Neuro-Ophthalmology & Neuro-Otology
Third nerve palsy
Mar. 24, 2021
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This article includes discussion of orbitopathies affecting vision and ocular alignment, idiopathic orbital inflammatory syndrome, thyroid-related immuno-orbitopathy, thyroid-related immunoorbitopathy, malignant orbital tumors, orbital cellulitis, and orbital inflammatory syndrome. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.
Orbital pathology can result in neuro-ophthalmic manifestations such as optic neuropathy and ocular misalignment, leading to vision loss and diplopia. Among the common orbital conditions are thyroid-related orbitopathy (TRO), orbital tumors, and orbital inflammatory syndromes. Other orbitopathies include IgG-4-related disease and orbital infections such as cellulitis.
• History taking and clinical examination of the orbit are important parts of the evaluation.
• Early detection may prevent or reduce visual dysfunction.
• Orbital pathology may lead to restrictive ocular movements manifesting as diplopia.
• Orbital pathology can easily be missed if the orbit is not considered as a site of pathology.
• Proptosis is the hallmark of orbital pathology, but it is not always present. To detect it, one could use a Hertel Exophthalmometer and check for increased resistance to retropulsion.
• The most common orbital condition is thyroid-related orbitopathy.
Orbital pathology can be categorized according to disease mechanism:
a. Thyroid-related orbitopathy
2. Infection (cellulitis)
This chapter will cover thyroid-related orbitopathy, idiopathic orbital inflammatory syndrome, malignant orbital tumors, and orbital cellulitis.
The most common orbital disease is thyroid-related orbitopathy, accounting for 47% of orbital disease, followed by lymphoproliferative disorders in 10.2% (56). The third most common is orbital inflammatory syndrome, accounting for 4.7% to 6.3% (76).
Thyroid-related orbitopathy is also called Graves orbitopathy. The historical background behind naming the disease “Graves” goes back to 1835 when the Irish physician Robert James Graves described a patient with goiter and proptosis. The German physician Karl von Basedow reported the same group of symptoms independently in 1840. Other names for the same disease are Parry disease, Begbie disease, Flajani disease, and Marsh disease. These names are derived from physicians in the early 1800s. But in the 12th century, a Persian physician named Sayyid Ismail Al-Jurani had noted the association between goiter and proptosis, reporting it in his “Thesaurus of the Shah Khwarazm” (39).
Proptosis. Proptosis is the hallmark manifestation of orbital disease. The most common orbital condition that causes unilateral or bilateral proptosis is thyroid-related orbitopathy. Proptosis, however, can be secondary to other orbital conditions such as inflammatory orbital disease, vascular conditions, infections, or tumors. Proptosis can be axial, indicating an intraconal process, or nonaxial, indicating an extraconal process.
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 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 might occur such as that in thyroid-related orbitopathy caused by the extraocular muscles compressing the optic nerve at the orbital apex causing a “compressive” optic neuropathy. Less commonly, “stretch” optic neuropathy can occur, particularly if the proptosis exceeds 8 mm from the 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 fissure.
Gaze-evoked amaurosis occurs when a lesion within the orbit compresses the optic nerve as the nerve kinks when the eye moves into an eccentric gaze position.
Thyroid-related orbitopathy (TRO).
Clinical manifestations. Thyroid-related orbitopathy is the most common extrathyroidal manifestation of Graves disease, occurring in about 25% to 50% of patients. It may be present in patients with hyperthyroidism, hypothyroidism, or euthyroidism (26).
Patients with thyroid-related orbitopathy may have symptoms related to the periorbital tissues, 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 cellulitis. Thyroid-related orbitopathy usually involves both orbits symmetrically.
Lid retraction is the most common and pathognomonic feature of thyroid-related orbitopathy. It is defined as exposure of the sclera above the superior limbus, but patients can also have inferior lid retraction. A plausible mechanism for lid retraction is sympathetic overdrive and muscle hypertrophy. The differential diagnosis of lid retraction includes dorsal midbrain syndrome, systemically-administered sympathomimetics, previous ocular surgery, and aberrant regeneration of the third nerve. When lid retraction is accompanied by proptosis, the most likely diagnosis is thyroid-related orbitopathy.
Lid lag, which describes a delay in relaxation of the levator muscle as the eye is moved into downgaze, is a common feature of thyroid-related orbitopathy.
Proptosis is 1 of the most common features of thyroid-related orbitopathy and is present in two thirds of patients (14). It is often measured with the Hertel exophthalmometer. This procedure may be supplemented with checking for resistance to retropulsion.
Conjunctival hyperemia, particularly around the lateral recti muscle insertions, as well as swelling and erythema of the caruncular area, dry eyes, exposure keratopathy, superior limbic keratoconjunctivitis, and corneal ulceration are all features of thyroid-related orbitopathy.
Inflammation of the extraocular muscles may cause a feeling of tightness in the eyes in addition to diplopia created by reduced ocular movements and consequent ocular misalignment. Patients may adjust to diplopia by gradually adopting an abnormal face turn or chin position. The extraocular muscle most often affected is the inferior rectus, followed by the medial rectus, superior rectus, and lateral rectus. Depending on the most prominent muscles involved, the eyes may be misaligned vertically or horizontally.
The range of excursions of the eyes is often graded on a scale from 0 to -4 (with -4 indicating no movement beyond primary gaze position in a particular direction). Ocular alignment is measured with the cover test or the Maddox rod with the aid of prisms.
