Computational planning tools in ophthalmology: Intrastromal corneal ring surgery

This thesis addresses the problem of the simulation of intrastromal corneal ring segment surgery for the reduction of myopia and astigmatism, as well as the stabilisation of keratoconus (KC). This disease causes high myopia, irregular astigmatism and reduction of the patient's visual acuity to the point of blindness. Therefore there are several techniques to try to stabilise it and, thus, prevent its progression. For mild keratoconus, it is enough to use special spectacles or lenses to try to correct it, but in more advanced cases it would be necessary to use refractive surgery to try to stop the progression of the disease. The most common ones to avoid the cornea transplant (PK) are the cross-linking and the additive surgery of intrastromal rings. The current planning tools are empirical, based on the nomograms of the ring manufactures, and rely on the experience of the surgeon. Unfortunately, deterministic tools able to estimate the postsurgical visual results of this treatment do not exist. Therefore, the aim of the current thesis is to establish a realistic numerical framework to simulate intrastromal ring surgeries and estimate the mechanical and optical postsurgical outcomes. There are different types of rings depending on their angle and cross-section. There are two large groups of rings: segments which have an angle of less than 360º and those that cover the entire circumference. In the first group we find rings of triangular section such as the Keraring (Mediaphacos, BeloHorizonte, Brazil) and the Ferrara (AJL Ophthalmic Ltd, Spain) and rings of hexagonal section like the Intacs (Additional Technology Inc.). In the second group we can find the MyoRing (Dioptex, GmbH.) whose cross-section is the combination of a parabola and a circumference and the Intacs SK whose section is oval. Due to the complexity of the simulation, since multiple variables are involved, such as the type of rings, the model of the corneal material, the contact conditions between them, etc., two methodologies arised which simulated the insertion of the rings. Both are based on generating a hole in the corneal stroma, introducing the ring and closing the hole with the ring inside, establishing contact until the simulation is completed. In the first of the methodologies the hole was generated by introducing a pressure, while the second was used to an auxiliary tool, such as balloon angioplasty to introduce endovascular stents, which is displaced generating enough hole to insert the rings. As with all numerical simulations, they were not exempt of limitations, although with the first of the methodologies only circular cross--section rings were simulated and in some configurations, there was pressure inside the hole, so it was decided to focus on the second. Nevertheless, interesting conclusions were obtained: the greatest correction was obtained by placing the rings with the largest section near the apex, and whether the ring is located near the epithelium, the stresses generated in the stroma can cause the ring to extrude. With the second methodology based on a displacement control, it was possible to simulate most of the cross-sections and very interesting studies were carried out that gave conclusive results. The most important were: i) the most influential parameter is the depth of insertion; ii) considering the physiological depth of the surgery, the greater optical change is provided by the diameter of the ring, and the fine adjusted is reached with the size of the implant cross--section, i.e the diameter of the implant and the size of the cross--section are the key on regulating the refractive correction; iii) the friction between ring and stroma is important to consider it because a prediction of 2 or 3 diopters could be lost; iv) whether the KC progression is stress-driven, only MyoRing can stop its progression; v) when the covered arc of the segments is more than 320º, axisymmetric model could be used instead of tridimensional model, saving computational time; vi) the anisotropy of the model does not play an important role because the rings are much stiffer than corneal tissue; vii) the implants cannot consider such as second limbus since they act as a dynamic pivot that moves along the circadian cycles of intraocular pressure (IOP); viii) preliminary nomograms is built which allow the estimation of the optical outputs according to the size and typology of the ring and optical zone of implantation.Additionally, a characterisation of ring material was carried out by means two complementary methods: uncertainty analysis and iFEM optimisation, concluding that the manufacturing process of the rings could be the cause of the alteration of the material between the raw PMMA and the ring already prepared for its insertion.<br /

