Sarcoid Uveitis

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Original article contributed by: Parvathy Pillai, MD
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Disease Entity[edit | edit source]

Sarcoid Uveitis

Disease[edit | edit source]

Sarcoidosis is a systemic inflammatory disease characterized by the formation of noncaseating granulomas in affected organs, most commonly the lungs, lymph nodes, skin, and eyes. The disease was first described in 1878 by noted surgeon Sir Jonathan Hutchinson as a dermatologic disorder[1]. It was not until 1909 that a Danish ophthalmologist, Heerfordt Christian Frederik[2], described uveitis as part of the disease process. His eponymous “Heerfordt Sydrome” consisted of uveitis, parotitis and fever (uveoparotid fever) +/- facial palsy.


Etiology[edit | edit source]

While the etiology of sarcoidosis is unknown, several hypothesis regarding genetic and environmental factors have been studied. Some hypothesize that it is a clinical syndrome consisting of different diseases with different underlying etiologies. Associations between sarcoid and HLA-DRB1[3] and M. tuberculosis DNA[4] are currently being evaluated.

Risk Factors[edit | edit source]

In the United States, the incidence of systemic sarcoidosis ranges from 5-40 per 100,000 population[5]. This prevalence is 10 times greater for African Americans when compared to white Americans. African Americans are also more likely to have an acute presentation of the disease and a more severe clinical course whites.

A large retrospective chart review from the University of Illinois uveitis service indicated that in biopsy-proved sarcoidosis, African-American patients were more likely to be diagnosed as having uveitis than whites. African-Americans younger than 50 years were more likely to present with uveitis.[6]

Several studies have noted a slight female preponderance, with most symptomatic patients being between 20-50 years old.


Pathology[edit | edit source]

Histologically, sarcoid nodules are composed of collections of noncaseating eptheliod histiocytes and lymphocytes. Multinucleated giant cells, asteroid bodies and Schaumann bodies may be seen within the giant cells.

Pathophysiology[edit | edit source]

The exact etiology of sarcoidosis is unknown, making it largely a diagnosis of exclusion. It is characterized by the appearance of noncaseating granulomas in affected tissue, most frequently seen in the lungs as bilateral hilar lymphadenopathy or pulmonary infiltration. Granulomas can also be seen on the skin, in the eyes, liver, spleen, salivary glands, heart, bones and nervous system. Ocular involvement occurs in approximately 25% of patients with sarcoidosis. The uveal tract is the most common site of ocular involvement by sarcoidosis. In most large series, sarcoidosis accounts for between 3-10% of all cases of uveitis.


Diagnosis[edit | edit source]

Sarcoid is a systemic inflammatory disease and can manifest itself in multiple ways. Therefore, clinical suspicion is often the driving force behind correct diagnosis. A thourough review of systems if necessary in all patients with recurrent uveitis. An individual with pumlonary or dermatologic complaints consistent with sarcoid should be further evaluated. Uveitis can also precede pulmonary symptoms by several years. Orbital and eyelid granulomas are also common, as well as lacrimal gland infiltration.

History[edit | edit source]

Clinical presentation of sarcoidosis depends on the severity and organ involved. A history of pulmonary disease in an individual with granulomatous uveitis should raise the suspicion of sarcoidosis.

Physical examination[edit | edit source]

Granulomatous anterior uveitis, either acute or chronic, is the most common ocular manifestation of sarcoidosis. Less than 1/3 presenting with posterior uveitis without anterior involvement.

In 2009, an international group of uveitis specialists met for the International Workshop On Ocular Sarcoidosis (IWOS)[7]. They determined the following criteria for the diagnosis of ocular sarcoid:

Seven Signs of Intraocular Sarcoidosis

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

2. trabecular meshwork (TM) nodules and/or tent-shaped peripheral anterior synechiae (PAS)

3. vitreous opacities displaying snowballs/"strings of pearls"

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

5. nodular and/or segmental peri-phlebitis (+/- candlewax drippings) and/or retinal macroaneurism in an inflamed eye

6. optic disc nodule(s)/granuloma(s) and/or solitary choroidal nodule

7. bilaterality

Posterior segment lesions occur in 14-20% of patients with ocular sarcoidosis. Cystoid macular edema is frequently present in the setting of posterior segment involvement.


Symptoms[edit | edit source]

Ocular sarcoid can manifest itself with blurred vision, photophobia, floaters, redness, and pain from uveitis. Cranial nerve palsies causing diplopia and decreased vision from optic nerve infiltration have also been reported. Lacrimal gland involvement may cause proptosis and diplopia secondary to mass affect.

Systemic symptoms of sacroidosis include febrile illness with cough and dyspnea, fatigue, erythema nodosum, acute polymyositis, arthritis, musculoskeletal anomalies, or sarcoid nodules of the skin

Diagnostic Criteria[edit | edit source]

The IWOS refers to definitive ocular sarcoidosis as biopsy-supported diagnosis with a compatible uveitis. Presumed ocular sarcoidosis was defined as a chest x-ray showing bilateral hilar lymphadenopathy associated with a compatible uveitis. If a biopsy was not done and the chest x-ray did not show BHL but there were 3 of the above intraocular signs and 2 positive laboratory tests, the condition was labeled as probable ocular sarcoidosis. Finally, if lung biopsy was done and the result was negative but at least 4 of the above signs and 2 positive laboratory investigations were present, the condition was labeled as possible ocular sarcoidosis.

