Uveitis — Anterior and Posterior

• Immune Dysregulation and Breakdown of Ocular Immune Privilege: The eye maintains immune privilege through multiple mechanisms including the expression of FasL and TGF-β that induce regulatory T cell (Treg) differentiation, physical barriers via tight junctions in the blood-retinal barrier (claudins, occludin, ZO-1), and production of immunosuppressive cytokines (IL-10, TGF-β). In uveitis, autoreactive T cells (particularly CD4+ Th1 and Th17 cells) circumvent these mechanisms through molecular mimicry (pathogen antigens cross-react with uveal antigens), bystander activation (local tissue damage recruits non-specific immune cells), or epitope spreading. The key role of Th17 cells—which produce IL-17, IL-6, and TNF-α—drives neutrophil recruitment and amplifies the inflammatory cascade. Loss of Treg function or failure of ACAID initiation permits sustained antigen-presenting cell activity in the eye, perpetuating inflammation.

• Blood-Retinal Barrier Disruption and Inflammatory Cell Infiltration: In anterior uveitis, breakdown of the blood-aqueous barrier occurs through upregulation of adhesion molecules (ICAM-1, VCAM-1) on vascular endothelium and leukocytes, mediated by TNF-α and IL-1β. This permits trans-endothelial migration of CD4+ T cells, CD8+ T cells, and macrophages into the aqueous humor. In posterior uveitis, the blood-retinal barrier (outer retinal pigment epithelium and inner retinal endothelial layers) similarly breaks down, allowing inflammatory cell accumulation in the subretinal space, retina, and vitreous. The resulting infiltration increases aqueous humor protein concentration (exudate formation), elevates intraocular pressure (IOP) through trabecular obstruction by inflammatory cells and debris), and causes photoreceptor dysfunction and death via direct cytotoxicity and bystander effects from inflammatory mediators.

• Pathogen-Specific Mechanisms in Infectious Uveitis: Infectious agents trigger uveitis through direct invasion and local inflammation or through immune-mediated mechanisms. Toxoplasma gondii causes focal necrotizing retinitis with adjacent vitritis through direct parasitization of retinal cells and Th1-mediated immune response; organisms are typically visible in the retinal lesion itself. Tuberculosis (TB) triggers granulomatous inflammation through Th1 response to mycobacterial antigens (PPD-reactive CD4+ T cells) and formation of epithelioid granulomas in the choroid. Cytomegalovirus (CMV) in immunocompromised hosts causes hemorrhagic retinal necrosis with minimal vitritis ("granary pattern"), progressing centripetally due to direct viral cytotoxicity. Herpes simplex virus and varicella-zoster virus cause acute retinal necrosis (ARN) with fulminant vitritis and vasculitis. Syphilis causes vascular inflammation (vasculitis), potentially affecting both anterior and posterior segments. Understanding these mechanisms guides both diagnostic workup and treatment intensity.

• Molecular Patterns and Innate Immunity: Pathogen-associated molecular patterns (PAMPs) from infectious agents activate pattern recognition receptors (TLRs, NOD-like receptors) on resident ocular immune cells (microglia, dendritic cells) and epithelial cells, triggering rapid IL-6, TNF-α, and chemokine (CCL2, CXCL8) production. This initiates the inflammasome cascade, activating caspase-1 and amplifying IL-1β and IL-18 production. Danger-associated molecular patterns (DAMPs) from tissue damage similarly activate innate immunity. In autoimmune uveitis (e.g., HLA-B27 associated), adaptive immunity predominates; however, innate immunity amplifies the response.

• Role of HLA-B27 and Genetic Susceptibility: HLA-B27 is present in 50–90% of patients with anterior uveitis in Western populations and carries a 6–15-fold increased risk. The mechanisms include: (1) presentation of arthritogenic bacterial peptides (molecular mimicry with Klebsiella, Yersinia), (2) unusual HLA-B27 homodimer formation that may serve as a ligand for KIR3DL2 on natural killer cells, and (3) misfolding of HLA-B27 triggering endoplasmic reticulum stress and the unfolded protein response, which recruits IL-23-producing dendritic cells that enhance Th17 differentiation. This explains the strong association of HLA-B27 with seronegative spondyloarthropathies (ankylosing spondylitis, reactive arthritis, inflammatory bowel disease-associated arthritis, psoriatic arthritis) and their frequent co-occurrence with acute anterior uveitis.

