March 2021

REFRACTIVE

The utility of epithelial mapping


by Liz Hillman Editorial Co-Director

 
Epithelial mapping technologies
OCT
• MS-39 anterior segment OCT and
tomographer (CSO Italia)
• Avanti OCT System (Optovue)
• SPECTRALIS OCT (Heidelberg Engineering)
• CIRRUS HD-OCT (Carl Zeiss Meditec)
VHF ultrasound
• Insight 100 VHF digital ultrasound scanner (ArcScan)

Epithelial thickness mapping was FDA approved in the U.S. in 2017, but awareness about its utility—and in some minds, its necessity—is growing. Three international ophthalmologists—Francesco Carones, MD, Arthur Cummings, MD, and Dan Reinstein, MD—shared their experience with the technology and offered insights on where they think it fits in ophthalmic practices now and in the future.
Dr. Carones said he has been using epithelial mapping for 4 years. It’s a routine part of his practice, and he thinks it will become routine for anterior segment ophthalmology in the future. “Many anterior segment surgeons are not doing this on a routine basis yet because anterior segment OCT technology being able to map epithelial thickness became available only recently, and this kind of technology has some significant cost. We are still in that phase of early adoption where surgeons have to buy the instrument,” Dr. Carones said.
Dr. Reinstein developed epithelial mapping and applications as a bioengineering research fellow working in D. Jackson Coleman’s lab with Ronald Silverman, PhD. Dr. Reinstein was the first to measure the epithelium of the cornea in vivo in 1991 using very high frequency (VHF) digital ultrasound and the first to produce a map of the epithelium in 1993. He went on to develop the first method of mapping the full epithelial profile of the cornea by 1997 when he began scanning and elucidating the epithelial changes in LASIK and analyzing the complications of corneal refractive surgery. With this work and the commercialization of the first epithelial mapping device (ArcScan Insight 100 VHF and other anterior segment OCT devices with this capability), Dr. Reinstein is considered to be the “father” of this new diagnostic field of layered corneal diagnostics.
“Having developed and worked with VHF digital ultrasound for 20 years prior, I was excited to help Optovue develop the first OCT prototype device to map the corneal epithelium in 2012 and commercially launched in 2015. Most anterior segment OCT manufacturers are now developing this capability for their devices,” Dr. Reinstein said. “This is becoming the standard of care for refractive surgery diagnostics.”
Dr. Carones described epithelial mapping as a diagnostic and screening tool that can help ensure the right treatment is pursued in certain cases. It’s first important to understand what a normal epithelial map looks like so it can be used as a baseline for comparison. Dr. Reinstein and colleagues published in 2008 that normal epithelium was 5.7 µm thicker inferiorly than superiorly and 1.2 µm thicker nasally than temporally.1 The mean central thickness was 53.4 µm.
According to Dr. Reinstein’s work, the average central epithelial thickness was 53.4 µm with a standard deviation of 4.6 µm.
“This indicated that there was little variation in central epithelial thickness in the population,” he said. “The thinnest epithelial point within the central 5 mm of the cornea was displaced on average 0.33 mm (±1.08) temporally and 0.90 mm (±0.96) superiorly with reference to the corneal vertex. Studies using OCT have confirmed this superior-inferior and nasal-temporal asymmetric profile for epithelial thickness in normal eyes.”2
Dr. Reinstein first postulated in 1994 that this inferior/superior asymmetry is produced by the balance of forces of epithelial outward growth and the combined inward forces produced by the eyelids, the upper eyelid producing more inward force than the lower lid, he explained.3

