Anita G. Prasad,
Daniel Wee,
Russell N. Van Gelder
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Overview |
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Sarcoidosis is a multiorgan inflammatory disease of unknown etiology that is a frequent cause of ocular inflammation. The histologic hallmark of disease is the noncaseating granuloma. Posterior segment findings include vitritis, choroiditis, vasculitis, retinal ischemia, and retinal neovascularization. The differential diagnosis for sarcoidosis is broad; defiitive diagnosis requires biopsy, although certain laboratory tests such as CT scanning, gallium scanning, and ACEs have adjunctive diagnostic value. Treatment requires corticosteroid medications and/or immunomodulation, and frequently requires systemic treatment, particularly if organs besides the eye are involved. |
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Key Features |
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Sarcoidosis is a chronic, multiorgan inflammatory disease of unknown etiology. Sarcoidosis can be a very frustrating disease for the patient and clinician alike. The pathogenesis of the disease is largely unknown, risk factors for its acquisition are not well understood, its clinical manifestations are protean, clinical diagnosis is challenging, treatments are nonspecific, and prognosis is variable. As sarcoidosis is a relatively common cause of uveitis (in both the anterior and posterior segment), it belongs on the differential diagnosis in many cases. It is important for the clinician to be aware of the varied clinical appearances of sarcoidosis and to be facile with the diagnostic workup and management of this disease.
EPIDEMIOLOGY
The incidence and prevalence of sarcoidosis vary markedly with geographic location. Because strict diagnostic criteria are not always followed in epidemiologic studies of sarcoidosis, accurate estimates of disease rates are not available. Older data from the United States suggest an annual incidence in African-Americans of 82 per 100000 person-years, compared with 8 per 100000 person-years in the Caucasian population.[1] It is believed that Latino-Americans are more commonly affected than Caucasians. The disease is also common in northern Europe, with an incidence of 20 per 100000 in the United Kingdom, and 24 per 100000 in Sweden.[2] There is no firm consensus on the relative rates of disease between the genders; some studies have suggested a female preponderance up to 2:1, while others report equal incidence between the genders. The disease is most typically diagnosed in the third decade.[2]
Several studies have attempted to identify risk factors for development of sarcoidosis. The predominant risk factor in the Isle of Man study was living in close proximity to an individual with known sarcoidosis.[3-6] Husband-wife pairs with disease have been identified frequently. There is a familial association in first- and second-degree blood relatives as well, although this appears stronger in Caucasian cases than in African-American cases.[7] Nurses have a sevenfold higher lifetime risk of sarcoidosis than the average population.[8] These findings suggest a transmissible agent responsible for at least triggering, if not causing, chronic disease. Consistent with this, organ transplantation studies have suggested that the disease may be transferred with diseased organs.[9-11] In one study, an individual with a known history of sarcoidosis served as a bone marrow donor for his brother, who did not have disease. Despite aggressive immunomodulation post-transplant, the sibling developed sarcoidosis within several weeks of the transplant. Sarcoidosis has also been associated with cardiac transplantation from an affected donor. Interestingly, sarcoid-positive recipients typically redevelop disease in naïve organs.[12] The estimated rate of redevelopment of pulmonary sarcoidosis in lung transplant recipients is close to 80%.
Several candidate pathogens have been proposed as causative for sarcoidosis. L-form mycobacteria are cell wall-less bacteria that have been found in a subset of lymph nodes affected with sarcoidosis[13]; myobacterial DNA has been detected sporadically in lymph nodes from confirmed sarcoidosis cases as well.[14,15] Other studies have suggested an association with human herpes virus 8 (HHV-8) with sarcoidosis in Europe,[16] although this association has not been confirmed in several other populations.[17,18] Most recently, members of the genus Propionibacterium, particularly Propionibacterium granulosum, have been found with high frequency in lymph node biopsies of patients with proven sarcoidosis.[15,19] To date, however, Koch's postulates have not been fulfilled for any infectious organism in sarcoidosis.
