Clinical manifestations

Presentation and course

Proptosis. Proptosis is the hallmark manifestation of orbital disease and is a common finding in thyroid eye disease, which is the most common cause for unilateral and bilateral proptosis in adults.

Enophthalmos. Enophthalmos can also be a feature of orbital disease such as silent sinus syndrome, which causes retraction of the orbital bones, or in metastatic breast cancer, which causes cicatricial shortening of the extraocular muscles and orbital fat.

Lid retraction, ptosis, and diplopia. 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.

Optic neuropathy. Optic neuropathy can occur in orbital disease, as is the case in thyroid eye disease. It is caused by compression of the extraocular muscles on the optic nerve at the orbital apex causing a “compressive” optic neuropathy. Less commonly, “stretch” optic neuropathy may occur, particularly if the proptosis exceeds 8 mm from baseline.

Facial hypesthesia. Facial hypesthesia may be a manifestation of impaired trigeminal function when orbital lesions also involve the cavernous sinus or superior or inferior orbital fissures.

Gaze-evoked amaurosis. 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 eye disease.

Clinical manifestations. Thyroid eye disease is the most common extrathyroidal manifestation of Graves disease, occurring in 25% to 50% of patients. Although 90% of patients with thyroid eye disease have hyperthyroidism, the condition may be present in hypothyroidism or euthyroidism. Onset of orbital disease may occur before, after, or simultaneously with clinical dysthyroidism (03). Although this disease is more common in women, it tends to be more severe in men.

Patients with thyroid eye disease may also have symptoms related to the lids, orbit, anterior segment, or uncommonly, the optic nerve. Symptoms are usually gradually progressive over weeks to months.

Patients may complain of periocular soft tissue swelling, lid retraction, proptosis, dry eye-related symptoms, photophobia, mild pain and irritation, or vision loss. If the pain is acute and severe, other causes should be considered, such as orbital inflammatory syndrome (idiopathic or otherwise) or cellulitis. Thyroid eye disease usually involves both orbits symmetrically, but unilateral or asymmetrical presentations are not uncommon.

Lid retraction, present in up to 70% of cases, is the most common sign of thyroid eye disease (13). It is defined as exposure of the sclera above the superior limbus, but patients can also have inferior lid retraction. The differential diagnosis of lid retraction includes dorsal midbrain syndrome, systemically administered sympathomimetics, previous ocular or orbital surgery, and aberrant regeneration of the third nerve. When lid retraction is accompanied by proptosis, the most likely diagnosis is thyroid eye disease.

Proptosis is present in two thirds of patients (13). It can be quantified with the Hertel exophthalmometer. This procedure may be supplemented with checking for resistance to retropulsion, which is usually increased in this condition.

Additional common clinical signs include lid lag, a delay in relaxation of the levator muscle as the eye is moved into downgaze, and periocular inflammation. Conjunctival hyperemia, particularly around the lateral rectus muscle insertions, together with swelling and erythema of the caruncular area, dry eyes, exposure keratopathy, superior limbic keratoconjunctivitis, and corneal ulceration, may be present.

Restrictive strabismus may be present in 63% of patients (13). 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, which, at times, may lead them to falsely think that they have improved. 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, the eyes may be misaligned vertically or horizontally, or in both planes.

Optic neuropathy may occur in up to 8% of patients with thyroid eye disease (22). In 90% of cases, it is related to extraocular muscle crowding at the orbital apex; in 10%, it is related to stretch optic neuropathy (10). Patients may present with reduced visual acuity, visual field defects, reduced color vision, and sometimes 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.

Classification. Grading of clinical manifestations in thyroid eye disease has been described by several classification systems. These include the NO SPECS classification, the Clinical Activity Score, the VISA classification, and the European Group on Graves Orbitopathy severity scale.

In the NO SPECS classification, clinical involvement is scored on an ordinal scale in increasing severity: no physical signs or symptoms, only signs, soft tissue involvement, proptosis, extraocular muscle signs, corneal involvement, and sight loss. This system assesses clinical severity but does not differentiate between active and inactive thyroid eye disease. In contrast, the Clinical Activity Score (CAS) considers signs of active inflammation (pain, redness, swelling, and reduced function); CAS 3/7 or greater is indicative of active disease.

Idiopathic orbital inflammatory syndrome. Idiopathic orbital inflammation is the third most common orbital disorder, after thyroid eye disease and lymphoproliferative disease. Clinical presentations mimic orbital cellulitis and lymphoma. Systemic disorders can produce an orbital inflammatory syndrome indistinguishable from the idiopathic variant. Important differential diagnoses are sarcoidosis and vasculitides, such as granulomatosis with polyangiitis.

