AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

This type of corneal ulcer is usually associated with a connective tissue disease, such as rheumatoid arthritis (RA), Sjögren syndrome, Mooren ulcer, or a systemic vasculitic disorder (eg, systemic lupus erythematosus [SLE], Wegener granulomatosis, polyarteritis nodosa).

RA is the most common systemic vasculitic disorder to involve the ocular surface. Patients with severe RA often present with indolent progressive ulceration of the peripheral or pericentral cornea with minimal inflammation that eventually may result in corneal perforation.

Sjögren syndrome is a particular multisystem disease that commonly occurs in middle-aged women, but it can be seen in both sexes and all ages in association with other autoimmune disorders.

Mooren ulcer is an idiopathic noninfectious ulceration of the peripheral cornea that has been classified into 2 clinical types. One is a milder, unilateral, less progressive form of the disease generally seen in elderly patients that responds well to therapy. The second type is a much more aggressive, frequently bilateral, relentless disease usually seen in younger patients that is poorly responsive to any therapy and often leads to corneal destruction.

SLE is a multisystem autoimmune disorder with ocular complications in the anterior and posterior segments, including keratitis sicca, episcleritis, corneal ulceration, uveitis, and retinal vasculitis.

Polyarteritis nodosa, Wegener granulomatosis, and scleroderma are other vasculitides that also may result in a corneal ulcer.

Polyarteritis nodosa is a vasculitis of small- and medium-sized arteries, which leads to multiple organ disease.

Wegener granulomatosis is a necrotizing, granulomatous vasculitis involving the upper respiratory tract, lungs, and kidneys. A limited form of Wegener granulomatosis exists in which renal lesions are not present.

Scleroderma is a connective tissue disorder characterized by extreme skin tautness, resulting in vascular insufficiency, vasospasm, and Raynaud phenomenon.

Paracentral corneal melting has been reported in a patient with Vogt-Koyanagi-Harada syndrome, psoriasis, and Hashimoto thyroiditis.

Recently, several cases of corneal melts associated with topically applied nonsteroidal anti-inflammatory drugs have been reported in the literature. Furthermore, corneoscleral melting has been reported following amniotic membrane in a patient who had undergone multiple previous ophthalmologic surgical procedures.

Pathophysiology

The pathogenesis for these corneal ulcers is not clear. Possibilities include immunologic responses to unknown antigens and genetic susceptibility, such as genetic predisposition to the development of defective suppressor T-lymphocyte function, production of autoantibodies (eg, antinuclear antibodies), and activation of the complement pathway.

Genetic and environmental factors are associated with SLE. In a genetically susceptible individual, certain environmental stimuli, such as a viral infection or contact with certain drugs, induce alterations in DNA, immunoregulatory networks, or both, with resultant formation of autoantibodies, including antinuclear antibody (ANA).

The pathogenesis of polyarteritis nodosa is not clear, but, in some patients, it may be related to hepatitis B antigen-associated immune complex disease or other immune complexes.

Recently, an association has been reported between Mooren ulcer and hepatitis C infection.

Frequency

United States

The incidence of corneal ulcers is uncommon.

Mortality/Morbidity

• Development of a corneal ulcer associated with a connective tissue disease or a vasculitis carries a poor prognosis.
• Patients who have RA with scleritis and a corneal melt die within 5 years without aggressive treatment. This type of corneal ulcer may lead to corneal thinning and perforation in the perilimbal region or paracentrally.

Race

No racial predilection exists with Wegener granulomatosis.

Sex

RA primarily affects middle-aged females.

• Scleroderma is 3-4 times more common in women than in men.
• Polyarteritis nodosa is 2.5 times more likely to affect males than females.
• No sexual predilection exists with Wegener granulomatosis.

Age

This type of corneal ulcer does not affect children. Except for the malignant form of Mooren ulcer, patients with this pathology are usually older than 30 years.

• Wegener granulomatosis can affect all age groups.
• Scleroderma usually starts in individuals aged 30-50 years.
• Polyarteritis nodosa is more frequent in middle-aged males.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

A complete systemic medical history and a review of systems are imperative in these patients, including questions regarding the presence of weight loss, malaise, muscle pain, or weakness, and symptoms involving the neurologic, respiratory, and renal systems.

