Continuing Education Activity

Orbital pseudotumor, orbital inflammatory pseudotumor (OIP), or idiopathic orbital inflammation (IOI) is a benign, non-infectious, non-neoplastic, space-occupying, inflammatory condition of the orbit and peri-orbit without identifiable local or systemic causes. This article presents the current theories on the etiology, clinical manifestation, pathogenesis, differential diagnosis, laboratory and imaging tests, and treatment options for the management of orbital pseudotumor. The role of the interprofessional team will be reviewed in this activity.

Objectives:

• Identify the etiology and epidemiology of orbital pseudotumor.
• Review the appropriate history, physical, and evaluation of orbital pseudotumors.
• Outline the treatment and management options available for orbital pseudotumors.
• Explain interprofessional team strategies for improving care coordination and communication to advance the diagnosis and treatment of orbital pseudotumor and improve outcomes.

Introduction

Orbital pseudotumor, also known as orbital inflammatory pseudotumors (OIP), idiopathic orbital inflammation (IOI), orbital inflammatory syndrome (OIS),  idiopathic orbital inflammatory pseudotumor (IOIP), or nonspecific orbital inflammation (NSOI) is a benign, space-occupying, and non-infectious inflammatory condition of the orbit but may extend in the peri-orbital area.[1] There is no identifiable infectious, systemic, or neoplastic disorder. It is the third most common orbital disease in adults, after thyroid orbitopathy and lymphoproliferative diseases.[2]  A significant number of orbital inflammations may be associated with systemic conditions or remote organ dysfunction. Categories of orbital pseudotumor according to location include anterior, diffuse, posterior, or apical. Other classifications include myositis, dacryoadenitis, periscleritis, perineuritis, and focal mass.[3]

Orbital pseudotumor is rare in children. The most common ophthalmic findings are periorbital edema and blepharoptosis. A palpable mass may be present. On orbital radiography, common findings are dacryoadenitis, orbital mass, or myositis.[4] In children, systemic signs are present in up to 50% of patients. Headache, emesis, anorexia, lethargy, and fever are the most common systemic signs. Additionally, there are likely associations with iritis, uveitis, disc edema, and peripheral eosinophilia.[5] 

Etiology

The exact etiology is unknown, but researchers have considered infection elsewhere besides the orbit and autoimmune disorders. Among infections, the presence of Streptococcal pharyngitis or viral upper respiratory infection has reportedly correlated with the occurrence of orbital pseudotumor. Molecular mimicry of the foreign antigen with self-antigens is one theory to explain IOI after infection.[3]

Various rheumatologic disorders such as granulomatosis with polyangiitis (formerly called Wegener granulomatosis), giant cell arteritis, systemic lupus erythematosus, rheumatoid arthritis, polyarteritis nodosa, multifocal fibrosclerosis (now categorized as IgG4-related disease), Crohn disease, and ulcerative colitis are associated with orbital inflammation.[5][6][5]

There are several theories proposed to explain the inflammation that causes orbital pseudotumor. Reports exist of high levels of inflammatory cytokines such as interleukins, interferon (IFN), tumor necrosis factor (TNF) in histopathological specimens, as well as increased expression of CD20 and CD25.[3] Gene expression profiling methods have recently shown upregulation involving immunoglobulin and receptors but with downregulation of alcohol dehydrogenase 1B, adiponectin, leptin receptor, and C1Q.[3]

Epidemiology

Orbital pseudotumor accounts for approximately 8% to 11% of all orbital tumors.[2] Another study estimates the incidence of 6% to 16% of orbital tumors.[4] It is more prevalent in adults, especially middle-aged females[1], and has been reported all over the world. The most common site of involvement is the lacrimal gland.[1] The mean age of presentation is the third to sixth decade of life, and it is rarely bilateral in adults.[4] However, in children, bilaterality is more common. The recurrence rate in the pediatric population is as high as 76%, and the rate may or may not be associated with bilaterality.[7] The reported recurrence rate of nonspecific orbital inflammation (NSOI) following resolution is from 33% to 58% of patients.[7]

Histopathology

There is a debate on whether there is a need for orbital biopsy since typical idiopathic orbital inflammation cases can be treated with systemic corticosteroids without a biopsy.[3] Since treatment with steroids is effective in a large percentage of patients, reports have advocated doing biopsies only if there is none or incomplete response to steroids should biopsies be done.[8]  Those patients who have a history of systemic malignancy or continued diagnostic uncertainty should have a biopsy.[9]

Histopathologic examination through either fine-needle aspiration biopsy or incisional/excisional biopsy is the gold standard for definitive diagnosis.[10] However, since the tumor is usually firm, fine needle biopsy has a low yield. Refinement of immune-staining has led to increased specificity and sensitivity in differentiating lymphoma from pseudotumor.

