Ophthalmology – Sarcoidosis

What the Disease Is

Sarcoidosis is a multisystem inflammatory disorder characterized by formation of:

Noncaseating granulomas

in affected tissues.

The cause remains uncertain, but the disease likely reflects an abnormal immune response in genetically susceptible individuals after exposure to one or more environmental or infectious triggers.

Frequently involved organs include:

• Lungs
• Intrathoracic lymph nodes
• Skin
• Eyes
• Nervous system
• Heart

Ocular disease may occur:

• Before systemic sarcoidosis is recognized
• During established systemic disease
• Occasionally as the predominant manifestation

Why It Matters to Ophthalmologists

Sarcoidosis can affect nearly every ocular structure, including:

• Conjunctiva
• Lacrimal gland
• Orbit
• Anterior chamber
• Vitreous
• Retina
• Choroid
• Optic nerve

The most important ophthalmic manifestation is:

Uveitis

which may be:

• Anterior
• Intermediate
• Posterior
• Panuveitic

Untreated inflammation can cause permanent visual loss through:

• Cystoid macular edema
• Glaucoma
• Cataract
• Retinal/choroidal damage
• Optic neuropathy

Who Is More Likely to Be Affected

Sarcoidosis occurs worldwide, but incidence varies considerably according to:

• Ethnicity
• Geography
• Age
• Genetic background

It commonly presents in:

Young and middle-aged adults

although children and older adults can also be affected.

Certain populations, including people of African ancestry and some Northern European groups, have higher rates of systemic disease.

Hereditary Susceptibility

Sarcoidosis is not inherited in a simple Mendelian pattern.

However:

• Familial clustering occurs
• First-degree relatives have increased risk
• Several HLA associations have been identified

One important susceptibility locus is:

HLA-DRB1

Genetic background can also influence:

• Clinical phenotype
• Organ involvement
• Prognosis

How Granulomas Develop

The current model involves exaggerated cell-mediated immunity.

A proposed sequence is:

Antigen exposure → macrophage activation → CD4+ T-cell recruitment → cytokine release → granuloma formation

Important immune mediators include:

• Tumor necrosis factor-α
• Interferon-γ
• Interleukins

Granulomas are composed mainly of:

• Epithelioid histiocytes
• Multinucleated giant cells
• T lymphocytes

What the Biopsy Shows

The characteristic pathologic finding is:

Noncaseating epithelioid granulomatous inflammation

However, this is not uniquely diagnostic of sarcoidosis.

Similar granulomas can occur with:

• Tuberculosis
• Fungal infection
• Foreign-body reactions
• Other granulomatous inflammatory disorders

Therefore infection must be excluded when clinically appropriate.

Typical Systemic Symptoms

Patients may report:

• Cough
• Dyspnea
• Chest discomfort
• Fatigue
• Fever
• Weight loss
• Arthralgia
• Skin lesions

Some patients are:

Completely asymptomatic systemically

despite radiographic disease.

Classic Systemic Presentations

Löfgren Syndrome

An acute sarcoidosis phenotype characterized by combinations of:

• Bilateral hilar lymphadenopathy
• Erythema nodosum
• Ankle arthritis or periarthritis
• Fever

It generally carries a:

Favorable prognosis.

Heerfordt Syndrome

Also called:

Uveoparotid fever

Classically includes:

• Uveitis
• Parotid gland enlargement
• Facial nerve palsy
• Fever

Not every component must be present.

What Patients With Eye Disease Notice

Ocular symptoms may include:

• Blurred vision
• Photophobia
• Ocular pain
• Redness
• Floaters
• Reduced contrast
• Metamorphopsia

Orbital or neurologic involvement may cause:

• Diplopia
• Ptosis
• Proptosis
• Visual field defects

Some patients remain asymptomatic despite active ocular inflammation.

Typical Anterior Segment Pattern

Sarcoidosis classically produces:

Granulomatous anterior uveitis

Typical findings include:

• Mutton-fat keratic precipitates
• Anterior chamber cells and flare
• Iris nodules
• Posterior synechiae

Iris Nodules

Two classic types are:

Koeppe Nodules

Located at the:

Pupillary margin

Busacca Nodules

Located on the:

Anterior iris surface

Neither is specific for sarcoidosis.

