The primary organ affected by sarcoidosis is the lung, with up to 95 % of patients demonstrating involvement by chest X-ray [1]. X-ray findings have been classified into five categories by the modified Scadding system [9]. Stage zero patients have no evidence of hilar adenopathy or pulmonary infiltrate. Stage 1 disease shows bilateral hilar lymphadenopathy without pulmonary infiltration. Stage 2 shows bilateral hilar lymphadenopathy with pulmonary infiltration. Stage 3 patients demonstrate just pulmonary infiltration without hilar lymphadenopathy, and Stage 4 patients demonstrate evidence of pulmonary fibrosis. Prognostic information can be gained by scoring pulmonary involvement, with 90 % of Stage 1 patients entering disease remission within 2 years of diagnosis, while 30 % or less of patients with stage III disease will enter remission. Overall half of patients with systemic sarcoidosis will experience remission within 3 years of diagnosis with two-thirds experiencing remission by 10 years [10]. However, one-third of patients will have persistent, progressive disease that can lead to significant organ damage and functional impairment. Fortunately, the disease is only rarely fatal with <5 % mortality, usually as a result of pulmonary fibrosis, cardiac, or neurologic involvement [10].

Skin involvement is also common, occurring in 25–35 % of patients [10]. Erythema nodosum only occurs in about 10 % of patients, but is a classic rash that can present as part of Lofgren’s syndrome (Erythema nodosum, fever, arthralgias, and bilateral hilar lymphadenopathy). Lupus pernio is another distinctive sarcoid-associated rash that appears as indurated violaceous lesions on the nose, cheeks, lips, and ears. Other less specific skin findings include macules, papules, and plaques on the trunk and extremities. When present, skin findings provide good tissue to biopsy for diagnostic histology.

Almost any tissue can be affected in sarcoidosis, and many patients will present with clinical involvement of the liver (11 %), central nervous system (5 %), the parotid gland (4 %), the bone marrow (4 %), or within the heart (2 %) [1]. On autopsy, more widespread organ involvement can be documented. Some organ systems will manifest simultaneous involvement as part of well-described acute clinical syndromes. The eye is involved in the acute presentation known as Heerfordt’s syndrome with uveitis, fever, parotid gland enlargement, and cranial nerve palsies. The potential for widespread and variable organ involvement in sarcoidosis emphasizes the importance of a good review of systems and complete exam in patients with this disease.

Sarcoidosis is found throughout the world, but prevalence and typical presentation can vary by region and ethnicity [11]. The highest incidence is reported in Finland at 28 cases for 100,000 people. In comparison, Japan has the lowest reported incidence of 3.7 cases per 100,000 people [12]. In the United States, African Americans are affected three times more often than Caucasians, and are more likely to develop chronic disease [13].

Most patients will present in their third or fourth decade, and most are diagnosed before the age of 50 [10]. Peak incidence is around age 30, but sarcoidosis can present at any age. While older children and adolescents typically present with a similar array of organ involvement as seen in adults, pediatric patients with the early onset form of the disease present more commonly with joint involvement [14]. Blau–Jabs syndrome, which presents with granulomatous arthritis, uveitis, and dermatitis, is a familial form of early onset sarcoidosis due to mutations in the CARD15/NOD2 gene [15].

Differences in ocular disease prevalence have also been identified in association with gender, race, and geographic location [4, 11, 16, 17]. Reports of ocular involvement in systemic sarcoidosis range widely from <10 % in Finland [18], to 12–80 % in the United States [1, 2, 7, 19], 27–50 % in England [20, 21], 41 % in the Netherlands [4], and to 50–80 % in Japan [18, 22]. Ocular involvement has different definitions in these studies, and prevalence rates exceeding 50 % usually reflects the inclusion of keratoconjuctivitis sicca as a manifestation of ocular sarcoidosis. Ocular involvement can also be influenced by race and gender, with multiple studies identifying an increased risk for eye involvement in women and black patients [1, 4]. A further racial predisposition toward anterior uveitis in black patients and posterior uveitis in white patients has also been described [4, 23].

