Sarcoidosis is a multisystem granulomatous disorder of unknown etiology with protean systemic and ocular manifestations. Although pulmonary manifestations are most common (90%), other sites frequently involved include the lymph nodes, skin, eyes, CNS, bones and joints, liver, and heart. Ocular involvement may be present in up to 50% of patients with systemic disease, and uveitis is the most frequent manifestation. In most large series, sarcoidosis accounts for up to 10% of all cases of uveitis. The basic lesion of sarcoidosis is a noncaseating granuloma without histologic evidence of infection or foreign body (Fig 9-41). See BCSC Section 4, Ophthalmic Pathology and Intraocular Tumors, for a more detailed description of the pathology of sarcoidosis.
Sarcoidosis has a worldwide distribution and affects all ethnic groups; the highest prevalence is in the northern European countries (40 cases per 100,000 people). In the United States, the disease is up to 20 times more prevalent among African Americans than whites. Both sexes are affected, albeit with a slight female predominance. Although onset usually occurs between the ages of 20 and 50 years, sarcoidosis is also an important diagnostic consideration in older patients. In a recent review, sarcoidosis was a common cause of newly diagnosed uveitis among patients ages 60 years and older. Patients with late-onset sarcoidosis may be more likely to have uveitis and less likely to have asymptomatic chest radiograph abnormalities than younger patients with the disease.
Pediatric involvement is uncommon, and the clinical course is atypical. Children with early-onset sarcoidosis (younger than 5 years) are less likely than adults to manifest pulmonary disease and far more likely to have cutaneous and articular involvement; the disease course in older children (8–15 years) approximates that in adults.
Figure 9-41 Sarcoidosis. Histologic view of conjunctival biopsy. Note the giant cells and granulomatous inflammation.
Although numerous environmental, infectious, and genetic factors have been implicated in causing the disease, no single etiologic agent or genetic locus has been clearly identified in the pathogenesis of sarcoidosis. For instance, the ACCESS (A Case Control Etiologic Study of Sarcoidosis) project suggested that exposure to microbe-rich environments may modestly increase the risk of developing sarcoidosis; however, no dominant factor could be determined. Molecular studies of tissue specimens provide evidence suggesting that mycobacteria and, less convincingly, propionibacteria may be important etiologic factors. A genetic predisposition for the disease is suggested by familial clustering; siblings of patients have a fivefold-increased risk of developing the disease.
Systemic sarcoidosis may present acutely, frequently with associated anterior uveitis in young patients, and spontaneously remit within 2 years of onset. One form of acute sarcoidosis, called Löfgren syndrome, consists of erythema nodosum, febrile arthropathy, bilateral hilar adenopathy, and acute iritis. This syndrome is quite responsive to systemic corticosteroids and has a good long-term prognosis. Another, termed Heerfordt syndrome (uveoparotid fever), is characterized by uveitis, parotitis, fever, and facial nerve palsy. Chronic sarcoidosis presents insidiously and is characterized by persistent disease of more than 2 years’ duration, frequently with pulmonary involvement and chronic uveitis. Extended corticosteroid therapy may be required. Pulmonary disease is the major cause of morbidity; overall mortality from sarcoidosis approaches 5% but may be as high as 10% with neurosarcoidosis.
Sarcoidosis can affect any ocular tissue, including the orbit and adnexa. Cutaneous involvement is frequent, and orbital and eyelid granulomas are common (Fig 9-42). Palpebral and bulbar conjunctival nodules may also be observed and provide a readily accessible site for tissue biopsy (Fig 9-43). Lacrimal gland infiltration may cause dacryoadenitis and keratoconjunctivitis sicca.
Figure 9-42 Sarcoidosis. Skin lesions.
Figure 9-43 Sarcoidosis. Conjunctival nodules.