• Chronic versus Acute Inflammatory States: Acute uveitis (onset <6 weeks) typically features Th1-predominant responses with neutrophil infiltration (acute inflammatory cells in aqueous humor). Chronic uveitis (>6 weeks) involves Th2 and regulatory responses with lymphocyte and plasma cell predominance, granuloma formation (if granulomatous), and fibrosis. Intermediate uveitis, even when idiopathic, often becomes chronic, suggesting a persistent antigen or immune dysregulation. The shift from acute to chronic inflammation influences disease course, treatment response, and risk of complications.

• HLA-B27-Associated Anterior Uveitis and Seronegative Spondyloarthropathies: HLA-B27 is the single strongest risk factor for acute anterior uveitis in North America and Europe, present in 50–90% of non-infectious anterior uveitis cases. Associations include ankylosing spondylitis (prevalence of uveitis ~25%), reactive arthritis (formerly Reiter's syndrome; uveitis in ~10%), inflammatory bowel disease (Crohn's disease and ulcerative colitis; uveitis in ~1–3%), and psoriatic arthritis. Patients often present with acute, unilateral, non-granulomatous anterior uveitis with rapid symptom onset and resolution within weeks if treated; recurrences are common. The uveitis may precede systemic manifestations, requiring HLA-B27 testing and rheumatologic/gastroenterologic evaluation even in isolated ocular disease.

• Sarcoidosis: The most common granulomatous anterior uveitis in immunocompetent populations, sarcoidosis causes uveitis in 25–80% of patients with systemic disease (higher when multisystem involvement). Sarcoid uveitis characteristically presents as chronic, bilateral, granulomatous anterior uveitis with "mutton-fat" granulomas on the inferior limbus and anterior synechiae formation. It may also cause posterior segment disease (choroidal granulomas, retinal periphlebitis) and intermediate uveitis. Diagnosis requires multisystem evaluation: chest imaging (bilateral hilar lymphadenopathy), serum ACE and calcium levels, and tissue biopsy with non-caseating granulomas. Sarcoid uveitis is typically steroid-responsive, though some cases require immunosuppressive therapy.

• Tuberculosis: TB is the leading infectious cause of uveitis globally and must be excluded in any patient with granulomatous uveitis, especially those with systemic TB exposure or risk factors (immunosuppression, immigration from TB-endemic regions, healthcare workers). TB causes choroidal granulomas, serpiginous choroiditis, retinal vasculitis, and sometimes anterior granulomatous uveitis. Diagnosis requires tuberculin skin test (TST) or interferon-gamma release assay (IGRA), often with chest imaging to identify pulmonary or miliary TB; however, ocular TB can occur as isolated disease without pulmonary involvement. Treatment requires anti-tuberculous chemotherapy (typically isoniazid, rifampin, pyrazinamide, ethambutol) combined with topical corticosteroids.

• Toxoplasmosis: The most common infectious cause of posterior uveitis and retinitis worldwide. Reactivation of latent Toxoplasma gondii occurs in immunocompetent hosts but is more severe in AIDS (CD4 <100/μL) and other immunocompromised states. Presents as focal necrotizing retinitis with adjacent "headlight in the fog" vitritis (mild inflammation relative to retinal necrosis). Multiple simultaneous lesions may occur. Diagnosis is primarily clinical; serology (IgG, IgM, IgA) is supportive but not diagnostic of active infection. Treatment includes trimethoprim-sulfamethoxazole (first-line in immunocompetent), pyrimethamine plus sulfadiazine with folinic acid (especially in sulfa-allergic patients), or atovaquone in severe allergy. Immunocompromised patients require systemic prophylaxis to prevent recurrence.

• Cytomegalovirus (CMV) Retinitis: Almost exclusively seen in AIDS with CD4 <50/μL or other severe immunosuppression (advanced hematologic malignancy, post-transplant immunosuppression). Two clinical patterns: "hemorrhagic" (fulminant, rapid centripetal spread with hemorrhages and minimal vitritis) and "indolent" (granular lesions, slower progression). Diagnosis is clinical, supported by PCR of aqueous or vitreous humor showing CMV DNA. Treatment includes ganciclovir (IV or intravitreal injection/implant), foscarnet, cidofovir, or valganciclovir, often combined with immune reconstitution (ART in HIV). Risk of immune recovery uveitis (IRU) occurs weeks to months after immune reconstitution.