Early interventions in keratoconus

Keratoconus is a condition in which the corneal shape becomes steeper and more irregular between adolescence and the mid-thirties. It is a common cause of visual impairment with disease progression typically managed with rigid contact lens. Traditionally, no intervention has been available to arrest or slow disease progression. As a result, keratoconus is the commonest indication for corneal transplantation in young people. Over the last decade, outcome data has accumulated for new interventions for keratoconus that have radically altered the treatment options for these patients and promises to avoid the sight loss associated with this condition. These interventions include corneal collagen cross-linking (CXL), intracorneal ring implantation and photorefractive keratectomy (PRK). The laboratory and clinical work presented in this thesis explores these new interventions under two key headings: corneal shape stabilisation and visual rehabilitation. I have developed two novel ex vivo techniques which provide quantitative means of measuring riboflavin across the whole cornea in both epithelium-off and –on techniques. Using these methods I have concluded that no existing commercial transepithelial CXL protocol matches the riboflavin penetration achieved following epithelial debridement. I present novel iontophoretic protocols that, by increasing riboflavin concentration, soak duration and current dosage, matches epithelium-off absorption. I additionally report prospective outcomes of an accelerated version of CXL in keratoconus confirming it is a safe and effective iteration of the original ‘Dresden’ protocol. Finally, I present interim outcomes from a prospective study of simultaneous ocular wavefront-guided PRK and CXL showing significant improvements in corrected distance visual acuity beyond that expected with standard CXL

Cambios en la superficie corneal y calidad óptica en pacientes con queratocono pre y post implantación de anillos intraestromales

El queratocono es un desorden, generalmente bilateral y asimétrico que cursa con un adelgazamiento progresivo del espesor del estroma central y/o paracentral corneal y una modificación de la curvatura que produce en mayor o menor medida un astigmatismo irregular, un incremento de las aberraciones de alto orden (HOA) y una protrusión corneal o ectasia que provoca una disminución de calidad visual. La adaptación de lentes de contacto rígidas (LCRPG) es habitualmente el primer tratamiento para recuperar la función visual y el cross-linking (CXL) es el tratamiento aplicado principalmente para estabilizar la córnea y frenar el progreso del queratocono, procurando el fortalecimiento del estroma corneal. La queratoplastia o trasplante total o parcial del centro corneal está indicada cuando la córnea muestra un alto grado de deterioro y perdida de transparencia. Se maneja de cualquier modo como una solución con menos garantías de éxito, ya que la irregularidad superficial corneal resultante aporta mala calidad visual en la mayoría de los casos..

A predictive tool for determining patient-specific mechanical properties of human corneal tissue

A computational predictive tool for assessing patient-specific corneal tissue properties is developed. This predictive tool considers as input variables the corneal central thickness (CCT), the intraocular pressure (IOP), and the maximum deformation amplitude of the corneal apex (U) when subjected to a non-contact tonometry test. The proposed methodology consists of two main steps. First, an extensive dataset is generated using Monte Carlo (MC) simulations based on finite element models with patient-specific geometric features that simulate the non-contact tonometry test. The cornea is assumed to be an anisotropic tissue to reproduce the experimentally observed mechanical behavior. A clinical database of 130 patients (53 healthy, 63 keratoconic and 14 post-LASIK surgery) is used to generate a dataset of more than 9000 cases by permuting the material properties. The second step consists of constructing predictive models for the material parameters of the constitutive model as a function of the input variables. Four different approximations are explored: quadratic response surface (QRS) approximation, multiple layer perceptron (MLP), support vector regressor (SVR), and K-nn search. The models are validated against data from five real patients. The material properties obtained with the predicted models lead to a simulated corneal displacement that is within 10% error of the measured value in the worst case scenario of a patient with very advanced keratoconus disease. These results demonstrate the potential and soundness of the proposed methodology.The research leading to these results has received funding from the European Union’s Seven Framework Program managed by REA Research Executive agency http://ec.europa.eu/research/rea (FP7/2007–2013) under Grant Agreement FP7-SME-2013 606634, the Spanish Ministry of Economy and Competitiveness under the Grant Agreement DPI2014-54981R, the Government of Aragón (predoctoral contract of the author), the Ibercaja-CAI mobility program (mobility funding for research stay of the author) and the Swiss Federal Department of Economic Affairs, Education and Research (Federal Commission for Scholarships for Foreign Students)

A review of artificial intelligence applications in anterior segment ocular diseases

