Introduction

Sarcoidosis is a multisystem granulomatous disease, characterized by the presence of noncaseating granulomas in involved organs. The disease usually presents with bilateral hilar adenopathy,

C.Y. Lowder, M.D, Ph.D. ( )

Cole Eye Institute, Cleveland Clinic, 9500 Euclid Avenue I-32, Cleveland, OH 44195, USA e-mail: lowderc@ccf.org

B. da Rocha Lima, M.D.

Department of Ophthalmology, Cleveland Clinic, Cole Eye Institute, 9500 Euclid Avenue, Cleveland, OH 44195, USA

e-mail: LimaB@ccf.org

pulmonary infiltrates, and skin or eye involvement. It affects people of all racial and ethnic groups, typically developing before the age of 50 years, with a peak incidence at 10–39 years. The incidence varies widely among geographical regions, and it is highest in northern European countries (5–40 cases per 100,000 people). Sarcoidosis is approximately three times more common in black Americans than white Americans (35.5 cases per 100,000, as compared with 10.9 per 100,000). A slight preponderance of cases in women is consistent in different ethnic groups throughout the world [1].

The first case of the disease was described in 1869 at the Blackfriars Hospital for Skin Diseases

by Jonathan Hutchinson [2]. Ocular involvement in sarcoidosis was first recognized by Schumaker in 1909. In the same year, the Danish ophthalmologist Heerfordt described uveoparotid fever (Heerfordt’s syndrome), which was later characterized as a variant of sarcoidosis [3].

The eyes and ocular adnexa are involved in up to 80 % of affected patients during the course of the disease and may even predate the development of systemic signs of sarcoidosis. Uveitis precedes systemic disease in 30 % of cases. Although anterior segment involvement is more common (conjunctival granulomas, episcleritis, scleritis, nonspecific conjunctivitis, anterior uveitis), posterior segment involvement, which may include vitritis, vasculitis, choroidal lesions, and optic neuropathy, has been reported to occur in nearly 30 % of the patients with ocular sarcoidosis and may be accompanied by central nervous system (CNS) disease [4, 5].

Etiology

The etiology remains unknown, and the immune reaction in sarcoidosis is thought to be triggered by infectious organisms or exposure to environmental substances. Susceptibility to the disease also depends on genetic factors.

Exposure to irritants found in rural settings— such as tree pollen, insecticides, and emissions from wood-burning stoves—has been linked to sarcoidosis. Environmental exposure to certain elements (aluminum, beryllium, zirconium) is also thought to have a role in the pathogenesis of the disease. Several occupations have been associated with sarcoidosis, including fire fighters, metal workers, service in the US Navy, and the handling of building supplies [6, 7].

Some authors have identified antibodies to mycobacterial antigens in the serum of sarcoid patients.DetectionofDNAfromPropionibacterium acnes in lymph nodes of sarcoid patients has also been reported. Viruses, Nocardia-like organisms, have been proposed as potential causative agents [8].

Interferon-alpha, used in the treatment of different viral, autoimmune, and malignant diseases,

has been implicated to induce systemic and ocular sarcoidosis [9].

Genetic Features

Although no formal twin study has been reported, the concordance of sarcoidosis seems to be higher in monozygotic twins than in dizygotic twins [1]. A significant elevated risk of the disease has been observed among firstand seconddegree relatives of sarcoid patients, particularly in Caucasians [10].

Class I HLA-B8 antigens have been associated with sarcoidosis [11]. Several studies have also shown an association between HLA-DRB1 and the susceptibility and prognosis of the disease [12, 13].

Genes encoding for tumor necrosis factor- a(alpha) (TNF-a), interferon-g(gamma), and chemokine receptors have not been confirmed to be related to sarcoidosis [14].

Two genome scans have been reported in sarcoidosis: one in German families, reporting linkage to chromosome 6, and the other in African-Americans, reporting linkage to chromosome 5 [15].

