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Disease Entity

Corneal Ulcer, Unspecified (ICD9 370.00)

Disease

Peripheral ulcerative keratitis (PUK) is a group of inflammatory diseases whose final common pathway is peripheral corneal thinning.

Etiology

Peripheral ulcerative keratitis has an incidence of 3 cases per million per year, equally affecting both males and females. It has been associated with many autoimmune disorders, including:

Rheumatoid arthritis, present in 34%–42% of patients with PUK
Polyarteritis nodosa
Inflammatory bowel disease
Collagen vascular diseases
- Systemic Lupus erythematosus (SLE)
- Relapsing polychondritis
- Progressive systemic fibrosis
ANCA (anti-neutrophil cytoplasm antibodies)-associated vasculitides
- Granulomatosis with polyangiitis (GPA; formerly Wegener's)
- Churg–Strauss syndrome
- Microscopic polyangiitis

Risk Factors

Autoimmune disorders are the primary risk factors for peripheral ulcerative keratitis, as described above.

General Pathology

Peripheral ulcerative keratitis occurs when immune complexes activate the complement system, resulting in chemotaxis of inflammatory cells (neutrophils and macrophages). These cells release collagenase and protease that destroy corneal stroma. Proinflammatory cytokines induce stromal keratocytes to produce matrix metalloproteases, which contribute to the breakdown of the cornea.

Pathophysiology

There are several theories regarding the etiology of PUK. The disease may be an autoimmune reaction to corneal antigens. In Mooren ulcer—which by definition is of unknown etiology and not associated with systemic autoimmune disease—dysregulated helper Th1 cells have been shown to produce autoreactive antibodies. The disease may also be caused by circulating immune complex deposition. Dysregulated production of autoreactive antibodies in autoimmune diseases promotes the Th2 response. Finally, PUK may be a hypersensitivity reaction to exogenous antigens.

Diagnosis

History

Patients with PUK may present with pain, redness, tearing, photophobia, and decreased vision. They may also have a history of autoimmune disorders.

Physical Examination

Evaluation of patients with suspected PUK includes a complete ophthalmological examination to assess the patient's vision, intraocular pressure, and pupils, and to examine the eyes with a slit lamp. The examination should focus on the peripheral cornea to assess the degree of involvement, depth of corneal thinning, extent of epithelial defect, and degree of inflammation.

Signs

Peripheral ulcerative keratitis presents with a crescent-shaped destructive lesion of the juxtalimbal corneal stroma. The lesion is characterized by stromal degradation and inflammatory cells with an overlying epithelial defect. Thirty-six percent of patients also have scleritis.

The appearance of the peripheral cornea will be dependent upon the severity of corneal thinning. Progressive thinning may lead to descemetocele formation and corneal perforation.

Figure 1 shows a peripheral ulcer that has progressed to perforation. Note the peaked pupil and prolapse of iris tissue at the 4–5 o'clock position and the injection surrounding the crescentic area of thinning.

Figure 1. Peripheral ulcerative keratitis

Symptoms

Patients may present with pain, redness, tearing, photophobia, and decreased vision.

Clinical Diagnosis

Diagnosis is based on history and physical exam. Patients should also be evaluated for underlying systemic autoimmune disease using laboratory testing and/or referral to a rheumatologist.

Diagnostic Procedures

Corneal scrapings for cultures may be done if an infectious etiology is suspected. As 36% of patients with PUK also have scleritis, an ultrasound of the eye (B-scan) may be performed to evaluate for posterior scleritis.

Laboratory Tests

Systemic evaluation for underlying autoimmune diseases may include:

Complete blood count (CBC)
Complete metabolic profile (CMP)
Urinalysis with microscopic analysis (UA & micro)
Antinuclear antibody (ANA)
Anti-neutrophil cytoplasmic antibody (ANCA)
Rheumatoid factor (RF)
Anti-cyclic citrullinated peptide (anti-CCP)
Rapid plasma reagin (RPR)
Fluorescent treponemal antibody (FTA-Abs)
Chest X-ray (CXR)
Purified protein derivative (PPD)
Sacroiliac joint X-ray
CAT scan of sinuses
Hepatitis B virus screen
Hepatitis C virus screen
Corneal culture
Ultrasound of the eye

Differential Diagnosis

The differential diagnosis of PUK is broad and includes other inflammatory conditions (e.g., Mooren ulcer, rheumatoid furrow) as well as degenerative conditions (e.g., Terrien marginal degeneration, senile furrow degeneration, pellucid marginal degeneration). Infectious or neoplastic etiologies (e.g., corneal ulcer, carcinoma in situ) are also in the differential.