Common presenting symptoms and signs of idiopathic orbital inflammatory syndrome include periorbital pain (71%), periorbital edema (63%), ophthalmoplegia (37%), and conjunctival injection/chemosis (37%); ptosis and proptosis are each present in one quarter of patients (16). The relatively acute onset and severe periocular pain are important distinguishing factors from thyroid eye disease. Visual acuity and visual field loss can occur. Unilateral involvement is typical, although bilateral involvement can occur in up to one quarter of adults (47). Bilateral presentations suggest an underlying systemic etiology, although in children, idiopathic orbital inflammatory syndrome may be bilateral in up to 50% of cases.

Idiopathic orbital inflammation may be subdivided into dacryoadenitis (which is the most common presentation), myositis, scleritis, perineuritis, diffuse orbital inflammatory syndrome, and periostitis, sometimes extending into the intracranial space (idiopathic hypertrophic pachymeningitis, previously known as Tolosa-Hunt syndrome) (47). Idiopathic hypertrophic pachymeningitis affects the orbital periosteum (dura) and dura of the superior orbital fissure, cavernous sinus, or other locations at the cranial base. It can present with severe pain, vision loss, sympathetic dysfunction, and third, fourth, and sixth nerve palsies.

Malignancy is an important differential diagnosis. A retrospective case series of 93 patients with extraocular muscle enlargement who underwent extraocular muscle biopsy indicated that predictors of malignancy were diplopia and a prior history of malignancy (14).

Conversely, pain and lid erythema were predictors of benign nonmalignant conditions.

IgG4-related disease is increasingly recognized as an important differential diagnosis for idiopathic orbital inflammatory syndrome (28). This is a systemic disease characterized by tumefactive lesions in various organs, including the biliary tree, retroperitoneum, salivary glands, orbit, lymph nodes, kidneys, lungs, meninges, aorta, breast, prostate, thyroid, pericardium, and skin. Orbital disease may occur in isolation, although almost 9 of 10 patients with ophthalmic manifestations of IgG4-related disease have other organ involvement. Dacryoadenitis (inflammation of the lacrimal gland) and enlargement of orbital nerves are typical.

Presentations of orbital IgG4-related disease may mimic idiopathic orbital inflammation; bilateral disease and enlargement of the infraorbital nerve are more common in IgG4-related disease than in idiopathic orbital inflammatory syndrome (01). In a study of 165 patients originally diagnosed with idiopathic orbital inflammatory syndrome, 60% were later found to be histopathologically positive for IgG4-related disease. These patients were found to have less pain and a longer duration of symptoms, as well as less lower lid hyperemia, than their truly idiopathic counterparts (07).

Sclerosing orbital inflammation is a rare variant of idiopathic orbital inflammation. It has a more gradual onset and less pain. 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. Corticosteroids are rarely able to reduce or eliminate this process, and careful surgical release of muscles from the fibrous sheath can help return the orbit to a more functional state. There is controversy as to whether it is a separate pathologic entity. It can be present in IgG4-related disease.

Malignant orbital tumors. A study of 1264 patients with suspected orbital tumors found that vascular tumors were the most common (17%), followed by melanoma, metastases, lymphoproliferative disease, and neoplasms of the lacrimal gland, optic nerve, meninges, and peripheral nerve origin (42). Other rare conditions included fibrocytic, lipogenic, and myxoid tumors.

Lymphoproliferative disease. Nine of ten cases are unilateral at presentation. The most common symptoms are periorbital swelling (49%), a mass (49%), and proptosis (37%). The most common clinical signs are an objective mass (68%) and proptosis (48%). Limited motility is present in one third of patients. The conjunctiva is the most common site of local invasion. Pain is uncommon, and erythema is rare (1%) (35).

Lymphoid hyperplasia is a benign lymphoproliferative disorder that is clinically indistinguishable from ocular adnexal lymphoma. It presents with slowly progressive mass effect of the orbit; features include tissue swelling, proptosis, and ocular motility limitation, generally in the absence of pain. There is a risk of malignant transformation.

Metastatic tumors. About 1% to 3% of orbital masses are metastases. Orbital metastasis is detected before the primary tumor in 30% of cases. In a pooled analysis of 873 cases of orbital metastasis, breast was the most common primary tumor in more than one third, followed by melanoma (10%) and prostate (9%). Symptoms and signs included proptosis (52%), relative afferent pupil defect (39%), diplopia (36%), palpable/visible mass (22%), and orbital pain (19%) (36). Metastatic tumors of the orbital develop and progress more rapidly than primary orbital tumors.

