Year : 1997 | Volume
: 45 | Issue : 1 | Page : 7--17
Mooren's ulcer : Current concepts in management
VS Sangwan, P Zafirakis, CS Foster
Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Boston, USA
V S Sangwan
Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Boston
Mooren«SQ»s ulcer is strictly a peripheral ulcerative keratitis (PUK) with no associated scleritis. It occurs completely in absence of any diagnosable systemic disorder that could be responsible for the progressive destruction of the cornea. The aetiology of Mooren«SQ»s ulcer remains uncertain. However, recent studies indicate that it is an autoimmune disease directed against a specific target molecule in the corneal stroma, probably triggered in genetically susceptible individuals by one of several possible provocateurs. Advances have been made in the management of this disease. Immunosuppressive therapy has been shown increasingly successful in patients unresponsive to conventional treatment and in bilateral progressive destructive ocular disease.
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Sangwan V S, Zafirakis P, Foster C S. Mooren's ulcer : Current concepts in management.Indian J Ophthalmol 1997;45:7-17
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Sangwan V S, Zafirakis P, Foster C S. Mooren's ulcer : Current concepts in management. Indian J Ophthalmol [serial online] 1997 [cited 2019 Oct 14 ];45:7-17
Available from: http://www.ijo.in/text.asp?1997/45/1/7/15030
Mooren's ulcer was first described by Bowman in 1849, and then by McKenzie in 1854 as "chronic serpiginous ulcer of the cornea or ulcus roden". Mooren's name, however, became attached to this rare disorder because of his publication of cases in 1863 and 1867. He was the first to clearly describe this insidious corneal problem and define it as a clinical entity. In 1902, Nettleship summarized the accumulated reported experience with the disorder in a classic article wherein he reviewed 67 previously published cases and added 11 new cases from his experience. Mooren's ulcer is a painful, relentless, chronic ulcerative keratitis that begins peripherally and progresses circumferentially and centrally. Mooren's ulcer is, by definition, idiopathic occurring in complete absence of any diagnosable systemic disorder that could be responsible for the progressive destruction of the cornea. It also is strictly a peripheral ulcerative keratitis (PUK), with no associated scleritis. Absence of scleritis is of substantial importance, since many of the misdiagnosed cases had the peripheral ulcerative keratits (PUK) in association with adjacent scleritis, necrotizing or otherwise. Its exact pathophysiology remains uncertain, although a growing body of evidence indicates that it is an autoimmune disease directed against a specific target molecule in the corneal stroma, probably triggered in the genetically susceptible individuals by one of several possible provocateurs. Despite the advances made in management of this disorder, a significant percentage of cases remain refractory to available therapies and end in severe visual morbidity. There are 287 cases described in world ophthalmic literature ; some of the cases included in reports of "Mooren's ulcer" are in fact not true Mooren's ulcer, but rather instances of individuals with PUK as the presenting manifestation of an occult systemic disease.
Mooren's ulcer is a rare disorder, typically seen in healthy adult men with no evidence of systemic disease. It has been documented in a 3-year old child. Wood and Kaufman having reported 9 cases, concluded that there were two clinical types of Mooren's ulcer. The first, limited type, is usually unilateral, with mild to moderate symptoms, generally responds well to medical and surgical treatment. This type is believed to occur in older patients and has became known as typical or benign Mooren's ulcer. In contrast, the second type is bilateral, with relatively more pain and generally a poor response to therapy. The bilateral variety, once believed to occur primarily in younger patients, became known as atypical or malignant Mooren's ulcer. The benign type is quater time bilateral and the malignant type 75% time bilateral,. Usually bilateral progressive form of this disease occurs in older individuals. Keitzman published a series of 37 cases of progressive Mooren's ulcer in Nigeria affecting primarily healthy men between the age of 20 and 30 years and the clinical course was very rapid, with total involvement and destruction of the cornea within 6 weeks. Perforation occurred in 36% of the patients. A later report confirmed that the malignant form was the more common form occurring in the young Nigerian men. As a result, the generalized belief has developed that the progressive and relentless atypical form of Mooren's ulcer has a predilection for young, black men. Lewallen and Courtright, in their review of the published series of Mooren's ulcer, suggest that many of our current concepts of epidemiology of Mooren's ulcer are not supported by available data. They found that younger patients had bilateral disease less frequently than older patients (1.5:1) regardless of race and Caucasians were more than twice as likely to have bilateral disease than blacks. Although they found that men were 1.6 times more likely to have Mooren's ulcer than are women, it was pointed out that it could be due to factors such as increased incidence of ocular trauma in men (an association with Mooren's ulcer is reported by some) or cultural patterns that discourage female clinic attendance in certain countries.
