KEY CONCEPTS
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Epithelial thickness maps provide a higher sensitivity and specificity in the detection of keratoconus than topography and tomography alone.
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Epithelial thickness maps may help identify keratoconus in patients who have an otherwise normal topography/tomography.
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Epithelial thickness maps can be used to help rule out keratoconus in some patients with equivocal topography/tomography.
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Epithelial thickness maps are also essential for evaluating complex corneas in the assessment and therapeutic planning of refractive surgery.
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Epithelial thickness maps are becoming the gold standard in corneal laser refractive surgery for detecting or excluding keratoconus.
Introduction
Keratoconus is a progressive corneal disorder that manifests as corneal thinning and the formation of a cone-shaped protrusion. Because laser refractive surgery may lead to accelerated postoperative ectasia in patients with keratoconus, , the accurate detection of early keratoconus is a major safety concern. The reported prevalence of keratoconus in the Caucasian population is approximately 1/2000. The incidence of undiagnosed keratoconus presenting to refractive surgery clinics tends to be much higher than this, as patients with keratoconus develop astigmatism that is more difficult to correct by contact lenses or glasses, leading them to consider refractive surgery. The challenge for keratoconus screening is to have high sensitivity, combined with high specificity to minimize the number of atypical normal patients who are denied surgery.
Significant efforts have been made to develop methods for screening of early keratoconus over the last 30 years. In 1984 Klyce introduced color-coded maps derived from computerized front surface Placido topography, which have made the diagnosis of keratoconus easier, as patterns including inferior steepening, asymmetric bow tie, and skew bow tie typical of keratoconus can be seen early in the progression of the disease. , Placido-based instruments producing maps of anterior surface topography and curvature became available by the early 1990s and their use in keratoconus screening was demonstrated. Characterization of corneal thickness and topography of both corneal surfaces using scanning-slit tomography was introduced commercially in the mid-1990s by the Orbscan scanning-slit system (Bausch & Lomb, Rochester, NY) and later by the Pentacam rotating Scheimpflug-based system (OCULUS Optikgeräte, Wetzlar, Germany) , and other tomography scanners. Wavefront assessment and biomechanical parameter evaluation with the Ocular Response Analyzer (Reichert, Depew, NY) and Corvis ST (OCULUS Optikgeräte, Wetzlar, Germany) have also been employed as means to detecting early keratoconus.
Topographic and tomographic evaluation has evolved from qualitative observation to quantitative measurements, and many parameters have been described to aid the differentiation of normal from keratoconus eyes. Several statistical and machine-based or computerized learning models have been employed for keratoconus detection, and automated systems for screening based on front and back surface topography and whole corneal tomography and pachymetric profile have been developed. ,
Although these approaches have improved the effectiveness of keratoconus screening, there are still equivocal cases where a confident diagnosis cannot be made, and undiagnosed keratoconus probably remains the leading cause of corneal ectasia after LASIK. The addition of quantitative parameters that are independent of those now obtained by topographic and tomographic analysis could potentially improve screening.
The corneal epithelial and stromal thickness profiles may represent such an independent parameter and will be the focus of this chapter. As will be described later, the corneal epithelium has the ability to alter its thickness profile to reestablish a smooth, symmetrical optical outer corneal surface and either partially or totally mask the presence of an irregular stromal surface from front surface topography. , Therefore the epithelial thickness profile would be expected to follow a distinctive pattern in keratoconus to partially compensate for the cone.
