Sarcoidosis is a multisystem disorder of unknown etiology that is characterized histologically by granulomatous inflammation in the affected organs (Fig. 24.9).

Ocular involvement is seen in approximately 25 % of patients with sarcoidosis [6]. Anterior uveitis is the most common ocular manifestation, but sarcoidosis may involve any part of the eye, orbit, or lacrimal system. Orbital and adnexal manifestations of sarcoid are less common than ocular involvement with conflicting data on incidence due to the different diagnostic criteria for sarcoidosis employed in various studies [7–9]. Nevertheless, both orbital apex and cavernous sinus syndromes have been reported as presenting manifestations of sarcoidosis [10, 11]. Orbital involvement is most commonly seen in the fifth to seventh decades and is more frequent in women [12].

The diagnosis of sarcoidosis can be determined by biopsy demonstrating noncaseating granulomas; a constellation of typical clinical features such as restrictive lung disease, erythema nodosum/lupus pernio, and uveitis; chest imaging demonstrating hilar lymphadenopathy and/or parenchymal infiltrates; or a combination of these findings. In addition, lymphocytosis with a CD4/CD8 ratio >5 on bronchoalveolar lavage strongly suggests the diagnosis of sarcoidosis [13]. Although both serum and CSF angiotensin-converting enzyme levels often are elevated in patients with systemic sarcoidosis, normal values do not eliminate the diagnosis.

The management of patients with sarcoidosis involving the orbital apex depends on the extent of disease, degree of functional impairment, and presence or absence of active systemic disease. Although up to two-thirds of cases of systemic sarcoidosis show spontaneous remission [14], there are insufficient data on the natural history of orbital and adnexal disease to recommend observation as a plan of management. Oral steroids are the mainstay of treatment in these patients, and most reported cases show a good response. In cases without active systemic disease, a short course of oral prednisolone (starting at 1 mg/kg and tapering over 3 months) may be considered for initial therapy. In those patients who fail to respond or are steroid intolerant, cytotoxic agents such as methotrexate may be used. In localized orbital disease, periocular steroids (1-mL injection of triamcinolone acetonide 40 mg/ml) may be considered [15]. Unfortunately, although treatment with corticosteroids often results in significant improvement in patients with sarcoidosis, nearly 50 % of patients subsequently experience a recurrence of the disease when steroids are tapered, in which case they may require a prolonged course of treatment with a very slow taper.

Noninfectious vasculitis may be classified based on the pathologic findings and size of vessels involved in the pathologic process as large-vessel vasculitis (e.g., giant cell arteritis), medium-vessel vasculitis (e.g., polyarteritis nodosa (PAN)), and small-vessel vasculitis. Small-vessel vasculitis may be divided into ANCA-associated small-vessel vasculitis (e.g., Wegener’s granulomatosis, Churg-Strauss syndrome) and non-ANCA-associated small-vessel vasculitis (e.g., lupus vasculitis).

Although rare, a number of different noninfectious systemic vasculitides can cause orbital inflammation [16]. These include Wegener’s granulomatosis, Churg-Strauss syndrome, polyarteritis nodosa, giant cell arteritis, and systemic lupus erythematosus.

Wegener’s granulomatosis, also called “granulomatosis with polyangiitis,” is the most common noninfectious vasculitis causing orbital inflammation. It thus must be considered in patients presenting with an orbital apex syndrome. It is an autoimmune disease characterized by inflammation involving small blood vessels, most often of the upper respiratory tract, lungs, kidneys, and skin. The vasculitis and associated granulomatous inflammation lead to vascular occlusion, tissue ischemia, and localized necrosis (Fig. 24.10).

Wegener’s granulomatosis also is known as ANCA-associated vasculitis, as antineutrophil cytoplasmic antibodies are present in 80–90 % of cases [17, 18]. These antibodies are thought to be related to the pathogenesis of the disease. c-ANCA (which reacts with proteinase 3) is more commonly associated with Wegener’s granulomatosis than p-ANCA (which reacts with myeloperoxidase), with the presence of c-ANCA antibodies having an overall sensitivity of 91 % and a specificity of 99 % for the disease [18].