Optic neuropathy has been documented to occur in up to 8% of patients with thyroid-related orbitopathy (33). It is usually the result of optic nerve compression related to extraocular muscle crowding at the orbital apex. 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 the severity of the clinical manifestations in thyroid-related orbitopathy has been described in several classification systems since 1969. These include the NO SPECS classification, the European Group on Graves Orbitopathy severity scale, the Clinical Activity Score of Mourits, and the VISA classification (12).
Werner was 1 of the first to establish the NO SPECS classification, which stands for no physical signs or symptoms, only signs, soft tissue involvement, proptosis, extraocular muscle signs, corneal involvement, and sight loss (77). The NO SPECS system was modified by its author in 1977. The modified system assesses clinical severity but does not differentiate between active and inactive thyroid-related orbitopathy.
In 1989, Mourits and colleagues established and introduced the clinical activity system (CAS) that takes into account active inflammation (pain, redness, swelling, and reduced function) (48). This system was modified in 1997.
Two of the currently used systems are the VISA classification (vision, inflammation, strabismus, appearance) (11), used commonly in North America (03), and the European Group of Graves’ Orbitopathy (EUGOGO) Classification used commonly in Europe (05). These latter 2 classification systems allow for early diagnosis, recognition of cases that are more susceptible to serious complications, and clues to appropriate management.
Another classification system was developed in order to predict the risk of diplopia after orbital decompression (49). The author classified 58 patients into type 1 and type 2 prior to a 2-wall orbital decompression. Type 1 had normal versions and no diplopia. Type 2 had diplopia within 20 degrees of the primary position and restricted motility. Only 4% of patients with type 1 experienced new or worsening diplopia following surgery, whereas 61% of patients with type 2 experienced new diplopia or worsening of diplopia.
A retrospective case control study showed that race, ethnicity, active cigarette smoking, serum thyroid peroxidase antibody positivity, serum thyroglobulin antibody positivity, antithyroidal medication use, and corticosteroid use did not reliably predict thyroid-related orbitopathy (38).
Imaging. Orbital imaging assesses extraocular muscle caliber and orbital fat volume, excludes other pathology, and aids in surgical planning. Imaging features are increased orbital fat, usually without enhancement, and enlarged muscles with sparing of muscle tendons, a feature purported to distinguish thyroid-related orbitopathy from orbital myositis.
Diagnosis. Diagnosis of thyroid-related orbitopathy is principally based on clinical criteria. If lid retraction is present with proptosis, the diagnosis is very likely (07). If lid retraction is not present, laboratory markers including abnormal thyroid function tests (thyroxine and thyroid stimulating hormone levels) or a history of thyroid dysfunction help support the diagnosis. Thyroid-stimulating hormone is thought to be highly sensitive for active Graves disease. Among patients with thyroid-related orbitopathy, 10% are euthyroid. In atypical situations, CT, MRI, or ultrasound might be helpful with the diagnosis (12).
Idiopathic orbital inflammatory syndrome (orbital pseudotumor). Idiopathic orbital inflammation is the third most common orbital disorder, after thyroid-related orbitopathy and lymphoproliferative diseases. Estimated to constitute 4.7% to 6.3% of all orbital disease, it is characterized by nongranulomatous inflammation often limited to the orbit.
Bilateral involvement in adults suggests an underlying systemic vasculitis. In children, this disorder may be relapsing, refractory to treatment, and bilateral in up to 50% of cases.
Clinical presentations mimic orbital cellulitis, connective tissue disorders, sarcoidosis, and lymphoma. Patients usually present with an acute or subacute onset of painful ophthalmoplegia, diplopia, lid swelling, and conjunctival chemosis. The acute onset is an important distinguishing factor from thyroid-related orbitopathy. Clinical manifestations may also include impaired visual acuity or visual field deficits.
Idiopathic orbital inflammation may be subdivided into dacryoadenitis, myositis, scleritis, perineuritis, orbital pseudotumor, diffuse orbital inflammatory syndrome, and Tolosa-Hunt syndrome. It presents differently depending on the orbital structures affected. One study that evaluated the distribution of affected tissues in 90 eyes found that the inflammation was based in the lacrimal gland in 21 patients, in extraocular muscle in 19 patients, in lacrimal gland and muscle in 5, in the orbital apex in 6, and in the preseptal region, supraorbital region, sclera, Tenon capsule, orbital fat, or optic nerve in 14 (81). Tolosa-Hunt syndrome, now often called idiopathic hypertrophic pachymeningitis, may affect the orbital periosteum (dura), superior orbital fissure, cavernous sinus, or other locations at the cranial base. It can present with severe pain, vision loss, sympathetic dysfunction, and third, fourth, and sixth nerve palsies.
The diagnosis of idiopathic orbital inflammation is based on combining clinical history and examination, laboratory results, imaging, biopsy, and sometimes on its rapid response to steroid treatment.
Autoimmune and infectious etiologies have been proposed as the basis of idiopathic orbital inflammation. However, IgG4-related disease has been implicated, at least for a subset (23).
