Testing, Testing

It was not long ago that keratoconus was seen as a rare disease, with a commonly cited paper from 1986 indicating an incidence of 0.054 percent in the US population (1). We now recognize that is not nearly as rare, with keratoconus incidence being different worldwide, more commonly seen in hotter climates and in eye rubbers. As a community, we have accepted the condition is increasingly more commonplace – which is something I see reflected in my own patient population, which is more skewed from the point of view of a corneal specialist. One out of every three corneal consultations in my clinic involves a keratoconus suspect. It seems obvious to say that advanced keratoconus is not difficult to diagnose. You can almost diagnose the condition in a more advanced keratoconus case by reviewing the level of astigmatism in the manifest refraction, coupled with the best-corrected vision that it yields, especially if there is a limitation to the spectacle-corrected vision.  You know with more certainty if their topography/tomography demonstrates inferior steepening or irregularly-skewed bowties. But the real problem with diagnosis lies in mild cases. The issue is particularly critical for younger patients who are coming in for refractive surgery consultations, because ophthalmologists run the risk of inducing clinically relevant keratoconus by performing surgery. Also, keratoconus that starts in a younger age is often more aggressive in its progression, and this lends these patients to be more susceptible to requiring corneal transplantation at a younger age.

Prior to the approval of collagen cross-linking in 2017, doctors in the US were only able to warn patients against eye rubbing and aim for best corrected vision, either with glasses or therapeutic contact lenses. There was no medical option to truly halt or stop keratoconus progression. Various surgical therapies have been available, but reserved to surgically treat those who are contact lens intolerant or uncorrectable due to scarring or corneal steepness.  Surgical options include corneal ring segments (INTACS) and corneal transplantation, either with a deep anterior lamellar keratoplasty (DALK) or a full penetrating keratoplasty (PKP). Collagen cross-linking (CXL) acts as a bridge between these extremes and offers patients new hope. Though its approval has been delayed in the US, there is over a decade’s worth of global data that does appear to demonstrate the ability of cross-linking to halt the disease progression in some patients.

Regarding the CXL procedure itself, in the US, the standard cross-linking treatment follows the Dresden protocol, which is epithelium-off (“epi-off”), a 3-milliwatt epicurean at a 30-minute exposure. Other off-label CXL treatments include a higher fluence UV therapy for a shorter time duration (same total UV exposure) and an epithelium-on (“epi-on”) protocol. Since the penetration of riboflavin is inhibited by the intact epithelium in an “epi-on” technique in the US, surgeons use different creative approaches to help embed the riboflavin into the corneal stroma (topical tetracaine, longer soak period, micropuncture).

I perform CXL both epi-off and epi-on, but lean towards “epi-off” for those who have more advanced disease. For the advantages mentioned above, my  preferred treatment for patients with a less advanced form of keratoconus  is “epi-on”, but for anyone with high risk of failure – be it K values over 53-54 dioptres, those with poor spectacle-corrected visual acuity, or extremely young patients – I prefer the “epi-off” Dresden protocol because it offers the greatest chance at halting progression and flattening a steep corneal apex. Pain, corneal haze, and delayed corneal re-epithelialization are the more common side effects of “epi-off” CXL.  With an “epi-on” CXL, pain is minimal and corneal haze is infrequent, thus requiring less overall medication in the post-operative healing period. Topical steroids are key to mitigate corneal scarring and haze, and may require a very slow taper over four to six months, in order to prevent or treat corneal haze. In my own experience, delayed healing of the corneal epithelium status-post collagen cross-linking is more commonly seen than in my PRK cases, leading me to believe there is a possibility that exposure to UV light temporarily stuns the limbal stem cells. Though I don’t have data to prove this theory, I have certainly seen it in my own practice.

It is important to take a moment to counsel patients that their vision may continue to change. To accommodate any potential prescription shifts, I recommend for patients to maintain their current spectacles or contact lenses for the first six months. In the first few months after surgery, it is not uncommon to see epithelial hypertrophy and a bump of corneal steepening centrally as a result, especially after epi-off therapy. After six months or so, the corneal epithelium slowly smooths and flattens out. There is the possibility that some patients will continue to flatten over time – with some studies showing evidence of progressive flattening upwards of six years post-surgery – though it is hard to identify exactly which patients will experience this phenomenon.

Keratoconus screening has advanced significantly over the last decade, including various screening protocols, tomography advancements, corneal hysteresis and epithelial mapping. While these all provide insight and guardrails, there is yet to be a true definitive tool to rule patients in or out for sub-clinical disease. These “unknowns” are what makes genetic testing so exciting. It allows us to base our assessments on genuine insight rather than best-educated guesses – something that will hugely benefit non-obvious keratoconus suspects. Though we know family history is a huge marker for keratoconus, it does not indicate speed or risk of progression. It is also useful in terms of deciding which patients are suitable for corneal refractive surgery. Studies have proven that there is a higher prevalence of stromal dystrophies that manifest after LASIK or PRK, particularly in East Asian populations. Knowing this, we should be able to correctly identify patients genetically predisposed to go from sub-clinical to clinical – before their vision begins to seriously deteriorate. And that is the true power of genetic testing.

When the tests become available, I will personally recommend them to every corneal refractive patient in my practice, and strictly require it to be performed on any refractive evaluation that has a suspicious risk factor (such as irregular astigmatism, steep Ks, thin corneas). Additionally, young patients with rapidly shifting astigmatism or myopic errors are a target audience to genetically test. The ability to identify and treat patients at a younger age could truly change the clinical manifestation of keratoconus. Cross-linking patients early could ultimately prevent the potential need for corneal transplantation, which, in turn, could halt the repeated transplants over the lifetime of a young patient. In my mind, it is worth the small investment to determine the likelihood of a successful surgical outcome and reduce further complications in the future.