History of the Measurement of Epithelial Thickness
The first real measurement of the epithelium in vivo was made in 1979 by Holden and Payor using optical pachymetry. In 1993 we started measuring epithelial thickness using very-high-frequency (VHF) digital ultrasound and published a 3-mm diameter map in 1994. By 2000 this method had been improved to generate a 10-mm map. , VHF digital ultrasound was further developed and is now commercially available as the Artemis Insight 100 VHF digital ultrasound arc-scanner (ArcScan Inc, Golden, CO), which has been previously described in detail. , ,
During the 1990s, optical pachymetry was used for a number of studies measuring epithelial thickness. Epithelial thickness was studied using histology from 1992, Moller-Pedersen et al. started using confocal microscopy in 1997, and optical coherence tomography (OCT) was first used for measuring the epithelium in 2001. Epithelial thickness maps in an 8-mm diameter using OCT were published by Haque et al. in 2008, followed Li et al. in 2012, and are now commercially available using the RTVue/Avanti OCT (Optovue, Fremont, CA). Since then, other OCT devices have been developed that include epithelial thickness mapping, such as the MS-39 OCT (CSO, Florence, Italy) and Cirrus HD-OCT (Carl Zeiss Meditec, Jena, Germany).
EPITHELIAL THICKNESS PROFILE IN NORMAL EYES
Before looking at more complicated situations, it is useful to consider the epithelial thickness profile in a population of 110 normal eyes. We have demonstrated using VHF digital ultrasound that the epithelium is not a layer of homogeneous thickness as had previously been thought but follows a very distinct pattern. On 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 ( Fig. 18.1 ). The average central epithelial thickness was 53.4 µm and the standard deviation was only 4.6 µm. This indicated that there was 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 mm) temporally and 0.90 mm (±0.96 mm) 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.
Fig. 18.2 , column 1 shows the keratometry, Atlas 995 (Carl Zeiss Meditec, Jena, Germany) corneal topography map and PathFinder corneal analysis, Orbscan II (software version 3.00) anterior elevation best-fit-sphere (BFS), Orbscan II posterior elevation BFS, and Artemis epithelial thickness profile of a normal eye.
This normal non-uniformity seems to provide evidence that the epithelial thickness is regulated by eyelid mechanics and blinking, as we suggested in 1994. The eyelid might effectively be chafing the surface epithelium during blinking, and the posterior surface of the semirigid tarsus provides a template for the outer shape of the epithelial surface. During blinking, which occurs on average between 300 and 1500 times per hour, the vertical traverse of the upper lid is much greater than that of the lower lid. Doane studied the dynamics of eyelid anatomy during blinking and found that during a blink the descent of the upper eyelid reaches its maximum speed at about the time it crosses the visual axis. As a consequence, it is likely that the eyelid applies more force on the superior cornea than inferior cornea. Similarly, the friction on the cornea during lid closure is likely to be greater temporally than nasally as the outer canthus is higher than the inner canthus (mean intercanthal angle = 3 degrees), and the temporal portion of the lid is higher than the nasal lid (mean upper lid angle = 2.7 degrees). Therefore, it seems that the nature of the eyelid completely explains the nonuniform epithelial thickness profile of a normal eye.
Further evidence for this theory is provided by the epithelial thickness changes observed in orthokeratology. In orthokeratology, a shaped contact lens is placed on the cornea overnight that sits tightly on the cornea centrally but leaves a gap in the midperiphery. Therefore the natural template provided by the posterior surface of the semirigid tarsus of the eyelid is replaced by an artificial contact lens template designed to fit tightly to the center of the cornea and loosely paracentrally. We found significant epithelial thickness changes with central thinning and mid-peripheral thickening showing that the epithelium had remodeled according to the template provided by the contact lens, that is, the epithelium is chafed and squashed by the lens centrally whereas the epithelium is free to thicken paracentrally where the lens is not so tightly fitted.
EPITHELIAL THICKNESS PROFILE IN KERATOCONIC EYES
It is well known that the epithelial thickness changes in keratoconus as extreme steepening leads to epithelial breakdown, as is often seen clinically. Epithelial thinning over the cone has been demonstrated using histopathologic analysis of keratoconic corneas by Scroggs and Proia and later using custom software and a Humphrey-Zeiss OCT system (Humphrey Systems, Dublin, CA) by Haque et al.