Management

The primary goals in the treatment of PUK are to minimize inflammation, prevent superinfection, promote healing of the ulcer, and prevent perforation.

Medical Therapy

Ocular

Preservative-free artificial tears and ointments and closure of puncta with plugs or cautery are used to treat associated dry eye symptoms and promote epithelialization of the ulcer.

Topical cyclosporine may be employed to decrease inflammation. Oral doxycycline may be used due to its anti-collagenase activity, along with Vitamin C to help promote collagen rebuilding. Topical corticosteroids should be used with extreme caution, given the possibility of accelerating keratolysis. The use of topical medroxyprogesterone and topical N-acetylcysteine has also been described.

Cyanoacrylate adhesive may be applied to the ulcer bed to limit ulceration in cases of impending perforation. This may also prevent influx of white blood cells from the tear film.

Topical antibiotics are used to prevent or treat bacterial superinfection.

Systemic

Systemic immunosuppression is often required to control ocular inflammation. Initial treatment is typically with steroids in the form of prednisone (1 mg/kg/day) or methylprednisolone (1 g/day x 3 days). Steroid-sparing agents are indicated in cases of impending perforation, disease uncontrolled with steroids, or in patients with associated rheumatoid arthritis, as these patients are at increased risk for vascular events. These steroid-sparing agents include antimetabolites (e.g., methotrexate, azathioprine, mycophenolate mofetil), T cell inhibitors (e.g., cyclosporine, tacrolimus), alkylating agents (e.g., cyclospophosphamide, chlorambucil), and biologic agents (e.g., infliximab, rituximab).

Medical Follow-Up

Medications and dosages are adjusted based on the level of clinical response. Systemic medications may be managed in collaboration with a rheumatologist or other medical specialist.

Surgery

Corneal perforation or excessive corneal thinning with impending perforation are indications for surgical intervention. Surgical options include lamellar, penetrating, or crescentric keratoplasty (Figure 2), as well as possible corneoscleral keratoplasty with a partial-thickness scleral resection in cases of scleral melting.

Figure 2. Post-operative appearance of a PUK melt surgically managed with crescentric keratoplasty, conjunctival resection, and amniotic membrane placement. Image by Adam Gerstenblith, edited by Brad Feldman Surgery by A. Gerstenblith and B Feldman

Resection or recession of the conjunctiva adjacent to the area of peripheral ulcerative keratitis may also be performed to limit inflammation originating from the conjunctiva.

Surgical Follow-Up

Patients should be monitored closely after surgery for recurrence of disease as well as infection or rejection of the graft.

Complications

Complications include infection and perforation of the ulcer.

Prognosis

Visual prognosis is related to the severity of disease. Patients with associated systemic disease have an increased mortality rate from vascular events.

Additional Resources

Turbert D, Jimenez EM. Corneal Ulcer. American Academy of Ophthalmology. EyeSmart/Eye health. https://www.aao.org/eye-health/diseases/corneal-ulcer-list. Accessed March 07, 2019.

References

Mortality rate in rheumatoid arthritis patients developing necrotizing scleritis or peripheral ulcerative keratitis. Effects of systemic immunosuppression. Foster CS, Forstot SL, Wilson LA. Ophthalmology. 1984 Oct;91(10):1253-63.
Twenty-five-year panorama of corneal immunology: emerging concepts in the immunopathogenesis of microbial keratitis, peripheral ulcerative keratitis, and corneal transplant rejection. Dana MR, Qian Y, Hamrah P. Cornea. 2000 Sep;19(5):625-43
The taming of the shrew? The immunology of corneal transplantation. Plever U, Schlickeiser S. Acta Ophthalmol. 2009 Aug;87(5):488-97.
A rare case of peripheral ulcerative keratitis in temporal arteritis. Papathanassiou M, Elezoglu A, Nikita E, Theodossiadis PG, Vergados I. Eur J Ophthalmol. 2009 Sep – Oct;19(5):866-9.
Visual outcome and corneal topography after eccentric "shaped" corneal grafts. Parmar P, Salman A, Jesudasan CA. Cornea. 2009 May;28(4):379-84.

Peripheral Ulcerative Keratitis

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