Most investigations suggest that genetic susceptibility to sarcoidosis is complex and polygenic in nature. Future studies on large, clinically defined cohorts may help elucidate the genetic impact on sarcoidosis [16, 17].

Immunopathogenesis

Sarcoidosis is a chronic granulomatous condition characterized by the presence of noncaseating granulomas. Histologically, epithelioid cells, radially arranged, with pale-staining nuclei, enclose the inner circle. A few multinucleated cells are present, and activated T cells surround the outer border of the granuloma (Figs. 11.1 and 11.2).

There have been remarkable advances in the past few years in understanding general immunologic and molecular aspects of the mechanisms leading to granuloma formation in sarcoidosis.

Fig. 11.1 Conjunctival biopsy demonstrating noncaseating granuloma. A Langhans giant cell is present in the center of the granuloma

Fig. 11.2 Noncaseating granuloma in a patient with sarcoidosis

A cardinal feature is the presence of CD4+ T cells that interact with antigen-presenting cells to initiate the formation and maintenance of the granulomas [18]. The disease may be manifest clinically by an inverted CD4/CD8 ratio. Activated CD4+ cells differentiate into type 1 helper T cells and secrete interferon-g(gamma) and IL-2, augment macrophage TNF-a(alpha) production, and amplify the local cellular immune response. TNF receptors are also increased. There is also evidence of B cell hyperreactivity and immunoglobulin production [19, 20].

The evolution of the granuloma results from a complex interplay between diverse cells types, chemokines and cytokines. The efficiency of antigen processing, presentation, and cytokine release is probably under the influence of different genes. Sarcoidal granulomas may persist, resolve, or lead to fibrosis [20].

Diagnosis

The diagnosis of sarcoidosis may be challenging in some cases, due to the wide variety of presentations affecting different organs. A definite diagnosis is established on the basis of compatible clinical and radiologic features, supported by histological evidence of noncaseating granulomas on biopsy of involved organs. Material for biopsy can be collected from the lungs, hilar and peripheral lymph nodes, liver, skin lesions, conjunctiva, and salivary and lacrimal glands. Endoscopic ultrasound-guided, fine-needle aspiration of intrathoracic lymph nodes has been reported to provide a diagnostic yield of up to 94 % [21, 22]. In some cases, physicians rely on less invasive blood and imaging studies to obtain a presumptive diagnosis of sarcoidosis [4, 5].

Macrophages within sarcoidal granulomas produce angiotensin-converting enzyme (ACE), which has been shown to be elevated in approximately 60 % of patients with sarcoidosis. The test is not useful in patients taking ACE inhibitors. Several series have shown that measurement of ACE level alone has poor sensitivity and specificity as a diagnostic tool and is a poor therapeutic guide. Romer et al. found it to be more frequently elevated in patients with chronic active sarcoidosis (duration more than 2 years) [23, 24].

Serum lysozyme levels have been demonstrated to have better sensitivity and specificity than ACE levels. Hosoya et al. studied 125 patients with sarcoidosis, and serum lysozyme levels were elevated in 76 % of them [25].

Bilateral hilar lymphadenopathy is the most frequent radiologic finding in systemic sarcoidosis and may be found in 50–89 % of the cases by chest radiography. Chest computed tomography (CT) imaging has been shown to be helpful in patients with normal or equivocal chest X-rays (Fig. 11.3). Paratracheal, subcarinal, and periaortic lymph node chains can be completely masked by large vessels and the trachea, and lymphadenopathy may be missed by chest X-rays alone. Moreover, chest CT is useful to rule out certain conditions and to guide bronchoscopy to obtain

Fig. 11.3 Chest CT scan demonstrating paratracheal and hilar lymphadenopathy

tissue for histopathologic analysis and definite diagnosis [1, 26–28].

One of the most important conditions that may present with findings similar to ocular sarcoidosis is tuberculosis. Interferon-g(gamma) release assays, such as the QuantiFERON-Gold test, may help the clinician distinguish between the two entities [29].

