This chapter will cover thyroid-related orbitopathy, idiopathic orbital inflammatory syndrome, malignant orbital tumors, and orbital cellulitis.

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1 Orbital disease in neuro-ophthalmology Danah Albreiki MBBS ( Dr. Albreiki of the Ottawa Eye Institute has no relevant financial relationships to disclose. ) Jonathan D Trobe MD, editor. ( Dr. Trobe of the University of Michigan has no relevant financial relationships to disclose.) Originally released October 12, 2000; last updated March 9, 2017; expires March 9, 2020 Introduction This article includes discussion of orbitopathies affecting vision and ocular alignment, idiopathic orbital inflammatory syndrome, thyroid-related immuno-orbitopathy, thyroid-related immunoorbitopathy, malignant orbital tumors, orbital cellulitis, and orbital inflammatory syndrome. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations. Overview Orbital pathology can result in neuro-ophthalmic manifestations such as optic neuropathy and ocular misalignment, leading to vision loss and diplopia. Among the common orbital conditions are thyroid-related orbitopathy (TRO), orbital tumors, and orbital inflammatory syndromes. Other orbitopathies include IgG-4-related disease and orbital infections such as cellulitis. Key points History taking and clinical examination of the orbit are important parts of the evaluation. Early detection may prevent or reduce visual dysfunction. Orbital pathology may lead to restrictive ocular movements manifesting as diplopia. Orbital pathology can easily be missed if the orbit is not considered as a site of pathology. Proptosis is the hallmark of orbital pathology, but it is not always present. To detect it, one could use a Hertel Exophthalmometer and check for resistance to retropulsion. The most common orbital condition is thyroid-related orbitopathy. Historical note and terminology Orbital pathology can be categorized according to disease mechanism: 1. Inflammation a. Thyroid-related orbitopathy b. Orbital inflammatory syndrome (specific or idiopathic) 2. Infection (cellulitis) 3. Tumor a. Benign b. Malignant 4. Vasculopathy 5. Anomaly This chapter will cover thyroid-related orbitopathy, idiopathic orbital inflammatory syndrome, malignant orbital tumors, and orbital cellulitis. The most common orbital disease is thyroid-related orbitopathy, accounting for 32% of all orbital disorders. Next in order of frequency are lymphoproliferative orbital disease (9%), idiopathic orbital inflammatory syndrome (4.3% to 6.3%), vasculopathy (6%), orbital cellulitis (5%), and conditions of unknown cause (5%). A comprehensive review reported that thyroid-related orbitopathy accounted for 47% of orbital disease, with inflammatory disorders accounting for 10% and vasculopathy for 3% (Rootman 2001). Thyroid-related orbitopathy is also called Graves orbitopathy. The historical background behind naming the disease Graves goes back to 1835 when the Irish physician Robert James Graves described a patient with goiter and

2 proptosis. The German physician Karl von Basedow reported the same group of symptoms independently in Other names for the same disease are Parry disease, Begbie disease, Flajani disease, and Marsh disease. These names are derived from physicians in the early 1800s. But in the 12th century, a Persian physician named Sayyid Ismail Al- Jurani had noted the association between goiter and proptosis, reporting it in his Thesaurus of the Shah Khwarazm (Ljunggren 1983). Clinical manifestations Presentation and course Orbital pathology can manifest as a disturbance of vision or ocular alignment. The hallmark for orbital disease is proptosis. The most common orbital condition that causes unilateral or bilateral proptosis is thyroid-related orbitopathy. If the proptosis is accompanied by lid retraction, thyroid-related orbitopathy would be the most likely diagnosis. Proptosis, however, can be secondary to other orbital conditions such as inflammatory orbital disease, vascular conditions, infections, or tumors. Proptosis can be axial, indicating an intraconal process, or nonaxial indicating an extraconal process. Orbital disease can affect vision by causing a stretch optic neuropathy if the proptosis exceeds 8 mm from the baseline. More commonly, optic neuropathy results from pressure exerted on the optic nerve by enlarged muscles. Enophthalmos can be a feature of orbital disease such as silent sinus syndrome, which causes retraction of the orbit bones, or by metastatic breast cancer, which causes cicatricial shortening of the extraocular muscles and orbital fat. Lid retraction, ptosis, and diplopia from a restrictive or a paralytic process affecting the levator palpebrae superioris and extraocular muscles can all be features of orbital disease. Facial hypesthesia may be a manifestation of impaired trigeminal function when orbital lesions also involve the cavernous sinus. Gaze-evoked amaurosis occurs when a lesion within the orbit compresses the optic nerve as the nerve kinks when the eye moves into an eccentric gaze position. Thyroid-related orbitopathy (TRO). Thyroid-related orbitopathy is the most common extrathyroidal manifestation of Graves disease, occurring in about 25% to 50% of patients. It may be present in patients with hyperthyroidism, hypothyroidism, or euthyroidism (Heufelder 2000). Patients with thyroid-related orbitopathy may have symptoms related to periorbital tissues, lids, orbit, anterior segment, or uncommonly, the optic nerve. Symptoms are usually gradually progressive over weeks to months. Patients may complain of periorbital soft tissue swelling, lid retraction, proptosis, dry eye-related symptoms, photophobia, or vision loss. Moreover, patients may adopt an abnormal head posture or complain of diplopia. They may also complain of pain and irritation. However, if the pain is acute and severe, other causes should be considered, such as orbital inflammatory syndrome or cellulitis. Thyroid-related orbitopathy usually involves both orbits symmetrically. The most common and pathognomic feature of thyroid-related orbitopathy is lid retraction, defined as exposure of the sclera above the superior limbus, but patients can also have inferior lid retraction. A plausible mechanism for lid retraction is sympathetic overdrive and muscle