Keratoconus (KCN) is a leading cause of visual frustration for patients — it is progressive and can even lead to the need for corneal transplantation, a major life event that requires a lifetime of care with the possibility of rejection or need for specialty contact lenses.

With the new approach of corneal cross-linking (CXL), the management of KCN has radically changed.

CORNEAL CROSS-LINKING

Overview

Since Avedro’s CXL system received FDA approval for the treatment of progressive KCN and post-refractive ectasia in April 2016, CXL has become the gold standard to halt progression of these conditions. CXL is a minimally-invasive, in-office procedure that combines the application of commercially manufactured ophthalmic riboflavin (vitamin B2) solution and ultraviolet radiation (UV-A) to the corneal stroma.¹ Free oxygen radicals are produced during CXL, which ultimately results in the formation of new covalent bonds in stromal collagen.² The FDA-approved epithelium-off technique utilizes the “Dresden protocol.”^3-5 Clinical results of CXL include arresting progression of the condition, vision preservation, possible improvement of topographic shape and preventing the future need for keratoplasty.

The initial laboratory investigation in CXL started in the late 1990s² and has now spread to different clinical applications worldwide, including strengthening ectatic corneas, preventing post-refractive surgery myopic or hyperopic regression and treatment of infectious keratitis. It can also be used in conjunction with other treatment modalities, including intacs, conductive keratoplasty (CK) or topography-guided photorefractive keratectomy (PRK). Additionally, a less invasive, off-label, epithelium-on technique can reduce risks associated with epithelial removal. An epithelium-on FDA trial is currently underway. Combining CXL with other technologies at this time is considered off label.

Diagnosis and timing

If progression of ectasia is documented, CXL is warranted. Documentation of progression can be a challenge in some cases, however. Insurance companies require documentation of progression, the definition of which may include:

• An increase of at least 1.0 D in the manifest cylinder of steepest keratometry measurement
• An increase of at least 0.5 D in manifest refraction spherical equivalent
• Failure of spectacle correction or rigid contact lenses
• Relative inferior steepening with inferior-superior difference of at least 1.5 D on topography
• Corrected distance visual acuity worse than 20/20
• Corneal thickness of at least 300 µm at the thinnest area

Because corneal ectasia never improves without treatment, CXL may also be warranted without clear signs of progression. Given that humans aren’t born with ectasia, the presence alone of topographic findings suggests that progression occurred at some point. Therefore, CXL should be considered in all cases, despite “recent” documentation of progression.

The pediatric population and young adults in their early 20s are amongst the highest at risk for KCN progression, although no-one is ever “safe” from progression. For this reason, CXL should be considered a sight-preserving treatment in patients of all ages to avoid the risk of progression and continued vision impairment. In the future, screening programs in schools or pediatricians offices may allow for early detection and treatment before progression occurs, with the goal of sight preservation, in contrast to the current approved treatment requiring recent progression documentation.

Office implementation and insurance

Office implementation of CXL requires space — a clean room and possibly an extra exam room. The procedure should not compromise practice efficiency as it can be incorporated into the daily clinical flow. The procedure is typically performed in the office during clinic hours under oral sedation, such as low-dose benzodiazepine.

CXL also requires an experienced, educated team of office support staff to assist with patient scheduling, counseling, care and reimbursement. This includes the assistance of a trained technician who is comfortable staying with the patient during the loading of the riboflavin and light treatment and able to review the details about postoperative care.

The follow-up schedule for patients who undergo CXL includes a return visit at 1-day postop along with careful evaluation thereafter in the first week until epithelial healing. Patients typically are seen at 4 to 6 weeks, 3 to 4 months, 6 to 9 months and then at 1 year and then yearly post CXL. Younger patients, however, are seen more regularly in subsequent years because they are at high risk for KCN progression.

Insurance coverage for CXL has come a long way since the procedure first became commercially available, and it is continuing to improve. Currently, six national and 60 regional health plans cover the procedure, which encompasses more than 95% of commercial lives. In 29 states, eight or more plans cover CXL.

Progression and retreatments

CXL is thought to be a one-time treatment but can be repeated in cases of continued progression after the procedure. Establishing progression can be challenging, however, especially in advanced cases that require rigid contact lenses for functional vision. Accurately and consistently obtaining quality tomography, topography and Kmax can be extremely challenging, even impossible at times. Additionally, Kmax alone may not be the best indicator of progression. It is possible that if the same eye is imaged on the same day three separate times that three unique Kmax values could be obtained. Rigid contact lens use can cause significant warpage on corneal topography, so requiring patients to undergo a contact lens holiday of at least 7 to 10 days prior to testing is recommended. Being out of contact lenses can be a logistical challenge for the patient; however, eyes that rely on rigid lenses for functional vision are inevitably more advanced, harder to image consistently and are at higher risk for progression.

