Marginal keratitis is an inflammatory disease that causes stromal infiltration in the peripheral cornea. It is also called catarrhal corneal ulcer or staphylococcal peripheral corneal infiltrates.
This disease is not a direct bacterial infection. It is essentially a type III allergic reaction (immune complex hypersensitivity) to exotoxins of staphylococci present on the eyelid margin. Gram staining of scrapings from the lesion shows no bacteria, and bacterial cultures are negative. It is characterized by “sterile” infiltration with only neutrophils.
It is more common in middle-aged and older adults, and most cases are associated with chronic staphylococcal blepharitis. When only infiltration is present in the peripheral cornea, it is called peripheral corneal infiltrate; when accompanied by epithelial defects, it is called catarrhal corneal ulcer.
Main complaints include redness, pain, foreign body sensation, photophobia, and tearing. Symptoms are mild to moderate and nonspecific, generally milder than infectious keratitis.
Characteristics of Infiltrates
One or more round to oval gray infiltrates appear in the peripheral cornea.
The infiltrates are located 1–2 mm away from the limbus.
It is diagnostically important to observe a clear zone between the limbus and the infiltrative lesion without infiltration.
The infiltrates spread concentrically parallel to the limbus.
Predilection sites and associated findings
They commonly occur at the 2, 4, 8, and 10 o’clock positions intersecting the eyelid margin.
Corresponding bulbar conjunctiva shows localized hyperemia.
When infiltration is severe, the epithelium may slough off, forming erosions or ulcers.
In recurrent cases, superficial vascular invasion may be observed.
Most cases are complicated by blepharitis. Eyelid margin erythema and edema with telangiectasia, hard scales at the base of eyelashes, and madarosis are observed.
Marginal keratitis is localized to the peripheral cornea, has a clear zone between the limbus, and the corresponding conjunctival hyperemia is localized. In contrast, infectious keratitis often involves the central cornea, is accompanied by diffuse ciliary injection, and presents with severe ocular pain and purulent discharge. When epithelial defects are present, differentiation from infection is important, and corneal scraping culture is recommended.
The main cause of marginal keratitis is an immune reaction to exotoxins of staphylococci (mainly Staphylococcus aureus) that normally reside on the eyelid margin. Infiltrates form as a result of an antigen-antibody reaction (type III allergic reaction) in the peripheral corneal stroma, involving complement activation and neutrophil infiltration.
Major risk factors include chronic staphylococcal blepharitis, meibomianitis (meibomian gland dysfunction), and rosacea-associated blepharitis.
Contact lens (CL)-related marginal corneal infiltrates are also known. They are caused by adherence of inadequately disinfected soft CLs or exposure of color CL pigments. They are common in wearers who have not replaced their lens case for more than 3 months, and biofilm formation and bacterial toxins in the case are thought to be involved.
In recent years, immune checkpoint inhibitor (ICI)-induced marginal keratitis has been reported. In a case of bilateral ring-shaped marginal infiltration after administration of the PD-L1 inhibitor atezolizumab, there were no findings of blepharitis or meibomian gland dysfunction, and an autoimmune mechanism was suspected1).
Cases after COVID-19 mRNA vaccination have also been reported. Approximately 2.5 weeks after vaccination, peripheral corneal infiltration appeared and improved with steroid and antibiotic eye drops2).
Improper contact lens care can cause marginal corneal infiltrates. The risk is especially high when soft contact lenses are inadequately disinfected or when the lens case is not replaced. Symptoms resolve in about a week after discontinuing lens wear and using antibiotic and low-concentration steroid eye drops, but lens and care habits need to be reviewed.
Diagnosis is based on characteristic slit-lamp microscope findings of the cornea and confirmation of blepharitis. The presence of infiltrates parallel to the limbus in the peripheral cornea and a clear zone are key to diagnosis.
In typical cases, additional tests are unnecessary. However, if epithelial defects are present, differentiation from infectious keratitis is essential, and corneal scraping culture should be performed.
Non-infectious stromal infiltrates can also be caused by CL wear or antigens related to local or systemic bacterial infections. In addition to phlyctenular keratitis and staphylococcal marginal keratitis, peripheral ulcerative keratitis associated with autoimmune diseases should be considered in the differential diagnosis3).
Differentiation from Infectious Keratitis
Infectious keratitis is often central, progressive, and accompanied by purulent discharge.
Marginal keratitis is localized to the periphery, has a clear zone, and is culture-negative.
If epithelial defects are present, corneal scraping culture should be performed to rule out infection.
Differential diagnosis from Mooren's ulcer
Mooren’s ulcer does not show a clear zone between the ulcer and the limbus.
It presents as a deep, excavated ulcer and progresses more aggressively.
It is not associated with systemic autoimmune diseases, but requires immunosuppressive therapy.
Peripheral ulcerative keratitis (PUK) associated with collagen disease develops in the context of systemic diseases such as rheumatoid arthritis and granulomatosis with polyangiitis. It is more severe than marginal keratitis and often accompanied by scleritis. It responds poorly to steroid eye drops and requires systemic immunosuppressive therapy.
Terrien’s marginal degeneration presents with thinning of the peripheral cornea, but inflammatory findings are scarce and progression is slow. It shows a clear zone, no epithelial defect, and is often accompanied by lipid deposition.
