Atlas Of Anterior Segment OCT vol.3 by Rivista Sfogliabile

C.S.O. COSTRUZIONE STRUMENTI OFTALMICI

ISBN: 978-88-31256-33-9

FABIANO EDITORE

CONTRIBUTORS J. F. Alfonso Sánchez, J. L. Alió del Barrio, J. Aramberri, B. A. Bartolozzi, U. Bassi, L. Buratto, F. Carones, M. Cennamo, M. Fantozzi, E. Favuzza, C. L. Fernández, L. Fernández-Vega CuetoFelgueroso, S. Ferrandes, O. Findl, D. Gore, N. Hirnschall, K. A. Knutsson, M. Leucci, O. Li, C. Macaluso, D. Madrid Costa, M. Mammone, R. Mencucci, M. Phylactou, A. Poo López, P. Rama, G. Savini, A. Schlatter, C. Tredici, J. M. Varas, F. Versaci, G. Vestri, L. Vicchio, P. Vinciguerra, R. Vinciguerra

FABIANO EDITORE

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C.S.O. S.R.L. COSTRUZIONE STRUMENTI OFTALMICI Via degli Stagnacci 12/E 50018 Scandicci - Florence, Italy http://www.csoitalia.it/

The Authors and the Editor decline any responsability for any errors in the text. All rights reserved. Reproduction of this book - total or partial - is strictly forbidden. ISBN: 978-88-31256-33-9 Printed in: September 2021

C.S.O. COSTRUZIONE STRUMENTI OFTALMICI

FABIANO EDITORE

INDEX

AS-OCT

ATLAS

INTRODUCTION CLINICAL CASES

INTRODUCTION

he evaluation of corneal and anterior segment morphology and structure has been recently improved thanks to several diagnostic instruments, which allow us to obtain even more detailed and precise information. In my thirty year-long career, I have had the pleasure of being part of the birth, the growth and the global diffusion of several diagnostic technologies that, today, are part of our routine armamentarium for the anterior segment analysis. Since my graduation as a medical doctor in 1988, I have witnessed the entire process starting from idealization to commercialization of videokeratography for the measurement of the anterior corneal curvature. I experienced the advent of the first Scheimpflug cameras for the visualization of the anterior chamber and the evaluation of the posterior corneal curvature. I saw great ideas arise and then fall (corneal holography, raster-stereography), other ones taking off but never becoming widely spread (high-frequency ultrasonography) either due to the high associated costs, or from difficult to understand strategical and commercial decisions. I have also observed techniques for the anterior segment developed and applied to the posterior segment, such as optical coherence tomography (OCT). This Atlas celebrates the introduction of a combined diagnostic technology that allows to obtain very high-resolution images, and consequently extremely accurate and precise anatomy-topographical data, related to several structures of the anterior segment: tear film, corneal epithelium, Bowman membrane, corneal stroma, corneal endothelium, anterior and posterior corneal curvature, anterior chamber, iris-scleracorneal angle, iris, pupil size and dynamics, crystalline lens. All of this is possible due to the combination of the highest technology for the analysis of the anterior corneal curvature (videokeratography Placido-disc based), with quality spectral domain OCT, found in a single instrument that has yet many other innovative technical features. In the time of a “click”, this instrument provides a complete, yet detailed panorama of the anterior segment.

In other words, this is the coupling of the best corneal topographer and the best anterior segment OCT, with a commercial name, MS-39, that recalls the founder of the company, the father of this technology. This system is perfectly integrated with the CSO diagnostic platform (aberrometer, Scheimpflug camera, corneal topographer, etc.) which connects in an interactive way to provide even more diagnostic information. I had the opportunity to use one of the first MS-39 prototypes in my clinical practice. After 4 years of daily use, I can honestly say that I could no longer practice without it. If I had to choose one single diagnostic tool to work with, no doubt, this one would be my choice. As a corneal, refractive and cataract surgeon I have to admit I learned so much from the information, previously unknown, provided by this technology. There are countless clinical examples, most of them illustrated in this Atlas, that helped me find an easier diagnostic/surgical direction only through the use of this instrument. And it has been so wonderfully exciting, over my thirty years of ophthalmology practice, to witness the path CSO has made side by side with the ophthalmologists. Indeed, for ophthalmology, CSO was already there thirty years ago when, beside slit lamps and keratometers, its innovation was demonstrated by the launch of one of the very first videokeratographers. Today CSO is present with this one-of-a-kind technology and it is destined to force all the competitors to strive to keep up with this shining example of the Italian excellence. For all these reasons, I strongly wish that CSO achieves all the popularity that it deserves for the innovation and development of this diagnostic technology. Empowered by this technology, future achievements of the scientific community will arise by enabling research thanks to an instrument capable to evaluate, measure and visualize information that was not accessible before. These advances will make our profession easier and more efficient, allowing us to provide our patients, the final consumers, with continuously better and more efficient services. Milan, September 2021 Francesco Carones

KERATOCONUS SCREENING FRANCESCO VERSACI, GABRIELE VESTRI

C.S.O. S.R.L. (Florence, Italy)