In addition to sporadic cases, familial variants of sarcoidosis (with juvenile onset) are well documented. Blau syndrome is a multisystem granulomatous disease presenting in childhood. Unlike sarcoidosis, Blau syndrome typically spares the lungs; however, uveitis can be a presenting complaint and the clinical appearance of Blau syndrome can be identical to sarcoidosis. Patients will often present with juvenile arthritis. Recently, Blau syndrome has been shown to be due to mutations in CARD15/NOD2, a gene involved in regulation of inflammation and apoptosis (and also associated with Crohns' disease).[20,21]However, sarcoidosis (and in particular the uveitis associated with sarcoidosis) does not appear to be associated with these mutations.[22,23]
HISTOPATHOLOGY
The defining feature of sarcoidosis is the formation of the noncaseating granuloma (Fig. 171.1). These granulomas may be found in nearly any organ of the body, but typically target the lungs, thoracic lymph nodes, skin, and eyes. The granulomas are predominantly composed of epithelioid multinucleated giant cells, which are essentially aggregated macrophages. The predominant lymphocytic cell type is the CD4+ T-cell, which is found in the periphery of the granuloma. Smaller numbers of CD8+ T-cells and B-cells are also present within the granuloma. The histopathology is consistent with an exaggerated immune response in target organs. The predominant inflammatory response is Th1 mediated, with a preponderance of interferon gamma and interleukin-2, as well as production of tumor necrosis factor and interleukin-6 by macrophages. Progression of granulomas culminates in tissue damage, fibrosis, and end organ destruction.
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FIGURE 171.1 Sarcoid granulomas in the choroids from an enucleated eye. |
The noncaseating granuloma is not specific for sarcoidosis, however. Noncaseating granulomas can also be seen in response to hypersensitivity pneumonitis (including berylliosis, asbestosis, or silicosis), mycobacterial infections, or fungal infection. Diagnosis is considered defiitive when the noncaseating granuloma is seen in the setting of characteristic clinical findings.
SYSTEMIC CLINICAL FINDINGS
Sarcoidosis can affect nearly any organ in the body. The lung is the most frequently involved organ, with greater than 90% of patients affected. The next most commonly affected organs include the lymph nodes, skin, eyes, and liver, each affected in approximately one-quarter of patients.[24] Pulmonary findings range from asymptomatic discovery on routine chest radiograph, to severe pulmonary fibrosis and restrictive lung disease. A standardized staging scheme is employed in the reading of chest radiographs of patients with sarcoidosis. Bilateral hilar adenopathy constitutes stage 1 disease. Parenchymal involvement with hilar adenopathy defies stage 2; in stage 3 disease, parenchymal involvement is seen without hilar adenopathy. In stage 4 disease, pulmonary fibrosis is seen, which may be accompanied by bronchiectasis.
The skin is involved in an estimated 18-32% of cases. The most typical skin lesion is erythema nodosum. These are typically elevated red lesions often found on the lower extremity (such as the shins). These are a nonspecific fiding and can be identified in a number of hypersensitivity conditions. Since these lesions do not contain granulomas, it is not worthwhile to biopsy them to make a diagnosis; biopsy will typically demonstrate septal panniculitis.
Central nervous system sarcoidosis occurs in ~5% of patients with systemic sarcoidosis, and is most commonly associated with cranial neuropathy, which may be multiple or bilateral. Facial nerve involvement is most common. Optic neuropathy occurs in ~3% of patients with systemic sarcoidosis. Rarely, more generalized aseptic meningitis may be the presenting sign of sarcoidosis.
In addition to these chronic presentations of sarcoidosis, the disease can occasionally present acutely. Lofrgren syndrome is characterized by acute fever, arthralgias, erythema nodosum, and bilateral hilar adenopathy. Heerfordt-Waldenström syndrome (also called uveo-parotid fever) is the combination of fever, parotid enlargement, and uveitis.