Childhood orbital malignancies. Childhood orbital tumors often develop rapidly, mimicking inflammatory or infectious processes.

Orbital rhabdomyosarcoma. Orbital rhabdomyosarcoma accounts for one third of all head and neck rhabdomyosarcomas in children. Patients typically present with rapidly progressive (over weeks) 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. There are four types: (1) embryonal, occurring more commonly in childhood and comprising botryoid and spindle cell subtypes; (2) alveolar, occurring at any age and having a poor prognosis; (3) anaplastic (pleomorphic); and (4) mixed (18).

Neuroblastoma. Neuroblastoma originates from the sympathetic nervous system at the adrenal medulla and other abdominal sites, or at paraspinal sites, sympathetic nodes, and mediastinum. Accounting for approximately 10% of all childhood cancer, it is the most common metastatic orbital malignancy in children. A third or more metastatic neuroblastoma cases involve the orbit; the site of metastasis is bone. Between 30% and 43% of metastatic neuroblastoma cases land in the orbit. The adrenal gland is usually the primary site, followed by the abdomen and mediastinum. Most children with orbital neuroblastoma have periorbital ecchymosis and proptosis. The presentation is strikingly similar to that of rhabdomyosarcoma. However, neuroblastoma presents at an earlier age, is frequently bilateral, and shows erosive changes on CT that are especially pronounced. A preexisting diagnosis of neuroblastoma and the presence of multiple lesions help establish the diagnosis. Patients diagnosed at a relatively young age may have a better prognosis.

Orbital cellulitis. Orbital cellulitis requires immediate attention as blindness and intracranial extension leading to death may follow.

This condition is divided into “preseptal” and “postseptal” subtypes (“postseptal cellulitis” and “orbital cellulitis” are terms often used interchangeably). Disease occurring anterior to the orbital septum is considered preseptal; disease occurring posterior to the septum is considered postseptal or orbital. It is important to differentiate between these two subtypes by means of history and clinical examination because post-septal orbital cellulitis requires immediate hospitalization, intravenous antibiotics, and often sinus and orbital surgery. Patients with postseptal cellulitis often present with fever, vision loss, proptosis, and diplopia, manifestations that are not part of the preseptal variant. The common sources of infection in postseptal cellulitis are the ethmoid and frontal sinuses; the common sources of infection in preseptal cellulitis are the lid skin and the ethmoid sinus. Children under the age of 10 years are most at risk for orbital cellulitis (15).

Prognosis and complications

Thyroid eye disease. Clinically, thyroid eye disease goes through an initial phase of inflammatory changes referred to as the active phase. The disease then stabilizes and inflammation “burns out.” From onset, it generally takes 18 to 24 months for disease to become inactive (03). Recurrent disease may occur in up to 15% of patients. Optic neuropathy occurs in 4% to 8% of the patients, in whom it is permanent in 2.2%. Persistent diplopia occurs in 2.2%. Residual signs of thyroid eye disease may persist for years after diagnosis.

Idiopathic 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. After treatment, recurrence may occur in 10% of cases (16).

Malignant orbital tumors.

Lymphoproliferative disease. Prognosis and outcome largely depend on the underlying histopathological type, with high-grade lymphomas, such as diffuse large B-cell lymphomas and mantle cell lymphomas, being associated with poorer prognosis. Low-grade lymphomas, such as extranodal marginal zone B-cell lymphomas and follicular lymphomas, have a better prognosis (34). Among patients with isolated orbital lymphomas, 30% will develop systemic lymphomas within 10 years.

Metastatic tumors. Without treatment, progression of local disease is the rule and may be rapid. Systemically, metastasis is associated with a poor prognosis. In a pooled analysis of 873 patients with orbital metastasis from 272 studies, overall survival was 35% after a mean follow-up of 14 months (36).

Orbital cellulitis. 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. Patients with orbital abscess or severe sphenoid sinusitis are more likely to develop ophthalmoplegia and blindness (05). With antibiotic treatment, orbital cellulitis has an excellent prognosis.