hypertrophy. The differential diagnosis of lid retraction includes dorsal midbrain syndrome, systemically-administered sympathomimetics, previous ocular surgery, and aberrant regeneration of the third nerve. Lid lag, which describes a delay in relaxation of the levator muscle as the eye is moved into downgaze, is a common feature of thyroid-related orbitopathy. Proptosis is one of the most common features of thyroid-related orbitopathy. It is often measured with the Hertel exophthalmometer. This may be supplemented with checking for resistance to retropulsion. Proptosis is present in about two thirds of patients (Eichhorn et al 2010). Conjunctival hyperemia, particularly around the lateral recti muscle insertions, as well as swelling and erythema of the caruncular area, dry eyes, exposure keratopathy, superior limbic keratoconjunctivitis, and corneal ulceration are all features of thyroid-related orbitopathy. Inflammation of the extraocular muscles may cause a feeling of tightness in the eyes in addition to diplopia created by reduced ocular movements and consequent ocular misalignment. Patients may adjust to diplopia by gradually adopting an abnormal face turn or chin position. The extraocular muscle most often affected is the inferior rectus, followed by the medial rectus, superior rectus, and lateral rectus. Depending on the most prominent muscles involved,

3 the eyes may be misaligned vertically or horizontally. The range of excursions of the eyes is often graded on a scale from 0 to -4 (with -4 indicating no movement beyond primary gaze position in a particular direction). Ocular alignment is measured with the cover test or the Maddox rod with the aid of prisms. Optic neuropathy occurs in up to 8% of patients with thyroid-related orbitopathy. It is usually the result of compressive optic neuropathy related to extraocular muscle crowding at the orbital apex. Patients may present with reduced visual acuity, visual field defects, reduced color vision, and sometimes with a relative afferent pupillary defect (RAPD). The optic nerve may appear normal, swollen, or pale. Patients need not have proptosis to be vulnerable to compressive optic neuropathy. Clinical manifestations of thyroid-related orbitopathy have been assessed by different classification systems since Werner was one of the first to establish the NO SPECS classification, which stands for no physical signs or symptoms, only signs, soft tissue involvement, proptosis, extraocular muscle signs, corneal involvement, and sight loss. The NO SPECS system was modified by its author in The new system assesses clinical severity but does not differentiate between active and inactive thyroid-related orbitopathy. In 1989, Mourits established a clinical activity system (CAS) that accounts for active inflammation (pain, redness, swelling, and reduced function) (Mourits 1989). This system was modified in Two of the currently used systems are the VISA classification (vision, inflammation, strabismus, appearance) (Dolman 2012), used commonly in North America (Barrio-Barrio et al 2015), and the European Group of Graves' Orbitopathy (EUGOGO) Classification used commonly in Europe (Bartalena et al 2008). Another classification system was developed in order to predict the risk of diplopia after orbital decompression (Nunery et al 1997). The author classified 58 patients into type I and type II prior to a two-wall orbital decompression. Type I had normal versions and no diplopia. Type II had diplopia within 20 degrees of the primary position and restricted motility. Only 4% of patients with type I experienced new or worsening diplopia following surgery, whereas 61% of patients with group II experienced new or worsening of diplopia. A study proposed that thyroid-related orbitopathy reactivates in 5% of patients after more than 5 years of inactive disease (Selva et al 2004). Diagnosis of thyroid-related orbitopathy is principally based on clinical criteria. If lid retraction is present with proptosis, the diagnosis is very likely (Bartley and Gorman 1995). If lid retraction is not present, laboratory markers can be sought. Orbital imaging assesses extraocular muscle caliber and orbital fat volume, excludes other pathology, and aids in surgical planning. Imaging features are increased orbital fat, usually without enhancement, and enlarged muscles with sparing of muscle tendons, which is a feature that is said to distinguish thyroid-related orbitopathy from orbital myositis. Idiopathic orbital inflammatory syndrome (orbital pseudotumor). Idiopathic orbital inflammation is the third most common orbital disorder, after thyroid-related orbitopathy and lymphoproliferative diseases. Estimated to constitute 4.7% to 6.3% of all orbital disease, it is characterized by nongranulomatous inflammation often limited to the orbit. Bilateral involvement in adults suggests an underlying systemic vasculitis. In children, this disorder may be relapsing, refractory to treatment, and bilateral in up to 50% of cases. Clinical presentations mimic connective tissue disorders, sarcoidosis, or lymphoma. Patients usually present with an acute or subacute onset of painful ophthalmoplegia, diplopia, lid swelling, and conjunctival chemosis. The acute onset is an important distinguishing factor from thyroid-related orbitopathy. Clinical manifestations may also include impaired visual acuity or visual field deficits. Idiopathic orbital inflammation may be subdivided into dacryoadenitis, myositis, scleritis, perineuritis, orbital pseudotumor, diffuse orbital inflammatory syndrome, and Tolosa-Hunt syndrome. It may present differently depending on the orbital structures affected. One study that evaluated the distribution of affected tissues in 90 eyes found that the inflammation was based in the lacrimal gland in 21 patients, in extraocular muscle in 19 patients, in lacrimal gland and muscle in 5, in the orbital apex in 6, and in the preseptal region, supraorbital region, sclera, Tenon capsule, orbital fat, or optic nerve in 14 (Yuen and Rubin 2003). Tolosa-Hunt syndrome, now often called idiopathic hypertrophic pachymeningitis, may affect the orbital periosteum (dura), superior orbital fissure, cavernous sinus, or other locations at the cranial base. It can present with severe pain, vision loss, and third, fourth, and sixth nerve palsies.

