Ophthalmology – Peripheral Corneal Ulcers / Peripheral Ulcerative Keratitis

Basics

Description

Peripheral ulcerative keratitis (PUK) is a potentially vision- and globe-threatening inflammatory disorder characterized by:

• Peripheral corneal epithelial defect
• Stromal inflammation
• Progressive stromal thinning or “melting”

It occurs within the peripheral cornea adjacent to the limbus, where the cornea is exposed to:

• Limbal blood vessels
• Immune complexes
• Complement
• Inflammatory cells

PUK may be:

• Immune-mediated
• Infectious
• Postoperative or post-traumatic

The most clinically important form is immune-mediated PUK associated with systemic vasculitis.

Clinical Importance

PUK can progress rapidly to:

• Severe stromal thinning
• Descemetocele
• Corneal perforation
• Permanent visual loss

When associated with systemic vasculitis, it may also signal:

Potentially life-threatening systemic disease

Therefore severe or progressive PUK requires urgent:

• Corneal evaluation
• Infectious exclusion
• Systemic investigation
• Rheumatologic collaboration

Peripheral Cornea and Immunology

The peripheral cornea is particularly susceptible to immune injury because of its proximity to the:

Limbal vascular arcade

Immune complexes and inflammatory mediators can enter the peripheral cornea and activate:

• Complement
• Neutrophils
• Macrophages
• Matrix metalloproteinases

leading to:

Collagen degradation and stromal melt

Etiology

Immune-Mediated

Important causes include:

• Rheumatoid arthritis
• Granulomatosis with polyangiitis (GPA)
• Polyarteritis nodosa
• Systemic lupus erythematosus
• Relapsing polychondritis
• Inflammatory bowel disease
• Other systemic vasculitides

Rheumatoid Arthritis

RA is one of the most common systemic associations.

PUK often occurs in patients with:

• Long-standing
• Seropositive
• Severe systemic disease

However:

Ocular severity does not necessarily parallel joint activity.

A patient with apparently quiet arthritis may still develop severe corneal vasculitis.

Granulomatosis With Polyangiitis

Formerly called:

Wegener granulomatosis

GPA-associated PUK may occur with:

• Necrotizing scleritis
• Orbital inflammation
• Pulmonary disease
• Renal disease

This combination should be treated as a systemic vasculitic emergency.

Infectious Peripheral Ulceration

Infectious keratitis must always be excluded.

Potential organisms include:

Bacterial

• Staphylococcus
• Streptococcus
• Pseudomonas
• Moraxella
• Neisseria gonorrhoeae

Fungal

• Fusarium
• Aspergillus
• Candida
• Other fungi depending on exposure

Viral

• Herpes simplex
• Herpes zoster

Important Principle

Do not assume that a peripheral ulcer in a patient with rheumatoid arthritis is sterile.

Immune-mediated patients may simultaneously develop:

• Bacterial keratitis
• HSV keratitis
• Fungal infection

particularly if they are immunosuppressed.

Risk Factors

Important risk factors include:

• Rheumatoid arthritis
• Systemic vasculitis
• Autoimmune disease
• Previous ocular surgery
• Trauma
• Severe dry eye
• Exposure keratopathy
• Lagophthalmos
• Immunosuppression
• Contact lens use
• Ocular surface disease

Postoperative PUK

PUK may occur after ocular surgery, including:

• Cataract surgery
• Corneal surgery
• Scleral surgery

In predisposed patients, surgery may trigger:

Aberrant immune activation against corneal antigens

Pathophysiology

Immune-mediated disease involves:

1. Immune complex deposition around limbal vessels
2. Complement activation
3. Recruitment of inflammatory cells
4. Release of proteases and collagenases
5. Stromal collagen destruction
6. Progressive corneal thinning

Matrix metalloproteinases contribute substantially to:

Corneal melting

Association With Scleritis

PUK may occur with:

Necrotizing anterior scleritis

This strongly suggests:

• Severe systemic autoimmune disease
• Systemic vasculitis

and generally requires aggressive systemic immunosuppression.