Angle Involvement

Gonioscopy may reveal:

• Trabecular meshwork nodules
• Peripheral anterior synechiae
• Characteristic tent-shaped PAS

Angle involvement may contribute to:

Secondary glaucoma.

Intermediate Uveitis Features

Sarcoidosis may produce:

• Vitreous cells
• Vitreous haze
• Inferior snowballs

A classic description is:

“String of pearls” vitreous opacities

These findings reflect inflammatory aggregates within the vitreous.

Retinal Vascular Inflammation

One of the classic posterior findings is:

Retinal periphlebitis

usually affecting retinal veins.

The typical ophthalmoscopic appearance is described as:

“Candle-wax drippings”

representing segmental perivascular inflammatory exudation.

Retinal and Choroidal Lesions

Posterior involvement may include:

• Peripheral punched-out chorioretinal scars
• Active choroiditis
• Multifocal choroidal lesions
• Choroidal granulomas
• Retinal vascular leakage
• Retinal ischemia
• Neovascularization in advanced disease

Optic Nerve Involvement

Sarcoidosis may affect the optic nerve through:

• Optic disc granuloma
• Optic neuritis
• Perineuritis
• Infiltration
• Compression
• Raised intracranial pressure

Possible findings include:

• Disc swelling
• Disc nodules
• Reduced acuity
• Dyschromatopsia
• RAPD
• Visual field loss

Optic nerve involvement is potentially:

Vision-threatening and often requires systemic therapy.

Lacrimal Gland Disease

Sarcoidosis can infiltrate the lacrimal glands and cause:

• Painless enlargement
• Dry eye
• Palpable superotemporal mass

Lacrimal gland enlargement may be:

• Unilateral
• Bilateral

and may provide an accessible biopsy site.

Orbital Disease

Orbital sarcoidosis may involve:

• Lacrimal gland
• Extraocular muscles
• Orbital fat
• Optic nerve sheath
• Other orbital tissues

Possible symptoms include:

• Proptosis
• Diplopia
• Eyelid swelling
• Pain
• Restrictive motility

It can mimic:

• Thyroid eye disease
• Idiopathic orbital inflammation
• Lymphoma
• IgG4-related disease

How Ocular Sarcoidosis Is Diagnosed

Diagnosis is based on a combination of:

• Compatible ocular findings
• Systemic evidence
• Imaging
• Laboratory support
• Histologic confirmation when available
• Exclusion of important mimics

A biopsy-proven diagnosis remains the strongest confirmation.

Modern Diagnostic Framework

Current approaches, including updated International Workshop on Ocular Sarcoidosis (IWOS) concepts, categorize disease according to the strength of:

• Ocular signs
• Systemic investigations
• Biopsy evidence

The exact category depends on whether systemic tissue has been histologically confirmed.

Why Biopsy Is Important

Whenever feasible, biopsy should target the:

Safest accessible involved tissue

rather than the eye.

Potential sites include:

• Skin lesion
• Enlarged lymph node
• Conjunctival nodule
• Lacrimal gland
• Pulmonary or mediastinal lymph node

Pulmonary tissue is often obtained using:

Bronchoscopy with endobronchial ultrasound-guided biopsy

when thoracic lymphadenopathy is present.

Conjunctival Biopsy

If visible conjunctival nodules are present, biopsy may be attractive because it is:

• Relatively accessible
• Less invasive than pulmonary biopsy

Random conjunctival biopsy has a lower yield than biopsy of:

Clinically abnormal tissue.

Chest Imaging

Thoracic imaging is one of the most useful systemic investigations.