We have characterized the in vivo epithelial thickness profile in a population of 54 eyes with keratoconus. The average epithelial thickness profile in keratoconus revealed significantly greater irregularity compared with 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 Fig. 18.1 ). Whereas 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. In addition, there was a statistically significant correlation between the thickness of the thinnest epithelium and the difference in thickness between the thinnest and thickest epithelium. This indicated that as the epithelium thinned, there was an increase in the irregularity of the epithelial thickness profile, that is, there was an increase in the severity of the keratoconus. The location of the thinnest epithelium within the central 5 mm of the cornea was displaced on average 0.48 mm (±0.66 mm) temporally and 0.32 mm (±0.67 mm) inferiorly with reference to the corneal vertex. The mean epithelial thickness for all eyes was 45.7 ± 5.9 µm (range: 33.1–56.3 µm) at the corneal vertex, 38.2 ± 5.8 µm (range: 29.6–52.4 µm) at the thinnest point, and 66.8 ± 7.2 µm (range: 54.1–94.4 µm) at the thickest point.
Fig. 18.2 , column 2 shows the keratometry, Atlas 995 corneal topography map and PathFinder corneal analysis, Orbscan II anterior elevation BFS, Orbscan II posterior elevation BFS, and Artemis epithelial thickness profile of a keratoconic eye. As expected, the front surface topography shows inferotemporal steepening with steep average keratometry and high astigmatism; the anterior and posterior elevation BFS maps demonstrate that the apex of the cone is located inferotemporally; the epithelial thickness profile shows epithelial thinning at the apex of the cone surrounded by an annulus of thicker epithelium. The steepest cornea coincides with the apex of the anterior and posterior elevation BFS as well as with the location of the thinnest epithelium.
Recently, the MS-39 OCT device has been introduced, which combines Placido topography with OCT scanning. This enables the MS-39 to simultaneously capture front surface topography and pachymetry data, producing epithelial thickness, corneal thickness, front surface topography, and back surface elevation maps that are all registered to the same measurement location ( Fig. 18.3 ). This greatly helps to assess coincidence between these maps.
The epithelial thickness profile for keratoconus as described here has been confirmed by studies using OCT. , The study by Sandali et al. elegantly described the different stages of advanced keratoconus, demonstrating that as keratoconus moves into its latter stages, a very different epithelial thickness profile becomes apparent. In advanced keratoconus, there is stromal loss often in the location of the cone, for example, because of hydrops. This means that rather than the cone being elevated relative to the rest of the stroma, this region is now a depression. Therefore, the epithelium changes from being thinnest over the cone to being thickest in this region, as it is compensating for a depression instead of an elevation (see next section). Stromal loss in such advanced keratoconus can be significant, so the epithelium can be as thick as 200 µm in some cases. Examples of this epithelial thickening were also reported by Rocha et al. who concluded that focal central epithelial thinning was suggestive but not pathognomonic for keratoconus (i.e., the presence of an epithelial doughnut pattern did not prove beyond any doubt that an eye has keratoconus). However, as described by Sandali et al., these cases only appear in very advanced keratoconus, which means that they are of no interest with respect to keratoconus screening. Eyes with early keratoconus will never present with epithelial thickening in the location of the cone, as by definition if there has been stromal loss, the keratoconus must be more advanced and the cornea will be obviously abnormal.
Understanding the Predictable Behavior of the Corneal Epithelium
Epithelial thickness changes in keratoconus provide another example of the very predictable mechanism of the corneal epithelium to compensate for irregularities on the stromal surface. Epithelial thickness changes have also been described after myopic excimer laser ablation, , , , hyperopic excimer laser ablation, radial keratotomy, intracorneal ring segments, irregularly irregular astigmatism after corneal refractive surgery, , , , and in ectasia.