Patients with Wegener’s granulomatosis typically present with a several-month history of flu-like symptoms, including fever, myalgias, arthralgias, headache, malaise, anorexia, and weight loss. The condition most often affects the lower and upper respiratory tracts (85 %) and kidneys (80 %). Thus, affected patients often have pulmonary (dyspnea, cough, hemoptysis, obstructive symptoms) and/or renal (hematuria, proteinuria) manifestations; however, the peripheral nervous system may be affected, causing numbness, tingling, and weakness of the extremities. Cutaneous manifestations also are common, including rash, purpura, and nodules.

Ocular involvement, including conjunctivitis, episcleritis, retinal vasculitis, and uveitis, is common in patients with Wegener’s granulomatosis, occurring in 50–60 % of patients [17, 19]. Orbital involvement is less frequent, being recognized in 15–20 % of patients [20–22]. Orbital disease can be primary or secondary to the extension of sinus disease. Orbital masses are a rare manifestation and are characterized by a refractory course and a high rate of local damage with significant visual morbidity, sometimes leading to a complete vision loss [23, 24]. Both of the systemic forms of Wegener’s granulomatosis (pulmonary and renal) as well as its so-called “limited” form may involve the orbital apex or cavernous sinus [25].

The diagnosis of orbital apex syndrome associated with Wegener’s granulomatosis usually is made by biopsy of a firm mass that demonstrates a vasculitis, granulomatous inflammation, and/or necrosis. Prior to biopsy, however, imaging may help distinguish the condition from other etiologies. CT scanning with contrast usually shows a hyperintense lesion relative to the nasal mucosa with obliteration of tissue planes and bony erosion [26]. MR imaging reveals lesions that are hypointense relative to orbital fat on both T1- and T2-weighted images and enhance after intravenous injection of gadolinium. Positron emission tomographic (PET) scanning may reveal high uptake [27, 28].

The current standard of management of patients with Wegener’s granulomatosis is a combination of corticosteroids and immune modulators such as cyclophosphamide, methotrexate, or azathioprine to induce remission, followed by maintenance therapy to sustain the remission, prevent relapse, and allow repair of disease-related damage. Survival rates are up to 95 % at 5-year follow-up and 80 % at 10 years [29, 30]. More recently, rituximab combined with pulse corticosteroids has been found to be beneficial in patients who fail to respond to other immunomodulatory agents [31], including patients with orbital involvement [32].

Churg-Strauss syndrome is a systemic allergic disease that initially manifests with asthma and allergic rhinitis. It is characterized by a necrotizing vasculitis of small- to medium-sized vessels and granulomatous inflammation that is rich in eosinophils (Fig. 24.11) [33].

Churg-Strauss syndrome primarily affects the lungs, sinuses, and peripheral nervous system. In 1990, the American College of Rheumatology determined that four of the following six criteria must be met to make the diagnosis: (1) asthma, (2) hyper-eosinophilia, (3) mononeuropathy or polyneuropathy, (4) pulmonary infiltrates, (5) paranasal sinus abnormality, and (6) extravascular eosinophil infiltration in biopsy specimens [34].

Ocular manifestations are rare in patients with Churg-Strauss syndrome but can be separated into two clinical presentations: ischemic vasculitis and orbital inflammation. Ischemic vasculitis may cause amaurosis fugax, ischemic optic neuropathy, and/or central or branch retinal artery occlusions. Orbital inflammation may be diffuse or may present as dacryoadenitis, myositis, periscleritis, and/or perineuritis. Both orbital apex syndrome and cavernous sinus syndrome have been reported in patients with Churg-Strauss syndrome [35].