4 The diagnosis of idiopathic orbital inflammation is based on combining clinical history and examination, laboratory results, imaging, biopsy, and sometimes on its rapid response to steroid treatment. Autoimmune and infectious etiologies have been proposed as the basis of idiopathic orbital inflammation. However, IgG4-related disease has been implicated, at least for a subset (Hamano et al 2001). IgG4 disease includes enlargement in at least 1 organ demonstrated by examination and imaging, high serum IgG4 levels, and plasmocytic and lymphocytic infiltration demonstrated histopathologically. IgG4-related disease is thought to be a generalized process that may involve the pancreas, salivary glands, hepatobiliary ducts, retroperitoneal space, lymph nodes, kidneys, lungs, aorta, and skin (Plaza et al 2011). The most reliable data for IgG4 disease incidence come from Japan, where this disease accounts for 0.28 to 1.08 cases per 100,000 (Sato et al 2008). Sclerosing orbital inflammation has been considered a rare subset of idiopathic orbital inflammation, but it may be a separate entity. It has a more gradual onset and less pain. Desmoplasia affects orbital structures, replacing them with fibrosis. There is only a sparse inflammatory response of plasma cells, lymphocytes, histiocytes, eosinophils, and neutrophils. In the evaluation of suspected idiopathic orbital inflammation, infectious causes, including orbital cellulitis, must be ruled out. Its presentation is more like that of a neoplasm, and the work-up frequently requires a biopsy. At surgery, a tough fibrous sheath of tissue can sometimes be found surrounding the muscles and other compartments. Steroids are rarely able to reduce or eliminate this, and careful surgical release of muscles from this sheath can help return the orbit to a more functional state. There is a debate as to whether sclerosing orbital pseudotumor is a completely different pathologic entity. Malignant orbital tumors. A study of 1264 patients with suspected orbital tumors found that vasculogenic tumors were the most common (17%), followed by those of lymphoid, lacrimal gland, optic nerve and meningeal, metastatic, and peripheral nerve origin, as well as melanoma (Shields et al 2004). Other rare conditions included fibrocytic, lipogenic, and myxoid tumors. Lymphoproliferative tumors account for most primary malignant tumors in the orbit in patients over age 60. Malignant lymphomas are most common, accounting for 24%. They may present as primary orbital tumors or in combination with systemic lymphoma. Among patients with isolated orbital lymphomas, 30% will develop systemic lymphoma within 10 years. Orbital lymphomas are of the low grade, B cell, non-hodgkin lymphoma type. The most common subtype is the extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT). The other principal orbital lymphoproliferative disorder is reactive lymphoid hyperplasia (Jenkins et al 2000). This tumor presents as progressive painless proptosis with a palpable mass and ocular dysmotility. The painless nature of this condition helps differentiate it from idiopathic orbital inflammation, which is usually painful. One manifestation is the salmon-colored conjunctival mass, also known as fish-flesh. Another manifestation is boggy edema of the eyelids and periorbital skin. Lymphoproliferative lesions may show benign histopathologic features, such as reactive lymphoid hyperplasia, or malignant features, such as atypical cells and nuclear membrane abnormalities typical of lymphoma. Classification is performed with the aid of immunologic markers. Orbital imaging discloses unilateral lesions in 76% of lymphoproliferative cases, most often in the extraconal space. About half of tumors are ill-defined and diffuse, the remainder appearing more well-circumscribed and smooth. Uniform enhancement is the rule. The lacrimal gland is involved in 40%. Imaging does not reliably distinguish between benign and malignant lymphoproliferative tumors and IOI. These tumors tend to mold around orbital structures, with remodeling of bone rather than its erosion. On MRI imaging, these lesions typically appear isointense on T1 and hyperintense on T2. About 1% to 3% of orbital masses are metastases, the most common being breast cancer, accounting for 48% to 53% of metastases. Others are prostate cancer, melanoma, and lung cancer. Metastatic tumors of the orbit often develop more rapidly than primary orbital tumors. CT imaging usually shows bony erosive changes. Childhood orbital malignancies. Childhood orbital tumors often develop rapidly, mimicking inflammatory or infectious processes.