The etiology of sarcoidosis remains unknown, but there is increasing evidence for an infectious or environmental trigger that in susceptible populations leads to the characteristic chronic granulomatous inflammatory response [24]. Possible infectious agents vary by population with nontuberculosis mycobacterial exposure linked to patients in North American and Europe, while Propionibacterium has been linked with Japanese cases [25]. An infectious agent is also implicated by the transmission of sarcoidosis from affected donors to previously unaffected patients undergoing bone marrow [26, 27] and cardiac [28] transplantation. The case for mycobacterial exposure is strongly support by the results of biochemical exploration of the Kveim reagent. This reagent was used in the Kveim-Siltzbach test, a historical clinical test for sarcoidosis. The test utilized a protease resistant extract of spleen or lymph node tissue from patients with known sarcoidosis. This extract was injected subcutaneously into patients with suspected sarcoidosis. A positive test consisted of a granulomatous reaction occurring at the injection site [29]. Within the insoluble and protease resistant fraction of the Kveim reagent, mycobacterial catalase was identified [30]. Subsequent studies found that a significant number of sarcoidosis patients demonstrate a specific immune response to catalase peptides, supporting a role for mycobacterial exposure in the development of sarcoidosis [31]. Other environmental factors have also been suggested by studies identifying sarcoidosis in association with exposure to inorganic particles [32, 33], increased incidence in the spring [34], and in association with certain occupations such as metal working, firefighting, nursing, and first responders to the World Trade Center attack in 2001 [35–38].

In addition to an environmental trigger, genetic susceptibility influences disease development and pathogenesis. Case-controlled epidemiology studies, candidate gene studies, and genome wide association studies (GWAS) have identified an increased prevalence of sarcoidosis among family members as well as susceptibility and phenotype modifying gene associations [39–42]. Many susceptibility genes have a known role in immune function and regulation, most notably two HLA class II antigens HLA-DRB1 and HLA-DQB1 which have been repeatedly associated with disease [43, 44].

Genetic factors have also been implicated in influencing the ocular manifestations of sarcoidosis. Association studies have identified an increased likelihood of ocular involvement developing in the siblings of patients with known ocular disease (OR 3.0, 95 % CI 1.7–5.4) [45]. And a recent study suggests the complement factor H (CFH) polymorphism Tyrosine 402 histidine genotype may predispose to more severe posterior segment disease [40].

The immunopathologic hallmarks of sarcoidosis includes epitheliod noncaseating granulomas with activated CD4+ T cells and macrophages, a Th1 polarized cytokine response, and local tissue production of immunoregulatory cytokines such as TNF-α, IL-10, IL-12, and IL-18 [46, 47]. The stimulus for granuloma formation and maintenance in sarcoidosis is still not completely understood. However, a growing body of evidence supports a two-step model of disease [48]. The first step entails exposure to an environmental agent such as infection with a Mycobacterium or Propionibacterium species. The infection is rendered inactive by the host immune response, but clearance of certain protease resistant or other insoluble antigens is delayed and activates the characteristic sterile granulomatous response. The course of this second stage of the disease (i.e., acute vs. chronic) would then be modified by genetically encoded immune systems variations leading to the protean phenotypic manifestations.

Ocular sarcoidosis most commonly presents as uveitis. However, any part of the orbit or adnexa can be affected, and sarcoidosis should be considered in the differential diagnosis of any patient with inflammatory disease. Classic findings that suggest sarcoidosis include granulomatous or “mutton fat” keratic precipitates (Fig. 36.1), iris nodules (Fig. 36.2), vitreous snowballs, nodular segmental periphlebitis (Fig. 36.3), atrophic peripheral chorioretinal lesions (Fig. 36.4), and active granulomas of the retina (Fig. 36.5), optic nerve (Fig. 36.6), or choroid [49]. Bilateral involvement is typical (86–98 %), but involvement can be asymmetric [32, 50]. Keratoconjunctivitis sicca is an another common manifestation of ocular sarcoidosis, second only to uveitis in one case series [7], with lacrimal gland involvement described in almost one-third of patients with chronic disease [2]. A full discussion of all ophthalmic manifestations of sarcoidosis is beyond the scope of this chapter. We will focus on the intraocular and uveitic manifestations of sarcoidosis except to note that when the eyelids or conjunctiva are involved, biopsy of these structures can be an excellent and minimally invasive source of tissue for pathological diagnosis, with yields of 36–75 % [51, 52]. Nondirected biopsy, on the other hand, is of very low yield and not advised. In cases where suspicion is high, but initial biopsy results are negative, additional analysis of biopsy samples with multiplane sectioning may increase yield [53].

