Mooren’s Ulcer is a painful, progressive, and chronic disease of the cornea, which often is bilateral and may cause severe vision loss or even loss of the eye. It is characterised by painful peripheral corneal ulceration of unknown aetiology. The disease generally begins with intense limbal inflammation and swelling in episclera and conjunctiva. Corneal changes begin 2- 3mm from the limbus as grey swelling that rapidly furrows. It affects superficial one- third of cornea and then it progresses circumferentially and centrally. There is usually infiltration and undermining of the leading edge of the circumferential peri-limbal ulceration. The bed of the furrow becomes vascularised with vessels advancing into the base of the undermined edges. The central edges of the ulcer can develop an overhanging edge extending from limbus into the ulcer bed, with or without opacification and neovascularisation. Neovascularisation may occur up to the advancing edge of the ulcer but not beyond it. Tissue destruction and ulceration of the cornea is initially confined to the periphery, but it may progress in some patients to involve the entire cornea. Destruction of the cornea generally affects stromal tissue only, leaving behind an intact epithelium and endothelium. The ulcers are crescent- shaped and may leave behind either an opaque oedematous cornea or is replaced with a thin fibro-vascular membrane. It does not affect underlying Descemet’s membrane. There is no associated scleral inflammation. Intense pain is a hallmark of Mooren’s ulcer, which is generally lacking in other peripheral ulcerative keratitis. The disease may be refractory to all forms of available therapy.
Bowman (1849) first described what we now call Mooren’s ulcer of the cornea (also known as chronic serpiginous ulcer and ulcus rodens). Mooren’s ulcer as a clinical entity was first described in detail by Mooren (1867).
Wood and Kaufman (1971) postulated that there are two distinct populations of patients with Mooren’s ulcer. These two clinical types of primary Mooren’s ulcer are:
Type I: The limited type is typically unilateral, not associated with significant pain, and occurs in older patients (fourth decade and older). It is more responsive to local medical and surgical therapy.
Type II: Relentless, progressive type is more resistant to systemic immune-suppression. It is painful, bilateral and causes relentless, progressive destruction of the cornea, usually in younger individuals (third decade), many of whom are of African descent. It may progress to corneal perforation.
However, the categorisation described by Wood and Kaufman has been refuted by Lewallen S and Courtright P (1990).
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Mooren’s ulcer may produce symptoms such as:
Severe ocular pain.
Foreign body sensation.
Blurring of vision.
The cause of Mooren’s ulcer is unknown, but evidence suggests an autoimmune basis. Supportive evidence includes:
Presence of plasma cells and lymphocytes in the conjunctiva adjacent to the ulcer.
Serum of patients shows circulating antibodies to conjunctival and corneal epithelium.
Elevation of serum levels of immunogobulin (Ig) like IgA, IgG and IgM and lymphocytes sensitised to saline- soluble corneal antigen.
Increased antibody levels to a cornea- specific stromal protein antigen.
Increased helper T cell to suppressor T cell ratio.
Favourable response to immunosuppressive agents in some patients.
Presence of Calgranulin C, a unique cornea associated protein that is present in the cornea and is the target of auto-antibodies from patients with Mooren’s ulcer. This calcium- binding protein is identical to a neutrophil protein found on the surface of filarial nematodes. Recognition of this complex on a filarial nematode is suspected to lead to autoimmunity to the cornea in patients with persistent parasitic infection resulting in Mooren’s ulcer.
Mooren’s ulcer may represent a final common pathway to a variety of insults to the cornea in susceptible patients. Trauma or infection may alter normal corneal antigens, which may lead to an autoimmune response. The cornea is damaged further, liberating altered corneal antigens that aggravate and perpetuate the process until the corneal stroma is completely destroyed.
Certain conditions may be associated with Mooren’s ulcer:
Herpes simplex infection.
Herpes zoster infection.
In the past, Mooren’s ulcer has been related to:
Trophic disturbances involving the trigeminal cranial nerve.
Deficiency of vitamin B1.
Some patients have been identified who have an underlying chronic hepatitis due to hepatitis C virus infection. This infection should be excluded because it alters therapy and the potential outcome of treatment.
The majority of the cases, however, appear to be idiopathic and the disorder is a diagnosis of exclusion.
By definition, primary Mooren’s ulcer is not associated with any systemic abnormality, except for the occasional association with hepatitis C. It is not associated with scleritis, which distinguishes it from other more common types of peripheral ulcerative keratitis associated with collagen vascular disease. Patients having other systemic disease including leukaemia, pyoderma gangrenosum and syphilis may also develop peripheral ulcerative keratitis. This classic idiopathic variety may manifest as either type I or type II.