Other clear signs of progression including worsening of BCVA, increased consistent tomographic and topographic steepening of the cone and subjective worsening of vision. When clear signs of progression are encountered, CXL retreatment is warranted. Given the limited research on CXL retreatments and progression, it is important to gather reproducible data, sometimes with a series of evaluations several weeks apart. A detailed surface exam looking for punctate keratopathy, scarring or nodule formation is also performed as these signs may affect topography and tomography readings. The data points should show consistent worsening to proceed with retreatment. When the data is not clear or reproducible or the signs are not consistent (for example, improved BCVA with increased steepening on tomography), repeat the testing again in 6 to 8 weeks to reevaluate.

Additional aspects to consider are whether the patient has maintained quality vision worth preserving despite progression and whether the cornea is thick enough for CXL. If there is significant scarring or limited vision with the current lens system, a deep anterior lamellar or penetrating keratoplasty could be indicated. The same considerations for initial CXL treatments should be reviewed.

There have been no case reports of more than one retreatment in the literature on any one eye. While there is limited information of the efficacy of repeat CXL treatments, the risk of progression after a retreatment is likely to be very low. Reevaluation of the rigid contact lens system to maximize vision and fit may also be indicated.

CONTACT LENSES FITTING

Challenges and goals

An irregular keratometric shape presents many challenges for clinicians attempting to achieve optimal vision and fitting with contact lenses. The increased higher-order aberrations (HOAs), dysphotopsias and impaired visual function untreated with spectacles render ideal contact lens fitting extremely important in providing optimized vision. Fortunately, many customizable options are available in a wide range of parameters and materials, including soft specialty lenses, rigid gas permeable lenses (RGPs), hybrid lenses and scleral contact lenses.

In general, clinicians should have three goals in mind when approaching a KCN fit: adequate visual function for the patient’s daily needs, acceptable comfort throughout the wearing period and a good physiological fit, ensuring there is sufficient oxygen permeability to promote long-term ocular surface health.^6-8

The initial lens choice may be based on a patient’s prior lens wearing experience. If the patient is comfortable and functioning well in the current lens system, there may be no need to make significant changes.

Specialty soft lenses

Another fitting strategy is to choose the initial lens based on the severity of the patient’s KCN. A forme fruste patient may do well, for example, with a standard soft contact lens, while a patient with a mild to moderate KCN may be best suited for a specialty soft lens designed for the ectatic cornea. The design of these lenses with a center thickness that is typically three to six times that of a traditional soft lens masks the corneal irregularities and improves symptoms associated with HOAs. Additionally, they are more comfortable with increased tolerability. Due to their more frequent disposal schedule, patients often have sealed lenses in reserve, which may ultimately reduce the anxiety of losing a lens.^6-8

Corneal gas permeable lenses

The standard for visual optimization management with KCN has traditionally been with corneal RGP lenses. They are still routinely prescribed and, amongst the available lenses, are the least disruptive to corneal oxygenation due to their movement and smaller size. They are an excellent choice for fitting any stage of KCN and are especially effective when the patient has a more centrally located or mild paracentral oval cone. Due to their smaller size, they are often the only contact lens option for patients with small apertures, deep sockets or disabilities that prevent the successful handling of larger lens designs.^6-8 The back surface of the lens, however, bears weight on the cornea and, together with the lens’ edge profile, can lead to longer adaptation time and greater lid-lens interaction.

In patients with moderate to severe KCN, GP lenses may bear excessive weight on the cornea. Piggybacking or fitting a soft contact lens under this lens serves to protect the epithelium and relieves discomfort from mechanical trauma and thus promotes corneal health, but not all patients appreciate taking care of a double lens system. Using a single-use, daily disposable silicone hydrogel lens can overcome the increased maintenance of the dual lens system as well as provide the necessary enhanced oxygen transmissibility. For advanced cones, it may be difficult to find a well-fitting soft lens, making this system less useful.^6-8

Hybrid lenses

Hybrid contact lenses (SynergEyes) are good options for mild to moderate stages of KCN. They offer choice of lens design in an expanded range of fitting parameters, so the clinician can best fit the lens to the cone. The central GP lens provides consistent quality of vision, while the surrounding soft skirt contributes to lens comfort, centration and ease of adaptation. The newer generation hybrid lenses provide improved oxygen permeability thanks to an increasing Dk value of the RGP lens and the use of silicone hydrogel materials for the skirt. Proficiently fitting these lenses requires a steep learning curve.^6-8 Also, the lens presents some challenges for patients. In particular, the technique for insertion and removal requires patience and practice.