In all these cases, the epithelial thickness changes are clearly a compensatory response to the change to the stromal surface and can all be explained by the theory of eyelid template regulation of epithelial thickness. Compensatory epithelial thickness changes can be summarized by the following rules:
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The epithelium thickens in areas where tissue has been removed or the curvature has been flattened (e.g., central thickening after myopic ablation , , or radial keratotomy and peripheral thickening after hyperopic ablation ).
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The epithelium thins over regions that are relatively elevated or the curvature has been steepened (e.g., central thinning in keratoconus, , , ectasia, and after hyperopic ablation ).
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The magnitude of epithelial changes correlates to the magnitude of the change in curvature (e.g., more epithelial thickening after higher myopic ablation, , , after higher hyperopic ablation, and in more advanced keratoconus , , ).
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The amount of epithelial remodeling is defined by the rate of change of curvature of an irregularity , ; there will be more epithelial remodeling for a more localized irregularity. , , , The epithelium effectively acts as a low pass filter, smoothing local changes (high curvature gradient) almost completely, but only partially smoothing global changes (low curvature gradient). For example, there is almost twice as much epithelial thickening after a hyperopic ablation compared with a myopic ablation, , , and there is almost total epithelial compensation for small, very localized stromal loss such as after a corneal ulcer.
DIAGNOSING EARLY KERATOCONUS USING EPITHELIAL THICKNESS PROFILES
Mapping of the epithelial thickness reveals a very distinct thickness profile in keratoconus compared with that of normal corneas, owing to the compensatory mechanism of the epithelium for stromal irregularities. The epithelial thickness profile changes with the progression of the disease. As the keratoconus becomes more severe, the epithelium at the apex of the cone becomes thinner, and the surrounding annulus of epithelium in the epithelial doughnut pattern becomes thicker. Therefore the degree of epithelial abnormality in both directions (thinner and thicker than normal) can be used to confirm or exclude a diagnosis of keratoconus in eyes suggestive but not conclusive of a diagnosis of keratoconus on topography at a very early stage in the expression of the disease.
In early keratoconus, we would expect to see the 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 subsurface stromal cone that does represent keratoconus (see Fig. 18.2 ). Conversely, finding thicker epithelium over an area of topographic steepening or an eccentric posterior elevation BFS apex would imply that the steepening is not due to a keratoconic subsurface 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 a diagnosis of keratoconus and, in many cases, before there is any detectable corneal front surface topographic change.
Case Examples
Fig. 18.2 shows three further selected examples in which epithelial thickness profiles helped to interpret and diagnose anterior and posterior elevation BFS abnormalities. In each case, the epithelial thickness profile appears to be able to differentiate cases in which the diagnosis of keratoconus is uncertain, from normal.
Case 1 (OS) represents a 25-year-old male, with a manifest refraction of –1.00 –0.50 × 150 and a best spectacle-corrected visual acuity of 20/16. Atlas corneal topography demonstrated inferior steepening that would traditionally indicate keratoconus. The keratometry was 45.25/43.25 D × 76, and PathFinder corneal analysis classified the topography as normal. Orbscan II posterior elevation BFS showed that the posterior elevation BFS apex was decentered inferotemporally. Corneal pachymetry minimum by handheld ultrasound was 479 µm. Contrast sensitivity was slightly below the normal range measured using the CSV-1000 (Vector Vision Inc, Greenville, OH). There was –0.30 µm (OSA notation) of vertical coma on WASCA aberrometry. Corneal hysteresis was 7.5 mmHg and corneal resistance factor was 7.1 mmHg, which are low, but these could be affected by the low corneal thickness. The combination of inferior steepening, an eccentric posterior elevation BFS apex, and thin cornea raised the suspicion of keratoconus although there was no suggestion of keratoconus by refraction, keratometry, or PathFinder corneal analysis. Artemis epithelial thickness profile showed a pattern typical of keratoconus with an epithelial doughnut shape characterized by a localized zone of epithelial thinning displaced inferotemporally over the eccentric posterior elevation BFS apex, surrounded by an annulus of thick epithelium. The coincidence of an area of epithelial thinning with the apex of the posterior elevation BFS, as well as the increased irregularity of the epithelium, confirmed the diagnosis of early keratoconus.
