AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Sarcoidosis is an inflammatory multisystem granulomatous disease of unknown etiology. Although it predominantly affects the lungs, the illness often manifests within the eye, in addition to the skin, lymph nodes, liver, spleen, heart, central and peripheral nervous systems, musculoskeletal system, and salivary glands.

Sarcoidosis was first identified over 125 years ago by 2 dermatologists working independently, Dr. Jonathan Hutchinson in England and Dr. Caesar Boeck in Norway, both of whom described its skin findings. Sarcoidosis was originally called Hutchinson disease or Boeck disease. Dr. Boeck went on to fashion today's name for the condition from the Greek words sark and oid, meaning fleshlike. The term describes the skin eruptions that are frequently caused by the illness.

Sarcoidosis is diagnosed when the classic clinical and radiologic findings are supported by histologic evidence of widespread noncaseating epithelioid granulomata. Although best known for its thoracic involvement, the extrapulmonary, ocular, and neurologic manifestations of sarcoidosis may cause significant complications, including blindness, meningitis, arthritis, renal disease, systemic morbidity, dermatitis, and death.

Pathophysiology

Sarcoidosis is characterized by the formation of noncaseating granulomas in tissues without another known cause for granulomatous disease. Sarcoidosis is ultimately a diagnosis of exclusion. The true causative organism or antigen has not yet been identified, although some form of atypical mycobacteria continues to be suspected.

Clinical disease occurs when granulomata affect the involved tissues as space-occupying lesions, distorting normal architecture and, hence, function. Most frequently, sarcoidosis presents with bilateral hilar lymphadenopathy, pulmonary infiltration, and ocular and skin lesions. Other organs involved include the liver, spleen, lymph nodes, salivary glands, joints, heart, nervous system, muscle, and bones. Remote effects of sarcoidosis also may be seen with overproduction of 1,25-dihydroxyvitamin D, which may cause hypercalcemia and hypercalciuria. Clinical manifestations depend on ethnicity, chronicity of illness, site and extent of tissue involvement, and activity of the granulomatous process.

Extrathoracic manifestations involving the liver, skin, heart, and/or eye are the presenting findings in 40% of patients with sarcoidosis. Immunological features of sarcoidosis include suppression of delayed-type hypersensitivity, heightened helper T-cell–type 1 immune response at disease sites, B-cell hyperactivity with circulating immune complexes, and increased levels of fibrinogenic cytokines. Ocular involvement occurs in approximately 25% of patients with sarcoidosis.

Frequency

United States

The prevalence of sarcoid is estimated to be 10-20 cases per 100,000 people. The incidence varies among geographic regions as well as with ethnicity. In the United States, African Americans have a 3-fold increased risk for sarcoid compared to whites, while Asians are rarely affected. African Americans are more likely to present acutely and to have more severe disease than whites who tend to present with asymptomatic and chronic disease. A number of studies have demonstrated a rural predominance in American adults with this disorder.

International

Sarcoidosis is a relatively common disease with worldwide distribution, affecting all genders, races, and ages. In Europe, the prevalence ranges from 3-50 cases per 100,000 people. In Japan, the incidence is less than 2 cases per 100,000 people. Ascertaining the true rate in underdeveloped nations is difficult because of the frequent failure to diagnose the disease and its misdiagnosis as tuberculosis.

Mortality/Morbidity

Pulmonary fibrosis and cardiac involvement are the 2 leading causes of death. Overall mortality ranges from 1-5%. Cardiac disease is the most commonly reported cause of death in Europe, while pulmonary disease accounts for the majority of the mortality in US patients.

Race

Sarcoidosis is much more frequent in certain ethnic and racial groups, ranging from less than 1 case up to 64 cases per 100,000 people worldwide.

• In studies by Crystal, Newman, and Rybicki, a preponderance of disease occurred in American blacks as compared to whites. The reported ratio of American blacks to whites ranges from 3:1 to 17:1.
• Sarcoidosis tends to be more severe and chronic in American blacks, with a higher risk of extrathoracic manifestations.
• American blacks have twice the ocular and ocular adnexal involvement as American whites.

Sex

A slight female preponderance and susceptibility have been noted in several studies as noted by Bresnitz.

Age

Most symptomatic patients are aged 20-40 years. Sarcoidosis also can be seen in children and elderly persons. Children do not appear to show the female predominance that is noted in adults. Additionally, in the United States, children do not seem to demonstrate the higher prevalence in African Americans that is seen in adult populations.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

Sarcoidosis may present with symptoms referable to a single organ or to multiple organ systems. Historical presentation depends on the severity of the organ(s) involved. Five percent of cases are asymptomatic; the diagnosis is suspected and pursued after a chest radiograph is performed for an unrelated reason.

• Constitutional symptoms: Most patients have symptoms of fatigue, malaise, anorexia, weight loss, and fever at onset.
• Pulmonary symptoms: Dyspnea on exertion, retrosternal chest pain, and cough may occur in one third to one half of all patients. Even in patients with primarily extrathoracic sarcoidosis, subclinical pulmonary sarcoidosis is often present.
• Systemic syndromes
• • Löfgren syndrome represents a more acute presentation, comprising hilar lymphadenopathy, erythema nodosum, and polyarthralgia.
  • Heerfordt syndrome (uveoparotid fever) includes uveitis, salivary gland involvement, and cranial nerve palsies.
• Extrapulmonary involvement: This includes (in order of frequency) lymphadenopathy, skin lesions, ocular lesions, and upper respiratory, marrow and splenic, hepatic, renal, neurologic, musculoskeletal, cardiac, and endocrine manifestations.
• Neurologic sarcoidosis: General symptoms include headache, dizziness, facial weakness, hemiparesis, paresthesias, gait disturbances, impaired memory, decreased hearing, seizures, and rarely psychiatric symptoms.
• Neuro-ophthalmologic involvement: Symptoms include diplopia from cranial nerve palsies and decreased vision with or without scotoma from optic nerve infiltration or edema. Visual symptoms from glaucomatous optic nerve damage may be superimposed.
• Ocular sarcoidosis: Symptoms from uveitis include blurred vision, photophobia, floaters, redness, scotomata, and pain. Periocular lesions may produce dry eye symptoms, as well as disfiguring lid, periocular, and adnexal lesions. Orbital involvement may cause proptosis and diplopia.

