As already noted, idiopathic orbital inflammation comprises about 6% of all orbital lesions in various series. No strong sex predilection has been described, except for orbital myositis, which has a 2:1 female predominance. One study reported an overall 1.8:1 female predominance for IOID, with orbital apex syndrome having the highest ratio of 5:1 women to men. There is also no reported racial preference.³ Although it is most common in the third through fifth decades of life, it has been reported in children as well as older adults.^23,24,25 It tends to be unilateral, although bilateral disease has been reported and it may even alternate between one orbit and the other.^3,26,27 Resistant and recurrent disease occasionally occurs despite appropriate management.

The manifestations of idiopathic orbital inflammation (Figs. 35-1, 35-2, 35-3) vary depending upon which orbital structures are involved.^3,6,9 The most common features of this process are pain and proptosis. These symptoms develop rapidly, usually within hours to days, although in some cases they may develop over several weeks. In addition, generally there is chemosis and conjunctival injection often over the extraocular muscle insertions, as well as eyelid edema and ptosis. However, these findings are not always present, and painless, quiet proptosis may occur. Proptosis may not be present in instances of dacryoadenitis.^6,9 Instead, eyelid edema and a palpable painful mass in the lateral eyelid may be present. Diplopia and painful disturbances of ocular motility are usually present in the diffuse form of the disease, the superior orbital fissure syndrome, or in myositis but are less common in cases of localized inflammatory masses. Visual loss is unusual but may be associated with intraocular inflammation as well as perineuritis of the optic nerve. Nonspecific constitutional symptoms of malaise and fatigue may also be associated with these various orbital symptoms.¹⁷

The most useful imaging modality in the evaluation of the majority of orbital diseases is the CT scan (Figs. 35-1, 35-3). Advantages of the CT scan include cost, speed, wide availability, and good delineation of bony anatomy. At least two views of the orbit, most commonly axial and coronal views, with thin cuts should be ordered. Contrast improves the sensitivity and specificity of the study and should be ordered in most cases.⁸⁵ In a series of 65 patients evaluated for IOID, orbital CT scan was the imaging study of choice in 91%.⁷ Common CT findings include retrobulbar fat infiltration and apical fat edema, proptosis, enlargement of extraocular muscles with or without tendon involvement, uveal scleral thickening, Tenon capsule edema, and lacrimal gland enlargement or infiltration.⁷ In addition, it will show if there is any associated sinus disease or bony erosion, which would suggest a neoplastic process or one of the necrotizing vasculitides such as WG.

MRI is useful if more definition of soft tissue is required. Any process with suspected intracranial spread should also be evaluated with MRI because of its superior sensitivity for brain pathology. Disadvantages of MRI are increased cost, length of exam, decreased availability, contraindication in patients with ferromagnetic implants, and potential for inducing claustrophobia.⁸⁵ Contrast enhanced MRI with axial and coronal views and fat suppression should be ordered.⁸⁶ IOID is typically revealed as a lesion hypointense to fat on T1-weighted images and isointense or minimally hyperintense to fat on T2-weighted images.⁸⁷

Other imaging studies that may be useful include ultrasonography, positron emission tomography (PET), orbital venography, and gallium scanning. Ultrasonography is helpful for demonstrating exudative retinal detachment, edema in Tenon fascia, enlargement and “doubling” of the optic nerve shadow (the T sign), enlargement of the extraocular muscles, and the presence of a distinct orbital mass.^4,77,81,82 Orbital venography may be helpful in demonstrating vascular deformities that are seen in the Tolosa-Hunt syndrome and occasionally in other forms of inflammatory orbital inflammation.⁵⁸ Gallium scanning has also been used to image in order to differentiate it from other entities involving the orbit.⁸⁸

Patients suspected of IOID should have a full hematologic work-up with complete blood count, electrolytes, erythrocyte sedimentation rate (ESR), antineutrophil cytoplasmic antibodies (ANCA), antinuclear antibodies, anti-dsDNA, angiotensin converting enzyme (ACE), rapid plasma reagin test, serum protein electrophoresis (SPEP),⁸⁶ and cerebral spinal fluid (CSF) analysis. The ESR may be elevated in cases of orbital inflammation, but this should bring to mind the possibility of a concurrent systemic disease such as one of the collagen vascular diseases.^3,53,89 The antinuclear and anti-dsDNA antibodies may also be positive in these diseases. Testing for ANCAs, which are highly specific for WG, will also help to differentiate this entity from idiopathic causes of scleritis and idiopathic orbital inflammation.⁹⁰ Elevation of the ACE level, which occurs in granulomatous diseases, is suggestive of sarcoidosis. Cerebrospinal fluid evaluation is rarely helpful, but pleocytosis has been reported due to meningeal irritation.³ Also, CSF can be useful in questionable cases to rule out lymphoma.⁸⁶

