Corneal ectasia part 3: OCT epithelial thickness measurements allow monitoring of corneal changes

This is the third in a series of articles that summarises an afternoon of presentations, plus a debate, on the topic of corneal ectasia that was held as part of the recent 29th Cologne Adventsymposium, an annual meeting organised by Laserforum e.V., in Cologne, Germany. Chaired by Drs Omid Kermani and Georg Gerten, the presentations each considered the condition from a different perspective and are available online.

Part 1, published in the June 2022 issue of Ophthalmology Times Europe®, considered the contribution of eye rubbing to the development of keratoconus. Part 2, published in the July/August 2022 issue, looked at developments in diagnostics and classification methods for ectatic corneal diseases. This third part of the series covers epithelial imaging and is based on the presentation by Prof. Dan Reinstein and Dr Tim Archer.

Reviewed by Dr Omid Kermani, Prof. Dan Reinstein and Dr Tim Archer.

Prof. Reinstein began his talk by introducing the concept of the epithelial thickness profile, explaining that he had been the first to publish 10-mm epithelial thickness maps of the normal virgin cornea with 1 µm precision.¹ As expected, he found the central thickness to be around 50 µm but, going against everything that had been published previously, found that the epithelium does not have an even profile, being an average of 6 µm thinner superiorly than inferiorly and about 1 µm thicker nasally than temporally. Right and left eyes have mirror asymmetry.

His group has now published around 40 papers on the epithelium alone. “OCT is now confirming many of the things that we discovered originally with ultrasound,” he explained. “What we have learned is that the epithelium changes in all situations where you change the stromal surface curvature.”

According to Prof. Reinstein, looking at how the epithelium behaves in different situations allows four basic rules to be written on how the epithelium acts and how it remodels after a stromal surface change, as follows.

1. The epithelium thickens to fill any relative depressions.
2. The epithelium thins over relative peaks within the stroma.
3. The change in the epithelium is proportional to the change in the stroma. Higher myopicablation produces more central epithelial thickening and peripheral thinning;² higher hyperopic ablation produces more peripheral epithelial thickening and central thinning.³ Epithelial changes are more marked the more severe the keratoconus.⁴
4. The amount of change is defined by the rate of change of curvature (or curvature gradient). For example, a depression from a corneal ulcer that is 1-mm wide and 200-µm deep will be almost entirely smoothed by the epithelium, but a 4.5-mm zone depression made in the stroma by PRK is compensated for less. This corresponds with the improvement in refractive stability and reduction in regression when using larger optical zones.^5,6

Epithelial changes in keratoconus

The cornea has a front (stromal) surface and a back surface. In keratoconus, the front and back surfaces extrude and the epithelium remodels over the peak to become thinner, but it also becomes thicker around the peak to form a “doughnut” shape. As Prof. Reinstein explained, interestingly, when you have a very mild back surface extrusion yoked to a very mild front surface extrusion, the epithelium is able to fully compensate.⁷

This leads to focal thinning of the epithelium in a doughnut pattern overlying the back surface elevation, which is eccentric. The front and back surface data alone may get lost in the soup of statistical variation and therefore fail to signal keratoconus with enough sensitivity.

Commercially, what has become of interest, and what spawned the OCT epithelial thickness industry, was Prof. Reinstein’s demonstration that you could have inferior steepening that could be confirmed by an epithelial thickness map not to be keratoconic but rather due to a thicker inferior epithelium.

His study of 1,500 eyes demonstrated that mapping the epithelium allowed exclusion of keratoconus in 84% of these highly equivocal back surface elevation abnormalities.⁸ This then led to an increase in patients eligible for excimer laser surgery.

Having studied the epithelial thickness profile in keratoconus and established that the more advanced the keratoconus, the thinner the epithelium becomes over the cone and the thicker it becomes around the doughnut, Prof. Reinstein then sought to try and parameterise how this difference in epithelial modelling could be exploited in the very mildest keratoconic cases.

In one of the earliest machine-based pattern-recognition studies from topographic maps,⁹ Prof. Reinstein’s researchers set up around 160 variables in epithelial profiles that they thought might be relevant with respect to keratoconus screening, only six of which turned out to be relevant. This provided an automated algorithm with exceedingly high specificity and sensitivity for keratoconus. It detects a 1- or 2-µm change in epithelial thickness profile, which is much more sensitive than the 1- or 2-µm elevation detected by a topographic or tomographic device with back surface mapping.

Prof. Reinstein explained that the epithelial thickness profile can be used as an adjunctive tool in cases of suspected keratoconus and has applications in cases with seemingly normal topography, cases where both topography and tomography are suspect, and most importantly, those that have normal topography and normal tomography.

Figure 1 shows a case with normal front surface topography, normal Belin/Ambrósio and BAD-D (Belin/Ambrósio display, D value) and nothing remarkable between the back and front surfaces. The epithelial thickness profile shows quite significant focal thinning in the centre of the cornea and the pattern deviation map also shows inferior thinning in an unexpected location.