INTRODUCTION Keratoconus is an ectatic, usually bilateral, disease characterized by progressive thinning and steepening and an apical cone-shaped protrusion of the cornea.1,2 Clinical diagnosis of moderate to advanced keratoconus is relatively easy, due to the presence of classical retinoscopic and biomicroscopic signs like Munson’s sign, the scissoring reflex , the Vogt’s striae and the Fleischer’s ring, but identification of early cases with good visual acuity and no specific corneal findings is often challenging. Indeed, since keratoconus is known to weaken the corneal stroma leading to an increased risk of iatrogenic ectasia3-6 the detection of early cases is probably the main concern during the evaluation of patient’s eligibility for refractive surgery. In the general population, the consequences of missing a keratoconus diagnosis are relatively small, as the disease typically progresses and a definitive diagnosis will eventually be clear. Conversely, a missed diagnosis of keratoconus in a candidate for refractive surgery may have severe consequences in a relatively short time lapse. It is for this reason that early keratoconus detection in refractive surgery candidates is crucial. EVOLUTION OF THE DIAGNOSIS OF KERATOCONUS The instruments of choice to measure and diagnose morphological and refractive aspects of corneal layers are reflection-based corneal topographers and optical scanning topographers (adopting either the Scheimpflug or the OCT technologies). Since the introduction of the corneal topography, many methods have been proposed for differentiating between normal and keratoconic eyes, and detection schemes have been introduced to enable the objective identification of keratoconus. They include quantitative descriptors derived from the analysis of several topographic data, such as the KISA% index proposed by Rabinowitz et al.,7 the Cone Location and Magnitude Index (CLMI) proposed by Mahmoud et al.,8 and the Keratoconus Prediction Index (KPI) and the Keratoconus Index proposed by Maeda et al.9,10 Alternative automated detection systems have been described by Smolek and Klyce, who developed a neural network for classification based on corneal topography indices11, Chastang et al., who developed binary decision trees based on corneal topography indices12, and Twa et al., who developed an automated decision-tree classification of corneal shape through Zernike polynomial analysis13, as well as Maeda et al, who incorporated the KPI into a binary

decision tree9, and later relied on a neural network to classify topographic maps10. Other detection schemes based on Zernike decomposition of the anterior corneal surface had been previously described by Schwiegerling et al.14 (Z3 index) and Langenbucher et al15 Since, slit-scanning corneal topographers have made it possible also to evaluate the posterior cornea and corneal thickness, and these measurements have been included in algorithms for the diagnosis of keratoconus. Bessho et al., who used the Orbscan II (Bausch & Lomb, Rochester, NY), proposed an automated keratoconus classifier applying a keratoconus-detection index (FKI) based on information obtained by Fourier analysis from anterior and posterior corneal surfaces and corneal thickness16. With the same technology, Fam et al. found that anterior corneal elevation parameters had higher sensitivity when detecting keratoconus than posterior corneal elevation17, whereas Saad and Gatinel observed that the indices generated from corneal thickness and curvature measurements over the entire cornea can identify form fruste keratoconus undetected by a Placido-based neural network18. Posterior corneal curvature and pachymetric data provided by Scheimpflug imaging have been investigated by Ambrósio et al, who showed that corneal-thickness spatial profile, corneal-volume distribution, percentage increase in thickness, and percentage increase in volume were different in keratoconic and normal eyes.19 Measurements obtained from the posterior corneal curvature using a Scheimpflug camera have been evaluated in several other papers.20-22 In 2012, CSO, supported by a group of clinicians expert in keratoconus detection, developed a bench of indices and an method based on SVM classifiers23-25, designed to label an eye as abnormal, keratoconus, suspect keratoconus, myopic post-op or normal relying on the classification by Support Vector Machine (SVM), a machine learning technique.26 The idea behind this screening was to highlight variations against normality, and since in keratoconus such variations take place in the same position, the bulging area, to report the coincidence of the location of such variations. With Sirius being able to measure the curvature and elevations of both the anterior and posterior corneal surfaces and to provide measurements of corneal thickness, a wide range of indices derived from several tomographic maps was used to feed the SVM classifiers. In parallel, corneal epithelium assessment has become a hot topic for keratoconus detection and numerous reports have been published describing epithelial thickness changes in early stages of keratoconus: in keratoconic eyes, epithelial thickness in the region of the cone has been reported to be thinner than that of normal eyes.27-29 It has also been shown that the epithelial thickness profile across the central 8-mm diameter follows a doughnut pattern characterized by a thinning region over the cone surrounded by an annulus of thickening.30,31