Possible findings include:

• Bilateral hilar lymphadenopathy
• Mediastinal lymphadenopathy
• Interstitial pulmonary infiltrates

Chest X-Ray vs Chest CT

Chest radiography may detect typical hilar adenopathy, but:

Chest CT is more sensitive

especially in patients with:

• Normal or equivocal chest X-ray
• High clinical suspicion
• Ocular disease without obvious systemic manifestations

Serum ACE

Serum:

Angiotensin-converting enzyme (ACE)

may be elevated in active sarcoidosis.

However:

• Sensitivity is limited
• Specificity is imperfect
• Normal ACE does not exclude sarcoidosis

Levels may also be influenced by:

• ACE inhibitor therapy
• Age
• Other granulomatous diseases

Therefore ACE should be viewed as:

Supportive rather than diagnostic.

Soluble IL-2 Receptor

Serum:

Soluble interleukin-2 receptor (sIL-2R)

is increasingly used as a biomarker of sarcoid immune activity.

In many settings it may have:

Greater diagnostic sensitivity than ACE

although availability varies.

Serum Lysozyme

Lysozyme may also be elevated.

It can provide supportive evidence but is:

Neither sufficiently sensitive nor specific to establish the diagnosis alone.

Calcium Abnormalities

Sarcoid granulomas can increase vitamin D activation and cause:

• Hypercalcemia
• Hypercalciuria

Therefore evaluation may include:

• Serum calcium
• Renal function

depending on the systemic context.

Tuberculosis Must Be Excluded

One of the most important diagnostic alternatives is:

Tuberculosis

particularly in regions where TB is common.

Evaluation may include:

• Interferon-γ release assay
• Tuberculin skin testing
• Chest imaging
• Microbiologic testing when indicated

A negative TB screening test does not absolutely exclude:

Active tuberculosis.

Syphilis Must Also Be Considered

Because ocular syphilis can mimic nearly any form of uveitis, testing commonly includes:

• Treponemal testing
• Nontreponemal testing

before committing a patient to prolonged immunosuppression.

Why the Old Anergy Test Is Less Useful

Historical teaching emphasized:

• PPD anergy
• “Anergy panels”

These are now much less important in routine diagnosis.

Modern evaluation favors:

• Targeted TB testing
• Imaging
• Biomarkers
• Tissue diagnosis

Role of FDG-PET

FDG-PET/CT can help identify occult active systemic sites when:

• Routine imaging is unrevealing
• Biopsy is needed
• Neurosarcoidosis or multisystem disease is suspected

It is not required for every patient.

Gallium Scanning Today

Gallium scanning historically demonstrated:

• Lacrimal uptake
• Parotid uptake
• Pulmonary inflammation

including the classic:

Panda sign

but it has largely been replaced by:

• CT
• MRI
• FDG-PET

in modern practice.

OCT in Ocular Sarcoidosis

Macular OCT is essential for detecting:

• Cystoid macular edema
• Epiretinal membrane
• Subretinal fluid
• Vitreomacular traction

CME is one of the most important treatable causes of visual loss.

Fluorescein Angiography

FA can demonstrate:

• Retinal vascular leakage
• Periphlebitis
• Disc leakage
• Capillary nonperfusion
• Macular leakage
• Neovascularization

Wide-field FA is especially useful for:

Peripheral retinal vasculitis.

Indocyanine Green Angiography

ICGA may reveal:

• Choroidal inflammatory lesions
• Hypofluorescent dark dots
• Choroidal granulomatous involvement

It is particularly useful when choroidal disease is suspected.

Fundus Autofluorescence

FAF can document:

• Active and inactive chorioretinal lesions
• RPE damage
• Areas of previous inflammation

It is supportive rather than diagnostic.

OCT Angiography

OCTA may demonstrate:

• Capillary dropout
• Choriocapillaris abnormalities
• Secondary choroidal neovascularization

but it does not show:

Vascular leakage

and therefore does not replace FA for vasculitis assessment.

