Thyroid-Associated Orbitopathy

Updated: Sep 30, 2016
  • Author: Edsel Ing, MD, MPH, FRCSC; Chief Editor: Hampton Roy, Sr, MD  more...
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Overview

Overview

Thyroid-associated orbitopathy (TAO), frequently termed Graves ophthalmopathy, is part of an autoimmune process that can affect the orbital and periorbital tissue, the thyroid gland, and, rarely, the pretibial skin or digits (thyroid acropachy). [1, 2, 3] Although the use of the term thyroid ophthalmopathy is pervasive, the disease process is actually an orbitopathy in which the orbital and periocular soft tissues are primarily affected with secondary effects on the eye. See the images below.

Long-standing thyroid ophthalmopathy with typical Long-standing thyroid ophthalmopathy with typical features of lid retraction (upper and lower) and scleral show with proptosis. This patient's chief complaint was binocular vertical diplopia. A small right hypotropia was observed on alternate cover testing.
Thyroid acropachy imitates the appearance of clubb Thyroid acropachy imitates the appearance of clubbing and is an uncommon finding in patients with thyroid ophthalmopathy. This patient required bilateral orbital decompression and strabismus surgery.

Thyroid-associated orbitopathy may precede, coincide, or follow the systemic complications of dysthyroidism. The ocular manifestations of thyroid-associated orbitopathy include eyelid retraction, proptosis, chemosis, periorbital edema, and altered ocular motility with significant functional, social, and cosmetic consequences. Of those patients affected, 20% indicate the ocular morbidity of this condition is more troublesome than the systemic complications of dysthyroidism.

The annual incidence rate of thyroid-associated orbitopathy has been estimated at 16 cases per 100,000 women and 2.9 cases per 100,000 men in one rural Minnesota community. [4] There appears to be a female preponderance in which women are affected 2.5-6 times more frequently than men; however, severe cases occur more often in men than in women. In addition, most patients are aged 30-50 years, with severe cases appearing to be more frequent in those older than 50 years.

Although most cases of thyroid-associated orbitopathy do not result in visual loss, this condition can cause vision-threatening exposure keratopathy, troublesome diplopia, and compressive optic neuropathy. Therefore, although the prognosis is generally favorable for patients with this condition, and most patients do not require surgical intervention, [5, 6] all clinicians should be able to recognize thyroid-associated orbitopathy.

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Etiology

The thyroid gland itself does not cause thyroid-associated orbitopathy (TAO), and regulation of thyroid function does not abort this condition. Rather, the thyroid gland, eye muscles, and pretibial skin are especially subject to the autoimmune attack. However, restoration of the euthyroid state (with antithyroid drugs and thyroxine) may improve the eye status to some extent.

Thyroid state and irradiation

Many patients with thyroid-associated orbitopathy are hyperthyroid, but euthyroidism (20%), Hashimoto thyroiditis, thyroid carcinoma, and neck irradiation are also associated with thyroid-associated orbitopathy. Even if the patient is euthyroid, thyroid-associated orbitopathy may progress. In patients who are hyperthyroid, the eye signs of thyroid-associated orbitopathy usually develop within 18 months of dysthyroidism; very often, they develop concurrently.

Radioactive iodine

Although somewhat controversial, several publications have suggested that thyroid ablation with orally ingested radioactive iodine-131 (RAI) (131 I) may exacerbate thyroid-associated orbitopathy compared with antithyroid drugs or surgical ablation. However, several studies have not shown that radioiodine is a significant risk for initiation or progression of mild thyroid-associated orbitopathy. [7, 8]

131 I is believed to cause a release of thyroid antigens. In a study by Bartalena, approximately 15% of patients treated with only radioactive iodine developed or had worsening of thyroid-associated orbitopathy. [9] However, some authors feel the threshold for diagnosis of thyroid-associated orbitopathy was low (eg, ocular irritation). In contrast, none of the patients treated with both radioactive iodine and prednisone had progression of thyroid-associated orbitopathy, and two thirds showed improvement. [9] Only 3% of patients treated with methimazole showed worsening of thyroid-associated orbitopathy.

Diseases associated with thyroid-associated orbitopathy

Autoimmune diseases such as myasthenia gravis, Addison disease, vitiligo, and pernicious anemia have been described with thyroid-associated orbitopathy. In one study, 8% of patients with this condition had positive acetylcholine receptor antibodies [10] ; however, at 4.5-year follow-up visits, none of the patients with positive serology was identified clinically to have myasthenia gravis.

Yersinia enterocolitica infection has been also associated with thyroid-associated orbitopathy.