• Acute Retinal Necrosis (ARN) and Progressive Outer Retinal Necrosis (PORN): ARN is caused by herpes simplex virus (HSV)-1, HSV-2, or varicella-zoster virus (VZV); PORN is almost always VZV in AIDS patients. ARN presents with fulminant vitritis, retinal whitening/necrosis at the junction of vascular and avascular retina, and vasculitis; typically painful and progresses rapidly without treatment. PORN has minimal vitritis (hence the name) but rapidly progressive outer retinal necrosis. Both require emergency high-dose IV acyclovir or valacyclovir and careful monitoring for retinal detachment (occurs in up to 50% of ARN cases without prophylactic laser). Diagnosis via PCR of aqueous/vitreous.

• Syphilis (Neurosyphilis): Secondary or tertiary syphilis can cause anterior uveitis (interstitial keratitis in congenital syphilis), diffuse vasculitis affecting retinal vessels, papillitis, or chorioretinitis. Diagnosis via RPR/VDRL (titer correlates with activity) and treponemal-specific tests (FTA-ABS, TP-PA). Serology of aqueous humor or CSF may be required if neurosyphilis is suspected. Treatment: IV penicillin G for neurosyphilis; IM benzathine penicillin G for other stages. Systemic corticosteroids are often required to manage ocular inflammation without suppressing antimicrobial therapy.

• Viral Hepatitis (Hepatitis B, Hepatitis C) and HIV: Hepatitis B is associated with HLA-B27 and can trigger vasculitis and anterior uveitis. Hepatitis C is linked to cryoglobulinemia-associated vasculitis and retinal findings. HIV itself causes cotton-wool spots (retinal nerve fiber layer infarcts) and immune recovery uveitis upon immune reconstitution. Patients with viral hepatitis presenting with uveitis warrant serologic screening.

• Idiopathic Intermediate Uveitis: Intermediate uveitis (vitritis inflammation with minimal anterior chamber reaction) is idiopathic in 70–80% of cases in developed countries. It predominantly affects young to middle-aged adults and shows a slight female predominance. Bilateral involvement occurs in 60–80%. Associations to exclude include multiple sclerosis (especially in those with concurrent optic neuritis or brain lesions), sarcoidosis, syphilis, and TB. The condition is typically chronic, often requiring long-term immunosuppression.

• Medication-Induced Uveitis: Rifabutin (used in TB prophylaxis) can cause anterior or intermediate uveitis, especially at higher doses or with drug interactions. Bisphosphonates (rarely), topiramate, and some biologics (TNF-α inhibitors paradoxically can cause or unmask uveitis) are implicated. History of recent medication changes is essential.

• Masquerade Syndromes: Malignancy (lymphoma, leukemia), inflammation (chronic cyclitis from severe dry eye), and other conditions can mimic uveitis. Young patients with "uveitis" and systemic lymphadenopathy, or older patients with atypical features, warrant evaluation for lymphoproliferative disease.

• Pain: A hallmark of anterior uveitis, pain is caused by ciliary body inflammation and muscle spasm. Patients report deep, dull, aching periocular or orbital pain that may worsen with accommodation (ciliary muscle contraction). Pain is typically absent or minimal in posterior uveitis (photoreceptors lack sensory innervation), which is a critical distinguishing feature; posterior uveitis presenting with pain raises suspicion for anterior involvement or associated anterior scleritis. Intermediate uveitis may present with mild discomfort or floaters. Severe pain should prompt assessment for secondary angle-closure glaucoma or endophthalmitis (infectious uveitis).

• Photophobia: Caused by iris inflammation and increased sensitivity to light, photophobia is prominent in acute anterior uveitis. The mechanism involves both direct irritation of pain-sensing iris nerve endings and overflow of inflammatory mediators. Photophobia in posterior uveitis is typically mild or absent unless substantial vitritis is present.

• Floaters and Visual Symptoms: Floaters result from inflammatory cells (white blood cells, red blood cells, exudate) suspended in the vitreous in posterior uveitis and intermediate uveitis. Patients describe them as "cobwebs," "dots," or "shadows." Posterior uveitis characteristically presents with floaters and blurred vision without pain, distinguishing it from anterior uveitis. Visual symptoms may also reflect macular involvement (decreased visual acuity, metamorphopsia) or optic nerve inflammation.