Most patients with sarcoid uveitis will present with symptoms such as redness, sensitivity to light, and decreased vision. However some patients with will be asymptomatic, or have minimal complaints such as floaters and ocular disease will only be identified on screening evaluation [4]. The International Workshop on Ocular Sarcoidosis (IWOS) identified seven clinical signs that are suggestive of ocular sarcoidosis (Table 36.3). These are considered characteristic, but not pathognomonic for sarcoid uveitis since they can also be found in other forms of uveitis, particularly infection with TB.

Anterior uveitis is the most common form of uveitis presenting in around two-thirds of patients. Most patients will have a single occurrence that corresponds to the initial diagnosis of systemic disease, but some patients will develop chronic anterior uveitis [2]. Granulomatous features such as mutton fat keratic precipitates (KP) or iris nodules are classic. Nodules at the papillary margin (Koeppe), on the iris surface (Busacca), and in the angle (Berlin nodules) are present during disease activity. As the peripheral granulomas resolve spontaneously or with treatment, they can form synechia to the anterior lens capsule, or tent-shaped peripheral anterior synechia (PAS) [54]. Extensive PAS and posterior synechia can lead to chronic or acute angle closure glaucoma which portends a poor visual prognosis [55]. Documentation of the new synechia and PAS can help detect episodes of disease activity between office visits, and prompt reevaluation of the treatment strategy before permanent damage has occurred.

Intermediate uveitis is a less frequent manifestation of ocular sarcoidosis (4–21 %) [7, 56], however it is important to identify and treat effectively as it can be significantly associated with decreased vision [55]. Symptomatic patients will report blurred vision or floaters with minimal pain and redness. Vitreous signs classic for sarcoid include snowballs and “strings of pearls” vitreous opacities. Intermediate uveitis can also present with segmental periphlebitis that may take on the classic appearance of “candle wax drippings” also known as “taches de bougie”. Complications of intermediate uveitis such as cystoid macular edema can occur, and can lead to permanent vision loss if untreated.

Posterior involvement is second to anterior uveitis in prevalence occurring in around a third of patients, but is associated with a higher risk for poor visual prognosis [55]. Vitritis and vasculitis are frequent findings. Involvement of the retinal venules with segmental periphlebitis is typical, but less commonly vascular involvement can be significant and include arteriolitis, aneurysm formation, and branch retinal vein occlusion with neovascularization [57, 58]. Round punched out choroidal lesions, most often in the inferior peripheral retina are common, particularly in elderly Caucasian women [59]. Posterior segment granulomas, appearing as solitary or multiple elevated whitish masses, are uncommon (~6 % of patients), but can involve the retina, choroid, and optic nerve [50].

The gold standard for diagnosis of ocular sarcoidosis requires identification of noncaseating granulomas in ocular tissue samples. However, due to the low diagnostic yield from nondirected conjunctival biopsy and the risk of morbidity associated with in intraocular biopsy, this gold standard is rarely achieved. Therefore a validated criteria based on a combination of seven clinical and five laboratory or imaging findings has been established in order provide a standardized level of diagnostic certainty for ocular sarcoidosis [49, 50]. Using the International Workshop on Ocular Sarcoidosis (IOWS) criteria for the diagnosis ocular sarcoidosis (Table 36.2), four levels of diagnostic certainty were established. The highest level of certainty “definitive ocular sarcoidosis” requires the combination of a compatible clinical presentation (Table 36.3) with a positive biopsy of any involved tissue (eye biopsy not required). Other laboratory and imaging studies have varying positive and negative predictive values for establishing the diagnosis of ocular sarcoidosis (Table 36.4), but can be used to support the lower levels of certainty in the absence of biopsy confirmation [50]. Due to the presence of lung involvement in 90 % of patients with systemic sarcoidosis, demonstration of bilateral hilar lymphadenopathy by chest X-ray or CT is considered strong support for the diagnosis of ocular sarcoidosis, and confers the diagnosis of “presumed ocular sarcoidosis.” Any evidence of pulmonary involvement should prompt further evaluation with a pulmonary specialist for pulmonary function testing and consideration of bronchoalveolar lavage and transbronchial lymph node biopsy. In the absence of hilar lymphadenopathy and without biopsy confirmation, a patient can still be diagnosed with “probable” sarcoidosis or “possible” sarcoidosis in the presence of a compatible uveitis and the specified combination of supportive ocular findings and laboratory studies.