IgG4 disease includes enlargement in at least 1 organ demonstrated by examination and imaging, high serum IgG4 levels, and plasmacytic and lymphocytic infiltration demonstrated histopathologically. This disease is thought to be a generalized process that may involve the pancreas, salivary glands, hepatobiliary ducts, retroperitoneal space, lymph nodes, kidneys, lungs, aorta, and skin (54). The most reliable data for IgG4 disease incidence come from Japan, where this disease accounts for 0.28 to 1.08 cases per 100,000 (60). More recently, a retrospective study of 88 patients with IgG4-related disease found that 87% of patients with ophthalmic IgG4-related disease had other organ involvement (73). Diagnosis was best made by an incisional biopsy of lacrimal glands and salivary glands followed by morphological and immunomorphological studies. Lymphoplasmacytic infiltration with an IgG4/IgG ratio of more than 40%, together with advanced fibrosis in the biopsy specimen, were required for the proper diagnosis.
Sclerosing orbital inflammation has been considered a rare subset of idiopathic orbital inflammation, but it may be a separate entity. It has a more gradual onset and less pain. Desmoplasia affects orbital structures, replacing them with fibrosis. There is only a sparse inflammatory response of plasma cells, lymphocytes, histiocytes, eosinophils, and neutrophils.
Its presentation is more like that of a neoplasm, and the work-up frequently requires a biopsy. At surgery, a tough fibrous sheath of tissue can sometimes be found surrounding the muscles and other compartments. Steroids are rarely able to reduce or eliminate this process, and careful surgical release of muscles from this sheath can help return the orbit to a more functional state. There is a debate as to whether “sclerosing orbital pseudotumor” is a completely different pathologic entity.
Malignant orbital tumors. A study of 1264 patients with suspected orbital tumors found that vasculogenic tumors were the most common (17%), followed by those of lymphoid, lacrimal gland, optic nerve and meningeal, metastatic, and peripheral nerve origin, as well as melanoma (64). Other rare conditions included fibrocytic, lipogenic, and myxoid tumors.
Lymphoproliferative disease. Lymphoproliferative tumors constitute 50% to 60% of ocular adnexal lymphomas in patients over age 60. According to a study of 2211 cases of orbital lymphoma, 97% of orbital lymphomas are of B-cell origin, of which extranodal marginal zone B cell lymphomas constitute 59%, followed by large B cell lymphomas (23%), follicular lymphomas (9%), and mantle cell lymphomas (5%). 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 whereas low-grade lymphomas such as extranodal marginal zone B cell lymphomas and follicular lymphomas having a better prognosis (51). Immunohistochemical and molecular biological studies have been reliable in differentiating these entities. Among patients with isolated orbital lymphomas, 30% will develop systemic lymphomas within 10 years.
The other principal orbital lymphoproliferative disorder is reactive lymphoid hyperplasia (28). This tumor presents as progressive painless proptosis with a palpable mass and ocular dysmotility. The painless nature of this condition helps differentiate it from idiopathic orbital inflammation, which is usually painful. It can manifest as a “fish-flesh” salmon-colored conjunctival mass or boggy edema of the eyelids and periorbital skin.
Orbital lymphoproliferative tumors are unilateral in more than 90% of the cases, 72% occurring within the extraconal space. About half of these tumors are ill-defined and diffuse, the remainder appearing more well-circumscribed and smooth. Uniform enhancement is the general rule. In 1 study, imaging showed the superior rectus muscle involved in 74% of cases and the lacrimal gland involved in 47% of cases (55).
Imaging does not reliably distinguish between benign and malignant lymphoproliferative tumors and idiopathic orbital inflammatory syndrome. These tumors tend to mold around orbital structures, with remodeling of bone rather than its erosion. On MRI imaging, these lesions typically appear isointense on precontrast T1 and iso or hyperintense on T2. They have a predilection for the superior lateral orbit (55).
Metastasis. About 1% to 3% of orbital masses are metastases, the most common originating from breast cancer, accounting for 48% to 53% of metastases. Others are prostate cancer, melanoma, and lung cancer. Metastatic tumors of the orbit often develop more rapidly than primary orbital tumors. CT imaging usually shows bony erosive changes.
Childhood orbital malignancies. Childhood orbital tumors often develop rapidly, mimicking inflammatory or infectious processes.
Orbital rhabdomyosarcoma. Orbital rhabdomyosarcoma accounts for 32.1% of all head and neck rhabdomyosarcomas in children (25). Patients typically present with rapidly progressive proptosis, ptosis, conjunctival and lid swelling, a palpable mass, and pain. In older children and adults, the course of the disease may be more gradual. There are 4 types: (1) embryonal, occurring more commonly in childhood and comprising botryoid and spindle cell subtypes; (2) alveola, occurring at any age and having a poor prognosis; (3) anaplastic (pleomorphic); (4) mixed (25).
Neuroblastoma. Neuroblastoma originates from the sympathetic nervous system at the adrenal medulla or at paraspinal sites. Accounting for 12% to 15% of all childhood cancer (29), it is the most common metastatic orbital malignancy. Up to 30% to 43% of metastatic neuroblastoma cases occur in the orbit (66; Harreld et al 2016). 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 rhabdomyosarcoma. However, neuroblastoma presents at an earlier age, is frequently bilateral, and shows bony 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. These orbital tumors require urgent biopsy, metastatic work-up, and coordinated care with pediatric hematology and oncology services.
Orbital cellulitis. Orbital cellulitis requires immediate attention lest blindness and intracranial extension leading to death 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 2 subtypes by means of history and clinical examination because post-septal orbital cellulitis requires immediate hospitalization, intravenous antibiotics, and often sinus and orbital surgery. Patients with postseptal cellulitis often present with fever, vision loss, proptosis, and diplopia, manifestations that are not part of the preseptal variant. However, preseptal cellulitis may proceed to postseptal cellulitis if not treated promptly. Postseptal disease may result in visual loss from optic neuropathy and may spread via orbital venous emissaries into the cavernous sinus, leading to thrombosis, meningitis, stroke, abscess, and death. The common 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).