History

Patients commonly present with:

• Red eye
• Severe pain
• Photophobia
• Tearing
• Foreign-body sensation
• Reduced vision

Pain may be particularly severe when:

Scleritis accompanies PUK

Systemic History

Ask about:

• Rheumatoid arthritis
• Sinus disease
• Hemoptysis
• Cough
• Dyspnea
• Hematuria
• Renal disease
• Skin rash
• Joint pain
• Oral ulcers
• Neurologic symptoms

These may indicate systemic vasculitis.

Infectious History

Ask about:

• Trauma
• Vegetable matter injury
• Contact lens use
• Recent ocular surgery
• Lagophthalmos
• Hospitalization
• Immunosuppression
• Previous HSV or HZO

Physical Examination

Typical PUK demonstrates:

• Peripheral epithelial defect
• Adjacent stromal infiltrate
• Stromal thinning
• Limbal inflammation

The lesion may extend:

• Circumferentially
• Centrally

Corneal Melt

Progressive stromal destruction may produce:

• Marked thinning
• Descemetocele
• Microperforation
• Frank perforation

The central edge may appear:

• Undermined
• Steep
• Actively melting

Corneal Epithelial Defect

True PUK generally has an:

Overlying epithelial defect

If the epithelium remains intact, consider alternative diagnoses such as:

• Marginal keratitis
• Peripheral stromal inflammation

rather than classic ulcerative keratitis.

Associated Scleritis

Look carefully for:

• Deep scleral injection
• Violaceous hue
• Severe tenderness
• Areas of scleral necrosis

Necrotizing scleritis with PUK is particularly concerning for systemic vasculitis.

Infectious Keratitis Findings

Features suggesting infection include:

• Dense focal stromal infiltrate
• Purulent discharge
• Significant anterior chamber reaction
• Hypopyon
• Rapid progression
• Satellite lesions in fungal disease
• Contact lens or trauma history

Herpetic Peripheral Keratitis

HSV or HZO may produce:

• Peripheral epithelial disease
• Stromal infiltrates
• Corneal thinning
• Reduced corneal sensation

However, corneal hypoesthesia may not always be obvious.

Herpetic disease must be excluded before escalating immunosuppression.

Gonococcal Keratitis

Neisseria gonorrhoeae can penetrate intact corneal epithelium and cause:

• Rapid stromal destruction
• Hyperpurulent discharge
• Perforation

This is an ophthalmic emergency requiring:

Immediate systemic and topical antimicrobial treatment

Diagnostic Approach

The main diagnostic questions are:

1. Is this infectious or sterile?
2. Is there associated scleritis?
3. Is there underlying systemic vasculitis?
4. Is the cornea at risk of perforation?

Corneal Scraping

Perform corneal scraping when there is:

• Epithelial defect with infiltrate
• Significant suppuration
• Rapid progression
• Atypical appearance
• Immunosuppression
• Concern for bacterial or fungal infection

Tests may include:

• Gram stain
• Culture
• Fungal stain/culture

HSV Testing

HSV PCR may be useful when:

• Clinical suspicion is high
• Presentation is atypical
• Diagnosis remains uncertain

It is not routinely required for classic cases.

Systemic Laboratory Evaluation

In unexplained or suspected immune-mediated PUK, consider:

• CBC
• ESR
• CRP
• Renal function
• Urinalysis

Autoimmune testing may include:

• Rheumatoid factor
• Anti-CCP antibodies
• ANCA
• PR3-ANCA
• MPO-ANCA
• ANA
• Complement levels when indicated

Infectious Screening Before Immunosuppression

Depending on context and planned therapy, consider:

• Syphilis serology
• Tuberculosis screening
• Hepatitis B
• Hepatitis C
• HIV

especially before major systemic immunosuppression or biologic therapy.

Urinalysis

Urinalysis is particularly important when GPA is suspected.

Look for:

• Hematuria
• Proteinuria
• Cellular casts

which may indicate:

Glomerulonephritis

Chest Imaging

Chest radiography or CT may be appropriate when there is concern for:

• GPA
• Sarcoidosis
• Tuberculosis
• Systemic vasculitis

Biopsy

Systemic tissue biopsy may occasionally be required to establish:

• GPA
• Other vasculitic disease

Potential sites include:

• Kidney
• Lung
• Upper respiratory tract

depending on clinical disease.