Smoking

Thyroid-associated orbitopathy is associated strongly with smoking [11, 12] ; the more severe the eye disease, the stronger the association. In one study, smokers of European ethnicity had a 2.4 times increased risk for this condition compared with their Asian counterparts. Active smokers require more strabismus surgery than nonsmokers, independent of orbital decompression surgery. [13]

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Pathophysiology

In simplest terms, the underlying pathophysiology of thyroid-associated orbitopathy is thought to be an antibody-mediated reaction against the thyroid-stimulating hormone (TSH) receptor with orbital fibroblast modulation of T-cell lymphocytes. T-cell lymphocytes are believed to react against thyroid follicular cells with shared antigenic epitopes in the retroorbital space. An active phase of inflammation is initially present.

Lymphocytic infiltration, fibroblast reaction, and increased orbital volume

Lymphocytic infiltration of the orbital tissue causes a release of cytokines (eg, tumor necrosis factor [TNF], interleukin 1 [IL-1]) from CD4+ T cells stimulating the orbital fibroblasts to produce mucopolysaccharides, which, by hyperosmotic shift, cause tissue edema in the extraocular muscles.

Fibroblasts are believed to be the target and effector cells in thyroid-associated orbitopathy. Fibroblasts are extremely sensitive to stimulation by cytokines and other soluble proteins and immunoglobulins that are released in the course of an immune reaction. The cytokines activate previously quiescent fibroblasts to secrete hyaluronic acid, a glycosaminoglycan. Doubling the hyaluronic acid content in the orbital tissue causes a 5-fold increase in the tissue osmotic load. In addition, preadipocyte fibroblasts are influenced to transform into adipocytes, especially in young patients.

The orbit can be described as a pear-shaped box with an anterior opening; the stalk of the pear represents the optic nerve. In thyroid-associated orbitopathy, the increase in orbital volume from the extraocular muscles and fat causes forward protrusion (proptosis or exophthalmos) and, occasionally, optic nerve compression at the narrow posterior apex of the orbit. The edema results in tissue damage and fibrosis, with restriction in extraocular motility and lagophthalmos.

Usually within 1-2 years of the onset of orbital involvement, the inflammation settles to a more quiescent, fibrotic phase predominated by scarring of the orbital tissues.

Potential pathoimmunology

Thyroid-associated orbitopathy may be part of a more generalized disorder of connective tissue and striated muscle. [14] A more extensive discussion on the pathoimmunology of thyroid-associated orbitopathy is beyond the scope of this article. However, some of the research in this field is outlined below.

The insulinlike growth factor 1 receptor (IGF-1R) is an autoantigen that may be important in thyroid-associated orbitopathy, because of its aberrant expression by thyroid-associated orbitopathy fibroblasts, the promotion of T-cell recruitment, and the presence of circulating activating autoantibodies. T helper 2 cytokines (IL-4 and IL-13) may induce the expression of 15-lipoxygenase-1, with upregulation in the production of 15-hydroxyeicosatetraenoic acid (15-HETE), causing tissue activation and remodeling.

Cyclooxygenase 2 (COX-2) is expressed at higher levels in the orbital fibroadipose tissues of thyroid-associated orbitopathy. There is a positive correlation with increasing severity of orbital disease, suggesting a possible relationship with COX-2 expression and orbital inflammation in thyroid-associated orbitopathy.

Variants in the IL-23R gene are strongly associated with Graves ophthalmopathy (or thyroid-associated orbitopathy). These variants may predispose to this condition by changing the expression and/or the function of IL-23R, thereby promoting a proinflammatory signaling cascade.

The role of clathrin-mediated signalling pathways, [15] palmitate, [16] and Thy-1 surface markers [17] on orbital fibroblasts as they relate to the pathogenesis of TAO remains to be seen.

Peroxisome Proliferator-Activated Receptor (PPAR)- γ expression has been shown in thyroid tissue and extraocular muscles. [18] PPAR-γ agonists, such as the oral hypoglycemic pioglitazone, expand the orbital fat in diabetic patients with or without thyroid-associated orbitopathy. Although pioglitazone (a PPAR-γ agonist) has been suggested as a treatment for autoimmune thyroid disease [18] , orbital fat expansion (via adipocyte proliferation) in patients with thyroid-associated orbitopathy may be problematic.

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Clinical Evaluation

Thyroid-associated orbitopathy (TAO) usually has a self-limited course over 1 or more years. Stable disease can occasionally reactivate, but this is uncommon.

