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Orbital disease in neuro-ophthalmology …
- Updated 08.05.2024
- Released 10.12.2000
- Expires For CME 08.05.2027
Orbital disease in neuro-ophthalmology
Introduction
Overview
Orbital pathology can produce neuro-ophthalmic manifestations, such as optic neuropathy and ocular misalignment, leading to vision loss and diplopia. Among the common orbital conditions are thyroid eye disease, lymphoproliferative disease, and idiopathic orbital inflammatory syndrome.
Key points
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• Early detection of orbital pathology may prevent or reduce visual dysfunction. | |
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• Orbital pathology may lead to restrictive ocular movements manifesting as diplopia. | |
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• Orbital pathology can easily be missed if the orbit is not considered as a site of pathology. | |
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• 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 increased resistance to retropulsion. | |
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• The most common orbital condition is thyroid eye disease. |
Historical note and terminology
Orbital pathology can be categorized according to disease mechanism:
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1. Inflammation | ||
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a. Thyroid eye disease | ||
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2. Infection (cellulitis) | ||
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a. Benign | ||
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4. Vasculopathy | ||
This essay will cover thyroid eye disease, idiopathic orbital inflammatory syndrome, malignant orbital tumors, and orbital cellulitis.
The most common orbital disease is thyroid eye disease, accounting for 47% of orbital disease, followed by lymphoproliferative disorders, accounting for 10.2% (41). The third most common disease is orbital inflammatory syndrome, accounting for approximately 5%.
Thyroid eye disease was previously called Graves orbitopathy. The historical background behind naming the disease dates to 1835 when the Irish physician Robert James Graves described a patient with goiter and proptosis. The German physician Karl von Basedow reported the same symptoms independently in 1840. Other names for the same disease are Parry disease, Begbie disease, Flajani disease, and Marsh disease 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” (27).
Idiopathic orbital inflammatory syndrome, or nonspecific orbital inflammation, was previously known as orbital pseudotumor due to a tendency to simulate orbital malignancy. It is a benign, noninfective clinical syndrome characterized by orbital inflammation without an identifiable local or systemic cause. It must be differentiated from specific causes of orbital inflammation, which may produce a clinically indistinguishable syndrome.
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. However, orbital disease often exists without proptosis.
Enophthalmos. Enophthalmos can also be a feature of orbital disease. Examples are silent sinus syndrome, which causes shrinkage of orbital walls, and metastatic breast cancer, which causes cicatricial shortening of the extraocular muscles and atrophy of 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 by compression of the enlarged extraocular muscles or a sinus mucocele that has eroded into the orbit. Less commonly, “stretch” optic neuropathy may occur, particularly if the proptosis exceeds 8 mm from baseline. Inflammatory damage to the optic nerve is a third mechanism.
Trigeminopathy. Hypesthesia in the first or second trigeminal divisions may occur 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 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. Orbital disease may occur before, after, or simultaneously with clinical dysthyroidism (03). Clinical manifestations are more common in women, but 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 or orbital cellulitis. Thyroid eye disease usually involves both orbits symmetrically, but unilateral or asymmetrical presentations also occur.
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. Digital pressure on the closed eyelids is a useful way to judge resistance to retropulsion, which is usually increased in this condition.
Additional common manifestations include lid lag, which is a delay in relaxation of the levator muscle as the eye is moved into downgaze, and congestive ocular and ocular adnexal signs. 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.
Reduced ocular excursions 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 often adjust to diplopia by adopting an abnormal face turn or chin position, which, may lead them to falsely think that their condition has improved. The extraocular muscle most often affected by inflammation 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 occurs in up to 8% of patients with thyroid eye disease (22). It is usually related to extraocular muscle crowding at the orbital apex; however, in a minority, it is related to forward stretch of the optic nerve (09). 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 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, from an absence of clinical manifestations to soft tissue involvement, including proptosis, impaired ocular excursions, exposure keratopathy, and sight loss from keratopathy or optic nerve damage. The NO SPECS classification assesses clinical severity but does not differentiate between active and inactive 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. Clinical presentations mimic orbital cellulitis and lymphoma. Manifestation may be limited to the orbit or part of a systemic inflammatory process. In a series of 172 patients with orbital inflammation, a specific etiology was identified in just 16.9% (50). Important systemic associations are with sarcoidosis and vasculitides, particularly granulomatosis with polyangiitis.