Background: Artificial intelligence (AI) has great potential for interpreting and analyzing images and processing large amounts of data. There is a growing interest in investigating the applications of AI in anterior segment ocular diseases. This narrative review aims to assess the use of different AI-based algorithms for diagnosing and managing anterior segment entities. Methods: We reviewed the applications of different AI-based algorithms in the diagnosis and management of anterior segment entities, including keratoconus, corneal dystrophy, corneal grafts, corneal transplantation, refractive surgery, pterygium, infectious keratitis, cataracts, and disorders of the corneal nerves, conjunctiva, tear film, anterior chamber angle, and iris. The English-language databases PubMed/MEDLINE, Scopus, and Google Scholar were searched using the following keywords: artificial intelligence, deep learning, machine learning, neural network, anterior eye segment diseases, corneal disease, keratoconus, dry eye, refractive surgery, pterygium, infectious keratitis, anterior chamber, and cataract. Relevant articles were compared based on the use of AI models in the diagnosis and treatment of anterior segment diseases. Furthermore, we prepared a summary of the diagnostic performance of the AI-based methods for anterior segment ocular entities. Results: Various AI methods based on deep and machine learning can analyze data obtained from corneal imaging modalities with acceptable diagnostic performance. Currently, complicated and time-consuming manual methods are available for diagnosing and treating eye diseases. However, AI methods could save time and prevent vision impairment in eyes with anterior segment diseases. Because many anterior segment diseases can cause irreversible complications and even vision loss, sufficient confidence in the results obtained from the designed model is crucial for decision-making by experts. Conclusions: AI-based models could be used as surrogates for analyzing manual data with improveddiagnostic performance. These methods could be reliable tools for diagnosing and managing anterior segmentocular diseases in the near future in remote areas. It is expected that future studies can design algorithms thatuse less data in a multitasking manner for the detection and management of anterior segment diseases

Aplicación de métodos de aprendizaje automático a la planificación de la cirugía de implante de anillos intracorneales en pacientes con queratocono

Esta tesis se centra en la elaboraci´on de un predictor de la ganancia en visi´on para pacientes con queratocono tras el proceso quir´urgico de implante de anillos intracorneales. El queratocono se caracteriza por una disposici´on o crecimiento anormal de las fibras de col´ageno en la c´ornea que produce una p´erdida importante de visi´on en el paciente. En los ´ultimos a˜nos, el tratamiento que se ha elegido para la correcci´on de dicha enfermedad es el de la cirug´ıa de implante de anillos intracorneales. Sin embargo, actualmente, se desconoce la t´ecnica y nomograma ideal para la implantaci´on de estos anillos. Esta tesis se centra principalmente en resolver este problema, con el fin de ayudar a los oftalm´ologos a planificar el n´umero, el tipo y la ubicaci´on ´optima de estos anillos para conseguir la mayor ganancia posible en visi´on tras el implante. En particular, en esta tesis se describen y desarrollan modelos capaces de predecir cierta informaci´on en base a conocimientos adquiridos de casos reales y su aplicaci´on en cirug´ıa del queratocono. Los modelos presentados pertenecen al campo del aprendizaje autom´atico. El aprendizaje autom´atico hab´ıa sido utilizado con ´exito en multitud de campos de aplicaci´on y problemas diferentes, incluso en la detecci´on del queratocono, pero hasta el momento no ha sido utilizado para la predicci´on de la mejora en visi´on del paciente tras el implante de anillos. Es por ello, por lo que esta tesis implica una novedad en la planificaci´on de este tipo de cirug´ıa. Las principales contribuciones de esta tesis son: el desarrollo y la validaci´on de un modelo capaz de predecir la ganancia en visi´on en t´erminos de curvatura corneal (K1) y astigmatismo en pacientes con queratocono; un estudio riguroso de las variables refractivas, topogr´aficas o biomec´anicas que m´as relevancia tienen en la predicci´on de la recuperaci´on de la visi´on tras la cirug´ıa y por ´ultimo, el desarrollo de una interfaz de usuario para el uso en cl´ınica del modelo ´optimo desarrollado.Valdés Mas, MÁ. (2015). Aplicación de métodos de aprendizaje automático a la planificación de la cirugía de implante de anillos intracorneales en pacientes con queratocono [Tesis doctoral no publicada]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/48547TESI