Signs and symptoms may vary and depend on the stage that the patient is experiencing. Initially, an acute or subacute stage of active inflammation occurs. Later, the patient progresses to a more quiescent stage, which is characterized by fibrosis. [19]

Symptoms

Patients may complain of the following ocular symptoms:

  • Dry eyes
  • Puffy eyelids
  • Angry-looking eyes
  • Bulging eyes
  • Diplopia
  • Visual loss
  • Field loss
  • Dyschromatopsia
  • Photopsia on upgaze
  • Ocular pressure or pain

Hyperthyroidism symptoms include the following:

  • Tachycardia/palpitations
  • Nervousness
  • Diaphoresis
  • Heat intolerance
  • Skeletal muscle weakness
  • Tremor
  • Weight loss
  • Hair loss
  • Irritability
  • Goiter

Hypothyroidism symptoms include the following:

  • Bradycardia
  • Drowsiness
  • Poor mentation
  • Muscle cramps
  • Weight gain
  • Dry skin
  • Husky voice
  • Depression
  • Cold intolerance

Numerous eponymous signs are associated with thyroid-associated orbitopathy, including the following:

  • Vigouroux sign (eyelid fullness)
  • Stellwag sign (incomplete and infrequent blinking)
  • Grove sign (resistance to pulling down the retracted upper lid)
  • Joffroy sign (absent creases in the forehead on superior gaze)
  • Möbius sign (poor convergence)
  • Ballet sign (restriction of one or more extraocular muscles)

Proptosis and pseudoptosis

Thyroid-associated orbitopathy is the most common cause of unilateral and bilateral proptosis in adults. Proptosis or exophthalmos occurs, because the orbital contents are confined within the bony orbit, and decompression can only occur anteriorly. Unilateral proptosis of thyroid-associated orbitopathy usually reflects asymmetric muscle involvement.

Retropulsion (digital palpation of the globes through closed eyelids) is a useful test; it is decreased in patients with severe thyroid-associated orbitopathy. Various exophthalmometers can be used to measure orbital protrusion.

Pseudoptosis and true ptosis may be seen in patients with thyroid-associated orbitopathy. Pseudoptosis may be observed if contralateral lid retraction is present. Ptosis may occur with thyroid-associated orbitopathy if levator dehiscence is present. Patients with thyroid-associated orbitopathy may have concurrent myasthenia gravis, which may lead to ptosis.

Lacrimal gland enlargement is not uncommon.

Lid retraction, lid lag, and glabellar furrows

Normally, the upper lid is located 1-1.5 mm below the superior limbus, and the lower lid is located at the inferior limbus.

Upper lid retraction (Dalrymple sign), often with temporal flare and scleral show, is the most common ocular sign of thyroid-associated orbitopathy. This sign is an important differentiating feature to note in all patients with proptosis. Mechanisms for upper lid retraction include proptosis, sympathetic drive of the Muller muscle, upgaze restriction, fibrosis of the levator muscle, and contralateral ptosis (myasthenia).

Lid retraction may occur in both the upper and lower lids because of a sympathetically innervated tarsal muscle in both lids. Upgaze restriction, levator fibrosis, and very severe proptosis are other possible causes of lid retraction.

If eyelid retraction is absent, then thyroid-associated orbitopathy may be diagnosed only if: (1) proptosis, optic nerve involvement, or restrictive extraocular myopathy is associated with thyroid dysfunction or abnormal regulation, and (2) no other confounding ophthalmic features are apparent.

Lid lag on downgaze (von Graefe sign) is another important feature of thyroid-associated orbitopathy. While slowly moving the fixation object from upward to downward, the examiner should observe if the eyelid lags behind the globe on downgaze.

Other lid signs include lid edema and glabellar furrows. A statistically significant association of deep glabellar rhytids with thyroid ophthalmopathy has been described. This is presumably caused by hypertrophy of brow depressor muscles compensating for lid retraction.

Corneal and conjunctival findings

Anterior segment signs in thyroid-associated orbitopathy include superficial punctate keratitis, superior limbic keratoconjunctivitis, conjunctival injection usually over the rectus muscle insertions, and conjunctival chemosis.

With severe proptosis, corneal exposure with frank corneal ulceration may occur. Superior limbic keratoconjunctivitis is a chronic, often recurrent condition of ocular irritation, which some attribute to mechanical trauma transmitted from the upper eyelid to the superior bulbar and tarsal conjunctiva. Superior limbic keratoconjunctivitis has been a purported prognostic marker for severe thyroid-associated orbitopathy.

The corneal light reflexes should be examined closely, because asymmetric proptosis and lid retraction may mask the true relative positions of the globes.

Orbital muscle involvement

Strabismus is common, and it often presents as hypotropia or esotropia, because the inferior rectus muscle and the medial rectus muscle are the most commonly involved extraocular muscles in thyroid-associated orbitopathy.

The restrictive myopathy sometimes can be confirmed with forced ductions or elevated intraocular pressure with eye movement (eg, upgaze in hypotropic patients) if a diagnosis of thyroid-associated orbitopathy is not revealing.

Inferior rectus muscle restriction may mimic double elevator palsy.

Although esotropia is a more common finding with thyroid-associated orbitopathy, convergence insufficiency has been described. In patients with thyroid-associated orbitopathy and exotropia, the possibility of concurrent myasthenia gravis should be considered.

