New staging system may improve management of neurotrophic keratitis

The staging system used for neurotrophic keratopathy, or NK, is the Mackie classification from 1995 with recent modifications by Dua, which clusters a number of distinct and sometimes nonsequential phases of NK into three broad categories.

This system reflects a time in which the knowledge of NK as well as its management was still limited.

Nowadays, the therapeutic landscape for NK has expanded, and we can aim at diagnosing and treating the disease earlier, preventing it from progressing to the later stages and potentially saving vision. Therefore, we needed an updated staging system that allows us to more precisely classify the early signs and symptoms of NK, manage it proactively, and monitor progression, treatment effects and possible exacerbations.

With this aim, we formed the Neurotrophic Keratopathy Study Group, in which 11 experienced corneal specialists worked together and developed a novel six-step staging system, published in The Ocular Surface in 2023. The old classification emphasized the epithelium as a marker of disease severity, from the initial signs of mild staining to a persistent epithelial defect until the disease progresses to the more advanced stages of corneal thinning of the stroma. But the stroma can be even more significant at the earlier stages and has consequences in terms of visual prognosis. Therefore, in our new staging system, we gave the stroma a more prominent role. We also recognized that even before any signs become evident, there may be alterations in the corneal nerves that lead to loss of sensation. This is the stage that is classified as stage 1, altered sensation without keratopathy. At stage 2, the disease has progressed to punctate epithelial keratopathy (PEK), but no stromal haze is present. As the keratopathy worsens, we enter stage 3, in which a persistent or recurrent epithelial defect is present, still without stromal haze. At stage 4, we may have epitheliopathy, PEK or a persistent/recurrent epithelial defect but now with stromal haze. Subsequent degradation and thinning of the stroma lead to stage 5, with a persistent or recurrent epithelial defect, now with stromal ulceration. Finally, at stage 6, corneal perforation occurs.

Detecting and treating the disease within the first three stages are crucial to the prognosis because the eye can heal with fewer or no consequences. Until recently, we did not have any direct treatments. We were mostly trying to compensate the ocular surface in other areas with indirect treatments to make up for the lack of nerve sensation, but we could not bring the nerve sensation back. Now, with cenegermin, autologous serum tears (and other biologic tear substitutes) and neurotization, we can not only stabilize NK better, but we can potentially downgrade the staging and the disease with less visual sequelae if caught early (especially if before stage 4). When Mackie published his classification, these treatments were not readily available.

In studies, cenegermin was mainly used in eyes with a frank epithelial defect, but personally I start using it earlier, as soon as I see epitheliopathy becoming severe and refractory, especially if I start noticing the early signs of anterior stromal haze due to the sick epithelium. Halting progression of the disease before the onset of haze, which is a red flag for visually significant consequences, leads to a much more favorable prognosis. Over time, I have seen stromal haze diminish if healthy epithelium is maintained over the cornea following cenegermin or a tarsorrhaphy.

There has been slow adoption of our classification likely due to our lack of publicizing it and the fact that the Mackie classification has been around for so long. Moving to six stages instead of three stages might seem burdensome, but it will be easier for clinicians to communicate where in the course of NK progression their patient is as well as to better demonstrate improvement or worsening in their documentation. A primary goal of the staging system is to encourage testing corneal sensation earlier. I do this now with most of my patients when they come in, whether as a cornea, cataract or comprehensive appointment. You would be surprised how many people have decreased sensation, and having this information gives me better context to frame their overall care.

• References:
• Mackie IA. Neuroparalytic keratitis. In: Fraunfelder F, et al, eds. Current Ocular Therapy. WB Saunders; 1995.
• Neurotrophic Keratopathy Study Group. Ocul Surf. 2023;doi:10.1016/j.jtos.2023.09.001.

• For more information:
• Albert Y. Cheung, MD, of Virginia Eye Consultants, Norfolk, Virginia, can be reached at acheung@cvphealth.com or aycheung8@gmail.com.

Click here to read the Cover Story, “Neurotrophic keratitis more prevalent than previously thought.”

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Disclosures:
Cheung reports consulting for Brightstar Therapeutics and Sight Sciences and having ownership interest in Moya Ocular.

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