1. Signs and Symptoms

2. Causes

3. Pathophysiology

4. Diagnosis

5. Treatment
     Topical Treatment    Systemic Treatment    Surgical Treatment  

6. Prognosis

7. References

Peripheral ulcerative keratitis (PUK) describes a group of destructive inflammatory diseases which involve the peripheral cornea, which all eventually result in sloughing of corneal epithelium and keratolysis.^[1]

A patient will present with ocular irritation, pain, redness, photophobia and reduced visual acuity.^[2][3][4] It is associated with both infectious and non-infectious causes.^[2]

The exact pathophysiological mechanism is uncertain.^[1][2]

It has been proposed that autoimmune reactions to corneal antigens, hypersensitivity reactions to exogenous antigens and deposition of circulating immune complexes may be involved in the pathogenesis, with both humoral and cell-mediated immune mechanisms involved.^[1]

Diagnosis is confirmed by slit-lamp examination of the eye.^[3]

Treatment options include medical (topical or systemic) therapy and surgery. Medical therapeutic options available include topical corticosteroids, systemic corticosteroids and systemic immunosuppressive agents. Surgical options include conjunctival resection, cyanoacrylate adhesive, conjunctival flaps, amniotic membrane grafts, and tectonic lamellar and penetrating corneal grafts.

Prognosis depends on the underlying cause along with prompt and appropriate management.^[1]

Signs and Symptoms

A patient with PUK will present with ocular irritation, pain and redness. They will also present with photophobia and reduced visual acuity.^[2][3][4] As PUK progresses, these patients can go on to develop loss of vision.^[4]

Causes

Peripheral ulcerative keratitis is associated with both infectious and non-infectious causes.

In terms of infectious causes, a number of bacteria, viruses and fungi can play a role in the aetiology. These organisms can lead to either ocular or systemic infection, which in turn lead to PUK.^[2]

There are a number of non-infectious causes. The most common are systemic conditions including collagen vascular diseases such as rheumatoid arthritis, ANCA-associated vasculitides, granulomatosis with polyangiitis, polyarteritis nodosa, microscopic polyangiitis, Churg-Strauss syndrome, relapsing polychondritis, systemic lupus erythematous, systemic sclerosis and giant cell arteritis. Other non-infectious systemic autoimmune conditions which may be implicated include cicatricial pemphigoid, inflammatory bowel disease and Sjögren syndrome. Other non-infectious causes include acne rosacea and Mooren’s ulcer.^[2][1]

Pathophysiology

The precise pathophysiological mechanism of PUK remains unclear.^[2][1]

It has been proposed that autoimmune reactions to corneal antigens, hypersensitivity reactions to exogenous antigens and deposition of circulating immune complexes may be involved in the pathogenesis, with both humoral and cell-mediated immune mechanisms involved.^[1]

It has been suggested that immune complexes, either locally produced or circulating, are deposited in either the limbal or peripheral corneal blood vessels.^[1][5] This leads to activation of the classical pathway of the complement system in the presence of C1.^[1][2] This in turn results in chemotaxis of inflammatory cells, in particular, neutrophils and macrophages in the peripheral cornea.^[1][2][5] These neutrophils and macrophages can release collagenases and other proteases which destroy the corneal stroma.^[2][5] These inflammatory cells also release pro-inflammatory cytokines such as interleukin-1, which allows stromal keratocytes to produce matrix metalloproteinase-1 and matrix metalloproteinase-2, which can accelerate the destruction of the matrix.^[2]

Serum antibodies to corneal epithelial antigens have been found in patients with immune-mediated PUK, however the significance of their presence has yet to be determined.^[5]

The peripheral cornea has distinct characteristics in terms of morphology and immunology which predispose it to inflammation.^[2] Unlike the avascular central cornea, the peripheral cornea receives part of its oxygen and nutrient supply from the perilimbal capillary arcades.The proximity of the peripheral cornea to this vascular and lymphatic arcade means that it is readily exposed to inflammatory cells and mediators involved in the pathogenic process described previously.^[6]