Lewallen and Courtright assert that the available data are flawed by a collection period of more than 85 years, differences in the basic criteria for definition of the disease, poor documentation and follow-up, and problems inherent in non-population-based data collection done in 20 series from more than 14 different countries. It is concluded that an accurate epidemiologic understanding of Mooren's ulcer must await a standardized case definition, uniform documentation and follow-up of afflicted patients, and population-based data.
Different entities have been associated with Mooren's ulcer, often leading to conjecture that there may be a causal relationship. An association with helminthiasis has been suggested in Nigeria. Schanzlin speculated that the antigen-antibody reaction to helminth toxins deposited in the peripheral cornea provoked the inflammation and ulceration. However, the association of Mooren's ulcer is not proved even in endemic areas of ascariasis. Recently in 2 patients with bilateral Mooren's ulcers, chronic hepatitis C infection was documented., and they improved after treatment of the hepatitis with interferon α2b. The authors proposed that molecular mimicry may be involved, with the hepatitis C virus stimulating an autoimmune response to corneal antigens through cross-reacting epitopes. Alternatively, they also proposed that deposition of immune complexes in limbal or peripheral corneal tissues may lead to an immune response and release of proteolytic enzymes. Again, chronic hepatitis C infection is not a rare disorder and if a causal relationship is present, Mooren's ulceration would be expected to be seen more frequently. Other infections that have been associated with Mooren's ulcer include herpes simplex and zoster, syphilis and tuberculosis. Mooren's ulcer has also been reported following local corneal diseases. Specific associations have included physical trauma, foreign bodies, chemical burns and surgical procedures such as cataract extraction, penetrating keratoplasty, and lamellar keratoplasty. Some of these may not represent true cases of strictly defined Mooren's ulcer and even for those that do, definitive associations and causal relationships have not been demonstrated.
The precise pathophysiological mechanism of Mooren's ulceration remains unknown, but there is much evidence to suggest that it is an autoimmune process, with both cell-mediated and humoral components. On pathological examination plasma cells, neutrophils, mast cells and eosinophils have been found in the involved areas. Brown has demonstrated high levels of proteolytic enzymes in the affected conjunctiva. Foster and colleagues found numerous activated neutrophils in the involved areas and proposed that these neutrophils are the source of the proteases and collagenases that degrade the corneal stroma. They were able to stimulate the lymphocytes of a Mooren's patient to blastogenic transformation in response to normal corneal stroma. Additional evidence for cell-mediated autoimmune phenomena include demonstration of a positive macrophage migration inhibition response to corneal antigens presented to lymphocytes from Mooren's ulcer patients. Furthermore, Murray and Rahi noted that, systemically, there is a decrease in the number of suppressor T cells relative to the number of helper T cells in Mooren's ulcer patients. From this it was proposed that unregulated helper T cells could induce production of autoantibodies, resulting in the deposition of immune complexes, complement activation, inflammatory cell infiltration, and proteolytic enzyme release. Schaap and associates used indirect immunofluorescent techniques and demonstrated circulating IgG antibodies to human corneal and conjunctival epithelium in patients with Mooren's ulcer. In addition, antibodies and complement have been demonstrated bound to the conjunctival epithelium in the affected areas., Elevated serum IgA levels and circulating immune complexes in patients with Mooren's ulcer have also been reported. Martin and colleagues have proposed a mechanism for the perpetuation of the ulcerative process, suggesting that a systemic disease, infection, or trauma may alter corneal antigens, stimulating both humoral and cellular responses. In the process, complement activation leads to neutrophil chemotaxis and degranulation with release of collagenases, causing corneal melting and further alteration and exposure of altered corneal antigens, thus perpetuating the process. This cycle continues until the entire cornea is consumed. Gottsch and associates in immunologic studies of a patient with Mooren's ulcer demonstrated cellular and humoral immune responses to bovine corneal antigens. Serum from this patient was used to purify a cornea-associated antigen (Co-Ag) from bovine corneal stromal extracts. The amino acid sequence of Co-Ag has been studied. The protein contains 70 amino acids in a single chain and lacks cysteine, tryptophan, and methionine residues. The results of this study suggest that Co-Ag is a new member of the Ca2+-binding protein of the S-100 family of proteins and could provide an important framework to search for sequence similarity with microbial proteins as possible substrate for molecular mimicry and for identification of possible pathogenic epitopes in Co-Ag. Despite the accumulating evidence that cell-mediated and humoral immune mechanisms are present in Mooren's ulcer, it is not known with certainty that they are involved directly in the pathogenesis of the disease. It remains possible that they simply accompany the corneal destruction that is caused by another mechanism.