A secondary Mooren’s ulcer like peripheral ulcerative keratitis may occur following other types of corneal inflammation, including trauma, cataract surgery, herpes simplex, herpes zoster and chemical injury with alkalis. Although these are not diagnostic of true Mooren’s ulcer, they do support the involvement of an altered auto-antigen pathogenic mechanism. This is often unilateral and behaves clinically like type I.
A small group of patients with aggressive disease progression are seropositive for hepatitis C.
Diagnosis of Mooren’s ulcer depends upon medical history, clinical examination and laboratory investigations. Laboratory investigations are required to exclude other systemic diseases.
Mooren’s ulcer is characterised by a progressive, crescentic, peripheral corneal ulceration which is slightly towards the center from the corneoscleral limbus. It is associated with a characteristic undermined overhanging edge. It typically progresses with an anterior, stromal, yellow- white infiltrate at the advancing margin. An overlying epithelial defect then may develop. The ulcer progresses both circumferentially and centrally. Progressive stromal melting affects first the deeper and subsequently the anterior stroma. Following stromal melting, a re-epithelialised, conjunctivalised, scarred and thinned cornea remains. Patients with minimal stroma left may be predisposed to perforation either spontaneously or following minimal trauma.
In aggressive form of Mooren’s ulcer, inflammation may affect the entire cornea and perilimbal tissue. The cornea may perforate. It may have associated cataract, secondary glaucoma and uveitis.
Chronic Mooren’s ulcer ultimately results in central area of hazy stromal tissue with severe peripheral thinning. There is no scleral involvement, but associated conjunctival and episcleral inflammation may be present. There is no lucid interval (clear zone between ulcer and limbus). Scarring is common and it may be associated with irregular corneal astigmatism.
Corneal topography: Corneal topography shows peripheral steepening and severe irregular corneal astigmatism.
Srinivasan and colleagues (2007) described three patterns of corneal ulceration:
Partial peripheral ulceration: Partial peripheral ulceration may be sub-divided into nasal, temporal, superior and inferior ulceration. Nasal and temporal involvement is more common.
Complete peripheral ulceration: In complete peripheral ulceration, the disease encompasses the corneal periphery, leaving behind a central island of cornea that is often opacified.
Total corneal ulceration: In total corneal ulceration, the stroma is completely replaced with a fibro-vascular membrane.
Watson and colleagues (1997) classified the disease into three types based on clinical features, anterior segment fluorescein angiographic findings, and treatment response:
Unilateral Mooren’s ulceration: Unilateral Mooren’s ulceration is excessively painful and occurs in elderly. Affected eyes are red but inflammation does not extend beyond 3mm from the limbus. Ulceration extends around the globe and often leaves an opaque central cornea. The central corneal stroma is eventually removed. Anterior segment fluorescein angiography shows venular occlusion of local episcleral and conjunctival blood vessels along with disruption of the limbal arcade and vascular leakage from deep vessels at the limbus and base of the ulcer. In addition, vaso- obliteration of superficial vascular networks is characteristic of unilateral Mooren’s ulcer.
Bilateral aggressive Mooren’s ulcer: Bilateral aggressive Mooren’s ulcer occurs in younger patients and the pain is less severe. Grey patches occur in corneal stroma about 2mm from the edge of the limbus. These grey patches then aggregate and lead to a typical Mooren’s ulcer that progress first circumferentially and then centrally. Fluorescein angiography shows vascular leakage and new vessel formation that reaches the base of the ulcer. Angiography may also show changes in episcleral vessels and blockage in addition to break-up of the limbal arcade.
Bilateral indolent Mooren’s ulcer: Bilateral indolent Mooren’s ulcer occurs in middle aged patients who exhibit corneal guttering in both eyes with little inflammation. Both eyes tend to be involved at presentation, but the disease is often more severe in one eye. Most cases are gradually progressive but some heal spontaneously. Vascular architecture is normal with the exception that new vessels may extend into the base of the ulcer.
Since Mooren’s ulcer is a clinical diagnosis, it is not necessary to conduct all investigations, if Watson’s criteria is met.
Crescent shaped peripheral corneal ulcer.
Extensive undermining of the central edge of the ulcer.
Corneal infiltrations along the leading edge.
Absence of scleritis.
Absence of detectable systemic disease.
Laboratory investigations include:
Blood examination: It includes complete and differential blood cell count including platelet counts and erythrocyte sedimentation rate (ESR).
