Dr. Bokkwan Jun is a Neuro-Ophthalmologist and is currently assistant professor of Ophthalmology in University of Missouri, Columbia, MO, USA. He trained in Ophthalmology at Hanyang University, Neurology at Saint Louis University and Neuro-Ophthalmology at Johns-Hopkins University.
Neil R. Miller
Dr. Neil Miller is currently Professor of Ophthalmology, Neurology, and Neurosurgery at the Johns Hopkins Medical Institutions and also the Frank B. Walsh Professor of Neuro-Ophthalmology. Dr. Miller was President of the North American Neuro-Ophthalmology Society from 2000 to 2002 and Chairman of its Executive Board from 2002 to 2004. He has been past President of the International Neuro-Ophthalmology Society on three occasions: in 1982, 1992, and 2008. He is also an emeritus member of the International Orbital Society. In 2009, he was given the Lifetime Achievement Award by the American Academy of Ophthalmology (AAO). He has authored or co-authored 500 articles, 90 chapters, and 13 books in the fields of neuro-ophthalmology and orbital disease. Many of Dr. Miller’s previous fellows and residents hold faculty positions at major institutions throughout the United States and around the world.
A wide variety of pathologic processes can involve the structures located at the apex of the orbit. In this chapter, we will discuss only those due to inflammation.
The osseous anatomy of the orbital apex may be difficult to conceptualize because of the different shapes and orientations of the optic canal, superior and inferior orbital fissures, and foramen rotundum; however, understanding the anatomy is crucial in the understanding of the clinical manifestations produced by the pathologic processes that affect the orbital apex.
The orbits are conical or four-sided pyramidal cavities, each consisting of a base, an apex, and four walls. There are three main bony openings at the orbital apex: the optic canal, the superior orbital fissure, and the inferior orbital fissure (Fig. 24.1).
Bony anatomy of the orbit. Note locations of the superior and inferior orbital fissures and the optic canal
The optic canal is formed by the two roots of the lesser wing of the sphenoid bone. If projected forwards, its axis passes about through the middle of the inferolateral quadrant of the orbital opening. Through the canal pass the optic nerve and the ophthalmic artery . Thus, it connects the orbit with the subarachnoid intracranial space (Figs. 24.2 and 24.3).
Anatomy of the optic canals. Left, direction of the canals from anterolateral to posteromedial. Right, axial CT scan showing the canals
Axial view of the brain at the level of the optic canals showing the path of the optic nerves through the canals
The superior orbital fissure, a gap between the greater and lesser wings of the sphenoid bone, is located inferolateral to the optic canal and contains the superior and inferior divisions of the oculomotor nerve, the trochlear nerve, the ophthalmic division of the trigeminal nerve, the abducens nerve, the superior and, when present, inferior divisions of the ophthalmic vein, and the sympathetic fibers (Figs. 24.1 and 24.4). It connects the orbit with the cavernous sinus.
The structures at the apex of the orbit showing the location of the ocular motor nerves as they pass through the superior orbital fissure
The inferior orbital fissure is located between the lateral wall and the floor of the orbit. It is bounded anteriorly by the maxilla and the orbital process of the palatine bone and posteriorly by the entire lower margin of the orbital surface of the greater wing of the sphenoid (Fig. 24.1). It connects the orbit with the pterygopalatine and infratemporal fossae.
In addition to the structures described above, the orbital apex contains the origins of the four rectus muscles, the superior oblique muscle, and the levator palpebrae superioris (Figs. 24.4 and 24.5).
Drawing of the structures at the orbital apex
The four rectus muscles are attached posteriorly by a short tendinous ring that encloses the optic foramen and the inferomedial end of the superior orbital fissure (Fig. 24.5). The origin of the superior oblique muscle is located just superior and medial to the orbital end of the optic canal. The origin of the levator muscle is located just superior to the annulus. Thus, structures at the orbital apex include the optic nerve, the ocular motor nerves, the origins of all but one of the extraocular muscles, and the branches of the first and second divisions of the trigeminal nerve.
In view of the neural and muscular structures in close proximity at the orbital apex, it should not be surprising that lesions at the orbital apex typically cause a combination of visual loss and ocular motor dysfunction. The visual loss usually results from damage to the optic nerve, whereas the ocular motor dysfunction may result from damage to one or more ocular motor nerves, the extraocular muscles they innervate, or both. In addition, depending on the nature and extent of the process, there will be variable proptosis and pain in and around the orbit. In general, numbness in the territory of the ophthalmic (first) division of the trigeminal nerve is not present in the orbital apex syndrome. Indeed, patients in whom there is corneal anesthesia or hypesthesia and anesthesia or hypesthesia in the cutaneous distribution of the ophthalmic division of the trigeminal nerve are considered to have either a “sphenocavernous” syndrome or a pure cavernous sinus syndrome, particularly if there is no evidence of an optic neuropathy.