The histopathology of Mooren's ulcer suggests an immune process. Young and Watson studied the corneas of three patients who underwent grafting. They observed that the involved limbal cornea consisted of three zones. The superficial stroma was vascularized and infiltrated with plasma cells and lymphocytes. In this region, there was destruction of the collagen matrix. Epithelium and Bowman's layer were absent. The midstroma showed hyperactivity of fibroblasts with disorganization of the collagen lamellae. The deep stroma was essentially intact but contained a heavy macrophage infiltrate. Descemet's membrane and the endothelium were spared. Heavy neutrophil infiltration, as well as dissolution of the superficial stroma, were present at the leading edge of the ulcer., These neutrophils showed evidence of degranulation. The adjacent conjunctiva shows epithelial hyperplasia and a subconjunctival lymphocytic and plasma cell infiltration. Frank vasculitis is not present, and numerous eosinophils may present in the nearby involved conjunctiva during the course of healing.
Patients with Mooren's ulcer usually complain of redness, tearing, and photophobia, but pain is typically the outstanding feature. The pain often is incapacitating and may well be out of proportion to the inflammation. There may also be a complaint of decreased visual acuity, which may be secondary to associated iritis, central corneal involvement, or irregular astigmatism due to peripheral corneal thinning. On examination, the disease may be noted to begin with several patchy, peripheral stromal infiltrates that then coalesce, more often in the medial and lateral quadrants than in the superior and inferior ones. An epithelial defect and a shallow furrow then develop in this area [Figure:1].
Generally, there is involvement of the limbus, in contrast to some other forms of PUK, such as that seen with rheumatoid arthritis or staphylococcal marginal disease., The ulcerative process first spreads circumferentially and then centrally to involve the entire cornea eventually. The anterior one-third to one-half of the stroma is involved, characteristically with a steep, overhanging edge [Figure:2]. Healing and vascularization then follow, with the disease slowly running its course over 4 to 18 months.
Portions of the ulcer may be quiescent while others are active. The end- stage result is typically a scarred, vascularized cornea that may be thinned to less than half of its original thickness. As the end stage of the process approaches, the patient may experience sudden relief from the excruciating pain that has been present throughout the course of the disease.
Iritis sometimes is associated with Mooren's ulcer. Hypopyon is rare unless secondary infection is present. Glaucoma and cataract may complicate the process. Perforation has been noted in up to 36% cases, often associated with minor trauma to the weakened cornea.
As we have stated, Mooren's ulcer is idiopathic, and it must be reemphasized that the characteristic features reviewed must occur in absence of any systemic process that may cause PUK. Thus, it is a diagnosis of exclusion. The differential diagnosis is that of peripheral ulcerative keratitis and is extensive (Table).
