whose vision is stable, your doctor may advise a wait and watch approach. In this case, your doctor will still want to closely monitor your condition with regular exams every few months.

Considering the risks for keratoconus progression, some doctors may recommend CXL before there is evidence of advancement in order to avoid potential vision loss. This is especially the case for adolescent or teen-aged patients where disease progression is often more rapid and aggressive. You and your doctor must decide what is the best approach to take.

There are no other procedures that can slow or halt the progression of keratoconus.

You can choose to do nothing. Some people with mild keratoconus whose condition is stable find they are able to function with eyeglasses or contact lenses may decide to defer crosslinking (CXL). In these cases, it is important that you visit your eye doctor regularly who will closely monitor for changes.

If you choose to do nothing and have moderate to severe keratoconus or unstable disease, you may be risking permanent damage to your cornea, and you may find it difficult to achieve good vision. Once visual compromises occur, structural and visual deteriorations are not reversible. In the most severe cases, when you cannot achieve functional vision or comfort with highly customized keratoconus contact lenses, your doctor may recommend a corneal transplant to remove your irregular cornea and replace it with a donor cornea. That procedure is much more complicated than CXL and involves a lifetime of monitoring the health of the transplant. It may be possible that you will require multiple corneal transplants over a lifetime.

Your doctor will discuss the benefits of crosslinking (CXL) with you. In general, this is a minor procedure that can bring about major results.

Individuals who undergo successful CXL can expect that disease progression will halt or greatly slow down. About six months after the procedure, when new collagen cells have formed, cornea structure and vision should become stable.

Many people who undergo CXL may find that wearing contact lenses becomes easier because the lens fitting does not change as frequently and some of the steepening of the cornea may even decrease. CXL reduces the lifetime chance that an individual will need a more costly corneal transplant surgery.

Patients with severe keratoconus who undergo CXL report a more positive outlook about the future and an improved quality of life.

Your doctor can describe the risks of the procedure when you are discussing the treatment.

Crosslinking (CXL) is associated with very low rates of complications but no procedure can guarantee 100% success. Depending on the protocol your doctor uses, and the success of the treatment, you may find that the disease continues to progress after CXL.

There may be pain associated with the treatment, and in very infrequent circumstances, this discomfort may continue for several days. In rare cases, there is a residual glare or halo after CXL. Blurred or diminished vision can occur. In extremely rare cases, an ulcer or infection on the eye can develop. Corneal scars can form during the healing process.

These complications are very uncommon but serious and must be measured against the benefits. Only you can decide what is in your best interest after your doctor has explained the procedure to you.

Yes. In the days following crosslinking (CXL), your eye will react to the treatment. Your vision may be significantly worse during early healing stages and you may experience glare, halos and/or light sensitivity. Pending the exact symptoms that you are experiencing, majority of these episodes will resolve within a few days or within the first month. In the first three to six months after the CXL, you may experience a decrease in your best possible vision as new crosslinks form and the collagen remodels itself. After this, most people report that vision fluctuations resolve, and vision stabilizes; some even report an improvement in vision. However, you should not expect CXL will result in improved vision: it is performed to slow down or stop changes in vision and cornea physiology due to keratoconus.
Probably. Crosslinking does not cure keratoconus and is not vision correction surgery. If you needed glasses or contacts for good vision before the procedure, you should expect to rely on them after treatment. The good news is that your prescription will likely not change as frequently as it may have in the past, and the comfort and fit of your contact lenses may improve.
After the procedure, your doctor will fit a soft bandage contact lens on your eye. This is to protect your eye and promote healing during the early recovery period, but it will not offer the improved vision you get from your own prescription contact lenses. How soon you can start wearing your own lenses depends on what kind of crosslinking (CXL) procedure you have and what type of contact lenses you are wearing or will be wearing. In most cases, you may return to wearing soft lenses or scleral lenses sooner than rigid gas permeable (GP or RGP) lenses. If you had the FDA-approved epi-off protocol, you must give the epithelium time to heal, and it may be several weeks before your doctor allow you to resume wearing a contact lens on the treated eye. Those who undergo an investigational epi-on CXL may be able to return to wearing contact lenses within a few days after treatment.

At some point after the procedure, when your vision has stabilized, your doctor will retest your vision to see if the spectacles or contact lenses you wore prior to CXL are still the best prescription for you.