A diagnostic and screening tool

Epithelial mapping has been described by Dr. Reinstein and colleagues as a very sensitive and specific method to detect keratoconus even earlier than topographic and tomographic devices.4
“If the keratoconus is early enough, it cannot be detected on topography or tomography,” Dr. Cummings said. “If the epithelial maps show a thinning of the epithelium, however, that would indicate that the stroma beneath the thinned epithelium may be bulging or ectatic. The epithelium has the ability to mask corneal irregularities when they are sufficiently subtle.”
Diagnosing keratoconus early can ensure patients are being monitored closely for progression. If progression is observed, crosslinking could be performed to stop it before there are significant visual impacts. Dr. Reinstein explained that “epithelial mapping can demonstrate continued changes in the cornea after crosslinking that may not be apparent by just looking at surface topography.” Dr. Carones also uses epithelial mapping in screening candidates for laser refractive surgery. For example, a patient might be seen as having ectasia after refractive surgery when, if epithelial mapping had been performed preop, it might have been identified as early keratoconus.
While both VHF ultrasound and OCT can map the corneal epithelium, there are differences in accuracy and mapping coverage, Dr. Reinstein said.
“Our studies have demonstrated that VHF ultrasound epithelial measurement produces an accuracy of approximately 1 µm while OCT achieves approximately 3 µm,”5 Dr. Reinstein explained, adding, “the main reasons for the lower accuracy of OCT relate to the fact that OCT is measuring epithelium and tear film together, the tear film itself being a big variable, as well as the effects of unknown refractive index within the epithelium. In our practice every single patient undergoes OCT epithelial mapping screening. Approximately 15% of patients go on to require definitive epithelial mapping by VHF ultrasound, which also gives us the best posterior chamber measurements at the same time for improved ICL sizing if the cornea ends up being classified as keratoconic.”
Dr. Reinstein pointed out that histopathologic analysis of keratoconic corneas has confirmed the clinical observations of epithelial breakdown over an excessively steepened cone.6–7 He was the first to describe the epithelial profile in keratoconus, demonstrating how it was considerably different from that of normal corneas.8
“The epithelium was thinnest at the apex of the cone, and this thin epithelial zone was surrounded by an annulus of thickened epithelium,” he said. “While all eyes exhibited the same epithelial donut pattern, characterized by a localized central zone of thinning surrounded by an annulus of thick epithelium, the thickness values of the thinnest point and the thickest point as well as the difference in thickness between the thinnest and thickest epithelium varied greatly between eyes. There was a statistically significant correlation between the thinnest epithelium and the steepest keratometry, indicating that as the cornea became steeper, the epithelial thickness minimum became thinner.”
From there, Dr. Reinstein and colleagues developed an automated machine-based classifier of epithelial profiles for detecting keratoconus well before specific topography or tomographic changes.9
“The Insight 100 incorporates our machine- based algorithm that classifies the epithelial profile as keratoconic with 95% sensitivity and 99% specificity, levels much higher than can currently be achieved by topography or tomography,” he said.
“The epithelium can then be used to exclude keratoconus in cases of suspect topography, such as inferior steepening, or to confirm keratoconus in cases of equivocal topography or tomography,”10 Dr. Reinstein continued. “Our studies on screening with epithelial profiles in the presence of inferior steepening showed that 85% of the time the inferior steepening was due to the epithelium being thicker inferiorly, and not keratoconus, allowing us to rule in cases that we would have previously rejected for corneal surgery.”
Dr. Carones reiterated that he finds epithelial mapping helpful in detecting keratoconus-like patterns that are not in fact keratoconus.
“Sometimes we see some sort of steepening on corneal curvature maps, and you always have to question whether this is keratoconus or something else. The epithelial map helps discriminate because if we find some sort of corneal steepening and if steepening is related to epithelial thickness, we know this is not keratoconus,” he said.
Dry eye disease can also cause variability in epithelial maps, Dr. Cummings noted.
“Subclinical anterior basement disorder where there are no signs of map, dot, or fingerprints can also cause variability in the epithelial profile that can be misinterpreted as keratoconus,” Dr. Reinstein said.

A post-refractive surgery tool

After corneal surgery, Dr. Carones said epithelial maps can provide information prior to enhancements. If, for example, there was a myopic shift post-refractive surgery, epithelial maps can help distinguish between true progression vs. thicker epithelium acting as a positive contact lens.
“Sometimes it is just because the epithelium became thicker in the center compared to the mid-periphery, and removing the epithelium and doing the PRK enhancement may lead to a re-epithelialization where the epithelium is not even in the center so the amount of correction used by the laser would lead to an overcorrection,” Dr. Carones said.
Dr. Carones said he includes epithelial mapping assessments in all of his post-refractive surgery visits. During the early postop period, epithelial maps help him assess the healing process. If the epithelium is uneven or irregular, he said he knows healing is still taking place. Once it regularizes, the healing process is over. After several years, epithelial mapping can help detect ectasia but is also used to drive decisions about whether an enhancement is needed or if the epithelium has just become too thick.
Dr. Reinstein noted that the bulk of the compensatory epithelial changes after LASIK occur within the first postoperative day, most of the rest of the changes happen over the next few weeks, and very little changes after 3 months.11
“Epithelial maps are especially helpful when making a final decision for enhancement in patients who had a hyperopic correction,” Dr. Reinstein said. The central epithelial thickness can be a useful indicator as a measurement of potential risk for apical syndrome, which occurs if the epithelium is too thin (less than 25 µm).12
“For example, in one case from our study, the maximum simulated keratometry of 50.80 D would most likely prevent the surgeon from treating further hyperopia; however, the central epithelial thickness of 41.7 µm would suggest that the cornea could be steepened further without resulting in epithelial breakdown,” Dr. Reinstein said. “On the other hand, another case from this study demonstrated that the epithelial thickness can be thin (33.7 µm) although the cornea was still relatively flat postoperatively (46.40 D). The curvature limit would allow further hyperopic ablation, whereas the thin, central epithelium would indicate that further steepening might increase the risk of apical syndrome. Therefore, using epithelial thickness measurements, hyperopic retreatments might be performed without risk of apical syndrome while also allowing some patients to have retreatment who would otherwise have been rejected from further surgery due to high keratometry postoperatively.13
“The epithelium always masks stromal surface abnormalities beneath, becoming thinner over bumps and thicker over troughs,” Dr. Reinstein said. Relying on topography or wavefront-guided treatments alone can lead to suboptimal treatment and could even make things worse in attempting to correct corneal complications.
“In such cases with localized irregularities, a transepithelial PTK treatment is the better option as this uses the irregular epithelial thickness profile as a natural masking agent to target the ablation onto the relative peaks on the stromal surface, thus producing a smoother stromal surface,” he said.14–16
Epithelial mapping is also helpful for ensuring safe flap thickness for LASIK on an eye with previous PRK or LASIK after SMILE.
Dr. Cummings said that he thinks more education is needed about the value of epithelial mapping to drive more widespread adoption.
“People who I think would be most exposed are refractive surgeons initially and then corneal surgeons who know the value of this technology … and getting to cataract surgery eventually for quality of vision, too,” he said.