An International Workshop on Ocular Sarcoidosis, held in Japan in October 2006, aimed to reach a consensus on diagnostic criteria for intraocular sarcoidosis. A group of seven signs of intraocular inflammation were labeled as signs suggestive for the diagnosis, as follows: [30]

1.Mutton-fat/granulomatous keratic precipitates and/or iris nodules (Koeppe/Busacca)

2.Trabecular meshwork nodules and/or tentshaped peripheral anterior synechiae

3.Snowballs/string of pearls vitreous opacities

4.Multiple chorioretinal peripheral lesions (active and/or atrophic)

5.Nodular and/or segmental periphlebitis and/or retinal macroaneurysm in an inflamed eye

6.Optic disk nodule(s)/granuloma(s) and/or solitary choroidal nodule

7.Bilaterality

The following investigations were considered

important to support the diagnosis of sarcoidosis in patients presenting with suggestive signs [30]:

3.Chest X-ray (presence of bilateral hilar adenopathy)

4.Abnormal liver enzyme tests

5. Chest CT scan in patients with a negative chest X-ray

The consensus conference in Japan also determined four levels of certainty for the diagnosis of ocular sarcoidosis. A prerequisite was that the diagnosis of all other causes of uveitis, particularly tuberculosis, had been excluded.

Definite ocular sarcoidosis was attributed to patients with a biopsy-supported diagnosis with a compatible uveitis.

Presumed ocular sarcoidosis was considered for patients with a compatible uveitis, whose imaging studies showed the presence of bilateral hilar adenopathy, but no biopsy was performed.

Patients who had no biopsy performed and had no evidence of bilateral hilar adenopathy on chest X-ray but presented with three suggestive intraocular signs and two supportive investigations were labeled as probable ocular sarcoidosis.

The final category, possible ocular sarcoidosis, referred to patients with a negative lung biopsy who had at least four suggestive intraocular signs and at least two positive laboratory results.

Posterior Segment Findings

Posterior segment involvement has been observed in up to 30 % of patients with ocular sarcoidosis and may be the only manifestation of the condition in 11 % of cases. Studies have not shown a relationship between the severity of radiologic grading of pulmonary disease and the degree of ocular involvement [31].

Posterior segment disease has been shown to be more common in whites. European studies have reported a higher incidence of posterior segment involvement when compared to series from the United States. This dissimilarity, however,

Fig. 11.4 Fundus photograph of the right eye showing vitritis and blurred optic disk margins due to an optic nerve granuloma

Fig. 11.5 Vasculitis and intraretinal hemorrhages

Fig. 11.6 Severe vasculitis extending to the periphery in a sarcoid patient

Fig. 11.7 Fundus photograph of the right eye demonstrating blurred disk margins and areas of segmental periphlebitis and white perivenous retinal exudates

parameters associated with a lack of visual acuity improvement (odds ratio, 8.33) [33].

According to several studies, vitritis and vasculitis are among the most common posterior segment findings (Figs. 11.4, 11.5, and 11.6). Vitreous opacities were first characterized by Landers in 1949, as grayish white bodies frequently found in the inferior vitreous and occurring in chains like a “string of pearls.” [34]

Segmental periphlebitis typically involves the midperipheral or peripheral venules, resulting in

focal vascular narrowing. In more severe cases, patients may present with waxy, yellow, or white perivenous retinal exudates, described as “candlewax drippings” or “taches de bougie” (Figs. 11.7 and 11.8). This finding, although not pathognomonic, suggests the diagnosis of sarcoidosis [35]. There are reports of occasional occurrence of occlusive retinal vascular disease, particularly branch retinal vein occlusion [36, 37].