Common presenting manifestations include periorbital pain (71%), periocular edema (63%), ophthalmoplegia (37%), and conjunctival hyperemia and chemosis (37%). Ptosis and proptosis are each present in 25% of patients (16). Relatively acute onset and severe periocular pain distinguish this condition from thyroid eye disease. Visual acuity and visual field loss can occur. Unilateral involvement is typical in adults, although bilateral involvement can occur in up to 25% and suggests an underlying systemic etiology (49). By contrast, nonsystemic idiopathic orbital inflammatory syndrome in children may be bilateral in up to 50% of cases.
Idiopathic orbital inflammation may be limited to the lacrimal gland (dacryoadenitis). Other common target tissues are the extraocular muscles (myositis), sclera scleritis, optic nerve dural (perineuritis), and periosteal dura (periostitis), sometimes including the intracranial dura (idiopathic hypertrophic pachymeningitis, previously known as Tolosa-Hunt syndrome) (49). When the dural inflammation involves of the superior orbital fissure, cavernous sinus, or other locations at the base of the middle cranial fossa, it can cause severe trigeminal pain, optic neuropathy, Horner syndrome, and third, fourth, and sixth nerve palsies.
Orbital and middle fossa inflammation must be distinguished from malignancy. 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). Pain and lid erythema were predictors of nonmalignant conditions.
IgG4-related ophthalmic disease is increasingly recognized as an important alternative cause of orbital inflammatory syndrome (30). It is a systemic disease characterized by tumefactive lesions in various organs. Nearly all patients with IgG4-related ophthalmic disease have extraorbital involvement, most commonly of the lymph nodes, salivary glands, lung, kidney, hepatobiliary tree, and pancreas (23).
Bilateral orbital inflammation and especially 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 (06). Those with IgG4-related disease had less pain, longer duration of symptoms, and less lower lid hyperemia than those with the idiopathic variant.
Sclerosing orbital inflammation is a rare variant of idiopathic orbital inflammation. It manifests 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 tissues. Corticosteroids are rarely able to reduce or eliminate this process, and careful surgical release of muscles from the fibrous sheath can help relieve diplopia. There is controversy as to whether it is a separate pathologic entity. These cicatricial features can also 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 nerves (44). Other rare conditions included fibrocytic, lipogenic, and myxoid tumors.
Lymphoproliferative disease. Nine of 10 cases are unilateral at presentation. The most common manifestations are periocular swelling (49%), masses (49%), and proptosis (37%). Limited motility is present in many patients. Pain is uncommon, and ocular surface congestive features are rare (1%) (37).
Among lymphoproliferative variants, lymphoid hyperplasia is common. A benign disorder is clinically indistinguishable from lymphoma, and it presents as a slowly progressive orbital mass with eyelid 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. They are detected before the primary tumor in 30% of cases. In a pooled analysis of 873 cases of orbital metastases, breast cancer was the most common cause in 33% of cases, followed by melanoma (10%) and prostate (9%). Manifestations included proptosis (52%), relative afferent pupil defect (39%), diplopia (36%), palpable/visible mass (22%), and periocular pain (19%) (38). Metastatic tumors typically progressed more rapidly than did primary 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 proptosis, ptosis, conjunctival and lid swelling, a palpable mass, and periocular 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 is a tumor of the sympathetic nervous system. Accounting for approximately 10% of all childhood cancer, it is the most common metastatic orbital malignancy in children. Approximately 30% of metastatic neuroblastoma cases involve the orbit seated within its walls. The adrenal gland is usually the primary site, followed by the abdomen and mediastinum. Most children with orbital neuroblastoma display eyelid ecchymosis and proptosis, a presentation is strikingly similar to that of rhabdomyosarcoma. However, neuroblastoma presents at an earlier age, is frequently bilateral, and shows bone erosive changes on CT that are especially pronounced. A preexisting diagnosis of neuroblastoma and the presence of multiple lesions help establish the diagnosis. Diagnosis at a relatively young age is associated with a better prognosis.