RETINAL INVOLVEMENT
In most studies, the eye is reported to be involved in ~20-25% of cases of sarcoidosis,[25] although some studies suggest rates as high as 60%. Of those patients with ocular involvement, posterior segment disease is thought to occur in ~25%.[26] Sarcoidosis is thought to be responsible for between 4% and 8% of uveitis cases in referral centers.[27,28] Ocular involvement may be the initial manifestation of sarcoidosis, and patients may present with classic uveitic symptoms of redness, pain, photophobia, floaters, or scotomas, or they may be asymptomatic.[29,30] There are no specific signs unique to the eye; the disease can present in the anterior segment, as intermediate uveitis, in the posterior pole, or as panuveitis. Although posterior segment disease is typically associated with anterior segment inflammation, retinal findings may occur in isolation. Anterior segment disease can present as nongranulomatous or granulomatous inflammation. The latter is typified by large, 'mutton fat' keratic precipitates as well as iris nodules. Posterior synechia are commonly seen. The anterior segment can show significant ciliary flush or conjunctival injection; it can also be relatively quiet even with active anterior segment disease.
The most common posterior segment findings in sarcoidosis are vitritis, choroidal punched-out lesions, snowball lesions, cystoid macular edema, periphlebitis, and epiretinal membrane.[29] In cases associated with ischemia, neovascularization can develop. Isolated or optic nerve granulomas are also typical of the disease.
The intermediate uveitis associated with sarcoidosis can be isolated, or can be associated with punched-out choroidal lesions or retinal granulomas. Approximately 10% of sarcoidosis presents as an isolated intermediate uveitis,[31] and this entity must be considered in the differential diagnosis of isolated intermediate uveitis.
The choroidal lesions are often the principal posterior segment fiding in sarcoidosis. The lesions may be large, isolated granulomas (Fig. 171.2), or can be small, clustered yellowish lesions (Fig. 171.3). The lesions are most commonly found in the inferior equatorial retina. By themselves, these lesions rarely lead to visual dysfunction unless they are localized to the macula. They may be associated, however, with panuveitis, vitritis, or cystoid macular edema. Angiographically, the lesions will typically show early blockade of fluorescence, with late staining, typical of inflammatory lesions in the posterior pole. Resolved lesions may show only RPE window defects (Fig. 171.4). With treatment, choroidal granulomas secondary to sarcoidosis can resolve completely, without pigment epithelial change; however, chronic lesions may show evidence of scarring (Fig. 171.4). Rarely, sarcoidosis lesions may resemble serpiginous choroiditis lesions.[32]
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FIGURE 171.2 Resolving solitary choroidal granuloma in a patient with sarcoidosis. |
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FIGURE 171.3 Multiple small granulomas associated with sarcoidosis. |
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FIGURE 171.4 (a,b) Inactive peripheral choroidal lesions with window retinal pigment epithelial defects secondary to sarcoidosis. |
Retinal vasculitis may be the predominant fiding in sarcoidosis involving retina. Vasculitis is typically limited to the venous system, with sparing of the arteries, although arterial involvement has been reported. The location can be peripheral, or can be in the posterior pole (Fig. 171.5). Extensive perivascular exudates are called candle wax drippings or 'taches de bougies'. In severe cases, the vasculitis can lead to branch retinal vein occlusions which, in turn, may lead to ischemia and neovascularization.
