Ophthalmologic Manifestations of Sarcoidosis (Ocular Sarcoidosis)

Updated: Aug 04, 2017
  • Author: Andrew A Dahl, MD, FACS; Chief Editor: Hampton Roy, Sr, MD  more...
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Overview

Overview

Sarcoidosis is an inflammatory, multisystem, granulomatous disease of unknown etiology, and although it predominantly affects the lungs, sarcoidosis often has ophthalmologic manifestations. In addition to the disease’s pulmonary and ocular signs, other organ systems may be affected as well, including the skin, lymph nodes, liver, spleen, heart, central and peripheral nervous systems, musculoskeletal system, and salivary glands.

Sarcoidosis is diagnosed when the classic clinical and radiologic findings are supported by histologic evidence of widespread noncaseating epithelioid granulomata. Although best known for its thoracic involvement, the ocular, neurologic, and extrapulmonary manifestations of sarcoidosis may cause significant complications, including blindness, meningitis, arthritis, renal disease, systemic morbidity, dermatitis, and death.

Consultations

Consultation with a pulmonologist may be helpful in cases of possible ophthalmic sarcoidosis or neurosarcoid to aid in the diagnosis (eg, bronchoscopy with biopsy) and to coordinate therapy.

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Patient History

Sarcoidosis may present with symptoms referable to a single organ or to multiple organ systems. Historical presentation depends on the severity of the organ(s) involved.

Neuro-ophthalmic involvement

Symptoms include diplopia from cranial nerve palsies or orbital involvement and decreased vision with or without scotoma from optic nerve infiltration or edema. Visual symptoms from glaucomatous optic nerve damage may be superimposed.

Ocular sarcoidosis

Symptoms from uveitis include blurred vision, photophobia, floaters, redness, scotomata, and pain. Periocular lesions may produce dry eye symptoms, as well as disfiguring lid, periocular, and adnexal lesions. [1] Orbital involvement by a mass lesion may cause proptosis and diplopia. Orbital and adnexal involvement may involve the lacrimal gland, the eyelid, the orbit, and the lacrimal sac. In a series of patients with orbital and adnexal sarcoidosis alone at presentation, systemic disease developed in 8% by 5 years. [1]

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Physical Examination

Neuro-ophthalmic manifestations

Oculomotor, trochlear, or abducens nerve (cranial nerve III, IV, or VI) involvement is rare but may cause diplopia or ptosis.

The optic nerve is commonly involved, occurring in 5-38% of patients with neurosarcoid. Postmortem studies and physiologic studies (visual-evoked potentials) indicate a high degree of subclinical disease. Coexisting uveitis also may obscure optic nerve involvement. Optic nerve or chiasmal involvement is seen in one third to one half of patients with neurosarcoid, in two thirds of patients having unilateral involvement, and in one third of patients having bilateral disease. Nonspecific optic nerve head swelling (papillitis), direct invasion of the optic disc or nerve, or papilledema due to increased intracranial pressure may be present.

Examination of the optic nerve head may reveal edema, vascular engorgement, nerve head elevation, hemorrhage, or optic nerve pallor or frank atrophy. If the lesion is retrobulbar, the optic nerve may initially appear normal. Isolated infiltrative optic neuropathy as the initial manifestation of sarcoidosis is rare. Retrobulbar optic nerve lesions may masquerade as optic nerve glioma or meningioma. Neuro-ophthalmic findings may present without systemic evidence of disease and elude diagnosis until a biopsy is performed.

Ocular manifestations

Involvement of the eyes and adnexa occurs in 25-54% of patients. Most patients with ophthalmic sarcoidosis have evidence of systemic involvement at the time of the initial examination.

Heerfordt syndrome is characterized by uveitis, which may precede the associated parotid enlargement and occasionally papilledema. Löfgren syndrome, which is characterized by erythema nodosum, bilateral hilar adenopathy, and arthralgias, is associated with anterior uveitis in 6% of patients.

Lacrimal gland involvement occurs in 15-28% of patients; in these cases, it usually manifests as a painless, bilateral, palpable swelling of the gland. Moderate to severe keratitis sicca may result.