Orbital cellulitis. Children under the age of 10 years are most at risk for orbital cellulitis (15).
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.
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. Postseptal orbital cellulitis requires immediate hospitalization, intravenous antibiotics, and often sinus and orbital surgery to prevent spread of infection to the intracranial space.
Prognosis and complications
Thyroid eye disease. There is an initial phase of inflammatory changes referred to as the active phase. The disease then stabilizes and inflammation “burns out.” After 18 to 24 months, the disease becomes inactive (03). Recurrent disease may occur in up to 15% of patients. Optic neuropathy occurs in up to 8%, irreversibly in about 2%. Persistent diplopia occurs in a substantial number of patients, and residual soft tissues signs of thyroid eye disease may persist indefinitely.
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 tumors, including extranodal marginal zone B-cell lymphomas and follicular lymphomas, have a better prognosis (36). 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. Metastasis is associated with a poor survival. 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 (38).
Orbital cellulitis. Pre-septal cellulitis may proceed to post-septal cellulitis if not treated promptly. Post-septal 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.
Goldmann visual field testing for progressive compressive optic neuropathy
(A) Visual field testing of the left eye at presentation. In the visual field of the left eye, defects include an inferior nasal step and an inferior altitudinal defect to less visible stimuli. The right eye shows similar defec...
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 process 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.
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. Genetic mapping localizes to chromosome 14. There is no exact mapping of the HLA region, and there is still 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.
Because patients often report psychological stress prior to developing thyroid eye disease, immunologic rebound hyperactivity related to 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 disease 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 (26).
Infiltration by 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 becomes inactive, 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 have been attenuated by inhibiting insulin-like growth factor type 1 receptor (IGF-IR) in active thyroid eye disease.
In a study of 292 patients with newly diagnosed Graves disease, the levels of vitamin D were significantly lower than in 2305 normal controls (39). 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 by mature lymphocytes, plasma cells, macrophages, and polymorphonuclear leukocytes. 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.
The American College of Rheumatology/European League Against Rheumatism issued classification criteria in 2019 for IgG4-related disease that reflects the importance of integrating information from clinical, serological, radiological, and pathological assessments in order to confirm a diagnosis (46).
Malignant orbital tumors
Lymphoproliferative disease. A study of 2211 cases of orbital lymphoma found that 97% of them 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%) (36).
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 (25). The sinuses harbor Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus, and anaerobes as normal flora. Facial trauma is a contributory cause of pre-septal cellulitis. The incidence of hemophilus-associated bacteremia in patients with pre-septal 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 peaks in the fifth and seventh decades 5 years earlier in women than in men. The incidence of moderate to severe disease was reported to be 16.1 cases per million per year (26.7 in women and 5.4 in men) (24). The prevalence of this disease in the general population is between 90 to 300 per 100,000 persons (03).
Idiopathic orbital inflammatory syndrome. Incidence and prevalence rates of idiopathic orbital inflammatory syndrome are difficult to assess given the wide clinical spectrum. In an American cohort of 20,584 patients with autoimmune or idiopathic orbital idiopathic orbital inflammation, the mean of onset was 51.7 years; 67% were female (28).
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, with a median age of 59 years at diagnosis in a pooled series of 873 patients (38). Orbital metastasis may be slightly more common in women, reflecting the large proportion of cases with breast cancer.