The diagnosis of ocular sarcoidosis is particularly challenging in patients with no evidence of

Fig. 11.8 Fundus photograph of the left eye of the same patient, with similar findings

systemic disease who present with atypical findings. DeRosa et al. described a patient whose initial manifestation was a unilateral hemorrhagic retinopathy. The diagnosis of sarcoidosis in this particular patient was delayed for over a year, due to the atypical retinal findings and normal systemic work-up. Surgical enucleation of the eye once it was blind demonstrated a large noncaseating granuloma of the ciliary body, and inflammation and thrombosis of several large caliber retinal veins were found [38].

Retinal neovascularization may also be seen, particularly in the periphery. It has been reported to occur in less than 5 % of patients with ocular sarcoidosis but may be associated with prominent visual loss due to vitreous hemorrhage. The peripheral neovascular lesions may simulate a sea fan, as seen in sickle cell disease. Neovascularization of the disk may also develop, mainly in association with a branch or central vein occlusion [4, 35, 39].

Two hypotheses have been proposed to explain the etiology of the proliferative changes seen in sarcoid uveitis. One theory is based on the idea that sarcoid granuloma and inflammatory cells may infiltrate the retinal vascular walls, causing vascular occlusion and retinal ischemia, being a predisposing factor for retinal neovascularization. Another is that the development of neovascularization is accelerated by severe inflammation in the eye.

Fig. 11.9 Peripheral retinal granulomas

Duker et al. reviewed the clinical features in 11 eyes with retinal neovascularization secondary to sarcoid. In all cases, the new retinal vessels were associated with concomitant peripheral retinal capillary nonperfusion. The authors postulated that capillary nonperfusion secondary to microvascular shutdown, rather than a direct effect of inflammation, was the stimulus for the formation of retinal neovascularization [40].

Retinal arteriolitis has also been linked to sarcoidosis, resulting in weakening of the arterial wall and ectasia. Systemic arterial hypertension appears to play a role in the pathogenesis of the ectasias by increasing the pressure on the arterial wall weakened by inflammation [41, 42].

High-resolution optical coherence tomography may be useful in the documentation of retinal granulomas, which may break through into the vitreous cavity, as demonstrated by Wong et al. (Fig. 11.9) [43].

The appearance of choroidal lesions is variable, and they may mimic other conditions, such as ocular tuberculosis. Sarcoidosis may present as multifocal choroiditis, consisting of small, discrete creamy lesions in the inferior or nasal periphery (Fig. 11.10). It may also mimic birdshot chorioretinopathy with larger, posterior, pale yellow-orange streaks.

Deeper chorioretinal lesions have also been described (Figs. 11.11 and 11.12). They can vary from large choroidal nodules simulating a metastatic tumor to small “Dalen-Fuchs-like” granulomas

Fig. 11.11 Inferior atrophic choroidal lesions

Fig. 11.12 Multiple peripheral atrophic lesions in a patient with sarcoidosis

that also occur in sympathetic ophthalmia and Vogt-Koyanagi-Harada syndrome. These lesions might be vision threatening if located in the macular region.

Large nodular chorioretinal granulomas may be complicated by exudative retinal detachments, which appear to be an overlying detachment of the neurosensory retina [44]. An uncommon form of ocular sarcoidosis is a solitary choroidal granuloma (Fig. 11.13). It can simulate a choroidal neoplasm, such as amelanotic melanoma, choroidal metastasis, or lymphoma.

Watts et al. reported an unusual case of serous retinal detachment at the macula in a patient with a history of sarcoidosis, without any other ocular features [45].

Salchow and Weiss described the case of a 54-year-old Hispanic man, with biopsy-proven sarcoidosis, who was found to have multiple retinal pigment epithelium (RPE) detachments on fluorescein angiography, confirmed by optical coherence tomography. The RPE detachments were followed for several years without any treatment, and the visual acuity remained stable. It is uncertain whether the RPE detachments represented small inner choroidal granulomata, which could only be confirmed by histology [46, 47].

Optic nerve involvement, in particular granuloma of the optic nerve head, has been reported to affect up to 7 % of patients with ocular sarcoidosis.