Pseudo-fourth nerve palsies have been described with thyroid-associated orbitopathy.

Optic nerve and fundus findings

Compressive optic neuropathy may present with blurry vision, visual loss, dyschromatopsia, or field loss. Patients with optic nerve compression may not have marked proptosis or have seemingly mild proptosis, but they usually show markedly decreased retropulsion (tight orbits). In addition, most cases of compressive thyroid optic neuropathy occur without visible optic nerve edema. For this reason, documenting visual acuity, color vision, and the presence or absence of a relative afferent pupillary defect is important during each visit.

Choroidal folds can occur with thyroid associated orbitopathy.

Increased intraocular pressure

Glaucoma may result from decreased episcleral venous outflow. Because of restrictive myopathy, intraocular pressure may rise more than 8 mm Hg on upgaze.

Cutaneous findings

Pretibial dermopathy and thyroid acropachy (which mimics the appearance of clubbing) are less commonly encountered dramatic, cutaneous signs of dysthyroidism. See the images below.

Thyroid acropachy imitates the appearance of clubb Thyroid acropachy imitates the appearance of clubbing and is an uncommon finding in patients with thyroid ophthalmopathy. This patient required bilateral orbital decompression and strabismus surgery.
Pretibial myxedema and thyroid acropachy. Pretibial myxedema and thyroid acropachy.
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TAO Classification

Numerous classification systems for thyroid-associated orbitopathy (TAO) exist, but they all have shortcomings.

Types I and II

The simplest classification for thyroid-associated orbitopathy is type I and type II; these 2 types are not mutually exclusive. Type I is characterized by minimal inflammation and restrictive myopathy. Type II is characterized by significant orbital inflammation and restrictive myopathy.

NOSPECS

The Werner NOSPECS classification system (and its modifications) is one of the most commonly known systems and is used in many endocrine studies. NOSPECS uses a mnemonic to describe the presence or absence of signs or symptoms (NO) and grade and classify the severity and rank order of various clinical features (SPECS) (s oft-tissue involvement, p roptosis, e xtraocular muscle involvement, c orneal involvement, and s ight loss).

Unfortunately, the NOSPECS classification has some weaknesses that may limit its prognostic value. Patients may fall into more than 1 particular class, and they may not progress in an orderly fashion from class 1 to class 6. In addition, patients with visual loss from compressive optic neuropathy may not show marked proptosis or other signs of severe disease.

VISA and EUGOGO

To determine disease severity, the grading systems most frequently employed in clinical studies of TAO are the VISA Classification (vision, inflammation, strabismus, and appearance), especially in North America, and the European Group of Graves’ Orbitopathy (EUGOGO) Classification in Europe. Both grading criteria have roots in the NOSPECS and clinical activity score classifications. [20]

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Diagnostic Considerations

Orbital and preseptal cellulitis are included in the differential diagnosis when evaluating a patient with suspected thyroid-associated ophthalmopathy (TAO). In orbital cellulitis, the onset of proptosis is often quicker, and the patient has other evidence of infection (eg, fever, leukocytosis). On neuroimaging, the paranasal sinuses often are opacified.

In patients with carotid cavernous fistula, the patient may have a cranial bruit, and the dilated episcleral vessels extend to the limbus.

Orbital inflammatory syndrome (orbital pseudotumor) is often more painful than thyroid-associated orbitopathy with faster progression; the tendons are involved in orbital myositis. Orbital inflammatory syndrome is associated more often with ptosis than lid retraction. Isolated enlargement of the lateral rectus muscle is more likely to represent a process such as orbital inflammatory syndrome rather than thyroid-associated orbitopathy.

Other causes of thickened muscles include sarcoidosis, metastases, lymphoma, amyloid, and acromegaly. Orbital ultrasound can quickly confirm if the patient has thickened muscles or an enlarged superior ophthalmic vein.

Dorsal midbrain syndrome (Parinaud syndrome) is a condition in which patients may present with lid retraction and upgaze problems. In contrast to thyroid-associated orbitopathy, in Parinaud syndrome, the globes elevate on the doll's head maneuver and the eye tends not to be injected or proptotic.

 

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Thyroid Disease Studies

In screening for thyroid disease, the combination of free T4 (thyroxine) and TSH (thyroid-stimulating hormone) or serum TSH (thyrotropin) are highly sensitive and specific. However, because of cost, some authors recommend initially only using the TSH to screen for thyroid disease.

Serum TSH (thyrotropin) is useful to establish a diagnosis of hyperthyroidism or hypothyroidism. Usually, the TSH is low in hyperthyroidism and high in hypothyroidism.