Advances in Ophthalmology

This book focuses on the different aspects of ophthalmology - the medical science of diagnosis and treatment of eye disorders. Ophthalmology is divided into various clinical subspecialties, such as cornea, cataract, glaucoma, uveitis, retina, neuro-ophthalmology, pediatric ophthalmology, oncology, pathology, and oculoplastics. This book incorporates new developments as well as future perspectives in ophthalmology and is a balanced product between covering a wide range of diseases and expedited publication. It is intended to be the appetizer for other books to follow. Ophthalmologists, researchers, specialists, trainees, and general practitioners with an interest in ophthalmology will find this book interesting and useful

Análisis morfogeométrico de la estructura hemiesférica del segmento anterior del ojo humano y su aplicación clínica

[SPA] Esta tesis doctoral se presenta bajo la modalidad de compendio de publicaciones.La superficie refractiva más importante del ojo humano es la córnea, que presenta una estructura de forma hemiesférica localizada en el segmento ocular anterior. Esta estructura, incluso en un escenario no patológico, no es perfecta, dado que presenta asimetrías que provocan deformaciones, desalineamientos y descentramientos entre ambos ojos del mismo individuo. Cuando además existen patologías corneales, como pueden ser las ectasias, esta asimetría, y por tanto sus efectos, se acentúan, provocando en el paciente un deterioro ciertamente importante de la capacidad visual, lo que da cuenta de la importancia de disponer de sistemas que permitan una caracterización corneal precisa que facilite la detección, diagnóstico y clasificación de las ectasias. En esta tesis doctoral se ha propuesto un sistema integrado capaz de detectar (fase preclínica) y diagnosticar (fase clínica), de manera eficiente y desde un punto de vista óptico-geométrico, la progresión de la ectasia corneal, permitiendo de esta forma incidir de manera directa en el proceso de toma de decisiones relativas a la calidad visual de los pacientes. Para ello, y partiendo de un modelo sólido personalizado en 3D generado con herramientas de Diseño Asistido por Ordenador, se han propuesto diversos parámetros morfogeométricos macroscópicos de tipo lineal, superficial, volumétrico y angular, con el objetivo de caracterizar la progresión de la ectasia corneal más importante, el denominado queratocono. La estructura microscópica también se ha estudiado, programando una aplicación que permite cuantificar el polimegatismo y el pleomorfismo de las células endoteliales corneales. Posteriormente, se han revisado los distintos sistemas univariantes y multivariantes de diagnóstico y clasificación del queratocono, y se ha comprobado que los parámetros morfogeométricos permiten tanto la detección como la clasificación del queratocono en base a su grado de severidad de acuerdo con las escalas RETICS, Amsler-Krumeich y Alió-Shabayek. Además, se han propuesto dos modelos predictivos (demográfico-óptico-geométricos) de clasificación del grado de la enfermedad en base a la escala RETICS, que han dado lugar al desarrollo de dos aplicaciones informáticas denominadas EMKLAS y KERATOSCORE, que a su vez dan cuenta de la dificultad inherente a la detección de esta enfermedad en la fase preclínica. Por último, se ha aplicado un modelo sólido personalizado obtenido mediante impresión 3D a la educación del paciente, comprobándose que la percepción visual y táctil del modelo permite a los pacientes entender mucho mejor su enfermedad y el tratamiento indicado para ella, mejorando la percepción de calidad del servicio prestado en las clínicas oftalmológicas.[ENG] This doctoral dissertation has been presented in the form of thesis by publication. The most important refractive surface of the human eye is the cornea, which has a hemispherical-shaped structure located in the anterior ocular segment. This structure, even in a non-pathological scenario, is not perfect, since it presents asymmetries that cause deformations, misalignments and decenterings between the two eyes of the same individual. When there are also corneal pathologies, such as ectasias, this asymmetry, and therefore its effects, are accentuated, causing in the patient a certainly significant deterioration of the visual capacity, something that shows the importance of having systems that allow precise corneal characterization to facilitate the detection, diagnosis and classification of ectasias. In this doctoral thesis, an integrated system capable of efficiently detecting (preclinical phase) and diagnosing (clinical phase), from an optical-geometric point of view, the progression of corneal ectasia, has been proposed, thus allowing a direct impact on the decision-making process concerning the visual quality of patients. To do so, and starting from a solid model customized in 3D generated with tools of Computer Assisted Design, several macroscopic morphogeometrical parameters of linear, superficial, volumetric and angular type have been proposed, with the aim of characterizing the progression of the most important corneal ectasia, the so-called keratoconus. The microscopic structure has also been studied, having programmed an application that allows to quantify the polymegatism and pleomorphism of the endothelial corneal cells. Subsequently, several univariate and multivariate diagnostic and classification systems for keratoconus have been revised, and it has