Prevention
Thyroid eye disease. Smoking is an important risk factor for thyroid eye disease and its progression to severe disease. Selenium supplementation (100 mg twice daily for 6 months) may be used on the basis that oxidative stress is a provocative factor.
Orbital cellulitis. Orbital cellulitis is best prevented with prompt treatment of bacterial sinusitis or other conditions on predisposing to infectious sinusitis. Options include prophylactic antibiotics in immunocompromised children, sinus ostia enlargement, and surgical drainage in 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 carotid cavernous fistula, infectious and noninfectious inflammation, tumors, and aneurysms. Concurrent involvement of the orbit and basal middle fossa suggests idiopathic hypertrophic pachymeningitis (Tolosa-Hunt syndrome).
Diagnostic workup
The appropriate evaluation of patients with suspected orbital disorders involves an ophthalmologic examination, including measurement of best-corrected visual acuity, pupil size and reactivity, color vision, automated threshold perimetry, ocular motility and alignment, Hertel exophthalmometry, measurement of intraocular pressure, slit lamp biomicroscopy, and ophthalmoscopy.
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. Laboratory assessment includes thyroid-stimulating hormone (TSH), T3, free T4, TSH receptor antibody activity (TSH-binding inhibition immunoglobulin [TBII] and thyroid-stimulating immunoglobulin [TSI]), or antithyroid peroxidase antibody level (31).
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 because CT provides better visualization of bone. Otherwise MRI, is the choice because it provides more detailed visualization of soft tissues, including 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. Imaging is confirmatory and provides adjunctive information (10).
Idiopathic orbital inflammatory syndrome. The diagnosis of idiopathic orbital inflammation is based on clinical history and examination, laboratory results, imaging, and a rapid response to corticosteroid treatment. Orbital biopsy is generally withheld in typical cases because of its morbidity, especially when imaging shows diffuse disease or a focal lesion in the orbital apex. Biopsy becomes a credible option if there are atypical manifestations, a poor response to corticosteroids, recurrences, or the suggestion of a related systemic disorder (34). The presence of systemic manifestations or a previously diagnosed relevant systemic disorder should prompt further testing.
Testing should include a complete blood count with differential (noting eosinophilia or other abnormalities), erythrocyte sedimentation rate, C-reactive protein, urinalysis, antinuclear antibodies, and antineutrophil cytoplasmic antibody panel. For atypical cases (see previous paragraph), testing extends to serum angiotensin-converting enzyme, lysozyme, syphilis serology, serum IgG4, and chest x-ray CT.
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 tendons are spared.
IgG4-related disease. Although IgG4-related disease is a clinicopathologic diagnosis, history, physical examination, and laboratory markers can be suggestive (07). 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: (1) presence of tumefactive lesions in the pancreas, liver, salivary glands, pachymeninges, retroperitoneum, lung, or lymph nodes; (2) synchronous or metachronous involvement of multiple organs; (3) subacute onset; (4) elevated serum IgG4; (5) elevated plasmablast levels; and (6) rapid response to immunosuppressive therapy (08).
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 the critical diagnostic maneuver. On imaging, many of these tumors appear ill-defined or diffuse; the remainder appear well-circumscribed with smooth contours. They enhance uniformly. These lesions are nearly always unilateral, 72% occurring within the extraconal space. In one study, imaging showed the superior rectus muscle involved in 74% of cases and the lacrimal gland involved in 47% of cases (40).
Imaging does not reliably distinguish between benign and malignant lymphoproliferative tumors and idiopathic orbital inflammatory syndrome. All three lesions 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 (40).
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. Before treatment, patients should undergo ophthalmologic examination, including assessment of visual acuity, color vision, confrontation visual fields, pupil reactions, and ocular motility checks. Posttreatment monitoring is advisable. The yield of blood cultures is low. Nasopharyngeal swabs are not helpful in specifying a particular agent (02). Consultation with an otolaryngologist is advised.
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 (32).
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). That risk is reduced with a short course of prednisone (0.3 to 0.5 mg/kg), 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 treatment with antithyroid medications compared to those who underwent radioactive iodine ablation (45).
