Epithelial thickness profiling: unmasking keratoconus

An epithelial doughnut-like pattern may provide an important clue

With permissin: Reinstein, D. Z., Archer, T. J., & Gobbe, M. (2009). Corneal epithelial thickness profile in the diagnosis of keratoconus. Journal of Refractive Surgery, 25(7), 604-610.

A unique epithelial thickness pattern may help to point the way to definitive identification in cases of potential keratoconus, according to Dan Z. Reinstein, M.D., medical director, London Vision Clinic, London. In the July 2009 issue of the Journal of Refractive Surgery, Dr. Reinstein reported on how epithelial thickness maps could be used to help diagnose or exclude keratoconus in cases with uncertain keratoconus on standard clinical, topography, and tomographical screening.
“The epithelium is a highly active layer that very rapidly remodels to compensate for any change in the stromal surface shape,” Dr. Reinstein said. “We are taking advantage of this property together with our ability to map the epithelial layer with 1 micron precision over the whole cornea with Artemis technology to detect sub-surface anterior stromal cones, which may not be evident on topography.” While back surface changes in early keratoconus can be mapped by optical tomography, front surface changes, if small, can be completely masked by epithelial remodeling. “Essentially, the map of the epithelium enables us to distinguish which corneas with a slight back surface abnormality are likely keratoconic and which are most likely not,” Dr. Reinstein said.
Using the Artemis very high frequency digital ultrasound arc scanner (ArcScan, Golden, Colo.), investigators obtained the epithelial thickness profiles of 110 normal eyes. “What we found was that the average thickness of the epithelium in the population was fairly tightly controlled: central epithelial thickness was 53 microns with a standard deviation of about 3 microns,” Dr. Reinstein said. “The interesting thing was that while it was fairly similar all over the eye, the epithelium was slightly thinner superiorly than inferiorly and ever so slightly thinner temporally than nasally.”
Dr. Reinstein and colleagues theorized that blinking is at the root of this pattern. “Because the upper lid is much more active than the lower lid we theorize that there was more force coming down from the superior part of the cornea than coming up from the lower lid,” Dr. Reinstein said. “The action of the upper lid causes chafing of the superior epithelial cells preferentially, relative to the inferior cornea.” Investigators found that this pattern was very repeatable between patients, giving them a benchmark to consider in cases of potential keratoconus where the epithelial pattern deviated from this norm.
Distinct “epithelial doughnut pattern”
Likewise, when they mapped the epithelium in clear-cut cases of keratoconus they found a unique pattern. “We found that in keratoconus the epithelium has a very distinct pattern of thinner epithelium over the cone, surrounded by an annulus of thickened epithelium,” Dr. Reinstein explained. The difference between the thickest and thinnest epithelium was dramatically different than in “normal” patients. “The epithelium over the cone in corneas with keratoconus can be very thin—it can get down to 25 or 26 microns,” Dr. Reinstein said.“Similarly, in the surrounding annulus of thicker epithelium, the epithelium can thicken to a very high degree, sometimes reaching up to and beyond 100 microns.” These extremes are well outside the values possible within the normal corneal population.
In early cases this pattern can help to mask a keratoconus cone. “In advanced keratoconus the epithelium sometimes breaks down because of excess thinning, but in very early keratoconus the anterior surface cone will be so mild that epithelial thinning occurs in such a way as to completely mask the anterior surface cone,” Dr. Reinstein said. “Front surface topography can look normal even though a mild sub-surface stromal cone exists.”
This distinctive pattern can potentially help make a diagnosis in cases where anterior surface topography is equivocal. “You can look at the topography and think that it looks funny but not know whether it’s keratoconus or not,” Dr. Reinstein said. “It might be that the corneal surface is asymmetric with no underlying keratoconus, or it might be that there is indeed keratoconus that is being masked by epithelial remodeling.”

Cases on the epithelial edge

In the recent paper, investigators presented five cases including one of a normal eye, one of a definitive keratoconus case, and three cases where the keratoconus diagnosis was in question.
In the first case topography showed a bit of inferior steepening. “This is one of the patterns that can be suggestive of keratoconus,” Dr. Reinstein said. “The computerized diagnosis from the Atlas placido topographer (Carl Zeiss Meditec, Dublin, Calif.) said that the eye was normal, and the Orbscan (Bausch & Lomb, Rochester, N.Y.) anterior best fit sphere plot also looked relatively normal. However, the back surface best fit sphere on Orbscan showed an eccentric, elevated apex—a sign of a possible cone.”
When investigators considered the epithelial profile in conjunction with the Atlas and Orbscan information, they were able to make a definitive diagnosis. “The epithelial thickness profile showed a clear pattern of thinner epithelium surrounded by an annulus of thicker epithelium, the pattern similar to that of corneas with keratoconus,” Dr. Reinstein said. “It had thin epithelium overlying the region where the equivocal back surface eccentric elevation occurred. While there were no changes on the front surface topography, the epithelium gave away the fact that there was indeed a sub-surface anterior stromal surface cone coincident with the back surface eccentric elevation. In addition, the epithelium was thickened in the characteristic doughnut pattern, thus alerting us that this purportedly normal eye was in fact mildly keratoconic.”
The second case involved an eye that had topography that was virtually identical to the first. “It had ever so slight inferior steepening and the automatic output from the topographer says that there is suspect keratoconus,” Dr. Reinstein said. “Again, the Orbscan anterior and posterior best fit sphere plots were relatively normal.” In this case, however, the epithelial profile told a different story from the first. “When we looked at the epithelial thickness profile we saw a pattern that was identical to a normal patient—ever so slightly thinner on top and thicker on bottom,” Dr. Reinstein said. “In this case, the epithelium overlying the zone of inferior steepening on placido topography was thicker, not thinner, implying that there could not have been a sub-surface anterior stromal cone.”
In the third case described here, the topography was completely normal. The only thing that hinted at potential keratoconus was an eccentric, elevated apex on the back surface best fit sphere plot. When investigators looked at the epithelium they found that it was actually thinning over the back surface “cone,” with the typical thickening pattern around the area of epithelial thinning. “In that case, the epithelium was able to compensate 100% for the cone on the back surface to make the front surface look completely symmetrical and normal,” Dr. Reinstein said.
Another study, published in the May 2009 issue of the Journal of Refractive Surgery, lends credence to the fact that eyes deemed normal by the epithelial profile are in fact non-keratoconic. “We were showing the stability of refraction in eyes where we had done LASIK in cases where the topography was slightly suspicious but the epithelium proved them to be normal,” Dr. Reinstein said. “When we compared these eyes to a control group of patients who were completely normal on topographic screening—and did not require Artemis epithelial mapping to prove so—we found that there was no difference between the two groups in the stability of the refraction and the topography at one year.”
Going forward investigators are working to quantify the changes that occur in the epithelial maps in early keratoconus. “We’re working to develop indices that can identify keratoconus from normal rather than just looking at the pattern,” Dr. Reinstein said. “The holy grail is to be able to put all the topography, refraction, epithelial, and corneal thickness data into a big pot and work out some multivariate derived function that will tell us whether the patient has keratoconus or not.”

Editors’ note: Dr. Reinstein has financial interests with Carl Zeiss Meditec (Dublin, Calif.), has a proprietary interest in the Artemis technology (ArcScan, Golden, Colo.), and is the author of patents related to VHF digital ultrasound administered by the Cornell Research Foundation (New York).

Contact information

Reinstein: +44 207 224 1005, dzr@londonvisionclinic.com