eMedicine Specialties > Ophthalmology > Orbit

Thyroid Ophthalmopathy

Author: Edsel Ing, MD, FRCSC, Assistant Professor, Department of Ophthalmology & Vision Sciences, University of Toronto: Consulting Staff, Toronto East General Hospital
Contributor Information and Disclosures

Updated: Apr 30, 2008

Introduction

Background

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). 

The first description of an individual with possible TAO was Bodhidharma (Daruma), the founder of Zen Buddhism and Kung Fu, in the 6th century.  

The association of goiter and exophthalmos has been recognized by many clinicians, including Sayyid Ismail Al-Jurjani in Persia in the 12th century, the Irish doctor Robert Graves in 1835, and the German physician Karl Adloph von Basedow in 1840.^1,2

TAO may precede, coincide, or follow the systemic complications of dysthyroidism. The ocular manifestations of TAO 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 TAO is more troublesome than the systemic complications of dysthyroidism. 

Although most cases of TAO do not result in visual loss, TAO can cause vision-threatening exposure keratopathy, troublesome diplopia, and compressive optic neuropathy; therefore, all clinicians should be able to recognize TAO.

Pathophysiology

In simplest terms, the underlying pathophysiology of TAO is thought to be an antibody-mediated reaction against the 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 of the orbital tissue causes a release of cytokines (eg, tumor necrosis factor, 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 TAO. 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 TAO, 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.

TAO may be part of a more generalized disorder of connective tissue and striated muscle.

A more extensive discussion on the pathoimmunology of TAO is beyond the scope of this article. Some of the more recent research in this field is outlined below.

The insulin-like growth factor 1 receptor is an autoantigen that may be important in TAO because of its aberrant expression by TAO 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 up-regulation 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 TAO. There is a positive correlation with increasing severity of orbital disease, suggesting a possible relationship with COX-2 expression and orbital inflammation in TAO.

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

Frequency

United States

In a rural Minnesota community, the annual incidence rate was estimated at 16 cases per 100,000 women and 2.9 cases per 100,000 men.

Mortality/Morbidity

Monitoring of thyroid exophthalmos may help prevent corneal and optic nerve damage.

Sex

• Various studies suggest that TAO affects women 2.5-6 times more frequently than men.
• Severe cases of TAO occur more often in men than in women.

Age

• TAO mostly affects patients aged 30-50 years.
• Severe cases of TAO are believed to be more frequent in patients who are older than 50 years.

Clinical

History

• TAO usually has a self-limited course over 1 or more years. Stable TAO 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.
• 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
• Symptoms of hyperthyroidism include the following:
  • Tachycardia/palpitations
  • Nervousness
  • Diaphoresis
  • Heat intolerance
  • Skeletal muscle weakness
  • Tremor
  • Weight loss
  • Hair loss
  • Irritability
  • Goiter
• Symptoms of hypothyroidism include the following:
  
  
  • Bradycardia
  • Drowsiness
  • Poor mentation
  • Muscle cramps
  • Weight gain
  • Dry skin
  • Husky voice
  • Depression
  • Cold intolerance