Research has described five patterns of acute inflammatory pseudotumor: anterior and diffuse acute pseudotumors, anterior or diffuse orbital infiltration, lacrimal involvement, posterior or apical involvement, and myositic infiltration.[1]

On histopathology, there is a pleomorphic inflammatory cellular response consisting of pleomorphic response by lymphocytes, plasma cells, macrophages, polymorphonuclear leukocytes, and eosinophils.[1][3] Fibrovascular tissue reaction is common, and when extensive, it leads to a diagnosis of sclerosing orbital pseudotumor.  Other features include myositis, perineuritis, periscleritis, and sometimes, a lacrimal gland mass may be present.  Granulomatous inflammation is uncommon, but one granulomatous inflammatory variant mimics sarcoidosis. Histiocytic infiltration and well-formed noncaseating granulomas may be present.

The presence of granulomatous inflammation, vasculitis, or necrosis generally excludes the diagnosis of IOI.[11] The immunohistochemical assessment of plasma cells for IgG4 positivity is required to exclude IgG4-RD. Tissue plasma cell IgG4 positivity is not a prominent finding in IOI.

History and Physical

Orbital pseudotumor is diagnosed by excluding other orbital diseases with similar presentations. Thus, systemic diseases such as sarcoidosis, granulomatosis with polyangiitis, Sjogren syndrome, IgG4-related disease (IgG4-RD), lymphoproliferative and histiocytic disorder, xanthogranulomatous disease, or metastatic disease may be elicited through a careful history-taking and a review of previous medical conditions.[11] A negative history may necessitate further laboratory testing to rule out conditions that orbital pseudotumor may mimic definitively. 

Signs and Symptoms

Idiopathic orbital inflammation has highly variable clinical features ranging from a diffuse process to a specific focal target like the lacrimal gland and extraocular muscles.[12] The presentation can be acute, subacute or insidious, chronic, and relapsing.[3][13] An acute proptosis is the usual manifestation that brings the patient to the emergency room. Insidious cases present as gradual proptosis, swollen eyelids, and eye movement restriction that may result in diplopia. A frank orbital mass may be present on radiologic examination.

Another typical presentation is that of a patient with an acute onset of orbital pain and headache. In adults, there may be eyelid and periorbital erythema and edema, conjunctival congestion, proptosis, ptosis, diplopia, light sensitivity, decrease in eye motility, and pain on eye movement.[2][5][14] There may be dacryoadenitis, myositis, trochleitis, or diffuse soft-tissue inflammation. In the pediatric age group, periorbital edema, ptosis, pain, and decreased extraocular muscle movements were more common in some studies.[1] Symptoms are usually unilateral in adults but bilateral in children.[5]

Dacryoadenitis accounts for 50% of all IOI’s. It typically presents with a painful, firm, mass with edema in the lateral upper eyelid, and S-shaped ptosis. It may be bilateral. Some patients with idiopathic dacryoadenitis have gotten relabeled as having immunoglobulin G4-related ophthalmic disease (IgG4-ROD).[3] This recently described clinical entity reportedly affects the orbital soft tissue, optic nerve, and trigeminal nerve branches.

Orbital myositis may be acute, subacute, or recurrent. It may involve one or multiple ocular muscles. The most commonly involved muscles are the medial rectus, followed by the superior, lateral, and inferior recti muscles.[1] Orbital myositis affects young adults in the third to the fourth decade of life with a female predominance.[3]

Systemic disorders have correlations with orbital pseudotumor. There are reports of immunologic diseases such as rheumatoid arthritis, Crohn's disease, systemic lupus erythematosus, and scleritis, causing orbital inflammatory disease. Implications also point to sinusitis. Concurrent systemic diseases such as flu, asthma, colitis, and severe anemia are also reportedly correlated with NSOI, as are hepatitis C, rheumatoid arthritis, and xanthogranuloma.

Evaluation

Laboratory Findings

Laboratory evaluation usually includes hematologic work-up, routine biochemistry, inflammatory markers, and a comprehensive autoimmune panel. Hematologic work-up consists of a complete blood cell count, erythrocyte sedimentation rate, C-reactive protein, electrolytes, thyroid function studies, sedimentation rate, antinuclear antibodies, antineutrophil cytoplasmic antibodies, rheumatoid factor, angiotensin-converting enzyme level, and rapid plasma regain test.[5][15] Laboratory findings that are within normal limits yield little diagnostic value.