Anterior uveitis, presenting either acutely or as a chronic granulomatous uveitis, is the most common ocular manifestation, occurring in approximately two-thirds of patients with ocular sarcoidosis. Symptoms of uveal involvement are variable and frequently include mild-to-moderate blurring of vision and aching around the eyes. Typical biomicroscopic findings include
mutton-fat keratic precipitates (KPs; Fig 9-44), including those involving the anterior chamber angle
Koeppe and Busacca iris nodules at the pupil margin and in the iris stroma, respectively (Fig 9-45)
white clumps of cells (“snowballs”) in the anterior vitreous, typically settling inferiorly
Although the cornea is infrequently involved, nummular corneal infiltrates and inferior corneal endothelial opacification may be present; band keratopathy may develop as a result of either chronic uveitis or hypercalcemia. Large iris granulomas may also be noted. Extensive posterior synechiae may lead to iris bombé and angle-closure glaucoma. Peripheral anterior synechiae may also be extensive, encompassing the entire angle in advanced cases. Secondary glaucoma, together with sarcoid uveitis, may be severe and portends a poor prognosis with associated severe vision loss.
Posterior segment manifestations occur in up to 20% of patients with ocular sarcoidosis. Vitreous involvement is common and often presents as clumps of snowballs with or without diffuse cellular infiltration. Vitreous cells may also form linear strands known as “strings of pearls.” Nodular granulomas measuring from ¼ to 1 disc diameter may be present on the optic nerve, in both the retina and the choroid, either posteriorly or peripherally (Fig 9-46). Perivascular sheathing is also common, appearing most commonly as either a linear or segmental periphlebitis (Fig 9-47). Retinal artery macroaneurysms can occur. Irregular nodular granulomas along venules have been termed candlewax drippings or taches de bougie. Occlusive retinal vascular disease, especially branch retinal vein occlusion and, less commonly, central retinal vein occlusion, together with peripheral retinal capillary nonperfusion, may lead to retinal neovascularization and vitreous hemorrhage. Macular edema is frequently present, and optic disc edema without granulomatous invasion of the optic nerve may be observed in patients with papilledema and neurosarcoidosis. In addition, sarcoidosis may be associated with an inflammatory optic neuropathy, with or without concurrent intraocular inflammation.
Figure 9-44 Sarcoidosis with keratic precipitates and anterior uveitis.
Figure 9-45 Sarcoidosis. Iris nodules (Koeppe and Busacca nodules).
Figure 9-46 Fundus photograph showing numerous retinal and choroidal nodular granulomas, perivasculitis with candlewax drippings, and vitritis in a patient with sarcoidosis-associated posterior segment involvement.
(Courtesy of Albert T. Vitale, MD.)
Figure 9-47 Sarcoidosis. Fundus photograph showing retinal vascular sheathing.
Acharya NR, Browne EN, Rao N, Mochizuki M; International Ocular Sarcoidosis Working Group. Distinguishing features of ocular sarcoidosis in an international cohort of uveitis patients. Ophthalmology. 2018;125(1):119–126.
Kidd DP, Burton BJ, Graham EM, Plant FT. Optic neuropathy associated with systemic sarcoidosis. Neurol Neuroimmunol Neuroinflamm. 2016;3(5):e270.
Given its heterogeneous presentation, sarcoidosis should be considered in the differential diagnosis of any patient presenting with intraocular inflammation. Early-onset sarcoidosis in children (5 years of age or younger) must be differentiated from JIA-associated anterior uveitis and from familial juvenile systemic granulomatosis (Blau syndrome), given the overlap of ocular and articular involvement. Familial juvenile systemic granulomatosis, an autosomal dominantly inherited syndrome with 100% phenotypic correspondence to mutations in the NOD2 gene (also known as CARD15), may produce ocular disease that is virtually identical to sarcoidosis and should be suspected in patients with a family history of granulomatous disease.
Chest radiograph abnormalities are present at some point in up to 90% of sarcoid patients, but these abnormalities do not persist throughout the disease course and thus may be absent at the time of workup. High-resolution chest computed tomography is a more sensitive imaging modality and may be particularly valuable in patients with a normal appearance on chest radiograph but for whom a high clinical index of suspicion remains; the risk of increased radiation must be weighed against the clinical utility of the information gained in such cases.
