Keratoconus: novel investigations in the analysis of the cornea in the diseased state

Abstract

Keratoconus is a relatively common, potentially blinding, disease of the cornea. Although clinically defined more than 150 years ago, the disease is still not wellunderstood. In New Zealand, keratoconus has a higher prevalence than elsewhere in the world, frequently presents to ophthalmology services at an advanced stage, and is the most common indication for corneal transplantation. The inter-related series of studies comprising this thesis was therefore developed to investigate two poorly understood areas associated with keratoconus: the natural history of acute corneal hydrops and the measurement/variation of intraocular pressure (IOP) in the disease process. The current understanding, methods of investigation and management of acute hydrops in keratoconus were defined through a succinct review of the published scientific literature, supplemented by the personal experience and perspective of the author and senior collaborators. This enabled the investigator to create appropriate studies in the context of our knowledge of the disease process and this critical review was published as a “Perspective” in the American Journal of Ophthalmology at the completion of the studies contained in this thesis. Subsequently, patient demographic details, ocular and medical history, family history, presentation and course of disease were analysed in a large series of keratoconus patients in order to identify the predictors and risk factors for acute corneal hydrops in a New Zealand population. Notably, subjects with hydrops were more likely to be of Pacific ethnicity and less likely to be of New Zealand European ethnicity. Affected individuals were more likely to have a history of eyerubbing, but less likely to have a family history of keratoconus. Somewhat paradoxically, such subjects were not identified to have increased likelihood of undergoing corneal transplantation compared to the non-hydrops, keratoconic subjects in the study population. The in vivo confocal microscopy and ex vivo microstructural changes associated with acute hydrops were assessed in a comprehensive, longitudinal manner hitherto unreported in the literature. The microstructural changes occurring throughout the course of acute hydrops in keratoconus were documented and analysed using in vivo confocal microscopy in a prospective study of ten subjects. This study identified unusual cells in the epithelium and stroma of four corneas and in two corneas, which subsequently developed neovascularisation, large stromal cells with branching processes persisted until three months postpresentation. The corneal buttons of five of these ten subjects with acute hydrops were subsequently collected, following penetrating keratoplasty, for ex-vivo immunohistochemical and histological analyses. This latter study highlighted pronounced inflammatory and fibrotic changes following acute corneal hydrops, and a novel finding of dendritic cells in the endothelial layer. The majority of subjects with advanced keratoconus and acute hydrops progress to corneal transplantation. Anecdotally subjects with keratoconus have been reported to have a greater risk of corticosteroid-related elevation of IOP. The incidence of post-keratoplasty IOP elevation in keratoconus and the relationship to corticosteroid administration was therefore assessed in 48 subjects. The incidence of IOP elevation post-surgery in this keratoconic population was higher than reported elsewhere (35%) and was presumed to be steroid-related. Interestingly, IOP elevation was less likely to occur in Maori/Pacific peoples compared to New Zealand Europeans post-keratoplasty. In relation to IOP measurement in the setting of abnormal corneal thinning and shape as occurs in keratoconus, the new Corvis Scheimpflug Tonometer was compared to Goldmann applanation tonometry, rebound tonometry and dynamic contour tonometry in the assessment of IOP measurement in keratoconic eyes. Among the instruments, the Corvis tonometer and the Goldmann tonometer demonstrated the least agreement in keratoconic eyes. IOP obtained by the Corvis tonometer was strongly associated with deformation amplitude of the cornea. Evidence suggests that none of the devices should be used interchangeably in measuring IOP in abnormal corneas such as those exhibiting keratoconus. In conclusion, the series of studies that constitute this thesis have significantly increased our insight into what is still a relatively enigmatic disease: keratoconus. These studies have particularly considered the disease as it manifests in New Zealand and in the New Zealand populations. The data presented highlight relatively late and severe presentation with acute hydrops in Pacific and Maori populations. In addition to analyses of aetiological associations, a longitudinal in vivo confocal microscopy clinical study has provided a unique perspective on the microstructural features of hydrops, and this has been further consolidated by extensive histological analyses of corneal buttons excised at corneal transplantation. Inflammatory changes were identified during the course of hydrops that may predispose to neovascularisation, and some inflammatory processes persist even in the clinically “quiescent stage” prior to corneal transplantation. Following corneal transplantation it appears that patients with keratoconus are more likely to develop corticosteroid- related elevation of IOP than previously reported. An analysis of methods of IOP assessment in keratoconus highlights the benefits and limitations of contemporary devices and that these cannot be used interchangeably in this disease. While a number of future research questions have been raised in the process of these inter-related studies, I hope that the foundation upon which subsequent research is built has been significantly augmented by this work on keratoconus, corneal hydrops and the assessment of IOP in this disease.