Physical

• Pulmonary system: Physical signs of pulmonary involvement include dry rales, restricted lung volumes, abnormal gas exchange, abnormal arterial blood gas parameters, and occasional hemoptysis. Clinical staging is completed using international radiologic criteria. Radiologic findings reflect interstitial lung disease involving alveoli, vessels, and bronchioles.
• Lymphatic system: Hilar lymphadenopathy may be seen in up to 90% of patients.
• Cardiovascular system: Serious cardiac dysfunction is noted in 5-10% of patients with sarcoidosis.
• Skin: Up to 25% of patients with sarcoidosis will have 1 or more skin lesions. Cutaneous manifestations include erythema nodosum and chronic maculopapular lesions.
• Renal and endocrine systems: Clinically significant renal tubular, glomerular, and arterial involvement is rare.
• Gastrointestinal system: Liver biopsy results reveal granulomatous involvement in 40-90% of patients, but clinically significant liver abnormalities are rare.
• Neurologic system
• • Lesions may occur anywhere in the central or peripheral nervous systems. Neurosarcoidosis carries a mortality rate of 10%, twice the overall mortality rate of sarcoidosis.
  • Cranial neuropathy and hypothalamic/pituitary lesions tend to occur early and respond favorably to treatment. Space-occupying lesions, peripheral neuropathy, and neuromuscular involvement tend to occur later and portend a chronic course. Neurosarcoid usually presents with other systemic manifestations.
  • Cranial nerve involvement commonly occurs and may be bilateral. Classically, the most common lesion of neurosarcoid is a unilateral seventh (facial) nerve palsy. Most cases of seventh nerve palsy are lower motor neuron type lesions. Nerve palsies involving the auditory, glossopharyngeal, or vagus nerves have been described.
  • Peripheral mononeuropathy or polyneuropathy may occur.
  • Sarcoidosis may present with seizures or meningitis. Cerebrospinal fluid (CSF) findings in patients with central nervous system (CNS) involvement may include pleocytosis (mainly lymphocytosis), elevated protein levels or cells (up to 81% of patients), and decreased glucose levels (20% of patients). CSF angiotensin-converting enzyme (ACE) levels may be elevated in 50% of patients, and lysozyme levels, beta2-macroglobulin levels, and CD4/CD8 ratio may be increased.
  • Space-occupying lesions may occur in any part of the CNS. Supratentorial granulomatous lesions are more common than infratentorial masses. Symptoms are nonspecific and include headaches, lethargy, seizures, papilledema, and optic atrophy. The most common intracranial sites of involvement are the hypothalamus, the third ventricle region, and the pituitary gland. Intraspinal lesions occasionally are seen and may mimic multiple sclerosis (MS). One third of patients with spinal cord involvement are asymptomatic.
• Neuro-ophthalmologic manifestations
  • Oculomotor, trochlear, or abducens nerve (cranial nerve III, IV, or VI) involvement is rare but may cause diplopia or ptosis.
  • The optic nerve is commonly involved, occurring in 5-38% of patients with neurosarcoid. Postmortem studies and physiologic studies (visual-evoked potentials) indicate a high degree of subclinical disease. Coexisting uveitis also may obscure optic nerve involvement. Optic nerve or chiasmal involvement is seen in one third to one half of patients with neurosarcoid, with two thirds of patients having unilateral involvement and one third of patients having bilateral disease. Nonspecific optic nerve head swelling (papillitis), direct invasion of the optic disc or nerve, or papilledema due to increased intracranial pressure may be present.
  • Examination of the optic nerve head may reveal edema, vascular engorgement, nerve head elevation, hemorrhage, or optic atrophy. If the lesion is retrobulbar, the optic nerve may appear normal. Isolated infiltrative optic neuropathy as the initial manifestation of sarcoidosis is rare. Retrobulbar optic nerve lesions may masquerade as optic nerve glioma or meningioma. Neuro-ophthalmic findings may present without systemic evidence of disease and elude diagnosis until a biopsy is performed.
• Ocular manifestations
  • Involvement of the eyes and adnexa ranges from 25-54% of patients. Most patients with ophthalmic sarcoidosis have evidence of systemic involvement at the time of the initial examination.
  • Ocular syndromes: Heerfordt syndrome is characterized by uveitis, which may precede the parotid enlargement and occasionally papilledema. Löfgren syndrome, which is characterized by erythema nodosum, bilateral hilar adenopathy, and arthralgias, is associated with anterior uveitis in 6% of patients.
  • Skin and adnexa: Lacrimal gland involvement occurs in 15-28% of patients. Lacrimal gland involvement is usually a painless, bilateral, palpable swelling of the gland. Moderate-to-severe keratitis sicca may result.
• Anterior segment disease
  • Conjunctiva: Granulomatous nodules are the most common lesions. Keratoconjunctivitis sicca presumably results from infiltration of the lacrimal and minor lacrimal glands or from chronic inflammation of the lacrimal ductules.
  • Cornea: Interstitial keratitis rarely may occur. Band keratopathy is infrequent. Scleritis is rare. Cataract is a frequent complication of uveitis and/or the corticosteroids used in treatment.
• • Uveitis
    • Anterior uveitis is the most common ocular manifestation of sarcoidosis, although up to one third of patients with posterior uveitis may have no signs of anterior segment inflammation.
    • The signs of anterior uveitis typically include granulomatous or mutton-fat keratic precipitates, iris nodules, posterior synechiae, and peripheral anterior synechiae.
    • Sequelae of chronic uveitis include anterior and posterior synechiae, iris bombé, glaucoma, cystoid macular edema, vitritis, retinal neovascularization, and cataract.
  • Glaucoma: Both open-angle and angle-closure mechanisms may be seen in sarcoidosis. Most patients with intraocular pressure elevation have a chronic open-angle–type glaucoma. This picture is complicated by steroid-responsive glaucoma, in which approximately 6% of the population develops open-angle glaucoma when given topical corticosteroids for 4-6 weeks. Therefore, gonioscopy is essential in the evaluation of patients with elevated intraocular pressure.
• Posterior segment disease: Posterior findings occur in 25-30% of patients with sarcoidosis.
  • Vitreous: Clinical features seen in the vitreous cavity comprise cellular infiltrates, opacities, haze, syneresis, posterior vitreous detachment, and hemorrhages. Grayish green-white opacities (or snowballs) may be seen in the anterior inferior vitreous. The opacities often occur in chains and are described as a string of pearls. Vitreous hemorrhage is rare and may result from retinal neovascularization.
  • Vessels: Periphlebitis is not uncommon; in sarcoidosis, perivasculitis is limited to the retinal veins, tends to be segmental, and involves the small branch veins. En taches de bougie (candle-wax drippings) is used to describe the perivenous exudates. Periphlebitis tends to resolve dramatically on steroid therapy. Central retinal vein occlusions are rare.
  • Retina: Neovascularization was found in approximately one fourth of Spalton's patients and was the most significant factor contributing to poor prognosis. Sequelae included vitreous hemorrhage, ischemia, and retinal detachment. Neovascularization may respond to corticosteroids and warrant a therapeutic trial. Panretinal photocoagulation and/or vitrectomy may be required for neovascularization. Retinal detachment is rare.
• • Cystoid macular edema (CME) is the accumulation of extracellular fluid in the outer plexiform layer of the retina. Intravenous fluorescein angiography (IVFA) may demonstrate dye leakage in the perifoveal area when frank cystoid spaces are not identified ophthalmoscopically.
  • Retinal pigment epithelium (RPE): Focal and discrete subretinal mottling may be seen in the inferior equatorial RPE but occasionally may be seen in the posterior pole.
  • Pars plana exudates may be indistinguishable from idiopathic pars planitis. Histopathology may reveal fibrinous exudates overlying the pars plana and extending into the vitreous.
  • Choroid: Lesions are typically multiple, yellowish, elevated nodules.