About the physicians

Francesco Carones, MD

Carones Vision
Milan, Italy

Arthur Cummings, MD
Wellington Eye Clinic
Dublin, Ireland

Dan Reinstein, MD
London Vision Clinic
London, U.K.

References

1. Reinstein DZ, et al. Epithelial thickness in the normal cornea: three-dimensional display with Artemis very high-frequency digital ultrasound. J Refract Surg. 2008;24:571–581.
2. Li Y, et al. Corneal epithelial thickness mapping by Fourier- domain optical coherence tomography in normal and keratoconic eyes. Ophthalmology. 2012;119:2425–2433.
3. Reinstein DZ, et al. Epithelial and corneal thickness measurements by high-frequency ultrasound digital signal processing. Ophthalmology. 1994;101:140–146.
4. Reinstein DZ, et al. Corneal epithelial thickness profile in the diagnosis of keratoconus. J Refract Surg. 2009;25:604–610.
5. Reinstein DZ, et al. Comparison of corneal epithelial thickness measurement between Fourier-domain OCT and very high-frequency digital ultrasound. J Refract Surg. 2015;31:438–445.
References (cont.)
6. Scroggs MW, Proia AD. Histopathological variation in keratoconus. Cornea. 1992;11:553–559.
7. Haque S, et al. Corneal and epithelial thickness in keratoconus: a comparison of ultrasonic pachymetry, Orbscan II, and optical coherence tomography. J Refract Surg. 2006;22:486–493.
8. Reinstein DZ, et al. Epithelial, stromal, and total corneal thickness in keratoconus: three-dimensional display with Artemis very-high frequency digital ultrasound. J Refract Surg. 2010;26:259–271.
9. Silverman RH, et al. Epithelial remodeling as basis for machine-based identification of keratoconus. Invest Ophthalmol Vis Sci. 2014;55:1580–1587.
10. Reinstein DZ, et al. Corneal epithelial thickness profile in the diagnosis of keratoconus. J Refract Surg. 2009;25:604–610.
11. Reinstein DZ, et al. 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;28:195–201.
12. Reinstein DZ, et al. Epithelial thickness after hyperopic LASIK: three-dimensional display with Artemis very high-frequency digital ultrasound. J Refract Surg. 2010;26:555–564.
13. Reinstein DZ, et al. LASIK for the correction of high hyperopic astigmatism with epithelial thickness monitoring. J Refract Surg. 2017;33:314–321.
14. Reinstein DZ, Archer T. Combined Artemis very high-frequency digital ultrasound-assisted transepithelial phototherapeutic keratectomy and wavefront- guided treatment following multiple corneal refractive procedures. J Cataract Refract Surg. 2006;32:1870–1876.
15. Reinstein DZ, et al. Refractive and topographic errors in topography-guided ablation produced by epithelial compensation predicted by 3D Artemis VHF digital ultrasound stromal and epithelial thickness mapping. J Refract Surg. 2012;28:657–663.
16. Reinstein DZ, et al. Transepithelial phototherapeutic keratectomy protocol for treating irregular astigmatism based on population epithelial thickness measurements by Artemis very high-frequency digital ultrasound. J Refract Surg. 2014;30:380–387.

Relevant disclosures

Carones: CSO Italia

Cummings: Alcon
Reinstein: ArcScan, Carl Zeiss Meditec

Contact

Carones
: fcarones@carones.com
Cummings: abc@wellingtoneyeclinic.com
Reinstein: dzr@londonvisionclinic.com

The utility of epithelial mapping The utility of epithelial mapping
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