5 Orbital rhabdomyosarcoma accounts for 25% to 35% of all head and neck rhabdomyosarcomas, usually occurring between age 3 and 5. Patients typically present with rapidly progressive proptosis, ptosis, conjunctival and lid swelling, a palpable mass, and pain. In older children and adults, the course of the disease may be more gradual. Subtypes of this condition include: 1) embryonal, occurring more commonly in childhood; 2) botryoid, a subset of the embryonal type, most commonly observed in mucosal surfaces of the orifices of the body such as the bladder, nares, and vagina; 3) pleomorphic, typically occurring in adults; 5) alveolar, occurring at any age with poor prognosis, and 6) pleomorphic/anaplastic mixed and spindle cell, each subtype occurring in less than 2% of children with rhabdomyosarcoma. Neuroblastoma is the second most common pediatric orbital malignancy, as well as the most common metastatic orbital malignancy. It metastasizes from the adrenal medulla in 35% of cases and from extra-adrenal peritoneum in 30% to 35%. The other primary sites are the posterior mediastinum (20%), neck (1% to 5%), and pelvis (2% to 3%). Most children with orbital neuroblastoma have periorbital ecchymosis and proptosis. The presentation is strikingly similar to rhabdomyosarcoma. However, neuroblastoma presents at an earlier age, is frequently bilateral, and bony changes on CT are usually more pronounced. A pre-existing diagnosis of neuroblastoma and the presence of multiple lesions help establish the diagnosis. Younger patients may have a better prognosis, but these orbital tumors require urgent biopsy, metastatic work-up, and coordinated care with pediatric hematology and oncology services. Orbital cellulitis. Orbital cellulitis requires immediate attention as blindness and intracranial extension leading to death may occur. This condition is divided into preseptal and postseptal subtypes ( postseptal cellulitis and orbital cellulitis are terms often used interchangeably). Disease anterior to the orbital septum is preseptal, and disease posterior to the septum is considered postseptal or orbital. It is important to differentiate between the 2 subtypes by means of history and clinical examination because post-septal orbital cellulitis requires immediate hospitalization, intravenous antibiotics, and often sinus and orbital surgery. Postseptal cellulitis often includes fever, vision loss, proptosis, and diplopia, which are manifestations that are not part of the preseptal variant. However, preseptal cellulitis may proceed to postseptal cellulitis if not treated promptly. Postseptal disease may result in visual loss from optic neuropathy and may spread via orbital venous emissaries into the cavernous sinus, leading to thrombosis, meningitis, stroke, abscess, and death. The common source of infection in postseptal cellulitis is the ethmoid sinus, whereas the common sources of infection in preseptal cellulitis are the ethmoid sinus and the periocular skin. Children under the age of 10 years are most at risk for orbital cellulitis. Prognosis and complications Thyroid-related orbitopathy. Thyroid-related orbitopathy usually remains active for 18 to 36 months, after which it gradually abates, often leaving behind tissue abnormalities (Kahaly 2001). A retrospective review disclosed, however, that 8 (5%) of 193 patients experienced late reactivation, defined as active orbitopathy that occurred after more than 5 years of inactive disease (Selva et al 2004). One-third of patients report displeasure with their facial appearance even when the disease has become inactive (Bartley et al 1996). Optic neuropathy occurs in 4% to 8% of patients, being permanent in 2.2%. Persistent diplopia occurs in 2.2%. Orbital inflammatory syndrome. Untreated idiopathic orbital inflammation may progress to visual loss, diplopia, and rarely to cavernous sinus thrombosis and death. Early detection and treatment yield a generally favorable prognosis. In the bilateral, frequently relapsing, variant, fibrosis causes persistently restricted eye movements and proptosis. First-line therapy consists of corticosteroids. Resolution of manifestations is generally prompt. In patients with corticosteroid intolerance or unresponsiveness, radiation therapy may be used, but complications include cataracts, dry eyes, radiation retinopathy, and optic neuropathy. Malignant orbital tumors. Primary orbital lymphoproliferative disorders are typically treated effectively with low-dose radiotherapy and appropriate eye shielding. The 5-year survival rate reaches 90% to 100% with 30 Gy, which causes infrequent side effects. A single-center retrospective study of 44 patients with orbital lymphoma treated with radiation therapy reported a 5-year local control rate of 98% and a 5-year regional control rate of 95% (Kharod et al 2015). Overall survival rate at 5 and 10 years was 76% and 61%, respectively. One patient developed a recurrence elsewhere after radiation of a lacrimal tumor. Thirteen (46%) of 28 patients treated without lens shielding developed cataracts, whereas only 4 (25%) of 16 patients treated with lens shielding developed cataracts.

6 Adult metastatic tumors are usually treated with radiotherapy, chemotherapy, or both. Lack of resolution of the primary tumor after treatment usually portends a poor prognosis. Orbital cellulitis. Treated orbital cellulitis has an excellent prognosis. However, patients with orbital abscess or severe isolated sphenoid sinusitis are more likely to develop rapid ophthalmoplegia and blindness. Clinical vignette Case 1. A 72-year-old man complained of puffy eyelids and blurred vision for 2 months. Four days after the operation, the patient's visual acuity was 20/50 in the right eye and 20/80 in the left eye. However, the paracentral scotoma in the left eye remained. One month after the operation, the patient was 20/50 in both eyes, and color plates were 10/15 bilaterally. The steroid taper was continued for several months, and the visual acuity remained reduced and was attributed to cataract. Case 2. An 8-year-old girl was referred by her pediatrician for a 6-month history of painless left periocular swelling and progressive left upper lid ptosis. The patient's mother had systemic lupus erythematosus. Best-corrected visual acuity was 20/20 in the right and left eye. There was no afferent pupillary defect. Color vision and ocular motility were normal in each eye. There was some periorbital edema in the left eye with a fixed palpable mass below the superior orbital rim. The left upper lid was ptotic by