General Approach to and Management of Specific Causes of the Orbital Apex Syndrome
An orbital apex lesion should be considered in all patients who present with unilateral blurred vision, ophthalmoplegia, and proptosis (Fig. 24.6).
Patient with right orbital apex syndrome. Note ptosis, ophthalmoplegia, and proptosis. The patient also had right-sided visual loss due to an optic neuropathy
When the presentation is acute and associated with pain, an infectious or inflammatory process should be suspected, even though other processes such as primary or metastatic tumors can cause a similar or identical presentation.
In patients suspected of harboring an infectious or noninfectious inflammatory process in the orbital apex, urgent laboratory studies and neuroimaging need to be performed as may a biopsy of any abnormal tissue identified by the imaging.
Laboratory tests that may be performed in patients with known or suspected inflammation at the orbital apex include a complete blood count with differential, serum chemistry, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), hemoglobin A1c, rapid plasma reagin, microhemagglutination assay for antibody to Treponema pallidum, fluorescent treponemal antibody test, antinuclear, anti-double-stranded DNA antibody, and anti-smooth muscle antibody assays, serum protein electrophoresis, antineutrophil cytoplasmic antibody assays (both p-ANCA and c-ANCA), angiotensin-converting enzyme, and human immunodeficiency virus assessment. A lumbar puncture is appropriate if a generalized central nervous system (CNS) process is suspected, with the cerebrospinal fluid (CSF) assessed for cell count and differential as well as protein and glucose concentration. Depending on the presentation, culture of the CSF for bacterial, fungal, or mycobacterial disease may be performed.
Neuroimaging should be performed on all patients with a known or suspected orbital apex syndrome. Both computed tomographic (CT) scanning and magnetic resonance (MR) imaging have pros and cons. CT scanning is superior to MR imaging for the depiction of bony anatomy and is especially helpful in determining if there is bone destruction from inflammation or infection is suspected clinically (Fig. 24.7) .
Axial CT scan showing lesion of the left orbital apex. Note absence of bony destruction
In addition, by obtaining both axial and direct coronal views, one can identify any extension of the process to (or from) the adjacent paranasal sinuses or the cavernous sinus. Indeed, abnormal material in the paranasal sinuses often can be seen with CT scanning when it is not evident on MR imaging. On the other hand, MR imaging usually provides excellent detail of soft tissue in the orbit and shows the cavernous sinus much better than CT scanning, particularly when appropriate sequences such as T1-weighted images with fat suppression and contrast are included (Fig. 24.8).
MR imaging, axial (left) and coronal (right) views, shows a well-circumscribed mass at the left orbital apex
3-Tesla (3-T) MR machines have been found to be superior to the standard 1- and 1.5-T machines in defining parasellar anatomy and identifying invasion of the cavernous sinus by infections, inflammation, and tumors . To rule out and investigate a vascular lesion of the cavernous sinus, MR or CT angiography may be helpful. If the index of suspicion remains high despite negative neuroimaging studies, conventional diagnostic cerebral angiography can be considered. Although orbital apex inflammation or infection may be suspected on the basis of the results of laboratory studies and neuroimaging, a culture or biopsy of abnormal material for pathologic confirmation may be required to determine the correct diagnosis and direct treatment. A variety of surgical techniques can be used to reach the orbital apex with relative safety, including both transcaruncular and endoscopic endonasal approaches.
The management of patients with orbital apex inflammation is aimed at the underlying etiology. If a specific etiology cannot be determined, the primary management options may include close observation, an empiric trial of systemic corticosteroids, antibiotics, or both, and biopsy and/or culture of abnormal material. The distinction between inflammation, infection, and other etiologies, especially neoplasms, can be difficult, particularly as all may respond – at least initially – to corticosteroids. However, in patients with occult infections, particularly those caused by fungi, systemic corticosteroids may result in severe morbidity or mortality. Thus, if symptoms and signs progress despite steroid treatment, one must consider repeat neuroimaging and obtaining tissue for culture or biopsy. In many cases, neurosurgical and otolaryngological consultations are warranted, particularly if a cavernous sinus or paranasal sinus lesion is accessible for biopsy . Consultations with a specialist in internal medicine, infectious diseases, rheumatology, and/or neurology may be appropriate.
Inflammatory Conditions That Can Cause an Orbital Apex Syndrome
Inflammatory conditions that can cause an orbital apex syndrome may be infectious or noninfectious (Table 24.1). Noninfectious inflammatory etiologies include sarcoidosis, vasculitis (e.g., Wegener’s granulomatosis, Churg-Strauss syndrome, giant cell arteritis (GCA), and systemic lupus erythematosus (SLE), Tolosa-Hunt syndrome, and both idiopathic and IgG4-related orbital inflammations .