TSH receptor assays

The nomenclature for the various TSH receptor assays is confusing and inconsistent. Assays that measure the binding of TSH to a solubilized receptor are often referred to as TRAb (thyroid receptor antibody), TBII (TSH-binding inhibitor immunoglobulin), and LATS (long-acting thyroid stimulator) assays. Assays that measure the ability of immunoglobulin G (IgG) to bind to the TSH receptor on cells and to stimulate adenylate cyclase production have generally been referred to as the TSI (thyroid-stimulating immunoglobulin) assays. TSIs may show more significant association with the clinical features of TAO than TBII and may be regarded as functional biomarkers for TAO. [21]

Other blood tests that may be useful include calculated free T4 (thyroxine) index, thyroid-stimulating immunoglobulin, antithyroid antibodies, and serum T3 (triiodothyronine). The introduction of direct assays for TSH, free T4, and free T3 has superseded the usefulness of total T4 and T3 resin uptake testing.

Thyroid peroxidase studies

Thyroid peroxidase antibodies and antibodies to thyroglobulin may be useful when trying to associate eye findings with a thyroid abnormality, such as euthyroid Graves disease.

The thyroid peroxidase test is also called the antimicrosomal antibody test and the antithyroid microsomal antibody test. The antithyroglobulin test is also called the antithyroid antibody test.

The serum level of hyaluronan is not a sensitive indicator of its presence within the extraocular muscles.

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CT Scanning and MRI

If the diagnosis of thyroid-associated orbitopathy (TAO) can be established clinically, then it is not necessary to routinely order a computed tomography (CT) scan or a magnetic resonance image (MRI). However, if these studies are required, obtain axial and coronal views. [22] MRI is more sensitive for showing optic nerve compression, whereas CT scanning is performed before bony decompression, because it shows better bony architecture.

Neuroimaging usually reveals thick muscles with tendon sparing. The inferior rectus muscle and the medial rectus muscle are usually involved. Bilateral muscle enlargement is the norm; unilateral cases usually represent asymmetric involvement rather than normality of the less involved side.

Isolated rectus muscle involvement may occur in up to 6% of patients; in this subgroup of patients, the superior rectus muscle may be the most frequently involved muscle. Isolated lateral rectus muscle enlargement without other evidence of muscle enlargement is uncommon in thyroid-associated orbitopathy and suggests another disease process (eg, orbital myositis).

Neuroimaging may also show a dilated superior ophthalmic vein. In addition, apical crowding of the optic nerve is well visualized (see the image below). Occasionally, the proptosis of thyroid-associated orbitopathy results in straightening of the optic nerve.

Axial computed tomography (CT) scan in a patient w Axial computed tomography (CT) scan in a patient with congestive thyroid orbitopathy. The recti muscles are thickened with apical compression. The tendons are spared.

On CT scans, orbital fat density is higher in TAO patients, and it is negatively correlated to fat volume but positively correlated to muscle volume and muscle density. [23]

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Histologic Features

Findings on histologic examination of thyroid-associated orbitopathy include the following:

  • Fibrosis with degenerative changes in the eye muscles
  • Lymphocytic cell infiltration
  • Enlargement of fibroblasts
  • Accumulation of mucopolysaccharides
  • Interstitial edema
  • Increased collagen production
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Outpatient Management

Most patients with thyroid-associated orbitopathy (TAO) can be observed; the follow-up interval depends on disease activity.

Monitor for visual loss from corneal exposure and optic neuropathy and for strabismus development. The author does not recommend the use of eye exercises for patients with severe restrictive strabismus; doing so may elevate intraocular pressure.

Visual field and color vision testing may help in early detection of visual loss.

In patients with diplopia, prisms may be beneficial to those with small-angle or relatively comitant deviations. Tape occlusion of one lens or segment of the glasses may be helpful. If this does not work, try an occluder or vaulted eye patch (with care not to touch the cornea or compress the orbit).

Patients with dry eye symptoms or corneal exposure should use artificial tears during the day, lubricating ointment at night, and consider punctal plugs. 

Patient education

Inform patients that thyroid-associated orbitopathy usually runs a self-limited but prolonged course over 1 or more years. Patients should also realize that no immediate cure is available. [24]  Encourage patients to stop smoking to decrease the risk of congestive orbitopathy.

Sleeping with the head of the bed elevated may decrease morning lid edema.

For patient education information, see the Thyroid & Metabolism Center as well as Thyroid Problems.

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Steroids

Systemic steroids are usually reserved for patients with severe inflammation or compressive optic neuropathy in thyroid-associated orbitopathy (TAO). The consensus statement of the European Group on Graves' Orbitopathy (EUGOGO) suggests 4.5-5 g intravenous methylprednisolone for patients with advanced thyroid-associated orbitopathy. [3]  Liver failure does not usually occur in patients using less than 8 g of methylprednisolone.

