What are the causes of necrotizing granulomatous inflammation in the eye?

Causes of Necrotizing Granulomatous Inflammation in the Eye

Necrotizing granulomatous inflammation in the eye is primarily caused by infectious agents (tuberculosis, syphilis, fungi) and systemic vasculitides (granulomatosis with polyangiitis, sarcoidosis), with tuberculosis being the most critical infectious cause to exclude before initiating immunosuppression.

Infectious Causes

Bacterial Infections

• Tuberculosis (Mycobacterium tuberculosis) is a major cause of necrotizing granulomatous uveitis, particularly in endemic regions, and can present with interstitial keratitis and anterior uveitis 1
• Localized periocular tuberculosis can cause progressive necrotizing ocular surface disease with granulomas showing patchy necrosis, and may require repeated biopsies for culture confirmation 2
• Syphilis (Treponema pallidum) causes infectious retinal vasculitis and granulomatous inflammation, requiring prompt serologic testing 1
• Mycobacterial infections including tuberculosis and leprosy can cause necrotizing granulomatous lesions with ulceration and necrosis 3

Fungal Infections

• Invasive fungal infections (Mucor, Rhizopus, Aspergillus species) can progress from sinuses to cause necrotizing disease in immunocompromised patients with diabetes, hematologic malignancies, or chronic renal failure 3
• Fungal infections can cause granulomatous inflammation requiring special staining and cultures for definitive diagnosis 3

Viral Infections

• Herpes simplex virus (HSV) and varicella-zoster virus (VZV) produce retinal vasculitis with immunologically mediated infiltrates and can cause necrotizing stromal disease 1, 3
• Cytomegalovirus (CMV) causes focal necrotizing retinitis, particularly in immunocompromised patients with CD4+ counts <50 cells/µL, presenting as perivascular fluffy yellow-white retinal infiltrates 3, 1

Parasitic Infections

• Toxoplasmosis is the most common parasitic cause of retinal vasculitis and retinochoroiditis, representing the most frequent infectious cause of retinitis overall 4, 1
• Onchocerca volvulus can involve the uvea and retina, particularly in endemic areas 4, 1

Noninfectious/Autoimmune Causes

Systemic Vasculitides

• Granulomatosis with polyangiitis (GPA) is characterized by necrotizing granulomatous inflammation of small and medium-sized vessels, producing necrotizing scleritis, peripheral ulcerative keratitis, retinal vasculitis, and optic disc swelling 3, 1, 5
• GPA presents with granulomas in 47.7% of cases and is associated with c-ANCA positivity in 59.2% of patients 6
• Necrotizing scleritis in GPA is the most destructive and vision-threatening form, requiring aggressive combination immunosuppressive therapy 5

Granulomatous Inflammatory Diseases

• Sarcoidosis is the most common noninfectious granulomatous disease in the United States, characterized by non-necrotizing granulomas (unlike the necrotizing pattern in tuberculosis) 3, 7
• Sarcoidosis presents with bimodal age distribution (peak 20-39 years), featuring conjunctival nodules, choroidal granulomas, and vitreous opacities 3, 1
• Ocular sarcoidosis occurs in 25-50% of patients and most commonly manifests as anterior uveitis 7

Other Systemic Conditions

• Eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome) is associated with retinal vasculitis and granulomatous inflammation 3, 1
• Systemic lupus erythematosus and rheumatoid arthritis can cause retinal vasculitis with granulomatous features 4, 1
• Kawasaki disease (primarily in children) may involve retinal vessels with granulomatous inflammation 3, 4

Critical Diagnostic Algorithm

Step 1: Exclude Infectious Causes First

• Always screen for tuberculosis and syphilis before initiating immunosuppressive therapy, as these are the most common infectious causes requiring specific antimicrobial treatment 1, 7
• Obtain tissue biopsy with special staining and cultures for mycobacteria and fungi when granulomatous lesions show ulceration or necrosis 3
• Consider repeated biopsies and cultures if initial workup is negative but clinical suspicion remains high for mycobacterial infection 2

Step 2: Differentiate Necrotizing vs. Non-Necrotizing Pattern

• Necrotizing granulomas are prototypical of mycobacterial infections (tuberculosis) and fungal infections 8
• Non-necrotizing granulomas are characteristic of sarcoidosis 7, 8
• This histologic distinction is critical as it fundamentally changes management approach 8

Step 3: Assess Immunocompromised Status

• Patients with AIDS (CD4+ <50 cells/µL), prolonged hospitalization, indwelling catheters, diabetes, hematologic malignancies, or systemic immunosuppression are at higher risk for CMV, Candida, and invasive fungal infections 3, 1

Step 4: Look for Systemic Disease Markers

• Obtain c-ANCA and p-ANCA testing when scleritis, proptosis, or orbital mass is present to evaluate for GPA 6
• Screen for sarcoidosis with chest X-ray, ACE levels, and assessment by internal medicine specialist 7
• Evaluate for rheumatoid arthritis and other connective tissue diseases in patients with necrotizing scleritis 5

Common Pitfalls to Avoid

• Never initiate immunosuppression without excluding tuberculosis and syphilis, as this can lead to fulminant progression of infection 1, 7
• Do not rely on single negative biopsy results for mycobacterial infection; repeated sampling may be necessary for culture confirmation 2
• Recognize that necrotizing scleritis in GPA requires aggressive combination immunosuppressive therapy, not monotherapy 5
• Be aware that CMV retinitis presents with characteristic perivascular fluffy infiltrates with little vitreous inflammation unless immune recovery occurs 3