THE MS-39 AND ITS NOVEL KERATOCONUS SCREENING The MS-39 (C.S.O srl, Florence, Italy) is made up of a Placido disk, providing a uniform light at 635 nm and an OCT scanning system using a radiation source centered at 850 nm with a spectral width of about 80 nm. The working distance is chosen to be 80 mm resulting in a good compromise between keratoscopy coverage and patient comfort: the Placido disk is far enough not to stimulate an excessive tearing and at the same time the system provides a sufficient coverage to map (solely through its reflection) up to 10 mm for a diopter with an 8mm radius. The spectrometer inside the instrument ensures an axial resolution of 4.8 μm in air (about 3.5 μm in tissue) and an imaging depth of about 10 mm in air. The scanning subsystem is based on two galvanometric mirrors, which deviate the beam according to the numerous preset or configurable trajectories and it allows for a maximum transversal field of 16 mm and a transversal resolution of 35 μm. The scanning process acquires one Placido videokeratoscopic image and, in parallel, a sequence of tomographic OCT images of the anterior segment. The MS-39 provides topographic mapping of the anterior and posterior corneal surfaces (in terms of curvature, elevations, and refractive powers) as well as thickness information: its 3.5 μm of axial resolution in fact not only allows for an extremely accurate measurement of total corneal pachymetry, but also of some of its sublayers (epithelial and stromal thickness). When CSO released the MS-39 in 2017, the supplied software included the same keratoconus screening provided for the Sirius (C.S.O srl, Florence, Italy) Scheimplug Camera. Soon it became clear that the proposed method was restricting and limiting the superior diagnostic capabilities of an OCT instrument and for this reason, starting from version 4.0, the supplied software was provided with a new, highly comprehensive and more sensitive Keratoconus summary. CURVATURE MAPS Sagittal and tangential maps Sagittal (or Axial) curvature was the very first map used in modern corneal topography. Conceptually, we can consider modern videokeratoscopes as advanced versions of ophthalmometers, so much so that the first method developed in this regard is based on the same principles of the ophthalmometer32: indeed, we can consider a topographic measurement as many keratometries with ever larger fixed mires, centered on the same axis. The corneal curvature measured in this way can be defined as the radius of an arc of a circle, centered on the keratoscopic axis when this is well aligned to the corneal vertex. A map of sagittal curvature is able to adequately represent the optical character-

istics of the corneal surface, but it is not able to accurately describe the morphological aspects of the cornea, especially in the periphery. For this reason, it is deemed necessary to support the sagittal curvature with a representation that best shows the details of the shape of the corneal surface. The tangential (or local) curvature does meet this requirement for each point belonging to a meridional section of the surface as the radius of the osculating circle calculated. Unlike the sagittal curvature, the center of tangential curvature is not constrained to a reference axis. Gaussian curvature Both sagittal and tangential curvature maps, indeed, have their limitations, mainly because they are based on a two-dimensional definition, which can only be applied to an individual meridian. Even if tangential maps largely resolved the lack of sensitivity of sagittal curvature representation, in some cases it may lead to some clinical misinterpretations. It is known that for each point on a regular surface, there are two directions in which the curvature takes on maximum and minimum values – the so-called principal directions and principal curvatures respectively - and none of those necessarily lie in the meridional plane used in the definition of sagittal and tangential curvatures. Due to this, morphological information along the azimuthal direction is not considered at all in these kinds of maps. A better representation of surface curvature can be found in Gaussian curvature, defined by the German mathematician and physicist Carl Friedrich Gauss in 1828 in his Theorema Egregium and introduced in ophthalmology by Barsky at alii.33 in 1997. Gaussian curvature at a point P = (x, y) of a surface is defined as the geometrical mean of the two principal curvatures (i.e. the root square of their product.) 𝐾𝐾 𝑥𝑥, 𝑦𝑦 =

𝐾𝐾!"#$ 𝑥𝑥, 𝑦𝑦 ×𝐾𝐾 !"##$ (𝑥𝑥, 𝑦𝑦)

By definition, Gaussian curvature is a more faithful three-dimensional description of surface shape than axial and tangential curvatures. It has proved to be a suitable representation when detecting subtle shape abnormalities and for the diagnosis of keratoconus and other similar diseases sharing the same features such as pellucid marginal degeneration and post-refractive surgery ectasia, which are characterized by ! ! a local increase in corneal (𝛼𝛼 curvature. Thanks to its unique feature of removing the ! ) 𝑐𝑐! , astigmatic component, it was chosen in the new screening as the basis to quantify of keratoconus such as the locations of the cone peak, some geometric parameters symmetry indices and central-periphery comparison indices. As an example of what we argued, we present the following case of keratoconus on a right eye: observing the anterior and posterior tangential maps (upper and lower left-hand side in Figure 1) 𝑇𝑇𝑇𝑇% 𝜌𝜌 =

𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶 𝜌𝜌 − 𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶 0 𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶 0

the cone appears to be nasal inferior, which is a possible but unlikely morphology, as keratoconus usually develops infero-temporal. Observing the anterior and posterior elevation maps (center upper and lower), we can see the typical astigmatic pattern on the 30°-120° axis. From the Gaussian curvature map, however, it becomes clear that the conus is located infero-temporally as expected and in accordance with the appearance of elevation maps: the combination of a previous or induced astigmatism can indeed add its effect on the tangential map leading to an incorrect identification of the steepest point (and consequentially of the keratoconus barycenter). Conversely, by “averaging” the two principal curvatures at each point of the map, as in Gaussian curvature, the effect of the astigmatism is removed and that of ectasia is maintained.

Figure 1. Maps of a keratoconic eye. From the top left corner: tangential anterior curvature, anterior elevation, Gaussian anterior curvature, tangential posterior curvature, posterior elevation, Gaussian posterior curvature. ! definition Using the same example as a reference and literally applying the 𝐾𝐾!"# (the point with the highest curvature value) we would identify it in the temporal superior quadrant on the tangential curvature map. This point is indicated by!the ★ on the 𝐾𝐾!"# left-hand side of Figure 2. This location is further away from where we would expect it to be and, even if the formal definition is correctly applied, it results in an unexpected 𝒇𝒇 and clinically misleading result. However, by applying to same definition𝑲𝑲and 𝒎𝒎𝒎𝒎𝒎𝒎 algorithm to the Gaussian posterior map we find that the location of the steepest point (indi cated by the μ on the right hand side of Figure 2) is exactly where we expect this to be 𝑲𝑲𝒃𝒃𝒎𝒎𝒎𝒎𝒎𝒎 and in perfect accordance with other notable points of the same eye.

