Natural history
Clinical presentation varies depending on the involved tissues, ranging from a diffuse inflammatory process to a more localized inflammation of muscle, lacrimal gland, or orbital fat. Without treatment, fibrosis with loss of function of the involved tissues is expected.
Pediatric IOI (17% of cases) can present slightly differently than in the adult population, with more common bilateral involvement. The most common sign is proptosis, followed by redness and pain.
- Uveitis, disc edema, and tissue eosinophilia are also more common in the pediatric population. Presence of uveitis generally implies a poorer outcome.
- Pediatric IOI often involves the lacrimal gland.
- Bilateral presentation might have a higher incidence of coexisting systemic disease.
IgG4-associated sclerosing IOI (see IgG4-Related Disease section for more detail):
- Can be seen in the pediatric and adult populations (Lindfield 2012, Griepentrog 2013).
- Often involves the lacrimal gland, and can be bilateral or unilateral
- Is recognized as, and evolves into, a multisystem disease
- Can be associated autoimmune pancreatitis, bile duct/gallbladder (sclerosing cholangitis), salivary glands, retroperitoneal fibrosis or inflammation, nephritis, interstitial lung disease, prostate, lymphadenopathy, Hashimoto's thyroiditis
- IgG4 normally accounts for only 4% of total IgG (as opposed to IgG1, 2, or 3) and is inefficient at inducing both Fc-receptor-mediated clearance and the activation of the complement cascade, however, it is produced in parallel with IgE in response to allergens.
- The recently recognized syndrome of orbital disease characterized by widespread tissue infiltration by IgG4-positive plasma cells and elevated serum levels of IgG4 (> 135mg/dl) is described in more detail in the IgG4-Related Disease section.
- Long-term follow-up is necessary because some patients can develop lymphoma.
Tolosa-Hunt syndrome variant of IOI is characterized by extension into the cavernous sinus through superior orbital fissure, with associated cranial nerve findings.
Sclerosing IOI:
- This subtype often presents bilaterally and can have an elevated erythrocyte sedimentation rate (Winn 2012).
- Sclerosing IOI can be associated with systemic multifocal fibrosclerosis or other systemic inflammatory disease.
- Pemberton and Fay's literature review showed no ethnicity, gender, or comorbidity predilection (Pemberton 2012).
- It typically presents in fourth decade of life with proptosis as most common feature (73%), pain (49%), normal vision (44%).
- It can extend into the sinuses.
- It is a recurrent or recalcitrant disease with no clear consensus on treatment regimen.
Medical therapy
Oral corticosteroid is the mainstay of therapy:
- The clinician often will see a dramatic response to oral corticosteroid in the first 24–48 hours, which has been viewed as pathognomonic for acute nonsclerosing IOI.
- The average prednisone starting dose is 60–80 mg/day.
- Gradually taper by 10–20 mg q week if tolerated without relapse of symptoms. The myositis subtype can require longer, slower taper (Yuen 2003).
- Closely monitor with medical doctor for side effects of steroids.
- Consider pulse-dosed intravenous dexamethasone prior to oral corticosteroids:
- 500 mg IV q week x 6
- 250 mg IV q week x 6
- About 37% patients treated with steroids show failure to resolve, in which case, consider biopsy.
Empiric therapy can be effective if an idiopathic diagnosis is confident (tissue diagnosis not required).
Biopsy is an option with an atypical presentation or examination.
Many surgeons choose to biopsy all infiltrative orbital lesions prior to subjecting a patient to long-term corticosteroid therapy. Exceptions to this include presumed orbital myositis or orbital apex lesions.
If there no improvement or the IOI recurs, consider performing an orbital biopsy.
Second-line pharmacologic treatment options for steroid-intolerant or -resistant patients as part of a steroid-sparing strategy:
- Adjunctive nonsteroidal anti-inflammatory drugs (NSAID) can be helpful:
- Mycophenolate mofetil (brand name: Cellcept, Hatton 2005, Patel 2011):
- Immunosuppressant and prodrug of mycophenolic acid
- Purine nucleotide synthesis blocker that reversibly inhibits T and B lymphocyte proliferation
- Antifibrotic effects
- Common side effects were GI upset or abdominal pain, nausea, elevated cholesterol levels, hyperkalemia, hypocalcemia, coughing, and back pain.
- Increased infection, with leukopenia and anemia, reflect the immunosuppressive and myelosuppressive effects of the drug on lymphocyte production.
- Typical starting dosage was 500 mg daily, increased to a maximum of 1.5–3 g daily.
- Work with a PCP or rheumatologist to monitor electrolytes, CBC, and serum lipids.