been proven that morphogeometrical parameters allow both the detection and classification of keratoconus, basing on its degree of severity according to the RETICS, Amsler-Krumeich and Alió-Shabayek scales. In addition, two classification predictive models (demographical-optical-geometrical) of the disease degree based on the RETICS scale have been proposed, resulting in the development of two computer applications called EMKLAS and KERATOSCORE, which show the inherent difficulty of detecting this disease in its preclinical phase. Finally, a 3D printed personalized solid model has been applied to patient’s education, showing that the visual and tactile perception of the model allows patients to better understand their illness and the treatment indicated for it, improving the perception of quality of service provided in ophthalmological clinics.Las investigaciones que componen esta tesis doctoral se han llevado a cabo con el apoyo de la Red Temática para la Investigación Cooperativa en Salud (RETICS), referencia RD16/0008/0012, y han sido financiadas por el Instituto de Salud Calos III – Subdirección General de Redes y Centros de Investigación Cooperativa (Plan Nacional de I+D+I 2013-2016), el Fondo Europeo de Desarrollo Regional (FEDER), y el programa de Valorización de Resultados de la Universidad Politécnica de Cartagena (PROVALOR-UPCT).Esta tesis doctoral se presenta bajo la modalidad de compendio de publicaciones. Está formada por un total de doce documentos, todos ellos previamente publicados o aceptados para publicación. En concreto, 9 corresponden a artículos en revistas listadas en el ISI-JCR del Sciences Citation Index, mientras que los 3 restantes corresponden a capítulos de libro de la editorial Springer (Ranking Scholarly Publishers Indicators 4/200). Dichos documentos se enumeran a continuación de acuerdo con el orden cronológico en que han sido publicados durante el desarrollo de la investigación: 1. Cavas-Martínez F, Fernández-Pacheco DG, Cañavate FJF, Velázquez-Blázquez JS, Bolarín JM, Alió JL. Study of Morpho-Geometric Variables to Improve the Diagnosis in Keratoconus with Mild Visual Limitation. Symmetry. 2018;10(8):306. DOI: 10.3390/sym10080306. 2. Cavas-Martinez F, Fernandez-Pacheco DG, Canavate FJF, Velázquez-Blázquez JS, Bolarín J, Tiveron M, Alió J. Early keratoconus detection by patient-specific 3D modelling and geometric parameters analysis. Dyna. 2019. 94(2). DOI: 10.6036/8895. 3. Velázquez-Blázquez JS, Cavas-Martínez F, Alió del Barrio J, Fernandez-Pacheco DG, Cañavate FJF, Parras-Burgos D, Alió J. Detection of Subclinical Keratoconus Using Biometric Parameters. In: Rojas I., Valenzuela O., Rojas F., Ortuño F. (eds) Bioinformatics and Biomedical Engineering. IWBBIO 2019. Lecture Notes in Computer Science, vol 11466. Springer, Cham. DOI: 10.1007/978-3-030-17935-9_44. 4. Velázquez JS, Cavas F, Alió Del Barrio J, Fernández-Pacheco DG, Alió J. Assessment of the Association between In Vivo Corneal Morphogeometrical Changes and Keratoconus Eyes with Severe Visual Limitation. J Ophthalmol. 2019;2019:8731626-8731626. DOI: 10.1155/2019/8731626. 5. Velázquez-Blázquez JS, Cavas-Martínez F, Campuzano VA, Alió del Barrio J, Cañavate FJF, Alió J. Automatic image processing applied to corneal endothelium cell count and shape characterization. Dyna. 2020;95(2). DOI: 10.6036/9275. 6. Velázquez-Blázquez JS, Fernández-Pacheco DG, Alió del Barrio J, Alió JL, Cavas-Martínez F. Efficacy of Morpho-Geometrical Analysis of the Corneal Surfaces in Keratoconus Disease According to Moderate Visual Limitation. In: Cavas-Martínez F., Sanz-Adan F., Morer Camo P., Lostado Lorza R., Santamaría Peña J. (eds) Advances in Design Engineering. INGEGRAF 2019. Lecture Notes in Mechanical Engineering. Springer, Cham. 10.1007/978-3-030-41200-5_29. 7. Velázquez JS, Cavas F, Bolarín JM, Alió JL. 3D Printed Personalized Corneal Models as a Tool for Improving Patient’s Knowledge of an Asymmetric Disease. Symmetry. 2020;12(1):151. 10.3390/sym12010151. 8. Bolarín JM, Cavas F, Velázquez JS, Alió JL. A Machine-Learning Model Based on Morphogeometric Parameters for RETICS Disease Classification and GUI Development. Applied Sciences. 2020;10(5):1874. 10.3390/app10051874. 9. Velázquez JS, Cavas F, Bolarín JM, Alió JL. Comparison of Corneal Morphologic Parameters and High Order Aberrations in Keratoconus and Normal eyes. In: Rojas I., Valenzuela O., Rojas F., Ortuño F. (eds) Bioinformatics and Biomedical Engineering. IWBBIO 2020. Lecture Notes in Computer Science, vol 12108. Springer, Cham. DOI: 10.1007/978-3-030-45385-5_8. 10. Toprak I, Cavas F, Velázquez JS, Alió del Barrio JL, Alió JL. Subclinical keratoconus detection with three-dimensional (3-D) morphogeometric and volumetric analysis. Acta Ophthalmologica. (in press). 10.1111/aos.14433. 11. Velázquez JS, Cavas F, Piñero DP, Cañavate FJF, Alió del Barrio J, Alió JL. Morphogeometric analysis for characterization of keratoconus considering the spatial localization and projection of apex and minimum corneal thickness point. Journal of Advanced Research. (in press). DOI: 10.1016/j.jare.2020.03.012. 12. Velázquez-Blázquez JS, Bolarín JM, Cavas-Martínez F, Alió JL. EMKLAS: A New Automatic-Scoring System for Early and Mild Keratoconus Detection. Translational Vision Science & Technology. (in press). (2020).Escuela Internacional de Doctorado de la Universidad Politécnica de CartagenaUniversidad Politécnica de CartagenaPrograma de Doctorado en Tecnologías Industriale