𝑐𝑐!! 𝛼𝛼

Figure 2. Maps of a keratoconic eye. Tangential posterior curvature (left) and Gaussian anterior curvature (right).

Again, the tangential curvature based on a two-dimensional approach fails in faithfully representing the true shape of the ectasia, whereas Gaussian curvature is able to provide the correct information. More recently, the value of apical keratoscopy ! (or 𝐾𝐾!"# ) has been branded as unreliable, unrepeatable, and clinically useless as a descriptor of the progression of the cone: one of our proposals for the near future is to clinically evaluate a new set of Gaussian curvature-based indices. 𝒇𝒇 ! 𝐾𝐾!"#

𝑲𝑲𝒎𝒎𝒎𝒎𝒎𝒎

Curvature-based indices 𝑲𝑲𝒎𝒎𝒎𝒎𝒎𝒎 Index of the anterior and posterior curvature Symmetry The Symmetry Index of the anterior and posterior curvature (SI f – Symmetry Index b Front 𝑐𝑐!! and SI – Symmetry Index Back respectively) are defined as the difference of the mean Gaussian curvature (expressed in diopters) of two circular zones centered in the inferior and superior hemispheres on the axis at 81°/261° or 99°/279° (according 𝛼𝛼 to the! right or left laterality respectively). With reference to Figure 3, the two circular are centered at a distance of 1.5mm from the origin and their radius is 1.5 mm. zones ! As keratoconus is known to develop inferiorly SI f and SI b are designed to measures 𝐾𝐾!"# vertical asymmetry: positive values indicate an inferior hemisphere that is steeper than the superior one, vice versa negative values indicate a superior hemisphere that ! 𝐾𝐾!"# is steeper than the inferior one. Note that for SI b, as the index is expressed as a difference of diopters and the index jump has an opposite sign in comparison with the case f 𝒇𝒇 air-stroma, 𝑲𝑲𝒎𝒎𝒎𝒎𝒎𝒎 the sign of the difference is changed to keep the compatibility with SI . 𝒃𝒃

Center-surrounding index of the anterior and posterior curvature As shown in Figure 3, the Center Surrounding Index of the anterior curvature (CSI f) 𝑲𝑲𝒃𝒃𝒎𝒎𝒎𝒎𝒎𝒎 is defined as the difference of the mean anterior Gaussian curvature (expressed in

𝒇𝒇

∆𝒛𝒛𝒎𝒎𝒎𝒎𝒎𝒎 ∆𝒛𝒛𝒃𝒃

diopters) of a central circular zone with a radius of 1.5 mm and the concentric annulus with a major radius of 3 mm and a minor radius of 1.5 mm. The same geometry can be applied to the Gaussian posterior curvature to define the Center Surrounding Index of the back curvature (CSI b)

! 𝐾𝐾!"#

𝐾𝐾!"#

Figure 3. From left: SI f, SI b, CSI f, CSI b !

𝒇𝒇

𝐾𝐾!"#

𝑲𝑲

𝑲𝑲𝒃𝒃

𝑐𝑐!!

𝒎𝒎𝒎𝒎𝒎𝒎 Anterior and posterior apices Among the curvature-based indices we also have to mention the anterior and pos𝒇𝒇 terior apices ( 𝑲𝑲𝒎𝒎𝒎𝒎𝒎𝒎 and 𝑲𝑲𝒃𝒃𝒎𝒎𝒎𝒎𝒎𝒎 respectively) defined as the value and position of the steepest point of the anterior and posterior Gaussian curvature maps.

Elevation maps 𝒎𝒎𝒎𝒎𝒎𝒎 Elevation maps are useful in a keratoconus screening context in order to visualize pos𝛼𝛼! measured surface against a regular reference surface. In 𝑐𝑐!! of the sible bulging zones CSO screening, the reference surface is an asphero-toric surface with a best-fit apical radius and toricity on a circular 8 mm-diameter zone, and asphericity fixed ! 𝛼𝛼! calculated 𝐾𝐾!"# to the “physiological” value (Q = -0.2 for the anterior, Q = -0.3 for the posterior corneal surface). The reference surface is subtracted from the measured elevation and then ! ! up to the seventh order. The Zernike fitted surface is 𝐾𝐾!"# 𝐾𝐾!"# polynomials fitted with Zernike the elevation map shown in CSO keratoconus screening, where it is called Elevation vs. Normality. 𝒇𝒇 ! 𝐾𝐾!"# 𝑲𝑲𝒎𝒎𝒎𝒎𝒎𝒎 This kind of representation that removes the contribution of astigmatism and average corneal radius, is particularly useful since it emphasizes the higher orders and 𝒇𝒇 𝑲𝑲𝒃𝒃𝒎𝒎𝒎𝒎𝒎𝒎 𝑲𝑲𝒎𝒎𝒎𝒎𝒎𝒎of keratoconus, therefore, in case the ectatic area and the height of the bulging zone against the regular reference surface. 𝒇𝒇