Anterior segment disease

In the conjunctiva, granulomatous nodules are the most common lesions. Keratoconjunctivitis sicca presumably results from infiltration of the lacrimal and minor lacrimal glands or from chronic inflammation of the lacrimal excretory ductules. [2]

In the cornea, interstitial keratitis rarely may occur. Band keratopathy is infrequent, and scleritis is rare. Cataract is a frequent complication of uveitis and/or the corticosteroids used in treatment of sarcoid inflammatory disease of the anterior segment.

Anterior uveitis is the most common ocular manifestation of sarcoidosis, although up to one third of patients with posterior uveitis may have no signs of anterior segment inflammation. [3] The signs of anterior uveitis typically include granulomatous or mutton-fat keratic precipitates, iris nodules, posterior synechiae, and peripheral anterior synechiae.

Sequelae of chronic uveitis include anterior and posterior synechiae, iris bombé, glaucoma, cystoid macular edema, vitritis, retinal neovascularization, and cataract.

Glaucoma also may occur in sarcoidosis. Either or both secondary open-angle and secondary angle-closure glaucoma mechanisms may be seen. Most patients with intraocular pressure elevation have a chronic open-angle–type glaucoma. This picture is complicated by steroid-responsive glaucoma, in which approximately 6% of the population develops open-angle glaucoma when given topical corticosteroids for 4-6 weeks. Gonioscopy is essential in the evaluation of patients with elevated intraocular pressure. Iris bombe may occur secondary to posterior synechiae and pupillary block.

Posterior segment disease

Posterior findings occur in 25-30% of patients with sarcoidosis. For example, choroid lesions, which are typically multiple, yellowish, elevated nodules, may be found.

Clinical features seen in the vitreous cavity include cellular infiltrates, opacities, haze, syneresis, posterior vitreous detachment, and hemorrhages. Grayish green ̶ white opacities (or snowballs) may be seen in the anterior inferior vitreous. The opacities often occur in chains and are described as a string of pearls. Vitreous hemorrhage is rare and may result from retinal neovascularization.

Periphlebitis is not uncommon. In sarcoidosis, perivasculitis is limited to the retinal veins, tends to be segmental, and involves the small branch veins. En taches de bougie (candle-wax drippings) is the term used to describe the perivenous exudates. Periphlebitis tends to resolve dramatically on steroid therapy. Central retinal vein occlusions are rare.

Neovascularization of the retina was found in approximately one fourth of Spalton's patients with sarcoid retinitis and was the most significant factor contributing to poor prognosis. [4] Sequelae included vitreous hemorrhage, ischemia, and retinal detachment. Neovascularization may respond to corticosteroids and warrants a therapeutic trial. Panretinal photocoagulation and/or vitrectomy may be required for neovascularization. Retinal detachment is rare.

Cystoid macular edema (CME) is the accumulation of extracellular fluid in the outer plexiform layer of the retina. Intravenous fluorescein angiography (IVFA) may demonstrate dye leakage in the perifoveal area when frank cystoid spaces are not identified ophthalmoscopically. CME can also be demonstrated with optical coherence tomography (OCT).

Focal and discrete subretinal mottling may be seen in the inferior equatorial retinal pigment epithelium but occasionally may be seen in the posterior pole.

Pars plana exudates may be indistinguishable from idiopathic pars planitis. Histopathology may reveal fibrinous exudates overlying the pars plana and extending into the vitreous.

Orbital disease

Approximately 20% of patients with ophthalmic findings of sarcoid have soft tissue involvement of the orbit or lacrimal gland. Sarcoidosis involving the orbital space may present as a mass lesion with proptosis, ptosis, or ophthalmoplegia. The lacrimal gland may be enlarged on the basis of sarcoid infiltration.

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Differential Diagnosis

Ocular involvement (particularly uveitis) and neurosarcoid may be difficult to diagnose. A high level of suspicion and periodic retesting may be warranted when the initial workup is negative.