Thyroid-related orbitopathy. The average duration of activity in thyroid-related orbitopathy ranges between 18 and 36 months. The condition abates gradually, often leaving behind tissue abnormalities (30). However, 5% of patients experience late reactivation, defined as active orbitopathy occurring after more than 5 years of inactive disease (61). One-third of patients report displeasure with their facial appearance even after the disease has become inactive (06). Optic neuropathy occurs in 4% to 8% of the patients, in whom it is permanent in 2.2%. Persistent diplopia occurs in 2.2%. Some residual signs of thyroid-related orbitopathy are present as long as 10 years after diagnosis (58).
Orbital inflammatory syndrome. Untreated idiopathic orbital inflammation may progress to visual loss, diplopia, and rarely to cavernous sinus thrombosis and death. Early detection and treatment yield a generally favorable prognosis. In the frequently-relapsing bilateral variant, fibrosis causes persistently restricted eye movements and proptosis. First-line therapy consists of corticosteroids. Resolution of manifestations is generally prompt. In patients with corticosteroid intolerance or unresponsiveness, radiation therapy may be used, but complications include cataracts, dry eyes, radiation retinopathy, and optic neuropathy.
A retrospective comparison study of 153 patients with nonspecific orbital inflammatory syndrome followed over a 24-month period found that the risk factors for multiple recurrences included age less than or equal to 16 years, bilateral disease, presence of optic nerve head edema or T-sign on B scan ultrasonography, sclerosis, a steroid taper over less than 4 weeks, and an underlying autoimmune disease in first-degree relatives (08). Moreover, an interval between the initial episode and first recurrence of 3 months or less was predictive of further recurrences.
Malignant orbital tumors. Primary orbital lymphoproliferative disorders are typically treated effectively with low-dose radiotherapy and appropriate eye shielding. The 5-year survival rate reaches 90% to 100% with 30 Gy, which causes infrequent side effects. A single-center retrospective study of 44 patients with orbital lymphoma treated with radiation therapy reported a 5-year local control rate of 98% and a 5-year regional control rate of 95% (31). Overall survival rate at 5 and 10 years was 76% and 61%, respectively. One patient developed a recurrence elsewhere after radiation of a lacrimal tumor. Thirteen (46%) of 28 patients treated without lens shielding developed cataracts, whereas only 4 (25%) of 16 patients treated with lens shielding developed cataracts.
Metastatic tumors in adults are usually treated with radiotherapy, chemotherapy, or both. Lack of resolution of the primary tumor after treatment usually portends a poor prognosis.
Orbital cellulitis. Orbital cellulitis has an excellent prognosis after antibiotic treatment. However, patients with orbital abscess or severe isolated sphenoid sinusitis are more likely to develop ophthalmoplegia and blindness (09).
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 a nonresponsive “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 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 greater than right. CT examination showed diffuse muscle enlargement with severe apical crowding.
The diagnosis was thyroid-related orbitopathy with compressive optic neuropathy. He was treated with prednisone 100 mg per 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 orbital apex and medial orbital wall was performed utilizing digital CT-driven 3D localization technology. This allowed safe, extensive, and precise decompression of both the apex and the mid- and anterior optic canal. Once this was performed, the superior, lateral, and inferior walls were decompressed through a lower lid transconjunctival approach. Postoperative CT demonstrated decreased apical congestion in the right (from steroid therapy) and left eye (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 was 20/50 in both eyes, and color plates were 10/15 bilaterally. The steroid taper was continued for several months, and the visual acuity remained reduced and was attributed to cataract.
Case 2. An 8-year-old girl was referred by her pediatrician for a 6-month history of painless left periocular swelling and progressive left upper lid ptosis. The patient’s mother had systemic lupus erythematosus. Best-corrected visual acuity was 20/20 in the right and left eye. There was no afferent pupillary defect. Color vision and ocular motility were normal in each eye. There was some periorbital edema in the left eye with a fixed palpable mass below the superior orbital rim. The left upper lid was ptotic by several millimeters, and the levator function (upper eyelid excursion from extreme downgaze to extreme upgaze) was severely reduced to 7 mm.
CT scan was performed because the differential diagnosis included orbital pseudotumor, malignancy, and necrotizing vasculitis.
CT showed a dense left superior lateral orbital mass. Careful examination of the CT showed bony changes in the bony cortex of the orbital roof. Urgent orbital biopsy was performed through a lid crease incision. Pathology demonstrated areas of inflammation and fibrosis consistent with orbital pseudotumor, but there was a prominence of infiltrative patches with small vessel vasculitis, with neutrophils and eosinophils. Preliminary diagnosis based on pathology was granulomatosis polyangiitis. The patient was referred to a pediatric rheumatologist for treatment. Treatment was commenced when the extensive preoperative work-up yielded a positive antineutrophil cytoplasmic antibody panel. There was no evidence of respiratory or renal involvement. The final diagnosis was limited granulomatosis polyangiitis. The patient was treated with a prolonged course of oral prednisone. After 6 weeks of 60 mg prednisone per day, the swelling and ptosis had virtually resolved.
Case 3. A 67-year-old man was referred by his ophthalmologist for evaluation of a proptotic right eye.
