For many patients who have keratoconus (KCN), early detection of the disease and timely treatment with corneal cross-linking (CXL) can stabilize the cornea. This may eliminate the need for more invasive procedures, such as penetrating keratoplasty (PRK). The corneal stability that results from CXL also may translate into greater success with contact lens fitting outcomes.

In this article, we’ll first provide background on CXL and then take you through the journey of a patient who undergoes this treatment.

UNDERSTAND CXL CHEMISTRY

CXL uses UV light and a photosensitizer to strengthen the cornea by way of creating new covalent bonds within stromal tissues. A similar polymerization process also occurs within our body, which is why the rigidity of our connective tissue is expected to gradually increase over time. Naturally occurring cross-linking is facilitated by an endogenous enzyme (lysyl oxidase) to harvest energy needed from oxidative reactions for the eventual formations of new covalent bonds. These new tissue “bridges” can occur within the same collagen fibril or among neighboring fibrils, resulting in increased biological tensile strength.¹ The cumulative effects of the biological cross-linking is a proposed reason for why a majority of KCN becomes more stable as patients enter their fourth or fifth decade of life. However, given that these naturally occurring effects are slow to manifest, they are not particularly helpful in protecting KCN patients against deteriorations, especially in those who have early disease onset.

Investigators from the University of Dresden in Germany started exploring photochemical induction of CXL and published their initial findings in 2003. After removing the epithelial barrier to improve efficiency of CXL reactions within stromal target sites, riboflavin was selected as the photosensitizer to absorb energy emitted by a carefully calibrated UV light source. Consequently, these photochemical reactions activate the lysyl oxidase enzymatic pathway, resulting in the additions of new covalent bonds. (Figure 1)

EDUCATE PATIENTS ON THE CXL PROCEDURE

Understanding the complexity of the KCN diagnosis may be challenging for patients; this can reduce patient compliance with recommended treatment options. At Wills Eye, we incorporate a straightforward discussion template into our patient education at the time of diagnosis. An example:

“Keratoconus is an eye condition that leads to progressive weakening in your cornea — that is the front clear covering of the eye. The shape of your cornea determines how well-focused your vision is. With keratoconus, the cornea becomes fragile and unable to maintain its shape, which creates blurred vision, halos, glare and other visual defects that glasses can no longer fully correct. Certain types of contact lenses can still help to maintain good vision, but they will not stop keratoconus from getting worse.”

CXL uses UV light and a riboflavin eye drop — think of it as a liquid form of Vitamin B — to strengthen corneal tissue layers and stop the disease from worsening. Currently, CXL is the only proven method to stop KCN progression in about 95% of treated patients. CXL does not reverse this eye condition, which is why early CXL intervention will lead to better long-term visual outcome. After CXL, most patients can be re-evaluated for contact lens fitting to assist with regaining the best possible vision at about one month after the procedure.”

Additional education points: A mild amount of apical flattening is often observed after CXL, and some patients may even experience slightly improved vision. However, the primary purpose of CXL is corneal stabilization — instead of refractive improvements. Hence, after CXL, KCN patients will still need contact lenses and/or glasses. As such, during the pre-operative baseline exam, O.D.s should educate the patient about waiting before either a new contact lens fitting or checking on whether it is still appropriate for the patient to resume wearing his or her habitual contact lens in the CXL-treated eye. At Wills Eye, we recommend waiting at least three to four weeks before resuming contact lens wear.

Also, KCN patients will continue to require ongoing monitoring after CXL, either on an annual basis or sooner, pending individual patient profile.

WHEN TO REFER FOR CXL CONSULTATION

Given the main treatment purpose of CXL is to provide corneal stability, an early referral is critical to reduce or prevent risks of further visual loss.

Conservatively, any amount of detectable progression deserves a referral for a CXL consultation. While physicians’ own criteria on progression and insurance reimbursement guidelines may dictate this referral time, common clinical criteria have been utilized in study trials to determine potential KCN progression over a 12-month period.² (Table 1)

Although clinical criteria may alert clinicians to possible KCN progression, it is also worth noting many corneal specialists purport that KCN progression is not mandatory prior to CXL. Given the proven safety profile of CXL, and under this more progressive treatment principle, a confirmed diagnosis of KCN by corneal tomography in a young patient who is at high risk for progression may be sufficient clinical evidence for CXL to be offered, or at least discussed.³

Once the need for referral is established, patients can be referred for CXL at the clinicians’ own preferred treatment centers. However, if ECPs are not familiar with local CXL resources or don’t yet have a preferred co-management CXL clinic nearby, we’d suggest contacting the International Keratoconus Academy (https://www.keratoconusacademy.com ) or the National Keratoconus Foundation (NKCF) (https://www.nkcf.org ) for help.