𝑲𝑲𝒃𝒃𝒎𝒎𝒎𝒎𝒎𝒎

∆𝒛𝒛𝒎𝒎𝒎𝒎𝒎𝒎

𝒇𝒇

∆𝒛𝒛𝒎𝒎𝒎𝒎𝒎𝒎 ∆𝒛𝒛𝒃𝒃𝒎𝒎𝒎𝒎𝒎𝒎

∆𝒛𝒛𝒃𝒃𝒎𝒎𝒎𝒎𝒎𝒎 15

Elevation-based indices Ectasia Index of the anterior and posterior surfaces The idea of considering different expressions of Zernike decomposition to discriminate between the normal healthy population and a population of keratoconus is not original and dates back to the publication of Schwiegerling et al.14 in 1996. A similar approach,𝐾𝐾but one which was extended at the posterior corneal surface, was used on the ! !"# f BCV and BCV b26,34 and introduced into CSO keratoconus screening from version 2.6. A new version of such indices called Ectatic Index of the anterior surface and Ectatic ! !"#$ 𝑥𝑥, 𝑦𝑦 ×𝐾𝐾 !"##$ (𝑥𝑥, 𝑦𝑦) f 𝐾𝐾=!"# 𝐾𝐾 𝑥𝑥, 𝑦𝑦of Index the𝐾𝐾 posterior surface (EI and EI b respectively) has been developed in Phoenix 4 based on a wider analysis. To give an idea, Figure 4 shows the different expression of most𝒇𝒇 significant Zernike coefficients between a normal healthy population and a the 𝑲𝑲𝒎𝒎𝒎𝒎𝒎𝒎 keratoconus population for the anterior and posterior surfaces. The EI f and EI b could be expressed as a multi-quadratic combination of Zernike coefficients so as to maxi 𝑲𝑲𝒃𝒃𝒎𝒎𝒎𝒎𝒎𝒎 mize the difference between the two populations as (𝛼𝛼! )! 𝑐𝑐!! ,

where 𝑐𝑐!! is the Zernike coefficient with radial degree n and azimuthal degree m, αp is relative weight, and k its power. the

𝛼𝛼!

! 𝜌𝜌 − 𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶 0 𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶 𝐾𝐾!"# 𝑇𝑇𝑇𝑇% 𝜌𝜌 = 𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶 0

! 𝐾𝐾!"#

𝒇𝒇

𝑲𝑲𝒎𝒎𝒎𝒎𝒎𝒎

𝑇𝑇 𝑥𝑥, 𝑦𝑦 − 𝜇𝜇(𝑥𝑥, 𝑦𝑦) 𝑃𝑃𝑃𝑃 𝑥𝑥, 𝑦𝑦𝑲𝑲𝒃𝒃= 𝒎𝒎𝒎𝒎𝒎𝒎 𝜎𝜎(𝑥𝑥, 𝑦𝑦)

𝒇𝒇

∆𝒛𝒛𝒎𝒎𝒎𝒎𝒎𝒎

∆𝒛𝒛𝒃𝒃𝒎𝒎𝒎𝒎𝒎𝒎

Figure 4. difference expression of most significant Zernike coefficients in a normal healthy population (green) keratoconus400 population 𝑇𝑇 𝑥𝑥! , 𝑦𝑦and − 500 (red) for anterior (above) and posterior ! − 𝜇𝜇(𝑥𝑥! , 𝑦𝑦! ) 𝑃𝑃𝑃𝑃 𝑥𝑥 , 𝑦𝑦 = = = −2𝜎𝜎 ! ! (below) corneal surfaces. 𝜎𝜎(𝑥𝑥! , 𝑦𝑦! ) 50

! 𝐾𝐾!"#

𝐾𝐾!"#

𝒇𝒇

𝐾𝐾!"#

𝑲𝑲

𝑲𝑲𝒃𝒃𝒎𝒎𝒎𝒎𝒎𝒎

𝑐𝑐!!

𝑲𝑲𝒃𝒃𝒎𝒎𝒎𝒎𝒎𝒎

∆𝒛𝒛𝒎𝒎𝒎𝒎𝒎𝒎

Ectasia Index of the 𝒎𝒎𝒎𝒎𝒎𝒎 anterior and the posterior surface Among the curvature-based indices we also must mention the anterior and posterior apices ( 𝑲𝑲𝒇𝒇𝒎𝒎𝒎𝒎𝒎𝒎 and 𝑲𝑲𝒃𝒃𝒎𝒎𝒎𝒎𝒎𝒎 respectively) defined as the value and position of the steepest point of the anterior and posterior Gaussian curvature maps. Corneal thickness Corneal thickness evaluation is mandatory in the process of assessment of a !"##$ (𝑥𝑥, 𝑦𝑦) 𝛼𝛼! 𝐾𝐾 and 𝑥𝑥, 𝑦𝑦 = 𝐾𝐾!"#$ 𝑥𝑥, 𝑦𝑦in×𝐾𝐾 𝑐𝑐!! patient’scorneal health status, is relevant different clinical situations, such as the patient’s eligibility for keratorefractive surgical procedures and the evaluation of ! corneal 𝛼𝛼ectatic diseases. 𝐾𝐾!"# Many studies demonstrated the relationship between the ! variation of corneal thickness and the keratoconus stage, and modern screening sys tems cannot do without evaluations based on pachymetry. ! ! 𝐾𝐾!"# 𝐾𝐾!"# %TI (𝛼𝛼! )! 𝑐𝑐!!to , adopt the path suggested by Ambrosio19: the Ofthe several proposals, CSO decided 𝒇𝒇 performed by defining a Corneal Thickness Spatial Profile (CTSP) ! original analysis was 𝐾𝐾!"# 𝑲𝑲𝒎𝒎𝒎𝒎𝒎𝒎 chart first as the sequence of pachymetric values, starting at the thinnest point, fol lowed by the averages of thickness values of the points within circles centered on the 𝒇𝒇 𝑲𝑲𝒃𝒃𝒎𝒎𝒎𝒎𝒎𝒎 𝑲𝑲𝒎𝒎𝒎𝒎𝒎𝒎 thinnest point. The percentage of thickness increase (TI%) is thus defined starting as from CTSP 𝒇𝒇