Infectious aetiologies should be excluded by appropriate cultures, because microbial keratitis can rapidly progress and are usually amenable to antibiotic therapy. Mooren's ulcer is easily distinguished from the noninflammatory corneal degenerations, such as Terrien's or Pellucid marginal degeneration, in which the epithelium remains intact and pain is absent. The presence of Mooren's-like ulcer requires an extensive search for occult and potentially lethal systemic diseases. A thorough medical history and examination is mandatory, as is comprehensive laboratory investigation. This investigation may include a complete blood count with evaluation of the differential count, platelet count, erythrocyte sedimentation rate, rheumatoid factor, complement fixation, antinuclear antibodies (ANA), antineutrophil cytoplasmic antibody (ANCA), circulating immune complexes, liver function tests, VDRL and fluorescent treponemal antibody absorption (FTA-ABS) tests, blood urea nitrogen and creatinine, serum protein electrophoresis, urinalysis, and a chest roentgenogram. Additional testing is done as indicated by the review of systems and physical examination.
Rheumatoid arthritis is a frequent cause of PUK. The clinical appearance of the peripheral ulceration is not unique in rheumatoid arthritis. Frequently, there may be an associated scleritis, a feature not characteristic of typical Mooren's ulcer. Other associated ophthalmic findings include keratoconjuctivitis sicca (the most common ophthalmic finding), episcleritis, and sclerosing keratitis. Advanced systemic involvement is usually apparent at time of ocular involvement., The patient's clinical profile and positive serologic studies, in particular rheumatoid factor, will help establish the appropriate diagnosis. Low titers, however, may be found in 1 to 5% of normal subjects, usually elderly, in a variety of other rheumatic conditions and chronic inflammatory diseases.
Wegener's granulomatosis is a rare multisystem granulomatous necrotizing vasculitis with upper and lower respiratory tract and renal involvement. Ocular involvement may be seen in up to 58% of patients, including proptosis due to orbital involvement, scleritis with or without PUK, PUK alone, uveitis, and vasculitis., Orbital involvement and scleritis are the most common ophthalmic manifestations. However, PUK can be an initial clinical manifestation and the presenting or only sign of the disease., Prompt diagnosis is imperative because the initiation of immunosuppressive therapy, such as cyclophasphamide, can be both sight and life saving., A careful review of systems may disclose a history of upper or lower respiratory signs or symptoms (epistaxis, sinusitis, rhinorrhea, hoarseness, dysphagia, cough, or pleurisy), a history of microscopic hematuria, arthralagias, or skin lesions as the result of the underlying vasculitis process. The work-up should include a haematologic and serologic survey, including serum ANCA analysis. ANCAs are serum antibodies directed against components of primary granules of normal monocytes and neutrophils. ANCA testing has been demonstrated to be an extremely sensitive, specific marker for systemic Wegener's granulomatosis or a closely related group of vasculitides. In general, ANCA titers tend to parallel the extent and severity of Wegener's granulomatosis and fall with the remission of disease. Although ANCA testing has been reported to be less sensitive for limited Wegener's granulomatosis, our experience with patients presenting with scleritis has found it to be exquisitely sensitive and specific.
Classic polyarteritis nodosa (PAN) is a rare multisystem disease characterized by necrotizing vasculitis of small and medium-sized muscular arteries. The systemic manifestations may be protean, with various constitutional symptoms. Multiple organs may be involved, including kidney, skin, bone marrow, central nervous system, lungs, heart, gastrointestinal and genital tract. The aetiology is unknown, and the diagnosis rests on the histopathologic identification of typical vascular changes. Visceral angiography is helpful in establishing the diagnosis of PAN when accessible tissue is not available for biopsy. Microaneurysms at the bifurcation of the medium and small arteries is highly characteristic of the disease, especially in the kidney and mesentery. Choroidal vasculitis is the most common ophthalmic manifestation. Other ophthalmic findings include PUK, conjunctival lesions, scleritis, choroiditis, retinal vasculitis, optic atrophy, papilledema, exudative retinal detachment, central artery occlusion. The clinical characteristics of the PUK associated with PAN are similar to Mooren's ulcer. Serologic tests for hepatitis B surface antigen (HBsAg) should be obtained because approximately 50% of patients with PAN are seropositve. Therapy with local medical and surgical strategies may temporarily retard progression of the ulcer until control with systemic prednisone and cyclophosphamide is achieved.