One of the most important diagnostic aids in the evaluation of idiopathic orbital inflammation is the utilization of a trial of high-dose corticosteroids,^5,9,91 as the disease is almost always exquisitely responsive to systemic steroids. An 80-mg daily oral dose for a week will usually result in significant improvement or complete resolution of the inflammatory process. If this does not occur, consideration must be given to other diagnoses, and orbital biopsy should be performed in order to obtain a tissue diagnosis.^5,51,91,92

In general idiopathic orbital inflammation (Figs. 35-5, 35-6) is polymorphic in nature.^{3,4,9,24,91,93,94} The cellular response seen in this disease consists of lymphocytes, plasma cells, macrophages, histiocytes, occasional neutrophils and eosinophils, epithelioid cells, and fibroblasts. These are present in varying numbers depending upon the chronicity of the inflammatory process. Intranuclear Dutcher bodies and intracytoplasmic Russell bodies may be present within many of the plasma cells, as they actively participate in the inflammatory response. Children tend to have a significant number of eosinophils in their biopsy specimen. Lipogranulomatous inflammation with fat necrosis may also be present. However, the presence of noncaseating granulomas is relatively uncommon.⁹⁵ This is often associated with foreign body giant cells that are responding to the release of lipid. Perivascular lymphocytic cuffing and capillary proliferation are quite common.⁴ Occasionally, lymphoid follicles may also be seen.

Vasculitis is a very unusual feature of idiopathic orbital inflammation.^4,42 When this is present there is destruction of the muscularis layer of the orbital vessels by lymphocytes and neutrophils, as well as eosinophilic infiltration. There is also focal vascular necrosis with leukocytoclasis or collections of debris from degenerated neutrophils.^4,5 When it appears that a vasculitis is present, consideration must be given to a diagnosis of polyarteritis nodosa, WG, or one of the collagen vascular diseases.

With progression of the disease process, there is increased fibrosis and collagen deposition, which separates the various inflammatory elements. There is also an associated thickening of the connective tissue within the extraocular muscles. With chronicity there will be actual loss of muscle tissue and its replacement with connective tissue. In the lacrimal gland there is hyperplasia of the periductal and periacinar connective tissue. As this progresses, there will be actual destruction of the lacrimal acini.⁸² In the sclerosing types of idiopathic orbital inflammation, there is extensive fibrosis surrounding and replacing all normal orbital tissues.^82,96,97 There is only a minimal cellular response present in such instances. At times this connective tissue reaction may be so dense as to have the consistency of cartilage.

It is important to differentiate between idiopathic orbital inflammation and lymphoma or its precursors.⁹⁸ Lymphoid follicles, a polymorphic infiltrate, and the absence of monoclonality are essential aspects of idiopathic orbital inflammation.⁹ By contrast, lymphomas and atypical lymphoid hyperplasia tend to be monomorphic in nature, without lymphoid follicle, and monoclonal. Capillary proliferation is not common in lymphomas, nor is the presence of histiocytes and macrophages.

Nodular or pseudosarcomatous fasciitis (Fig. 35-7), while not usually considered part of the spectrum of idiopathic orbital inflammation, does represent a localized inflammatory disease of idiopathic origin. It appears to be a reactive process involving a proliferation of immature connective tissue elements along with acute and chronic inflammatory foci.^{120,121,122,123,124} This entity can develop periorbitally in the eyelid as well as in the epibulbar tissue. It may also occur in the anterior or deep orbit. There have been 23 cases of nodular fasciitis reported in the English language literature. The majority of these patients were adults, but 8 of 23 of these patients were younger than 20 years old, one of which was an infant.¹²⁵ It appears as a rapidly growing mass arising over several weeks or months. It may or may not be associated with pain. On imaging studies, it is difficult to distinguish nodular fasciitis from malignant soft tissue tumors such as rhabdomyosarcoma and granulocytic sarcoma. For this reason, surgical excision is recommended.¹²⁵ At surgery, the lesion appears fairly well demarcated and slightly reddish in color.