Steroids may decrease the production of mucopolysaccharides by the fibroblasts. Pulse intravenous steroids (eg, methylprednisolone 1 g every other day for 3-6 cycles) can be considered but may only marginally improve long-term disease outcome. Thus, if necessary, high-dose steroids and higher intravenous doses are given for compressive optic neuropathy. If no response occurs after 48-72 hours, steroids probably will not work; at this point, the patient should have surgical decompression and maintain steroids.

Adjunctive rituximab, cyclosporine, octreotide, and intravenous immunoglobulin (IVIg) are less common modalities of medical treatment for optic nerve compression. If a good steroid response occurs, orbital radiation may be considered. In severe cases of thyroid-associated orbitopathy, combined steroids, radiation, and surgery may be required. In patients with worsening TAO despite orbital decompression, intranasal steroids can be used.

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Potential Medical Therapies

The antioxidant selenium (200 mcg daily) was shown in one study to help patients with mild Graves orbitopathy. [25] However, if thyroid-associated orbitopathy (TAO) patients are not selenium deficient, they may not benefit from supplementation.

Quercetin, a natural plant product found in food such as capers, may inhibit proinflammatory cytokines [26] and has been suggested as a treatment for thyroid-associated orbitopathy.

Anti-CD20 (rituximab) therapy [27] to deplete B-cell lymphocytes and antitumor necrosis factor (anti-TNF) drugs (eg, etanercept, infliximab) have been used in patients with thyroid-associated orbitopathy, but more studies are required to determine their risk-benefit ratio. Two small randomized control trials of rituximab with different time windows for study enrollment showed conflicting results. [28, 29]  Potential side effects of rituximab include infusion reactions and, rarely, increased risk of infection and progressive multifocal leukoencephalopathy.

Octreotide, pentoxifylline, nicotinamide, plasmapheresis, and intravenous immunoglobulin are not mainstream medical treatments of thyroid-associated orbitopathy. Octreotide, a potent synthetic somatostatin analogue, has a beneficial effect in this condition, especially in patients with a positive OctreoScan-111 (indium-111 [111 In] pentetreotide). Lanreotide is a longer-acting somatostatin analogue, which is administered only once every 2 weeks; this agent may provide some benefit. Pentoxifylline and nicotinamide may be useful; both agents are believed to inhibit cytokine-induced glycosaminoglycan synthesis by the retroorbital fibroblasts.

The role of plasmapheresis and intravenous immunoglobulin (IVIg) is not well delineated. One randomized trial of IVIg (1 g Ig/kg body weight × 2 consecutive d every 3 wk) versus oral prednisolone (for 20 wk, with initial dose of 100 mg/d) showed both treatments to be equally effective in patients with active thyroid-associated orbitopathy. [30] Fewer adverse effects were observed in the IVIg treatment group.

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Orbital Radiation

Orbital irradiation is sometimes is prescribed for moderate to severe inflammatory symptoms, diplopia, and visual loss in patients with thyroid-associated orbitopathy (TAO). The radiation (1500-2000 cGy fractionated over 10 d) is usually administered via lateral fields with posterior angulation. Radiation is believed to damage orbital fibroblasts or perhaps lymphocytes.

The radiation requires several weeks to take effect, and it may transiently cause increased inflammation. Thus, most patients are maintained on steroids during the first few weeks of treatment. In addition, better response to radiation is observed in patients with active inflammation who are treated within 7 months of the onset of thyroid-associated orbitopathy. Radiation may be more effective if combined with steroid treatment.

Studies that suggest that radiotherapy is ineffective in thyroid-associated orbitopathy must be scrutinized to ensure that the radiation was administered to appropriate candidates at the appropriate time. For example, the Gorman et al study used serum thyroid-stimulating immunoglobulin [TSI] as a surrogate of active eye disease. [31] Although the blood test is an indicator of immunologic activity, it may not reflect the clinical progression of thyroid-associated orbitopathy. Furthermore, the patients in that study were enrolled at a median of 1.3 y after the onset of eye symptoms, suggesting that many of the patients in the study would not have progressive eye symptoms or signs indicative of an ongoing orbital process. [31]

Although improvement of motility disturbances can occur with radiotherapy, radiation is limited when used in isolation to treat diplopia.

Potential adverse effects and contraindications

Cataract, radiation retinopathy, and radiation optic neuropathy are possible risks. These effects are not common if treatment is appropriately fractionated and the eyes are shielded. Marquez et al found 12% of their study patients developed cataracts after irradiation (median follow-up, 11 y). [32]

Wakelkamp et al also believed that orbital irradiation for thyroid-associated orbitopathy is a safe treatment modality, except possibly for patients with diabetes mellitus. [33] Radiation may be a relative contraindication for patients with diabetes mellitus because of the risk of worsening retinopathy.