several millimeters, and the levator function (upper eyelid excursion from extreme downgaze to extreme upgaze) was severely reduced to 7 mm. CT scan was performed because the differential diagnosis included orbital pseudotumor, malignancy, and necrotizing vasculitis. CT showed a dense left superior lateral orbital mass. Careful examination of the CT showed bony changes in the bony cortex of the orbital roof. Urgent orbital biopsy was performed through a lid crease incision. Pathology demonstrated areas of inflammation and fibrosis consistent with orbital pseudotumor, but there was a prominence of infiltrative patches with small vessel vasculitis, with neutrophils and eosinophils. Preliminary diagnosis based on pathology was granulomatosis polyangiitis. The patient was referred to a pediatric rheumatologist for treatment. Treatment was commenced when the extensive preoperative work-up yielded a positive antineutrophil cytoplasmic antibody panel. There was no evidence of respiratory or renal involvement. The final diagnosis was limited granulomatosis polyangiitis. The patient was treated with a prolonged course of oral prednisone. After 6 weeks of 60 mg prednisone per day, the swelling and ptosis had virtually resolved. Case 3. A 67-year-old man was referred by his ophthalmologist for evaluation of a proptotic right eye. The patient stated that there had been progressive unilateral swelling around the right eye for more than 6 months. He also felt that the right eye was becoming more prominent. He finally presented for examination when he had diplopia in all fields of gaze. Best-corrected visual acuity was 20/30 in the right eye and 20/25 in the left eye, which was consistent with the degree of cataractous lens changes in both eyes. There was no afferent pupillary defect, and color vision was normal in both eyes. The globe was displaced superiorly by 3 mm. Hertel exophthalmometry measured 22.5 mm in the right eye and 19 mm in the left eye at a base of 99. (Hertel exophthalmometry is a method of measuring the protrusion of the cornea relative to the lateral orbital rim by a particular device. Upper limits of normal are defined based on sex and racial group. Any difference between eyes of greater than or equal to 2 mm is considered abnormal). Motility was severely limited, especially infraduction of the right eye. There was significant boggy edema to the lower lid, with a diffuse conjunctival chemosis (edema). Intraocular pressure in the right eye was 22 mm Hg and increased to 37 mm Hg with attempted upgaze. The rest of the ocular examination was within normal limits. CT examination had been read at another facility as a well-defined intraconal orbital tumor. Axial cuts showed what appeared to be an intraconal or optic nerve tumor. Biological basis Etiology and pathogenesis Thyroid-related orbitopathy. Thyroid-related orbitopathy is an autoimmune inflammatory disease that results from auto-reactive T-lymphocytes attacking antigens shared by the thyroid gland and orbital tissues. T-lymphocytes trigger orbital fibroblast proliferation and secretion of glycosaminoglycans, leading to enlargement of the extraocular muscles, and causing their dysfunction, as well as precipitating edema in the orbital tissues.

7 Orbital inflammatory syndrome. Idiopathic orbital inflammation encompasses dacryoadenitis, myositis, scleritis, perineuritis, orbital pseudo tumor, diffuse orbital inflammatory syndrome, and Tolosa- Hunt syndrome now known as idiopathic hypertrophic pachymeningitis. Autoimmune and infectious etiologies are considered causative. IgG4-related disease, discovered in 2001, may account for a subset of patients. Orbital rhabdomyosarcoma. Children with localized orbital rhabdomyosarcoma now have a 5-year survival rate of 70% compared to 25% in the 1970s (Meza et al 2006). Multiple risk factors were discovered over the years that were seen to play a role in the prognosis. For one, the embryonic subtype was shown to have a better prognosis than the other subtypes (Gaiger et al 1981). Orbital cellulitis. The most common cause of orbital cellulitis is underlying sinus infection. As children grow, the ostia that drain the paranasal sinuses remain constant in size, becoming less able to drain these sinuses, increasing the likelihood of infection. Ethmoid and maxillary sinus infections with a single aerobic agent are most common before 5 years of age. Mixed infections become more prevalent as the sphenoid and frontal sinuses become pneumatized. Face trauma is a contributory cause of pre-septal cellulitis. The incidence of hemophilus-associated bacteremia in patients with preseptal cellulitis has decreased dramatically over the past 10 years with the introduction of the vaccine, making Streptococcus species the predominant cause. Case reports document orbital cellulitis after periocular injections of anesthetic (Chin and Kumar 2013). Several cases of orbital cellulitis have been reported in association with glaucoma surgery (Esporcatte et al 2016). Thyroid-related orbitopathy. The main risk factor for thyroid-related orbitopathy is the development of hyperthyroidism, although a subset of patients may be hypothyroid or euthyroid. This condition is more common in African-Americans than it is in Asians or Caucasians. There may be an underlying genetic predisposition, as evidenced by a concordance rate of 20% to 40% among monozygotic twins and in more than 10% of siblings. Women are more susceptible to this condition than men, with a ratio of 7 females to 1 male. An immunogenic predisposition may be based on an association with human leukocyte antigens HLA-B8, HLA-Bw35, HLA-Cw3, and HLA-DR3. Stimulation of this expression in orbital fibroblasts has resulted in a greater prevalence of the disease state. In Graves disease, genetic mapping localizes to chromosome 14. There is no exact mapping of the HLA region, and there is still significant heterogeneity regarding the location of the thyroid-stimulating hormone receptor (TSHr) gene. Accumulating evidence points to a complex balance of cytokines that control both adipocyte differentiation and regulation or expression of TSHr in the orbit. Differences in human lymphocyte antigen predisposition or cytokine expression may dictate susceptibility to orbitopathy. With regard to extraocular muscle involvement, antibodies directed against extraocular muscle proteins G2s and Fp are considered pathogenetic. Estrogen-induced immunologic reactivity was formerly believed to play a role, but susceptibility continues through menopause, suggesting that perhaps it