Anterior Segment OCT

AS-OCT is useful for documenting:

• Location of thinning
• Residual stromal thickness
• Progression
• Response to treatment

It is particularly helpful in severe or impending perforation.

Differential Diagnosis

Important differentials include:

• Infectious keratitis
• Marginal keratitis
• Mooren ulcer
• Terrien marginal degeneration
• Pellucid marginal degeneration
• Dellen
• Neurotrophic keratopathy
• Exposure keratopathy
• HSV/HZO keratitis

Mooren Ulcer

Mooren ulcer is a painful progressive peripheral ulcerative keratitis occurring:

• Without associated scleritis
• Without identifiable systemic vasculitic disease
• After infectious and systemic causes have been excluded

It is therefore largely a:

Diagnosis of exclusion

Mooren Ulcer Features

Typical findings include:

• Severe pain
• Peripheral crescentic ulcer
• Undermined central edge
• Circumferential progression
• Later central progression

Scleral involvement argues against classic Mooren ulcer.

Marginal Keratitis

Staphylococcal marginal keratitis usually shows:

• Peripheral infiltrates
• Clear interval between infiltrate and limbus
• Associated blepharitis

It is generally less destructive than PUK.

Terrien Marginal Degeneration

Terrien degeneration is usually:

• Painless
• Noninflammatory
• Slowly progressive

with:

• Peripheral thinning
• Lipid deposition
• Intact epithelium

This contrasts with painful inflammatory PUK.

Treatment Principles

Management has three simultaneous goals:

1. Exclude and treat infection
2. Suppress destructive inflammation
3. Preserve globe integrity

Immune-Mediated PUK

Severe immune-mediated PUK generally requires:

Systemic immunosuppression

Topical treatment alone is insufficient.

Systemic Corticosteroids

High-dose systemic corticosteroids may be used for rapid control of severe inflammation.

However:

Steroids are usually a bridge rather than definitive long-term therapy

because steroid-sparing immunosuppression is often required.

Immunosuppressive Therapy

Treatment depends on the underlying systemic disorder.

Agents may include:

• Methotrexate
• Mycophenolate mofetil
• Azathioprine
• Cyclophosphamide
• Rituximab

GPA-Associated PUK

Severe GPA-related ocular disease may require induction therapy with:

• Rituximab
• Cyclophosphamide

usually combined initially with systemic corticosteroids.

Management should be coordinated urgently with:

Rheumatology

Rheumatoid Arthritis-Associated PUK

Systemic treatment may involve:

• Methotrexate
• Mycophenolate
• Biologic therapy
• Rituximab
• Other disease-modifying agents

depending on systemic disease and severity.

Biologic Therapy

Refractory disease may respond to biologic agents such as:

• Rituximab
• Anti-TNF therapy in selected conditions

Choice depends on:

• Underlying systemic disease
• Previous treatment
• Infectious risk

Topical Corticosteroids

Topical corticosteroids require caution.

They may reduce inflammation but can also:

• Delay epithelial healing
• Promote collagenolysis
• Worsen undiagnosed infection

Therefore:

Do not use topical steroids indiscriminately in an actively melting peripheral ulcer.

They may be considered after infection is excluded and systemic inflammation is being appropriately treated.

Topical Lubrication

Use aggressive ocular-surface support with:

• Preservative-free artificial tears
• Lubricating ointment

Treat associated:

• Dry eye
• Exposure
• Blepharitis

Oral Doxycycline

Doxycycline may be used as an adjunct because it inhibits:

Matrix metalloproteinases

and may reduce corneal collagenolysis.

It is not being used primarily for its antimicrobial effect in sterile PUK.

Vitamin C

Oral vitamin C may be used as an adjunct because it supports:

• Collagen synthesis
• Stromal healing

It is supportive rather than definitive therapy.

Infectious Bacterial Ulcer

Treatment may include:

• Intensive topical fluoroquinolone
• Fortified antibiotics for severe disease

Choice depends on:

• Size
• Depth
• Location
• Gram stain
• Culture

Fungal Keratitis

Treatment depends on organism.

Common options include:

• Natamycin for filamentous fungi
• Amphotericin B for selected yeasts
• Voriconazole in selected cases

Treatment should be culture-guided when possible.