A new approach based on Machine Learning for predicting corneal curvature (K1) and astigmatism in patients with keratoconus after intracorneal ring implantation

Keratoconus (KC) is the most common type of corneal ectasia. A corneal transplantation was the treatment of choice until the last decade. However, intra-corneal ring implantation has become more and more common, and it is commonly used to treat KC thus avoiding a corneal transplantation. This work proposes a new approach based on Machine Learning to predict the vision gain of KC patients after ring implantation. That vision gain is assessed by means of the corneal curvature and the astigmatism. Different models were proposed; the best results were achieved by an artificial neural network based on the Multilayer Perceptron. The error provided by the best model was 0.97D of corneal curvature and 0.93D of astigmatism. © 2014 Elsevier Ireland Ltd. All rights reserved.This work was supported by the Spanish Ministry of Science and Innovation, MICINN (reference TIN2010-20999-C04-01).Valdés Mas, MÁ.; Martin-Guerrero, JD.; Rupérez Moreno, MJ.; Pastor, F.; Dualde, C.; Monserrat, C.; Peris-Martinez, C. (2014). A new approach based on Machine Learning for predicting corneal curvature (K1) and astigmatism in patients with keratoconus after intracorneal ring implantation. Computer Methods and Programs in Biomedicine. 116(1):39-47. https://doi.org/10.1016/j.cmpb.2014.04.003S3947116