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Keratoconus Inflammatory Associations and Treatment Characteristics KERATOCONUS INFLAMMATORY ASSOCIATIONS and TREATMENT CHARACTERISTICS

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Keratoconus Inflammatory Associations and Treatment Characteristics KERATOCONUS INFLAMMATORY ASSOCIATIONS and TREATMENT CHARACTERISTICS Robert Wisse Keratoconus Inflammatory associations and treatment characteristics KERATOCONUS INFLAMMATORY ASSOCIATIONS AND TREATMENT CHARACTERISTICS Thesis, Utrecht University, The Netherlands Copyright © by Robert PL Wisse, 2015 ISBN ISBN 978-94-6233-177-8 Printed by Gildeprint Drukkerijen BV, Enschede Cover Silence et Lumières des Glaces Olieverf op doek, Robert Amrouche, Parijs 2005 Lay out Annelies Wisse, Amsterdam, www.annelieswisse.nl CORRESPONDENCE R.P.L. Wisse, Ophthalmologist | Corneal Specialist Utrecht Cornea Research Group | Department of Ophthalmology Office E.03.136 PO Box 85500 3508 GA Utrecht, The Netherlands Telephone +31 88 75 51683 Email [email protected] Keratoconus Inflammatory associations and treatment characteristics Over de rol van inflammatie en behandeling in keratoconus (met een samenvatting in het Nederlands) Proefschrift ter verkrijging van de graad van doctor aan de Universiteit Utrecht op gezag van de rector magnificus, prof.dr. G.J. van der Zwaan, ingevolge het besluit van het college voor promoties in het openbaar te verdedigen op dinsdag 22 december 2015 des middags te 2.30 uur door ROBERT PIETER LEENDERT WISSE geboren op 31 maart 1983 te Delft PROMOTOR Prof.dr. S.M. Imhof CO-PROMOTOR Dr. A. van der Lelij The research described in this thesis was financially supported by the Dr. F.P. Fischer- stichting, the Landelijke Stichting voor Blinden en Slechtzienden, and the Stichting Vrienden van het UMC. Printing of this thesis was kindly financially supported by Zeiss Nederland; Thea Pharma Benelux; Visser Contactlenzen BV; de Hoornvlies Patienten Vereniging; EyeMed BV; Simovision; Synga Medical; Ophtec BV; Eye Wish Opticiens Wisse, Raadhuisstraat Roosendaal Aan Julia en Roosmarijn Contents Chapter 1 9 General introduction and thesis outline Chapter 2 37 Does lamellar surgery for keratoconus experience the popularity it deserves? Acta Ophthalmologica 2014 Chapter 3 55 Partial endothelial trepanation in addition to deep anterior lamellar keratoplasty in keratoconus patients. The PENTACON trial. Chapter 4 69 Objective and subjective evaluation of the performance of medical contact lenses fitted using a contact lens selection algorithm. Submitted Chapter 5 93 Transepithelial versus epithelium-off corneal crosslinking for the treatment of progressive keratoconus: a randomized controlled trial. American Journal of Ophthalmology 2015 Chapter 6 113 A multivariate analysis and statistical model for predicting visual acuity and keratometry one year after cross-linking for keratoconus. American Journal of Ophthalmology 2013 Chapter 7 133 The independent effects of higher-order aberrations one year after corneal crosslinking for keratoconus. Submitted Chapter 8 151 A comparison of the reliability of the Diaton transpalpebral tonometer with Goldmann applanation tonometry for the assessment of intraocular pressure in keratoconus patients. International Journal of Ophthalmology 2015 Chapter 9 165 Cytokine expression in keratoconus and its corneal micro-environment, a systematic review. Ocular Surface 2015 Chapter 10 199 The role of aging processes and the MTOR pathway in keratoconus. Submitted Chapter 11 221 DNA-damage in keratoconus and the mediating role of UV radiation. Submitted Chapter 12 237 Summary and Discussion 238 Nederlandse samenvatting Chapter 13 252 Review committee 253 Contributors 255 Acknowledgements |Dankwoord 259 List of publications 261 Curriculum Vitae 1 General introduction Robert PL Wisse INTRODUCTION TO THIS THESIS The field of keratoconus research and treatment underwent major changes is the past decades, owing to increased diagnostic possibilities, improved lamellar grafting techniques, advances in contact lens care, and the advent of corneal crosslinking. The body of literature on keratoconus is therefore rapidly expanding. This thesis is the result of 5 years of keratoconus research and reflects the consequences of these developments to our department. A shift in patient selection towards crosslinking rather than corneal grafting prompted the exploration of keratoconus treatment beyond surgery. The collaboration between our department and the laboratory of translational immunology enabled the investigation of etiologic factors in the development of keratoconus. Chapter 1 10 KERATOCONUS; AN OVERVIEW A brief history of keratoconus The first scientific report of keratoconus is attributed to the German pioneer in ophthalmology prof. Burchard David Mauchart, who wrote a doctoral dissertation on this subject in 1748.1 A full century later it was John Nottingham, a British surgeon at the Liverpool St. Anne Eye and