Corneal collagen cross-linking (CXL) has rapidly become the standard of care for treatment of progressive keratoconus. Knowing when the disease is actually progressing and how rapidly the cornea might change is important, both for providing appropriate care and for ensuring the patient’s access to coverage of the procedure by their insurance carrier.

Most insurance carriers, with the glaring exception of Medicaid, now cover both the drugs (Photrexa Viscous [riboflavin 5’-phosphate in 20% dextran ophthalmic solution] and Photrexa [riboflavin 5’-phosphate ophthalmic solution], Glaukos) and the CXL procedure when performed with the FDA-approved iLink platform (Glaukos). Private insurance carriers have wisely decided that the costs of CXL are more than offset by the savings of avoiding penetrating keratoplasty and/or vision loss. A recent study found that, even using very conservative estimates for the expected rates of progression, CXL has a much faster return on investment for the health-care system than many other widely used treatments.¹ It also substantially reduces the lifetime economic burden and increases patient quality-of-life years for patients with keratoconus in the United States.¹

However, insurance carrier requirements for documentation of keratoconus progression vary. The most commonly used definition was one of the key inclusion criteria in clinical trials leading to FDA approval of what is now called the iLink platform: A ≥1.0 D change in maximum keratometry (Kmax), the steepest point on the cornea as measured by the Pentacam (Oculus), within a 24-month period. Although Kmax is an important metric, it should be considered in the context of other signs and subjective measures for the most accurate diagnosis.

In some cases, the normal variations in patients’ visit frequency can obscure true progression. Some insurance carriers may want to see documented progression over 1 year, for example. Imagine a keratoconus suspect who was first evaluated on June 15, 2019. That patient’s next appointment, scheduled for a few days beyond the 1-year mark in 2020, was cancelled due to a vacation and, by the time it was rescheduled, it had been 16 months since the last exam. At that visit, Kmax had increased by 1.5 D, but it is impossible to say how much of the change occurred within 12 months. This patient may fail to meet a 1-year Kmax definition for progression, even if he has also lost vision and I am confident he is progressing.

Here is a review of the other factors that should be considered as part of a determination of progression.

VISUAL ACUITY

Visual acuity is an extremely important factor in how I screen for keratoconus and monitor progression of the disease. In young patients, we should all have a heightened level of suspicion when there is a myopic shift of ≥0.5 D or an increase in cylinder of ≥1.0 D within 12 months.^2,3 High astigmatism by itself doesn’t necessarily point to progressive keratoconus, especially if it is regular. However, I watch high astigmats very closely for any signs of thinning or ectasia. Those with irregular, asymmetrical (greater in one eye than the other) or progressing astigmatism should have regular topography exams.

A big concern for me is unexplained loss of BCVA. Even on an initial visit with a patient for whom no refractive history is available, BCVA below 20/20 can be evidence of progression. I saw a 15-year-old male with 20/40 BCVA OD. That is not terrible vision, and it would be easy to overlook this in a primary care setting, but topography and tomography to closely evaluate both surfaces of the cornea are warranted even for this modest loss of BCVA. His topography (Figure) shows an obvious cone. This teen underwent CXL soon thereafter. His BCVA improved to 20/25 post-treatment, and we continue to monitor for any further corneal changes.

Similarly, a teen or young adult who presents with 2 D of cylinder and 20/30 UCVA while claiming to have been able to see “just fine” without glasses in the past most likely has progression of their keratoconus. While we may not have two topographies to compare, these patients have progressed, from plano/normal to abnormal. If we wait to show progression of Kmax 12 months later, that patient could lose another line or two of BCVA. That is the equivalent of telling a glaucoma patient, “You only have mild visual field damage, come back in a year and we’ll see if it has gotten worse.” At the very least, young keratoconus suspects with no history should be seen again in 3 months, rather than 12. However, young people can progress very quickly, so my preference is to use multiple factors (vision change, imaging, etc.) as evidence of progression, so the patient can be treated quickly and further vision loss can be prevented.

It is important to educate referring clinicians that any loss of best spectacle-corrected acuity is problematic and calls for a referral. Too often, if the patient is correctable to 20/20 with contact lenses, the optometrist or general ophthalmologist thinks, “This is not a surgical patient. I’m going to continue managing.” The next year, BCVA drops to 20/25, then 20/30. Finally, the patient is referred to a corneal specialist when he reaches 20/40. In reality, that patient has been progressing all along, but now we have no imaging to confirm the rate of change. The patient may still be a candidate for CXL, but documentation is more challenging — and the patient has irretrievably lost vision.