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FIGURE 171.5 Circinate subretinal granulomas with focal periphlebitis (taches du bougie). |
Complications from ocular manifestations of posterior segment sarcoidosis are common. Cystoid macular edema has been noted in approximately three-fourths of patients with posterior segment sarcoidosis, cataract in about half, and glaucoma in about one-third. Retinal ischemia and neovascularization are reported to occur in 16% and 11%, respectively.[29]
DIFFERENTIAL DIAGNOSIS
The differential diagnosis for posterior segment inflammation containing features seen in sarcoidosis is remarkably broad. Isolated intermediate uveitis may be due to Lyme disease, syphilis, tuberculosis, pars planitis, multiple sclerosis, or intraocular lymphoma. Disease associated with retinal or choroidal granulomas has a similar differential diagnosis, but also includes birdshot chorioretinopathy, multifocal choroiditis with panuveitis, acute posterior multifocal placoid pigment epitheliopathy (APMPPE), cat scratch disease, toxoplasmosis, toxocariasis, Vogt-Koyanagi-Harada syndrome, sympathetic ophthalmia, brucellosis, Whipple's disease, and ocular candidiasis. With marked phlebitis, collagen vascular diseases (including Wegener's granulomatosis, systemic lupus erythematosus, Behcet's disease, Eales' disease, and frosted branch angiitis) should also be considered. If the patient is immunocompromised, cytomegalovirus (CMV) retinitis and other HIV-associated diseases must be considered.
LABORATORY TESTING
Unfortunately, there is no highly specific and sensitive laboratory test for the diagnosis of sarcoidosis, except for tissue biopsy. It is always worth examining the conjunctiva carefully for the presence of granulomas, which have been reported to occur in as many as 40% of sarcoidosis patients.[26] In older patients with either chest radiograph abnormalities or elevated angiotensin converting enzyme (ACE) levels, the yield on nondirected conjunctival biopsy may exceed 50%[33]; in other populations, the yield is lower.[34] Probably, the most effective means for fiding tissue to make a defiitive biopsy is performing CT scan of the chest; in one recent series of elderly women with uveitis typical for either sarcoidosis or lymphoma, 57% had hilar adenopathy on CT scan, and 82% of these were found to have sarcoidosis on biopsy or bronchoscopy. However, before commencing with this test, one should consider carefully whether one is prepared to follow the CT with bronchoscopy or mediastinoscopy; in many cases, it may not be essential to make a defiitive diagnosis in order to guide therapy.
The ACE test measures serum levels of the hydrolase enzyme involved in blood pressure regulation. It is present on the luminal surface of vascular endothelial cells, as well as in cells of the macrophage-monocyte system. The ACE level is thought to be a measure of total granuloma load on the body. The test, unfortunately, is neither highly sensitive nor highly specific. Sensitivity varies in different studies between approximately 40% and 80%.[35-38] The specificity is somewhat higher, and has been estimated to be as high as 90%. This yields a positive predictive value for an elevated ACE level of ~84-90%. However, negative predictive values are very poor. In addition, patients who are taking ACE inhibitors will have depressed levels, as will patients who are already on anti-inflammatory (such as corticosteroid) treatment. Other diseases to consider in the setting of elevated ACE level include miliary tuberculosis, atypical mycobacterial infections, asbestosis and silicosis, primary biliary cirrhosis, and hyperthyroidism.
A number of other tests have been advocated for the diagnosis of sarcoidosis, including serum lysozyme, serum calcium, and cutaneous anergy. All suffer from low sensitivity and specificity. Human Leukocyte Antigen (HLA) typing is not useful in the diagnosis of sarcoidosis, although weak disease susceptibility has been associated with HLA-B8 and HLA-DRB1.[39-41] Gallium scanning measures the uptake of gallium-67, which localizes to areas of active inflammation. This may be useful in distinguishing lymphoma from sarcoidosis; in the former, peripheral lymph node uptake is increased, while in the latter bilateral hilar uptake is noted. The fiding of increased uptake in the lacrimal and parotid glands (the panda sign) has been seen between 60% and 87% of the time in sarcoidosis patients.[35,36] Specificity is relatively high. The combination of a positive gallium scan and elevated ACE level has high specificity (>90%) for sarcoidosis; however, this does not serve as a substitute for tissue biopsy for defiitive diagnosis.
The older literature refers to the Kveim-Siltzbach reaction.[42] In this test, intradermal injection of a tissue suspension derived from the spleen of a sarcoidosis patient results in local development of sarcoid granuloma. The lesions typically form 2-6 weeks after injection. The inciting antigen in this preparation is unknown. The test is not used in routine clinical settings.