Case 2 (OD) represents a 31-year-old female, with a manifest refraction of –2.25 –0.50 × 88 and a best spectacle-corrected visual acuity of 20/16. Atlas corneal topography demonstrated a very similar pattern to case 1 of inferior steepening, therefore suggesting that the eye could also be keratoconic. The keratometry was 44.12/44.75 D × 148, and PathFinder corneal analysis classified the topography as suspect subclinical keratoconus. Orbscan II posterior elevation BFS showed that the apex was slightly decentered nasally. Corneal pachymetry minimum by handheld ultrasound was 538 µm. Contrast sensitivity was in the normal range. There was 0.32 µm (OSA notation) of vertical coma on WASCA aberrometry. Corneal hysteresis was 10.1 mmHg and corneal resistance factor was 9.8 mmHg, which are well within normal range. The combination of inferior steepening, against-the-rule astigmatism, and high degree of vertical coma raised the suspicion of keratoconus, which was also noted by PathFinder corneal analysis. Artemis epithelial thickness profile showed a typical normal pattern with thicker epithelium inferiorly and thinner epithelium superiorly. Thicker epithelium inferiorly over the suspected cone (inferior steepening on topography) was inconsistent with an underlying stromal surface cone, and therefore the diagnosis of keratoconus was excluded. This patient would have been rejected for surgery given a documented PathFinder corneal analysis warning of suspect subclinical keratoconus, but given the epithelial thickness profile, this patient was deemed a suitable candidate for LASIK.
The anterior corneal topography in case 3 (OD) bears no features related to keratoconus. The patient is a 35-year-old female with a manifest refraction of –4.25 –0.50 × 4 and a best spectacle-corrected visual acuity of 20/16. The refraction had been stable for at least 10 years, and the contrast sensitivity was within normal limits. The keratometry was 43.62/42.62 D × 74 and PathFinder analysis classified the topography as normal. Orbscan II posterior elevation BFS showed that the apex was slightly decentered inferotemporally, but the anterior elevation BFS apex was well centered. Corneal pachymetry minimum by handheld ultrasound was 484 µm. Pentacam (OCULUS, Wetzlar, Germany) keratoconus screening indices were normal. WASCA ocular higher-order aberrations were low (RMS = 0.19 µm), as was the level of vertical coma (coma = 0.066 µm). Corneal hysteresis was 8.9 mmHg and corneal resistance factor was 8.8 mmHg, both within normal limits. In this case, only the slightly eccentric posterior elevation BFS apex and the low-normal corneal thickness were suspicious for keratoconus, whereas all other screening methods gave no indication of keratoconus. However, the epithelial thickness profile showed an epithelial doughnut pattern characterized by localized epithelial thinning surrounded by an annulus of thick epithelium, coincident with the eccentric posterior elevation BFS apex. Epithelial thinning with surrounding annular thickening over the eccentric posterior elevation BFS apex indicated the presence of probable subsurface keratoconus. In this case, it seems that the epithelium had fully compensated for the stromal surface irregularity so that the anterior surface topography of the cornea appeared perfectly regular. Given the regularity of the front surface topography and the normality of nearly all other screening parameters, it is feasible that this patient could have been deemed suitable for corneal refractive surgery and subsequently developed ectasia. As we were able to also consider the epithelial thickness profile, this patient was rejected for corneal refractive surgery. This kind of case may explain some reported cases of ectasia “without a cause.”
Fig. 18.4 shows an example of early keratoconus in which the front surface topography and Pentacam tomography appear normal; however, the epithelial thickness profile demonstrates focal thinning that is identified as keratoconus by this automated algorithm.