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 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 (45).
Control of active disease. Dry eye 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.
Systemic corticosteroids have been used to control moderate or severe active thyroid eye disease. Intravenous administration is more effective and better tolerated than oral administration. 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 (51). 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, which have a benefit of reduced systemic adverse effects, have also been utilized effectively in active disease (31).
Among patients who have a long duration of active disease, recurrences after corticosteroid withdrawal, or intolerance to corticosteroids, other immune-modulating therapy may be useful, including mycophenolate mofetil, cyclosporine, azathioprine, and methotrexate (31).
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 (47). 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 (43). Interleukin-6 receptor blockade with tocilizumab may be effective. Other promising treatments include TSH receptor antagonists (48).
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). This FDA-approved medication reduces proptosis and appears to be a substitute for orbital surgery in this disease. However, hearing loss has been a disturbing side-effect.
The efficacy of radiation therapy as a sole treatment remains controversial. However, combining it with corticosteroid therapy may be effective, particularly in early stages. In a retrospective study comparing 144 patients treated with corticosteroids alone to 105 patients treated with a combination of corticosteroids and radiation (42), 17% of patients treated with corticosteroids alone developed compressive optic neuropathy, whereas none with combination therapy developed optic neuropathy. The orbital radiation (10 to 20 Gy in 10 sessions over 2 weeks) produced no significant adverse effects. Combination treatment also produced better effects on ocular excursions.
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. Adjunctive 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 must be carried out.
Treatment of inactive disease. Four surgical procedures are used: (1) orbital decompression to restore normal globe position; (2) extraocular muscle surgery to correct diplopia; (3) eyelid lowering for retraction; and (4) removal of excess eyelid skin and herniated orbital fat (blepharoplasty).
A trial of teprotumumab in patients with chronic and low level disease activity demonstrated efficacy with respect to improvement in proptosis (11).
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 (34). 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 an option in such cases.
Additional immunomodulating therapy may be considered in refractory or relapsing cases, including methotrexate, azathioprine, cyclophosphamide, mycophenolate mofetil, and calcineurin inhibitors. Tumor necrosis factor-alpha blockers can be used.
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 effectively, 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 as beneficial (30).
Malignant orbital tumors.
Lymphoproliferative disease. A typical orbital radiation dose of 30 Gy is effective and well-tolerated. A single-center retrospective study of 44 patients with orbital lymphoma 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 (37). 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), vincristine and actinomycin D, are now used with or without radiation therapy (35). 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 (33). 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 without abscess drainage) is acceptable when the patient’s age is under 9 years, the abscess involves the medial orbital wall, there is no vision loss or relative afferent pupillary defect, 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 non-ethmoid 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 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 (29). 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.
