Orbital and Ocular Adnexal Sarcoidosis

There are two schools of thought:

• One, that a diagnosis of orbital and ocular adnexal sarcoidosis should be made only in patients with evidence of systemic disease (Mombaerts 1996). Accordingly, isolated orbital and/or adnexal granulomatous inflammation, consistent with sarcoidosis, without evidence of systemic sarcoidosis, is considered a variant of idiopathic orbital inflammation.
• The second school of thought allows for a diagnosis of sarcoidosis limited to the orbit and ocular adnexa. In a retrospective review of 379 sarcoidosis patients managed by the Department of Ophthalmology at the Henry Ford Hospital in Detroit from 2000 to 2008, 30 patients had orbital and adnexal sarcoidosis (Demirci 2011).
• Systemic sarcoidosis was detected in only 70% (21/30).
• Systemic disease was evident before periocular presentation in only 11 of 30 (37%), and was discovered in another 8 at the time of the diagnosis.
• In 2 patients the systemic presentation was evident after the periocular presentation (7%) 9 may have had subclinical systemic disease.

Among 20 patients diagnosed with orbital sarcoidosis in Vancouver from 1976 to 2005 only 50% had evidence of systemic disease on follow-up (Mavrikakis 2007).

In a review of 532 systemic sarcoidosis patients, 10% had orbital and adnexal involvement, so it is fairly common among systemic sarcoidosis patients (Obenauf 1978).

Among ophthalmic sarcoidosis patients in Boston, 10% had orbital/adnexal involvement similar to the Detroit experience (Smith 1996).

The classic ocular involvement of systemic sarcoidosis with uveitis and retinal vasculitis most commonly does not occur in the same patient who develops orbital and adnexal disease. In a multicenter study of 26 patients with orbital and adnexal sarcoidosis, 6 had anterior uveitis at diagnosis, prior to diagnosis, or on follow-up (Prabhakaran 2007).

Eiology

Sarcoidosis seems to be an exaggerated granulomatous reaction to unidentified antigen(s) in individuals who are genetically susceptible (Valeyre 2014).

Two suspected infectious agents linked to sarcoidosis are mycobacteria (Haupert 1997) and propionibacteria (Eishi 2013).

• There is no evidence that it is an infectious disease.
• Killed or partly degraded pathogens seem to trigger the immune response.
• The high lipid content in the cell membranes of these 2 infectious agents make them resist degradation.
• Resistance to degradation is a constant in sarcoidosis.

The antigens in partly degraded mycobacteria and propionibacteria have “trigger patterns” that bind to trigger pattern receptors: Toll-like receptors 2 and 9, C-type lectins, and NOD-like receptors.

Macrophages typically suppress the effector T-cell response, whereas macrophages from patients with sarcoidosis have antigen-presenting capacities and are hyper-reactive to certain ligands.

Non-necrotizing granulomas are thought to trap remnants that cannot be further degraded. In the progressive disease, the antigen is postulated to persist, thereby inducing a chronic immune response.

A predisposing genetic background determines the course of the disease (Rybicki 2001).

• HLA- DRB1*03 predisposes to disease with spontaneous resolution (Ishihara 1995).
• HLA-DRB1*14 or HLA-DRB1*15 are predisposing for a chronic course.

Other organic and inorganic substances might also trigger sarcoidosis (Chen 2008).

Epidemiology

The lacrimal gland and orbit are involved about equally (each 40%) (Prabhakaran 2007). The eyelid and lacrimal sac are involved less frequently (each 10%).

It is commonly bilateral (about 25%).

It is most common in the fifth and sixth decade of life:

• Wide range of presentation from third to ninth decade
• Pediatric presentation rare

Patients with orbital and adnexal disease are commonly Caucasian (Evans 2007). This differs from patients with primarily systemic disease (Prabhakaran 2007).

There is no gender predilection.

The systemic sarcoidosis incidence in the US is estimated at 36 in 100,000 for the African American population (Iannuzzi 2007). It is about 3-4 times more common in African Americans than Caucasians.

There is lung involvement and mediastinal lymphadenopathy in 85–90% of cases.

A high incidence of sarcoidosis was reported in firefighters and other responders after the attacks on the World Trade Center (Perlman 2011).

History

The most common presenting complaint is a palpable periocular mass (Prabhakaran 2007). Other complaints include:

• Lacrimal gland enlargement
• Medial canthal mass
• Another periocular area
• Proptosis
• Ptosis
• Dry eye
• Diplopia
• Decreased vision
• Dacryocystitis: lacrimal sac involvement (Harris 1981).
• Epiphora: nasal mucosal and sinus involvement

Cinical features

Sarcoidosis occurs almost exclusively in the anterior orbit.

• 97% had anterior, not mid- or posterior, orbital disease in one study study (Demirci 2011).
• Mostly superior and extraconal

In skin, sarcoidosis can be similar to molluscum lesions with flesh colored nodules and umbilicated centers (Hall 1995). Umbilication can progress to destructive lesion (Moin 2001).

Unusual presentations include vision loss due to optic nerve sheath involvement (Mavrikakis 2007).