- Rituximab (brand name: Rituxan, MabThera, Zytux) is a chimeric monoclonal antibody that targets protein CD-20, which is primarily found on the surface of B cells (On 2006, Schafranski 2009, Lindfield 2012).
- Side effects include infusion site reactions, rash, rigors, fever, headache, infection, and bronchospasm.
- Work with a PCP or rheumatologist to monitor electrolytes and CBC.
- Infliximab (brand name: Remicade) is an intravenous antibody that blocks the effects of tumor necrosis factor alpha (TNF-alpha), thus decreasing signs and symptoms of inflammation (Garrity 2004; Wilson 2004).
- Risks: Reactivation of tuberculosis and possible risk of lymphoma
- Work with a PCP or rheumatologist to monitor electrolytes and CBC.
- Adalimumab (brand name: Humira) might be a safer alternative to infliximab (Adams 2005, Verma 2013).
- Also a recombinant IgG1 monoclonal antibody containing 100% human peptide sequences targeting tumor necrosis factor alpha (TNF-alpha)
- Induction dose 160 mg, 80 mg, 40 mg weekly
- Risks of lymphoma (particularly in patients with long-standing rheumatoid arthritis), infection, and optic neuritis
- Work with a PCP or rheumatologist to monitor electrolytes and CBC.
- Other immunosuppressants for recalcitrant cases (methotrexate, cyclosporine, azathioprine)
- Cytotoxic agents (chlorambucil, cyclophosphamide) can be useful for sclerosing pseudotumor.
Radiation
Radiation can be a primary treatment or an adjunctive option after medical therapy has been optimized.
Studies have shown about 75% improvement with 2500 cGy over 15 days (Orcutt 1983) and benefits at doses of 2500–3000 cGy over 10 days (Kennerdell 1979) or 1000–2000 cGy over 10–15 days (Sergott 1981). There is risk of developing a cataract at dosage of 2000 cGy.
Radiation can be less effective in fibrotic/sclerotic or granulomatous variants (compared to better response in myositis lesions) and in patients with a longer interval between diagnosis and treatment.
Surgery
Biopsy is an option for diagnostic purposes, particularly if the IOI is not improved with steroid treatment.
Complete excision of areas of involvement is usually not indicated or possible.
Surgical approach depends on area of orbital involvement; in general, the representative specimen(s) should be biopsied from an area with the least visual morbidity.
- Preoperative imaging with MRI or CT is necessary to guide the approach:
- Upper-lid crease incision approach:
- Mark the upper eyelid crease.
- Use local anesthesia and sedation.
- If lacrimal gland involvement is present, the orbital septum is incised laterally and the enlarged gland carefully biopsied from the orbital lobe anterior to the levator complex. Take care to avoid excision of the palpebral lobe because this risks injury to the excretory ducts that drain from the orbital to the palpebral lobe to exit the superior fornix.
- Orbital fat specimens or other involved tissue can also be biopsied if indicated.
- Inferior forniceal approach:
- Use local anesthesia and sedation.
- Perform a transconjunctival incision and blunt dissection to expose involved tissue and protect globe with Sewall or malleable retractors.
- After hemostasis, closure is usually not necessary.
- Other typical approaches include the transcaruncular incision or via lateral orbital incisions.
Fine-needle aspiration
- Not common practice with advent of other options
- Can be performed under CT guidance
- Shown to be able to differentiate lymphoma from orbital inflammatory lesions
Other management considerations
- In cases of extraorbital extension (about 9% of cases), biopsy is indicated to rule out infectious and neoplastic diseases.
- In bilateral cases in adults, lymphoma and thyroid dysfunction must be ruled out.
- Close collaboration with rheumatologist is often necessary.
- Strict medication compliance must be discussed with the patient, e.g., do not self-discontinue prednisone.
- Carefully taper the schedule of prednisone; it should be gradual enough to keep symptoms from flaring.
- Prescribe concurrent medications (antacids, proton pump inhibitors) for gastrointestinal protection during steroid use
Common treatment-responses, follow-up strategies
IOI typically responds quickly to prednisone, however, recurrent inflammatory episodes requiring corticosteroid use have been seen in up to 55% of patients. Instruct the patient to return immediately with worsening of signs/symptoms on prednisone or if breakthrough inflammation occurs:
- Additional treatment with other steroid-sparing agents, immunomodulators, or cytotoxic agents might be required.
- Biopsy might be indicated for reasons stated previously.
A clinical course could be more quiescent in patients who passed the critical period of the first year without developing systemic inflammatory diseases. Specific diseases tended to appear more often in diffuse forms of IOI (Maalouf 1999).