Clinical vignette

Case 1. A 72-year-old man complained of puffy eyelids and blurred vision for 2 months. He was sent from a general medicine clinic for evaluation of an unresponsive “conjunctivitis” after 1 month of treatment with a topical antihistamine and vasoconstrictor, along with erythromycin ointment. Best-corrected visual acuity was 20/70 in the right eye and 20/100 –1 in the left eye. There was significantly decreased ocular motility in all directions. Hertel exophthalmometer measurements were 25 mm right eye and 26 mm left eye at a base of 110. Dilated optic fundus examination showed trace temporal pallor in both optic discs, left eye more than right eye, but no optic disc edema. Goldmann visual fields showed bilateral inferior altitudinal defects, left eye greater than right eye. CT examination showed diffuse muscle enlargement with severe apical crowding.

The diagnosis was thyroid eye disease with compressive optic neuropathy. He was treated with prednisone 100 mg/day. After 1 week of treatment, visual acuity improved to 20/50 in the right eye but decreased to 20/200 –1 in the left eye. There was a left relative afferent pupillary defect. The visual field was also improved in the right eye but deteriorated in the left eye.

The prednisone treatment was continued. Endonasal decompression of the left orbital apex and medial orbital wall was performed utilizing digital CT-driven 3D localization technology, allowing safe, extensive, and precise decompression of both the medial orbital apex and the optic canal. The superior, lateral, and inferior walls were decompressed through a lower lid transconjunctival approach. Postoperative CT demonstrated decreased apical congestion in the right orbit (from corticosteroid therapy) and in the left eye orbital (after surgical decompression).

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’s visual acuity was 20/50 in both eyes, but Ishihara color plates vision was still abnormal in both eyes. The corticosteroid taper was continued for several months. Residual reduced visual acuity 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 eyes. There was no afferent pupillary defect. Color vision and ocular motility were normal in each eye. There was periocular edema of the left eye, with a fixed palpable mass below the superior superolateral orbital rim. The left upper lid was ptotic, and 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 idiopathic orbital inflammatory syndrome, malignancy, and necrotizing vasculitis.

CT showed a dense left superior superolateral 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.

The specimen. Pathology demonstrated areas of inflammation and fibrosis consistent with idiopathic orbital inflammatory syndrome, but there was small vessel vasculitis and perivascular neutrophils and eosinophils. Preliminary diagnosis 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. 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 60 mg/day. After treatment with prednisone 60 mg/day for 6 weeks, 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 reported 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). Ocular 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, increasing to 37 mm Hg in attempted upgaze. The rest of the ocular examination was within normal limits.

CT examination read at another facility disclosed a well-defined intraconal orbital tumor. Axial cuts showed what appeared to be an intraconal or optic nerve tumor. However, careful examination of the coronal images showed the mass to be somewhat inferior and located where the inferior rectus muscle should be located.

The clinical exam favored a diagnosis of an enlarged or fibrotic inferior rectus muscle. This abnormality, along with boggy edema and chemosis, was considered consistent with lymphoma. Because all remaining rectus muscles were normal and the rest of the clinical history was not consistent with thyroid eye disease, a presumed diagnosis of orbital lymphoma or orbital myositis was made. A frozen section of a biopsy of the inferior rectus muscle was performed. Frozen touch prep was performed and was read as showing a mixed lymphoid infiltrate; lymphoma could not be ruled out. Flow cytometry revealed a low-grade B-cell lymphoma. The patient was referred to oncology and radiation oncology. Systemic work up was negative, and the patient received a course of orbital radiation. He responded clinically to the treatment and will be followed carefully for recurrence or distant disease using local x irradiation.

Biological basis

Etiology and pathogenesis

Thyroid eye disease. Thyroid eye disease is an autoimmune inflammatory disease that results from autoreactive T-lymphocytes targeting antigens shared by the thyroid gland and orbital tissues. This results in orbital fibroblast proliferation and secretion of glycosaminoglycans, leading to enlargement and dysfunction of the extraocular muscles and precipitating edema in the orbital tissues.

The main associated factor for thyroid eye disease is 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 than men (7:1).

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 disease prevalence. 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 it is the X-chromosome that is the most influential.

Patients often report psychological stress prior to developing thyroid eye disease. Immunologic rebound hyperactivity related to stressful events or corticosteroid-induced immune suppression has been theorized as a possible mechanism. Another proposed mechanism with minimal evidence is that infection triggers a cascade of autoimmunity. There is strong evidence that smoking plays a role in development and progression, with odds ratios ranging from 7.7 to 20.2. 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 eye disease, perhaps by stimulating release of serum TSHr antibodies (25).

An infiltrative process of lymphocytes, plasma cells, and mast cells, as well as a 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, it becomes inactive, but fatty infiltration of the muscles persists.