Diagnosis

Diagnosis is confirmed by slit lamp examination of the eye.^[3]

Slit lamp examination shows –

• Opacity due to yellow-white infiltrates (composed of inflammatory cells) within the stroma adjacent to the limbus^[2][7]
• Crescent-shaped corneal ulcers, with breakdown of overlying epithelium
• Varying degrees of vascularisation and corneal thinning due to tissue loss in the underlying stroma. The degree of corneal thinning varies. In severe cases, tissue loss may progress to perforation with or without trauma.
• Inflammation of the adjacent conjunctiva, episclera and sclera may also be observed.^[2]

In order to determine the cause, a full ocular history should be taken, along with a comprehensive review of the systems. If a systemic cause of PUK is suspected upon review of the systems, a full physical examination should be performed. Laboratory testing can also assist one is determining the cause, for example testing for rheumatoid factor (RF) if rheumatoid arthritis is suspected.^[1]

Treatment

When treating PUK alone, the goal is to reduce inflammation, promote epithelial healing and minimise stromal loss. As discussed previously, the condition is frequently associated with a number of infectious and non-infectious aetiologies.^[2]

In particular the condition is frequently associated with systemic collagen vascular diseases, and may be a presenting feature of one of these diseases.^[1][2] Hence, another goal when treating PUK would be to control the associated disease if present.

The treatment modality selected will depend on a number of factors including the severity of disease on slit-lamp examination and the extent of associated disease if present.

The outcome of treatment depends on the timely diagnosis and treatment of PUK, along with the accompanying disease.^[2]

Prior to any other treatment, anti-microbial therapy should be administered if an infectious cause is suspected.^[1]

Topical Treatment

Topical corticosteroids may be used as an initial therapy in mild, unilateral cases of PUK which are typically not associated with a systemic collagen vascular disease.  

They may be a useful adjunct in milder cases of PUK associated with rheumatoid arthritis. However, in cases of PUK associated with granulomatosis with polyangiitis, microscopic polyangiitis, Churg-Strauss syndrome, and polyarteritis nodosa, the use of topical corticosteroids may promote progression and enhance perforation.

Topical cyclosporine A may be used as an adjunct when combined with the appropriate systemic agent.^[1]

Systemic Treatment

Systemic corticosteroids can be used for the acute management of more severe cases of PUK.^[1] Alone, they are not sufficient to inhibit disease progression or control the autoimmune disease if present. Immunosuppressive drugs may be used alongside corticosteroids in the case of severe PUK, where there is progression and potential for perforation. They may also be used as a replacement for corticosteroids when the systemic side effects of corticosteroids have become an issue for the patient.^[2][1] They may also be used in the cases of PUK associated with potentially lethal systemic disease or scleritis, bilateral Mooren’s ulcer and disease progression despite local conjunctival resection and tectonic procedures (e.g. tissue adhesive).^[1] There are a number of immunosuppressive drugs that can be used such as methotrexate, azathioprine, mycophenolate mofetil, cyclophasophamide, and cyclosporin A. Biological agents may also be used. The main agents suggested for used are infliximab, etanercept and rituximab.^[1][2]

There is no universal agreement on which immunosuppressive drug should be used in each case of PUK.^[2] The decision on which to administer comes down to the evidence for that drug in that particular clinical scenario.  

Surgical Treatment

There are a number of surgical treatment options in the management of PUK. Conjunctival resection may temporarily remove local cellular mediators and collagenases which are important in disease progression. However, this technique is limited to localised unilateral disease without any associated systemic inflammatory disorder.

Cyanoacrylate adhesive may be used alongside systemic immunosuppressive therapy in patients with impending perforation. It may delay the need for tectonic corneal surgery in the patients.

Conjunctival flaps, amniotic membranes grafts, and tectonic lamellar and penetrating corneal grafts may be required to maintain the integrity of the globe. These techniques should be used as an adjunct to systemic immunosuppressive therapy.^[1]

Prognosis

Prognosis greatly depends on the underlying cause of the patient’s PUK along with prompt and appropriate management.^[1]

References

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