Diagnostic procedures[edit | edit source]

When the diagnosis of sarcoid uveitis is suspected, a chest x-ray remains the single best screening test, it is abnormal in 90% of patients with sarcoidosis. In cases of a high clinical suspicion and normal chest radiograph, a thin-cut spiral CT scan of the chest may be valuable. In addition, serum angiotensin converting enzyme (ACE)and gallium scan are noninvasive diagnostic tools.

According to the IWOS, individuals with clinical signs of ocular sarcoidosis should receive the following diagnostic tests:

1. negative tuberculin skin test in a BCG-vaccinated patient or in a patient having had a positive tuberculin skin test previously

2. elevated serum ACE levels and/or elevated serum lysozyme

3. chest x-ray revealing bilateral hilar lymphadenopathy (BHL)

4. abnormal liver enzyme tests

5. chest CT scan in patients with a negative chest x-ray result

Definitive diagnosis of sarcoidosis requires a biopsy. Typically, the most accessible site with the lowest associated morbidity is chosen, such as a palpable lymph node. Conjuntival biopsies can also be performed. Bilateral blind conjunctival biopsies are more likely to be positive in biopsy-proven sarcoidosis from other sites. Conjunctival biopsies are particularly useful in the presence of conjunctival follicles, ocular abnormalities consistent with sarcoidosis, and in patients with pulmonary infiltrates on chest x-ray. If lacrimal gland involovement is noted on physical exam or gallium scan, a lacrimal gland biopsy can also be performed. In cases of active pulmonary disease, fiberoptic bronchoscopy can be biopsy positive in 63-80%, depending on the stage of disease[8].


Laboratory test[edit | edit source]

Serum level of ACE (Angiotensin Converting Enzyme) is often elevated in sarcoidosis and can be used to monitor disease activity. Higher serum ACE levels indicate more active disease. Elevated serum ACE is 73% sensitive and 83% specific for sarcoid when used alone. The specificity increases to almost 100% when used in combination with whole-body gallium (67GA) scanning.[9] This has also been shown in studies of ocular sarcoidosis with normal or equivocal chest radiographs. Serum lysozyme also plays a role in the diagnosis of ocular sarcoid. Serum lysozyme greater than 8mg/l was found to be 60% sensitive and 76% specific for sarcoid uveitis[10].

Differential diagnosis[edit | edit source]

The differential includes autoimmune and infectious causes of granulomatous uveitis, including syphilis, Lyme disease, tuberculosis, Behcet's disease, Vogt-Koyanagi-Harada disease, and sympathetic ophthalmoplegia.

Management[edit | edit source]

Management should be based on the ocular signs and symptoms. Careful attention should be paid to the amount of anterior segment inflammation and the presence of retinal involvement. Topical, periocular, and systemic corticosteroids are the mainstays of therapy. Systemic disease should be managed by a primary care physician.

Medical therapy[edit | edit source]

Aggressive management of uveitis should be initiated with topical steroids such as Pred Forte (prednisolone acetate 1%) and topical cycloplegics (e.g. homatropine 5%, scopolamine 0.25%, or atropine 1%, BID). Cycloplegia is useful for comfort and for prevention of synechiae. Topical steroids can be tapered as long as clinical signs continue to resolve. If topical steroids are unsuccessful, or intermediate uveitis is noticed, consider periocular subtenon steroid injections of Kenalog 40 (triamcinolone). Injections may be repeated at weekly, biweekly, or monthly intervals, up to 3-4 times, before maximal benefit is reached.

Oral prednisone may be indicated in anterior uveitis not responding to topical steroids. Individuals with posterior uveitis, neovascularization, or orbital disease with visual symptoms or optic nerve compromise can also benefit from oral steroid or antimetabolities (Methotrexate, Cyclosporin-A). Recently, the TNF-alpha inhibitor, infliximab, has been shown to be effective as well.

Regular monitoring of intraocular pressure for steroid-response glaucoma should be performed and treated appropriately with topical aqueous suppressants.

Cystoid macular edema can be treated with topical nonsteroidal anti-inflammatory agents such as Acular (Ketorolac tromethamine) and Voltaren (diclofenac sodium) QID. Intravitreal injections of Kenalog 40 (triamcinolone) may be necessary depending on the degree of edema. Retinal neovascularization with evidence of ischemia on angiography responds well to panretinal photocoagulation.

Medical follow up[edit | edit source]

Uveitis patients require close follow up during acute episodes and regular follow-up. Reevaluation of the inflammation and intraocular pressures at 1- to 2-week intervals for the first month after onset of treatment is routine. If inflammation is not improving at any given taper interval, maintain that dosing and taper only after the cells and flare decrease.

