Ocular Manifestations of Sarcoidosis
Ocular manifestations of sarcoidosis Disease Entity Sarcoidosis is a systemic inflammatory disease of unknown etiology characterized by the formation of noncaseating granulomas. The disease most commonly affects the skin, lungs, lymph nodes, and eyes but can affect virtually any organ . The first patient with confirmed sarcoid was described by dermatologist Jonathan Hutchinson in early 1880, whose skin lesions Hutchinson named “Mortimer’s malady” after the patient1. Later, Caesar Boeck coined the term “sarcoid” because of the lesion’s resemblance to sarcoma on histology . In 1909, Heerfordt described the first ocular manifestation of sarcoid in three men with uveitis, parotid enlargement, and fever . Epidemiology Sarcoidosis is a global disease but is more common in Nordic and African American populations . A recent comprehensive study found that incidence in the United States ranged from 8.1 per 100,000 in Caucasians to 17.8 in African Americans . Acute and more severe disease is more frequent in African American patients, whereas chronic and asymptomatic disease is more frequent in whites8. The prevalence of ocular involvement in systemic sarcoidosis ranges from 12%-76% with ocular involvement being the presenting symptom in 30-40% , , . The most common types of ocular involvement are uveitis and conjunctival nodules8.
Ocular manifestations The granulomatous inflammation of sarcoidosis can affect any part of the eye and its adnexa and can progress to severe visual impairment and blindness. Intraocular manifestations The most common ocular manifestation overall is uveitis, reported in 30-70% of cases . Sarcoidosis can present with anterior, intermediate, posterior or panuveitis and should be on the differential for any patient with uveitis. The most common type is bilateral anterior uveitis without posterior-segment involvement9. Anterior uveitis typically presents with pain, redness and photophobia, but these signs may be absent and thus delay diagnosis. Patients can develop permanent ocular damage from chronic inflammation before treatment is initiated. Slit-lamp exam may show granulomatous keratic precipitates, iris nodules, and anterior or posterior synechiae . Patients with intermediate uveitis more commonly complain of floaters and blurry vision. Characteristic fundoscopic findings in intermediate uveitis include vitreous opacities, snow balls (aggregates of inflammatory cells in the vitreous humor posterior to the lens), and snow banks (accumulation of white exudates over the pars plana and ora serrata)10. Posterior involvement in sarcoid uveitis is usually bilateral but can be asymmetric. Choroidal granulomas vary widely in size and can lead to visual impairment if they are centrally located and possibly retinal detachment if the granulomas are large7. Characteristic fundoscopic findings in posterior uveitis include periphlebitis and “candle wax drippings” (scattered whitish-yellow perivascular retinal exudates along the retinal veins)7,8. Complications of chronic uveitis include cataract formation, glaucoma and cystoid macular edema (CME), which can all lead to vision loss in sarcoidosis patients. Sarcoid uveitis can lead to increased intraocular pressure and glaucoma due to edema or inflammatory cells that cause trabecular meshwork obstruction. Out of 159 patients in one Japanese study, 61% of patients had trabecular meshwork nodules and 55% had tent-shaped peripheral anterior synechiae leading to abnormal gonioscopic findings7. Ocular surface manifestations Conjunctival involvement can include conjunctival nodules, acute follicular conjunctivitis and chronic cicatricial conjunctivitis. Nodules are some of the most common ocular manifestations of sarcoidosis and are typically asymptomatic9. Scleritis can occur with ocular sarcoidosis but is rare and has mostly been associated with older female patients aged 53 to 64 years old7. Sarcoidosis-related scleritis can present as anterior diffuse, anterior nodular, or posterior scleritis and is usually non-necrotizing7. Corneal involvement is rare but most commonly presents as superficial punctate keratitis secondary to keratoconjunctivitis sicca, but there are case reports of interstitial keratitis and peripheral ulcerative keratitis7. Chronic inflammation and hypercalcemia in sarcoidosis can also result in subepithelial deposition of calcium, leading to calcific band keratopathy.9, Adnexal and orbital manifestations Dermatologic manifestations of sarcoidosis are common, but eyelid involvement is rare and has mostly been reported in case reports. One case was reported in a 43-year old man with bilateral destructive sarcoidosis affecting the anterior and posterior lamella of the eyelid leading to full-thickness loss and cicatricial entropion. The most common extraocular orbital tissue