The Reinstein-Silverman-Keratoconus (RSK) score in this case implies a definitive keratoconus diagnosis.

Prof. Reinstein said, “The point is that keratoconus can be detected with high sensitivity. This avoids false negatives when screening for keratoconus using only topography by proving that the epithelial thickness profile has the doughnut configuration. [It also avoids] false positives in cases that machine algorithms classify as keratoconic … but use of an epithelial profile shows a thicker epithelium over the zone where there is increased steepening.”

Epithelial pliability

Prof. Reinstein explained that the epithelium is a dynamic layer that changes easily with all kinds of conditions and therefore contact lens warpage, anterior basement membrane dystrophy, tear film abnormalities, meibomian gland dysfunction, dry eye and eyelid forces can lead to epithelial redistribution. Figure 2 illustrates a cornea that (left) has been out of a soft contact lens for 3 days and appears very keratoconic and then (right) looks less keratoconic after 2 weeks; the difference is epithelial remodelling.

Figure 2. Contact lens warpage resembling keratoconus.

Anterior basement membrane dystrophy (ABMD) produces a very abnormal epithelial profile with duplication of the basement membrane and, therefore, thickening of the epithelium. Figure 3 shows an example of the epithelial profile showing doughnut-shaped thinning, which might well be mistakenly interpreted as being keratoconus but is actually ABMD.

Figure 3. Anterior basement membrane dystrophy resembling keratoconus.

As a way of indirectly proving that it is the eyelid forces that cause epithelial thickness changes, Figure 4 shows a patient with a Bell’s palsy, who does not blink very much with one of his eyes. The epithelium is thickened significantly in that eye, producing a myopic shift, whereas the epithelial thickness profile is much more even in the eye that blinks normally.

Figure 4. The eyelid shapes the epithelium. (All images courtesy of Prof. Dan Reinstein)

Thus, performing refractive surgery without epithelial maps, when there are multiple commercially available devices to provide such a map, seems unwise. Instead of relying entirely on machine learning, it is better to use one’s clinical skills in order to screen for keratoconus.

The debate

Following Prof. Reinstein’s presentation, Dr Archer debated its content with the other presenters—Dr Kermani (Germany), Prof. Damien Gatinel (France), Prof. Renato Ambrósio Jr. (Brazil) and Prof. Farhad Hafezi (Switzerland). The responses in italics below were not given at the time, because of time constraints, but have been provided during the review process.

Dr Kermani: Epithelial mapping seems to be a very important step in diagnosis in both keratoconus and ectasia. Do you use high-speed ultrasound or OCT?

Dr Archer: There are variety of machines on the market to map the epithelium. Most of the maps we showed in this presentation were from the ArcScan Insight 100 very-high-frequency digital ultrasound device but we also showed quite a few maps from the MS-39 OCT device, so yes, we use both systems.

Dr Kermani: If you look at epithelial mapping from a clinical perspective, if the epithelium is so delicate, would that be a reason not to do topo-guided LASIK? Or is that a procedure in which the epithelium already masks the effect of whatever we do to the stroma?

Dr Archer: Most topography-guided systems derive the ablation algorithm using the front surface topography, which means that it will be less accurate in eyes with an irregular epithelium. Most patients have a reasonably regular epithelium but some do not. In eyes with an irregularity on the epithelium, this will throw off the topography-guided algorithm and you may end up with an outlier.

If you have a global irregularity, like a decentration or a small optical zone, the epithelial remodelling is more global; most of the irregularities show through on the topography and topography-guided treatment works very well.

If you have localised irregularities, there is a lot more epithelial remodelling, which masks the defect, and so topography measurements cannot see the actual shape of the stroma. In this case, topography-guided treatments do not work very well and can actually make things worse.

The link between epithelial thickness and topography is very important. Topography-guided treatments should not be done without first measuring the epithelial thickness and ensuring that it is reasonably regular.

Dr Kermani: Damien, what is your opinion on epithelial mapping? Is it so sensitive and helpful in our daily diagnosis that we really need to add it to our multi-modality diagnostics? Do you use it?

Prof. Gatinel: My view is that I have not yet seen a patient for whom the epithelium was altered from what you expect in a normal patient, yet the cornea was not deformed on the anterior or posterior surface. I do not believe that there is a primitive deformation of the epithelium. As eye rubbing is exerted directly on the epithelium, you may expect to see some deformation, but it is not clinically obvious.

Of course, when you have keratoconus you have a specific pattern, which usually shows as a regularisation pattern. What I find fascinating is how the epithelium remodels itself. If I were involved in epithelial research I would hire a real surface scientist or a physicist or mathematician specialised in those things to understand what drives the epithelium to remodel itself. I know we blink 10,000 times a day but still, how does this work?

The epithelium feels the defects but it is fascinating that it remodels, probably in response to both biological and physical elements like surface tension. When you put a drop of water on a surface it takes a shape that depends on the hydrophilicity or hydrophobicity of the surface but also obeys physical laws. The epithelium probably obeys the same laws but I would love to see some research in that direction.