Infiltration can involve extraocular muscles (Stannard 1985). Can present as painful external ophthalmoplegia (Cornblath 1993)

• Mass effect
• Inflammation

Heerfordt syndrome is uveitis, parotid gland enlargement, chronic fever, and facial paralysis:

• Originally described as a manifestation of mumps
• Now considered a rare presentation of sarcoidosis
• Not related to orbital and adnexal sarcoidosis

Testing

• Biopsy of ocular adnexal tissue shows typical sarcoidal granuloma with epithelioid histiocytes and scattered giant cells. The tissue can be surrounded by lymphocytes or “naked” granuloma.
• Chest x-ray demonstrates hilar lymphadenopathy with or without parenchymal involvement in 60–70% of cases.
• Serum angiotensin converting enzyme (ACE) is elevated in 60%.
• Gallium scintigraphy can demonstrate additional areas of lymphadenopathy.
• Serum lysozyme
• Serum calcium
• Serum liver function tests
• Biopsy areas of inflammation or granuloma

Testing for staging, fundamental impairment

There is no staging system for this disease.

• The risk factors for orbital and ocular adnexal sarcoidosis are not known.
• Environmental and occupational factors might play a role.
• Exposure to organic, inorganic, and predisposing infectious pathogens

• Idiopathic orbital inflammation
• Lymphoproliferative disease
• Vasculitis
• Tuberculosis

Natural history

Many patients can be observed without treatment:

• Extent of disease does not warrant treatment.
• Stable disease or regression common
• Absence of active inflammatory disease

Medical therapy

First-line management can be oral corticosteroids:

• For inflammatory or bulky disease
• Initial prednisone dose 20–80 mg daily
• Tapered slowly over 3–9 months
• Regression in 70% of cases
• Stable disease in 20% of cases

Methotrexate (Maust 2003) is accepted second-line treatment (Schutt 2010).

• Can also be used as steroid sparing agent
• Can be for regression or incomplete response with steroids

Cyclosporine (Oh 2008) and azathioprine are alternative treatments (Mavrikakis 2007).

Intralesional steroid injection can be effective for orbital masses and/or inflammation.

Cutaneous nodules might respond to intralesional steroid injection (Cacciatori 1997).

Radiation

None

Surgery

• Excision of granulomatous inflammatory tissue might facilitate healing.
• Can help by removing partly degraded pathogen
• Removing tumor burden improves ocular function

Other management considerations

Immunobiologic agents that target tumor necrosis factor-β (Levy-Clarke 2014) such as infliximab might have efficacy in resistant cases (Doty 2005).

There are only isolated reports of immunobiologic use for orbital inflammation (Wilson 2004).

According to an expert panel of the American Uveitis Society, infliximab or adalimumab might be considered as second-line immunomodulatory therapy for patients with sarcoid uveitis (Levy-Clarke 2014). Etanercept does not have efficacy for ocular disease, though ocular adnexal disease has not been studied (Baughman 2005).

Common treatment responses, follow-up strategies

In half of systemic sarcoidosis patients, the disease resolves spontaneously within 2 years

• Remission has occurred up to 5 years after onset.
• Therefore, acute sarcoidosis has referred to disease that is present for up to 2 years.
• Chronic sarcoidosis can refer to disease present for 3–5 years.

After remission, disease can develop on the contralateral side (Mavrikakis 2007).

Relapse in patients with spontaneous remission is rare (Rizzato 1998).

Relapse has occurred after tapering steroids in patients treated medically.

Relapse has occurred months after steroid withdrawal.

If the disease has been stable for 2–3 years, then the likelihood of reactivation after medical treatment is low.

Side effects of systemic corticosteroids include glaucoma, cataracts, hyperglycemia, weight gain, mood changes, peripheral edema, systemic hypertension, immunosuppression, osteoporosis, and gastritis. Ongoing monitoring and prevention of medication-related morbidity should be coordinated with the patient’s other medical caregivers.

Persistence of tumor effect can create permanent deficits

Orbital mass effect has been found to cause central retinal artery occlusion (Kim 2014).

Affected tissue can be difficult to manipulate surgically with increased morbidity

Lacrimal system surgery is more prone to failure from excessive fibrosis (Chapman 1999).

External DCR surgery has successfully treated nasolacrimal duct obstruction associated with sarcoidosis (Lee 2012).

• Intralesional corticosteroid injection can limit reactive inflammation and fibrosis.
• Systemic immunosuppressive therapy can improve the surgical outcome.

Ptosis surgery is complicated by inflammation and fibrosis.

The effect of strabismus surgery is less predictable.

In earlier literature the disease was referred to as Boeck’s sarcoid.

Other terms include Besnier-Boeck disease, Besnier-Boeck-Schaumann disease, Shaumann’s disease, benign lymphogranulomatosis, noncaseating tuberculosis, pseudotuberculosis, paratuberculosis.

The term sarcoid was adopted by Boeck in 1899 because skin lesions simulated sarcomas.

The earliest observed cases were in Caucasian patients.

The first description of orbital soft tissue involvement in sarcoidosis was in 1939 (King 1939).

Boeck’s sarcoidosis of the lacrimal gland was reported in 1940 (Stallard 1940).

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