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Prevention of I-131-Associated TAO

To prevent progression of thyroid-associated orbitopathy (TAO) from radioactive iodine, pretreating and post treating the patient with low-dose steroids (eg, 0.5 mg/kg/d up to 2 mo posttreatment) has been suggested if no contraindications for steroids exist and this therapy is agreed to by the patient. Following radioactive iodine, the patient should be monitored closely for the development of hypothyroidism.

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Overview of Surgical Intervention

Approximately 5% of patients with thyroid-associated orbitopathy (TAO) may require surgical intervention. The patient should know that multiple-staged procedures may be required. [34, 35, 36] In elective cases, listen carefully to what the patient desires; the patient's expectations may not be realistic.

The timing of surgery is important. Unless compressive optic neuropathy or severe corneal exposure is present, surgery is generally delayed during the active inflammatory phase of thyroid-associated orbitopathy. Surgery is usually performed during the quiescent cicatricial phase of the disease.

Taking preoperative photographs is advised. With strabismus surgery, document prism measurements or fields of single binocular vision. Recording baseline-automated perimetry also is useful.

The sequence of surgery is also important. If the patient has marked proptosis, strabismus, and lid deformity, perform surgery in the following order:

  1. Orbital decompression
  2. Strabismus surgery
  3. Lid-lengthening surgery
  4. Blepharoplasty

These procedures will be briefly reviewed in the following sections.

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Orbital Decompression

Orbital decompression may be performed as the initial treatment of compressive optic neuropathy or used if medical treatment is ineffective. A combination of medical and surgical treatment may be required in compressive optic neuropathy.

Potential complications of orbital decompression include blindness, hemorrhage, diplopia, periorbital numbness, globe malposition, sinusitis, and lid malposition.

Procedure overview

Following bony orbital decompression, open the periorbita. Little reduction in proptosis occurs until the periorbita is slit.

To decompress the optic nerve, at least 2 orbital walls are usually decompressed (traditionally, the medial wall and floor of the orbit). Medial decompression for compressive neuropathy must be taken posteriorly all the way to the apex of the optic canal. Surgery can be approached from a transorbital or trans-sinus route. Transorbital routes include subciliary incisions, lid crease incisions, medial incisions (cutaneous, transcaruncular), and coronal incisions. Trans-sinus routes include transantral approaches and endoscopy.

Medial wall removal should not extend above the frontoethmoidal suture. This averts bleeding from the ethmoidal arteries and prevents cerebrospinal fluid (CSF) leaks.

When the orbital floor is removed, preservation of a strut of bone between the ethmoid and maxillary bones may reduce strabismus from inferomedial shift in the globe position.

Balanced decompression of the medial and lateral orbital walls is frequently described. Avoiding decompression of the orbital floor theoretically decreases the risk of postoperative diplopia and lid retraction.

Lateral wall decompression does little to relieve apical compression but helps to reproduce proptosis. Valgus repositioning of the orbital wall and orbital rim-onlay, porous-polyethylene grafts are adjunctive techniques to reduce proptosis.

Four-wall decompression (with decompression of the orbital roof) requires a neurosurgical approach.

Orbital fat decompression

Orbital fat decompression without bony removal has been described for thyroid-associated orbitopathy (TAO) without apical compression. Candidates for orbital fat decompression should show predominant enlargement of the orbital fat compartment, rather than the rectus muscles on orbital imaging.

Unlike cosmetic blepharoplasty, with orbital fat decompression, fat is also removed posterior to the equator of the globe. Inferiorly, the fat is removed through a transconjunctival approach, which may be facilitated with lateral canthotomy and cantholysis. Superiorly, fat removal is through a lid crease incision, usually confined to the nasal quadrant.

A study by Liao et al confirms that a reasonable and effective reduction in proptosis can be safely achieved by extensive orbital fat removal alone. [37] The study did not correlate individual case results with extent of extraocular muscle hypertrophy compared with degree of fat hypertrophy, thus greatly impacting results in individual cases. The risk of postoperative worsened strabismus was not addressed and likely still remains a (theoretical) risk. Relying solely on fat decompression in cases of impending or actual optic nerve compression is not advisable.

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Strabismus Surgery

Successful, early strabismus surgery during active thyroid ophthalmopathy has been described, but strabismus surgery generally is delayed until thyroid-associated orbitopathy (TAO) is inactive and the prism measurements have been stable for at least 6 months.

Patients should realize that the goal of surgery is to minimize diplopia in primary and reading positions. Expecting binocular single vision in all positions of gaze may not be realistic. Patients should also realize that multiple strabismus surgeries and prisms may be required.

