Mooren Ulcer

Introduction

Mooren ulcer is a painful, progressive, chronic ulcerative keratitis that begins peripherally and progresses circumferentially and centrally. The adjoining sclera and the underlying Descemet membrane are uninvolved. It is an idiopathic disease occurring in complete absence of any diagnosable systemic disorder that could be responsible for the progressive destruction of the cornea. Bowman published the first report of Mooren ulcer in 1849. Later, in 1854, McKenzie described it as a “chronic serpiginous ulcer of the cornea or ulcus roden .” The disorder was named after Mooren, who was the first to clearly describe this insidious corneal problem and defined it as a clinical entity in 1863 and 1867. Subsequently, a large number of reports, including a few recent ones, have been published describing the etiology, pathogenesis, clinical presentations, treatment, and treatment outcomes.

Epidemiology

Wood and Kaufman described two clinical types of Mooren ulcer. The first, limited type, is usually unilateral, with mild to moderate symptoms, and generally responds well to medical and surgical treatment. This type is believed to occur in older patients and is known as typical or benign Mooren ulcer. The second type is bilateral although both eyes may not be affected simultaneously, with relatively more pain and generally a poor response to therapy. The bilateral variety primarily occurs in younger patients and is sometimes referred to as atypical Mooren ulcer. This variety of the ulcer progresses relentlessly and is more likely to result in corneal perforation. It is also believed that the atypical Mooren ulcer has a predilection for young black males.

Watson in 1997 divided Mooren ulcer into three distinct varieties based on clinical presentation and anterior segment fluorescein angiographic findings. Unilateral Mooren ulceration is a painful progressive corneal ulceration in elderly patients and is associated with nonperfusion of the superficial vascular plexus of the anterior segment. Bilateral aggressive Mooren ulceration occurs in young patients, progressing circumferentially then centrally. These are associated with vascular leakage and new vessel formation, extending into the base of the ulcer. Bilateral indolent Mooren ulceration usually occurs in middle-aged patients presenting with progressive peripheral corneal guttering in both eyes, with little inflammatory response. There is no change from normal vascular architecture except an extension of new vessels into the ulcer. Ashar et al. described a severity-based stepladder approach for immunosuppression taking into consideration laterality, number of quadrants of corneal involvement, age, monocular status, and corneal perforation.

Although Mooren ulcer can occur in all age groups, including children, the vast majority of them present between 40 and 70 years. Although the disease presents in both genders, it is more common in men than women. Unilateral involvement is more common, and the majority of the affected eyes have partial peripheral corneal ulceration. The interpalpebral limbus is involved most often, followed by the inferior and then the superior limbus. ^,

Contrary to the classical description, a review of published series by Lewallen and Courtright found that 43% of older patients had bilateral disease, whereas bilateral disease was present in only one-third of patients younger than 35 years. In addition, more whites were affected with bilateral disease than blacks. They concluded that the current understanding of the epidemiology of Mooren ulcer might be flawed because of inconsistent definition of the disease, poor documentation and follow-up, and problems inherent in non–population-based data collection.

Etiology

Mooren ulcer has been associated with different entities, often leading to the conjecture that there may be a causal relationship. Multiple studies have reported association between Mooren ulcer and hepatitis C infection. ^, Many of these patients responded to interferon therapy. ^, Infectious associations have been reported with hookworm infestation. ^, These authors proposed that molecular mimicry might be involved, with the infecting agent stimulating an autoimmune response to corneal antigen calgranulin C through cross-reacting epitopes. Yet another theory proposed the deposition of immune complexes in limbal or peripheral corneal tissues leading to an immune response and release of proteolytic enzymes. Ocular trauma and surgery have also been attributed as etiologic agents, but the association has not been established.

Pathogenesis

The pathogenesis of Mooren ulcer remains uncertain. Mooren ulcer has the characteristics of an autoimmune process, and various authors have documented autoimmune phenomena, both in the eye and systemically, in patients suffering from this disorder.

The cellular population found in the conjunctiva and the peripheral edge of the ulcer is primarily plasma cells, lymphocytes, and macrophages. There is increased binding of immunoglobulin G (IgG), IgM, and C3 to the epithelium of conjunctiva adjacent to the ulcer. Shinomiya et al. showed that the conjunctival tissue adjacent to the ulcerative cornea contains CD3- and CD45RO-positive helper T-lymphocytes and CD68-positive macrophages, whereas infiltration of B-lymphocytes, neutrophils, and mast cells was minimal. Du Toit and Smit published a rare case of Mooren ulcer after immune reconstitution and attributed this to increase in CD4-positive cells after the therapy. Kafkala et al. demonstrated upregulation of various adhesion and costimulatory molecules in the conjunctival epithelium of Mooren ulcer patients. In this study, the ratios of CD4/CD8 cells and B7-2/antigen-presenting cells were significantly higher in Mooren ulcer specimen. Systemically, Mooren ulcer patients have a decrease in the number of suppressor T-cells relative to the number of helper T-cells, elevated IgA levels, and circulating IgG antibodies and immune complexes to human corneal and conjunctival epithelium. Gottsch and colleagues demonstrated antibodies to an autoantigen that exists in corneal stroma. Several studies have also identified association between human leukocyte antigen (HLA)-DR17 and the occurrence of Mooren ulcer. ^,

Li et al. investigated the expression of succinate receptor GPR91 in the pathogenesis of Mooren ulcer and found elevated expression of GPR91 mRNA. Succinate activation of GPR91 leads to increased production of proinflammatory cytokines interleukin-1β (IL-1β), vascular endothelial growth factor (VEGF), and matrix metalloproteinase 13 (MMP-13) in peripheral blood mononuclear cells (PBMCs). Inhibition of this pathway is having potential for developing a new drug for controlling Mooren ulcer.

From all evidences in published literature it appears that Mooren ulcer represents a final common pathway to a variety of insults to cornea in susceptible patients. Trauma or infection alters normal corneal antigens, which than lead to an autoimmune response. Altered antigen is taken up by macrophages that move through conjunctival vessels to peripheral lymph nodes, eventually resulting in T-cell activation, differentiation, and proliferation. The lymphocytes return through conjunctival vessels and cause ocular inflammation. The corneal edema from inflammation allows easier diffusion of immune components into peripheral cornea from the limbal vessels, which explains why Mooren ulcers typically begins in the periphery. The cornea is thus damaged, liberating more altered corneal antigens in turn aggravating and perpetuating the process until entire corneal stroma is completely destroyed.