Serology: It includes measurement of rheumatoid factor, antinuclear antibody, antineutrophil cytoplasmic antibodies, venereal disease research laboratory (VDRL) test and fluorescent treponemal antibody absorption (FTA-ABS) test.
In addition, certain tests like measurement of liver enzymes, blood urea nitrogen, serum protein electrophoresis and urinalysis may also be required.
In Mooren’s ulcer, three zones of corneal involvement have been described.
Superficial stroma: Superficial stroma contains plasma cells, lymphocytes, neutrophils, neovascular elements and disrupted collagen lamellae.
Midstroma: Midstroma shows an increase in number of fibroblasts.
Deep stroma: Deep stroma is infiltrated primarily by macrophages. The epithelial basement membrane is disrupted at the leading edge and the infiltrate contains primarily neutrophils.
Conjunctiva: Conjunctival resections show mononuclear infiltrate in the substantia propria, which contains plasma cells, histiocytes and eosinophils.
The presence of tissue- fixed auto-antibodies and complement also has been reported in the epithelial basement membrane of the cornea and conjunctiva.
Mooren’s ulcer is a rare disease. The differential diagnosis includes other inflammatory and non-inflammatory conditions causing peripheral thinning such as:
Terrien’s marginal degeneration: Terrien’s marginal degeneration is a non-inflammatory peripheral corneal thinning disorder that is usually bilateral, superior, and not associated with significant pain or inflammation unless there is an associated episcleritis or superficial scleritis. The corneal epithelium remains intact and the disease slowly progresses in circumferential manner without involving central cornea.
Pellucid marginal degeneration: Pellucid marginal degeneration causes inferior corneal thinning and irregular against-the-rule astigmatism but lacks the inflammation and pain seen in Mooren’s ulcer.
Senile furrow degeneration: Senile furrow degeneration causes thinning between the limbus and the arcus in elderly patients. However, no inflammation or vascularisation occurs.
Peripheral marginal keratitis (catarrhal ulcer): Peripheral marginal keratitis (catarrhal ulcer), seen in association with staphylococcal blepharitis, may also show peripheral infiltrates. The infiltrate is usually unilateral and is separated from the limbus by a lucid interval (a clear zone). Associated pain is not severe. The disease has a benign course, and is self- limited.
Collagen vascular diseases: Collagen vascular diseases, such as systemic lupus erythematosus, rheumatoid arthritis, polyarteritis nodosa, and Wegener’s granulomatosis, may also be associated with peripheral corneal infiltrates and ulcers with features similar to Mooren’s ulcer and an associated scleritis. The characteristic marginal furrows of rheumatoid arthritis are located about 1mm within the limbus and usually bilaterally in the inferior cornea. It may be superficial and nonprogressive, or it may progress to epithelial breakdown, marked stromal thinning with formation of descemetocele, and finally perforation. The marginal furrows may encircle the cornea. Occasionally, the entire superficial part of the remaining central corneal stroma may slough away.
Management should be carried out under medical supervision.
The objective and goal of therapy of Mooren’s ulcer is to stop the progression of the ulcerative process and promote re- epithelialisation of the ulcerated area. Symptoms of pain and photophobia and inflammatory signs of conjunctival hyperaemia and oedema generally disappear shortly after healing is complete.
Brown and Mondino (1984) suggested a stepladder approach that includes topical corticosteroids, conjunctival resection, and systemic immunosuppressives.
Topical corticosteroids: To begin with, patients with Mooren’s ulcer are treated with topical corticosteroids, as long as there is no sign or danger of imminent perforation. The frequency of topical steroids may be slowly tapered, if the ulcer heals completely. Aggressive therapy with topical corticosteroids may be effective in unilateral and bilateral non simultaneous cases, but not treated aggressively in bilateral simultaneous cases. Topical steroids must be used with extreme caution in patients having associated rheumatoid arthritis.
Patients with Mooren’s ulcer are prescribed antibiotics to prevent secondary bacterial infection, and cycloplegics to control pain from spasm of the ciliary body.
Systemic immunosuppressives: Systemic immunosuppressives may be employed in patients with bilateral and progressive disease, and also where conjunctival excision does not result in total healing of ulcer. If healing does not occur after one or two months, immunosuppressive therapy is slowly decreased and then discontinued. If some healing is observed, the medication is continued until complete healing. The dosage of the treatment is titrated to maintain haemoglobin and blood counts. Common immunosuppressive drugs used are cyclophosphamide, azathioprine with or without steroids, and methotrexate. Some treat Mooren’s ulcer with systemic and topical cyclosporine A. The efficacy of topical cyclosporine is attributed to local depression of ocular immune-pathologic reaction.