It is good that the epithelium regularises the cornea, but how much and how can we predict it? This is really fascinating to me. In refractive surgery, if you could predict how the epithelium would react to a specific profile of ablation you could maybe anticipate it and correct for it.

Prof. Reinstein and Dr Archer: We agree with Prof. Gatinel that there would not be epithelial thickness changes in an eye with keratoconus without a deformation of at least the posterior surface. However, the point that we are making is that the epithelial thickness profile is used as an adjunctive tool to confirm or exclude keratoconus in eyes with equivocal changes on tomography.

In general, keratoconus screening is improved with the addition of further measurement modalities. Epithelial thickness mapping and Corvis biomechanical measurements are two examples of how keratoconus screening can be improved beyond topography and tomography alone.

Dr Kermani: Kanellopoulos and Kahn performed hyperopic LASIK in combination with cross-linking and showed that the results are more stable with regard to regression and stability than without cross-linking,¹⁰ so your point is valuable and we should look into this.

Prof. Reinstein and Dr Archer: We do not agree with this statement. The Kanellopoulos study is interesting; however, the population included only 34 patients so the results have a very low statistical power and have not been replicated to date. As a comparison, our published results for hyperopic LASIK using the MEL 90 demonstrated better stability than the group that included cross-linking in the Kanellopoulos study.¹¹

The pathophysiology and pathomorphology of corneal ectasia: Part 1 | Part 2

Dan Reinstein, MD, MA (Cantab), FRCSC, DABO, FRCOphth, FEBO

E: dzr@londonvisionclinic.com

Timothy Archer, MA (Oxon) DipCompSci (Cantab) PhD

E: Timothy@londonvisionclinic.com

Omid Kermani, MD

E: o.kermani@augenportal.de

Prof. Reinstein is the medical director of the London Vision Clinic and holds professorships at Ulster University (Coleraine, UK), Columbia University (NY, USA) and the Sorbonne University (Paris, France). Prof. Reinstein is a consultant for Carl Zeiss Meditec (Jena, Germany) and CSO Italia (Florence, Italy) and acknowledges a financial interest in Artemis Insight 100 VHF digital ultrasound (ArcScan Inc.).

Dr Archer has been the research manager at London Vision Clinic since 2003. Dr Archer has no financial interest regarding the topic of the article.

Dr Kermani is specialised in cataract and refractive surgery and has worked in private practice since 1993. He is based at the Augenklinik am Neumarkt in Cologne. He has no financial interest regarding the topic of the article.

References

1. Reinstein DZ, Archer TJ, Gobbe M, et al. Epithelial thickness in the normal cornea: three-dimensional display with Artemis very high-frequency digital ultrasound. J Refract Surg. 2008;246:571-581.

2. Reinstein DZ, Archer TJ, Gobbe M. Change in epithelial thickness profile 24 hours and longitudinally for 1 year after myopic LASIK: three-dimensional display with Artemis very high-frequency digital ultrasound. J Refract Surg. 2012;283:195-201.

3. Reinstein DZ, Archer TJ, Gobbe M, et al. Epithelial thickness after hyperopic LASIK: three-dimensional display with Artemis very high-frequency digital ultrasound. J Refract Surg. 2010;268:555-564.

4. Reinstein DZ, Gobbe M, Archer TJ, et al. Epithelial, stromal, and total corneal thickness in keratoconus: three-dimensional display with Artemis very-high frequency digital ultrasound. J Refract Surg. 2010;264:259-271.

5. O’Brart DP, Corbett MC, Verma S, et al. Effects of ablation diameter, depth, and edge contour on the outcome of photorefractive keratectomy. J Refract Surg. 1996;121:50-60.

6. O’Brart DP, Gartry DS, Lohmann CP, et al. Excimer laser photorefractive keratectomy for myopia: comparison of 4.00- and 5.00-millimeter ablation zones. J Refract Corneal Surg. 1994;102:87-94.

7. Reinstein DZ, Archer TJ, Gobbe M. Corneal epithelial thickness profile in the diagnosis of keratoconus. J Refract Surg. 2009;257:604-610.

8. Reinstein DZ, Archer TJ, Gobbe M. Stability of LASIK in topographically suspect keratoconus confirmed non-keratoconic by Artemis VHF digital ultrasound epithelial thickness mapping: 1-year follow-up. J Refract Surg. 2009;257:569-577.

9. Silverman RH, Urs R, Roychoudhury A, et al. Epithelial remodeling as basis for machine-based identification of keratoconus. Invest Ophthalmol Vis Sci. 2014;553:1580-1587.

10. Kanellopoulos AJ, Kahn J. Topography-guided hyperopic LASIK with and without high irradiance collagen cross-linking: initial comparative clinical findings in a contralateral eye study of 34 consecutive patients. J Refract Surg. 2012;2811 Suppl:S837-S840.

11. Reinstein DZ, Carp GI, Archer TJ, et al. Outcomes for hyperopic LASIK with the MEL 90® excimer laser. J Refract Surg. 2018 1;3412:799-808.