Causes

The etiology of sarcoidosis remains unknown. Genetic and environmental factors may play a role, but a review of the literature strongly suggests that hereditary and environmental factors alone may not account for all cases of sarcoidosis.

Sarcoidosis appears to be an antigen-mediated granulomatous process characterized by cytokine dysregulation. Sarcoidosis is not a malignancy nor is it an autoimmune disorder. Various infectious, allergic, chemical, and drug causes have been suggested and dismissed for lack of conclusive evidence. Mycobacteria and atypical pathogens have been repeatedly suggested as etiologic factors. One hypothesis is based on mounting evidence of mycobacterial DNA in granulomas. DNA from slow-growing mycobacteria, preferentially persisting in macrophages, has been found to elicit an allergic reaction in the setting of a hyperresponsive host. Whether the exogenous DNA in the granulomas is incidental or causal in the pathogenesis remains to be seen.

Two leading hypotheses have evolved regarding the etiology. One hypothesis is that sarcoidosis is most likely the result of exposure of a susceptible host to a potential etiologic agent. An alternative hypothesis cedes that sarcoidosis may be a clinical syndrome that includes a collection of different diseases, each with a different etiology.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Neurosarcoid

Giant cell arteritis, epidemic parotitis, Hodgkin disease, leprosy, syphilis, tuberculosis (TB), MS, Lyme disease (facial nerve palsies and nerve root syndromes), Wegener granulomatosis, Behçet disease, meningeal carcinomatosis

Ocular sarcoid

Eyelid granulomatous processes include chalazia, dermal tuberculosis, fungal infections, juvenile xanthogranuloma, and foreign bodies.

Orbital granulomatous pathologies comprise lipogranulomas, Wegener granulomatosis, TB, syphilis, fungal infections, parasites (eg, microfilariae, nematode larvae), and panophthalmitis.

Uveitic entities in the differential diagnosis of granulomatous uveitis: Infectious entities include nonpyogenic systemic infections associated with TB, cat-scratch disease, syphilis, brucellosis, leprosy, and leptospirosis. Protozoan infections include amebiasis, toxoplasmosis, and trypanosomiasis. Fungal infections include actinomycosis, aspergillosis, blastomycosis, candidiasis, coccidioidomycosis, cryptococcosis, histoplasmosis, mucormycosis, nocardiosis, and sporotrichosis. Helminth infestations include Ascaris, cysticercosis, taeniasis, Diptera larvae, and nematode infestations (onchocerciasis and Toxocara, Ancylostoma, and Necator species). Viral uveitis includes herpes simplex, herpes zoster, vaccinia, and cytomegalovirus.

Other entities in the differential diagnosis are lens-induced uveitis, lymphoma, histiocytosis X, and neoplastic and posttreatment of ocular melanoma with proton beam irradiation.

Differential diagnosis of posterior uveitis that may clinically mimic sarcoidosis includes the following: birdshot chorioretinopathy; Vogt-Koyanagi-Harada syndrome; sympathetic ophthalmia; toxoplasmosis; Behçet disease; acute multifocal choroiditis; MS; TB; syphilis; vasculitides due to Wegener granulomatosis, systemic lupus erythematosus (SLE), Whipple disease, ankylosing spondylitis, Crohn disease, and relapsing polychondritis; acute multifocal placoid pigment epitheliopathy (AMPPE); and CNS lymphoma.