There is evidence that the insulin-like growth factor-I receptor (IGF-IR) may play a role in the pathogenesis of thyroid eye disease. Activating antibodies against IGF-IR have been detected in patients with Graves disease. Signaling activities of these activated antibodies entice signaling of fibroblasts. These signals could be attenuated by inhibiting insulin-like growth factor type 1 receptor (IGF-IR) in active thyroid eye disease.

In a study the levels of vitamin D in 292 patients with newly diagnosed Graves disease were significantly lower than in 2305 normal controls (37). There was no association with thyroid hormone levels or thyroid eye disease. In a case-control retrospective trial, vitamin D levels were lower in the thyroid eye disease group compared to their normal counterparts (19). Further studies are required to assess the role of vitamin D supplementation.

Idiopathic 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 eosinophilic granulomatosis with polyangiitis (Churg-Strauss disease). Desmoplasia and fibrosis are atypical and more characteristic of the sclerosing orbital pseudotumor variant.

IgG4-related disease remains a differential diagnosis of orbital inflammatory syndromes. The American College of Rheumatology/European League Against Rheumatism issued classification criteria in 2019 reflecting the importance of integrating information from clinical, serological, radiological, and pathological assessments in order to confirm a diagnosis of IgG4-related disease (44).

Malignant orbital tumors.

Lymphoproliferative disease. A study of 2211 cases of orbital lymphoma found that 97% of primary orbital lymphomas were of B-cell origin, including extranodal marginal zone B-cell lymphoma (EMZL; 59%), diffuse large B-cell lymphoma (23%), follicular lymphoma (9%), and mantle cell lymphoma (5%) (34).

Orbital cellulitis. The most common cause of orbital cellulitis is an underlying sinus infection. As children grow, the ostia that drain the paranasal sinuses remain constant in size and become less able to drain the 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 (24). The sinuses harbor Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus, and anaerobes as normal flora. When there is a fluid and mucous build up from an upper respiratory tract infection, these commensal bacteria become pathogenic and typically mount a mixed infection within the sinuses (06). Facial 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 30 years with the introduction of the vaccine, making Streptococcus species the predominant cause.

Epidemiology

Thyroid eye disease. The age-adjusted incidence of thyroid eye disease is 16 per 100,000 per year among women and 2.9 per 100,000 per year in men (04). The incidence peak is bimodal, with peak incidence in the fifth and seventh decades; peak incidence occurs 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) (23). The prevalence of this disease in the general population is between 90 to 300 per 100,000 persons (03).

Idiopathic orbital inflammatory syndrome. Prevalence and incidence rates of idiopathic orbital inflammatory syndrome are difficult to assess given the wide clinical spectrum. Peak incidence of idiopathic orbital inflammatory syndrome appears to be around middle age. Most reports suggest either no strong sex predilection or a slight predominance in women.

Malignant orbital tumors.

Lymphoproliferative disease. Orbital lymphoma constitutes 50% to 60% of ocular adnexal lymphomas in patients over 60 years of age. Orbital lymphoma is diagnosed at a median age of 64. There is no strong sex predilection.

Orbital metastasis. Metastatic disease to the orbit can occur at any age, and a median age at diagnosis among a large pooled series of 873 patients was 59 (36). Orbital metastasis may be slightly more common in women, reflecting the large proportion of cases with a primary breast cancer.

Prevention

Thyroid eye disease. Smoking is an important risk factor for new thyroid eye disease as well as progression to severe disease. Selenium supplementation may be used on the basis that oxidative stress is present. A course of selenium 100 mg twice daily for 6 months has been suggested.

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 refractory sinusitis.

Differential diagnosis

Associated or underlying disorders

Cavernous sinus syndrome. Disease of the cavernous sinus may present with ophthalmoplegia, proptosis, chemosis, and orbital pain. The differential diagnosis includes vascular (eg, carotid cavernous fistula), inflammatory (eg, sarcoidosis), mass (eg, meningioma), and infectious processes. In some instances, there may be contiguous involvement of the posterior orbit and ipsilateral cavernous sinus, such as in idiopathic hypertrophic pachymeningitis (Tolosa-Hunt syndrome).

Diagnostic workup

The appropriate ophthalmologic evaluation for patients with orbital disorders includes best-corrected visual acuity, pupil size and reactivity, color vision, visual field (automated threshold perimetry), ocular motility and alignment, Hertel exophthalmometry, measurement of intraocular pressure, slit lamp biomicroscopy, and fundoscopy.

Thyroid eye disease. The clinical examination should also include assessment of typical features of thyroid eye disease, including eyelid retraction and lid lag.