is the X-chromosome that influences the development of this condition. Patients often report psychological stress prior to developing thyroid-related orbitopathy. Immunologic rebound hyperactivity related to stressful events or steroid-induced immune suppression has been theorized as a possible mechanism. Another proposed mechanism with minimal evidence is that infection triggers a cascade of autoimmune inflammatory response. There is strong evidence that smoking plays a role in development and progression, with odds ratios ranging from 7.7 to Iodine and iodine-containing medications such as amiodarone have been proposed to cause damage to the thyrocytes, exposing the thyroid gland to the immune system. In fact, iodine treatment for hyperthyroidism has been shown to worsen progression of thyroid-related orbitopathy, perhaps by stimulating release of serum TSHr antibodies (Li et al 2016). An infiltrative process of lymphocytes, plasma cells, and mast cells, as well as deposition of hydrophilic glycosaminoglycans and collagen, reflect an autoimmune inflammatory process. In the chronic phase, collagen deposition is accompanied by muscle degeneration and scarring. When the disease is in remission, fatty infiltration of the muscles remains. Orbital inflammatory syndrome. The typical histopathologic picture consists of diffuse and multifocal infiltration of mature lymphocytes, plasma cells, macrophages, and polymorphonuclear leukocytes. It is common to see a few eosinophils, but prominent eosinophilia is atypical and should raise the possibility of a specific vasculitis, such as Churg-Strauss (also known as eosinophilic granulomatosis with polyangiitis). Granulomatous inflammation and

8 vasculitis are unusual and raise suspicion for other entities. Desmoplasia and fibrosis are atypical, being more characteristic of sclerosing orbital pseudotumor. In IgG4-related disease, the inflammatory process includes high serum IgG4 levels, histopathologic evidence of an abnormally high ratio of IgG4:IgG cells, as well as lymphocytic and plasmacytic infiltration, obliterative phlebitis, and storiform fibrosis (Glass and Freitag 2015). IgG4-related disease is believed to account for a subset of patients once labeled as idiopathic orbital inflammatory syndrome. Epidemiology" Thyroid-related orbitopathy. A large review reported an annual age-adjusted incidence of 16 per 100,000 in women and 2.9 per 100,000 in men (Bartley et al 1996). The peak incidence is 5 years earlier in women than in men. The incidence of moderate to severe disease was reported at 16.1 cases per million per year (26.7 in women and 5.4 in men) (Laurberg et al 2012). The reported prevalence of this disease in the general population is 0.1% to 0.3% (Lazarus 2012). There is a bimodal age peak in both men and women in the 40s and 60s. Although this disease is more common in women, it tends to be more severe in men. In 1 study, thyroid-related orbitopathy occurred in approximately 26% of patients with Graves disease, but it was severe in only 5.8% and affected the optic nerve in only 0.3% (Tanda et al 2013). Progression to severe orbitopathy occurred in 6 out of 237 patients (2.5%) within 18 months. Type 1 orbitopathy occurs primarily in women (greater than 8:1), with an average age at of 36 years at diagnosis, whereas type 2 is slightly more common in women (1.5:1), with an average age of 52 years at diagnosis (Nunery et al 1997). Orbital inflammatory syndrome. There is no reported incidence available for idiopathic orbital inflammatory syndrome. In IgG4-related disease, a study estimated a national annual incidence of 0.28 to 1.08 per 100,000 individuals (Sato et al 2008). Another Japanese study, IGg4 disease accounted for approximately 21.6% of Japanese lymphoproliferative orbital disease (Japanese study group of IgG4-related ophthalmic disease 2013). Malignant orbital tumors. Not available. Orbital cellulitis. Not available. Prevention Thyroid-related orbitopathy. There is no known prevention, but cessation of smoking may help. Correcting hyperthyroidism and hypothyroidism with concurrent steroid and thyroid ablative therapy and early total thyroid ablation may also be helpful (Bartalena et al 2008). Orbital inflammatory syndrome. No prevention is available. Malignant orbital tumors. No prevention is available. Orbital cellulitis. Orbital cellulitis is best prevented with prompt treatment of bacterial sinusitis or any condition predisposing to infectious sinusitis, such as prophylactic antibiotics in immunocompromised children, sinus ostia enlargement, or drainage of chronic nonresolving sinusitis. Differential diagnosis Orbital diseases mimic each other. Thyroid-related orbitopathy and lymphoproliferative diseases are usually gradual in onset and painless, whereas orbital cellulitis, orbital inflammatory syndrome, and metastatic or pediatric malignant tumors have a rapid onset. Thyroid-related orbitopathy results in increased orbital fat and enlarged extraocular muscles and usually affects both orbits (although sometimes asymmetrically). Lymphoproliferative diseases are usually unilateral. They often cause significant periorbital edema or quiet infiltration. There is also frequently displacement of the eye ( dystopia ). Orbital cellulitis, orbital inflammatory syndrome, and malignant tumors of the pediatric population often present in a similar fashion. Rhabdomyosarcoma can present with unilateral proptosis without concomitant signs of infection. Fever and a left-shifted leukocytosis are almost universal. Patients with orbital manifestations of undiagnosed leukemia or those in blast crisis may also have extremely elevated white counts. Orbital cellulitis is a unilateral process, and orbital