Additional investigational tests that have been used to suggest the diagnosis of sarcoidosis including elevated angiotensin converting enzyme (ACE), elevated serum lysozyme, abnormal liver enzymes, and anergy to PPD testing [60]. None have sufficient positive or negative predictive values to definitively diagnose or rule out disease in isolation. However, in the correct clinical context two or more positive tests can support the diagnosis of “probable or possible ocular sarcoidosis.” Among these tests, serum ACE and lysozyme levels are commonly ordered despite the low sensitivity or specificity. Angiotensin converting enzyme is generated by the macrophages involved in granuloma formation, and serum ACE levels can reflect the total granuloma burden present in a systemic granulomatous disease like sarcoidosis. An elevated serum ACE can be identified in 60 % of patients with sarcoidosis [50, 60], but a normal or low ACE level does no rule out disease. ACE levels will also be lowered in patients taking ACE inhibitor medications for hypertension. Particular care needs to exercised in the interpretation of ACE levels in the pediatric population as ACE activity can be markedly increased through puberty in normal healthy children [61]. Although not included in the IWOS criteria, gallium scintigraphy in combination with serum ACE levels has been reported to have a high specificity for the diagnosis of sarcoidosis in patients with a negative chest X-ray [62]. However gallium scanning can be difficult to interpret, and a negative test does not rule out disease so it is not routinely recommended. Like ACE, lysozyme is also produced by granulomata, and can be elevated in patients with sarcoidosis. Typically elevations in lysozyme and ACE will occur together, but occasionally, patients with sarcoidosis will only demonstrate an elevation in serum lysozyme. However, once again this result is not specific for sarcoidosis, and lysozyme can also be elevated in other conditions such as leprosy, tuberculosis, acute leukemia, pernicious anemia, and osteoarthritis [60].

In addition to the above tests and considerations, two critical components in the evaluation of any patient with ocular sarcoidosis include the exclusion of other granulomatous diseases, particularly tuberculosis, and a complete examination to determine the presence and extent of any systemic involvement with appropriate subspecialty referral.

Patients with ocular sarcoidosis are at risk for vision loss from complications such as cataract, glaucoma, macular edema, retinal ischemia, and optic nerve involvement [2, 55, 56, 63]. The first goal of treatment is to control inflammation using corticosteroids. The route of delivery should be tailored to best target the anatomic location or locations of inflammation. In addition, medical management of complications including elevated pressure and cystoid macular edema (CME) should be initiated as indicated. Surgical management for complications such as cataract, vitreous opacity, CME, and advanced glaucoma requiring surgical intervention should ideally be planned after 3 months of quiescence has been achieved [64–67].

Topical therapy is generally effective for anterior segment involvement, with periocular steroids reserved for refractory cases or for treatment of any associated cystoid macular edema. For acute anterior uveitis, frequent administration, of a topical steroid is recommended until improvement in the inflammation is noted. Once improvement has been achieved (by SUN criteria [68]), topical steroids should be tapered to the minimal required to maintain quiescence. During periods of active inflammation, a cycloplegic may also be administered to reduce the development of posterior synechia and minimize photosensivity. For many patients, topical therapy will provide sufficient control for anterior disease. However, in patients with persistent inflammation and frequent (more than 4 per year) or vision threatening recurrences, systemic therapy may be needed.