Symptoms

May be acute, recurrent, or chronic. An explosive, painful onset is the hallmark of IOIS, but is present in only 65% of patients; the remainder may have a more insidious and relatively painless presentation. Pain, prominent red eye, “boggy” pink eyelid edema, double vision, or decreased vision. Children may have concomitant constitutional symptoms (fever, headache, vomiting, abdominal pain, and lethargy) and bilateral or sequential presentation, neither of which is typical in adults.

Signs

Other

Boggy, pink eyelid erythema and edema, conjunctival injection and chemosis, lacrimal gland enlargement or a palpable orbital mass, decreased vision, uveitis, increased IOP, hyperopic shift (typically in posterior scleritis), optic nerve swelling or atrophy (uncommon), and chorioretinal folds.

NOTE:

Bilateral IOIS in adults can occur, but should prompt a careful evaluation to rule out a systemic cause (e.g., sarcoidosis, GPA, IgG4-related orbitopathy, metastases [especially breast cancer], and lymphoma). Children may have bilateral disease in one-third of cases and may have associated systemic disorders.

Differential Diagnosis

• Orbital cellulitis and/or abscess.
• TED.
• Other noninfectious orbital inflammatory conditions: sarcoidosis, GPA, IgG4-related orbitopathy, amyloidosis, eosinophilic GPA, Sjögren syndrome, rheumatoid arthritis, systemic lupus erythematosus, histiocytosis, etc.
• Lymphoproliferative disease (including lymphoma).
• Primary orbital malignancy (e.g., rhabdomyosarcoma).
• Metastasis.
• Leaking dermoid cyst.
• Lymphangioma with acute hemorrhage.
• Vascular malformation, including carotid-cavernous fistula (CCF).
• Spontaneous orbital hemorrhage.
• Necrotic uveal melanoma.

Workup

See 7.1, ORBITAL DISEASE, for general orbital workup.

1. History: Previous episodes? Any other systemic symptoms or diseases? History of cancer? Smoking? Last mammogram, chest X-ray, colonoscopy, prostate examination? History of breathing problems? A careful review of systems is warranted. Fever, night sweats, and weight loss?
2. Complete ocular examination, including color vision, extraocular motility, exophthalmometry, IOP, and dilated funduscopic evaluation.
3. Vital signs, particularly temperature.
4. Imaging: Orbital CT (axial, coronal, and parasagittal views) with contrast: may show a thickened posterior sclera (the “ring sign” of 360 degrees of scleral thickening), orbital fat or lacrimal gland involvement, or thickening of the extraocular muscles (± their tendons). Bony erosion is very rare in IOIS and warrants further workup. Orbital MRI with contrast and fat suppression: May show EOM enlargement, infiltration of orbital fat, enlargement of the lacrimal gland, thickening of posterior Tenon/sclera, and enhancement along the optic nerve (perineuritis). In IOIS, the enhancement tends to “spill over” from an anatomic nidus into adjacent tissue (e.g., from EOM into surrounding orbital fat).
5. Blood tests as needed (e.g., bilateral or atypical cases): Westergren ESR, CBC with differential, ANA, ACE, cANCA, pANCA, LDH, IgG4/IgG levels, SPEP, BUN/creatinine, and fasting blood sugar/hemoglobin A1c (before instituting systemic corticosteroids). If sarcoidosis is suspected, consider chest CT which is significantly more sensitive than chest X-ray (CXR). Mammography and prostate evaluation are warranted in specific or atypical cases. Consider QuantiFERON-TB Gold testing before instituting corticosteroids in at-risk patients.
6. If possible, perform an incisional biopsy of involved orbital tissue if easily accessible with minimal morbidity before instituting corticosteroid therapy (corticosteroid therapy may mask the true diagnosis). The lacrimal gland is often involved in IOIS and is relatively easy to access surgically; strong consideration should be given to biopsy all cases of suspected inflammatory dacryoadenitis. However, a biopsy of other orbital structures (extraocular muscle and orbital apex) is typically avoided in cases of classic IOIS because of the potential surgical risks; biopsy of these structures is reserved for atypical or recurrent cases. Always be suspicious of metastatic disease in any patient with a history of cancer.

Treatment

1. Prednisone 1 to 1.2 mg/kg/d as an initial dose in adults and children, along with gastric prophylaxis (e.g., omeprazole 40 mg p.o. daily). All patients are warned about potential systemic side effects and are instructed to follow up with their primary physicians to monitor blood sugar and electrolytes.
2. Low-dose radiation therapy may be used when the patient does not respond to systemic corticosteroids, when the disease recurs as corticosteroids are tapered, or when corticosteroids pose a significant risk to the patient. Radiation therapy should only be used once orbital biopsy, if anatomically and medically feasible, has excluded other etiologies.
3. Steroid-sparing agents (e.g., methotrexate, cyclophosphamide, etc.) in cases that do not respond to or recur with corticosteroid therapy. Biopsy of affected tissue, when feasible, is indicated to rule out malignancy.
4. Biologic therapy may be considered in cases that fail other modalities. The efficacy of specific biologic agents (e.g., CD20 antibody, tumor necrosis factor-α (TNF-α) antibody, etc.) in IOIS is not known. There is evidence that IOIS is a T-cell driven process with elevated cytokines (including TNF-α); infliximab and adalimumab may be reasonable biologics to consider in recalcitrant or recurrent IOIS.

Follow Up

Re-evaluate in 1 to 2 days. Patients who respond dramatically to corticosteroids are maintained at the initial dose for 3 to 5 days, followed by a slow taper to 40 mg/d over 2 weeks, and an even slower taper below 20 mg/d, usually over several weeks. If the patient does not respond dramatically to appropriate corticosteroid doses, biopsy should be strongly considered. Recurrences of IOIS are not uncommon, especially at lower corticosteroid doses.

NOTE:

IgG4-related disease is a recently described fibroinflammatory condition typified by lymphoplasmacytic infiltration of soft tissues by IgG4+ plasma cells, often with systemic involvement. Elevated serum levels of IgG4 may be present. Clinical management follows the typical algorithm of other orbital inflammations: systemic corticosteroids followed by steroid-sparing agents in chronic or recalcitrant cases. IgG4-related orbitopathy may involve any of the orbital soft tissues, but does not usually present in the explosive fashion of classic IOIS; enlargement and infiltration of sensory nerves on orbital imaging studies is a classic feature of IgG4-related orbitopathy. Definitive diagnosis requires histopathologic confirmation and IgG4 immunostaining. There is evidence from East Asia that IgG4-related disease may increase the risk of eventual lymphoma.