Ear Institution, who described the condition in greater detail and distinguished it from other forms of corneal ectasia, most notably the ectasia ex ulcus.2 He also postulated the notion that the conical shape of the cornea resulted in severe astigmatism, short sightedness and difficulties in prescribing adequate glasses. The increased prevalence of keratoconus in Down’s syndrome was described in 1948 by Rados et al3 and the relationship with an atopic constitution was described by Rahi et al4 in 1977 and by Gasset et al5 in 1978. For long, auxiliary investigations are used to establish a keratoconus diagnosis better and quicker. Bowman in 1859 for instance employed the recently developed ophthal- moscope by von Helmholtz to diagnose keratoconus, using the instruments mirror under an angle to best appreciate the conical shape of the cornea. In 1881 Javal and Scholtz improved their keratometer, where two movable colored reflectors are used to assess corneal curvature. This device proved its value in clinical practice and is still in use today. Placido in 1880 devised his archetypical black and white ringed keratoscopy target to asses corneal shape. The actual inventor of the photokeratoscope is a matter of discussion6, but Amsler in 1938 published a treatise on a photographic placido disk that diagnosed keratoconus before clinical signs could be detected.7 The advent of computer-assisted topographical and pachymetric analyses in the nineties have dramatically improved the sensitivity of detection of keratoconus.8 These analyses have been of great value in refining study populations for genetic studies, the follow-up of disease progression, and is an integral part of the screening examination prior to refractive procedures. Especially the latter can be considered a major driving force behind the development of optical diagnostic devices and cameras, since an ectasia can be induced by a routine LASIK refractive procedure in the wrongly selected patient.9 introduction General 11 To improve visual acuity in keratoconus patients several treatment strategies can be employed and the mainstay of these treatments has been unchanged for decades, until recently. Firstly, contact lenses can be fitted to correct the astigmatic error in keratoconus eyes. In 1888, keratoconus became one of the first practical applications of the newly invented glass contact lens by the French physician Eugène Kalt.10 Improvements in manufacturing and materials led to scleral lenses made from celluloid and PMMA in the thirties, but the lack of oxygen permeability remained an issue. In 1983, Ezekiel et al. introduced an oxygen permeable contact lens.11 Small rigid lenses and soft contact lenses quickly gained popularity, replacing the existing scleral lens types. Nowadays, major improvements in scleral lens geometry and choice of oxygen permeable materials have led to a reinvention of scleral lenses for keratoconus, and an increased application worldwide.12 Advances in surgical instrument making and anesthesia enabled the micro-surgery of corneal grafting procedures in the beginning of the 20th century. Eduard Zirm was the first to successfully transplant a human cornea in 1905.13 Improvements in ophthalmic microscopes and suture material increased its popularity, and in 1936 Ramón Castroviejo was the first to transplant a full-thickness keratoconus cornea in the Columbia Presbyterian Medical Center, NY, USA. Poor graft survival was a major issue, since the concepts of graft rejection and its inflammatory constituents were largely unknown. The clouding of the graft was attributed to uveitis, for which no effective treatment existed, since prednisolone was only commercially available from 1955 onwards. Nevertheless, this concept of full-thickness corneal transplantation is still in use today. Lamellar surgery regained popularity from the nineties onward with the advent of better mechanized surgical knives to split the cornea in layers.14 This enabled surgeons to tailor their procedures to the actual localization of the pathology; posterior lamellar surgery revolutionized the treatment for patients with endothelial diseases.15 The advances in anterior lamellar surgery are covered in the section Innovations in the surgical treatment of keratoconus. Epidemiology The prevalence of keratoconus is often reported as 1:2000, but may vary widely due to variations in diagnostic criteria and racial predilections.16 A more realistic estimate is between 50 to 230 per 100.00017,18, but no data with stratification for disease severity Chapter 1 exist. Solid estimates on the incidence, severity and treatment outcomes on population level are mandatory to assess the burden of keratoconus to society. 12 The vast majority of keratoconus occurs bilaterally, and is often asymmetric.19 Strictly unilateral cases have been reported, tough incidence plummeted with the advances in disease detection by corneal topography. It has
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