Lacrimal gland enlargement in the absence of systemic disease without dry eye symptomatology has been termed benign lymphoepithelial lesion (BLL) (Fig. 35-8).^4,126 Previously this entity was known as Mikulicz syndrome or disease. However, due to confusion as to the exact definition of these terms, they have been abandoned. Histologically, sheets of lymphocytes and plasma cells, which replace the normal acinar and ductular structure of the gland, characterize this condition. Lymphoid follicles may be present. The remaining ductular elements may proliferate to form solid nests of cells outlined by excessive basement membrane production. Hyalinization may sometimes occur within these ductular remains. The cells within these nests are for the most part epithelial elements of the ducts. These structures are commonly called myoepithelial islands due to the incorrect belief that normal ducts have myoepithelial cells present in their wall. This has been disproved on electron microscopic evaluation.¹²⁷ On superficial examination these formations may resemble lymphoid follicles. The presence of these ductular nests helps to differentiate this disorder from lymphomatous involvement of the gland, which is not associated this these structures. From one third to one half of patients with Sjögren syndrome may have similar nests of ductular elements. Historically, this has led to some confusion as to whether BLL was a distinct entity from Sjögren. This confusion has been resolved by a study that demonstrated that BLL has higher serologic levels of IgG4 with infiltration of the lacrimal glands with IgG4-positive plasmocytes.¹²⁸ Another study showed that the acinar cells in BLL did not undergo apoptosis as in Sjögren, and therefore, sicca syndrome is not observed in BLL.¹²⁹ The difference between BLL and IOID involving the lacrimal gland is based on the more monomorphic infiltrate seen in BLL in contrast to the relatively more polymorphic infiltrate seen in IOID. In addition, IOID contains more plasma cells and fibrotic tissue and is associated with lymphoid follicles with active germinal centers. Finally, the lacrimal gland capsule is usually preserved in BLL, in contrast to IOID, which is a more destructive process.

Amyloidosis (Fig. 35-9) is a disease process characterized by the deposition of amorphous hyaline material in various body tissues including nerves, blood vessels, muscles, skin, spleen, adrenal glands, liver, heart, tongue, and orbit.¹³⁰ Two types of primary amyloidosis have been identified. One is a localized process restricted to the ocular and orbital structures without systemic manifestations.^4,131,138 Radiologically, this type has a homogeneous mass with irregularity of adjacent bone and intralesional calcification on CT scan.¹³⁷ The second is characterized by ocular as well as systemic deposition of amyloid.^4,139 This may also occur in a familial form, with amyloid infiltrating the heart, peripheral nerves, and blood vessels.⁴ Retinal deposits occur due to extension of the amyloid from the retinal vasculature, and infiltration of the trabecular meshwork can result in glaucoma. Secondary amyloidosis occurs as part of a variety of chronic disease entities including tuberculosis, rheumatoid arthritis, leprosy, osteomyelitis, multiple myeloma and other plasma cell dyscrasias, and occasionally lymphoma.⁴ A systemic evaluation for these conditions should be performed in any patient presenting with amyloidosis.

Symptomology and clinical findings associated with this disease process depends upon the tissues that are invaded by the amyloid. Most lesions hemorrhage quite easily due to vascular infiltration. Patients can present with periorbital or subconjunctival hemorrhage. Loss of extraocular motility and ptosis from muscle involvement, vitreous opacities and retinal deposits secondary to intraocular infiltration, and pupillary abnormalities from deposits in the cervical lymph nodes can occur.^{131,140,141,142} Ocular involvement in secondary amyloidosis is unusual. However, the presence of waxy yellow skin nodules that bleed with only slight trauma is characteristic of systemic amyloidosis. Congestive heart failure, gastrointestinal motility disturbances and malabsorption, hepatosplenomegaly, and proteinuria and the nephrotic syndrome occur with systemic involvement of the associated organ systems.