Physical

• Keratitis sicca is quite common with these patients. Superficial punctate keratitis, chemosis, recurrent episcleritis, and scleritis also are common findings.
• In the case of SLE, retinal vasculitis is evident on fluorescein angiography, with intraretinal hemorrhages and cotton-wool spots. Of patients, 95% develop arthralgia and articular findings, and 70-80% of patients develop skin lesions at some point. The butterfly rash across the nose and cheek occurs in about 30% of patients with SLE.
• Mooren ulcer begins as a gray-white infiltrate in the peripheral cornea followed by epithelial breakdown and stromal melting. Eventually, it develops into a chronic, painful peripheral corneal ulcer that progresses circumferentially and centrally, creating an overhanging edge at its central border. The adjacent conjunctiva and sclera usually are inflamed and hyperemic.
• Wegener granulomatosis is characterized by nasal or oral inflammation, necrotizing and granulomatous inflammation of the vessels of the upper and lower respiratory tract, glomerulonephritis, and other organ involvement with small vessel inflammation.

Causes

All the underlying systemic conditions leading to these types of corneal ulcers are likely to have an autoimmune etiology that is linked to genetic susceptibility.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Topical anesthetic abuse
Corneal neovascularization (pathologic, posttraumatic, postinfectious)

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Polymyositis and dermatomyositis - Elevated serum muscle enzyme levels, especially creatine phosphokinase (CK), serum glutamic-oxaloacetic transaminase (SGOT), serum glutamic-pyruvic transaminase (SGPT), and lactate dehydrogenase (LDH), as well as elevated ANA levels
• Wegener granulomatosis - Abnormal chest x-ray; urinary sediment-microhematuria or red blood cell casts; positive antineutrophil cytoplasmic antibody (C-ANCA) appears to be the most sensitive and specific test outside of biopsy for the diagnosis this condition.
• Polyarteritis nodosa - Elevated blood urea nitrogen or creatinine level; presence of hepatitis B surface antigen or antibody in serum; arteriographic evidence of aneurysms or occlusions (nonarteriosclerotic); presence of polymorphonuclear cells in artery walls on biopsy of small- or medium-sized arteries
• Mooren ulcer - A deficiency of suppressor T cells has been found in the serum of a patient with Mooren ulcer, while another study showed a helper T cell/suppressor cell ratio of greater than 1:1 in 6 of 9 patients with Mooren ulcer. Recent studies have shown that most of the resident cells from specimens with Mooren ulcers express the class 2 antigens, human leukocyte antigen DR (HLA-DR) or human leukocyte antigen DQ (HLA-DQ). Another study demonstrated that the sera from patients with Mooren ulcer had high antibody titers to a cornea-specific stromal protein antigen.
• Systemic lupus erythematosus - Of patients with SLE, 50-60% have antibodies to cardiolipin. The American College of Rheumatology has suggested 11 classification criteria for SLE. Patients are considered to have SLE if they meet 4 of the following criteria:
• • Malar rash
  • Discoid rash
  • Photosensitive rash
  • Oral ulcers
  • Nonerosive arthritis in 2 or more joints
  • Pleuritis or pericarditis
  • Glomerulonephritis or proteinuria
  • Seizures or psychosis
  • Hemolytic anemia, leukopenia, lymphopenia, or thrombocytopenia
  • Immunologic laboratory abnormality, such as antibodies to double-stranded DNA or the SM antigen or a false-positive serologic test for syphilis
  • Positive ANA test that is not caused by a medication
• Wegener granulomatosis - C-ANCA
• Scleroderma - Anti-Sci-70 antibody tests and anticentromere antibodies (CREST variant)
• Rheumatoid arthritis - Approximately 80% of patients with RA have a positive test for rheumatoid factor.

Histologic Findings

In Wegener granulomatosis, histologic findings include necrotizing, granulomatous vasculitis with infiltrative neutrophils, lymphocytes, plasma cells, histiocytes, and giant cells.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

Medical care is frequently ineffective.

• Systemic immunosuppressive agents (eg, azathioprine, cyclophosphamide, methotrexate, cyclosporine) are occasionally helpful. Start with 1 g/d of intravenous methylprednisolone in 4 divided doses; then, switch to 1 mg/d of oral prednisone, plus 1 of the chemotherapeutic agents outlined below. These medications must be prescribed by a rheumatologist or internist who is familiar with their dosages and adverse effects.
• • Methotrexate 7.5-10 mg PO once a week administered with 1 mg/d folic acid
  • Azathioprine 2 mg/kg/d
  • Cyclophosphamide 2 mg/kg/d
  • Cyclosporine A 3-5 mg/kg/d
• Topical agents
• • Cycloplegic agents (eg, 0.5% scopolamine tid)
  • Immunosuppressive agents (eg, topical cyclosporine 0.5% in alpha-cyclodextrin qid)
  • Prophylactic broad-spectrum topical antibiotics (eg, 0.3% ciprofloxacin qid)

Surgical Care

Surgical care includes resection of adjacent conjunctival tissue. If there is perforation, lamellar or penetrating keratoplasties may be necessary.