Physical

• TAO 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 TAO usually reflects asymmetric muscle involvement.
  • Retropulsion (digital palpation of the globes through closed eyelids) is a useful test.  Patients with severe TAO have decreased retropulsion. Various exophthalmometers can be used to measure orbital protrusion.
  • Lacrimal gland enlargement is not uncommon.
• 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 TAO. 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 TAO 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 TAO. While slowly moving the fixation object from upward to downward, the examiner should observe if the eyelid lags behind the globe on downgaze.
  • Pseudoptosis and true ptosis may be seen in patients with TAO. Pseudoptosis may be observed if contralateral lid retraction is present. Ptosis may occur with TAO if levator dehiscence is present. Patients with TAO may have concurrent myasthenia gravis, which may lead to ptosis.
  • Other TAO lid signs include lid edema and glabellar furrows.
• Anterior segment signs in TAO 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 TAO.
• Strabismus is common with TAO, 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.
  • The corneal light reflexes should be examined closely because asymmetric proptosis and lid retraction may mask the true relative positions of the globes.
  • 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 TAO is not revealing.
  • Inferior rectus muscle restriction may mimic double elevator palsy.
  • Pseudo-fourth nerve palsies have been described with TAO.
  • Although esotropia is a more common finding with TAO, convergence insufficiency has been described.
  • In patients with TAO and exotropia, the possibility of concurrent myasthenia gravis should be considered.
• Optic nerve compression may occur with seemingly mild proptosis. Also, 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.
• Glaucoma may result from decreased episcleral venous outflow. Because of restrictive myopathy, intraocular pressure may rise more than 8 mm Hg on upgaze.
• Choroidal folds may be seen with thyroid ophthalmopathy.
• Numerous other eponymous signs are associated with TAO, including the following:
  • Vigouroux sign (eyelid fullness)
  • Stellwag sign (incomplete and infrequent blinking)
  • Grove sign (resistance to pulling down the retracted upper lid)
  • Goffroy sign (absent creases in the forehead on superior gaze)
  • Möbius sign (poor convergence)
  • Ballet sign (restriction of one or more extraocular muscles)
• 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.
• Pretibial dermopathy and thyroid acropachy (which mimics the appearance of clubbing) are less commonly encountered dramatic, cutaneous signs of dysthyroidism.
• Numerous classification systems for TAO exist, but they all have shortcomings.
  • The simplest classification for TAO is type I and type II.
    • Type I is characterized by minimal inflammation and restrictive myopathy.
    • Type II is characterized by significant orbital inflammation and restrictive myopathy.
    • Type I and type II orbitopathy are not mutually exclusive.
  • Werner's NOSPECS classification system (and its modifications) is one of the most commonly known systems and is used in many endocrine studies.
    • Unfortunately, patients may fall into more than one particular class.
    • Patients may not progress in an orderly fashion from class 1 to class 6. Patients with visual loss from compressive optic neuropathy may not show marked proptosis or other signs of severe disease.
    • As with other classification systems, it may be of limited prognostic value.

Causes

• Relationship of thyroid status and TAO
  • The thyroid gland per se does not cause TAO. Instead, the thyroid gland, eye muscles, and pretibial skin are especially subject to the autoimmune attack. Regulation of thyroid function does not abort TAO. However, restoration of the euthyroid state (with antithyroid drugs and thyroxine) may improve the eye status to some extent.
  • Many patients with TAO are hyperthyroid, but the following also are associated with TAO: euthyroidism (20%), Hashimoto thyroiditis, thyroid carcinoma, and neck irradiation. Even if the patient is euthyroid, TAO may progress. In patients who are hyperthyroid, the eye signs of TAO usually develop within 18 months of dysthyroidism; very often, they develop concurrently.
• Radioactive iodine and TAO
  • Although somewhat controversial, several publications have suggested that thyroid ablation with orally ingested radioactive iodine (RAI; I-131) may exacerbate TAO compared to antithyroid drugs or surgical ablation.
  • I-131 is believed to result in a release of thyroid antigens.
  • In a study by Bartalena, approximately 15% of patients treated with only RAI developed or had worsening of TAO.³ In contrast, none of the patients treated with both RAI and prednisone had progression of TAO, and two thirds showed improvement. Only 3% of patients treated with methimazole showed worsening of TAO.
• To prevent progression of TAO from RAI, pretreating and posttreating 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 agreed to by the patient. Post-RAI, the patient should be monitored closely for the development of hypothyroidism. Several studies have not shown that radioiodine is a significant risk for initiation or progression of mild TAO. 

• Diseases associated with TAO

• Other autoimmune diseases, such as myasthenia gravis, Addison disease, vitiligo, and pernicious anemia, have been described with TAO.
• Yersinia enterocolitica infection has been associated with TAO .
• In one study, 8% of patients with TAO had positive acetylcholine receptor antibodies. At 4.5-year follow-up visits, none of the patients with positive serology were identified clinically to have myasthenia gravis.
• Smoking: TAO is associated strongly with smoking; 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 TAO compared to their Asian counterparts.
• The oral hypoglycemic pioglitazone has been suggested to cause adipocyte proliferation in patients with TAO. Until definitive studies are performed, alternatives to the thiazolidinediones might be considered in patients with TAO.

• Search for CME/CE on This Topic »

• Ophthalmopathy, Thyroid (Radiology)
• Hyperthyroidism (Endocrinology)
• Pretibial Myxedema (Dermatology)
• Optic Neuropathy, Compressive (Ophthalmology)

• Thyroid Problems Symptoms
• Thyroid Problems Causes
• Endocrine System Center
• Thyroid Problems Treatment
• Thyroid Problems Overview

• A 20-Month-Old With Bilateral Proptosis