Laboratory tests. The appropriate laboratory assessment for patients with suspected thyroid eye disease includes levels of thyroid-stimulating hormone (TSH), T3, free T4, TSH receptor antibody activities (assays include TSH-binding inhibition immunoglobulin [TBII] and thyroid-stimulating immunoglobulin [TSI]), or antithyroid peroxidase antibody level (29). CT is preferred over MRI if urgent bony decompression surgery is planned. MRI, however, is useful in providing more detailed visualization of orbital soft tissue structures and the degree of crowding at the orbital apex.

Imaging. Orbital imaging assesses extraocular muscle caliber and orbital fat volume, excludes other pathology, and aids in surgical planning. CT is preferred over MRI if urgent bony decompression surgery is planned. MRI, however, is useful in providing more detailed visualization of orbital soft tissue structures and the degree of crowding at the orbital apex. Imaging features are increased orbital fat, usually without enhancement, and enlarged muscles with sparing of muscle tendons.

Diagnosis. Diagnosis of thyroid eye disease is predominantly clinical, although serology and imaging are supportive. If lid retraction is present with proptosis, the diagnosis is very likely. If lid retraction is not present, laboratory markers, including abnormal thyroid function tests or a history of thyroid dysfunction, help support the diagnosis. TSH is highly sensitive for active Graves disease. CT, MRI, and ultrasound may be diagnostically helpful (11).

Idiopathic orbital inflammatory syndrome. The diagnosis of idiopathic orbital inflammation is based on clinical history and examination, laboratory results, imaging, biopsy, and occasionally rapid response to corticosteroid treatment. When idiopathic orbital inflammation is suspected, systemic disorders that mimic its presentation must be ruled out.

Investigations should include complete blood count with differential (noting eosinophilia or other abnormalities), erythrocyte sedimentation rate, C-reactive protein, urinalysis, antinuclear antibodies, antineutrophil cytoplasmic antibody panel, serum angiotensin-converting enzyme, lysozyme, syphilis serology, serum IgG4, and chest x-ray. CT of the chest as well as abdomen and pelvis can be considered to look for evidence of sarcoidosis, IgG4 related disease, or occult malignancy.

Orbital CT and MRI complement one another in assessing orbital structures. When myositis is present, enlargement of muscle and tendinous insertion suggests idiopathic orbital inflammation, in contrast to thyroid eye disease in which tenons are spared.

Clinical examination or orbital imaging may identify surgically accessible lesions for biopsy. If the patient presents with such a lesion, biopsy could be considered, especially if clinical features are atypical for idiopathic orbital inflammatory syndrome. Most experts recommend biopsy of suspected nonmyositic idiopathic orbital inflammatory syndrome at presentation (32). A biopsy is indicated in patients with recurrent or persistent disease.

IgG4-related disease. Although IgG4-related disease is a clinicopathologic diagnosis, history, physical examination, and laboratory markers can be suggestive (08). Diagnosis requires enlargement in at least one organ demonstrated by examination and imaging, elevated serum IgG4 levels, and plasmacytic and lymphocytic infiltration demonstrated on histopathology. Specifically, the following features can be suggestive of IgG4-related disease: presence of tumefactive lesions in the pancreas, liver, salivary glands, pachymeninges, retroperitoneum, lung, and lymph nodes; synchronous or metachronous involvement of multiple organs; subacute onset; elevated serum IgG4; elevated plasmablast levels; and rapid response to immunosuppressive therapy (09).

Malignant orbital tumors.

Lymphoproliferative disease. Orbital imaging with CT or MRI can suggest diagnosis and aid in surgical planning. However, tissue diagnosis via biopsy is diagnostic. Radiographically, half of these tumors are ill-defined and diffuse, and half are well-circumscribed and smooth. Uniform enhancement is the general rule. Orbital lymphoproliferative tumors are unilateral in more than 90% of the cases, 72% occurring within the extraconal space. In a study, imaging showed the superior rectus muscle involved in 74% of cases and the lacrimal gland involved in 47% of cases (38).

Imaging does not reliably distinguish between benign and malignant lymphoproliferative tumors and idiopathic orbital inflammatory syndrome. Lymphoproliferative tumors tend to mold around orbital structures, with remodeling of bone rather than its erosion. On MRI imaging, they typically appear isointense on precontrast T1 and iso- or hyperintense on T2. They have a predilection for the superior lateral orbit (38).

Orbital metastasis. CT imaging often shows bony erosive changes if the metastasis lies in the periosteum or the bone.