Other Collagen Vascular Diseases
Peripheral ulcerative keratitis may rarely be seen in other collagen vascular disorders such as systemic lupus erythematosus (SLE), progressive systemic sclerosis, and relapsing polychondritis. Diagnosis is based on a combination of clinical and laboratory criteria. Antibodies to nuclear antigen (ANA) are found in most patients with SLE but are not necessary for diagnosis when other pertinent laboratory tests are positive and classic features of the disease are present. ANA may be found in a wide variety of other conditions, including old age, drug therapy with particular compounds, infections such as subacute bacterial endocarditis, certain liver diseases, rheumatoid arthritis and other autoimmune diseases. However, antibodies to double-stranded DNA (ds DNA) are nearly unique to patients with SLE, although antibodies to single-stranded DNA may be found in other rheumatic conditions.
No laboratory tests are specific for relapsing polychondritis. The diagnosis is based on the clinical feature of the disease. Because the disease is episodic and tends to involve several different organ systems (ear, nose and tracheal cartilage, joints, and the eye), clinical criteria for the diagnosis have been established.,
Systemic sclerosis is a generalized disorder of connective tissue characterized by degenerative and inflammatory changes that subsequently lead to fibrosis. The skin, blood vessels, oesophagus, and synovium along with certain internal organs are affected. The most frequent ocular finding is keratoconjunctivitis sicca, which may be seen in as many as 70% of patients. Peripheral keratitis unrelated to dry eye may be seen. Specific antinuclear antibodies have been identified in scleroderma.
Inflammatory Bowel Disease
The association between ocular inflammation and inflammatory bowel disease is well established. Anterior uveitis, episcleritis, and scleritis are well known anterior segment ocular manifestations. Ocular manifestations may precede or follow the onset of the inflammatory bowel disease. There are case reports describing peripheral corneal infiltrates at times associated with corneal ulceration., We have not encountered cases with corneal ulceration.
Giant Cell Arteritis
Giant cell arteritis is an inflammatory disorder of large and medium-sized arteries occurring mainly in older people and it characteristically involves the temporal arteries. Ocular complications are due to the ischemia caused by the involvement of the ophthalmic artery or its branches. One case report documents peripheral corneal ulceration as the presenting sign of temporal arteritis.
Staphylococcal Marginal Keratitis
Staphylococcal marginal disease can present as a peripheral corneal infiltrate with overlying epithelial breakdown. There is a clear intervening zone between the infiltrate and limbus, and the keratitis is frequently accompanied by blepharitis. Patients complain of photophobia and irritation, but the severe and debilitating pain noted with Mooren's ulcer is not described. Rapid clinical improvement can usually be seen with mild topical steroids. The ulcers are believed to represent immune complex-mediated reactions to microbial antigens.
Local infectious Causes
Although microbial keratitis most commonly occurs centrally or paracentrally, infectious causes should always be excluded in a peripheral ulcer by appropriate clinical history, examination, and corneal cultures.
Herpes simplex may occasionally cause limbal ulceration. A history of previous herpetic disease and, occasionally a dendrite appearance to the edge of the ulcer will suggest the correct diagnosis. The herpetic process usually begins with epithelial ulceration and is followed by stromal infiltration. Corneal sensation may be markedly decreased. Although acanthamoeba keratitis is relatively uncommon, it is a potentially devastating corneal infection. It is frequently reported in young, healthy, immunocompetent patients who wear contact lenses. Contaminated contact lens solutions are frequently found. The patient typically has severe pain and may present with a recurrent erosion, psudodendrite, or a ring, and nummular and/or neural infiltrate. The diagnosis can be made from corneal scrapings but frequently requires a corneal biopsy.
Terrien's degeneration is an important cause of peripheral corneal thinning. It differs from Mooren's ulcer in that it is typically painless, does not ulcerate and is usually noninflammatory. It has been reported more frequently in men and may occur at any age. The disease is usually bilateral but may be asymmetrical. Terrien's degeneration usually begins in the superior cornea, in contrast to Mooren's ulcer, which typically begins in the interpalpebral region as a fine, punctate, stromal opacity. A clear zone exists between the infiltrate and the limbus, which becomes superficially vascularized. Slowly progressive thinning follows. The thin area has a sloping peripheral border and a sharp central edge that is highlighted by a white lipid line. The epithelium remains intact, although bulging of thin stroma causes significant astigmatism. The thinning slowly progresses circumferentially but rarely centrally. Perforation may be seen, usually with minor trauma. Visual symptoms are due to the astigmatism created by the ectatic cornea. An oblique pseudopterygium may be seen in about 20% of patients. Rarely, a patient may have recurrent episodes of inflammation and coexistent episcleritis or superficial scleritis.