9 inflammatory syndrome can be bilateral in up to 50% of pediatric cases. Metastatic malignant tumors, like neuroblastoma or Ewing sarcoma, are often bilateral. CT readily differentiates the malignant tumors, but orbital inflammatory syndrome and orbital cellulitis often appear similar in the absence of an abscess. In cases where history, vital signs, and laboratory studies do not differentiate between the sterile inflammation and infection, a 24-hour trial of intravenous antibiotics is in order. Orbital cellulitis responds rapidly to antibiotics, whereas orbital inflammatory syndrome will continue to smolder or progress. Any systemic vasculitis or autoimmune disease can affect the orbit and mimic orbital inflammatory syndrome. CT is almost always indicated. Diagnostic workup Thyroid-related orbitopathy. The appropriate tests are thyroid-stimulating hormone T3 and T4 levels. If the patient manifests clinical hyperthyroidism, one should order thyroid-stimulating antibodies. A study reported the benefits of a novel Mc4/TSI bioassay in assessing activity and severity (Lytton et al 2010). These authors found that Mc4/TSI demonstrated greater sensitivity and specificity for detection of TSHr autoantibodies than did conventional thyroid stimulating immunoglobulin (TSI) bioassays. A further advantage of Mc4/TSI is the direct assessment of TSI in unfractionated patient serum in one day, compared to traditional bioassays that require several days of culturing or preparation. CT imaging provides information on potential optic nerve compression, particularly in those with evidence of visual dysfunction. CT will guide potential orbital and orbital apex decompression. CT is preferred over MRI if urgent bony decompression surgery is planned. MRI, however, is useful in visualization of structures and the degree of crowding at the orbital apex. The necessary ophthalmologic evaluation for patients with thyroid disease includes best-corrected visual acuity, pupil size and reactivity, color vision, visual field (automated threshold perimetry preferred), diplopia field, motility evaluation, Hertel exophthalmometry, intraocular pressure, slit lamp exam, and dilated fundus exam. Patients with active disease should be evaluated every few weeks and instructed to return immediately if they perceive any significant changes in their vision. Orbital inflammatory syndrome. Any patient presenting with orbital disease needs a complete eye examination, including best-corrected visual acuity, pupil exam, color plates, visual field testing, motility exam, orbital exam, and dilated ophthalmoscopy. Orbital inflammatory syndrome must be differentiated from orbital cellulitis and orbital malignancies. Complete blood count and blood cultures and broad-spectrum antibiotics may be initially necessary. When entertaining the diagnosis of orbital inflammatory syndrome, a full vasculitis work-up should be done, including complete blood count with differential (eosinophilia or other abnormalities), urinalysis (looking for protein and true red cells seen with kidney disease), rheumatoid factor, antinuclear antibodies, antineutrophil cytoplasmic antibody panel, serum angiotensin-converting enzyme, lysozyme, and chest x-ray. In addition, CT scanning is necessary to rule out rhabdomyosarcoma or other processes. A biopsy is indicated in patients with recurrent or persistent disease (Mendenhall and Lessner 2010). However, if the patient presents with a lesion that is amenable to biopsy without risk of visual function, biopsy may be considered from the start. Exceptions are scleritis, myositis, and thyroid-related orbitopathy, in which a delay in immune suppression may result in visual dysfunction (Rose and Verity 2011). Malignant orbital tumors. Diagnostic biopsy is usually indicated. Flow cytometry on blood and cerebrospinal fluid, and bone marrow biopsy are performed for suspected pediatric malignant orbital tumors or adult metastatic malignant tumors. Orbital cellulitis. In addition to complete blood count, blood cultures, and possibly pharyngeal cultures, a complete eye examination and orbital imaging are necessary to rule out tumors and abscess formation. Vision, pupil, color vision, confrontation visual fields, and motility checks need to be frequent (every 6 to 12 hours) when treatment is initiated and until significant resolution is noted. Consultation by an otolaryngologist may be necessary for those with concomitant sinus disease. Orbital rhabdomyosarcoma. Imaging studies such as CT and MRI in conjunction with clinical signs aid in the diagnosis; however, diagnostic biopsy is the gold standard. Subsequent to the biopsy, the tumor must be staged according to the classification systems of the Intergroup Rhabdomyosarcoma Study (IRS) and the American Joint Commission on Cancer manual.

10 Management Thyroid-related orbitopathy. Treatment of thyroid disease requires a multidisciplinary approach including endocrinologists, oculoplastic surgeons/ophthalmologists, and radiologists. Medical management. Systemic. Restore euthyroidism. Treatment starts by ensuring restoration and stability of thyroid function as patients are more likely to express severe disease when the underlying thyroid hormones are abnormal (Bhan et al 2011). Monitoring of thyroid function tests every 4 to 6 weeks by the endocrinologist is crucial in ensuring normalization of hormones particularly in the early stages. There is no evidence to suggest that thyroid surgery or antithyroid medications influence the evolution (Leo et al 2012), but disease appears to worsen shortly after radioactive iodine treatment in about 15% of treated patients. The risk has been shown to be reduced with a short course of steroids (0.3 to 0.5 mg/kg) tapered daily, and by avoiding a hypothyroid state after iodine treatment (Bartalena et al 2008). A retrospective longitudinal cohort study found that the risk of developing thyroid-related orbitopathy was reduced substantially in patients who underwent thyroidectomy alone or in combination with antithyroid medications when compared with radioactive iodine ablation (Stein et al 2015). Smoking cessation. Smoking is a well-established independent risk factor for activity and severity. It is dose dependent. Even past smokers have a relatively worse response to immune-modulating therapy (Xing et al 2015). Local. Conservative measures. Patients should be encouraged to lubricate the eyes during the day and use ointment at night in case of lagophthalmos. Sunglasses and slight elevation of the head of the bed when going to sleep can be helpful. One study found that topical cyclosporine treatment improves dry eye and preserves conjunctival epithelial cells (Gurdal et al 2010). Medical management depending on the grade of disease. Mild disease. The natural history of this disease is self-limiting. About 50% of patients improve, 35% remain stable, and 15% progress (Menconi et al 2014). One study showed that selenium 100 mg twice daily for 6 months improved quality of life and reduced the rate of progression of ophthalmic manifestations (Marcocci et al 2011). Botulinum toxin may be used for upper lid retraction during active disease when lid surgery is contraindicated. When the disease becomes inactive, surgery can be considered for lid retraction. Moderate to severe disease. These patients may be treated with immune modulating therapy in the active stage and with eyelid