𝑇𝑇𝑇𝑇% 𝜌𝜌 =

𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶 𝜌𝜌 − 𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶 0 𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶 0

where𝒇𝒇 ρ represents the diameter of the circle centered on the thinnest point ∆𝒛𝒛𝒃𝒃𝒎𝒎𝒎𝒎𝒎𝒎 ∆𝒛𝒛𝒎𝒎𝒎𝒎𝒎𝒎 with increasing diameters as provided by the CTSP. Signiﬁcant differences of the TI% were found for all positions between normal eyes and keratoconus as the second has 𝒃𝒃 ∆𝒛𝒛 𝒎𝒎𝒎𝒎𝒎𝒎 a higher increase at all distances. With reference to Figure 5 above, the TI% of the examined eye data is displayed 𝑇𝑇 𝑥𝑥, 𝑦𝑦 − 𝜇𝜇(𝑥𝑥, 𝑦𝑦) population (blue navy dotted in a black bold line. The 1st percentile 𝑃𝑃𝑃𝑃 𝑥𝑥, 𝑦𝑦 = of the normal 𝜎𝜎(𝑥𝑥, 𝑦𝑦) line), 5th percentile of the normal population (cyan dotted line), median of the normal population (green dotted line), 95th percentile of the normal population (orange dot ted line) and 99th percentile of the normal population (red dotted line) are plotted as a reference. On the left chart, showing a normal healthy cornea %TI, it is clear how the black line lies within the limits of normality : on the contrary, on the right chart with keratoconus, we can easily notice that the increase of the thickness from the thinnest (the black line is beyond the red one). According to the point to the periphery is higher original paper, the chart is represented with top−left , 𝑦𝑦! origin − 𝜇𝜇(𝑥𝑥! ,on 𝑦𝑦! )the400 𝑇𝑇 𝑥𝑥!the 500corner with the 𝑃𝑃𝑃𝑃 𝑥𝑥! , 𝑦𝑦! = = = −2𝜎𝜎 𝜎𝜎(𝑥𝑥 50y-axis reversed and y-axis descending. Optionally, the same chart is available with the ! , 𝑦𝑦! ) on a ogarithmic scale to better distinguish the normality at the origin (Figure 5 below).

Figure 5. %TI chart with a linear scale for a normal patient (top left), a linear scale for keratoconus (top right), a logarithmic scale for a normal patient (bottom left), a logarithmic scale for keratoconus (bottom right).

Pachymetry-based indices Thickness Symmetry Index The Thickness Symmetry Index (TSI) is defined, similarly to the SIf, as the difference of the mean thickness of two circular zones centered in the inferior and superior hemispheres respectively on the axis at 81°/261° or 99°/279° (according to the right or left laterality respectively),. Maximum Thickness Increase With reference to the %TI description, the Maximum Thickness Increase (TImax) is defined as the maximum difference of Percentage Thickness Increase between current pachymetry and the 95th percentile of the normal healthy population as shown in Figure 5 (purple arrow). Thinnest point Among the thickness-based indices we must also mention the thinnest point (Thkmin) defined as the value and position of the point with minimum corneal thickness.

Stromal and Epithelial thickness It is by now widely acknowledged that epithelial thickness maps can be used as an adjunctive tool to improve the sensitivity and specificity of keratoconus screening32,35 During preoperative assessment for refractive surgery, epithelial thickness mapping can be highly valuable at least in three situations. Firstly, it can correctly detect or confirm a keratoconus diagnosis for certain patients where their anterior surface topography may be clinically deemed to be within normal limits and their posterior surface topography is outside normal limits. Epithelial information allows a more solid earlier diagnosis of keratoconus, as epithelial changes precede changes on the anterior corneal surface. An epithelial doughnut pattern, characterized by epithelial thinning surrounded by an annulus of thicker epithelium31,36-38, coincident with the bulging zone of the posterior elevation and the steepening of the posterior corneal surface, is consistent with keratoconus and it reinforces its diagnosis. As an example, we can observe in the tops section of Figure 6, that even if at first glance the right eye seems to be nothing more than a thin cornea, a more detailed analysis reveals a localized steepening on the posterior surface, in keeping with initial keratoconus changes. Interestingly, a localized thinning of the epithelium occurs in the same location of the posterior ectasia accompanied by an annulus of augmented epithelial thickness, while the anterior corneal curvature was remarkably regular: the corneal epithelium has a masking effect on the irregularities of the anterior stroma, thereby delaying the diagnosis of ectasia. The other eye, in bottom section of Figure 6, confirms the diagnosis of keratoconus. Secondly, epithelial thickness profiles may be helpful in excluding a misdiagnosis of keratoconus when the front surface topography is suspect. Epithelial thickening over an area of topographic steepening implies that the steepening is due to the epithelium and not to an underlying ectatic surface. For instance, in Figure 7, an asymmetrical anterior steepening typical of an early keratoconus pattern can be observed in both the right and left eyes. Despite this, the posterior surface did not show any sign of ectasia and the anterior steepening did not correspond to an area with a thinner corneal epithelium: the substantial inferior epithelial thickening could actually explain the abnormal anterior curvature, resulting in a keratoconus-like appearance. Asymmetrical topographic patterns and focal anterior steepening can sometimes be secondary to corneal warpage: analysis of the epithelial layer with high resolution AS-OCT allows for direct detection of the abnormality rather than just assuming it.