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• The serum level of ACE is frequently elevated in sarcoidosis and is of value in supporting the diagnosis of sarcoidosis. The ACE level may be useful in the monitoring of disease activity. This is particularly true in extrathoracic disease when typical chest radiologic findings are absent. Serum levels tend to be higher in clinically active disease but may be low at the onset of acute disease. Combined use of ACE levels with gallium scans increased the diagnostic specificity in cases of clinically active systemic sarcoidosis from 83% to 99% when compared to ACE levels alone, without sacrificing sensitivity. CSF ACE levels may be elevated in up to 50% of patients with neurosarcoid.
• The serum calcium level may be elevated in 5-18% of patients with sarcoidosis, reflecting the remote effects of 1,25-dihydroxyvitamin D metabolism.

Imaging Studies

• Chest x-rays have been used to stage disease activity. A good quality chest x-ray is sufficient when typical changes are observed. Requesting an evaluation for sarcoidosis is imperative when ordering a chest x-ray since the radiologist will be far more likely to make subtle observations supporting the diagnosis of sarcoidosis.
• Neuroimaging: In suspected neurosarcoidosis, MRI may be invaluable. MRI is generally more useful than CT scan, especially with posterior fossa disease. The most common lesions on MRI include multiple white matter lesions, meningeal enhancement, optic nerve enhancement and mass lesions in the brain parenchyma. The distinction from demyelinating disease can often be difficult.
• Nuclear studies: To highlight potential biopsy sites and to aid in tissue diagnosis, gallium scans are often obtained in cases of suspected neurosarcoidosis when both chest x-ray findings and serum ACE levels are normal. Gallium 67 citrate scans often are supportive when typical findings are lacking. This is especially true in neurosarcoidosis or uveitis when a biopsy may not be feasible.

Procedures

• Diagnosis requires a biopsy in most cases. As a rule, the most accessible site with the lowest morbidity should be considered. A biopsy should be performed on palpable lymph nodes or elevated superficial skin lesions, if present.
• • Conjunctival biopsy: Conjunctival tissue is readily available with low morbidity. A biopsy should be considered even in the absence of lesions. A blind or random conjunctival biopsy yields positive histologic evidence of sarcoidosis in 10-28% cases of suspected sarcoidosis.
  • Lacrimal gland biopsy: In cases of lacrimal gland enlargement or when the lacrimal glands are involved on gallium scan, a biopsy may be useful. A transconjunctival approach has been recommended to minimize the risk of secondary keratoconjunctivitis sicca.
• Bronchoscopy, particularly fiberoptic bronchoscopy, yields positive biopsy results in 60% of stage I disease and greater than 80% of stage II or III pulmonary sarcoidosis. Transbronchial or airway mucosal sampling is useful in the initial histologic confirmation of sarcoidosis.
• Pulmonary function tests (PFTs) primarily reflect interstitial lung disease with decreased lung volumes. PFT results may be abnormal before chest x-ray findings and are useful in determining the extent of pulmonary involvement.

Histologic Findings

The typical histologic findings obtained from biopsy specimens include diffuse noncaseating epithelioid granulomas. Infectious etiologies need to be excluded by culture and/or staining.

The epithelioid granulomas are well-formed compact aggregates, of varying age, ranging from highly cellular to relatively acellular collections.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

The elimination of symptoms is the chief goal in treating sarcoidosis. Asymptomatic cases need no treatment. Expectant observation is prudent before initiating therapy. Reserve treatment for documented disease progression.

Approximately 75% of patients with sarcoidosis will have mild, stable disease or even remission, requiring no therapy. Approximately 25% of patients require treatment, including 10% of patients who have extrathoracic indications in critical organs (eg, eye, brain, heart) and 15% of patients who have the indication of progressive pulmonary disease.

Few firm guidelines exist for the treatment of systemic disease. Oral corticosteroids are indicated as the first-line therapy for severe pulmonary disease (eg, symptomatic stage II, progressive stage II, stage III) and systemic disease (eg, cardiac manifestations, neurosarcoid, malignant hypercalcemia).