Orbital and Neurologic Imaging

MRI brain/orbits with contrast is important when there is:

• Optic neuropathy
• Cranial nerve dysfunction
• Proptosis
• Orbital mass
• Suspected neurosarcoidosis

Fat-suppressed orbital sequences can help define:

• Optic nerve enhancement
• Lacrimal gland disease
• Orbital infiltration

Major Diagnostic Mimics

Important alternatives include:

• Tuberculosis
• Syphilis
• Toxoplasmosis
• Vogt-Koyanagi-Harada disease
• Birdshot chorioretinopathy
• Sympathetic ophthalmia
• Multiple sclerosis-associated uveitis
• Primary vitreoretinal lymphoma
• Behçet disease
• Other retinal vasculitides

Orbital Conditions That Can Resemble Sarcoid

These include:

• IgG4-related orbital disease
• Lymphoma
• Idiopathic orbital inflammation
• Granulomatosis with polyangiitis
• Thyroid eye disease
• Lacrimal gland neoplasm

Tissue biopsy becomes particularly important when the diagnosis is uncertain.

Overall Treatment Strategy

Treatment depends on:

• Site of ocular inflammation
• Severity
• Laterality
• Threat to vision
• Systemic involvement

The goal is to:

Suppress active inflammation before irreversible structural damage occurs.

Managing Anterior Uveitis

For isolated anterior uveitis, first-line treatment usually includes:

Topical corticosteroid

such as prednisolone acetate, with frequency adjusted to severity.

Preventing Synechiae and Relieving Pain

Cycloplegic/mydriatic drops are useful when significant anterior chamber inflammation is present.

Benefits include:

• Relieving ciliary spasm
• Reducing pain
• Preventing or breaking posterior synechiae

Local Steroid Therapy

Intermediate or posterior disease may sometimes be treated with:

• Periocular corticosteroid
• Intravitreal corticosteroid
• Sustained-release steroid implant

particularly when inflammation or CME is:

• Unilateral
• Asymmetric

Risks include:

• Cataract
• Elevated IOP
• Glaucoma

When Systemic Corticosteroids Are Needed

Systemic corticosteroids are appropriate for:

• Bilateral posterior uveitis
• Severe panuveitis
• Optic nerve involvement
• Orbital disease
• Neurosarcoidosis
• Vision-threatening inflammation

Treatment generally begins with:

Oral prednisone or equivalent

with dose and taper individualized to severity and systemic disease.

When Steroid-Sparing Treatment Is Appropriate

Long-term immunomodulatory therapy should be considered when:

• Inflammation recurs during steroid taper
• High steroid doses are required chronically
• Steroid toxicity develops
• Disease is severe or bilateral

Common Immunomodulatory Options

Frequently used agents include:

• Methotrexate
• Mycophenolate mofetil
• Azathioprine

Methotrexate is one of the most commonly used steroid-sparing agents in ocular sarcoidosis.

Biologic Therapy

For refractory disease, anti-TNF monoclonal antibodies may be used, especially:

• Adalimumab
• Infliximab

These can be effective for:

• Refractory uveitis
• Retinal vasculitis
• CME
• Neurosarcoidosis

Important Safety Step Before Anti-TNF Therapy

Before starting anti-TNF therapy, screen for:

• Tuberculosis
• Hepatitis B
• Other significant infection risks

because TNF blockade can reactivate latent infection.

Treating Sarcoid Macular Edema

Cystoid macular edema should primarily be treated by:

Controlling inflammation

Options include:

• Topical steroid in selected mild anterior-associated cases
• Periocular steroid
• Intravitreal steroid
• Systemic steroid
• Steroid-sparing immunomodulation

OCT is used to monitor response.

Treating Secondary Glaucoma

IOP elevation may result from:

• Trabecular inflammation
• Peripheral anterior synechiae
• Chronic corticosteroid exposure

Treatment may include:

• Topical aqueous suppressants
• Other glaucoma medication
• Laser or surgery when necessary

Both:

Inflammation and IOP must be controlled.

Cataract Management

Cataract may result from:

• Chronic uveitis
• Corticosteroid treatment

Cataract extraction is best performed when intraocular inflammation has been:

Well controlled before surgery

whenever clinically possible.

Perioperative anti-inflammatory therapy is often required.