Systemic immunosuppressives may also be used for peripheral corneal ulcers associated with collagen vascular diseases. Systemic immunosuppressive agents, including corticosteroids, have been effective in the treatment of scleritis and ulcerative keratitis. Cytotoxic agents may improve long- term survival.
Systemic immunosuppression would likely be contraindicated in a patient with chronic hepatitis C infection, so it is important to exclude it beforehand.
Interferon- α2b: Recently, an association has been reported between Mooren’s ulcer and hepatitis C infection. Some cases of bilateral ulcer that did not respond to conventional therapy showed improvement with systemic interferon- α2b for the chronic active hepatitis.
Rebetron: Rebetron is a newer treatment option. It combines interferon with the antiviral drug ribavirin.
Topical lecithinated superoxide dismutase: A novel experimental therapy with topical lecithinated superoxide dismutase limited tissue destruction in patients who failed to topical corticosteroid therapy.
In addition, bandage contact lenses may reduce discomfort and promote epithelial healing. Subconjunctival heparin injections and topical collagenase inhibitors have also been used.
Conjunctival resection: Conjunctival resection may be performed adjacent to the ulcer in patients who show incomplete or no response to topical corticosteroids. About 3mm of conjunctiva is resected from the corneoscleral limbus and adjacent to the corneal ulcer. The epithelium in the bed of ulcer and less than 0.2mm of corneal epithelium central to the ulcer are removed by simple debridement.
Cryotherapy: Cryotherapy of the conjunctiva adjacent to the affected cornea. It gives similar results as are obtained with conjunctival excision.
Tissue adhesives (isobutyl- cyanoacrylate): Tissue adhesives (isobutyl- cyanoacrylate) may be applied if the corneal perforation is less than 1mm in size. There may be an arrest of ulceration if the application is done at an early stage before corneal perforation. The adhesive rapidly polymerises and becomes a solid adhesive on contact with water.
Keratoplasty: Keratoplasty may be required when the corneal perforation is too large for tissue adhesive to seal and prevent the leak.
- Patch graft: Patch graft may range from a tapered plug of corneal tissue to a peripheral penetrating keratoplasty. A small piece of corneal tissue is crafted into a tapering plug to fill the defect. The margins of the perforation site are cleaned of any necrotic material and epithelial tissue.
- Partial penetrating keratoplasty: Partial penetrating keratoplasty may be performed in cases with larger peripheral perforations.
- Penetrating keratoplasty: Penetrating keratoplasty shows poor results and has been described for patients with healed Mooren’s ulcer. Penetrating keratoplasty may be complicated by the recurrence and extension of the disease process into the donor tissue with resultant necrosis and sloughing. Penetrating keratoplasty may restore some vision in a healed and quiet eye with an opaque or scarred cornea.
- Crescentic annular lamellar graft: Crescentic annular lamellar graft is rarely used in cases of peripheral corneal thinning, when the cornea is not perforated.
- Central lamellar keratectomy: Some advocate removal of the presumed antigenic corneal stroma by central lamellar keratectomy, in an attempt to mediate a more rapid resolution of the inflammation.
Amniotic membrane transplantation: Amniotic membrane transplantation is an alternative treatment for reconstruction of ocular surface and corneal stroma damaged by an immunologic process. The exact mechanism of its function is not known but it has been shown to possess anti-inflammatory and anti- immunogenic qualities. A single layer amniotic membrane transplantation involves placing amniotic membrane stromal side down onto the ulcerated defect. Multilayer amniotic membrane may be placed into a stromal ulcer defect.
Keratoepithelioplasty: Keratoepithelioplasty is a new surgical procedure for the treatment of persistent epithelial defect in patients without healthy donor tissue in their fellow eyes. After a total superficial keratectomy, donor corneal lenticules covered by epithelium are placed at the corneoscleral limbus. The epithelium spreads from the lenticules and covers the center of the cornea.
Conjunctival flap: Conjunctival flap may provide comfort, reduce ocular inflammation, and promote healing in cases where medical/ surgical therapy fails, and patient experiences pain from recurrent epithelial breakdown with stromal ulceration. It is especially useful for elderly debilitated patients for whom prolonged hospitalisation and medical therapy may not be warranted.
Most patients with unilateral disease respond fairly well to topical corticosteroids and conjunctival resection.
The prognosis is poor for more severe bilateral cases, and the primary goal is to reduce the chances of perforation and preserve the structure of the eye.
Complications of Mooren’s ulcer may be:
End- stage cornea is thinned and conjunctivalised.