Unlike corneal transplant surgery, crosslinking (CXL) is offered as an in-office procedure and does not require a hospital operating room setting. In most cases, eye doctors perform crosslinking in the same type of room they perform minor procedures. In fact, many doctors choose to perform CXL in the same exam rooms where they perform laser surgery.

In cases where the patient has other serious medical conditions, or is likely to be uncooperative (for example, a patient who may become agitated or unable to focus on the ultraviolet treatment light), the doctor may recommend a hospital setting and perform CXL with the assistance of general anesthesia. Your doctor will explain where the procedure will take place and how long the CXL it is expected to take.

Pregnant women were excluded from the clinical trials that studied crosslinking (CXL). Even today there is limited information about the effects of the procedure and post-operative medications on unborn children or pregnant or lactating women.

Research has shown that some women with keratoconus finds their disease becomes ‘worse’ during pregnancy. Vision fluctuations may be evident and contact lenses may cause more discomfort. These changes may signal a connection between keratoconus and elevated hormone levels. For that reason, some doctors encourage women of child-bearing age, even if their keratoconus is mild, to consider CXL before planning a pregnancy.

The pivotal U.S. epi-off crosslinking (CXL) clinical trials conducted in support of FDA approval included patients between the ages of 14 and 65. However, there are published reports of CXL studies in the medical literature that evaluate patients of different age groups.

Many doctors encourage parents to consider CXL for their adolescent or teen-aged children with keratoconus due to the higher risk of disease progression. Pediatric keratoconus is usually more severe than cases that develop in individuals in their 20s or 30s, and so experts tend to be more aggressive in treating KC in younger patients, even those under the age of 14.

It is less likely that people older than 65 will need CXL as they are more likely to have achieved keratoconus stability, however, doctors may recommend that older patients undergo CXL if there are signs of active progression of disease. The changes to the structure of the cornea or vision fluctuations should be due to keratoconus and not those that normally occur after middle age, such as difficulty with reading or seeing small print (presbyopia or cataract).

There may be restrictions from your insurance company about reimbursement for CXL in patients who are either under age 14 or over 65. If your doctor has recommended CXL for a patient outside of these ages, make sure to find out if the procedure is a covered benefit.

The FDA-approved epi-off protocol is more than 95% effective; the results from experimental (non-FDA approved) protocols are much less consistent; meaning the crosslinking (CXL) procedure may not halt or slow disease progression. In those cases, your doctor may recommend that CXL is repeated. There are not many published studies about cases that require retreatment or their long term outcomes, but the limited data available seem to indicate that a second treatment or repeat CXL will be successful. Younger patients in their teens or pre-teens and whose disease progression is aggressive are the ones most likely to require a repeat CXL.
Many individuals with Down syndrome (DS) have thin and irregular corneas. As a group, they are much more likely than the general population to have keratoconus or keratoconus-like symptoms. They are also more likely to engage in eye rubbing and less likely to complain about changes in vision. For these reasons, these individuals should be evaluated for keratoconus and closely monitored by their doctors.

Many individuals with DS have successfully undergone crosslinking (CXL) using both epi-on and epi-off techniques. It requires cooperation during the procedure; if that seems unlikely, the doctor may opt to perform the procedure under general anesthesia. Some surgeons choose to perform CXL on both eyes during one session for these patients. This complicates the post-operative period but reduces the need for a second treatment and cuts down on overall recovery time. Family members should find a doctor who is comfortable working with special needs patients and discuss the specific risks and benefits of the procedure.

Intacs or other intrastromal corneal ring segments are tiny, crescent-shaped, plastic implants placed into a tunnel created in the cornea to flatten the “cone” area and improve contact lens tolerance. They are not intended to stop keratoconus progression. Generally, surgeons will leave them in place if no intacs-related complications were observed prior to crosslinking (CXL). Other doctors will choose to remove intacs before CXL and then decide if it is worthwhile to replace the inserts after vision becomes stabilized.

Some doctors are experimenting with a combined procedure involving CXL and placing intacs during the same surgery. There is limited scientific data on the results. While both procedures may be independently reimbursed by insurance, if they are done together, the combined same-day treatment of intacs and CXL would likely not be a covered benefit.

