Ophthalmology – Granulomatous Uveitis

Basics

Description

Granulomatous uveitis is a nonspecific term describing intraocular inflammation with granulomatous features. It may present with a painful red eye, photophobia, floaters, and decreased vision, although the symptoms vary depending on the site and severity of inflammation.

A classic finding is the presence of large, greasy keratic precipitates, often described as mutton-fat keratic precipitates, on the corneal endothelium.

The inflammation may involve predominantly the anterior segment as anterior uveitis or iritis, the vitreous as intermediate uveitis, the retina and choroid as posterior uveitis, or the entire uveal tract as panuveitis.

Granulomatous uveitis is more often associated with an underlying systemic disease, infectious process, or specific ocular syndrome than nongranulomatous uveitis. It may be unilateral or bilateral, acute or chronic, and can occur at any age.

Risk Factors

Risk factors depend on the underlying cause.

Geographic exposure is important, particularly residence in or travel to areas endemic for infections such as tuberculosis, Lyme disease, or coccidioidomycosis.

Animal exposure may also be relevant. For example, certain exposure histories may increase suspicion for toxoplasmosis.

Ethnicity can provide a clue to systemic associations. Sarcoidosis, for example, has varying prevalence among different populations.

A history of penetrating ocular trauma or surgery involving the fellow eye may suggest sympathetic ophthalmia.

Disruption of the lens capsule following trauma or surgery may predispose to lens-associated uveitis.

Genetics

Granulomatous uveitis itself does not have a single genetic pattern.

Some associated diseases have genetic markers. For example, Vogt–Koyanagi–Harada disease has been associated with certain HLA-DR alleles.

Pathophysiology

The exact mechanism varies with the underlying condition.

Granulomatous inflammation may result from an autoimmune response, persistent immune activation against ocular antigens, or the host response to an infectious organism.

The inflammatory reaction typically involves macrophages, epithelioid cells, lymphocytes, and multinucleated giant cells.

Etiology

A substantial proportion of cases remain idiopathic despite appropriate evaluation.

Possible infectious causes include syphilis, tuberculosis, herpes simplex virus, varicella-zoster virus, cytomegalovirus, toxoplasmosis, Lyme disease, leprosy, coccidioidomycosis, and brucellosis.

Important noninfectious causes include sarcoidosis, Vogt–Koyanagi–Harada disease, sympathetic ophthalmia, granulomatosis with polyangiitis, and lens-associated uveitis.

Because treatment differs considerably between infectious and noninfectious causes, identifying the underlying etiology is essential whenever possible.

Commonly Associated Conditions

Granulomatous uveitis may be associated with sarcoidosis, syphilis, HSV, VZV, CMV, tuberculosis, toxoplasmosis, Lyme disease, leprosy, Vogt–Koyanagi–Harada disease, sympathetic ophthalmia, granulomatosis with polyangiitis, coccidioidomycosis, brucellosis, and lens-associated inflammation.

Diagnosis

History

A detailed medical and ocular history should be obtained.

The clinician should ask about prior ocular surgery, trauma, infections, systemic inflammatory disease, and medications.

A complete review of systems should include questions about joint pain, skin rashes, shortness of breath, swollen lymph nodes, headaches, hearing changes, hair loss, skin depigmentation, neurologic symptoms, ocular trauma, insect bites, sexually transmitted infections, tuberculosis exposure, animal exposure, and recent travel.

These findings can help direct the diagnostic workup.

Physical Examination

Visual Acuity

Vision may remain normal in mild disease or may be reduced when inflammation is severe or involves the macula, optic nerve, lens, vitreous, retina, or choroid.

Intraocular Pressure

Intraocular pressure is often reduced during active anterior inflammation because ciliary body dysfunction decreases aqueous production.

However, elevated intraocular pressure may occur in viral uveitis, chronic inflammatory disease, secondary angle damage, or as a response to corticosteroid therapy.

External Findings

External examination may occasionally provide clues to systemic disease.

For example, lacrimal gland enlargement, parotid enlargement, or facial nerve palsy may suggest sarcoidosis.

Conjunctival injection may be present, often with a ciliary flush around the limbus.

In Vogt–Koyanagi–Harada disease, perilimbal depigmentation known as Sugiura sign may develop.

Corneal Findings

Keratic precipitates are deposits of inflammatory cells on the posterior corneal surface.

In granulomatous disease, they are typically large, greasy, and mutton-fat in appearance and are often concentrated inferiorly.

Anterior Chamber Findings

Anterior chamber cells and flare are common.

Cells represent inflammatory cells floating in the aqueous humor.