and other orbital surgery in the inactive stage. Medications. Immunosuppressives. Immune modulating therapy is useful in the active phase of the disease (Eichhorn 2010). Steroids. One study showed that 82% of the patients receiving intravenous steroids responded when compared to 53.4% of the oral steroid group (Zang et al 2011). Intravenous steroid pulses were found to have fewer side effects, require a shorter course of treatment, and provide a lower recurrence rate when compared with oral steroids. Treatment with oral steroids after the intravenous treatment did not alter the relapse rate. Another retrospective study compared high dose intravenous steroids (cumulative dose of 9 to 12 g) to low dose intravenous steroids (cumulative dose 4.5 gm) and showed no difference in the safety profile or efficacy (Ueda-Sakane et al 2016). If there are contraindications to intravenous steroids, oral steroids can be used as an alternative. Another study found orbital steroid injection for thyroid-related orbitopathy to be safe and effective when compared to oral steroid ingestion, with an added benefit of eliminating adverse effects associated with oral prednisone (Alkawas et al 2010). Other immune modulating therapy. For patients who have a longer phase of active disease, have recurrence with steroid withdrawal, or are intolerant to steroids, other immune modulating therapy may be used including methotrexate (Strianese et al 2014), a combination of cyclosporine A and steroids, azathioprine, or specific monoclonal

11 antibody agents such as rituximab. However, the latter has shown conflicting results in 2 randomized controlled trials perhaps due the different designs of the study (Salvi et al 2015; Stan et al 2015). There is some evidence for a benefit of tocilizumab, adalimumab, or etanercept (Bartalena 2014; Pérez-Moreiras et al 2014; Wiersinga 2017). Other promising treatments include TSHr antagonists, either as small molecule-ligand antagonists of TSHr or as monoclonal TSHr blocking antibodies (Galofré et al 2013). Orbital radiotherapy. The efficacy of radiation therapy as a sole treatment remains controversial. However, combining it with steroid therapy may be effective, particularly in early active thyroid-related orbitopathy. A retrospective study compared 144 patients treated with steroids alone to 105 patients treated with a combination of steroids and radiation therapy (Shams et al 2014). In that study, 17% of patients treated with steroids alone developed compressive optic neuropathy, whereas no patients with combination therapy developed optic neuropathy. Orbital radiation produced no important adverse effects. The radiation dose ranged between 10 and 20 Gy in 10 sessions over 2 weeks. This study also showed the benefit of radiation therapy in combination with steroids in patients with restricted ocular ductions and in compressive thyroid optic neuropathy. Surgical management. Lid and orbital surgery is useful in inactive disease and in active disease with compressive optic neuropathy. Four procedures are used: (1) orbital decompression, (2) extraocular muscle surgery, (3) eyelid malposition surgery, and (4) removal of excess skin and herniated orbital fat. The indications for orbital decompression include corneal exposure, restoration of the globe position, optic neuropathy secondary to compressive effects from enlarged extraocular muscles, and severe proptosis causing eyelid entrapment. These procedures may be followed by extraocular muscle and lid surgeries. Measures for patients with sight-threatening disease. Patients who develop compressive optic neuropathy must be treated on an urgent basis. The treatment can start with a high dose of intravenous steroids. If there is no response, the patient must undergo an urgent orbital decompression. Exposure keratopathy resistant to aggressive lubrication invites the use of moisture chambers, botulinum toxin, lid recession surgery, and tarsorrhaphy. If these measures are not successful, orbital decompression may be carried out. Treatment with intravenous steroids may be tried before decompression surgery if the disease is active. Orbital inflammatory syndrome. Systemic steroids are the first-line treatment modality. The usual initial dose is 1 mg/kg oral prednisone. Unfortunately, relapse after withdrawal of steroids is common. The recurrence may be the result of inadequate suppression of the immune activation. In 1 report of 65 patients, 41 (63%) represented treatment successes, with complete symptom relief at the time of the last follow-up, and 24 (37%) represented treatment failures, with partial or no relief of symptoms (Yuen and Rubin 2003). Other treatment modalities include nonsteroidal anti-inflammatory agents, low-dose radiotherapy in conjunction with steroids, and surgical debulking. Patients with relapsing and steroid-unresponsive conditions usually respond well to low-dose orbital radiation. Short-duration pulsed chemotherapy has been successfully and safely utilized (with limited numbers) for sclerosing pseudotumor. Exenteration has also rarely been used in such cases (Yuen and Rubin 2003). One study evaluated use of a monoclonal antibody (infliximab) directed against tumor necrosis factor alpha in 7 patients with chronic and difficult-to-control idiopathic orbital inflammation (orbital myositis) (Garrity et al 2004). All patients had some positive response without untoward effects after a mean follow-up of 15.7 months (range, 4 to 31 months). Another study reported methotrexate to be a well-tolerated and beneficial agent in steroid and radiotherapy failures (Smith and Rosenbaum 2001). The more recently described entity of IgG4-related disease is treated with steroid as the mainstay. If persistent or recurrent, other modalities can be used such as rituximab or radiation therapy. Malignant orbital tumors. Treatment is directed at the specific tumor type. Enucleation and exenteration were common treatments until the early 1970s, when they were supplanted by chemotherapy and radiation therapy. Based on the seminal works of the Intergroup Rhabdomyosarcoma Study (IRS), medications such as vincristine and actinomycin D are used with or without radiation therapy (Oberlin et al 2001). Tumor recurrence that has not been controlled by these systemic medications may necessitate exenteration. Orbital cellulitis. Treatment consists largely of anti-infectives. In 1 report from a tertiary care center, patients aged 9 years or younger who had a subperiosteal abscess were successfully treated with intravenous antibiotics in 93%