The diagnosis of orbital involvement secondary to Churg-Strauss syndrome should be suspected when a patient with an orbital process has hematologic evidence of eosinophilia and a positive assay for p-ANCA. The findings on CT scanning and MR imaging are nonspecific and include lacrimal gland and extraocular muscle enlargements. Ultimately, the diagnosis can be confirmed by biopsy, with the key histologic feature being a necrotizing vasculitis associated with extravascular infiltration by eosinophils [36, 37].

The treatment of patients with orbital involvement by Churg-Strauss syndrome consists of corticosteroids, sometimes combined with methotrexate or cyclophosphamide; however, as orbital involvement is fairly infrequent in Churg-Strauss syndrome, therapy is almost always in context with treatment of the systemic disease. There have been some reports showing the benefit of other agents in refractory or relapsing Churg-Strauss syndrome, although not specifically with respect to orbital involvement. Second-line drugs used in this setting include rituximab, infliximab, etanercept, mepolizumab, and omalizumab.

Polyarteritis nodosa is a systemic necrotizing vasculitis affecting small- and medium-sized arteries. Its cause is unknown, but an association with hepatitis B has been reported. The condition affects multiple organs, particularly the GI tract; the eyes and orbits are affected in approximately 10 % of patients [19, 38]. Ocular manifestations usually are limited to retinal vasculitis, ischemic optic neuropathy, and scleritis, but patients with diffuse orbital inflammation characterized by proptosis, ophthalmoplegia, conjunctival injection and chemosis, and decreased vision have been described [39, 40].

The diagnosis of polyarteritis nodosa usually is based on the physical examination and laboratory studies. Laboratory findings generally are nonspecific but include an elevated ESR, eosinophilia, positive antinuclear antibody assay, and positive rheumatoid factor. CT scanning and MR imaging findings are nonspecific, but catheter angiography may show arterial dilation with aneurysm formation, arterial constriction by inflammation, or both. Orbital biopsies of affected tissue typically reveal a mixed arterial and venous vasculitis with variable fibrosis (Fig. 24.12).

Treatment of orbital vasculitis secondary to polyarteritis nodosa is identical with the treatment of the systemic disease. The mainstay of therapy is a combination of systemic corticosteroids and cyclophosphamide; however, other immunomodulatory agents such as azathioprine and methotrexate also have been used, and there are case reports of disease remission with the use of rituximab in polyarteritis nodosa, although not specifically in patients with orbital disease.

Giant cell arteritis (GCA), also called temporal arteritis, is an idiopathic vasculitis of medium- to large-sized arteries. The condition is characterized histologically by segmental arterial inflammation consisting of giant cells, lymphocytes, plasma cells, and eosinophils in the media associated with thickening and disruption of its internal elastic lamina.

The systemic manifestations of GCA include headache, temple pain and/or tenderness, scalp tenderness, jaw claudication that may be mistaken for TMJ syndrome, migratory arthralgias, malaise, and fevers of unknown origin. Ocular manifestations include both anterior and retrobulbar ischemic optic neuropathy, central retinal artery occlusion, and diplopia from either ocular motor nerve paresis or extraocular muscle ischemia [41]. In addition, some patients develop an orbital ischemic syndrome characterized by corneal edema, cataract formation, hypotony, ophthalmoparesis, and visual loss from optic neuropathy [42]. A less common presentation of GCA is orbital inflammation; however, in this setting, patients can have signs and symptoms of an orbital apex syndrome (Fig. 24.13) [43–45].

The diagnosis of GCA-related orbital disease can be made from the combination of the clinical presentation, laboratory studies (elevated ESR, CRP, or both), imaging consisting of contrast enhancement of the orbit with an infiltrative appearance or a mass lesion on MR imaging, and, most importantly, a temporal artery biopsy showing giant cells, fragmentation or loss of the elastic lamina of arteries, and areas of fibrosis and necrosis [43, 45].