Orbital cellulitis. A complete blood count is useful in detecting leukocytosis. A complete eye examination and orbital imaging are necessary to rule out tumors and abscess formation. Orbital CT is used to identify subperiosteal abscess and predisposing sinusitis. Vision, pupil, color vision, confrontation visual fields, and ocular motility checks must occur every 6 to 12 hours after treatment is initiated and until significant resolution is noted. Blood cultures may be considered in admitted patients, although the yield is low. Nasopharyngeal swabs are not helpful in specifying a particular agent (02). Consultation by an otolaryngologist may be necessary for patients with concomitant sinus disease.

Management

Thyroid eye disease. Treatment of thyroid eye disease requires a multidisciplinary approach, including endocrinologists, oculoplastic surgeons/ophthalmologists, and radiologists. Outcomes should be measured against the natural history, which is that about 50% of patients improve, 35% remain stable, and 15% worsen (30).

Control of systemic disease. Thyroid function must be normalized, as patients are more likely to experience severe disease when the underlying thyroid hormones are abnormal. Monitoring of thyroid function tests every 4 to 6 weeks by the endocrinologist is recommended during the active stage. Thyroid eye disease can be precipitated or worsened after radioactive iodine treatment in about 15% of treated patients unrelated to dose (21). The risk has been shown to be reduced with a short course of prednisone (0.3 to 0.5 mg/kg) tapered daily, and by avoiding a hypothyroid state after iodine treatment. A retrospective longitudinal cohort study found that the risk of developing thyroid eye disease was reduced in patients who underwent thyroidectomy alone or with antithyroid medications compared to those who underwent radioactive iodine ablation (43).

Dyslipidemia has been associated with an increased risk of developing thyroid eye disease in patients with hyperthyroidism and should be corrected (03). Use of statins specifically was shown to decrease the hazard of developing thyroid eye disease by 40% and may reflect either cholesterol lowering or the anti-inflammatory effect of this class (43).

Control of active disease. Dry eye/ocular surface disease is very prevalent in thyroid eye disease and should be managed in the usual manner by an ophthalmologist. Patients should be encouraged to lubricate the eyes during the day and use ointment at night, especially when lagophthalmos (incomplete closing of lids) is present. Elevation of the head of the bed can help control periorbital edema. For mild active thyroid eye disease, such conservative measures are the foundation of management.

Traditionally, systemic corticosteroids have been used to control moderate to severe active thyroid eye disease. Compared to oral steroids, intravenous steroids are more effective and better tolerated. A typical treatment course would be a cumulative dose of 4.5 grams of intravenous methylprednisolone delivered over 12 weekly infusions. One study showed improvement in 82% of patients receiving intravenous steroids compared to 53.4% of patients receiving oral steroids (48). Intravenous steroid pulses were found to have relatively fewer side effects, require a shorter course of treatment, and provide a lower recurrence rate than oral steroids. Treatment with oral steroids after the intravenous treatment did not alter the relapse rate. Hepatotoxicity is a potentially fatal adverse effect of intravenous methylprednisolone with cumulative doses greater than 8 grams. Intraorbital injections of triamcinolone acetonide 20 mg and dexamethasone 4 mg have been utilized in active thyroid eye disease, which have a benefit of reduced systemic adverse effects (29).

For patients who have a longer phase of active disease, have recurrences after steroid withdrawal, or are intolerant to steroids, other immune-modulating therapy may be useful, including mycophenolate mofetil, cyclosporine, azathioprine, and methotrexate (29).

Targeted therapies, including biologics, have a growing role. A meta-analysis of rituximab for thyroid eye disease found that it reduced the Clinical Activity Score and normalized laboratory markers, including thyrotropin receptor antibody, thyroid-stimulating hormone, and interleukin-6 levels (45). Another meta-analysis concluded that rituximab was a relatively safe medication and that it produced results superior to those of corticosteroids or placebo in moderate-to-severe thyroid eye disease (41). Interleukin-6 receptor blockade with tocilizumab may be effective. Other promising treatments include TSH receptor antagonists (46).

A phase 3 multicenter, double-masked, randomized trial demonstrated the efficacy and safety of IGF-IR antagonist teprotumumab in patients with active thyroid eye disease in terms of proptosis, Clinical Activity Score, diplopia, and quality of life over placebo (12). Now FDA-approved, it is of benefit in reducing proptosis and in avoiding the need for orbital decompression. 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.