CXL is best for stabilization and prevention of vision loss, rather than recovery of lost vision. Therefore, while we have many patients who have dramatic improvements in their vision, we cannot count on this. If we wait too long to prove progression, we may doom the patient to permanent vision loss in the process. Often, this information needs to be discussed with the insurance carrier to obtain approval for treatment. We do not want to wait until a keratoconus patient suffers permanent vision loss from progression before treating.

QUALITY OF VISION

A progressing keratoconic cornea can induce higher-order aberrations leading to changes in visual quality, even before a loss in acuity or change in Kmax. For this reason, new subjective complaints of glare, halo or other distortions should be taken seriously. Some patients may have trouble articulating what specifically has changed and will just say their vision “isn’t as good as it used to be.” That may be a normal feature of lenticular changes in early presbyopia but should raise suspicions in a younger patient.

CORNEAL FINDINGS

Corneal striae, scarring, Fleischer ring, Munson’s sign and other corneal signs of keratoconus are generally indicative of more advanced disease. However, it is possible to have corneal signs of keratoconus prior to Kmax steepening by a significant amount, so corneal findings should certainly be taken into account in a patient with inadequate history to demonstrate progression.

RETINOSCOPY

Many primary eye-care practices have moved away from routine dilation, but it is still important to perform in pediatric patients, despite the inconvenience and discomfort of dilation. Cycloplegia remains the best way to get a good refraction in an eye with full accommodation and makes it easier to visualize scissoring on retinoscopy, a classic sign of keratoconus. Any irregular retinal reflex on retinoscopy should be factored into diagnosis and a decision to refer for advanced imaging.

PERSONAL AND FAMILY HISTORY

We should have a lower threshold for progression in any patient with a family history of keratoconus.⁴ Because everyone is familiar with the term “keratoconus,” I ask about family members who wore thick glasses, who had a lot of astigmatism, had eye surgery at a young age or who had trouble wearing contact lenses. When one child has been diagnosed with or treated for keratoconus, I recommend a full evaluation of any siblings.

Also, I ask about any personal history of atopy or eye rubbing.⁴ Eye rubbing is associated with keratoconus. While we don’t fully understand the relationship, it may be that the mechanical rubbing of the eyes initiates or accelerates progression. In a child with a history of eye rubbing, I recommend antihistamine allergy drops to try to prevent this. Pataday (olopatadine 0.1%, 0.2%, or 0.7%, Alcon) and Zaditor (ketotifen 0.025%, Alcon) are available over the counter, and the prescription agent Zerviate (cetirizine 0.24%, Eyevance Pharmaceuticals) also prevents itching.

ALGORITHMIC CHANGE

Some new algorithms can help in monitoring and quantifying meaningful change in keratoconus. I use the ABCD classification system that is integrated into the Pentacam. It creates a composite score of four different parameters: Anterior (A) and posterior or back (B) radius of curvature (taken from a 3-mm optical zone centered on the thinnest point); minimum corneal (C) thickness; and best spectacle-corrected distance (D) acuity.² A change in ABCD score can be used to document progression, even if the patient does not meet more traditional definitions of progression.

MONITORING PROGRESSION POST-CXL

Defining keratoconus progression is even more challenging after CXL treatment. With CXL, steep areas of the cornea get flatter and flat areas may get steeper, so it is important to look at the entire corneal configuration, not just maximum keratometry. Here, difference maps can be very helpful.

In seeking to determine whether a keratoconus patient is progressing, remember that we are treating patients, not numbers. A holistic evaluation that takes into account not just the numeric change in imaging metrics, but also the patient’s history, visual acuity, subjective complaints, and corneal and retinal signs is critical to determining whether progression has occurred or is likely to in the near future. OM

REFERENCES

1. Lindstrom RL, Berdahl JP, Donnenfeld ED, et al. Corneal cross-linking versus conventional management for keratoconus: a lifetime economic model. J Med Econ. 2020; online ahead of print.
2. Belin MW, Alizadeh R, Torres-Netto EA, et al. Determining progression in ectatic corneal disease. Asia Pac J Ophthalmol (Phila). 2020;9:541-548.
3. Ferdi A, Nguyen V, Kandel H, et al. Predictors of progression in untreated keratoconus: A Save Sight Keratoconus Registry study. Br J Ophthalmol. 2021;Online ahead of print.
4. Wagner H, Barr JT, Zadnik K. Collaborative Longitudinal Evaluation of Keratoconus (CLEK) Study: methods and findings to date. Cont Lens Anterior Eye. 2007;30:223-232.

About the Author

Kenneth A. Beckman, MD, FACS, is director of corneal surgery at Comprehensive Eyecare of Central Ohio in Westerville, Ohio, and a clinical assistant professor of ophthalmology at The Ohio State University in Columbus, Ohio. Email him at kenbeckman22@aol.com.

Disclosures: Dr. Beckman is a consultant for Alcon, Eyevance and Glaukos.