Differential diagnosis of inflammatory orbital apex syndromes
Giant cell arteritis
Systemic lupus erythematosus
Idiopathic and immunoglobulin G4 (IgG4)-related orbital inflammation
Staphylococcus aureus, Streptococcus pneumonia, Actinomyces israelii, Pseudomonas aeruginosa
Sarcoidosis is a multisystem disorder of unknown etiology that is characterized histologically by granulomatous inflammation in the affected organs (Fig. 24.9).
Histology of orbital sarcoidosis. Note noncaseating granulomatous inflammation with multiple multinucleated giant cells
Ocular involvement is seen in approximately 25 % of patients with sarcoidosis . 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 .
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 . 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 , 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 . 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 . 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 in a 70-year-old woman with a left orbital apex syndrome. Left, external appearance of patient. Right, biopsy of abnormal tissue reveals a vasculitis. The patient had c-ANCA antibodies in her serum
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 .
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 .
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 . 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 , including patients with orbital involvement .
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) .
Histology of Churg-Strauss syndrome. Note intense necrotizing vasculitis rich in eosinophils
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 .
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 .
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).
Polyarteritis nodosa (PAN) in a patient with a central retinal artery occlusion and a mass at the right orbital apex. Left, appearance of the right ocular fundus at the time of visual loss shows a partial central retinal artery occlusion. Right, biopsy of abnormal tissue at the orbital apex is consistent with PAN, showing a mixed arterial and venous vasculitis minimal variable fibrosis
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
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 . In addition, some patients develop an orbital ischemic syndrome characterized by corneal edema, cataract formation, hypotony, ophthalmoparesis, and visual loss from optic neuropathy . 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].
Giant cell (temporal) arteritis causing an orbital/ocular ischemic syndrome in a 76-year-old woman. Left, note right enophthalmos from fat atrophy due to ischemia. Center, the right eye is injected, and there is some corneal edema and a developing cataract. The intraocular pressure was low, and there was a general ophthalmoparesis. Right, the patient experienced a myocardial infarction and died. Pathology of the posterior orbital tissue revealed occlusion of the posterior ciliary arteries with fragmentation of the elastic lamina and a chronic inflammation characterized in part by giant cells
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 . Other treatments suggested include external beam radiation, TNF-alpha inhibitors, and tocilizumab, an anti-interleukin-6 antibody.
Systemic Lupus Erythematosus
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 . 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 . 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) . 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.
1997 update of the 1982 American College of Rheumatology revised criteria for classification of systemic lupus erythematosus 
Fixed erythema, flat or raised, over the malar eminences
Erythematous circular raised patches with adherent keratotic scaling and follicular plugging; atrophic scarring may occur
Exposure to ultraviolet light causes rash
Includes oral and nasopharyngeal ulcers, observed by physician
Nonerosive arthritis of two or more peripheral joints, with tenderness, swelling, or effusion
Pleuritis or pericarditis documented by ECG or rub or evidence of effusion
Proteinuria >0.5 g/d or 3+ or cellular casts
Seizures or psychosis without other causes
Hemolytic anemia or leukopenia (<4000/L) or lymphopenia (<1500/L) or thrombocytopenia (<100,000/L) in the absence of offending drugs
Anti-dsDNA, anti-Sm, and/or antiphospholipid
An abnormal titer of ANA by immunofluorescence or an equivalent assay at any point in time in the absence of drugs known to induce ANAs
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 .
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 .
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 .
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 .
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) .
Tolosa-Hunt syndrome in a patient with left-sided ophthalmoparesis and a mild left optic neuropathy. CT scan, axial, and coronal views show an ill-defined mass in the left orbital apex and cavernous sinus
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 . 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 , 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 , 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 .
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 .
Idiopathic and Immunoglobulin G4 (IgG4)-Related Orbital Inflammation
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) .
Patient with a right orbital apex syndrome characterized by the sudden development of right-sided orbital pain, injection, conjunctival chemosis, ophthalmoparesis, proptosis, and decreased vision associated with a right relative afferent pupillary defect. Left, axial CT scan shows a lesion at the orbital apex that is deviating the optic nerve medially. Because of concern for a lymphoma, the lesion was biopsied. Right, biopsy shows a nonspecific follicular inflammation. The lesion had both B- and T-lymphocytes. Staining for IgG4 was negative
In most cases, no cause can be found to account for the inflammatory process, hence the label “idiopathic” ; however, some cases are associated with autoimmune disease, trauma, or recent surgery , 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].
Previously recognized conditions that comprise or may comprise parts of the IgG4-related disease spectrum
Previous “idiopathic” conditions
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