The patient stated that there had been progressive unilateral swelling around the right eye for more than 6 months. He also felt that the right eye was becoming more prominent. He finally presented for examination when he had diplopia in all fields of gaze. Best-corrected visual acuity was 20/30 in the right eye and 20/25 in the left eye, which was consistent with the degree of cataractous lens changes in both eyes. There was no afferent pupillary defect, and color vision was normal in both eyes. The globe was displaced superiorly by 3 mm. Hertel exophthalmometry measured 22.5 mm in the right eye and 19 mm in the left eye at a base of 99. (Hertel exophthalmometry is a method of measuring the protrusion of the cornea relative to the lateral orbital rim by a particular device. Upper limits of normal are defined based on sex and racial group. Any difference between eyes of greater than or equal to 2 mm is considered abnormal). Motility was severely limited, especially infraduction of the right eye. There was significant boggy edema to the lower lid, with a diffuse conjunctival chemosis (edema). Intraocular pressure in the right eye was 22 mm Hg and increased to 37 mm Hg with attempted upgaze. The rest of the ocular examination was within normal limits.
CT examination had been read at another facility as a well-defined intraconal orbital tumor. Axial cuts showed what appeared to be an intraconal or optic nerve tumor.
However, careful examination of the coronal images showed the mass to be somewhat inferior where the inferior rectus muscle should be located.
The clinical exam favored 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-related orbitopathy, a presumed diagnosis of orbital lymphoma or orbital myositis was made. Biopsy of the inferior rectus muscle was performed. Frozen touch prep was performed and read as 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.
Thyroid-related orbitopathy. Thyroid-related orbitopathy is an autoimmune inflammatory disease that results from auto-reactive T-lymphocytes attacking antigens shared by the thyroid gland and orbital tissues. T-lymphocytes trigger orbital fibroblast proliferation and secretion of glycosaminoglycans, leading to enlargement and dysfunction of the extraocular muscles as well as precipitating edema in the orbital tissues.
The main risk factor for thyroid-related orbitopathy is the development of hyperthyroidism, although a subset of patients may be hypothyroid or euthyroid. This condition is more common in African-Americans than it is in Asians or Caucasians. There may be an underlying genetic predisposition, as evidenced by a concordance rate of 20% to 40% among monozygotic twins and in more than 10% of siblings. Women are more susceptible to this condition than men, with a ratio of 7 to 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 perhaps it is the X-chromosome that influences the development of this condition.
Patients often report psychological stress prior to developing thyroid-related orbitopathy. Immunologic rebound hyperactivity related to stressful events or steroid-induced immune suppression has been theorized as a possible mechanism. Another proposed mechanism with minimal evidence is that infection triggers a cascade of autoimmune inflammatory response. There is strong evidence that smoking plays a role in development and progression, with odds ratios ranging from 7.7 to 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-related orbitopathy, perhaps by stimulating release of serum TSHr antibodies (37).
An infiltrative process of lymphocytes, plasma cells, and mast cells, as well as deposition of hydrophilic glycosaminoglycans and collagen, reflect an autoimmune inflammatory process. In the chronic phase, collagen deposition is accompanied by muscle degeneration and scarring. When the disease is in remission, fatty infiltration of the muscles persists.
There is potential evidence that the insulin-like growth factor-I receptor (IGF-IR) may play a role in the pathogenesis of thyroid-related orbitopathy. 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 might be potentially attenuated by inhibiting IGF-IR in active thyroid-related orbitopathy. A therapeutic trial of teprotumumab, a human IGF-IR inhibiting antibody, in patients with moderate-to-severe active thyroid-related orbitopathy indicates the potential effectiveness and safety of this drug (67).
In 1 study the levels of vitamin D in 292 patients with newly diagnosed Graves disease were significantly lower than in 2305 normal controls (53). There was no association with thyroid hormone levels or thyroid-related orbitopathy.
Orbital inflammatory syndrome. Idiopathic orbital inflammation is believed to be related to autoimmune or infectious processes. The typical histopathologic picture consists of diffuse and multifocal infiltration of mature lymphocytes, plasma cells, macrophages, and polymorphonuclear leukocytes. It is common to see a few eosinophils, but prominent eosinophilia is atypical and should raise the possibility of a specific vasculitis, such as Churg-Strauss (also known as eosinophilic granulomatosis with polyangiitis). Granulomatous inflammation and vasculitis are unusual and raise suspicion for other entities. Desmoplasia and fibrosis are atypical, being more characteristic of sclerosing orbital pseudotumor. In IgG4-related disease, the inflammatory process includes high serum IgG4 levels, histopathologic evidence of an abnormally high ratio of IgG4:IgG cells, as well as lymphocytic and plasmacytic infiltration, obliterative phlebitis, and storiform fibrosis (21). IgG4-related disease is believed to account for a subset of patients once labeled as idiopathic orbital inflammatory syndrome.
Orbital rhabdomyosarcoma. Children with localized orbital rhabdomyosarcoma now have a 5-year survival rate of 70% compared to 25% in the 1970s (46). Multiple risk factors were discovered over the years that were seen to play a role in the prognosis. For one, the embryonic subtype was shown to have a better prognosis than the other subtypes (17).
