Overview
- Definition
Multisystem non-caseating granulomatous disease of unknown etiology
Ocular involvement in 30%, mostly chronic granulomatous anterior uveitis, but may involve posterior structures, retinal vessels, optic nerve
- Criteria for ocular sarcoidosis:
Definite – uveitis with biopsy positive
Presumed – uveitis with bilateral hilar lymphadenopathy (BHL), no biopsy
Probable – 3 suggestive intraocular signs and 2 labs, BHL negative, no biopsy done
Possible – 4 suggestive intraocular signs and 2 labs, biopsy negative
- Symptoms
Blurring
Redness
Floaters, flashes
- Pain, irritation
May be deep orbital pain
Photophobia
Scotomas
Diplopia (with orbital involvement)
- Laterality
Unilateral or bilateral
- Course
Acute or chronic
- Age of onset
- Two peaks of incidence:
20s to 30s (typically acute form)
50s to 60s (typically chronic form)
Early onset sarcoidosis (first decade) is actually sporadic form of Blau syndrome (NOD2 mutation)
- Gender/race
No specific gender predilection, but females may have more eye and neurologic involvement
More common in US blacks (often presents earlier, more severe) and northern European whites
Less common in Asians
- Systemic association
Multisystem non-caseating granulomas involving one or several organ systems including primarily lungs, but also lymph nodes (hilar and mediastinal most common), eyes, skin, heart, joints, spleen, liver, and nervous system
Hypercalcemia
Ocular symptoms may precede systemic signs
Exam: Ocular
Anterior Segment
- Granulomatous anterior uveitis (22–70%)
Bilateral, chronic
- Mutton-fat keratic precipitates
May also present with fine keratic precipitates
- More common
- Conjunctival nodules (variable %)
Solitary, yellow, “millet-seed,” often on bulbar surface
Posterior synechiae
- Iris nodules
Busacca (iris stroma)
Koeppe (pupil margin)
Peripheral anterior synechiae
Cataract
Orbital inflammation, myositis, lacrimal gland enlargement
Nasolacrimal duct obstruction
- Less common
- Band keratopathy
Associated with hypercalcemia
- Scleritis (rare), anterior or posterior
Angle closure (due to annular ciliochoroidal detachment)
Posterior Segment
- Vitritis or intermediate uveitis
Inferior vitreous (snowballs*) or pars plana exudates (snowbank*)
* not to be confused with inactive fibrotic changes along pars plana
String of pearls – vitreous exudate strands in chains
May also be posterior uveitis or panuveitis
Cystoid macular edema
- Retinal vasculitis (very common)
Segmental phlebitis
- “Taches de bougie” or candle wax drippings
Creamy white perivascular exudate or sheathing
Papillitis (may be only posterior manifestation)
- Retinal vein occlusion
Ischemic retinopathy with neovascularization, less common
Glaucoma
Choroidal nodules
- Multifocal punctate mid-peripheral chorioretinal scars
“Punched-out lesions,” very characteristic
Choroidal neovascularization, peripapillary or subfoveal
- Exudative retinal detachment (less common)
Posterior scleritis with annular ciliochoroidal detachment (angle closure)
Exam: Systemic
- Acute disease (weeks)
Fever, erythema nodosum, arthralgia, parotid enlargement
- Pulmonary (90%)
- Hilar and mediastinal lymphadenopathy
Mediastinal without hilar LAD is rare, alternative diagnosis
Pulmonary nodules
Calcification
May also involve upper respiratory mucosa
- Skin (9–37%)
Erythema nodosum
- Plaque-like lesions
Lupus pernio – indurated, chronic violaceous, often on face
Subcutaneous nodules
Glandular enlargement (salivary, parotitis)
- Neurologic (5–26%)
- May involve any part of nervous system
Occurs in 37% of patients with ocular involvement
Cranial neuropathies, most common
Hypothalamic or pituitary lesions may lead to endocrinologic disease
Meningeal
Spinal cord
- Cardiac (up to 25%)
Cardiomyopathy
Pericardial effusion or pericarditis
Conduction abnormalities
Cor pulmonale (with severe pulmonary disease)
Hepatosplenic enlargement with granulomas/nodules (>50%)
- Musculoskeletal
Arthritis – ankles, other joints
Bone resorption in marrow of phalanges
- Renal (uncommon)
Interstitial nephritis
Calculus
Renal failure
Imaging
OCT: CME, disc edema
ED-OCT: choroidal granuloma
OCT-A: retinal ischemia, microvascular disease
FA: venule (very common) or capillary leakage or staining, CME, diffuse chorioretinal leakage, disc leakage, peripapillary or subfoveal choroidal neovascularization, ischemia, retinal vein occlusion, choroidal granuloma
ICG: early lobular hypolucence, choroidal vasculitis, focal and diffuse late hyperlucence
VF: glaucoma, optic neuropathy, craniopathy
B-Scan: orbital inflammation, posterior scleritis, choroidal granuloma, papillitis
Laboratory and Radiographic Testing
ACE or lysozyme may be elevated in active disease, often normal, nonspecific
Elevated soluble interleukin-2 receptor (sIL2R)
Hypercalcemia, hypercalciuria
- Chest CT – occult or symptomatic pulmonary findings, cardiomyopathy
Chest X-ray often negative, nonspecific
MRI brain/orbits – CNS involvement, orbital inflammation
- Gallium scan
Panda sign – bilateral symmetric lacrimal and parotid uptake
Lambda sign – para- and infrahilar bronchopulmonary lymph nodes and right paratracheal (azygous) mediastinal lymph nodes
Biopsy – conjunctiva, vitreous (high levels of HMGB1), transbronchial lung, lacrimal gland, skin
- Other testing
Cutaneous anergy
Pulmonary function testing
Bronchoalveolar lavage
PET imaging
Differential Diagnosis
- Anterior uveitis
HLA-B27 associated uveitis
Fuchs’ heterochromic iridocyclitis
Herpes simplex or varicella zoster
Syphilis
Tuberculosis
Juvenile idiopathic arthritis
- Intermediate uveitis
Pars planitis
Multiple sclerosis
Lyme disease
- Posterior uveitis
Toxoplasmosis
Toxocariasis
Tuberculosis
Syphilis
Birdshot retinochoroidopathy
Multifocal choroiditis and panuveitis
Vogt-Koyanagi-Harada disease
Intraocular lymphoma
Sympathetic ophthalmia
Adamantiades-Behçet’s disease
Whipple’s disease
Treatment
- Acute AU: frequent topical corticosteroid +/− cycloplegia
Q1h steroid and atropine 1% BID with hypopyon
- Severe AU or any posterior involvement
Systemic corticosteroids, oral or intravenous
- Initiation of immunomodulatory therapy
Coordination with other specialists if necessary
- Immunomodulatory therapy
- Antimetabolites
Methotrexate particularly effective
Azathioprine or mycophenolate
- Calcineurin inhibitors (supplemental)
Cyclosporine, tacrolimus
- Biologics (especially with RV)
TNFα inhibitors – adalimumab, infliximab
Anti-IL6 - tocilizumab
CD20 inhibition – rituximab
Anti-IL1β – anakinra, canakinumab (used in some cases)
- Alkylating agents
Chlorambucil or cyclophosphamide
- Intravitreal therapy
Anti-VEGF
Corticosteroid injections, implants
Pan-retinal photocoagulation
- Other therapeutic measures
Hydroxychloroquine
IV-Ig
Subcutaneous corticotropin gel
Thalidomide
Referral/Co-management
Pulmonology
Rheumatology
Neurology
Cardiology
Dermatology
Endocrinology