Differential Diagnosis of Eye Inflammation
Eye inflammation encompasses a broad spectrum of conditions affecting different ocular structures, requiring systematic evaluation to distinguish between infectious, autoimmune, masquerade syndromes, and medication-related etiologies before initiating treatment.
Primary Anatomic Classification of Inflammatory Conditions
Anterior Segment Inflammation
Conjunctivitis - inflammation of the conjunctiva, which can be infectious (bacterial, viral), allergic, or immune-mediated 1. The American Academy of Ophthalmology distinguishes this from deeper inflammatory processes by the absence of vision loss and presence of discharge 1.
Episcleritis - inflammation of the episclera (thin tissue covering the sclera), commonly associated with systemic autoimmune diseases including rheumatoid arthritis 2. This presents with sectoral or diffuse redness without vision threat 2.
Scleritis - deeper inflammation of the sclera that is potentially blinding and frequently associated with systemic inflammatory diseases, particularly ANCA-associated vasculitis and seronegative spondyloarthropathies 2, 3.
Keratitis - corneal inflammation frequently associated with scleritis or occurring independently from infectious or autoimmune causes 2, 4.
Anterior Uveitis - inflammation of the iris and ciliary body, characterized by anterior chamber cells and flare 1. Acute anterior uveitis has diagnostic implications for seronegative spondyloarthritis 2.
Posterior Segment Inflammation
Posterior Uveitis - inflammation affecting the choroid and retina, assessed by vitreous haze, chorioretinal lesions, and retinal vascular lesions 1.
Panuveitis - inflammation involving both anterior and posterior segments 2.
Critical Differential Categories
Infectious vs. Noninfectious Uveitis
Before escalating immunosuppression, infection must be excluded through sampling and culturing of intraocular fluids, particularly in immunosuppressed patients with invasive procedures, indwelling catheters, or systemic sepsis 1, 3. Infection can closely mimic endogenous inflammation 3.
Masquerade Syndromes
Masquerade syndromes occur in up to 2.5% of noninfectious uveitis cases in tertiary centers 1. These include:
- Malignancy (particularly intraocular lymphoma) - requires diagnostic vitrectomy, cerebrospinal fluid cytology, and brain MRI 1
- Retinal degeneration mimicking inflammation 1
Systemic Autoimmune Disease-Associated
Juvenile Idiopathic Arthritis (JIA) - chronic anterior uveitis is a major complication requiring screening every 3 months in high-risk patients 1.
Behçet's Disease - causes severe panuveitis with retinal vascular involvement 1.
Sarcoidosis - granulomatous inflammation affecting multiple ocular structures 3.
ANCA-associated vasculitis - particularly affects the sclera and can cause orbital inflammation 2, 3.
Rheumatoid arthritis and Sjögren syndrome - commonly cause episcleritis and dry eye 2.
Medication-Induced Inflammation
Ocular Mucous Membrane Pemphigoid (OMMP) can be medication-induced, particularly by epinephrine and glaucoma medications (especially miotics) 1. Trial discontinuation should be attempted if suspected 1.
Iatrogenic complications from hydroxychloroquine, chloroquine, corticosteroids, and bisphosphonates must be considered 2.
Nonadherence
Treatment nonadherence must be evaluated before changing therapy in any patient not responding to immunomodulatory treatment 1.
Treatment Framework
Initial Management of Noninfectious Uveitis
Topical corticosteroids (prednisolone acetate 1%) are first-line for anterior uveitis, but should be limited to ≤3 months due to glaucoma and cataract risk 1. For neuropathic corneal pain with inflammation, loteprednol 0.5% suspension or gel is preferred due to lower intraocular pressure elevation and reduced neurotoxic preservative concentration 1.
The 3-month threshold is critical: if topical glucocorticoids are required beyond this period to maintain control, systemic immunomodulatory therapy must be added or changed 1.
Systemic Immunomodulatory Therapy
For JIA-associated uveitis and other chronic noninfectious uveitis, systemic DMARDs are indicated when topical therapy is insufficient 1:
- Methotrexate - first-line systemic agent 1
- Adalimumab - monoclonal TNF inhibitor for refractory cases 1
- Alternative agents: mycophenolate, cyclosporine, leflunomide, infliximab, abatacept, tocilizumab 1
Escalation Strategy for Inadequate Response
When initial therapy fails, follow this algorithm 1:
- First, exclude: nonadherence, infection, and masquerade syndromes 1
- Second, consider: dose escalation to maximum tolerated therapeutic dose 1
- Third, transition: to alternative or additional agent if disease remains uncontrolled 1
Therapy choice must account for: patient history (hepatitis status), underlying uveitis cause, cost, and convenience 1.
Specialized Conditions
Ocular Mucous Membrane Pemphigoid requires systemic immunosuppression to prevent progression 1:
- Mild/slowly progressive: mycophenolate mofetil, dapsone (check G6PD first), azathioprine, or methotrexate 1
- Severe/unresponsive: cyclophosphamide 1
- Refractory: combination intravenous immunoglobulin and rituximab 1
Monitoring Parameters
Visual acuity and ocular inflammation (by Standardization of Uveitis Nomenclature criteria) are the strongest evidence-based parameters for adjusting therapy 1. Additional parameters include anterior chamber cells/flare, vitreous haze, chorioretinal lesions, retinal vascular lesions, and macular/optic nerve involvement 1.
Inactive disease is defined as: grade <1+ anterior chamber cells without new complications from active inflammation 1.
Critical Pitfalls
Never assume inflammation is autoimmune without excluding infection, especially in immunosuppressed patients 1, 3. Always consider masquerade syndromes in treatment-refractory cases 1. Avoid prolonged topical corticosteroid monotherapy beyond 3 months due to glaucoma and cataract complications 1.