Ultrasound, Computed Tomography (CT), and Magnetic Resonance Imaging (MRI)

Orbital ultrasound, CT, and MRI may aid in the diagnosis when combined with clinical findings and treatment response. Ultrasonography may help in evaluating the globe and ocular complications such as retinal and choroidal detachments.[9] In anterior IOI, CT and MRI findings include an anterior orbital mass with a molded configuration and uveoscleral thickening.[3] Enlargement of extraocular muscles on CT-scan is a common finding in orbital myositis. IOI lesions enhance with contrast, and on MRI, may display fat-suppressed T2-weighted image signals depending on the degree of tissue edema. A diffuse lacrimal involvement typically affects the orbital and palpebral lobe.[11]

Enhancement is variable depending on the stage. In the acute stage, there is pronounced enhancement, while in the chronic and sclerosing type of inflammation, there is hypointensity on T2-W images noted. Diffuse IOI CT and MRI findings are similar to anterior IOI. Orbital lymphoproliferative may be challenging to differentiate. Apical IOI may show signs of intracranial involvement such as abnormal soft tissue extending into the middle cranial fossa, cavernous sinus, and meninges.[3]

Treatment / Management

Current therapeutic agents available for idiopathic orbital inflammation are:

1. Corticosteroids
2. Radiation therapy
3. (3) nonspecific steroid-sparing agents such as  (a) methotrexate; (b) cyclosporin-A; (c) mycophenolate mofetil; (d) cyclophosphamide; (e) rituximab and
4. (4) biologic agents such as (a) infliximab; (b) adalimumab; (c) etanercept; (d) daclizumab; (e) abatacept; (f) tocilizumab.

While a modest proportion of patients experienced resolution of their symptoms without treatment, orbital pseudotumor responds dramatically to steroids.[16] A corticosteroid response is a dramatic improvement of signs and symptoms within 48 hours after the administration of systemic prednisolone.[1] Idiopathic orbital myositis has this response. But other types of pseudotumors are not as readily assessed by this corticosteroid trial.[11][15] Reports exist of an erroneous diagnosis of idiopathic orbital inflammation based on a corticosteroid trial in lymphomas, metastatic disease, fungal infections, and sarcoidosis, among others.[17]

For adults, initial steroid treatment doses are typically 1 mg/kg of prednisone. For children, high-dose oral corticosteroids of 1.0 to 1.5 mg/kg/day are the preferred protocol.[18] The reported total dose is 60 mg to 100 mg per day for one to two weeks with a 5 to 6-week taper.[12] The steroids can begin tapering as soon as the clinical response is complete.

There is no consensus on the treatment protocol for cases that do not respond to steroid treatment. The reported cure rate is only 37% and a recurrence rate of 52% with corticosteroid therapy. Long-term use of steroids leads to systemic side effects, including insomnia, hyperglycemia, weight gain, and cataracts. Local corticosteroid injections for periorbital and orbital inflammation are also options.[19]

For patients who are non-responsive to steroid treatment or suffer relapses despite steroid treatment, antimetabolites, alkylating agents, T-cell/calcineurin inhibitors, lymphocyte inhibitors, tumor necrosis factor-a inhibitors, and surgical debulking may be employed.[3]  

Immunosuppressive or immunomodulatory therapy may be an option in selected cases. Cyclosporin-A (CsA) suppresses the lymphocyte-mediated responses. It inhibits T-cell activation via decreased production of interleukin-1 and interleukin-2. Renal function requires monitoring while on CsA.[5]  

Antimetabolites like methotrexate, which inhibits dihydrofolate reductase needed for DNA and RNA synthesis, result in the suppression of rapidly dividing B-cells and T-cells.[5] Azathioprine, a purine analog that interferes with DNA synthesis, especially of cells of the immune system, and mycophenolate mofetil, a purine synthesis inhibitor, have had therapeutic success.[3] Alkylating agents such as cyclophosphamide and chlorambucil, which damages proliferating cells by crosslinking DNA, have been reported to be effective, though infrequently used.

Infliximab, a chimeric monoclonal antibody that works against tumor necrosis factor-a, has been used for autoimmune diseases such as Crohn's disease, ulcerative colitis, and rheumatoid arthritis. Other therapeutic agents and immunomodulators in use for recalcitrant OIP are interferon-A, tacrolimus, rituximab (a B-lymphocyte inhibitor monoclonal antibody), daclizumab (T-lymphocyte inhibitor monoclonal antibody), and leflunomide.[5] Radiotherapy may also be an option in unresponsive cases, with a low dose of 20 to 30 Gy at 2Gy per fraction utilized.[16]

While idiopathic orbital inflammation is benign, its course can be clinically fulminant with vision loss and severe oculomotor dysfunction. Patients with optic nerve involvement may require admission for aggressive IV steroid therapy to prevent long-term visual impairment.[14] Thus, prompt diagnosis and treatment are imperative.  

