Sarcoidosis (from the Greek, meaning “tumor-like”) is a systemic inflammatory condition that may affect many organs. Its hallmark is the noncaseating granuloma, a nonspecific but highly suggestive pathologic finding. Although sarcoidosis most commonly affects the lungs and lymph nodes, the eyes are frequently affected. Because the ocular manifestations of sarcoidosis may be protean, this condition is considered in the differential diagnosis in nearly every case of ocular inflammatory disease. Significant progress has been made in the past several years in understanding the pathogenesis of sarcoidosis.
Sarcoidosis was first recognized by the London physician, Dr. Jonathan Hutchinson, who in 1877 described a series of patients with purple skin plaques on the hands and feet. Twelve years later, Dr. Cesar Boeck gave the name “sarcoid” to a disease process featuring multiple benign skin lesions. The first description of sarcoidosis affecting the eye was in 1909 with the description of Heerfordt syndrome, featuring parotid inflammation, uveitis, facial nerve palsy, and fever.
Key symptoms and signs
Sarcoidosis most often presents in the eye as uveitis. Uveitis is a general term referring to inflammation of the iris (iritis), vitreous body (intermediate uveitis), or retina and choroid (retinitis and choroiditis; retinal vasculitis may also accompany these findings). Typical symptoms of anterior uveitis are redness, pain, and aversion to bright lights (photophobia). Intermediate uveitis typically presents as new “floaters” in the patient’s vision. Posterior uveitis may present with loss of central visual acuity, new visual field defects, or generalized blurring of the vision (often macular edema).
Ocular sarcoidosis can present with many different signs ( Box 84.1 ). The conjunctiva may contain macroscopic granulomas that can be observed at the slit lamp. The lacrimal glands may be enlarged from granulomas, which may contribute to dry eye. The classic intraocular presentation of sarcoidosis is of an anterior or panuveitis, featuring large clumps of white blood cells adherent to the corneal endothelium, known as “mutton fat keratic precipitates” ( Figure 84.1 ). The anterior chamber frequently contains free-floating leukocytes. These are quantified on a standardized scale by the clinician, with 1+ cells corresponding to 6–15 visible cells in a 1 × 1 mm slit beam, to 4+ cells which are too numerous to count. The clinician may also observe flare in the anterior chamber as visible diffusion of the slit-lamp beam. This phenomenon arises from increased protein concentration in the aqueous humor due to compromise of the blood–aqueous barrier. The iris can develop adhesions to the lens, called posterior synechiae. Intraocular pressure may be elevated from trabecular meshwork inflammation or anterior synechiae from the iris to the peripheral cornea, blocking the trabecular meshwork. The pressure may also be reduced from ciliary body inflammation. The vitreous cavity often features white blood cell infiltration, which can be diffuse in the liquid anterior vitreous, or more clumped in the formed vitreous. The clumped cells are sometimes referred to as “snowballs.” Posteriorly, the most common manifestation of sarcoidosis is the choroidal granuloma ( Figure 84.2 ). These may be solitary or numerous, and may range from whitish in color to yellow. The vasculitis associated with sarcoidosis is most often seen on the veins. An unusual form of periphlebitis, called “tache de bougie” (candle wax drippings) occurs in patients with sarcoidosis. In a small proportion of cases sarcoid optic nerve head granulomas may be observed. Because of its protean ocular manifestations, sarcoidosis is often considered one of the “great masquerade” conditions, along with syphilis and tuberculosis.
White blood cells in anterior chamber
Keratic precipitates (clumped cells on corneal endothelium)
Posterior synechiae (adhesions between iris and lens)
White blood cells in vitreous cavity, diffuse or clumped
Retinal periphlebitis (taches de bougie)
Cystoid macular edema
Outside the eye, sarcoidosis typically presents in the lungs, where it may present as chronic cough or shortness of breath; approximately one-third of cases are found as an incidental finding on chest X-ray. Pulmonary sarcoidosis is staged based on the radiographic findings. The first stage is visible hilar adenopathy. In the second stage, pulmonary infiltrate is seen along with the hilar lymphadenopathy. In the third stage, the adenopathy is resolved but the infiltrates remain. Stage 4 sarcoidosis features pulmonary fibrosis; the prognosis for this stage of sarcoidosis is poor. Sarcoidosis may present in almost any other organ system. It is associated with liver granulomas, diffuse lymphadenopathy, deep brain granulomas, and skin findings, including erythema nodosum.
The incidence and prevalence of sarcoidosis vary markedly with geographic locale and patient population. The incidence in African-Americans and in the USA has been estimated at approximately 40–80 per 100 000 person-years, compared with 4–8 per 100 000 person-years in the Caucasian population. Hispanic individuals appear to be affected more commonly than Caucasians. The disease is also seen in Europe, with an incidence approximately 20 per 100 000 in the UK, and 24 per 100 000 in Sweden. There has been a suggestion of female preponderance in some studies, although this has not been observed consistently.