Orbital cellulitis. The most common cause of orbital cellulitis is underlying sinus infection. As children grow, the ostia that drain the paranasal sinuses remain constant in size, becoming less able to drain these sinuses, increasing the likelihood of infection. Ethmoid and maxillary sinus infections with a single aerobic agent are most common before 5 years of age. Mixed infections become more prevalent as the sphenoid and frontal sinuses become pneumatized. 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 10 years with the introduction of the vaccine, making Streptococcus species the predominant cause. Case reports document orbital cellulitis after periocular injections of anesthetic (10). Several cases of orbital cellulitis have been reported in association with glaucoma surgery (16).
Thyroid-related orbitopathy. A large review reported an annual age-adjusted incidence of 16 per 100,000 in women and 2.9 per 100,000 in men (06). The peak incidence is 5 years earlier in women than in men. The incidence of moderate to severe disease was reported at 16.1 cases per million per year (26.7 in women and 5.4 in men) (34). The reported prevalence of this disease in the general population is 0.1% to 0.3% (35).
There is a bimodal age peak in both men and women in the 40s and 60s. Although this disease is more common in women, it tends to be more severe in men. In 1 study, thyroid-related orbitopathy occurred in approximately 26% of patients with Graves disease, but it was severe in only 5.8% and affected the optic nerve in only 0.3% (71). Progression to severe orbitopathy occurred in 2.5% of patients within 18 months.
Type 1 orbitopathy occurs primarily in women (greater than 8:1), with an average age at of 36 years at diagnosis, whereas type 2 is slightly more common in women (1.5:1), with an average age of 52 years at diagnosis (49).
Orbital inflammatory syndrome. There is no reported incidence available for idiopathic orbital inflammatory syndrome. In IgG4-related disease, a study estimated a national annual incidence of 0.28 to 1.08 per 100,000 individuals (60). IGg4 disease accounted for approximately 21.6% of lymphoproliferative orbital disease in Japan (27).
Malignant orbital tumors. Not available.
Orbital cellulitis. Not available.
Thyroid-related orbitopathy. There is no known prevention, but cessation of smoking may help. Correcting hyperthyroidism and hypothyroidism with concurrent steroid and thyroid ablative therapy and early total thyroid ablation may also be helpful (05).
Orbital inflammatory syndrome. No prevention is available.
Malignant orbital tumors. No prevention is available.
Orbital cellulitis. Orbital cellulitis is best prevented with prompt treatment of bacterial sinusitis or any condition predisposing to infectious sinusitis, such as prophylactic antibiotics in immunocompromised children, sinus ostia enlargement, or drainage of chronic refractory sinusitis.
Thyroid-related orbitopathy and lymphoproliferative diseases are usually gradual in onset and painless, whereas orbital cellulitis, orbital inflammatory syndrome, and metastatic or pediatric malignant tumors have a rapid onset. Thyroid-related orbitopathy results in increased orbital fat and enlarged extraocular muscles and usually affects both orbits (although sometimes asymmetrically). Lymphoproliferative diseases are usually unilateral. They often cause significant periorbital edema or quiet infiltration. There is also frequently a displacement of the eye (“dystopia”).
Orbital cellulitis, orbital inflammatory syndrome, and malignant tumors in children have similar manifestations. Rhabdomyosarcoma can present with unilateral proptosis without concomitant signs of infection. Fever and a left-shifted leukocytosis are almost universal. Patients with orbital manifestations of undiagnosed leukemia or those in blast crisis may also have extremely elevated leukocyte counts. Orbital cellulitis is a unilateral process, and orbital inflammatory syndrome can be bilateral in up to 50% of pediatric cases. Neuroblastoma and Ewing sarcoma often involve both orbits. CT readily differentiates the malignant tumors, but orbital inflammatory syndrome and orbital cellulitis often appear similar in the absence of an abscess. In cases where history, vital signs, and laboratory studies do not differentiate between sterile inflammation and infection, a 24-hour trial of intravenous antibiotics is in order. Orbital cellulitis responds rapidly to antibiotics, whereas orbital inflammatory syndrome will continue to smolder or progress. Any systemic vasculitis or autoimmune disease can affect the orbit and mimic orbital inflammatory syndrome. CT is almost always indicated.
Thyroid-related orbitopathy. The appropriate laboratory tests include assessment of thyroid-stimulating hormone, T3, and T4 levels. If the patient manifests clinical hyperthyroidism, one should order thyroid-stimulating antibodies. A study reported the benefits of a novel Mc4/TSI bioassay in assessing activity and severity (41). These authors found that Mc4/TSI demonstrated greater sensitivity and specificity for detection of TSHr autoantibodies than did conventional thyroid stimulating immunoglobulin (TSI) bioassays. A further advantage of Mc4/TSI is the direct assessment of TSI in unfractionated patient serum in 1 day, compared to traditional bioassays that require several days of culturing or preparation.
CT imaging provides information on potential optic nerve compression, particularly in those with evidence of visual dysfunction. CT will guide potential orbital and orbital apex decompression. CT is preferred over MRI if urgent bony decompression surgery is planned. MRI, however, is useful in visualization of structures and the degree of crowding at the orbital apex.
The appropriate ophthalmologic evaluation for patients with thyroid disease includes best-corrected visual acuity, pupil size and reactivity, color vision, visual field (automated threshold perimetry), evaluation of ocular motility and alignment, Hertel exophthalmometry, measurement of intraocular pressure, slit lamp, and ophthalmoscopic examinations. Patients with active disease should be evaluated every few weeks and instructed to return immediately if they perceive changes in their vision.