Using the SUN grading system, anterior chamber cells are graded as follows: 0 for fewer than 1 cell, 0.5+ for 1–5 cells, 1+ for 6–15 cells, 2+ for 16–25 cells, 3+ for 26–50 cells, and 4+ for more than 50 cells in a standardized slit-lamp field.

Flare represents increased protein in the aqueous due to breakdown of the blood-aqueous barrier.

Flare is graded as 0 for none, 1+ for faint, 2+ for moderate with clear iris and lens details, 3+ for marked with hazy iris and lens details, and 4+ for intense flare with fibrin or a markedly turbid aqueous.

Iris Findings

Granulomatous uveitis may produce posterior synechiae, where the iris adheres to the anterior lens capsule.

Peripheral anterior synechiae may also occur.

Inflammatory iris nodules may develop at the pupillary margin, on the iris surface, or within the anterior chamber angle.

Lens Findings

Inflammatory deposits may be visible on the anterior lens capsule.

Patients with recurrent or chronic inflammation may develop posterior subcapsular cataracts, either from the inflammation itself or from prolonged corticosteroid therapy.

Vitreous Findings

Inflammatory cells in the vitreous indicate posterior involvement.

Aggregates of inflammatory cells may form snowballs, particularly in intermediate uveitis.

Posterior Segment Findings

Posterior inflammation may produce optic disc edema, retinal vascular sheathing, retinal vasculitis, focal retinal lesions, choroidal lesions, cystoid macular edema, choroidal granulomas, or exudative retinal detachment.

Diagnostic Tests and Interpretation

Laboratory Evaluation

Laboratory investigation should be directed by the history, review of systems, examination findings, and epidemiologic exposure.

Granulomatous uveitis generally warrants an etiologic evaluation even at the first presentation because of its stronger association with systemic and infectious disease.

A basic evaluation may include a complete blood count and syphilis testing.

Syphilis testing is particularly important because syphilitic uveitis can mimic almost any form of ocular inflammation.

Tuberculosis Testing

When tuberculosis is suspected, testing may include a tuberculin skin test or interferon-gamma release assay, together with appropriate chest imaging.

Sarcoidosis Testing

When sarcoidosis is suspected, chest imaging is important.

Serum ACE and lysozyme may provide supportive evidence but are not sufficiently specific to establish the diagnosis by themselves.

Lyme Disease

Lyme serology should be considered when there is an appropriate exposure history and compatible clinical findings.

Toxoplasmosis

Toxoplasma IgG and IgM testing may be supportive in selected cases, although ocular toxoplasmosis is often diagnosed primarily from the retinal appearance.

Granulomatosis With Polyangiitis

ANCA testing may be useful when granulomatosis with polyangiitis is suspected.

PCR Testing

Aqueous or vitreous PCR can be helpful when an infectious etiology is suspected.

PCR may be performed for HSV-1, HSV-2, VZV, CMV, and Toxoplasma, depending on the clinical pattern.

Imaging

B-Scan Ultrasonography

If media opacity prevents visualization of the posterior segment, B-scan ultrasound may identify vitritis, exudative retinal detachment, subretinal lesions, choroidal thickening, or optic nerve abnormalities.

Fluorescein Angiography

Fluorescein angiography can demonstrate retinal vasculitis, vascular leakage, papillitis, macular edema, and inflammatory retinal abnormalities.

Indocyanine Green Angiography

Indocyanine green angiography provides improved visualization of choroidal inflammatory abnormalities and may be especially useful in diseases such as VKH.

Chest Imaging

Chest radiography may identify hilar or mediastinal adenopathy associated with sarcoidosis or tuberculosis.

If chest radiography is nondiagnostic but suspicion for sarcoidosis remains high, chest CT may be considered.

Biopsy

Biopsy of an accessible conjunctival nodule, lacrimal gland lesion, lymph node, skin lesion, or other involved tissue can help establish diagnoses such as sarcoidosis.

Histopathology classically demonstrates epithelioid histiocytes and multinucleated giant cells within granulomas.

Differential Diagnosis

Important differential diagnoses include endophthalmitis, intraocular lymphoma, chronic retinal detachment, and lens-induced inflammatory disease.

Masquerade syndromes should be considered when the inflammation behaves atypically or does not respond as expected to therapy.

Treatment

Treatment depends critically on whether the uveitis is infectious or noninfectious.

First-Line Treatment

For noninfectious anterior granulomatous uveitis, topical corticosteroids, such as prednisolone acetate, are usually the main initial therapy.

Treatment is often started relatively aggressively and then tapered slowly according to the clinical response.

Cycloplegic agents, such as cyclopentolate, homatropine, or atropine, may be used to relieve pain and photophobia and to prevent or break posterior synechiae.