Media
References
- 01
- Aryasit O, Tiraset N, Preechawai P, Kayasut K, Sanghan N, Sittivarakul W. IgG4-related disease in patients with idiopathic orbital inflammation. BMC Ophthalmol 2021;21(1):1-9. PMID 34625052
- 02
- Aygun A, Doğan C, Hepokur M, Arslan OS, Çokuğraş H, Camcıoglu Y. Evaluation of patients with orbital infections. Turk Pediatri Ars 2017;52(4): 221-5. PMID 29483802
- 03
- Bartalena L, Piantanida E, Gallo D, Lai A, Tanda ML. Epidemiology, natural history, risk factors, and prevention of Graves’ orbitopathy. Front Endocrinol (Lausanne) 2020;11:615993. PMID 33329408
- 04
- Bartley GB, Fatourechi V, Kadrmas EF, et al. The incidence of Graves’ ophthalmopathy in Olmstead County, Minnesota. Am J Ophthalmol 1996;120(4):511-7. PMID 7573310
- 05
- Branson SV, McClintic E, Yeatts RP. Septic cavernous sinus thrombosis associated with orbital cellulitis: a report of 6 cases and review of literature. Ophthalmic Plast Reconstr Surg 2019;35(3):272-80. PMID 30320718
- 06
- Chen J, Zhang P, Ye H, et al. Clinical features and outcomes of IgG4-related idiopathic orbital inflammatory disease: from a large southern China-based cohort. Eye (Lond) 2021;35(4):1248-55. PMID 32661337
- 07
- Chwalisz BK, Stone JH. Neuro-ophthalmic complications of IgG4-related disease. Curr Opin Ophthalmol 2018;29(6):485-94. PMID 30199519
- 08
- Deshpande V. IgG4 related disease of the head and neck. Head Neck Pathol 2015;9(1):24-31. PMID 25804380
- 09
- Dolman PJ. Dysthyroid optic neuropathy: evaluation and management. J Endocrinol Invest 2021;44(3):421-9. PMID 32729049
- 10
- Dolman PJ. Grading severity and activity in thyroid eye disease. Ophthalmic Plast Reconstr Surg 2018;34(4S Suppl 1):S34-40. PMID 29952931
- 11
- Douglas RS, Couch S, Wester ST, et al. Efficacy and safety of teprotumumab in patients with thyroid eye disease of long duration and low disease activity. J Clin Endocrinol Metab 2023;109(1):25-35. PMID 37925673
- 12
- Douglas RS, Kahaly GJ, Patel A, et al. Teprotumumab for the treatment of active thyroid eye disease. N Engl J Med 2020;382(4):341-52. PMID 31971679
- 13
- Du B, Wang Y, Yang M, He W. Clinical features and clinical course of thyroid-associated ophthalmopathy: a case series of 3620 Chinese cases. Eye (Lond) 2021;35(8):2294-301. PMID 33139874
- 14
- Eade EL, Hardy TG, McKelvie PA, McNab AA. Review of extraocular muscle biopsies and utility of biopsy in extraocular muscle enlargement. Br J Ophthalmol 2018;102(11):1586-90. PMID 29352070
- 15
- Ekhlassi T, Becker N. Preseptal and orbital cellulitis. Dis Mon 2017;63(2):30-2. PMID 27884386
- 16
- Eshraghi B, Sonbolestan SA, Abtahi MA, Mirmohammadsadeghi A. Clinical characteristics, histopathology, and treatment outcomes in adult and pediatric patients with nonspecific orbital inflammation. J Curr Ophthalmol 2019;31(3):327-34. PMID 31528770
- 17
- Garcia GH, Harris GJ. Criteria for nonsurgical management of subperiosteal abscess of the orbit: analysis of outcomes 1988-1998. Ophthalmology 2000;107(8):1454-5; discussion 1457-8. PMID 10919887
- 18
- Haussler SM, Stromberger C, Olze H, Seifert G, Knopke S, Böttcher A. Head and neck rhabdomyosarcoma in children: a 20-year retrospective study at a tertiary referral center. J Cancer Res Clin Oncol 2018;144(2):371-9. PMID 29143871
- 19
- Heisel CJ, Riddering AL, Andrews CA, Kahana A. Serum vitamin D deficiency is an independent risk factor for thyroid eye disease. Ophthalmic Plast Reconstr Surg 2020;36(1):17-20. PMID 31568022
- 20
