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Corneal Physician Bulletin: Epithelial Thickness Mapping for Keratoconus Screening

Figure 1. Mean epithelial thickness profile for a population of 110 normal eyes (A) and a population of 54 keratoconic eyes (B). The epithelial thickness profiles for all eyes in each population were averaged using mirrored left eye symmetry. The color scale represents epithelial thickness in microns. A Cartesian 1 mm grid is superimposed with the origin at the corneal vertex. Reprinted with permission from SLACK Incorporated:Reinstein DZ, Gobbe M, Archer T,, Silverman R, Coleman J (2010). Epithelial, Stromal and Total Corneal Thickness in Keratoconus. Journal of Refractive Surgery, 26, 259-271.

Figure 2. 
MS-39 (CSO, Florence, Italy) 6 map display shows a patient with mild keratoconus showing correspondence between epithelial thinning, pachymetric thinning, curvature, and elevation maps.

Consider this approach when determining patient candidacy for refractive surgery
 
By Dan Z Reinstein, MD MA (Cantab) FRCSC FRCOphth,Timothy J Archer, MA (Oxon), DipCompSci (Cantab), PhDand Ryan S Vida, OD, FAAO

            Keratoconus screening is an important safety factor in corneal refractive surgerybecause laser refractive surgery may lead to accelerated postoperative ectasia in keratoconus patients.1,2Keratoconus screening should have high sensitivity combined with high specificity to minimize the number of patients mistakenly denied surgery. The corneal epithelial and stromal thickness profiles may represent this combination. The reason: The corneal epithelium has the ability to alter its thickness profile to re-establish a smooth, symmetrical optical outer corneal surface and either partially or totally mask the presence of an irregular stromal surface from front surface topography.3,4Therefore, the epithelial thickness profile would be expected to follow a distinctive pattern in keratoconus to partially compensate for the cone.* Let us explain. 
 
Epithelial Thickness Profile in Normal Eyes
It is useful to consider the epithelial thickness profile in a population of normal eyes.5On average, the epithelium was 5.7 µm thicker inferiorly than superiorly, and 1.2 µm thicker nasally than temporally, with a mean central thickness of 53.4 µm (Figure 1). The average central epithelial thickness was 53.4 µm with a standard deviation of 4.6 µm.5This indicated little variation in central epithelial thickness in the population. 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 confirm this superior-inferior and nasal-temporal asymmetric profile for epithelial thickness in normal eyes.6
 
Epithelial Thickness Profile in Keratoconic Eyes
The average epithelial thickness profile in keratoconus reveals significantly more irregularity compared to a normal population. The epithelium was thinnest at the apex of the cone, and this thin epithelial zone was surrounded by an annulus of thickened epithelium (see Figure 1). While all eyes exhibited the same epithelial doughnut 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 (D), indicating that as the cornea became steeper, the epithelial thickness minimum became thinner. 
            
Diagnosing Early Keratoconus Using Epithelial Thickness Profiles
In early keratoconus, we would expect to see a pattern of localized epithelial thinning surrounded by an annulus of thick epithelium coincident with a suspected cone on posterior elevation BFS. The coincidence of epithelial thinning together with an eccentric posterior elevation BFS apex may reveal whether to ascribe significance to an eccentric posterior elevation BFS apex occurring concurrently with a normal front surface topography. In other words, in the presence of normal or questionable front surface topography, thinning of the epithelium coincident with the location of the posterior elevation BFS apex would represent total masking or compensation for a sub-surface stromal cone, which doesrepresent keratoconus. Conversely, finding thicker epithelium over an area of topographic steepening or an eccentric posterior elevation BFS apex would imply that the steepening is notdue to a keratoconic sub-surface stromal cone, but more likely due to localized epithelial thickening. 

Evaluation of epithelial thickness profile irregularities provides a very sensitive method of examining stromal surface topography – by proxy. Therefore, epithelial thickness mapping provides increased sensitivity and specificity to aid in the diagnosis of keratoconus and, in many cases, before there is any detectable corneal front surface topographic change.
 
The Future of This Finding
Keratoconus detection is ever-evolving. We have demonstrated that the epithelial thickness profile was significantly different between normal eyes and keratoconic eyes. The epithelial thickness profile also progresses along with the evolution of keratoconus. The distinctive epithelial doughnut pattern associated with keratoconus can be used to confirm or exclude the presence of an underlying stromal surface cone in cases with normal or suspect front-surface topography, as well as being a “qualifier” for the finding of an eccentric posterior elevation BFS apex. Will epithelial thickness mapping become a part of the standard of care in preoperative refractive surgery patients? CSO seems to agree, as it has recently introduced the MS-39 OCT device. The currently non-FDA-approved device combines Placido topography with OCT scanning, enabling the simultaneous capture of front surface topography and pachymetry data, which produces epithelial thickness, corneal thickness and back surface elevation maps registered to the same measurement location (Figure 2). CP 
 
*While the epithelium is the most sensitive method for detecting very early keratoconus, it is important to recognize that epithelial changes associated with anterior basement membrane dystrophy (ABMD) may cause focal areas of a thickening that can be identified on clinical slit-lamp examination. In addition to ABMD, dry eye can also affect the epithelium.9
 
Reviewed by Mitchell A Jackson, MD. 

             Dr. Reinstein is the medical director of London Vision Clinic, London, UK. He also holds positions as Adjunct Professor of Ophthalmology at Columbia University Medical Center, New York, is visiting professor at Ulster University, Coleraine, UK, and Professeur Associe en Ophtalmologie at the Sorbonne Universite, in Paris. He is a consultant for Carl Zeiss Meditec, has a proprietary interest in ArcScan Inc, and is an author of patents related to VHF digital ultrasound administered by the Center for Technology Licensing at Cornell University, Ithaca, New York.
 
            Drs. Archer and Vida are part of the London Vision Clinic Research Department.  

References
1. Ambrosio R, Jr., Wilson SE.Complications of laser in situ keratomileusis: etiology, prevention, and treatment. J Refract Surg. 2001;17:350-379.
2. Seiler T, Koufala K, Richter G. Iatrogenic keratectasia after laser in situ keratomileusis. J Refract Surg. 1998;14:312-317.
3. 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.
4. Reinstein DZ, Archer TJ, Gobbe M. Rate of change of curvature of the corneal stromal surface drives epithelial compensatory changes and remodeling. J Refract Surg. 2014;30:800-802.
5. Reinstein DZ, Archer TJ, Gobbe M, Silverman RH, Coleman DJ. Epithelial thickness in the normal cornea: three-dimensional display with Artemis very high-frequency digital ultrasound. J Refract Surg. 2008;24:571-581.
6. Li Y, Tan O, Brass R, Weiss JL, Huang D. Corneal epithelial thickness mapping by Fourier-domain optical coherence tomography in normal and keratoconic eyes. Ophthalmology. 2012;119:2425-2433.
7. Scroggs MW, Proia AD. Histopathological variation in keratoconus. Cornea. 1992;11:553-559.
8. Haque S, Simpson T, Jones L. Corneal and epithelial thickness in keratoconus: a comparison of ultrasonic pachymetry, Orbscan II, and optical coherence tomography. J Refract Surg. 2006;22:486-493.
9. Kanellopoulos AJ, Asimellis G. In vivo 3-dimensional corneal epithelial thickness mapping as an indicator of dry eye: preliminary clinical assessment. Am J Ophthalmol. 2014;157:63-68.e62.