Tectonic graft is a useful therapeutic option in selected cases of corneal thinning and perforations because it effectively restores the integrity of the eye and allows acceptable visual rehabilitation.

• Cyanoacrylate glue application is frequently inadequate.
• A vascularized, thinned, and scarred cornea is left after the inflammation, often with diminished visual acuity.

Consultations

These patients must be treated and monitored closely with a rheumatologist because the treatment is systemic and can have serious adverse effects and the systemic implications of these disorders often can be life threatening.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Immune corneal ulcers are rare ocular surface diseases with multiple etiologies. Immunosuppressive drugs and systemic or topical steroids occasionally may control the inflammatory process, but, in more severe cases, the ulcer may progress to melting or perforations.

No suitable treatment is currently available for these patients. The medical treatment of this ulcer is primarily systemic and needs to be coordinated with a rheumatologist. The ophthalmologic treatment is mainly supportive with broad-spectrum antibiotics to prevent superinfections and lubricating agents. Topically applied nerve growth factor (NGF) has been used in some patients with corneal neurotrophic ulcers and corneal melting with success.

Drug Category: Immunosuppressant agents

Inhibit key factors in the immune system responsible for inflammatory responses.

Drug Name	Azathioprine (Imuran)
Description	Antagonizes purine metabolism and inhibits synthesis of DNA, RNA, and proteins. May decrease proliferation of immune cells, which results in lower autoimmune activity.
Adult Dose	1 mg/kg/d PO for 6-8 wk; increase by 0.5 mg/kg q4wk until response or dose reaches 2.5 mg/kg/d
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; low levels of serum TPMT
Interactions	Toxicity increases with allopurinol; concurrent use with ACE inhibitors may induce severe leukopenia; may increase levels of MTX metabolites and decrease effects of anticoagulants, neuromuscular blockers, and cyclosporine
Pregnancy	D - Unsafe in pregnancy
Precautions	Increases risk of neoplasia; caution with liver disease and renal impairment; hematologic toxicities may occur; check TPMT level prior to therapy and follow liver, renal, and hematologic function; pancreatitis rarely associated

Drug Name	Cyclosporine A (Sandimmune, Neoral)
Description	Cyclic polypeptide that suppresses some humoral immunity and, to a greater extent, cell-mediated immune reactions, such as delayed hypersensitivity, allograft rejection, experimental allergic encephalomyelitis, and graft vs host disease for a variety of organs. For children and adults, base dosing on ideal body weight. A compounded ophthalmic solution of this medication has been used experimentally (1 gtt qid) but has not demonstrated efficacy in patients with corneal ulcers.
Adult Dose	2.5-5 mg/kg/d PO in divided doses
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity; uncontrolled hypertension or malignancies; do not administer concomitantly with PUVA or UVB radiation in psoriasis since it may increase risk of cancer
Interactions	Carbamazepine, phenytoin, isoniazid, rifampin, and phenobarbital may decrease cyclosporine concentrations; azithromycin, itraconazole, nicardipine, ketoconazole, fluconazole, erythromycin, verapamil, grapefruit juice, diltiazem, aminoglycosides, acyclovir, amphotericin B, and clarithromycin may increase cyclosporine toxicity; acute renal failure, rhabdomyolysis, myositis, and myalgias increase when taken concurrently with lovastatin
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Evaluate renal and liver functions often by measuring BUN, serum creatinine, serum bilirubin, and liver enzymes; may increase risk of infection and lymphoma; reserve IV use only for those who cannot take PO