Pellucid degeneration causes bilateral, inferior corneal thinning that leads to marked, irregular, against-the-rule astigmatism. Pain and inflammation are lacking and the epithelium is intact, thus differentiating it from Mooren's ulcer.
Senile Furrow Degeneration
Thinning in the lucid interval between an arcus and limbus may occur in the elderly. However, the epithelium is intact and there is no infiltrate or inflammation. The furrow is shallow and not vascularized, with sloping central and peripheral edges. Progression is extremely slow, and has no risk of perforation.
Acne rosacea is a common disease characterized by persistent erythema, telangiectasias, sebaceous gland hyperplasia, and acneform pustules in the flush areas of the face and neck. The classic rhinophyma is also a typical feature of advanced stage of disease. Ocular involvement, reported in up to 58% of cases, ranges in severity from mild blephroconjunctivitis to corneal neovascularization and thinning. PUK may occasionally be seen, usually in neglected cases of acne rosacea. Inspection of the flush areas of the skin for evidence of acne rosacea in conjunction with blepharoconjunctivitis will guide one to the appropriate diagnosis. Both the cutaneous and ocular manifestations of acne rosacea respond well to treatment with oral tetracycline.
Rare cases of peripheral corneal infiltrates and PUK associated with leukemia have been reported. The clinical pattern is not distinctive, and the diagnosis must be made with peripheral blood count or bone marrow biopsy. The mechanism of injury is unknown but may be on the basis of vascular occlusion or corneal infiltration and release of collagenolytic enzymes by the leukemic cells.
Mooren's ulcer is typically progressive and relentless despite all attempts at management and therapy. Many treatments have been tried through the years. The disease is so uncommon that randomized and masked clinical trials to study different therapeutic regimens are impossible. Even so, because of improvement in our understanding of the natural history and pathophysiology of this disorder, our ability to manage Mooren's ulcer has improved over the past two decades.
Historically, the therapeutic agents tried for Mooren's ulcer include subconjunctival dichloride of mercury, carbonic and nitric acid, formalin and tincture of iodine, thricloroacetic acid, subconjunctival heparin, and cyanide of mercury. In addition, a number of procedures, such as irradiation, galvanocautery, paracentesis, vitamin B1 injections, tuberculin injections, and delimiting keratotomy, have been attempted with little success. More recently, Mooren's ulcer has been treated with plasma exchange, periosteal grafting, and Gore-Tex patch grafting. Clearly, more study and experience are needed for this and other potential therapies.
(For topical Cyclosporin, see below).
Today, most experts agree on a step-wise approach to the management of Mooren's ulcer, which is outlined as follows:
1. Topical steroids
2. Conjunctival resection
3. Systemic immunosuppressives
4. Additional surgical procedure
The overall goals of therapy are to arrest the destructive process and to promote healing and reepithelialization of the corneal surface.[72-75]
Initial therapy should include intensive topical steroids, consisting of prednisolone acetate or prednisolone phosphate 1%, hourly in association with topical cycloplegics and prophylactic antibiotics. If epithelial healing does not occur within 2 to 3 days, the frequency of topical steroid application can be increased to every half hour. Once healing occurs, the frequency can be reduced, and tapered slowly over a period of several months. Such management, especially in unilateral, benign form has met with good results. Some authors have advocated oral pulse therapy (60 to 100 mg daily of oral prednisone) when topical therapy is ineffective after 7 to 10 days or in cases where topical steroids may be dangerous because of precariously deep ulcer or infiltrate., Topical tetracycline or medroxyprogesterone may be used for anticollagenolytic properties of each. A therapeutic soft contact lens or patching of the eye may be beneficial at this stage. Also, any concomitant eye disease, such as acne rosacea, meibomeitis, blepharitis, dry eye, or eyelid abnormalities should be addressed.