The treatment of a patient with an orbital apex syndrome caused by GCA is no different from the treatment of patients without orbital disease. All patients should be placed on high-dose corticosteroids, with a slow taper once there is an initial clinical and laboratory response. There is no consistently effective agent other than steroids for patients with GCA, although some authors advocate cyclophosphamide or methotrexate in cases that are refractory to steroids [45]. Other treatments suggested include external beam radiation, TNF-alpha inhibitors, and tocilizumab, an anti-interleukin-6 antibody.

Systemic lupus erythematosus (SLE) is a chronic, systemic autoimmune-mediated connective tissue disease causing a vasculitis that affects the eye and visual system in 20 % of patients. In this condition, the deposition of pathogenic autoantibodies and immune complexes damages tissues and cells. Some common ocular manifestations of SLE include keratoconjunctivitis sicca, periocular skin lesions, retinal hemorrhages and vasculitis, retinal vaso-occlusive disease, iritis, scleritis, optic neuritis, ischemic optic neuropathy, and orbital inflammation. One rare clinical entity in the SLE spectrum is panniculitis, also known as lupus erythematosus profundus (LEP), which is a nodular inflammation of adipose tissue. Panniculitis involving orbital structures as the primary presenting symptom of SLE is quite unusual and only rarely has been reported in the literature [46]. Vascular inflammation consisting of a leukocytoclastic vasculitis affecting small vessels is a common finding in patients with SLE, with an incidence of 30–40 %. It is related to immune complex deposition within the vessels walls.

The most common manifestations of SLE vasculitis are cutaneous lesions (e.g., nail-fold infarcts, palpable purpura, and digital gangrene) and polyneuropathy. The most common ocular findings are retinopathy, keratoconjunctivitis sicca, and uveitis [47]. Orbital involvement is infrequent, but there have been a number of case reports in the literature describing diffuse orbital inflammation, orbital infarction, and myositis in association with SLE [48, 49].

The diagnosis of SLE can be made when 4 or more of 11 criteria (malar rash, discoid rash, photosensitivity, oral ulcers, nonerosive arthritis, pleuritis or pericarditis, renal disorder, neurologic disorder, hematologic disorder, immunologic disorder, positive ANA) are present (Table 24.2) [50]. In addition, the ANA assay is positive in 95 % of patients with SLE; thus, a negative ANA may be regarded as evidence against the condition, but a positive ANA is not diagnostic. If a patient meets the diagnostic criteria listed above and has a positive ANA, then no further test is required. On the other hand, if a patient has a positive ANA but does not meet the diagnostic criteria, he or she should undergo assays for antibodies to double-stranded DNA and smooth muscle nuclear antigen as positive results suggest the diagnosis.

Similar to most of other orbital vasculitides, orbital inflammation related to lupus vasculitis usually is treated with systemic corticosteroids. Immunomodulatory agents, biologics and rituximab, infliximab, and belimumab also have shown to be beneficial [51].

Tolosa-Hunt syndrome is the eponym used to describe idiopathic orbital inflammation causing painful ophthalmoplegia. It is characterized histologically by granulomatous inflammation consisting of epithelioid and occasional giant cells within the cavernous sinus, superior orbital fissure, orbital apex, or a combination of these structures [52–54]. It can affect people of any age with no sex predilection. The condition usually occurs spontaneously, although it has been reported to develop after ocular trauma [55].

The clinical manifestation of Tolosa-Hunt syndrome is an ophthalmoparesis associated with severe periorbital or hemicranial pain. In some cases, the ophthalmoparesis is associated with evidence of one or more ocular motor nerve paresis, whereas in other cases, it is related to inflammation of the extraocular muscles at the orbital apex. The periocular or hemicranial pain may precede the ophthalmoparesis by up to 2 weeks and typically is described as a severe, intense, boring, gnawing, or stabbing sensation. Pupillary reactions may be normal, or there may be either parasympathetic or sympathetic dysfunction. Tolosa-Hunt syndrome may have a relapsing and remitting course, and residual neurologic deficits may persist after remission [56].