• Corticosteroids are the mainstay of therapy for extraorbital sarcoid. The current corticosteroid protocol for systemic disease is 30-40 mg prednisone daily for 8-12 weeks. Gradually taper the dose to 10-20 mg every other day over a period of 6-12 months to establish the minimal effective dose. An alternate protocol is prednisone 1 mg/kg of body weight for 4-6 weeks, followed by slow taper over 2-3 months. Repeat if disease becomes clinically active. Most patients who require longer term steroids can be managed using 10-15 mg of prednisone every other day.
• Noncorticosteroid drugs are being used more frequently, including anti-inflammatory drugs (NSAIDs); antimalarial agents, such as hydroxychloroquine; and immunosuppressant agents, such as methotrexate, cyclosporine, and azathioprine. Infliximab and thalidomide have also been successfully used in refractory sarcoidosis. Cutaneous sarcoidosis has been successfully treated with tetracyclines.
• Treatment of neurosarcoid includes medical therapy and radiation.
• Medical treatment of ocular involvement
• • Corticosteroids are the mainstay of treatment. Topical corticosteroids, depot periocular injections, and oral corticosteroids may be used. Anterior uveitis responds well to topical corticosteroids and cycloplegia. Intermediate and posterior uveitis due to inadequate penetration of topical corticosteroids into the posterior segment responds well to depot (sub-Tenon) injections and/or oral corticosteroids. Factors favoring the oral route of administration for uveitis include optic nerve involvement; intermediate, posterior, or panuveitis; bilateral disease; and coexisting threshold systemic disease.
  • Topical corticosteroids are the treatment of choice for anterior uveitis. Pred Forte 1% (prednisolone acetate) is the criterion standard; generic prednisolone acetate is less effective. Prednisolone phosphate is effective but less potent than prednisolone acetate. Newer agents, such as loteprednol etabonate (Lotemax), may be effective second choices, with less chance of steroid-induced glaucoma. They are particularly useful for maintenance. Weaker steroids, such as rimexolone (Vexol) and fluorometholone (FML), may play a role for patients in remission.
  • No specific treatment guidelines are available, but the following treatment guideline for prednisolone acetate 1% is provided as a practical guideline for acute anterior uveitis. Similar topical corticosteroid regimens have been based in recent uveitis treatment protocols.
    • 1 drop every 1-2 hours while awake for 1 week
    • 1 drop 4 times daily for 1 week
    • 1 drop 3 times daily for 1 week
    • 1 drop 2 times daily for 1 week
    • 1 drop daily for 1 week
    • Discontinue if anterior chamber cells and flare are eliminated.
  • Reevaluate the inflammation and intraocular pressures at 1- to 2-week intervals for the first month after onset of treatment. If inflammation is not improving at any given taper interval, maintain that dosing and taper only after the cells and flare decrease.
  • Cycloplegia is indicated with acute intense inflammation to relieve ciliary spasm and to prevent formation of posterior synechiae.
  • Topical nonsteroidal anti-inflammatory agents may be used when there is evidence for or concern about steroid glaucoma or the possibility of cataract acceleration as a result of long-term topical steroid use.
  • Intermediate and posterior uveitis usually responds well to depot corticosteroid injections. Topical corticosteroids and cycloplegics may supplement oral and/or sub-Tenon injections. Injections may be repeated at weekly, biweekly, or monthly intervals, up to 3-4 times, before maximal benefit is reached. Oral prednisone treatment guidelines similar to the above systemic guidelines may be used.
  • Orbital sarcoidosis usually requires oral corticosteroids, but retrobulbar injections of corticosteroids may be helpful.
• Corticosteroid-sparing agents
  • Cyclosporine A: In cases of steroid failures or intolerance, cyclosporine A has been used with mixed results.
  • Methotrexate has been shown to be effective in recalcitrant uveitis.
• Oral monoclonal antibody therapy is being investigated in the treatment of otherwise nonresponsive uveitis. Interferon therapy is likewise being studied.

Surgical Care

• Surgical treatment of neurosarcoid: Surgery is indicated for hydrocephalus, expanding mass lesions, or lesions that cause increased intracranial pressure.
• Surgical treatment of ocular involvement: Cataract surgery may be performed when the intraocular inflammation is absolutely controlled. Vitrectomy may be required for severe vitreous opacification. If secondary glaucoma is unresponsive to maximal medical therapy, patients may require either trabeculectomy or glaucoma drainage device implant procedures.

Consultations

• Consultation with a pulmonologist may be helpful in cases of ophthalmic or neurosarcoid to aid in the diagnosis (eg, bronchoscopy with biopsy) and to coordinate therapy.
• Neurosurgical consultation may be warranted in cases of hydrocephalus that are resistant to medical therapy.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Corticosteroids remain the drug of choice for severe systemic disease, neurologic manifestations, and intraocular inflammatory disease.

In recalcitrant cases or those intolerant of corticosteroids, steroid-sparing drugs, such as MTX, and antimalarials have been used with varying success.

Uveitis may be treated with topical ophthalmic corticosteroid preparations and/or periocular corticosteroid injections. Cycloplegia is optimized with atropine or homatropine.

Drug Category: Corticosteroids

Used for systemic, neurologic, and severe ocular inflammation. Shown to be teratogenic in many species but no adequate and well-controlled studies in pregnant women (steroid-dependent asthmatic women have delivered normal, average weight, full-term infants).

Fluid and electrolyte disturbances include sodium retention, fluid retention, congestive heart failure in susceptible patients, potassium loss, hypokalemic alkalosis, and hypertension. Musculoskeletal associations include muscle weakness, steroid myopathy, loss of muscle mass, osteoporosis, compression fractures, osteonecrosis, and pathologic fractures. GI associations include peptic ulceration and bleeding, pancreatitis, and abdominal distention. Dermatologic associations include impaired wound healing, fragile skin, petechiae, ecchymoses, facial erythema, and increased sweating.

Metabolic associations include negative nitrogen balance due to protein catabolism. Neurologic associations include convulsions, pseudotumor cerebri, vertigo, and headache. Endocrine associations include menstrual irregularities, cushingoid state, secondary adrenocortical and pituitary unresponsiveness, growth retardation in children, decreased carbohydrate tolerance, and latent diabetes mellitus. Ophthalmic associations include cataracts, glaucoma, and exophthalmos.

Frequency of adverse effects is as follows: Weight gain of >20 lb 24%, diabetes mellitus (most common in patients with significant liver disease) 8%, aseptic necrosis 2%, aseptic ulcer 2%, and cataract 1%.

Osteoporosis is a well-recognized problem with chronic corticosteroid usage; calcium supplements and alendronate may be required to prevent fractures.

Drug Name	Prednisolone acetate (Pred Forte)
Description	Decreases inflammation and corneal neovascularization. Suppresses migration of polymorphonuclear leukocytes and reverses increased capillary permeability. In cases of bacterial infections, concomitant use of anti-infective agents is mandatory; if signs and symptoms do not improve after 2 days, reevaluate patient. Dosing may be reduced, but advise patients not to discontinue therapy prematurely.
Adult Dose	1 gtt q1-2h while awake for 1 wk 1 gtt qid for 1 wk 1 gtt tid for 1 wk 1 gtt bid for 1 wk 1 gtt qd for 1 wk Discontinue if anterior chamber cells and flare are eliminated
Pediatric Dose	Not established; in standard practice, uveitis regimens similar to adult dosages have been used safely
Contraindications	Documented hypersensitivity; acute untreated purulent ocular conditions; acute superficial herpes simplex dendritic keratitis; vaccinia, varicella, and most other viral corneal infections; ocular tuberculosis; fungal diseases of the eye
Interactions	None reported
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Ophthalmic adverse reactions include cataracts, increased intraocular pressure and glaucoma, secondary ocular infections from fungi or viruses, perforation of globe with scleral or corneal thinning; systemic adverse effects rarely may occur with extensive use of topical steroids