In an individual with uveitis, recurrent episodes warrant a work-up including: complete blood count (CBC with differential), fluorescent treponemal antibody absorption test (FTA-Abs), reactive plasma reagin (RPR), purified protein derivative with anergy panel (PPD with anergy panel), anti-nuclear antibody (ANA), angiotensin converting enzyme (ACE), Lyme titre, rheumatoid factor (RF), sickle prep, chest x-ray (CXR) and sacroiliac joint films.

Systemic involvement should be monitored by a primary care physician.


Surgical Therapy[edit | edit source]

Cataract surgery may be performed when the intraocular inflammation is absolutely controlled, typically for 3 months on or off medication. Vitrectomy may be required for severe vitreous opacification. Steroid-induced glaucoma that is unresponsive to maximal medical therapy, may require either trabeculectomy or glaucoma drainage device implant procedures.

Complications[edit | edit source]

Complications vary based on the involved organ system. Ocular complications from sarcoid uveitis are similar to complications seen from other types of uveitis: Band keratopathy, cataracts, glaucoma, cystoid macular edema (CME), vitreous hemorrhage, retinal detachment, and blindness from macular lesions

Nuero-ophthalmologic involvement can result in optic atrophy and diplopia.

Systemic complications include pulmonary fibrosis, cardiac dysrhythmias, seizures, hydrocephalus, deafness, and motor/sensory deficits from spinal lesions.

Prognosis[edit | edit source]

Prognosis of sarcoid uveitis is highly variable. In general, close to two-thirds experience a benign self-limiting course with spontaneous remission. Fundus lesions have an increased incidence of associated neurosarcoidosis.

Adverse prognostic factors include lupus pernio, chronic uveitis, glaucoma, CME, age older than 40 years at onset, chronic hypercalcemia, nephrocalcinosis, black race, progressive pulmonary sarcoidosis, nasal mucosal involvement, cystic bone lesions, neurosarcoidosis, myocardial involvement, and chronic respiratory insufficiency.

Additional Resources[edit | edit source]

The Ocular Immunology and Uveitis Foundation: MERSI www.uveitis.org

The Uveitis Resource Center for Eye Care Professionals www.preventblindness.org/uveitis/resources.html

References[edit | edit source]

  1. Young, Jr, Roscoe C MD; Rachal, Raylinda E, MD; Cowan Jr, Claude L., MD. Sarcoidosis – The Beginning: Historical Highlights of Personalities and Their Accomplishments During the Early Years. Journal of the National Medical Association. Vol 76. No 9, 1984. 887-896.
  2. Young, Jr, Roscoe C MD; Rachal, Raylinda E, MD; Cowan Jr, Claude L., MD. Sarcoidosis – The Beginning: Historical Highlights of Personalities and Their Accomplishments During the Early Years. Journal of the National Medical Association. Vol 76. No 9, 1984. 887-896.
  3. Grosser M, Luther T, Guessel M, et al. Clinical course of sarcoidosis in dependence on HLA-DRB1 allele frequencies, inflammatory markers, and the presence of M. tuberculosis DNA fragments. Sarcoidosis Vasc Diffuse Lung Dis. Mar 2005 22(1): 66-74
  4. Grosser M, Luther T, Muller L, et al. Detection of M. tuberculosis DNA in sarcoidosis: correlation with T-cell response. Lab Invest. Jul 1999 79(7):775-84
  5. Crystal RG. Sarcoidosis. In: Fauci AS, Isselbacher KJ, Braunwald E, et al, eds. Harrison's Principles of Internal Medicine. 14th ed. McGraw-Hill; 1998:1922-8.
  6. Birnbaum AD, Oh FS, Chakrabarti A, Tessler HH, Goldstein DA. Clinical features and diagnostic evaluation of biopsy-proven ocular sarcoidosis. Arch Ophthalmol. Apr 2011;129(4):409-13
  7. Herbort CP, Rao NA, Mochizuki M, et al. International criteria for the diagnosis of ocular sarcoidosis: results of the first International Workshop On Ocular Sarcoidosis (IWOS). Ocul Immunol Inflamm. 2009 May-Jun;17(3):160-9.
  8. Koonitz CH, Joyner LR, Nelson RA. Transbronchial lung biopsy via the fiberoptic bronchoscope in sarcoidosis. Annals of Internal Medicine. 1976 Jul;85(1):64-6.
  9. Nosal A, Schleissner LA, Mishkin FS, Lieberman J. Angiotensin-I-converting enzyme and gallium scan in noninvasive evaluation of sarcoidosis. Annals of Internal Medicine. 1979 Mar; 90(3): 328-31.
  10. Baarsma GS, La Hey E, Glasius E, de Vries J, Kijlstra A. The predictive value of serum angiotensin converting enzyme and lysozyme levels in the diagnosis of ocular sarcoidosis. American Journal of Ophthalmology. 1987 Sep 15;104(3):211-7
 

Ophthalmic Pathology and Intraocular Tumors, Section 4. Basic and Clinical Science Course, AAO, 2009: 185.

Intraocular Inlammation and Uveitis, Section 9. Basic and Clinical Science Course, AAO, 2009: 199-203.