• Conjunctival Injection: Anterior uveitis typically shows circumciliary (perilimbal) injection—vasodilation of episcleral vessels around the iris insertion—rather than diffuse conjunctival redness. This is more prominent in anterior uveitis than in conjunctivitis, where injection is diffuse. Posterior uveitis may show minimal conjunctival signs unless anterior inflammation or vasculitis is concurrent.

• Corneal Signs: Keratic precipitates (KP) are collections of inflammatory cells (lymphocytes, plasma cells, epithelioid cells) on the corneal endothelium. Fine KP (<0.5 mm, granular appearance) are characteristic of non-granulomatous anterior uveitis (HLA

Initial test — slit-lamp biomicroscopy with dilated fundus exam

• Slit-lamp examination: the first and most important step; a 1 mm × 1 mm high-intensity beam in a darkened room reveals cells (leukocytes) and flare (Tyndall effect from protein leaking across a broken blood–aqueous barrier). Cells indicate active inflammation; flare alone may persist as a chronic barrier defect and does not by itself mandate escalation.
• SUN Working Group criteria: the named system used for classification and grading. Anatomic site (anterior/intermediate/posterior/pan), onset, duration (limited <3 months vs persistent), and course (acute, recurrent, chronic) are recorded. Anterior chamber cell grade runs 0.5+ (1–5 cells per field) through 4+ (>50 cells); flare runs 0 to 4+, with 4+ meaning fibrinous or plasmoid aqueous. Vitreous haze is graded against standard fundus photographs.
• Key bedside findings: ciliary flush, miotic sluggish pupil, keratic precipitates (fine vs mutton-fat), hypopyon, posterior synechiae, and snowballs/snowbanking over the pars plana in intermediate uveitis.
• Tonometry: mandatory. Low IOP suggests ciliary body shutdown; markedly elevated IOP with unilateral granulomatous inflammation suggests herpetic (HSV/VZV/CMV) trabeculitis or Posner–Schlossman.

Imaging and laboratory confirmation

• OCT and fluorescein angiography: OCT detects cystoid macular edema, the leading cause of vision loss; FA shows petaloid macular leakage, disc leakage, and vascular staining in retinal vasculitis. B-scan ultrasound is used when media are opaque, to exclude retinal detachment.
• Targeted, not shotgun, serology: the AAO Preferred Practice Pattern advises no laboratory workup for a first episode of unilateral, non-granulomatous, acute anterior uveitis that responds to therapy. Recurrent, bilateral, granulomatous, or posterior disease warrants HLA-B27, treponemal antibody plus RPR, IGRA or TST with chest imaging, ACE/lysozyme, and ANA in children.
• Aqueous or vitreous sampling: the confirmatory gold standard for infectious and masquerade disease — PCR for HSV, VZV, CMV, and Toxoplasma, with cytology, flow cytometry, and IL-10/IL-6 analysis when vitreoretinal lymphoma is suspected.

First-line, non-infectious anterior uveitis (AAO Preferred Practice Pattern)

• Topical corticosteroid: prednisolone acetate 1% suspension, dosed frequently at onset and then tapered slowly against cell grade; abrupt cessation causes rebound. Difluprednate is more potent but more likely to raise IOP.
• Cycloplegic/mydriatic: cyclopentolate or homatropine (atropine for severe disease) paralyzes the ciliary muscle to relieve the deep aching pain and keeps the pupil mobile to prevent posterior synechiae.

Escalation

• Regional steroid: posterior sub-Tenon or intravitreal triamcinolone, or a dexamethasone or fluocinolone acetonide intravitreal implant, for macular edema or unilateral posterior disease.
• Systemic corticosteroid: oral prednisone for bilateral, posterior, or sight-threatening panuveitis.
• Steroid-sparing immunomodulation: antimetabolites (methotrexate, mycophenolate mofetil), calcineurin inhibitors (cyclosporine), then biologics. Adalimumab, a TNF-α inhibitor, is FDA-approved for non-infectious intermediate, posterior, and panuveitis; infliximab is favored in Behçet disease. Etanercept is not effective for uveitis. The ACR/Arthritis Foundation JIA-uveitis guideline endorses methotrexate first, then a monoclonal TNF inhibitor. Expert consensus favors keeping chronic prednisone at low maintenance doses rather than prolonged high-dose therapy.