If the ulcer progresses despite the steroid regimen, conjunctival resection should be performed.[ Under topical and subconjunctival anaesthesia, this consists of conjunctival excision to bare sclera extending at least 2 clock hours to either side of the peripheral ulcer, and approximately 4 mm posterior to the corneoscleral limbus and parallel to the ulcer. The overhanging lip of ulcerating cornea may also be removed. Postoperatively, a firm pressure dressing should be used., In Mondino's series, conjunctival resection healed 3 of 4 unilateral ulcers and 3 of 3 bilateral nonsimultaneous ulcers, but only 2 of 15 bilateral simultaneous ulcers. Tissue adhesive and a therapeutic soft contact lens may be beneficial. Multiple resections may be necessary. The rationale of this procedure is that the conjunctiva adjacent to the ulcer contains inflammatory cells that may be producing antibodies against the cornea and cytokines which amplify the inflammation and recruit additional inflammatory cell. Cryotherapy of limbal conjunctiva has been advocated by some authors and may have a similar effect., Brown reported that excision of the limbal conjunctiva adjacent to the progressing ulcer, resulted in healing of the ulcers in 8 of 10 eyes treated; however, it may be necessary to repeat this procedure three times before a beneficial effect is seen. On the other hand Stilma studied 38 Mooren's corneal ulcers and found that conjunctival excision with thermocoagulation gave some relief at the site of the ulcers, but recurrences at other places occurred in at least 52% of cases.
Kinoshita and colleagues reported success in their series of 20 Mooren's patients treated with keratoepithelioplasty. In this procedure, donor corneal lenticles are sutured onto the scleral bed after conjunctival excision. These authors postulate that the lenticles form a biological barrier between host cornea and the reepithelializing conjunctiva and the immune components it may carry. It should be emphasized, however, that whether or not the presence of this donor material added a therapeutic effect above and beyond the resection of tissue in preparation for the graft is unclear. Application of isobutyl cyanoacrylate, a tissue adhesive, may work in the same way but perhaps more simply and without the risk of epithelial rejection, glaucoma secondary to the chronic steroid use necessitated by keratoepithelioplasty and development of neurotrophic keratitis.
Systemic immunosuppressive chemotherapy
Those cases of bilateral or progressive Mooren's ulcer that fail the preceding therapeutic attempts will require systemic cytotoxic chemotherapy to bring a halt to the progressive corneal destruction. The most commonly used agents are cyclophosphamide (2 mg/kg/day), methotrexate (7.5 to 15 mg once weekly) and azathioprine (2 mg/kg body weight/day). The degree of fall in white blood cell count is considered as the most reliable indicator of immunosuppression produced by cyclophosphamide. Foster reported arrest of the inflammatory process and preservation of ocular anatomy and function in 8 of 9 patients with bilateral involvement treated with immunosuppressives for 6 to 24 months. The ninth patient, who developed perforation, did not seem to receive an adequate level of immunosuppression as measured by blood parameters., Mondino has reported that immunosuppressive drugs halted progression in 4 of 13 patients with Mooren's ulcer who did not respond to topical corticosteroids or conjunctival resection. In this series immunosuppressive drugs were reserved for only the most severe, resistant cases. We disagree with the statement by Schanzlin that "since the value of immunosuppressive therapy is less clear than other treatments, it is recommended only in the severest and most resistant cases". On the contrary, we believe that the evidence for the efficacy of systemic immunosuppressive chemotherapy for progressive bilateral Mooren's ulcer is quite strong, and further believe that such treatment should be employed sooner rather than later in the care of such patients, before the corneal destruction has become too extensive to need for surgery.