Although the serum angiotensin-converting enzyme (ACE) and lysozyme levels may be abnormally elevated, neither result is diagnostic nor specific; rather, they are reflective of total-body granuloma content and, as such, may be useful in tracking active disease. (Note that the ACE levels may be artificially low in patients taking ACE-inhibitor medications.) Other laboratory evaluations that may have utility include serum and urinary calcium levels and liver function tests; they are not specific for sarcoidosis but may suggest more widespread involvement in patients likely to have the disease.
Gallium scanning has been used to check for occult disease activity, but it has limited sensitivity. Fluorine-18-fluorodeoxyglucose positron emission tomography is considered more accurate in pulmonary and extrapulmonary sarcoidosis, but its utility in ophthalmic sarcoidosis is not well defined. The finding of mononuclear alveolitis with increased CD4+ lymphocytes, as revealed by bronchoalveolar lavage, can also help support the diagnosis.
The traditional approach for suspected ophthalmic involvement with sarcoidosis is to obtain a chest radiograph, possibly along with ACE and lysozyme levels. The additional tests mentioned above can then supplement the workup, depending on the degree of suspicion and/or preference of the managing physician.
Ultimately, the diagnosis of sarcoidosis is made histologically from tissue obtained from the lungs, mediastinal lymph nodes, skin, peripheral lymph nodes, liver, conjunctiva, minor salivary glands, or lacrimal glands. Readily accessible and clinically evident lesions (such as those on the skin, palpable lymph nodes, and nodules on the conjunctiva) should be sought for biopsy, because they are associated with a high yield and low morbidity and may obviate the need for more invasive transbronchial biopsy.
Currently, there is no gold standard for diagnosing ocular sarcoidosis. Diagnostic criteria for ocular sarcoidosis were proposed in an international workshop of ophthalmologists in 2009. These criteria consist of diagnostic grades ranging from “definitive” (based on tissue biopsy), to “presumed” (based on typical ocular findings in combination with bilateral hilar adenopathy), to “probable” or “possible” disease (with supporting ancillary evidence). When these criteria were evaluated using a large group of patients with uveitis, there was no clinical sign or test that was highly sensitive in the diagnosis of sarcoidosis, with the exception of bilateral hilar adenopathy; in fact, a large percentage (40%) of clinician-suspected cases did not meet any of the criteria.
Topical, periocular, and systemic corticosteroids are the mainstays of therapy for ocular sarcoidosis. Cycloplegia is useful for comfort and prevention of synechiae. Vision-threatening posterior segment disease generally requires, and is responsive to, systemic corticosteroids. Intravitreal corticosteroids, including the fluocinolone acetonide and dexamethasone implants, are potential treatment options for patients intolerant of systemic therapy, but they do not treat systemic disease.
Systemic IMT with methotrexate, azathioprine, mycophenolate mofetil, or cyclosporine can provide good control of the disease while minimizing the risks of long-term corticosteroid therapy. The TNF-α inhibitors infliximab and adalimumab have been shown to be effective in the treatment of sarcoidosis-associated uveitis. Paradoxically, the TNF-α inhibitor etanercept has been reported to cause a sarcoid-like syndrome in some patients. The likelihood of significant visual improvement is substantially increased with systemic therapy; patients with chronic vision-threatening sarcoidosis seem to respond better to IMT than to management with intermittent local or systemic corticosteroids.
Prognostic factors associated with vision loss in patients with ocular sarcoidosis include chronic intermediate or posterior uveitis, glaucoma, and a delay in presentation to a uveitis specialist of more than 1 year.
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Excerpted from BCSC 2020-2021 series: Section 9 - Uveitis and Ocular Inflammation. For more information and to purchase the entire series, please visit https://www.aao.org/bcsc.