Treatment of an Identified Cause

When an infectious cause is identified, treatment should specifically target the underlying pathogen.

For example, tuberculosis-associated uveitis requires appropriate antituberculous therapy, syphilitic uveitis requires systemic antibiotic treatment, and herpetic disease requires appropriate antiviral therapy.

Corticosteroids in infectious uveitis should generally be used only in combination with appropriate antimicrobial treatment.

Second-Line Treatment

If important infectious causes have been excluded and inflammation remains inadequately controlled with topical therapy, periocular or systemic corticosteroids may be necessary.

Long-term oral corticosteroid therapy requires monitoring for systemic complications such as hypertension, diabetes, osteoporosis, infection, mood changes, and gastrointestinal effects.

Calcium and vitamin D supplementation and other bone-protective measures may be appropriate when prolonged systemic treatment is anticipated.

Immunomodulatory Therapy

Patients with chronic, recurrent, steroid-dependent, or steroid-resistant noninfectious uveitis may require immunomodulatory or immunosuppressive therapy.

This may include antimetabolites, calcineurin inhibitors, biologic therapies, or other steroid-sparing agents.

Such treatment is usually coordinated with a uveitis specialist and often a rheumatologist.

Intravitreal Steroid Therapy

Intravitreal corticosteroids may be used in selected severe noninfectious cases, particularly when posterior inflammation or macular edema is prominent.

Potential complications include cataract formation and ocular hypertension or glaucoma.

Infectious etiologies should be excluded before intraocular corticosteroids are administered.

Management of Increased Intraocular Pressure

Secondary ocular hypertension or glaucoma should be treated with appropriate pressure-lowering medications.

Persistent elevation or progressive glaucomatous damage may require referral to a glaucoma specialist.

Referral

Patients receiving long-term systemic corticosteroids should be followed by a primary care physician or appropriate medical specialist for monitoring of blood pressure, blood glucose, bone health, and other systemic adverse effects.

Patients who require immunomodulatory therapy may need rheumatology involvement.

If an underlying systemic disease is identified, referral should be directed appropriately, such as pulmonology for sarcoidosis or infectious disease for tuberculosis.

Cystoid macular edema may require a vitreoretinal specialist.

Persistent, recurrent, or diagnostically uncertain inflammation should be referred to a uveitis specialist.

Surgery and Other Procedures

Chronic uveitis and corticosteroid treatment may lead to visually significant cataract requiring cataract extraction and intraocular lens implantation.

Glaucoma that cannot be controlled medically may require trabeculectomy, glaucoma drainage device implantation, or another pressure-lowering procedure.

Pars plana vitrectomy may be useful for persistent vitreous opacities, diagnostic sampling, or selected posterior segment complications.

Long-acting intraocular corticosteroid implants may be considered in selected patients with chronic noninfectious posterior uveitis, but they carry substantial risks of cataract and glaucoma.

Inpatient Considerations

Hospitalization is usually unnecessary when disease is confined to the eye.

Admission may occasionally be required for serious systemic infection or when intravenous therapy is needed, such as selected cases of neurosyphilis or severe viral retinitis.

Follow-Up

Patients should be followed closely while inflammation remains active.

The frequency of examination depends on the severity, location, underlying cause, and treatment being used.

Corticosteroids should be tapered slowly as inflammation resolves to minimize rebound disease.

After remission, patients require periodic ophthalmic evaluation because recurrence is common.

Patient Monitoring

Monitoring should include visual acuity, intraocular pressure, anterior chamber inflammation, vitreous activity, retinal and choroidal findings, and macular status.

Patients taking systemic corticosteroids or immunosuppressive medications also require appropriate systemic laboratory and clinical monitoring.

Patient Education

Patients should understand that granulomatous uveitis may be chronic or recurrent.

They should seek prompt evaluation for recurrence of redness, pain, photophobia, floaters, or decreased vision.

They should also understand the importance of following a prescribed corticosteroid taper rather than stopping treatment abruptly.

Untreated or inadequately treated inflammation can result in permanent visual loss.

Prognosis

The visual prognosis depends on the underlying etiology, severity and duration of inflammation, response to treatment, and development of complications.

Many patients maintain good visual function when the cause is identified and the inflammation is appropriately controlled.

The prognosis becomes less favorable when there is cataract, glaucoma, chronic cystoid macular edema, retinal or choroidal scarring, or recurrent severe inflammation.

Complications

Important complications include cataract, secondary glaucoma, cystoid macular edema, exudative retinal detachment, retinal pigment epithelial atrophy, posterior synechiae, band keratopathy, and permanent visual impairment.