Orbital inflammatory syndrome. Apart from thorough ophthalmic examinations, patients should undergo complete blood count and blood cultures. Treatment with broad-spectrum antibiotics may be initially necessary. When entertaining the diagnosis of orbital inflammatory syndrome, a full vasculitis work-up should be done, including complete blood count with differential (eosinophilia or other abnormalities), urinalysis (looking for protein and true red cells seen with kidney disease), rheumatoid factor, antinuclear antibodies, antineutrophil cytoplasmic antibody panel, serum angiotensin-converting enzyme, lysozyme, and chest x-ray. In addition, CT scanning is necessary to rule out rhabdomyosarcoma or other processes. A biopsy is indicated in patients with recurrent or persistent disease (45). However, if the patient presents with a lesion that is amenable to biopsy without risk of visual function, biopsy may be considered from the start. Exceptions are scleritis, myositis, and thyroid-related orbitopathy, in which a delay in starting immunosuppressive treatment may result in visual dysfunction (57).
An online survey of experts reached a consensus that: (1) tissue biopsy was appropriate in suspected nonmyositic idiopathic orbital inflammatory syndrome and in suspected malignancy; and (2) an initial trial of systemic corticosteroids was appropriate in suspected myositic idiopathic orbital inflammatory syndrome (47). A retrospective case series of 93 patients with extraocular muscle enlargement who underwent extraocular muscle biopsy indicated that predictors of malignancy were a previous prior history of malignancy and diplopia (13). On the other hand, pain and lid erythema were predictors of benign nonmalignant conditions.
IgG4-related disease should be on the differential diagnosis for idiopathic orbital inflammatory syndrome. Diagnosis of this condition is based on a typical clinical scenario, supportive laboratory data, expected radiological characteristics, and distinct histopathological and immunohistochemical features. The 3 major histopathological features associated with this condition are: (1) dense lymphoplasmacytic infiltrate with T lymphocytic predominance; (2) fibrosis arranged in a storiform (spiral or whorled) pattern; and (3) obliterative phlebitis. Two of the 3 major histological features are required for diagnosis.
Malignant orbital tumors. Diagnostic biopsy is usually indicated. Flow cytometry of blood and cerebrospinal fluid and bone marrow biopsy should be performed.
Orbital cellulitis. In addition to a complete blood count, blood cultures, and pharyngeal cultures, a complete eye examination and orbital imaging are necessary to rule out tumors and abscess formation. Vision, pupil, color vision, confrontation visual fields, and ocular motility checks must be frequent (every 6 to 12 hours) when treatment is initiated and until significant resolution is noted. Consultation by an otolaryngologist may be necessary for patients with concomitant sinus disease.
Orbital rhabdomyosarcoma. Imaging studies such as CT and MRI in conjunction with clinical signs aid in the diagnosis; however, diagnostic biopsy is the gold standard. Subsequent to the biopsy, the tumor must be staged according to the classification systems of the Intergroup Rhabdomyosarcoma Study (IRS) and the American Joint Commission on Cancer manual.
Thyroid-related orbitopathy. Treatment of thyroid 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% progress (44).
Thyroid function must be normalized, as patients are more likely to express severe disease when the underlying thyroid hormones are abnormal (02). Monitoring of thyroid function tests every 4 to 6 weeks by the endocrinologist is crucial in ensuring normalization of hormones particularly in the early stages. There is no evidence to suggest that thyroid surgery or antithyroid medications influence the evolution (36). Disease can be precipitated or worsened after radioactive iodine treatment in about 15% of treated patients unrelated to dose (32). The risk has been shown to be reduced with a short course of steroids (0.3 to 0.5 mg/kg) tapered daily, and by avoiding a hypothyroid state after iodine treatment (05). A retrospective longitudinal cohort study found that the risk of developing thyroid-related orbitopathy was reduced substantially in patients who underwent thyroidectomy alone or with antithyroid medications than in patients who underwent radioactive iodine ablation (69).
Smoking is a well-established independent risk factor for activity and severity. It is dose dependent. Even past smokers have a relatively worse response to immune-modulating therapy (82).
Patients should be encouraged to lubricate the eyes during the day and use ointment at night in case of lagophthalmos. Sunglasses and slight elevation of the head of the bed when going to sleep can be helpful. One study found that topical cyclosporine treatment improves dry eye and preserves conjunctival epithelial cells (22).
Patients with moderate degrees of inflammation may be treated with immune modulating therapy in the active stage and with eyelid and other orbital surgery in the inactive stage (14).
One study showed improvement in 82% of patients receiving intravenous steroids compared to 53.4% of patients receiving oral steroids (83). 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. Another retrospective study compared high dose intravenous steroids (cumulative dose 9 to 12 gm) to low-dose intravenous steroids (cumulative dose 4.5 gm) and showed no difference in the safety profile or efficacy (72). If there are contraindications to intravenous steroids, oral steroids can be used as an alternative. Another study found orbital steroid injection for thyroid-related orbitopathy to be safe and effective when compared to oral steroid ingestion, with an added benefit of eliminating adverse effects associated with oral prednisone (01).
A single-center retrospective study of patients treated with intravenous steroids found that early restoration of the euthyroid state was significantly correlated with a better outcome (75).
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 methotrexate (70), a combination of cyclosporine A and steroids, azathioprine, or rituximab. However, rituximab showed less uniform benefit in 2 randomized controlled trials, perhaps due different study designs (59; 68). A more recent metaanalysis of rituximab treatment for thyroid-related orbitopathy found that it reduced the clinical activity score and improved laboratory markers, including thyrotropin receptor antibody, thyroid-stimulating hormone, and interleukin-6 levels (74). A metaanalysis 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-related orbitopathy (63).