The condition can present as papilledema, secondary to increased intracranial pressure, papillitis, optic neuritis, and optic atrophy. The involvement may also be retrobulbar or chiasmatic. In this situation, progressive visual loss and visual field defect may occur, in the setting of a normal-appearing optic disk. Disturbance in color perception and contrast sensitivity is usually seen [48–51].

Posterior uveitis in sarcoid patients has been linked to CNS abnormalities in some studies. A study by Gould in 1961 showed a much higher rate of neurosarcoidosis in patients with fundus abnormalities when compared to all patients with sarcoidosis [52–54]. However, Desai et al. did not disclose any evidence of CNS involvement by clinical examination and magnetic resonance imaging (MRI) scanning in a group of patients with choroidal granulomas. Therefore, it is unclear if routine neuroimaging should be advocated in patients with posterior segment disease [55].

Some authors have implicated cystoid macular edema (CME) as a major cause of visual loss in ocular sarcoidosis. CME may occur as a result of chronic inflammation in association with anterior, intermediate, or posterior uveitis [56, 57]. Different utilization of ancillary tests among institutions, such as fluorescein angiography, could affect the detection rates of certain posterior segment findings, such as CME. A retrospective study by Khalatbari et al. found a higher rate of CME and worse visual acuity in females when compared to males. In the same study, patients older than 53 years were noted to have higher rates of CME compared to younger age groups [58].

Fluorescein angiography (FA) results in sarcoidosis are generally nonspecific and similar to other inflammatory diseases of the eye. The study may show retinal neovascularization, hyperfluorescent chorioretinal spots, leakage and late staining of the retinal vessels, cystoid macular edema, retinal nonperfusion, and optic nerve inflammation. A diagnosis of sarcoidosis-related granuloma cannot be made solely on angiography. FA may be useful to monitor response to therapy in patients with neovascularization.

Altan-Yaycioglu et al. described FA findings in a series of patients with ocular sarcoidosis.

Candle-wax drippings and vasculitis appeared hyperfluorescent in the early phases, increasing in intensity through the late phases. Another patient, who presented with papilledema, showed bilateral papillary hyperfluorescence in early phases, which increased in intensity through the arteriovenous phase [59].

The clinical usefulness and relevance of indocyanine green angiography (ICG) in the investigation of chorioretinal disorders was reviewed by Stanga et al. The authors did not recommend routine use of ICG in ocular sarcoidosis, because in most patients with retinal vasculitis, it did not provide additional information over FA. The group pointed that ICG may be helpful in monitoring the effect of treatment in some patients [60].

Nevertheless, a study by Wolfensberger et al. described ICG findings in a series of 19 patients with posterior ocular sarcoidosis. All patients were found to have choroidal involvement by ICG, but eight of them had no clinical or FA evidence of retinal involvement. Four distinct ICG features were described, as follows: [61]

1.Hypofluorescent dark dots with an irregular zonal distribution

2.Fuzziness of the choroidal vasculature

3.Late diffuse hyperfluorescence

4.Focal pinpoint hyperfluorescent spots appearing in the later phases of angiography

The first three features have been described in

conditions such as sympathetic ophthalmia, birdshot chorioretinopathy, multiple evanescent white-dot syndrome, and Vogt-Koyanagi-Harada disease. Choroidal vessel fuzziness is believed to represent choroidal vasculitis, as it was observed near zones of active inflammation [59]. The last feature might be rather specific for sarcoidosis, as it was not found in seven patients with ocular inflammation in whom sarcoidosis had been excluded [61].

Choroidal lesions can underlie sarcoidosis even in the absence of fundoscopic changes. Machida et al. described a 20-year-old woman diagnosed with ocular sarcoidosis with choroidal filling delay, manifested as punctate hypofluorescence in the early phases of ICG, without accompanying fundoscopically detectable retinal lesions or retinal functional disturbance [62].