Localized amyloid deposits in ocular disease can occur in any portion of the orbit and globe. Systemic disease is not usually associated with conjunctival, lacrimal gland, or orbital amyloid deposition.^{131,133,141,143} This is in contrast to skin deposition, which is usually associated with systemic amyloid. Pseudoptosis may be present due to a mass effect, although deposition in the Müller muscle and the levator aponeurosis is also a cause of ptosis.^134,140 Deposits palpated through the eyelid feel somewhat cystic in contrast to the more superficial infiltrates that appear as friable excrescences or nodules protruding from the conjunctiva. Lacrimal gland enlargement and proptosis can also occur due to localized amyloid deposition.¹³¹ Orbital and extraocular amyloid is not associated with pain. Vision is only rarely affected, usually from optic nerve infiltration.¹⁴⁴ Double vision may occur when there is amyloid deposition within the extraocular muscles.^142,145

Giant Cell Reparative Granuloma is an idiopathic inflammatory intraosseous tumor that rarely occurs in the orbit.^151,152,153 Usually it involves the maxilla and orbital floor and the mandible. Young persons are most often involved, but the condition has been reported in a patient as old as 85.¹⁵⁴ Trauma is frequently associated with the occurrence of this tumor, which is characterized by the presence of multinucleated giant cells within a stromal matrix of spindle cells. In addition to inflammatory cells, there are hemorrhage and vascular proliferation within the tumor. Giant cell reparative granuloma has been associated with cherubism, an autosomal dominant disease characterized by painless symmetrical swelling and polycystic destruction of the mandibular bone.^155,156 The differential diagnosis of this lesion includes the brown tumor of hypoparathyroidism, true giant cell tumors, malignant giant cell soft tissue tumors, and aneurysmal bone cysts. In brown tumor there is a hyperfunctioning parathyroid gland with increased calcium and parathormone levels.^157,158 This tumor may also occur in association with secondary hyperparathyroidism from metabolic derangement, as is seen in chronic renal failure. In true giant cell tumors there is an even distribution of these multinucleated cells throughout the surrounding spindle cells.⁴ This contrasts to the zonal arrangement of giant cells found in giant cell reparative granuloma and brown tumor. In these zonal areas, giant cells surround foci of hemorrhage and inflammation. Malignant giant cell tumor of soft parts is multinodular and contains very large multinucleated giant cells with stromal anaplasia, areas of fibrosarcoma, and osteoblastic transformation.¹⁵⁹ Finally, aneurysmal bone cysts have giant cells and reactive bone formation similar to brown tumor and other giant cell tumors.⁴ However, the characteristic feature of this entity is the presence of a nonendothelial-lined cavity. The treatment of all giant cell tumors involving bone is curettage and excision of all abnormal bony elements.

Retained orbital foreign bodies, especially vegetable matter and other organic substances, can result in chronic orbital inflammation including pain, proptosis, chemosis, and periorbital edema.^160,161 Chronic discharge, erythema, and fistulous tracts can also occur. Foreign body granuloma formation as well as areas of acute inflammation are characteristic of this process. CT and MRI are helpful in locating the offending foreign body.

Ruptured dermoid and hematic cysts, orbital hemorrhage, and cholesterol granulomas can also elicit an acute granulomatous inflammatory process.^{160,162,163,164,165,166} These ruptures usually occur secondary to trauma, although hematic cysts may rupture spontaneously. Ruptured dermoid cysts show cholesterol crystals and cyst wall remnants surrounded by the granulomatous inflammatory response. Ruptured hematic cysts are associated with hemosiderin deposition, macrophages, and fibrous capsule formation around blood breakdown products.

Pain, proptosis, periorbital edema and erythema, chemosis, and extraocular motility disturbances can occur as an inflammatory reaction to acute sinusitis.^{167,168,169,170} Patients will also manifest symptoms of sinusitis including sinus pain and congestion of the nasal passages, as well as systemic symptoms of fever, malaise, and distress. Orbital infection is not present. Obstruction of the venous outflow from the orbit and sinuses adds further to the increasing orbital edema. In severe cases, visual loss from optic nerve compression or corneal drying and exposure can occur. CT of the orbits and sinus cavities is an essential part of the evaluation of this complex of symptoms in order to eliminate other causes of acute orbital inflammation. Successful treatment of this condition is predicated upon aggressive antibiotic and surgical management of the underlying sinus infection.

Wegener granulomatosis (WG) (Figs. 35-10, 35-11) is characterized by inflammatory lesions of the upper respiratory tract, lower respiratory tract, and kidneys and, to varying degrees, by generalized small vessel vasculitis of other structures, including the eye. A limited form of the disease has been described that spares the kidneys, frequently involves the head and neck region, and may not progress to the systemic form.¹⁷¹ The definitive diagnosis is confirmed by biopsy.

As described below, ocular manifestations include orbital inflammation, scleritis, keratitis, and uveitis. The ocular involvement can occur from extension of sinus and nasal lesions or from focal small vessel vasculitis.