CO-MANAGE PATIENTS

CXL is performed under topical anesthesia, and a lid speculum is placed in the treatment eye during the 30-minute UV exposure phase. At the conclusion of a CXL session, excess riboflavin that remained on the corneal surface is rinsed with balanced salt solution.

Like a PRK procedure, a bandage soft contact lens (BSCL) is inserted after the instillation of a topical antibiotic and corticosteroid agents. Ice packs covering the eye for five minutes to 10 minutes at a time and pain medications may be prescribed for the first several post-operative days. The BSCL is kept on the treated eye for three to five days, or until epithelial closure. (Figure 2.) During the first week, both a topical antibiotic and a topical corticosteroid are used for four times per day in the treated eye.

After the initial week and discontinuance of the topical antibiotic, the tapering of the topical corticosteroid regimen generally ranges from two weeks to two months, pending physician preference. Also, most co-managing practices are ready to send patients back to the care of their original ECP on the first day after CXL. However, some ECPs may prefer to see patients at one week after the BSCL has been removed, so it’s important for referral ECPs to communicate with the partnering practice regarding this post-operative care time line. Either way, after CXL, it is customary to see patients one day, one week (or until full epithelial healing), one month, three months, six months and a year, at which point the O.D. can decide to monitor patients annually or more frequently.

Patients are educated to expect ocular discomfort and avoid eye rubbing in the early post-operative period. Swimming is discouraged for the first week or two. They also are educated to discontinue habitual contact lens wear for at least two to four weeks after CXL or until further instructed by their ECP. Additionally, patients can expect temporarily reduced VA for the first month, which may last three to six months before returning to pre-operative baseline or before experiencing mild VA improvement.

Nonetheless, once patients can resume contact lens wear or begin contact lens refitting, their VA associated with contact lenses tends to remain functional. Thus, one of the advantages of treating one eye at a time with CXL is that a patient can temporarily function with the fellow eye in the contact lens.

BEGIN CONTACT LENS WEAR AFTER CXL

There are two main approaches to CXL: the FDA-approved epi-off technique and non-FDA-approved epi-on. When to begin fitting contact lenses after CXL will depend on the exact CXL protocol utilized. For FDA-approved CXL procedure that involves epithelial debridement, clinical preference at Wills Eye is to wait three to four weeks prior to having patient begin daily contact lens wear.

Regardless of which protocol or treatment setting, refractive changes may occur with corneal remodeling associated with CXL recovery, therefore, it is best to educate patients about potential contact lens fitting changes — and corresponding financial expenditures — during the first year after CXL.

INSURANCE COVERAGE LANDSCAPE: A 2020 UPDATE

Since FDA approval in early 2016 for epi-off CXL, the number of insurance carriers that have a positive coverage policy for it has been on the rise. As of February 2020, six national and 61 regional health care plans across the U.S. actively cover CXL. A full listing of payers that offer positive coverage polices and links to those policies can be found at www.livingwith keratoconus.com . Due to the improving insurance reimbursement landscape, even those carriers with no published coverage policy may still approve epi-off CXL reimbursement on a case-by-case basis.

A new billing code (J2787), effective January 2019, helps to make billing for epi-off CXL easier for practices and, thus, provide greater patient access to the procedure. The billing codes for new treatment cases:

• 0402T - Collagen cross-linking of cornea (including removal or the corneal epithelium and intraoperative pachymetry when performed)
• J2787 – Riboflavin 5’- Phosphate, ophthalmic solution, up to 3 ml

Using the new billing codes, it has been our experience at Wills Eye Hospital, that the majority of our epi-off CXL procedures have been successfully reimbursed by various participating commercial insurance payers. And we hope that this will help to relieve the financial barriers for your patients. OM

REFERENCES

1. Schumacher S, Mrochen M, Wernli J, Bueeler M, Seiler T. Optimization model for UV-riboflavin corneal cross-linking. Invest Ophthalmol Vis Sci. 2012 Feb 16;53(2):762-9.
2. Chang CY, Hersh PS. Corneal collagen cross-linking: a review of 1-year outcomes. Eye Contact Lens. 2014 Nov;40(6):345-52.
3. Gomes JA, Tan D, Rapuano CJ, et al. Group of Panelists for the Global Delphi Panel of Keratoconus and Ectatic Diseases. Global consensus on keratoconus and ectatic diseases. Cornea. 2015 Apr;34(4):359-69.

DR. CHANG is director of cornea specialty lenses at Wills Eye Hospital Cornea Service and director of clinical services at TLC VIsion. He is a board member for International Keratoconus Academy and Optometric Cornea Cataract and Refractive Society and the host of “Chang Reaction” podcast.

DR. RAPUANO is chief of the Cornea Service at Wills Eye Hospital. Dr. Rapuano is a nationally and internationally recognized expert in corneal diseases, with a special interest in refractive surgery.