affected is the lacrimal gland, specifically the main lacrimal gland8, . Patients may be asymptomatic or may present with symptoms due to mass effect or inflammation7. Keratoconjunctivitis sicca (KCS) is commonly associated with sarcoidosis and is a result of decreased aqueous tear production secondary to lacrimal gland inflammation. Epiphora due to granulomatous inflammation of the lacrimal drainage system has also been reported7. Sarcoidosis can also affect extraocular muscles, orbital fat and the optic nerve sheath and can present with palpable masses, eyelid swelling, ptosis, proptosis and pain7. These manifestations resemble other orbital inflammatory conditions like thyroid ophthalmopathy, which can occur simultaneously with ocular sarcoidosis8. Complications of orbital masses caused by ocular sarcoid include central retinal artery occlusion and permanent blindness7. Neuro-ophthalmic manifestations Neurosarcoidosis causes a wide range of signs and symptoms depending on the areas of the nervous system affected and can mimic many other conditions. The most common manifestation, however, is cranial neuropathy most commonly of the facial and optic nerves7. However, any of the cranial nerves can be affected and will present with their corresponding deficits. Cranial nerve involvement can occur due to direct infiltration by sarcoid tissue or compression from space-occupying lesions. Neurosarcoidosis can also manifest as papilledema, nystagmus, and visual field defects9. Diagnosis Diagnosis of sarcoidosis is usually based on history and physical exam findings along with histological confirmation in affected tissue along with exclusion of other granulomatous diseases such as tuberculosis or syphilis. Since most patients with sarcoidosis have pulmonary involvement, chest X-rays are frequently used as a screening tool. Computerized tomography (CT) is more sensitive but is typically not recommended unless clinical suspicion is high and chest X-ray is negative . Serum ACE, calcium, and ESR may also be used and tissue biopsy is considered the gold standard. In 2017, the International Workshop on Ocular Sarcoidosis (IWOS) published criteria for diagnosing ocular sarcoidosis based on seven clinic signs, eight systemic investigation results, and three diagnostic criteria listed below. These criteria were revised from those previously suggested in 2009 due to limitations suggested by two validation studies . Revised International Workshop on Ocular Sarcoidosis (IWOS) criteria for the diagnosis of ocular sarcoidosis (OS): I. Other causes of granulomatous uveitis must be ruled out. II. Intraocular clinical signs suggestive of OS: 1. Mutton-fat keratic precipitates (large and small) and/or iris nodules at pupillary margin (Koeppe) or in stroma (Busacca). 2. Trabecular mesh work nodules and/or tent-shaped peripheral anterior synechia. 3. Snowballs/string of pearls vitreous opacities. 4. Multiple chorioretinal peripheral lesions (active and atrophic). 5. Nodular and/or segmental periphlebitis (candle wax drippings) and/or macroaneurysm in an inflamed eye. 6. Optic disc nodule(s)/granuloma(s) and/or solitary choroidal nodule. 7. Bilaterality (assessed by ophthalmological examination including ocular imaging showing subclinical inflammation). III. Systemic investigation results in suspected OS: 1. Bilateral hilar lymphadenopathy (BHL) by chest X-ray and/or chest computed CT scan. 2. Negative tuberculin test or interferon-gamma releasing assays. 3. Elevated serum angiotensin-converting enzyme (ACE). 4. Elevated serum lysozyme. 5. Elevated CD4/CD8 ratio (>3.5) in bronchoalveolar lavage fluid. 6. Abnormal accumulation of gallium-67 scintigraphy or 18F-fluorodeoxyglucose positron emission tomography imaging. 7. Lymphopenia. 8. Parenchymal lung changes consistent with sarcoidosis, as determined by pulmonologists or radiologists. IV. Diagnostic criteria: Definite OS: diagnosis supported by biopsy with compatible uveitis. Presumed OS: diagnosis not supported by biopsy, but BHL present with two intraocular signs. Probable OS: diagnosis not supported by biopsy and BHL absent, but three intraocular signs and two systemic investigations selected from two to eight are present. Management Treatment of ocular sarcoidosis aims to restore vision and prevent complications from inflammation, particularly uveitis because it is the most common presentation. Treatment of intraocular manifestations Corticosteroids Corticosteroids are the mainstay of treatment for sarcoid uveitis and can be administered topically in the form of eye drops, regionally in the form of periocular and intraocular injections or implants, or systemically in the form of oral corticosteroids. Topical corticosteroids are the first line treatment for anterior uveitis but can be ineffective in treating posterior segment inflammation7. Dose and