Herpetic Disease

HSV or HZO may require:

• Systemic antiviral therapy
• Topical antiviral therapy in appropriate epithelial HSV disease

Topical steroids should only be used in selected stromal disease under:

Antiviral cover

Corneal Perforation

Impending or actual perforation is an emergency.

Treatment depends on:

• Size
• Location
• Activity of inflammation
• Presence of infection

Cyanoacrylate Tissue Adhesive

For small focal perforations, cyanoacrylate glue may provide:

Temporary tectonic support

often with a bandage contact lens placed over the glue.

Bandage Contact Lens

A bandage lens may help protect:

• Tissue adhesive
• Small epithelial defects

However, caution is required in active infection because contact lenses may increase microbial risk.

Lamellar Keratoplasty

Peripheral lamellar or patch grafting may be required for:

• Severe thinning
• Larger peripheral perforation
• Failure of tissue adhesive

Penetrating Keratoplasty

Full-thickness grafting may be required for:

• Large perforation
• Central involvement
• Extensive structural failure

Outcomes are poorer when surgery is performed during:

Active uncontrolled inflammation

so systemic disease control remains critical.

Conjunctival Resection

Adjacent conjunctival resection was historically used to reduce delivery of:

• Inflammatory cells
• Immune complexes

to the peripheral cornea.

It now has a much more limited role because modern systemic immunosuppression and other therapies are generally preferred.

Tarsorrhaphy

Partial tarsorrhaphy may be useful when significant:

• Lagophthalmos
• Exposure keratopathy

contributes to peripheral thinning.

Dry Eye Management

Treat aggressively with:

• Preservative-free lubrication
• Ointment
• Punctal occlusion in selected patients
• Moisture protection
• Eyelid closure procedures when needed

Follow-Up

Active PUK may require examination:

Daily or every few days

depending on severity.

Monitor:

• Epithelial defect size
• Stromal thinning
• Infiltrate
• Anterior chamber inflammation
• Scleritis
• Signs of impending perforation

Rheumatologic Follow-Up

Immune-mediated disease requires close co-management with:

• Rheumatology
• Internal medicine

because controlling systemic vasculitis may:

• Preserve the eye
• Reduce systemic morbidity
• Improve survival

Prognosis

Prognosis depends on:

• Cause
• Speed of diagnosis
• Degree of stromal thinning
• Scleral involvement
• Infection
• Systemic disease control

Early aggressive therapy can preserve:

• Globe integrity
• Useful vision

Visual Loss

Vision may be reduced by:

• Corneal scarring
• Irregular astigmatism
• Central extension
• Perforation
• Surgical graft complications

Complications

Major complications include:

• Corneal melt
• Descemetocele
• Corneal perforation
• Severe scarring
• Irregular astigmatism
• Secondary infection
• Recurrent ulceration
• Necrotizing scleritis
• Permanent visual loss

Ophthalmology Pearls

• PUK is a peripheral corneal epithelial defect with stromal inflammation and progressive thinning.
• Always distinguish infectious keratitis from immune-mediated PUK before escalating corticosteroids or systemic immunosuppression.
• The strongest systemic associations include rheumatoid arthritis and granulomatosis with polyangiitis.
• PUK plus necrotizing scleritis should raise major concern for severe systemic vasculitis.
• Ocular PUK may be severe even when the patient’s systemic autoimmune disease appears clinically quiet.
• Urinalysis, renal function, ANCA, RF/anti-CCP, and inflammatory markers are important when systemic vasculitis is suspected.
• True PUK usually has an epithelial defect; peripheral stromal inflammation with intact epithelium should broaden the differential.
• Mooren ulcer is a diagnosis of exclusion and classically lacks associated scleritis or systemic vasculitis.
• Systemic immunosuppression is the cornerstone of treatment for severe autoimmune PUK; topical therapy alone is inadequate.
• Rituximab or cyclophosphamide may be required for severe GPA-associated disease.
• Oral doxycycline can be useful as an adjunct because of its anti-collagenase/MMP-inhibiting effect.
• Small perforations may be managed temporarily with cyanoacrylate glue, while larger defects may require tectonic keratoplasty.
• Peripheral ulcerative keratitis can be a marker of life-threatening systemic vasculitis, so treatment may improve not only vision but overall survival.