Surgery for Glaucoma

Uncontrolled inflammatory glaucoma may require:

• Trabeculectomy
• Glaucoma drainage device
• Other glaucoma procedures

Success is improved when:

Uveitis is adequately suppressed.

Long-Term Surveillance

Follow-up depends on disease activity.

Monitor:

• Visual acuity
• Anterior chamber activity
• Vitreous inflammation
• IOP
• Macular OCT
• Retinal vascular activity
• Medication toxicity

Systemic follow-up may involve:

• Pulmonology
• Rheumatology
• Neurology
• Cardiology
• Dermatology

depending on organ involvement.

Cardiac Sarcoidosis

Although primarily outside ophthalmology, cardiac involvement is important because it may cause:

• Conduction abnormalities
• Ventricular arrhythmias
• Heart failure
• Sudden cardiac death

Symptoms such as:

• Syncope
• Palpitations
• Unexplained dyspnea

warrant systemic evaluation.

Neurosarcoidosis

Neurologic involvement may cause:

• Cranial neuropathies
• Optic neuropathy
• Meningitis
• Hypothalamic/pituitary disease
• Myelopathy

Facial nerve palsy is a classic manifestation.

Expected Visual Outcome

Many patients retain good vision when:

• Inflammation is recognized early
• CME is treated promptly
• Glaucoma is controlled

The major predictors of poor visual outcome include:

• Chronic cystoid macular edema
• Posterior segment inflammation
• Optic nerve disease
• Secondary glaucoma
• Macular structural damage

Problems That Can Develop Over Time

Important ocular complications include:

• Chronic or recurrent uveitis
• Cystoid macular edema
• Secondary glaucoma
• Posterior synechiae
• Cataract
• Epiretinal membrane
• Retinal ischemia
• Neovascularization
• Optic neuropathy
• Permanent visual loss

Ophthalmology Pearls

• Sarcoidosis is a multisystem granulomatous disorder characterized by noncaseating granulomas, but infection—especially tuberculosis—must be excluded before attributing granulomas to sarcoid.
• Ocular sarcoidosis may precede the diagnosis of systemic disease.
• The classic anterior segment pattern is granulomatous anterior uveitis with mutton-fat KPs, Koeppe/Busacca nodules, and posterior synechiae.
• Trabecular nodules and tent-shaped peripheral anterior synechiae are characteristic angle findings.
• Vitreous snowballs or “string-of-pearls” opacities suggest intermediate involvement.
• The classic retinal vascular sign is segmental periphlebitis with “candle-wax drippings.”
• Sarcoidosis can produce choroidal granulomas, optic disc granulomas, lacrimal gland enlargement, and orbital disease.
• Cystoid macular edema is one of the most important treatable causes of visual loss.
• Chest CT is more sensitive than plain chest radiography for detecting hilar and mediastinal lymphadenopathy.
• Serum ACE is supportive but neither sensitive nor specific enough to diagnose or exclude sarcoidosis.
• Soluble IL-2 receptor can be a useful modern systemic biomarker and may outperform ACE in some settings.
• Gallium scanning is largely historical; modern evaluation more often uses CT, MRI, and FDG-PET when indicated.
• Tissue biopsy showing compatible noncaseating granulomas remains the strongest confirmation, preferably from an accessible extraocular site.
• Before immunosuppression, important mimics such as tuberculosis and syphilis should be excluded.
• Topical corticosteroid plus cycloplegia is standard for significant anterior uveitis.
• Posterior, bilateral, optic nerve, orbital, or severe disease often requires systemic corticosteroid therapy.
• Chronic or recurrent disease commonly requires steroid-sparing therapy such as methotrexate, mycophenolate, or azathioprine.
• Adalimumab or infliximab can be effective for refractory ocular sarcoidosis, with infection screening before treatment.
• The classic syndromes to remember are Löfgren syndrome = hilar adenopathy + erythema nodosum + ankle arthropathy, and Heerfordt syndrome = uveitis + parotid enlargement + facial nerve palsy ± fever.
• Long-term vision is determined mainly by control of macular edema, posterior inflammation, glaucoma, and optic nerve disease.