- Kharod SM, Herman MP, Morris CG, et al. Radiotherapy in the management of orbital lymphoma: a single institution's experience over 4 decades. Am J Clin Oncol 2018;41(1):100-6. PMID 26398063
- 21
- Khiyani N, Dadparvar S, Gish A, Intenzo CM, Malmud LS. Does the dose of iodine-131 influence the incidence of Graves' ophthalmopathy?. Nucl Med Commun 2019;40(5):455-60. PMID 30855542
- 22
- Khong JJ, Finch S, De Silva C, et al. Risk factors for Graves' orbitopathy; the Australian Thyroid-Associated Orbitopathy Research (ATOR) study. J Clin Endocrinol Metab 2016;101(7):2711-20. PMID 27055083
- 23
- Lai KKH, Aljufairi FMAA, Sebastian JU, et al. Systemic involvement in immunoglobulin g4-related ophthalmic disease. Ocul Immunol Inflamm 2024;32(8):1852-8. PMID 38055933
- 24
- Laurberg P, Berman DC, Bulow Pedersen I, Andersen S, Carle A. Incidence and clinical presentation of moderate to severe graves’ orbitopathy in a Danish population before and after iodine fortification of salt. J Clin Endocrinol Metab 2012;97(7):2325-32. PMID 22518849
- 25
- Leung AKC, Hon KL, Chu W. Acute bacterial sinusitis in children: an updated review. Drugs Context 2020;9:2020. PMID 33281908
- 26
- Li HX, Xiang N, Hu WK, Jiao XL. Relation between therapy options for Graves' disease and the course of Graves' ophthalmopathy: a systematic review and meta-analysis. J Endocrinol Invest 2016;39(11):1225-33. PMID 27220843
- 27
- Ljunggren JG. Who was the man behind the syndrome: Ismail al-Jurjani, Testa, Flajina, Parry, Graves or Basedow? Lakartidningen 1983;80(32-3):2902. PMID 6355710
- 28
- Lu JE, Ross C, Ivanov A, et al. Epidemiology of orbital inflammatory disease: an AAO IRIS registry study. Ocul Immunol Inflamm 2024:1-4. PMID 38489590
- 29
- Marx H, Amin P, Lazarus J. Hyperthyroidism and pregnancy. BMJ 2008;336(7645):663-7. PMID 18356235
- 30
- McNab AA, McKelvie P. IgG4-related ophthalmic disease. Part II: clinical aspects. Ophthalmic Plast Reconstr Surg 2015;31(3):167-78. PMID 25564258
- 31
- Men CJ, Kossler AL, Wester ST. Updates on the understanding and management of thyroid eye disease. Ther Adv Ophthalmol 2021;13:25158414211027760. PMID 34263138
- 32
- Menconi F, Profilo MA, Leo M, et al. Spontaneous improvement of untreated mild Graves' ophthalmopathy: Rundle's curve revisited. Thyroid 2014;24(1):60-6. PMID 23980907
- 33
- Meza JL, Anderson J, Pappo AS, Meyer WH. Analysis of prognostic factors in patients with nonmetastatic rhabdomyo-sarcoma treated on intergroup rhabdomyosarcoma studies III and IV: the Children’s Oncology Group. J Clin Oncol 2006;24(24):3844-51. PMID 16921036
- 34
- Mombaerts I, Bilyk JR, Rose GE, et al. Consensus on diagnostic criteria of idiopathic orbital inflammation using a modified Delphi Approach. JAMA Ophthalmol 2017;135(7):769-76. PMID 28570731
- 35
- Oberlin O, Rey A, Anderson J, et al. Treatment of orbital rhabodomyosarcoma: survival and late effects of treatment: results of an international workshop. J Clin Oncol 2001;19(1):197-204. PMID 11134213
- 36
- Olsen TG, Heegaard S. Orbital lymphoma. Surv Ophthalmol 2019;64(1):45-66. PMID 30144455
- 37
- Olsen TG, Holm F, Mikkelsen LH, et al. Orbital lymphoma—an international multicenter retrospective study. Am J Ophthalmol 2019;199:44-57. PMID 30419193
- 38
- Palmisciano P, Ferini G, Ogasawara C, et al. Orbital metastases: a systematic review of clinical characteristics, management strategies, and treatment outcomes. Cancers (Basel) 2021;14(1):94. PMID 35008259
- 39