Drug Name	Rimexolone (Vexol)
Description	Decreases inflammation and corneal neovascularization. Suppresses migration of polymorphonuclear leukocytes and reverses increased capillary permeability.
Adult Dose	Anterior uveitis: 1-2 gtt into conjunctival sac of affected eye Week 1: 1 gtt q1h during waking hours Week 2: 1 gtt q2h during waking hours Week 3 and on: Taper until uveitis is resolved See acute uveitis taper regimen in Medical Care
Pediatric Dose	Not established; in standard practice, uveitis regimens similar to adult dosages have been used safely
Contraindications	Documented hypersensitivity; acute untreated purulent ocular conditions; acute superficial herpes simplex dendritic keratitis; vaccinia, varicella, and most other viral corneal infections; ocular tuberculosis; fungal diseases of the eye
Interactions	None reported
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Corneal fungal infections are particularly prone to develop coincidentally with long-term local steroid application; ophthalmic adverse reactions include cataracts, increased intraocular pressure and glaucoma, secondary ocular infections from fungi or viruses, perforation of the globe with scleral or corneal thinning; systemic adverse effects rarely may occur with extensive use of topical corticosteroids

Drug Name	Loteprednol etabonate 0.5% suspension (Lotemax)
Description	A sterile topical anti-inflammatory corticosteroid for ophthalmic use. Indicated for the treatment of steroid-responsive inflammatory conditions of the palpebral and bulbar conjunctiva, cornea, and anterior segment of the globe.
Adult Dose	Up to 1 gtt q1h during first wk of initial treatment
Pediatric Dose	Not established; in standard practice, uveitis regimens similar to adult dosages have been used safely
Contraindications	Documented hypersensitivity; acute untreated purulent ocular conditions; acute superficial herpes simplex (dendritic keratitis); vaccinia, varicella, and most other viral corneal infections; ocular tuberculosis; fungal diseases of the eye
Interactions	None reported
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Corneal fungal infections are particularly prone to develop coincidentally with long-term local corticosteroid use; ophthalmic adverse reactions include cataracts, increased intraocular pressure and glaucoma, secondary ocular infections from fungi or viruses, perforation of the globe with scleral or corneal thinning; systemic adverse effects rarely may occur with extensive use of topical corticosteroids

Drug Category: Mydriatic and cycloplegic agents

Used to induce cycloplegia for pain control and prevention of posterior synechiae in uveitis.

Drug Name	Homatropine 2% or 5% solution (AK-Homatropine, Isopto Homatropine)
Description	Sterile topical anticholinergic agent for ophthalmic use. Parasympatholytic drug quite similar to atropine but weaker and with a shorter duration of action.
Adult Dose	1-2 gtt in the eyes tid
Pediatric Dose	Not established; use with extreme caution
Contraindications	Documented hypersensitivity; glaucoma or a predisposition to narrow-angle glaucoma
Interactions	None reported
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Lacrimal sac compression by digital pressure for 2-3 min after instillation may avoid systemic absorption; to avoid inducing angle-closure glaucoma, an estimation of anterior chamber depth should be made; ophthalmic adverse reactions include allergic lid reactions, local irritation, hyperemia, edema, follicular conjunctivitis, or dermatitis

Drug Category: Antineoplastics/antimetabolites

Several agents have been used for severe systemic, ocular, and neurosarcoid unresponsive to corticosteroids. Based on safety and efficacy, MTX and azathioprine are the preferred agents for most patients.

Drug Category: Cytotoxic agents

Inhibit cell growth and proliferation.

Drug Name	Cyclosporine (Sandimmune, Neoral)
Description	Cyclic polypeptide that suppresses some humoral immunity and, to a greater extent, cell-mediated immune reactions such as delayed hypersensitivity, allograft rejection, experimental allergic encephalomyelitis, and graft-vs-host disease for a variety of organs. For children and adults, base dosing on ideal body weight.
Adult Dose	2-5 mg/kg/d PO bid in divided doses
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; uncontrolled hypertension or malignancies; do not administer concomitantly with PUVA or UVB radiation in psoriasis since it may increase risk of cancer; renal impairment; severe hypertension; infections
Interactions	Carbamazepine, phenytoin, isoniazid, rifampin, and phenobarbital may decrease cyclosporine concentrations; azithromycin, itraconazole, nicardipine, ketoconazole, fluconazole, erythromycin, verapamil, grapefruit juice, diltiazem, aminoglycosides, acyclovir, amphotericin B, and clarithromycin may increase cyclosporine toxicity; acute renal failure, rhabdomyolysis, myositis, and myalgias increase when taken concurrently with lovastatin
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Monitoring should include complete blood count, serum creatinine, urinalysis, blood pressure; advise patients about adequate fluid intake and diuresis; avoid infections Newer formulations (Neoral) are absorbed much better than traditional preparation (Sandimmune) necessitating dosage adjustment and repeat serum levels

Drug Name	Cyclophosphamide (Neosar, Cytoxan)
Description	Chemically related to nitrogen mustards. As an alkylating agent, the mechanism of action of the active metabolites may involve cross-linking of DNA, which may interfere with growth of normal and neoplastic cells.
Adult Dose	1-3 mg/kg/d IV qmo
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; severely depressed bone marrow function
Interactions	Allopurinol may increase risk of bleeding or infection and enhance myelosuppressive effects; may potentiate doxorubicin-induced cardiotoxicity; may reduce digoxin serum levels and antimicrobial effects of quinolones; chloramphenicol may increase half-life while decreasing metabolite concentrations; may increase effect of anticoagulants; coadministration with high doses of phenobarbital may increase rate of metabolism and leukopenic activity; thiazide diuretics may prolong cyclophosphamide-induced leukopenia and neuromuscular blockade by inhibiting cholinesterase activity
Pregnancy	D - Unsafe in pregnancy
Precautions	Monitoring should include blood count, liver function tests, and urinalysis; advise patients about adequate fluid intake and diuresis and sperm bank storage; avoid infections Cyclophosphamide has been associated with early menopause and aspermia; all of the cytotoxic agents are teratogenic, and all patients of reproductive age (both men and women) should take birth control while on therapy

Drug Category: Antimalarials

Used for their anti-inflammatory properties.