Scleral lenses

Scleral contact lenses are believed to be among the best vision correction options for KCN in addition to other irregular-shaped corneas and ocular conditions. They can achieve a stable fit with improved comfort. While initially reserved for the most severely irregular corneas, scleral lenses have evolved to fit a much broader population. The peripheral aspect of these large diameter lenses rests on the conjunctiva overlying the sclera, while the central lens vaults over the irregular cornea. Notching or micro vaulting the lens periphery can help clear anatomical obstacles such as a pinguecula or pterygium. These lenses provide protection of the ocular surface, keeping it bathed in saline throughout the wearing period. Similar to SynergEyes, a level of skill and dexterity is required by the patient to master the handling of the lens. It is a great choice for those individuals involved in watersports, vigorous sport activities or for those exposed to dusty environments due to the seal preventing material from getting underneath the lens.

Timing of fitting/refitting after CXL

Patients are eager to undergo contact lens fitting after CXL, but the timing must be appropriate. It is critical to begin the fitting process after patients have allowed sufficient time for epithelial remodeling. After the classic epi-off Dresden protocol, the patient should wait at least 6 to 8 weeks, while patients who undergo off-label epi-on techniques may only require a 4- to 6-week waiting period. The visual recovery after epi-off is significantly slower, and these eyes appear to have more corneal sensitivity likely due to significant epithelial remodeling and greater impact on cornea nerve tissue.

Insurance

Some medical insurances recognize the necessity of contact lens wear for these patients and will allocate coverage for fittings and certain lens types. Other insurance companies have specific policies that limit coverage. It is important to have a point person in the office who can check insurance coverage and stay abreast to changes in policies and possible submission for prior authorization. Knowledge of the specific ICD-10 codes for lens fitting and materials helps to streamline the process.

CONCLUSION

CXL has revolutionized the treatment of KCN and post-refractive ectasia as the only treatment to halt progression of these conditions, thus preserving vision and preventing the need for keratoplasty. Contact lens fitting, done approximately 4 to 8 weeks after CXL, can provide optimal vision for the patient. Keep in mind that patients need long-term follow up and monitoring of their condition. OM

REFERENCES

1. Soeters N, Wisse RP, Godefrooij DA, Imhof SM, Tahzib NG. Transepithelial versus epithelium-off corneal cross-linking for the treatment of progressive keratoconus: a randomized controlled trial. Am J Ophthalmol. 2015;159:821-828.
2. Koller T, Mrochen M, Seiler T. Complication and failure rates after corneal crosslinking. J Cataract Refract Surg. 2009;35:1358-1362.
3. Wollensak G, Spoerl E, Seiler T. Riboflavin/ultraviolet-a-induced collagen crosslinking for the treatment of keratoconus. Am J Ophthalmol. 2003;135:620-627.
4. Chen X, Stojanovic A, Eidet JR, Utheim TP. Corneal collagen cross-linking (CXL) in thin corneas. Eye Vis (Lond). 2015;2:15.
5. Randleman JB, Khandelwal SS, Hafezi F. Corneal cross-linking. Surv Ophthalmol. 2015;60:509-523.
6. Eiden SB, Chang UC, Davis R, Brafman S. Contact lens options for managing keratoconus and keratectasias. Contact Lens Spectrum. 2013;28:38-44.
7. Morgenstern AS. The full spectrum of keratoconus care. Contact Lens Spectrum. 2019;34:22-28.
8. Chang CY, DeNaeyer GW. Specialty contact lenses: Treat your keratoconus patients right. Review of Optometry. 154:Review of Cornea and Contact Lens supplement. 2017;2;14-17.

About the Authors

Kathryn M. Hatch, MD, is the director of the Refractive Surgery Service at Massachsetts Eye and Ear, and the site director of Massachusetts Eye and Ear Waltham. She has a special interest in the area of diagnosis and treatment of keratoconus and is beginning a research program studying biomarkers for this condition.

Karen Zar, OD, practices full scope optometry with an interest in anterior segment and specialty contact lens fitting at the Massachusetts Eye and Ear Infirmary.

Disclosure: Dr. Hatch is a consultant and shareholder with Avedro.