Structural complications of inflammation

• Posterior synechiae → iris bombé → secondary angle-closure glaucoma: iris–lens adhesions become 360° (seclusio pupillae), blocking aqueous flow through the pupil; the peripheral iris balloons forward and closes the angle. Signals: markedly elevated IOP, a fixed irregular pupil, and a bowed iris. This is an ophthalmic emergency requiring urgent pressure lowering and laser peripheral iridotomy.
• Cystoid macular edema: cytokine-driven breakdown of the inner blood–retinal barrier; the commonest cause of permanent central vision loss in uveitis. Signals: loss of acuity out of proportion to visible inflammation, cystic spaces on OCT, petaloid leakage on angiography.
• Cataract: posterior subcapsular opacity from chronic inflammation compounded by corticosteroid exposure.
• Band keratopathy: calcium deposition in Bowman layer across the interpalpebral cornea; classic in chronic JIA-associated uveitis.
• Hypotony and phthisis bulbi: ciliary body shutdown or a cyclitic membrane collapses aqueous production; signals are low IOP with chorioretinal folds — a marker of irreversible damage.
• Retinal detachment: rhegmatogenous in necrotizing viral retinitis (ARN/PORN) from atrophic retinal holes; exudative in Vogt–Koyanagi–Harada. Sudden curtain-like field loss is an emergency.
• Choroidal neovascularization, epiretinal membrane, and optic atrophy cause late irreversible loss.

Complications of therapy

• Steroid-induced ocular hypertension: trabecular outflow resistance rises in genetic "steroid responders," typically weeks after starting potent topical or intravitreal steroid; detected only by serial tonometry, so every uveitis follow-up includes IOP.
• Herpes reactivation and infectious keratitis after topical steroid used without antiviral cover.
• Systemic corticosteroid toxicity: hyperglycemia, osteoporosis, adrenal suppression.
• Immunomodulator toxicity: methotrexate hepatotoxicity and cytopenias, mycophenolate GI intolerance and marrow suppression, cyclosporine nephrotoxicity and hypertension.
• TNF-α inhibitors: reactivation of latent tuberculosis — screen with IGRA and chest imaging before starting — and possible demyelination, making them a poor choice in intermediate uveitis linked to multiple sclerosis.
• Immune recovery uveitis: vitritis and macular edema after antiretroviral-driven CD4 recovery in treated CMV retinitis.

• Ciliary flush plus consensual photophobia is uveitis until proven otherwise: shining light in the unaffected eye causes pain in the inflamed eye because the consensual reflex contracts the inflamed iris sphincter. The single best next step is slit-lamp examination with tonometry, not empiric antibiotic drops.
• The association examiners love: acute, unilateral, painful, recurrent, non-granulomatous anterior uveitis with a hypopyon in a young man with inflammatory low back pain = HLA-B27-associated disease, most often ankylosing spondylitis. Check HLA-B27 and sacroiliac imaging.
• Buzzword-to-diagnosis map: mutton-fat keratic precipitates + bilateral hilar adenopathy = sarcoidosis; headlight in the fog = toxoplasmosis; pizza-pie hemorrhagic retinitis with CD4 <50 = CMV; snowbanking over the pars plana in a young adult = intermediate uveitis, screen for multiple sclerosis; oral and genital ulcers with hypopyon uveitis = Behçet.
• The dangerous distractor: never start a topical corticosteroid on a red eye before fluorescein staining. A branching dendritic ulcer means HSV epithelial keratitis, where steroids cause geographic ulceration and melt.
• Pediatric trap: ANA-positive oligoarticular JIA in a young girl causes chronic, asymptomatic, white-eye uveitis found only on scheduled slit-lamp screening (ACR/Arthritis Foundation and AAO recommend routine screening); RF-positive polyarticular JIA carries the lowest risk. Band keratopathy is the classic late finding.
• Painless floaters and blurred vision without redness localize posteriorly; a painful red eye localizes anteriorly. Conjunctivitis, the usual distractor, gives diffuse injection, discharge, a normal reactive pupil, and no photophobia.
• Any uveitis workup includes syphilis and tuberculosis — both are great mimics, and both are worsened by unopposed steroids.
• Sudden IOP spike with a fixed irregular pupil = iris bombé, an emergency needing laser peripheral iridotomy, not more steroid drops.