While sarcoidosis is not transmitted according to mendelian genetics, there have been suggestions of familial aggregation and racial differences which support the notion that sarcoidosis may occur preferentially in genetically susceptible hosts. For example, siblings of those affected with sarcoid have a modestly increased disease risk with an odds ratio of about 5. A genome-wide scan performed in German families with sarcoidosis has yielded a possible susceptibility gene on chromosome 6, called BTL2, which is a B7-family costimulatory molecule involved in immune regulation. Chromosome 5 has also been identified as potentially harboring candidate genes.
The differential diagnosis of sarcoidosis in the eye is broad. It nearly always includes other granulomas and inflammatory conditions such as tuberculosis and syphilis. Other etiologies, including atypical mycobacterial infection, endophthalmitis, herpetic eye disease, and autoimmune conditions such as Vogt–Koyanagi–Harada syndrome, may appear very similar to sarcoidosis clinically.
Definitive diagnosis of sarcoidosis requires pathologic examination of biopsy tissue. The source of this tissue is rarely the eye; frequently, bronchoscopy will be used to generate diagnostic material. Mediastinoscopy may also be used for the biopsy of the hilar lymph nodes. Surface lymphadenopathy may be biopsied transcutaneously. Nondirected conjunctival biopsy has a very low yield in sarcoidosis, but biopsy of visible conjunctiva granulomas may be an expeditious way for the ophthalmologist to make this diagnosis. Lacking tissue diagnosis, several laboratory tests may provide supportive (but not definitive) evidence for this diagnosis. Historically, the Kveim–Siltzbach test was used in the diagnosis of sarcoidosis. In this test, a standardized extract from the spleen of a patient with sarcoidosis was injected subcutaneously into an individual suspected of having sarcoidosis. Several days later, formation of a granuloma at the site of injection is suggestive of the recipient patient having sarcoidosis. This test is no longer used clinically, but has important implications for the pathophysiology of sarcoidosis (see below). The serum angiotensin-converting enzyme (ACE) level is frequently elevated in patients with sarcoidosis. The positive and negative predictive values of this test for the disease, however, are relatively low, of the order of 83% and 58%, respectively. Gallium-67 uptake scanning has been utilized in a number of studies and may be relatively specific for sarcoidosis, particularly if the “panda sign” is seen. This sign refers to the take-up of gallium by the lacrimose glands, parotid glands, and sinuses, resulting in an image of the face resembling a panda. The combination of elevated ACE level and positive gallium scan is thought to have a positive predictive value in excess of 95%. Elevated serum calcium and serum lysozyme have also been suggested as markers for systemic sarcoidosis but have low positive and negative predictive values. Definitive diagnosis of sarcoidosis always requires tissue biopsy.
Ocular sarcoidosis is typically treated with corticosteroids. Anterior disease is often responsive to topical or periocular medication alone. Posterior-segment disease frequently requires oral corticosteroids. As sarcoidosis may be chronic, this may require substitution of steroid-sparing medications for corticosteroids after several weeks. Methotrexate has been used in a number of studies and appears efficacious for this task. Additionally, tumor necrosis factor-α inhibitors may have good efficacy for the treatment of sarcoidosis.
Few data exist on the overall prognosis of patients with ocular sarcoidosis. Most cases are relatively easily treated, but a subset of patients may permanently lose vision from either the sarcoid granulomas themselves (i.e., optic nerve head granulomas or submacular granulomas), or complications secondary to chronic uveitis, such as a cystoid macular edema.
Granulomatous inflammation is a distinctive pattern of chronic inflammatory infiltrate in which the predominant cell type is an activated macrophage. A granuloma is a microscopic focus of inflammation characterized by a collection of modified epithelial-like (epithelioid) macrophages ( Figure 84.3 ). The epithelioid macrophage contains pale pink granular cytoplasm with indistinct cell membranes. Frequently epithelioid macrophages may fuse to form giant cells (40–50 µm) with multiple nuclei ( Figure 84.4 ). The pathologic diagnosis of sarcoidosis requires the histologic identification of epithelioid granulomas within involved tissue and the exclusion of known causes of granulomatous disease, especially those of infectious etiology. Granulomatous inflammation is encountered in association with a variety of infectious and noninfectious agents, including mycobacterial and some mycotic, bacterial and parasitic infections, berylliosis, some types of vasculitis, and as a reaction to poorly soluble particulate matter. Even after extensive workup many granulomatous lesions remain unclassified.