- Planck T, Shahida B, Malm J, Manjer J. Vitamin D in Graves disease: levels, correlation with laboratory and clinical parameters, and genetics. Eur Thyroid J 2018;7(1):27-33. PMID 29594051
- 40
- Priego G, Majos C, Climent F, Muntane A. Orbital lymphoma: imaging features and differential diagnosis. Insights Imaging 2012;3(4):337-44. PMID 22695946
- 41
- Rootman J. Inflammatory diseases of the orbit. Highlights. J Fr Ophtalmol 2001;24(2):155-61. PMID 11240487
- 42
- Shams PN, Ma R, Pickles T, Rootman J, Dolman PJ. Reduced risk of compressive optic neuropathy using orbital radiotherapy in patients with active thyroid eye disease. Am J Ophthalmol 2014;157(6):1299-305. PMID 24582992
- 43
- Shen WC, Lee CH, Loh EW, et al. Efficacy and safety of rituximab for the treatment of Graves' orbitopathy: a meta-analysis of randomized controlled trials. Pharmacotherapy 2018;38(5):503-10. PMID 29601105
- 44
- Shields JA, Shields CL, Scartozzi R. Survey of 1264 patients with orbital tumors and simulating lesions: the 2002 Montgomery Lecture, part 1. Ophthalmology 2004;111(5):997-1008. PMID 15121380
- 45
- Stein JD, Childers D, Gupta S, et al. Risk factors for developing thyroid-associated ophthalmopathy among individuals with Graves disease. JAMA Ophthalmol 2015;133(3):290-6. PMID 25502604
- 46
- Wallace ZS, Naden RP, Suresh C, et al. The 2019 American College of Rheumatology/European League Against Rheumatism classification criteria for IgG4-related disease. Ann Rheum Dis 2020;79(1):77-87. PMID 31796497
- 47
- Wang C, Ning Q, Jin K, Xie J, Ye J. Does rituximab improve clinical outcomes of patients with thyroid-associated ophthalmopathy? A systematic review and meta-analysis. BMC Ophthalmol 2018a;18(1):46. PMID 29452583
- 48
- Wiersinga WM. Advances in treatment of active, moderate-to-severe Graves' ophthalmopathy. Lancet Diabetes Endocrinol 2017;5(2):134-42. PMID 27346786
- 49
- Yuen SJ, Rubin PA. Idiopathic orbital inflammation: distribution, clinical features, and treatment outcome. Arch Ophthalmol 2003;121(4):491-9. PMID 12695246
- 50
- Yoon MK, Lu JE. An evidence-based approach to diagnosing patients presenting with orbital inflammatory syndromes (an American Ophthalmological Society thesis). Am J Ophthalmol 2024;266:156-81. PMID 38763497
- 51
- Zang S, Ponto KA, Kahaly JG. Clinical review: intravenous glucocorticoids for graves' orbitopathy: efficacy and morbidity. J Clin Endocrinol Metab 2011;96(2):320-32. PMID 21239515
Contributors
All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.
Author
-
Matthew P Quinn MD PhD
Dr. Quinn of the University of Ottawa received an educational grant from Bayer as a fellow.
See Profile
Editor
-
Jonathan D Trobe MD
Dr. Trobe of the University of Michigan has no relevant financial relationships to disclose.
See Profile
Former Authors
- Mark Duffy MD PhD
- John Pak MD PhD
- Pete Setabutr MD
- Ramesh Singa MD
- Danah Albreiki MBBS
Patient Profile
- Age range of presentation
-
- 2 to 65+ years
- Sex preponderance
-
- female>male, >2:1
- Heredity
-
- heredity may be a factor
- Population groups selectively affected
-
- none selectively affected
- Occupation groups selectively affected
-
- none selectively affected
ICD & OMIM codes
- ICD-10
-
- Disorders of orbit: H05
- Acute inflammation of orbit: H05.0
- Chronic inflammatory disorders of orbit: H05.1
- Orbital cellulitis: H05.0
- ICD-11
-
- Disorders of orbit, unspecified: 9A2Z
- Orbital inflammation, unspecified: 9A22.Z
- Orbital cellulitis: 9A21.0
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