In cases where sarcoidosis is clinically suspected, the following approach may be considered. First, common or medically threatening conditions with similar clinical appearances are ruled out. This will typically involve placing a PPD and obtaining a chest radiograph for evaluation of tuberculosis, testing FTA-ABS and/or RPR for syphilis, and possibly other serologic or blood tests for specific infections such as Lyme disease, toxoplasmosis, or toxocariasis. A careful examination for conjunctival granulomas or enlarged lacrimal gland should be performed; if found, this may be the easiest site for biopsy. If this workup is negative, consideration may be given to chest CT to identify hilar adenopathy; alternatively, ACE and gallium scanning may be performed (although the negative predictive value for such testing may be limited). In the setting of abnormal ACE or gallium scan, a nondirected conjunctival biopsy may be acquired.
If a diagnosis of sarcoidosis is made in the setting of positive chest radiograph, positive chest CT, or positive review of systems for shortness of breath or chronic cough, consideration should be given to obtaining pulmonary function tests. Given a positive workup, a complete blood count and comprehensive metabolic panel including hepatic and renal function tests should be obtained, both to seek possible signs of systemic sarcoidosis and to help tailor therapy.
Specific ocular testing may be required to fully characterize the ophthalmic manifestations of disease. Fluorescein angiography and optical coherence tomography may be of great value in characterizing and following cystoid macular edema. Angiography can also indicate areas of occult vasculitis, and can demonstrate optic nerve head leakage. ICG angiography reveals several potential patterns of choroidal disease, including focal hypo- and hyperfluorescence and late choroidal vessel leakage which are relatively nonspecific but may be useful in following disease activity.[43,44]
TREATMENT
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Treatment Options |
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In initiating therapy for posterior segment sarcoidosis, the primary consideration is whether the patient has systemic involvement warranting treatment; this will dictate whether the first approach must include systemic medication. Typically, pulmonologists will not treat stage 1 disease but will treat stage 2 or higher disease. The mainstay of treatment of sarcoidosis is corticosteroid therapy; for posterior segment disease, the treatment options include systemic administration, periocular injection, and intraocular administration. For bilateral or sight-threatening disease, systemic corticosteroids are frequently employed, unless the patient has absolute contraindications to this treatment (such as brittle diabetes or severe psychiatric disease). Cycloplegia should be employed to reduce the risk of posterior synechia formation.
With rare exceptions, posterior segment sarcoidosis will not respond to topical medication; however, topical corticosteroids are a mainstay of treatment for the anterior segment inflammation that often accompanies posterior segment inflammation. Periocular corticosteroids (typically triamcinolone acetonide admin istered 20-40 mg either applied beneath Tenon's capsule or retroseptally through inferior or superior approaches) offer the benefits of sustained continuous release and high intraocular concentrations. However, this approach is associated with iatrogenic cataract formation, steroid responsive ocular hypertension, cosmetic concerns, and rarely injury to the globe or its circulation. Recently, intravitreal corticosteroid administration has been used in small numbers of patients for the treatment of refractory cystoid macular edema and isolated choroidal granulomas associated with sarcoidosis, with encouraging short-term results.[45,46] The recently approved fluocinolone acetonide intravitreal implant releases a constant dose of corticosteroid intraocularly for over 2 years, and may be appropriate for patients with chronic posterior segment inflammation.[47,48]
As sarcoidosis is typically a chronic condition, patients will frequently require long-term treatment, which may require initiation of treatment with steroid sparing agents. All classes of immunomodulatory drugs, including antimetabolites (methotrexate, mycophenolate mofetil, and azathioprine), anti-T-cell activation factors (cyclosporine A, tacrolimus), biologics (infliximab and adalimumab), and alkylating agents (cyclophosphamide and chlorambucil), have been utilized.[49-51] Unfortunately, no well-controlled prospective clinical trials on the efficacy of these treatments has been performed to date.
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