Drug Name	Cyclophosphamide (Cytoxan, Neosar)
Description	Used to control severe collagen vascular diseases. Chemically related to nitrogen mustards. As an alkylating agent, the mechanism of action of the active metabolites may involve cross-linking of DNA, which may interfere with growth of normal and neoplastic cells.
Adult Dose	500-750 mg/m2 IV qmo
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity; severely depressed bone marrow function
Interactions	Allopurinol may increase risk of bleeding or infection and enhance myelosuppressive effects; may potentiate doxorubicin-induced cardiotoxicity; may reduce digoxin serum levels and antimicrobial effects of quinolones; chloramphenicol may increase half-life while decreasing metabolite concentrations; may increase effect of anticoagulants; coadministration with high doses of phenobarbital may increase rate of metabolism and leukopenic activity; thiazide diuretics may prolong cyclophosphamide-induced leukopenia and neuromuscular blockade by inhibiting cholinesterase activity
Pregnancy	D - Unsafe in pregnancy
Precautions	Regularly examine hematologic profile (particularly neutrophils and platelets) to monitor for hematopoietic suppression; regularly examine urine for RBCs, which may precede hemorrhagic cystitis

Drug Category: Antibiotics

Prevent superinfection in corneal ulcers with inadequate protection against bacterial keratitis.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• Inpatient care for patients with corneal ulcers is not required.

Further Outpatient Care

• Outpatient care for patients with corneal ulcers is necessary only if systemic manifestations are present.

Complications

• The most serious complications for these patients are systemic because, in many cases, their underlying conditions are associated with a high mortality rate.
• The most serious ocular complication includes corneal perforation with secondary infections, corneal scarring, and secondary cataracts and glaucoma.

Patient Education

• For excellent patient education resources, visit eMedicine's Eye and Vision Center. Also, see eMedicine's patient education article Corneal Ulcer.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Patients with an undiagnosed corneal ulcer must be referred to a rheumatologist because the underlying diagnosis could have significant implications for their general health and life, and the ophthalmologist should be careful not to overlook such an underlying diagnosis.

Special Concerns

• Because of the possibility of recurrence, any later surgical interventions should be performed with concurrent immunosuppression, even in apparently quiet eyes.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• Asai T, Nakagami T, Mochizuki M. Three cases of corneal melting after instillation of a new nonsteroidal anti-inflammatory drug. Cornea. Feb 2006;25 (2):224-7. [Medline].
• Bullen CL, Liesegang TJ, McDonald TJ, DeRemee RA. Ocular complications of Wegener''s granulomatosis. Ophthalmology. Mar 1983;90(3):279-90. [Medline].
• Flach AJ. Corneal melts associated with topically applied nonsteroidal anti-inflammatory drugs. Trans Am Ophthalmol Soc. 2001;99:205-10; discussion 210-2. [Medline].
• Foster CS, Forstot SL, Wilson LA. Mortality rate in rheumatoid arthritis patients developing necrotizing scleritis or peripheral ulcerative keratitis. Effects of systemic immunosuppression. Ophthalmology. Oct 1984;91(10):1253-63. [Medline].
• Guidera AC, Luchs JI, Udell IJ. Keratitis, ulceration, and perforation associated with topical nonsteroidal anti-inflammatory drugs. Ophthalmology. May 2001;108(5):936-44. [Medline].
• Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. Sep 1997;40(9):1725. [Medline].
• Jayson MI, Jones DE. Scleritis and rheumatoid arthritis. Ann Rheum Dis. Jul 1971;30(4):343-7. [Medline].
• Lambiase A, Rama P, Bonini S, et al. Topical treatment with nerve growth factor for corneal neurotrophic ulcers. N Engl J Med. Apr 23 1998;338(17):1174-80. [Medline].
• Lambiase A, Bonini S, Aloe L, et al. Anti-inflammatory and healing properties of nerve growth factor in immune corneal ulcers with stromal melting. Arch Ophthalmol. Oct 2000;118(10):1446-9. [Medline].
• Paroli MP, Pinca M, Speranza S. Paracentral corneal melting in a patient with Vogt-Koyanagi-Harada's syndrome, psoriasis, and Hashimoto's thyroiditis. Ocul Immunol Inflamm. Dec 2003;11(4):309-13. [Medline].
• Robin JB, Schanzlin DJ, Meisler DM, et al. Ocular involvement in the respiratory vasculitides. Surv Ophthalmol. Sep-Oct 1985;30(2):127-40. [Medline].
• Schechter BA, Rand WJ, Nagler RS. Corneal melt after amniotic membrane transplant. Cornea. Jan 2005;24(1):106-7. [Medline].
• Vanathi M, Sharma N, Titiyal JS. Tectonic grafts for corneal thinning and perforations. Cornea. Nov 2002;21(8):792-7. [Medline].
• West RH, Barnett AJ. Ocular involvement in scleroderma. Br J Ophthalmol. Dec 1979;63(12):845-7. [Medline].

Article Last Updated: Apr 21, 2006