Eyelid granulomatous processes to consider in the differential diagnosis of sarcoidosis include the following:

  • Chalazia
  • Dermal tuberculosis
  • Fungal infections
  • Juvenile xanthogranuloma
  • Foreign bodies

Orbital granulomatous pathologies to consider in the differential diagnosis include the following:

  • Lipogranulomas
  • Wegener granulomatosis
  • Tuberculosis [5]
  • Syphilis
  • Fungal infections
  • Parasites - Eg, microfilariae, nematode larvae
  • Panophthalmitis

Entities to consider in the differential diagnosis of granulomatous uveitis include lens-induced uveitis, lymphoma, histiocytosis X, and neoplastic and posttreatment of ocular melanoma with proton beam irradiation. Other conditions to consider include the following:

  • Infectious entities - Nonpyogenic systemic infections associated with tuberculosis, cat-scratch disease, syphilis, brucellosis, leprosy, and leptospirosis
  • Protozoan infections - Amebiasis, toxoplasmosis, and trypanosomiasis
  • Fungal infections - Actinomycosis, aspergillosis, blastomycosis, candidiasis, coccidioidomycosis, cryptococcosis, histoplasmosis, mucormycosis, nocardiosis, and sporotrichosis
  • Helminth infestations - Ascaris, cysticercosis, taeniasis, Diptera larvae, and nematode infestations (onchocerciasis and Toxocara, Ancylostoma, and Necator species)
  • Viral uveitis - Herpes simplex, herpes zoster, vaccinia, and cytomegalovirus

Differential diagnosis of posterior uveitis that may clinically mimic sarcoidosis includes the following:

  • Birdshot chorioretinopathy
  • Vogt-Koyanagi-Harada syndrome
  • Sympathetic ophthalmia
  • Acute retinal necrosis
  • Toxoplasmosis
  • Behçet disease
  • Acute multifocal choroiditis
  • Multiple sclerosis (MS)
  • Tuberculosis
  • Syphilis
  • Vasculitides due to Wegener granulomatosis, systemic lupus erythematosus (SLE), Whipple disease, ankylosing spondylitis, Crohn disease, and relapsing polychondritis
  • Acute multifocal placoid pigment epitheliopathy (AMPPE)
  • Central nervous system (CNS) lymphoma
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Neuroimaging

In suspected neurosarcoidosis, magnetic resonance imaging (MRI) may be invaluable. MRI is generally more useful than computed tomography (CT) scanning, especially with posterior fossa disease. The most common lesions on MRI include multiple white matter lesions, meningeal enhancement, optic nerve enhancement, and mass lesions in the brain parenchyma. The distinction from demyelinating disease can often be difficult.

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Nuclear Studies

To highlight potential biopsy sites and to aid in tissue diagnosis, gallium scans are often obtained in cases of suspected neurosarcoidosis when chest radiographic findings and serum angiotensin-converting enzyme (ACE) levels are normal. Gallium-67 citrate scans often are supportive when typical findings are lacking. This is especially true in neurosarcoidosis or uveitis when a biopsy may not be feasible.

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Vitreous Fluid Analysis

In patients with vitreous inflammation of unknown etiology and a high likelihood of sarcoidosis, vitreous tap and immunological analysis may provide additional evidence for sarcoidosis as the correct diagnosis. A recent study by Kojima et al showed that a CD4/CD8 ratio of vitreous-infiltrating lymphocytes greater than 3.5 provided a diagnosis of ocular sarcoidosis with a sensitivity of 100% and a specificity of 96.3%. [5]

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Biopsy

Diagnosis requires a biopsy in most cases. As a rule, the most accessible site with the lowest morbidity should be considered. A biopsy should be performed on palpable lymph nodes or elevated superficial skin lesions, if present.

Conjunctival biopsy

Conjunctival tissue is readily available with low morbidity. A biopsy should be considered even in the absence of lesions. A blind or random conjunctival biopsy yields positive histologic evidence of sarcoidosis in 10-28% cases of suspected sarcoidosis.

Lacrimal gland biopsy

In cases of lacrimal gland enlargement or when the lacrimal glands are involved on a gallium scan, a biopsy may be useful. A transconjunctival approach has been recommended to minimize the risk of secondary keratoconjunctivitis sicca.