If you have already undergone a corneal transplant your diseased or damaged cornea has been removed and replaced with a donor cornea. Crosslinking would not be indicated for you.
Until recently, about 10-20% of the most severe cases of keratoconus would eventually require a corneal transplant. Crosslinking (CXL) and improved contact lens technology have resulted in fewer individuals finding their keratoconus so debilitating that a corneal transplant is the only remaining option. It still happens, but much less often than in the past.
Individuals with keratoconus who have been diagnosed with cataracts need to have a conversation with their eye surgeon about the source of their vision problems. It is less common for older patients to experience vision changes due to keratoconus. The disease becomes less active and tends to stop progressing after middle age, although some still experience vision changes resulting from their irregular cornea. For most seniors, the source of their vision decline is the presence of cataract. Crosslinking (CXL) will probably not be necessary before cataract surgery.

Younger patients who develop cataracts may still be experiencing changes to their cornea due to keratoconus, and for those individuals it might be worth considering CXL before cataract surgery pending the medical advice of their eye surgeon.

Part of successful cataract surgery involves inserting an artificial lens with the correct optical power. A lens that offers good near or far vision may work in healthy corneas but may not provide optimal vision for someone with keratoconus. The more stable your vision and cornea, the easier it will be to calculate the correct lens power to implant. For those reasons, your surgeon may discuss CXL before cataract surgery. It may lead to a delay of several months before you can schedule cataract surgery while the collagen remodeling is underway.

Laser vision correction or LASIK is contraindicated for individuals with keratoconus because it can make the condition worse. Even after crosslinking (CXL), LASIK is not recommended. Some doctors are experimenting with treating patients who have undergone CXL and have stable corneas with vision correction surgery using laser including photorefractive keratectomy (PRK) to change the shape and smooth the surface of an irregular cornea. This treatment may improve vision or make contact lens wear more comfortable. These surgical vision correction options after CXL are still in the investigational stage in the U.S. and more research must take place to demonstrate both safety and efficacy.
Epi-off crosslinking (CXL), using the FDA-approved UV light device and riboflavin (Vitamin B2) eyedrops is covered by the majority of insurance plans. Your doctor may need to provide documentation to your insurer that your keratoconus is getting worse. This benefit comes through a medical plan (like Aetna or Blue Cross) and not a vision plan that covers eyeglasses and vision exams.

You can find up-to-date information on insurance coverage by visiting, a website sponsored by Glaukos (formerly Avedro), the maker of the FDA-approved device.

If your insurance company covers CXL and you are being treated by a doctor who has accepted this insurance in the past, you should not have to pay for CXL except for co-pays or deductibles.

If you choose to undergo a CXL procedure that is considered experimental or does not have FDA-approval, your insurer will probably not cover the costs and you will be expected to pay for the procedure out-of-pocket. If your doctor combines CXL with another procedure like ring segments (Intacs) or vision correction surgery, your insurer will probably not cover the combined procedure and you’ll have to pay out-of-pocket.

If you are participating in a formal clinical trial, you may not have to pay for the procedure, but will be expected to return for follow-up appointments so that the doctor can gather data on the treatment and outcomes.

Over the last decade, corneal collagen crosslinking (CXL) has become a very active field for research. Scientists are looking at new dispensing options and different photosensitizers. They are looking at using different light sources including portable light units and ways to maximize oxygen delivery. Improvements in the technology used to diagnose KC leads will result in earlier, effective treatment.

Clinicians are looking at ways to expedite the collagen remodeling process by investigating triggers to the photochemical reaction. Others hope to improve outcomes by delivering focused CXL to particular areas of the cornea, or by altering the CXL based on genetics or disease progression. Public health experts are examining ways to improve access to this procedure worldwide.

Surgeons are focusing on combining CXL with vision correction procedures so that individuals with keratoconus will not only experience a halt to disease progression, but may also gain back clear vision.

Worldwide clinical trials are underway to test many of these innovations. A clinical trial is underway to evaluate a patient-administered daily eyedrop that may result in a biomechanical reaction similar to CXL. A highly anticipated clinical trial in the U.S. enrolled 280 individuals with progressive keratoconus. The subjects will be followed for a year after CXL. The final results will be known in 2022 and may lead to FDA approval of a new drug and device combination for epi-on CXL.