Agents such as cyclophosphamide may be effective by suppressing B lymphocytes, which produce autoantibodies and promote immune complex disease. More recently, oral cyclosporin A (10 mg/kg/day) has been successfully used to treat a case of bilateral Mooren's ulcer unresponsive to local therapy with topical corticosteroids, silver nitrate, and conjunctival resection, as well as systemic immunosuppression with corticosteroids, cyclophosphamide, and azathioprine. This agent may work by suppression of the helper T cell population and stimulation of the depressed population of suppressor and cytotoxic T cells present in patients with Mooren's ulcer., Adverse effects of these cytotoxic and immunosuppressive medications, such as anaemia, alopecia, nausea, nephrotoxicity and hepatotoxicity, are likely and the administering physician must be vigilant about their onset. In most instances, systemic immunosuppressive therapy is best handled by close collaboration between an ophthalmologist and an oncologis.The potentially serious side effects of systemic immunosuppressive agents have led several groups to investigate the efficacy of topical applied cyclosporin A in the treatment Mooren's ulcer., In Holland's series of a variety of anterior segment inflammatory diseases; two patients had Mooren's ulcer. The first, with bilateral disease, showed reduced inflammation with minimal progression over 3 years, whereas the second, with unilateral disease, showed resolution of the ulcer on this medication. In Zhao and Jin's series,15 of 18 eyes with Mooren's ulcer improved, and 11 of these were cured with topical cyclosporin A therapy (0.5% solution). In both studies, local or systemic side effects attributable to topical cyclosporin A were not observed.
Additional Surgical Procedures
When these management steps fail, additional surgical procedures may be considered. Superficial lamellar keratectomy, has been shown to arrest the inflammatory process and allow healing. After refining the technique in previous series, Nian and colleagues found 34 of 40 eyes to be successfully healed after lamellar keratectomy. Four of 6 eyes with recurrent ulcer healed with retransplantation while the other patients refused further intervention
Some cases may progress to perforation despite management as just detailed. Small perforations may be treated with application of tissue adhesive and placement of a soft contact lens to provide comfort and to prevent dislodging of the glue., When a perforation is too large for tissue adhesive to seal the leak, some type of patch graft will be necessary. This may range from a small tapered plug of corneal tissue to a penetrating keratoplasty. In case of larger peripheral perforations, a partial penetrating keratoplasty may be performed. Rarely conjunctival flaps or even penetrating keratoplasty may be necessary. It should be emphasized that the prognosis of corneal graft in the setting of acute inflammation in patients with Mooren's ulcer is very poor.,
Once the active ulceration has ceased and the remaining cornea has been completely opacified, it is possible to perform penetrating keratoplasty on these patients, even in the face of a thinned and vascularized cornea., In these instances, a 13 mm tectonic corneal graft is first sutured in place with interrupted 10-0 nylon or prolene sutures with the recipient bite extending into the sclera so that the suture will not pull through the thin host cornea and then a 7.5 or 8.0 mm therapeutic graft is placed., Glaucoma and cystoid macular oedema have been a problem in these cases, and although the graft remains clear, the visual result may only be 6/60. Because of the immune system's remarkable memory, surgical attempts at rehabilitation in Mooren's ulceration should be done only with concurrent immunosuppression, even when the active disease has been arrested, or is 'burned out,' because attempts at penetrating keratoplasty often are associated with recurrence and graft failure.,, Some authors believe that the risk of recurrence is so great that patients are best served not by any intervention but by maintaining the current status - i.e., the vision provided by their own thinned, scarred cornea. It is also believed that patients with treated Mooren's ulcer should be immunosuppressed prior to cataract surgery or corneal grafting procedure. In absence of donor corneas Stilma has suggested the usage of a free lamellar scleral autograft to restore the corneal defect, followed by penetrating keratoplasty later. In his series of 38 eyes with corneal ulcer six eyes with a progressive iris prolapse and a flat anterior chamber were reconstructed with the above technique.
Mooren's ulcer although a distinct clinical entity, remains a diagnosis of exclusion. One should always look for associated scleritis, limbal involvement, corneal sensation, associated blepharitis and keratitis, lipid deposition, ulcerated corneal epithelium and stroma, and so on, to rule out other causes of peripheral ulcerative keratitis, including infections, collagen vascular diseases and degenerative processes. The precise pathophysiology of Mooren's ulcer remains uncertain. Advances have been made in its management, but significant percentage of cases still remain refractory to available therapies and result in severe visual morbidity.
The authors gratefully acknowledge the help of Dr. Benalexander Pedro, MD, for his editorial assistance.
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