Treatment of marginal keratitis aims to suppress local inflammation and remove the causative staphylococcal antigens.
Basic prescription is combined use of antibiotic and low-concentration steroid eye drops.
| Drug | Dosage |
|---|---|
| Antibiotic eye drops | Gatifloxacin etc. 4 times daily |
| Steroid eye drops | Fluorometholone 0.1% 4 times daily |
| Antibiotic eye ointment | Erythromycin eye ointment at bedtime |
When blepharitis is present, cleaning the eyelid margin and applying antibiotic eye ointment are important for long-term management. In cases with recurrent episodes, appropriate antibiotics should be selected based on bacterial culture and drug sensitivity testing of the eyelid margin and conjunctival sac.
In cases complicated by meibomianitis, an effective approach is to initially administer oral cephalosporin antibiotics, then switch to oral macrolide antibiotics to normalize the bacterial flora of the meibomian glands.
For contact lens-related marginal infiltrates, contact lens wear should be discontinued immediately. The epithelium is usually covered within about 3 days with antibiotic and low-concentration steroid eye drops, but infiltration and hyperemia persist for 1–2 weeks.
In immune checkpoint inhibitor-induced cases, a regimen of betamethasone sodium phosphate 0.1% eye drops and moxifloxacin 0.5% eye drops six times daily led to marked improvement of infiltration after 14 days in some cases. Steroid eye drops were maintained during continued chemotherapy, and no recurrence was observed1).
In vaccine-induced cases, combined antibiotic-steroid eye drops were also effective. At the time of the second vaccination, the drops were continued, and healing occurred without recurrence2).
In the treatment of bacterial keratitis, the use of concomitant steroids to suppress scar formation remains controversial. While the anti-inflammatory effect of steroid eye drops may reduce corneal melting and scarring, improving visual outcomes, there is also a risk of worsening infection4). In marginal keratitis with epithelial defects, it is safe to start steroids after confirming that infection has been ruled out.
If blepharitis is untreated, recurrence is common. For prevention, eyelid hygiene (warm compresses and eyelid cleaning) is most important. It is recommended to routinely apply antibiotic eye ointment to the eyelid margin, and if meibomianitis is active, to continue oral macrolide antibiotics as needed. The natural course resolves spontaneously in 2–3 weeks, with almost no long-term sequelae.
The essence of marginal keratitis is a type III allergic reaction (immune complex hypersensitivity) to exotoxins of staphylococci normally present on the eyelid margin.
In patients sensitized to staphylococcal antigens, antigens in the peripheral corneal stroma bind to antibodies diffusing from conjunctival vessels. The formed immune complexes activate the complement system, leading to neutrophil chemotaxis and infiltration, resulting in corneal stromal opacity. This lesion may progress to epithelial damage and form marginal ulcers.
Due to the distance between the central cornea and the limbal vessels, high molecular weight proteins such as IgM and C1 are present at higher concentrations in the corneal periphery. Langerhans cells are also abundant in the corneal periphery. The region 1–2 mm from the limbus has an antigen-antibody ratio that promotes the formation of larger immune complexes, creating an environment prone to inflammatory reactions.
The central cornea is thought to be protected from immune-mediated damage because the greater distance from the limbus reduces contact between antigens and the afferent immune pathway.
Toll-like receptor 2 (TLR2) and myeloid differentiation factor 88 (MyD88) have been shown to play important roles in neutrophil recruitment and inflammatory cytokine production in response to Staphylococcus aureus.
Recent studies are also elucidating the mechanism by which staphylococcal phenol-soluble modulins (PSMs) induce corneal inflammation through alarmin release and activation of the IL-36-dependent pathway.
The corneal epithelium, stroma, and endothelium constitutively express high levels of PD-L1, which contributes to maintaining corneal immune privilege. PD-L1 suppresses antigen-presenting cells in the corneal periphery and limits T cell infiltration. PD-1/PD-L1 inhibitors can cause activation of antigen-presenting cells and recruitment of T cells into the cornea, potentially triggering autoimmune keratitis1).
ACE2 receptors are significantly expressed in the cornea. It is hypothesized that antibodies against the spike protein produced by mRNA vaccines may form immune complexes at ACE2 receptor sites in the cornea, triggering a type III hypersensitivity reaction2).
With the widespread use of cancer immunotherapy, ICI-related ocular adverse events have gained attention. The incidence of ocular adverse events with PD-1/PD-L1 inhibitors is estimated at 3.3–7.4%, higher than previously assumed1). Atezolizumab is considered one of the ICI agents most strongly associated with ocular inflammation1). Marginal keratitis is being recognized as a novel adverse event related to ICIs, and attention to corneal complications during cancer treatment is necessary.
Reports of marginal keratitis after COVID-19 vaccination indicate that the cornea can be a target of systemic immune responses2). Similar cases have been reported after hematopoietic stem cell transplantation and intravitreal injection, suggesting that exposure to novel antigens can trigger marginal keratitis via type III hypersensitivity reactions2).
The roles of staphylococcal superantigens and PSMs in corneal inflammation are being elucidated. While superantigens are unlikely to play a central role in marginal keratitis, PSMs have been experimentally shown to induce significant corneal inflammation via alarmin release and IL-36-dependent pathways. These findings may lead to the development of future molecular-targeted therapies.