𝐾𝐾 𝑥𝑥, 𝑦𝑦 =

𝐾𝐾!"#$ 𝑥𝑥, 𝑦𝑦 ×𝐾𝐾 !"##$ (𝑥𝑥, 𝑦𝑦)

Figure 6. Early case of very early keratoconus on the right eye and evident keratoconus on the left eye.

Figure 7. In both the right and left eyes, the asymmetrical topographic pattern is secondary to an epithelial thickening.

(𝛼𝛼! )! 𝑐𝑐!! , Pattern deviation map In order to make it easier for the clinician in the interpretation of thickness maps, CSO new screening makes a pattern deviation map available for each of the three measured pachymetries (epithelial, stromal and corneal). This map provides the user with a visual intuitive tool to understand𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶 how𝜌𝜌thinner − 𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶or 0 thicker the current thickness 𝑇𝑇𝑇𝑇% 𝜌𝜌 = 𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶 map is at a certain location in comparison with the0normal value. For each point of the mapped zone, its local statistics have been calculated in terms of mean and standard deviation by analyzing 2000 normal eyes. The local value of the pattern deviation map PD(x,y) is the stated distance, expressed in units of standard deviation of the statistics in said location of the measured value from the average value of this location in the normal population 𝑃𝑃𝑃𝑃 𝑥𝑥, 𝑦𝑦 =

𝑇𝑇 𝑥𝑥, 𝑦𝑦 − 𝜇𝜇(𝑥𝑥, 𝑦𝑦) 𝜎𝜎(𝑥𝑥, 𝑦𝑦)

where T(x,y) is the measured thickness value, μ(x,y) and σ(x,y) are respectively the average and the standard deviation of the thickness of normal population in (x,y). For instance, if the patient’s thickness is 400 µm at point P0(x0,y0) and the de scriptive statistics of healthy population in the same point have a mean of 500 µm and a standard deviation of 50 µm, the value shown on the pattern deviation map will be