The International Headache Society defined the diagnostic criteria of Tolosa-Hunt syndrome as follows: (1) one or more episodes of unilateral orbital pain persisting for weeks if untreated; (2) associated paralysis of one or more of the third, fourth, or sixth cranial nerves; and/or (3) demonstration of a granuloma by MR imaging or biopsy; (4) the paresis coincides with the onset of pain and follows it within 2 weeks; (5) pain and paresis resolve within 72 h when treated adequately with corticosteroids (see below), but in this setting, the condition should only be diagnosed after exclusion of other potentially causative lesions [57].

MR imaging should be the initial screening study in patients with suspected Tolosa-Hunt syndrome. Coronal fast spin-echo T2-weighted images and fat-saturated T1-weighted coronal and transverse images with and without contrast show high sensitivity for the detection and follow-up of the inflammatory lesion (Fig. 24.14) [58].

The findings are nonspecific, however, and cannot be differentiated from certain tumors, such as meningiomas or lymphomas, not to mention the granulomatous lesions caused by sarcoidosis [59]. Although high-resolution CT scanning also can demonstrate soft tissue changes in the orbital apex, superior orbital fissure, and/or cavernous sinus, it is not sensitive to soft tissue changes because of superimposed beam hardening and bone artifacts. Cerebral angiography may detect abnormalities of the cavernous portion of the internal carotid artery in patients with Tolosa-Hunt syndrome [60], but, again, the findings are nonspecific. Some reports have documented elevation of the ESR and a leukocytosis in the acute stage of Tolosa-Hunt syndrome [61], and some patients have antinuclear antibodies despite having no evidence of a connective tissue disorder. CSF examination tends to be unremarkable but may show an elevated protein concentration and a mild pleocytosis. Although biopsy of abnormal tissue in the orbital apex or cavernous sinus is rarely employed to establish the diagnosis of Tolosa-Hunt syndrome, it should be considered in patients with rapidly progressive neurological deficits, lack of steroid responsiveness, or persistent abnormalities on neuroimaging studies.

In the final analysis, the diagnosis of Tolosa-Hunt syndrome usually is one of exclusion, requiring a careful evaluation to eliminate out other etiologies of painful ophthalmoplegia and other forms of inflammation within the cavernous sinus and superior orbital fissure. Some authors have suggested excluding other causative conditions by using serologic and CSF studies and, occasionally, biopsy, followed by serial clinical and imaging examinations for at least 2 years after steroids have been ceased before the diagnosis can be made with some degree of assurance [62].

The treatment of Tolosa-Hunt syndrome consists of high-dose systemic steroids to which the condition is markedly sensitive. Indeed, as noted above, most patients have dramatic resolution of pain within 24–72 h after onset of treatment, although the ophthalmoparesis can take weeks to months to resolve. Methotrexate and azathioprine have provided clinical benefit in a limited number of patients with Tolosa-Hunt syndrome [63, 64]. Radiotherapy also reportedly alleviated symptoms of Tolosa-Hunt syndrome in a patient refractory to immunosuppressive therapy and in another patient who became steroid dependent [65].

Idiopathic orbital inflammatory syndrome is the third most common orbital disorder in adults after thyroid orbitopathy and lymphoproliferative disorders, with a peak incidence in middle age and a predilection for women [66, 67].

Based on the extent and location of involvement, it can be categorized as myositis, dacryoadenitis, anterior, apical, or diffuse. Histopathologic analysis of affected tissue shows a spectrum of granulomatous inflammation admixed with non-granulomatous inflammation and fibrosis (Fig. 24.15) [68].

In most cases, no cause can be found to account for the inflammatory process, hence the label “idiopathic” [69]; however, some cases are associated with autoimmune disease, trauma, or recent surgery [70], and an increasing number of cases once thought to be “idiopathic” have been found to have pathologic findings consisting of plasma cells containing IgG4 (Table 24.3) [71–73].