frequency may vary based on the severity of the disease. Adverse effects include elevated IOP, early-onset cataract and delayed wound healing. Corticosteroid injections and implants may be considered in posterior segment involvement or in those who respond poorly to topical solutions. Periocular injections are most commonly administered into the sub-Tenon’s capsule or the orbital floor9. The most common preparation is triamcinolone acetonide (TA) 20-40mg which typically lasts 2-4 months. TA can also be administered via 1-4mg intravitreal injections, which can last 3-6 months. Adverse effects include elevated IOP, cataract progression, and injection-related side effects. Dexamethasone can also be administered in the form of a biodegradable implant through the pars plana, which has been shown to improve vision and macular edema in patients with non-infectious uveitis. The main disadvantage appears to be recurrence of macular edema, which occurred in 65% of patients within 6 months in one study7,10. Systemic corticosteroids may be considered in chronic, bilateral uveitis, in those who respond poorly to topical or regional therapy, or in systemic disease that also requires therapy. Systemic therapy usually entails short term courses of prednisone dosed at 1-1.5mg/kg/day that is then tapered down to the lowest effective dose. Systemic steroid therapy requiring prolonged courses or higher doses may be associated with many systemic adverse effects9. Immunosuppressive agents Systemic immunosuppressive agents may be considered in patients requiring long term courses of corticosteroids or when corticosteroids fail to treat patients with ocular sarcoidosis. The most common agents include methotrexate, mycophenolate mofetil, azathioprine and cyclosporine. Currently, there is no standardized approach to immunosuppressives in those with ocular sarcoidosis, and patients on these agents should be monitored for systemic side effects9. Biologic agents Biologic agents may be considered when corticosteroids or immunosuppressive agents fail to induce or sustain remission in patients with ocular sarcoidosis. Most of the agents studied to treat uveitis are Tumor Necrosis Factor (TNF)-α inhibitors, including adalimumab, infliximab, etanercept, and golimumab. These agents bind TNFα or block its receptor which may prevent granulomatous inflammation in sarcoidosis. Adalimumab is the only agent of these that is FDA approved for the treatment of non-infectious uveitis. Two Phase III trials reported that adalimumab lowered the risk of uveitic flare or loss of visual acuity in patients with active (VISUAL I) or inactive (VISUAL II) non-infectious intermediate uveitis, posterior uveitis, or pan-uveitis9,10. However, these agents still remain second-line due to limited long-term safety and efficacy data7. Interestingly, anti-TNFα agents have been associated with causing uveitis . Treatment of ocular surface manifestations Conjunctival lesions may respond to topical cyclosporine eye drops . Scleritis is usually treated with systemic corticosteroids or systemic immunomodulators. One case report suggested thalidomide as a possible therapy for scleritis after a woman in her early 50’s showed complete remission of bilateral nodular scleritis after treatment with thalidomide . Treatment of adnexal and orbital manifestations Cutaneous lesions on the eyelids may be treated with systemic corticosteroids, intralesional triamcinolone injections, or oral chloroquine7. KCS may respond to topical cyclosporine eye drops. Orbital lesions may be treated with systemic corticosteroids and biopsy or removal if suspicious for malignancy. Treatment of complications Chronic ocular inflammation secondary to sarcoidosis and treatment thereof can lead to a number of vision-threatening complications such as cataract, glaucoma, and CME which must also be considered. Steroid-sparing agents may be considered in patients with elevated IOP. Cataract surgery in patients with ocular sarcoidosis may be considered after ocular inflammation is quiescent for at least 3 months, similar to other causes of uveitis . CME, the major cause of vision loss in ocular sarcoidosis patients, can be monitored with Optical coherence tomography (OCT)8,10. Treatment options for uveitic macular edema include dexamethasone implants, immunomodulatory drugs, anti-vascular endothelial growth-factor agents, and pars plana vitrectomy in refractory cases . Summary It is important for the ophthalmologist to be aware of the ocular manifestations of sarcoidosis as they may be the first sign of systemic disease and can lead to severe complications. Early diagnosis using the IWOS criteria and intervention can be crucial in preventing severe vision loss. Appropriate management also requires long-term follow up to monitor for disease progression and drug-related adverse effects.