The efficacy of radiation therapy as a sole treatment remains controversial. However, combining it with steroid therapy may be effective, particularly in early stages. A retrospective study compared 144 patients treated with steroids alone to 105 patients treated with a combination of steroids and radiation therapy (40). In that study, 17% of patients treated with steroids alone developed compressive optic neuropathy, whereas none with combination therapy developed optic neuropathy. Orbital radiation produced no significant 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.

Treatment of vision-threatening disease. Patients who develop compressive optic neuropathy must be treated urgently. High-dose intravenous or oral steroids are a reasonable initial therapy. Orbital decompression may be considered. The addition of orbital radiation therapy may be an alternative to orbital decompressive surgery.

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 of inactive disease. Surgical management for inactive disease may be considered to restore normal function and anatomy. Four procedures are used, in the following sequence, should multiple surgeries be required: (1) orbital decompression to restore normal globe position, (2) extraocular muscle (strabismus) surgery to correct diplopia, (3) eyelid malposition surgery, and (4) removal of excess skin and herniated orbital fat.

Idiopathic orbital inflammatory syndrome. In mild cases, close observation with or without nonsteroidal anti-inflammatory drugs may be reasonable. For more severe disease, first-line therapy consists of corticosteroids (32). The usual initial dose is 1.0 to 1.5 mg/kg of oral prednisone. This dose is typically maintained for 2 to 4 weeks before a slow taper is attempted. Relapse during or after withdrawal of steroids is common. Low-dose orbital radiation delivered concurrently with a systemic steroid is often second line in such cases.

Additional immunomodulating therapy may be considered in refractory or relapsing cases, such as methotrexate, azathioprine, cyclophosphamide, mycophenolate mofetil, and calcineurin inhibitors. Tumor necrosis factor-alpha blockers can be used.

In atypical cases, there should be a low threshold to reinitiate systemic workup. Exenteration for recalcitrant disease is a last resort.

IgG4-related disease is treated with corticosteroids as a first-line agent, and response is usually dramatic; however, relapse is common after withdrawal. Other immunosuppressants have been used, including methotrexate, azathioprine, and mycophenolate mofetil. Dramatic clinical response to the anti-CD20 biological rituximab has been reported. Low-dose orbital radiation has been described (28).

Malignant orbital tumors.

Lymphoproliferative disease. Primary orbital lymphoproliferative disorders are typically treated effectively with low-dose radiotherapy. A typical dose of 30 Gy is effective and well-tolerated. 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% (20). The 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.

Chemotherapy and rituximab can be used in various combinations with or without external beam radiation therapy, particularly for higher stage disease and non–extranodal marginal zone lymphoma tumors (35). The role of surgery is typically limited to biopsy, although excision of small, well-circumscribed tumors can be considered.

Orbital metastasis. Treatment of orbital metastasis largely depends on the type of primary malignancy and the extent of systemic disease. Resection, radiation therapy, and chemotherapy have a role.

Rhabdomyosarcoma. Treatment depends on 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 now used with or without radiation therapy (33). Tumor recurrence may necessitate exenteration.

Children with localized orbital rhabdomyosarcoma now have a 5-year survival rate of 70%, compared to 25% in the past (31). The common embryonic subtype has a better prognosis than the other subtypes.

Orbital cellulitis. Treatment largely consists of antibiotics. When a subperiosteal abscess is present, observation with intravenous antibiotics alone (ie, without abscess drainage) is acceptable when age is under 9 years, there is no intracranial involvement, the abscess involves the medial orbital wall, there is no vision loss or relative afferent pupillary defect, there is no frontal sinus involvement, and there is no concomitant dental abscess (Garcia and Harris 2000). A large abscess is an indication for surgical drainage. Patients aged 9 to 15 years who have mixed infections of nonethmoid origin may require sinus and subperiosteal abscess drainage. Among patients older than 15 years, most infections come from the frontal sinus and contain a mixture of aerobic and anaerobic bacteria, requiring aggressive antibiotic therapy and surgery. Surgery should be performed for progressive ophthalmoplegia that persists for 24 or more hours after appropriate antibiotic treatment has been initiated.

Special considerations

Pregnancy

Thyroid eye disease. The systemic and ophthalmic manifestations of hyperthyroidism can worsen in the first trimester of pregnancy and immediately postpartum (27). Aggressive antithyroid treatment may be necessary. Orbitopathy should be treated in the same manner as in the nonpregnant state. However, medications, surgery, or radiation therapy need to be discussed with the endocrinologist, ophthalmologist, and obstetrician to ensure that there are no contraindications.