There is some evidence of benefit of tocilizumab, adalimumab, or etanercept (04; 52; 78). Other promising treatments include TSHr antagonists, either as small molecule-ligand antagonists of TSHr or as monoclonal TSHr blocking antibodies (18).
One study showed that selenium 100 mg twice daily for 6 months improved quality of life and reduced the rate of progression of ophthalmic manifestations (42). 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 active thyroid-related orbitopathy. A retrospective study compared 144 patients treated with steroids alone to 105 patients treated with a combination of steroids and radiation therapy (62). In this 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.
Lid and orbital surgery is useful in inactive disease and in active disease with compressive optic neuropathy. Four procedures are used: (1) orbital decompression, (2) extraocular muscle surgery, (3) eyelid malposition surgery, and (4) removal of excess skin and herniated orbital fat.
The indications for orbital decompression include corneal exposure, restoration of the globe position, optic neuropathy secondary to compressive effects from enlarged extraocular muscles, and severe proptosis causing eyelid entrapment. These procedures may be followed by extraocular muscle and lid surgeries.
Patients who develop compressive optic neuropathy must be treated urgently. High dose intravenous steroids are a reasonable initial therapy but most patients will require orbital decompression.
Exposure keratopathy resistant to aggressive lubrication invites the use of moisture chambers, botulinum toxin, lid recession surgery, and tarsorrhaphy. If these measures are not successful, orbital decompression may be carried out.
Orbital inflammatory syndrome. Systemic steroids are the first-line treatment modality. The usual initial dose is 1 mg/kg oral prednisone. Unfortunately, relapse after withdrawal of steroids is common. Recurrence may be the result of inadequate suppression of immune activation. In 1 report of 65 patients, 41 (63%) represented treatment success, with complete symptom relief at the time of the last follow-up, and 24 (37%) represented treatment failure, with partial or no relief of symptoms (81). Other treatment modalities include nonsteroidal anti-inflammatory agents, low-dose radiotherapy in conjunction with steroids, and surgical debulking. Patients with relapsing and steroid-unresponsive conditions usually respond well to low-dose orbital radiation. Short-duration pulsed chemotherapy has been successfully and safely utilized (with limited numbers) for sclerosing pseudotumor. Exenteration has also rarely been used in such cases (81).
One study evaluated the use of infliximab in 7 patients with chronic and difficult-to-control idiopathic orbital myositis (20). All patients had some positive response without untoward effects after a mean follow-up of 15.7 months (range, 4 to 31 months). Another study reported methotrexate to be a well-tolerated and beneficial in patients who failed to improve after steroid therapy and radiotherapy (65).
IgG4-related disease is treated with steroids. Refractory cases can be treated with rituximab or radiation therapy.
Malignant orbital tumors. Treatment is directed at the specific tumor type. Enucleation and exenteration were common treatments until the early 1970s, when they were supplanted by chemotherapy and radiation therapy. Based on the seminal works of the Intergroup Rhabdomyosarcoma Study (IRS), medications such as vincristine and actinomycin D are now used with or without radiation therapy (50). Tumor recurrence may necessitate exenteration. A retrospective study of 11 patients with orbital lymphoma treated with radiation at a median dose of 25.5 Gy found a 5-year local control rate of 98% and a 5-year regional control rate of 91% (31). Freedom from disease at 5 and 10 years was 70% and 55%, respectively. Cataracts developed in 17 patients but were less common when a lens-shielding technique was used. A robust retrospective study of 81 patients with low-grade orbital lymphoma who received local therapy with a median of 30 G found a local control rate of 100%, but 5% of patients experienced a disease relapse elsewhere (79). Cumulative acute toxicity rates were 51% (mainly erythema and conjunctivitis), and late toxicity rates were 8% (mainly cataract). The lens-sparing technique was associated with a significant reduction in cataract rate.
Orbital cellulitis. Treatment consists largely of anti-infectives. In 1 report from a tertiary care center, patients aged 9 years or younger who had a subperiosteal abscess were successfully treated with intravenous antibiotics in 93% (Garcia and Harris 2000). A large abscess may be an indication for surgical drainage. Patients aged 9 to 15 years who mixed organism infections of nonethmoid origin may more often 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.
Thyroid-related orbitopathy. Graves disease can worsen in the first trimester of pregnancy and immediately postpartum (43). Aggressive antithyroid treatment may be necessary to save the fetus and mother. Orbitopathy should be treated conservatively in the same manner as in the nonpregnant state. However, medications, surgery, or radiation need to be discussed with the endocrinologist, ophthalmologist, and obstetrician to ensure that there are no contraindications.
Orbital inflammation syndrome. No information is available.
Malignant orbital tumors. No information is available.
Orbital cellulitis. Not applicable.
Thyroid-related orbitopathy. Graves disease can result in calcium and vitamin D deficiency, with a higher incidence of postoperative tetany, particularly in the winter months (80).
Orbital inflammation syndrome. No information is available.
Malignant orbital tumors. No information is available.
Orbital cellulitis. No information is available.
Danah Albreiki MBBS
Dr. Albreiki of the Ottawa Eye Institute has no relevant financial relationships to disclose.See Profile
Jonathan D Trobe MD
Dr. Trobe of the University of Michigan has no relevant financial relationships to disclose.See Profile
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