Salivary gland biopsy

Blaise et al found that for patients with granulomatous uveitis and a radiologic pattern consistent with sarcoidosis, minor salivary gland biopsy is useful in a second-line investigation for assessing the diagnosis of sarcoid uveitis. [6]

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Pharmacologic and Surgical Therapy

Corticosteroids and other medications

Appropriate and timely treatment may avoid chronic CME, a common cause of visual disability. Discuss corticosteroid and/or immunosuppressive adverse effects in detail with the patient. The risks, benefits, and alternatives of chronic immunosuppression must be properly documented. Also, check the patient’s tuberculosis skin test and controls prior to initiation of corticosteroid therapy.

Corticosteroids are the mainstay of treatment. Topical corticosteroids, depot periocular injections, and oral corticosteroids may be used.

Anterior uveitis responds well to topical corticosteroids (the treatment of choice for this condition) and cycloplegia. Pred Forte 1% (prednisolone acetate) is the criterion standard; generic prednisolone acetate is less effective. Prednisolone phosphate is effective, but it is less potent than prednisolone acetate. Newer agents, such as loteprednol etabonate (Lotemax), may be effective second choices, with less chance of steroid-induced glaucoma. They are particularly useful for maintenance. Weaker steroids, such as rimexolone (Vexol) and fluorometholone (FML), may play a role for patients in remission.

No specific treatment guidelines are available, but the following treatment guideline for prednisolone acetate 1% is provided as a practical guideline for acute anterior uveitis (similar topical corticosteroid regimens have been based in uveitis treatment protocols):

  • 1 drop every 1-2 hours while awake for 1 week
  • 1 drop 4 times daily for 1 week
  • 1 drop 3 times daily for 1 week
  • 1 drop 2 times daily for 1 week
  • 1 drop daily for 1 week
  • Discontinue if anterior chamber cells and flare are eliminated

Reevaluate the inflammation and intraocular pressures at 1- to 2-week intervals for the first month after onset of treatment. If inflammation is not improving at any given taper interval, maintain that dosing and taper only after the cells and flare decrease. The presence of increasing posterior synechiae is an indication that more steroid is needed.

Cycloplegia is indicated with acute intense inflammation to relieve ciliary spasm and to prevent formation of posterior synechiae. Topical nonsteroidal anti-inflammatory agents may be used when there is evidence for or concern about steroid glaucoma or the possibility of cataract acceleration as a result of long-term topical steroid use.

Intermediate and posterior uveitis due to inadequate penetration of topical corticosteroids into the posterior segment respond well to depot (sub-Tenon) injections and/or oral corticosteroids. Factors favoring the oral route of administration for uveitis include optic nerve involvement; intermediate uveitis, posterior uveitis, and panuveitis; bilateral disease; and coexisting threshold systemic disease. Topical corticosteroids and cycloplegics may supplement oral and/or sub-Tenon injections. Injections may be repeated at weekly, biweekly, or monthly intervals, up to 3-4 times, before maximal benefit is reached. Oral prednisone treatment guidelines similar to the above systemic guidelines may be used.

Orbital sarcoidosis usually requires oral corticosteroids, but retrobulbar injections of corticosteroids may be helpful.

Corticosteroid-sparing agents

In cases of steroid failures or intolerance, cyclosporine A has been used with mixed results. In addition, methotrexate has been shown to be effective in recalcitrant uveitis. [7]

Oral monoclonal antibody therapy is being investigated in the treatment of otherwise nonresponsive uveitis. New strategies include rituximab, a chimeric monoclonal antibody against the protein CD20, which is primarily found on the surface of immune system B cells. Interferon therapy is also being studied.

Anti-tumor necrosis factor-alpha (TNF-alpha) therapy (ie, infliximab, etanercept, adalimumab) has been used in recalcitrant sarcoid uveitis when no response had been obtained with classical immunosuppressive therapies. [8, 9] Unfortunately, anti-TNF drugs are associated with significant toxic effects and are ineffective in some cases. If uveitis-associated choroidal/retinal neovascularization is present, intravitreal vascular endothelial growth factor (VEGF) agents, such as bevacizumab, may be helpful. [10]

Surgical treatment

Cataract surgery may be performed when the intraocular inflammation is absolutely controlled. With chronic inflammation of the anterior segment, risks of cataract surgery are much higher. Vitrectomy may be required for severe vitreous opacification. If secondary glaucoma is unresponsive to maximal medical therapy, patients may require either trabeculectomy or glaucoma drainage device implant procedures.

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