Drug Category: Nonsteroidal anti-inflammatory drugs

NSAIDs may be used for erythema nodosum and arthritis but have had little success in treating serious ocular inflammatory disease or neurosarcoidosis.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

In/Out Patient Meds

• See Medication.

Complications

• Systemic - Nephrocalcinosis, pulmonary fibrosis, and cardiac dysrhythmias
• Ocular - Band keratopathy, cataracts, glaucoma, CME, vitreous hemorrhage, retinal detachment, and blindness from macular lesions
• Neuro-ophthalmologic - Diplopia and optic atrophy
• Neurosarcoid - Seizures, hydrocephalus, deafness, motor/sensory deficits from spinal lesions, and pituitary dysfunction

Prognosis

• Prognosis of sarcoidosis is highly variable. Spontaneous remissions occur in nearly two thirds of systemic disease. The course may be chronic or progressive in 10-30%.
• Ocular involvement is similarly variable. In general, acute iritis, hilar adenopathy, and erythema nodosum tend to have a benign self-limiting course. Chronic uveitis, glaucoma, and CME bode poorly. Fundus lesions have an increased incidence of associated neurosarcoidosis.
• Neurosarcoid
• • In general, neurosarcoid carries a poorer prognosis than any of the protean manifestations of the disease. Of all deaths due primarily to sarcoidosis, 25% occur in patients with CNS localization.
  • Lesions involving the spinal cord, optic nerve lesions, and seizures carry a poor prognosis, while facial nerve pareses fare better.
  • The prognosis of sarcoid meningitis was excellent in Chapelon's series. Approximately two thirds of the patients with cranial neuropathy or CNS involvement recovered without deficit. Peripheral polyneuropathy and myopathy had a less favorable prognosis.
• Adverse prognostic factors include lupus pernio, chronic uveitis, 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.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Diagnosis: Ocular involvement (particularly uveitis) and neurosarcoid may be difficult to diagnose. A high level of suspicion and periodic retesting may be warranted when the initial workup is negative.
• Treatment
• • Discuss corticosteroid and/or immunosuppressive adverse effects in detail with the patient. The risks, benefits, and alternatives of chronic immunosuppression must be properly documented.
  • Check TB skin test and controls prior to initiation of corticosteroid therapy.
  • Appropriate and timely treatment may avoid chronic CME, a common cause of visual disability.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• Altan-Yaycioglu R, Akova YA, Akca S, Yilmaz G. Inflammation of the posterior uvea: findings on fundus fluorescein and indocyanine green angiography. Ocul Immunol Inflamm. Jun 2006;14(3):171-9. [Medline].
• Baarsma GS, La Hey E, Glasius E, et al. The predictive value of serum angiotensin converting enzyme and lysozyme levels in the diagnosis of ocular sarcoidosis. Am J Ophthalmol. 1987;104:211-7. [Medline].
• Baughman RP, Judson MA, Teirstein A, et al. Presenting characteristics as predictors of duration of treatment in sarcoidosis. QJM. May 2006;99(5):307-15. [Medline].
• Baughman RP, Judson MA, Costabel U. Randomized, double-blind, placebo-controlled trial of infliximab in patients with chronic pulmonary sarcoidosis. Chest. 2005;128:202S.
• Bresnitz EA, Strom BL. Epidemiology of sarcoidosis. Epidemiol Rev. 1983;5:124-56. [Medline].
• Burton BJ, Breen RA, Janossy G, et al. Use of pulmonary interferon {gamma} responses to mycobacterial antigen to distinguish sarcoid associated optic neuropathy from tuberculosis. Br J Ophthalmol. Jun 2006;90(6):802-3. [Medline].
• Caca I, Unlu K, Buyukbayram H, Ari S. Conjunctival deposits as the first sign of systemic sarcoidosis in a pediatric patient. Eur J Ophthalmol. Jan-Feb 2006;16(1):168-70. [Medline].
• Chapelon C, Ziza JM, Piette JC, et al. Neurosarcoidosis: signs, course and treatment in 35 confirmed cases. Medicine (Baltimore). Sep 1990;69(5):261-76. [Medline].
• Colover J. Sarcoidosis with involvement of the nervous system. Brain. 1948;71:451-75.
• 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.
• DeBroff BM, Donahue SP. Bilateral optic neuropathy as the initial manifestation of systemic sarcoidosis. Am J Ophthalmol. Jul 15 1993;116(1):108-11. [Medline].
• DeRosa AJ, Margo CE, Orlick ME. Hemorrhagic retinopathy as the presenting manifestation of sarcoidosis. Retina. 1995;15(5):422-7. [Medline].
• Delaney P. Neurologic manifestations in sarcoidosis: review of the literature, with a report of 23 cases. Ann Intern Med. Sep 1977;87(3):336-45. [Medline].
• Dev S, McCallum RM, Jaffe GJ. Methotrexate treatment for sarcoid-associated panuveitis. Ophthalmology. Jan 1999;106(1):111-8. [Medline].