Differential Diagnosis

The following diseases, among others, should be considered to prevent misdiagnosis.

1. Infections- orbital cellulitis
2. Systemic diseases such as thyroid ophthalmopathy
3. Malignancies: Lymphoma, metastatic carcinoma, leukemia
4. Autoimmune disorders: Systemic lupus erythematosus, rheumatoid arthritis
5. IgG4-related orbital disease
6. Sarcoidosis

Orbital and systemic diseases that may present with similar signs and symptoms include orbital cellulitis, thyroid eye disease, sarcoid, orbital lymphoma, lymphangioma, metastatic carcinoma, leukemia, lymphoproliferative disorder, and rhabdomyosarcoma.[14] Tolosa Hunt syndrome shares similar symptoms of periorbital pain, cranial nerve palsy, and an excellent response to steroids. The more serious conditions, such as metastases from rhabdomyosarcoma or Ewing sarcoma, chronic recurrent multifocal osteomyelitis (CRMO), and SAPHO ( synovitis, acne, pustulosis, hyperostosis, and osteitis) have been known to cause orbital pseudotumor.

Bilateral sclerosing orbital pseudotumor should alert the physician. This subset of IOI leads to serious morbidity with a chronic, severe, progressive disease commonly manifesting with proptosis, restricted ocular motility, and pain.[3] There is emerging evidence that sclerosing idiopathic orbital inflammation is a subset of IgG4-related disease. Ocular adnexal IgG4 disease should be a consideration if there is bilateral ocular or systemic involvement.[20]

In children, the differential diagnoses include orbital cellulitis, orbital trauma with retained foreign body, ruptured dermoid cyst, lymphangioma, neuroblastoma, Langerhans cell histiocytosis, and pediatric malignancies such as rhabdomyosarcoma, leukemia, neuroblastoma and, metastatic retinoblastoma.[3]

Distinguishing among the various clinical entities that mimic orbital pseudotumor may require the use of ancillary laboratory exams, CT, MRI, and biopsy.

Prognosis

While orbital pseudotumor resolves without treatment in some patients, steroids are the mainstay of treatment. Over 75% of patients show improvement within 24 to 48 hours of steroid treatment.[2] As mentioned previously, the reported cure rate is 37%. Recurrence is approximately 52%, even with corticosteroid treatment.[19] 

Complications

Vision loss and severe oculomotor dysfunction can be permanent if orbital pseudotumor is left untreated or is unresponsive to treatment. The inflammation can spread to contiguous structures such as the periorbital area, the optic nerve, and the intracranial cavity. Multiple cranial nerves may be affected, and sensorimotor hemiparesis may occur. Severe inflammation may cause secondary angle-closure glaucoma because of choroidal effusions that cause the anterior rotation of the ciliary body.[2] Progressive proptosis may lead to exposure keratitis and ulcer formation.

Deterrence and Patient Education

Patients should be educated that symptoms of vision loss or eye pain should be evaluated by a trained medical professional. If orbital pseudotumor has been diagnosed, patients should also be educated about the importance of continuing treatment for orbital pseudotumor.

Pearls and Other Issues

• The signs and symptoms of orbital pseudotumor may mimic other orbital diseases such as auto-immune disorders, thyroid disease, or malignancy.
• A careful history and a physical examination by an internist, primary care physician or medical specialist are particularly relevant to rule out systemic diseases that may be associated with orbital pseudotumor.
• The use of ancillary laboratory and diagnostic testing, including CT, MRI, and biopsy, must be used judiciously for a definitive diagnosis.
• Clinicians should carefully weigh treatment options for patients who are non-responsive to a steroid regimen.

Enhancing Healthcare Team Outcomes

Since orbital pseudotumor is diagnosed by excluding other diseases, the health care team should consist of an interprofessional team of pediatricians, primary care physicians, internists, rheumatologists, endocrinologists, allergologists, immunologists, radiologists, and auto-immune disease experts. A comprehensive systemic examination by qualified medical personnel and carefully documented history are vital to the ophthalmologist’s diagnosis and management. The use of systemic therapy should involve a follow-up with physicians to monitor the side effects or complications of treatment. The patient or the patient’s family should be always be informed of his prognosis at each stage of the disease and be actively involved in the choice of diagnostic procedures and management. Ophthalmology nurses often arrange follow-ups with patients, provide education, and report back to the team. Pharmacists review prescriptions for dosage and interactions. They assist the team by educating patients about the importance of compliance and discuss side effects. These are examples of how the interprofessional team approach can improve patient outcomes in orbital pseudotumor cases. [Level 5]