Historical Concepts of Ocular Surface Disease
Ocular Surface Disease: Advances in Diagnosis & Medical Management
Disorders of the ocular surface include a variety of conditions. Some of the more common conditions encountered in practice include dry eye disease, blepharitis, ocular allergies and pterygia. In addition, less common but more challenging conditions include limbal stem cell deficiency, and ocular surface disease (OSD) from systemic disease (Fig. 1.1). As our understanding of OSD has expanded, the availability of advanced diagnostic tools, medical and surgical therapeutic options, and treatment algorithms for various conditions has enhanced success with OSD. There are classic diagnostic tools for diagnosis of OSD, such as impression cytology, Schirmer testing, tear break-up time, and vital dye staining of the cornea and conjunctiva. These remain valuable tools, however, new diagnostic devices have emerged (Fig. 1.2). Devices, such as tear osmolarity analysis, matrix metalloproteinase-9 analysis, rapid antigen detection for various ocular infectious diseases, and comprehensive analysis of the tear film and lipid are just some of the new diagnostic devices available. Additional advanced diagnostic tools include confocal microscopy, optical coherence tomography (OCT) of the anterior segment, and Scheimpflug imaging of the cornea for advanced diagnosis of various OSD states.1,2 Confocal microscopy enables a detailed investigation of the tarsal and palpebral conjunctiva, central and peripheral cornea, tear film, and eyelids, while affording evaluation of the ocular surface at the cellular level. The device has been particularly useful as a diagnostic tool for cases of atypical keratitis and as a tool to detect phenotypic alterations of the conjunctival epithelium in dry eye disease.1–3
Two of the most common OSD challenges remain dry eye disease and blepharitis. Our knowledge of both of these conditions has expanded over the last few decades with both clinical and basic science research to support the key role of inflammation as a major factor in the development of symptoms and clinical findings of these diseases. The combination of factors leading to dry eye states, often referred to as ‘dysfunctional tear syndrome,’ refers to the compilation of lid margin disease, altered tear film composition, decreased tear volume, diminished corneal sensation, and the presence of anti-inflammatory factors in the tear film.4 The International Dry Eye Workshop (DEWS) included a panel of international ocular surface disease experts challenged to update and review new concepts of dry eye disease. The group developed current concepts of dry eye disease including definition and classification, diagnosis, epidemiology, treatment and management, and research. A fundamental change in our understanding of dry eye is evident in its current definition: ‘Dry eye is a multifactorial disease of the tears and ocular surface that results in symptoms of discomfort, visual disturbance, and tear film instability with potential damage to the ocular surface. It is accompanied by increased osmolarity of the tear film and inflammation of the ocular surface.’4 DEWS provided levels of disease severity with regard to symptoms and signs of dry eye followed by evidence and consensus-based treatment recommendations for dry eye treatment based on new research linking dry eye disease to inflammation.4 Similarly, the Meibomian Gland Workshop involved a panel of international experts challenged to expand our understanding of meibomian gland disease (MGD) (Fig, 1.3). The group developed a contemporary definition and classification of MGD, reviewed methods of diagnosis and evaluation, developed recommendations for the management and therapy of MGD, and presented recommendations for study designs and future research in MGD.5 The treatment recommendations from these workshops have afforded a better understanding of the underlying pathology of dry eye disease, dysfunctional tear syndrome and blepharitis.