• Doty JD, Mazur JE, Judson MA. Treatment of sarcoidosis with infliximab. Chest. Mar 2005;127(3):1064-71.
• Frohman L, Grigorian R, Slamovits T. Evolution of sarcoid granulomas of the retina. Am J Ophthalmol. May 2001;131(5):661-2. [Medline].
• Gould H, Kaufman HE. Sarcoid of the fundus. Arch Ophthalmol. 1961;65:453-6. [Medline].
• Henke CE, Henke G, Elveback LR, et al. The epidemiology of sarcoidosis in Rochester, Minnesota: a population- based study of incidence and survival. Am J Epidemiol. May 1986;123(5):840-5. [Medline].
• Honeybourne D. Ethnic differences in the clinical features of sarcoidosis in South- East London. Br J Dis Chest. Jan 1980;74(1):63-9. [Medline].
• Hunninghake GW, Costabel U, Ando M, et al. ATS/ERS/WASOG statement on sarcoidosis. American Thoracic Society/European Respiratory Society/World Association of Sarcoidosis and other Granulomatous Disorders. Sarcoidosis Vasc Diffuse Lung Dis. Sep 1999;16(2):149-73. [Medline].
• Ingestad R, Stigmar G. Sarcoidosis with ocular and hypothalamic-pituitary manifestations. Acta Ophthalmol (Copenh). 1971;49(1):1-10. [Medline].
• James DG, Neville E, Langley DA. Ocular sarcoidosis. Trans Ophthalmol Soc U K. Apr 1976;96(1):133-9. [Medline].
• Johns CJ, Michele TM. The clinical management of sarcoidosis. A 50-year experience at the Johns Hopkins Hospital. Medicine (Baltimore). Mar 1999;78(2):65-111. [Medline].
• Jones NP. Sarcoidosis. Curr Opin Ophthalmol. Dec 2002;13(6):393-6. [Medline].
• Kiryu J, Kita M, Tanabe T, et al. Pars plana vitrectomy for cystoid macular edema secondary to sarcoid uveitis. Ophthalmology. Jun 2001;108(6):1140-4. [Medline].
• Lama P, Frohman L. Annual review of systemic disease--1997--II. J Neuroophthalmol. Jun 1998;18(2):127-42. [Medline].
• Laval J. Ocular sarcoidosis. Am J Ophthalmol. 1952;35:551-4. [Medline].
• Levinsky L, Cummiskey J, Romer FK, et al. Sarcoidosis in Europe: a cooperative study. Ann N Y Acad Sci. 1976;278:335-46. [Medline].
• Lewis SJ, Ainslie GM, Bateman ED. Efficacy of azathioprine as second-line treatment in pulmonary sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis. Mar 1999;16(1):87-92. [Medline].
• Lucas DR. Tumours of the orbit. In: Greer's Ocular Pathology. 4th ed. Blackwell Publishers;1989:243.
• Mayers M. Ocular sarcoidosis. Int Ophthalmol Clin. Fall 1990;30(4):257-63. [Medline].
• Newman LS, Rose CS, Maier LA. Sarcoidosis. N Engl J Med. Apr 24 1997;336(17):1224-34. [Medline].
• Nosal A, Schleissner LA, Mishkin FS, Lieberman J. Angiotensin-I-converting enzyme and gallium scan in noninvasive evaluation of sarcoidosis. Ann Intern Med. Mar 1979;90(3):328-31. [Medline].
• Nussenblatt RB, Whitcup SM, Palestine AG. Uveitis: Fundamentals and Clinical Practice. 2nd ed. Mosby-Year Book;1996.
• Obenauf CD, Shaw HE, Sydnor CF, Klintworth GK. Sarcoidosis and its ophthalmic manifestations. Am J Ophthalmol. Nov 1978;86(5):648-55. [Medline].
• Oksanen V. Neurosarcoidosis: clinical presentations and course in 50 patients. Acta Neurol Scand. Mar 1986;73(3):283-90. [Medline].
• Power WJ, Neves RA, Rodriguez A, et al. The value of combined serum angiotensin-converting enzyme and gallium scan in diagnosing ocular sarcoidosis. Ophthalmology. Dec 1995;102(12):2007-11. [Medline].
• Reich JM. How common is sarcoidosis?. Sarcoidosis Vasc Diffuse Lung Dis. Mar 1999;16(1):108. [Medline].
• Roy FH. Ocular Differential Diagnosis. 7th ed. Philadelphia: Lippincott Williams & Wilkins;. 2002.
• Rybicki BA, Major M, Popovich J, et al. Racial differences in sarcoidosis incidence: a 5-year study in a health maintenance organization. Am J Epidemiol. Feb 1 1997;145(3):234-41. [Medline].
• Sheppard JD, Nozik RA. Practical diagnostic approach to uveitis. In: Duane TA, Jaeger EW, eds. Clinical Ophthalmology. Vol 4. Philadelphia:. JB Lippincott;1989.
• Sheppard JD. Posterior uveitis. In: Nozik RA, Michaelson JB, eds. Ophthalmology Clinics of North America. Vol 6. WB Saunders Co;1993.
• Shetty AK, Zganjar BE, Ellis GS, et al. Low-dose methotrexate in the treatment of severe juvenile rheumatoid arthritis and sarcoid iritis. J Pediatr Ophthalmol Strabismus. May-Jun 1999;36(3):125-8. [Medline].
• Siltzbach LE, James DG, Neville E, et al. Course and prognosis of sarcoidosis around the world. Am J Med. Dec 1974;57(6):847-52. [Medline].
• Smith JA, Foster CS. Sarcoidosis and its ocular manifestations. Int Ophthalmol Clin. Winter 1996;36(1):109-25. [Medline].
• Spalton DJ, Sanders MD. Fundus changes in histologically confirmed sarcoidosis. Br J Ophthalmol. May 1981;65(5):348-58. [Medline].
• Stern BJ, Krumholz A, Johns CJ. Neurosarcoidosis. Presentation and management. Ann N Y Acad Sci. 1986;465:722-30.