𝑃𝑃𝑃𝑃 𝑥𝑥! , 𝑦𝑦! =

𝑇𝑇 𝑥𝑥! , 𝑦𝑦! − 𝜇𝜇(𝑥𝑥! , 𝑦𝑦! ) 400 − 500 = = −2𝜎𝜎 𝜎𝜎(𝑥𝑥! , 𝑦𝑦! ) 50

! 𝑇𝑇 𝑥𝑥, 𝑦𝑦 − 𝜇𝜇(𝑥𝑥, 𝑦𝑦) 𝐾𝐾!"# 𝑃𝑃𝑃𝑃 𝑥𝑥, 𝑦𝑦 = 𝜎𝜎(𝑥𝑥, 𝑦𝑦) ! 𝐾𝐾!"# ! 𝐾𝐾!"# !! 𝐾𝐾!"# 𝐾𝐾 !"# ! 𝐾𝐾!"# ! 𝐾𝐾!"# 𝒇𝒇! 𝐾𝐾 𝑲𝑲!"# 𝒎𝒎𝒎𝒎𝒎𝒎 𝒇𝒇 𝑲𝑲 𝒇𝒇𝒎𝒎𝒎𝒎𝒎𝒎 𝑲𝑲𝒎𝒎𝒎𝒎𝒎𝒎 𝑇𝑇 𝑥𝑥! , 𝑦𝑦! − 𝜇𝜇(𝑥𝑥! , 𝑦𝑦! ) 400 − 500 𝒇𝒇 𝑃𝑃𝑃𝑃 𝑥𝑥! , 𝑦𝑦! = = = −2𝜎𝜎 𝑲𝑲𝒃𝒃𝒎𝒎𝒎𝒎𝒎𝒎 𝜎𝜎(𝑥𝑥! , 𝑦𝑦! ) 50 𝒃𝒃 𝑲𝑲𝒎𝒎𝒎𝒎𝒎𝒎 i.e. the point is two standard deviations thinner than normal in P0. 𝑲𝑲𝒃𝒃𝒎𝒎𝒎𝒎𝒎𝒎 !𝒃𝒃 𝑐𝑐𝑲𝑲!𝒎𝒎𝒎𝒎𝒎𝒎 point of epithelial and stromal thickness Thinnest ! The𝑐𝑐epithelium’s thinnest point (EpiThkmin) and the Stroma’s thinnest point (StrThkmin) ! ! are𝑐𝑐defined as the value and position of the minimum of the epithelial thickness map !! 𝑐𝑐 𝛼𝛼 !! or stromal thickness map respectively. 𝛼𝛼 ! points Notable 𝛼𝛼! ! The𝐾𝐾 points are those points, which are useful for the clinician to identify the 𝛼𝛼 notable ! !"# ! and the entity of the possible corneal thinning, steepening, and bulging. The position 𝐾𝐾!"# list 𝐾𝐾 of! the seven available notable points is as follows: ! !"# ! • EpiThk 𝐾𝐾!"# Min is the minimum value of the thickness of corneal epithelial layer expressed in !μm and its location. 𝐾𝐾 !"# ! • StrThk 𝐾𝐾!"# Min is the minimum value and of the thickness of corneal stromal layer ex !𝒇𝒇 𝐾𝐾 in μm and its location. pressed 𝑲𝑲!"# 𝒎𝒎𝒎𝒎𝒎𝒎 𝒇𝒇 • Thk 𝑲𝑲 Min is the minimum value and of the thickness of the whole corneal layer ex 𝒇𝒇𝒎𝒎𝒎𝒎𝒎𝒎 pressed 𝑲𝑲𝒎𝒎𝒎𝒎𝒎𝒎 in μm and its location. 𝒇𝒇 • 𝑲𝑲𝒃𝒃𝒎𝒎𝒎𝒎𝒎𝒎 is the maximum value in diopters (or the minimum in mm) and of the 𝒃𝒃 Gaussian 𝑲𝑲 curvature for the anterior corneal surface and its location. 𝒃𝒃𝒎𝒎𝒎𝒎𝒎𝒎 • 𝑲𝑲𝒎𝒎𝒎𝒎𝒎𝒎 is the minimum value in diopters (and in mm) of the Gaussian curvature for 𝒇𝒇 𝑲𝑲𝒃𝒃𝒎𝒎𝒎𝒎𝒎𝒎 the posterior corneal surface and its location. ∆𝒛𝒛 𝒎𝒎𝒎𝒎𝒎𝒎 𝒇𝒇 • ∆𝒛𝒛𝒎𝒎𝒎𝒎𝒎𝒎 is the maximum height of the bulging zone derived from the Anterior eleva 𝒇𝒇 tion vs. Normality map and its location. ∆𝒛𝒛𝒎𝒎𝒎𝒎𝒎𝒎 𝒇𝒇𝒃𝒃 • ∆𝒛𝒛𝒎𝒎𝒎𝒎𝒎𝒎 is the maximum height of the bulging zone derived from the Posterior el 𝒃𝒃 evation ∆𝒛𝒛𝒎𝒎𝒎𝒎𝒎𝒎 vs. Normality map and its location. 𝒃𝒃 ∆𝒛𝒛The of all notable points is referred to the corneal vertex. 𝒎𝒎𝒎𝒎𝒎𝒎 position 𝒃𝒃 ∆𝒛𝒛In 𝒎𝒎𝒎𝒎𝒎𝒎 a keratoconic eye, the notable points tend to be concentrated in a small area; in a normal eye they are instead spread out in a wider area. The more concentrated they are, the more likely it is for a keratoconus diagnosis: this consideration is behind the definition of the Notable Points Spread (NPS) index defined as the average distance of the notable points from their barycenter. To make the interpretation of this index easier, all the notable points are shown on the keratoscopy together with their spreading area (i.e. a circle centered on their barycenter with the NPS radius). In the same picture, the two ellipses delimiting the zones where the 95 and 99 percent of the barycenters of keratoconic eyes fall (calculated on a population of 2000 eyes) are shown as a reference.

Keratoconus screening Keratoconus is nowadays regarded as a bilateral progressive disease, although it can rarely appear unilaterally: Rabinowitz showed three decades ago that most cases of unilateral keratoconus were actually bilateral39 and the same findings were demonstrated using videokeratography to observe the progression of keratoconus in clinically normal eyes40. Researchers found that half the patients identified with unilateral keratoconus progressed to the bilateral form within 16 years. Nowadays experts agree that true unilateral keratoconus does not exist.41 Current clinical measurements may simply lack sensitivity in detecting the disease in both eyes. It is thus generally believed that normal-appearing eyes with cases of unilateral keratoconus represent a latent form of keratoconus. Several reports have evaluated the other eye for unilateral keratoconus as a test for the assessment of methods for early diagnosis of occult keratoconus using topographies, tomographies, and biomechanical indicators.42-47 That said, the presented keratoconus screening is designed to be binocular: it consists of four selectable panels: • OD and OS panels; • An enatiomorphism panel; • Summary panel, containing, for both eyes: o a user-selectable map among the ones listed above; o the notable point list and overlaid on the keratoscopy and the above-mentioned list of indices; o the morphological classification according to dr. Alfonso48; o the ABCD grading system according to its definition by Dr. Belin49. OD and OS panels The two panels, OD and OS, contain all the maps and parameters described thus far in a single comprehensive report that takes into account all the aspects of corneal morphology. The first column describes anterior surface in terms of the tangential/ sagittal anterior curvature map (the user can choose one of the two maps), the Gaussian curvature map and the Elevation vs Normality anterior map. In the same way, the second column describes the posterior surface with the same maps that are listed for the anterior surface. In following columns epithelial thickness, stromal thickness and total corneal thickness maps with their own pattern deviation maps are shown.