With expanded diagnostic tools and a better understanding of the pathophysiology of various forms of OSD, we have seen an explosion of new therapeutic strategies from novel medication classes to new therapeutic devices. In the past, treatment options for various conditions, such as dry eye disease were limited to environmental modifications, artificial tears, and punctal plugs. Current medical treatment advances for OSD include new topical and oral therapies for allergic eye disease, limbal stem cell deficiency, and dysfunctional tear syndrome. Topical nonsteroidal anti-inflammatory agents, cyclosporine A, mast cell stabilizer/antihistamine agents, and various new formulations of corticosteroids can aid in difficult inflammatory eye conditions, such as severe atopic keratoconjunctivitis and dysfunctional tear syndrome. Medical management of limbal stem cell deficiency includes therapeutic agents from topical vitamin A formulations to autologous serum, various topical growth factors, oral omega 3 fatty acid supplementation, and topical vascular endothelial growth factor (VEGF) inhibitors to counteract corneal neovascularization. In addition, new therapeutic devices, such as meibomian gland probing, intense pulse light therapy, and LipiFlow® can be additive to topical and oral medication regimens for relief of signs and symptoms of various types of OSD.5
Origins of the Surgical Management of Severe Ocular Surface Disease
An early concept for the surgical treatment of ocular surface disease (OSD) appeared in 1940 with use of amniotic membrane for the repair of conjunctival defects and symblepharon by De Rotth.6 In 1951, Hartman suggested the use of a free conjunctival graft for correction of pterygium, pseudopterygium, and symblepharon.7 This report suggested the benefit of using conjunctiva for grafting procedures and introduced the notion of harvesting conjunctiva from the contralateral eye in selected cases for the surgical treatment of unilateral disease.7 While Jose Barraquer is credited as the first surgeon to describe stem cell transplant techniques in ocular surface chemical burns,8 Thoft’s description of conjunctival transplantation for monocular chemical burns stands as the basis for the contemporary understanding of ocular surface disease and its treatment.9 Thoft employed autologous ‘conjunctival transplantation’ for the treatment of five cases involving unilateral chemical burns of the cornea. The technique required a complete lamellar keratectomy with removal of the epithelium and pannus formation on the corneal surface followed by 360 degrees of limbal conjunctival resection. Four conjunctival grafts were next harvested from the four bulbar conjunctival quadrants in the uninvolved eye, and each graft was fixated to an analogous quadrant of the diseased eye and secured with sutures.9 The autologous conjunctival graft has stood the test of time and remains the procedure of choice for unilateral stem cell disease as well as contemporary pterygium surgery.
Thoft later described the first allograft procedure, which he termed ‘keratoepithelioplasty,’ in patients with bilateral OSD. This procedure laid the groundwork for contemporary limbal stem cell transplantation techniques (Fig. 1.4).10 Keratoepithelioplasty employed four lenticules which included epithelium and a thin layer of stroma harvested from the peripheral cornea of a donor globe. Each lenticule was secured at the corneoscleral limbus of the surface-damaged eye in each of the four quadrants.10 While keratoepithelioplasty was the first attempt at transplantation of corneal epithelial stem cells in patients with severe bilateral OSD, neither the origin and location of the corneal limbal stem cells nor their functional physiology were clearly understood at that time.
Corneal Stem Cell Theory and Early Clinical Applications
Corneal epithelial stem cells are the progenitor cells and the source of epithelial regeneration after demise or loss of the corneal epithelium. Throughout the body, adult stem cells are found in limited numbers with long life spans, slow cell cycling capabilities, and less differentiation.11–15 Despite these characteristics, they do possess the ability to regenerate and repair tissue after injury. Upon activation, stem cells produce progeny, referred to as ‘transient amplifying cells’ that are responsible for proliferation, differentiation and migration in response to normal physiologic renewal or repair after injury. Daughter cells, in contrast, have short life spans, rapid cell cycling, and high mitotic activity. After epithelial injury, transient amplifying cells migrate centripetally from the limbus and vertically from the basal epithelial layers forward to promote epithelial renewal.15–19 This process of epithelial cell migration is critical in maintenance of the corneal epithelial mass and its ability to regenerate after injury. The limbus serves as a functional ‘barrier,’ preventing encroachment of the conjunctival epithelium onto the cornea during normal homeostasis.19 When this barrier function is impaired, conjunctival epithelium together with blood vessels and fibrous tissue encroach onto the cornea (Fig. 1.5). Loss of this barrier function is one of the first signs in corneal epithelial stem cell deficiency and may result in significant abnormality of the ocular surface.