Because of the restrictive myopathy of thyroid-associated orbitopathy, predominantly recessions, rather than resections, are performed. Whenever feasible, adjustable suture surgery is recommended. In patients intolerant of conscious suture adjustment, hang-back sutures can be adjusted using the corneal light reflexes. In select patients with thyroid-associated orbitopathy, strabismus surgery can be performed using topical anesthesia.

To prevent ocular ischemic syndrome, do not operate simultaneously on more than 2 muscles per eye.

Procedure considerations

Surgery of the inferior rectus muscle deserves special mention. Inferior rectus muscle recession may decrease upper lid retraction, but it also often results in lower lid retraction despite dissection of the lower lid retractors. Because the inferior rectus muscle has subsidiary actions (excyclotorsion and adduction), inferior rectus muscle recessions may lead to a component of intorsion and A-pattern strabismus.

If visualization during strabismus surgery is difficult, especially for the superior rectus muscle, a vertical lid split technique may be considered.

Botulinum toxin injections are used by some clinicians during the acute phase of thyroid-associated orbitopathy as a temporizing measure until orbital decompression can be completed. However, optic neuropathy following a botulinum toxin injection for strabismus in a patient with thyroid-associated orbitopathy has been reported.

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Lid-Lengthening Surgery

If restoration of the euthyroid state does not improve lid retraction, consider lid-lengthening surgery. This surgery decreases corneal exposure and can be used to camouflage mild-to-moderate proptosis. In patients unwilling to consider lid surgery, possible alternatives to upper-lid lengthening include botulinum toxin injections to the upper lid and subconjunctival triamcinolone.

Lateral tarsorrhaphies can decrease upper and lower lid retraction, but the author does not prefer this method.

Amelioration of 2-3 mm of upper lid retraction can be done with a Müller muscle excision. Lateral levator tenotomy is often helpful to decrease the temporal flare. If further amounts of lid recession are required, levator recession can be considered.

Lower lid-lengthening usually requires a spacer material. Graft materials include human acellular dermis, tarsus, and conjunctiva from the upper lid, hard palate, and ear cartilage.

Horizontal tightening procedures (eg, lateral tarsal strip) increase scleral show in patients with proptosis.

In the horizontally tight eyelid, lateral canthal advancement is a useful adjunct to enhance the effect of retractor recession and reduction of temporal flare.

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Blepharoplasty

Blepharoplasty is the last phase of restorative surgery in thyroid-associated orbitopathy (TAO). The transconjunctival approach to lower lid blepharoplasty can be used if no excess lower lid skin is present.

Upper lid blepharoplasty is performed transcutaneously with conservative skin excision. Brow fat resection may be considered. Dacryopexy may be required if lacrimal gland prolapse occurs.

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Consultations

Patients with thyroid-associated orbitopathy (TAO) benefit from consultation and follow-up care with an endocrinologist.

Orbital decompression can be performed in conjunction with an otorhinolaryngologist, especially when endoscopic procedures are contemplated.

Neurosurgical consultation is required when decompression of the orbital roof is performed.

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Pregnancy and TAO

The incidence of hyperthyroidism in women who are pregnant has been reported to be approximately 0.2%. Information on the management of thyroid-associated orbitopathy (TAO) during pregnancy is not widely available.

The author is not aware of literature that supports cesarean delivery over vaginal delivery in women with this condition who are pregnant. If a pregnant woman with thyroid-associated orbitopathy has compressive optic neuropathy, steroids can usually be administered in consultation with the obstetrician and an endocrinologist. Ideally, surgery should be deferred until after delivery when possible. However, if emergent orbital decompression is required, nonabdominal surgery may not impose the same risks to the fetus as that of abdominal surgery.

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Childhood TAO

In general, children with thyroid-associated orbitopathy (TAO) tend to have a more benign disease course, with less ophthalmoplegia, than adults. In comparison with adults, surgical intervention is infrequently required with children.

Children and their parents should be counseled to avoid smoking. Secondhand smoke seems to exacerbate autoimmune thyroid disease, and passive smoking may have a deleterious effect on childhood thyroid-associated orbitopathy.

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Special Considerations

The clinician should be aware that thyroid-associated orbitopathy (TAO) can be asymmetric. In addition, optic nerve compression in thyroid-associated orbitopathy can occur in the absence of obvious proptosis; for this reason, always check for retropulsion.

Thyroid-associated orbitopathy should not be mistaken for a dural arteriovenous malformation or a carotid cavernous fistula (see Diagnostic Considerations).

Early diagnosis and appropriate monitoring of thyroid-associated orbitopathy may decrease corneal exposure and compressive optic neuropathy.

In patients with thyroid-associated orbitopathy who have proptosis and inferior scleral show, simple horizontal tightening of the lower lid will result in increased globe exposure.

Before performing bony orbital decompression, computed tomography (CT) scan should be obtained, because these studies delineates bony anatomy better than magnetic resonance imaging (MRI).

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