INTRODUCTION	Section 2 of 11
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Pictures Bibliography

Background: Thyroid-associated ophthalmopathy (TAO), frequently called Graves ophthalmopathy, is an organ-specific autoimmune process that is strongly associated with dysthyroidism. The earliest recorded case of TAO may be Bodhidharma, also known as Daruma, who, in the sixth century, was the founder of Zen Buddhism and Kung Fu. In the medical literature, TAO was formally described by Graves in 1835 and by von Basedow in 1840. TAO may precede, coincide, or follow the systemic complications of dysthyroidism.

Twenty percent of patients indicate that the ocular morbidity of TAO is more troublesome than the thyroid problems. It may result in eyelid retraction, proptosis, chemosis, periorbital edema, and altered ocular motility, with significant functional and cosmetic consequences. Although most cases of TAO can be managed medically and without visual loss, it may result in vision-threatening exposure keratopathy and compressive optic neuropathy. As such, all clinicians should be able to recognize TAO.

Pathophysiology: An extensive discussion on the immunology of TAO is beyond the scope of this article. TAO generally is accepted as an autoimmune-mediated inflammation of the extraocular muscle and periorbital connective tissue.

T-cell lymphocytes are believed to react against thyroid follicular cells with shared antigenic epitopes in the retro-orbital space. Whether T cells are involved in a cell-mediated or a humoral immune response is not certain. Although evidence for cellular and humoral immunity against various orbital antigens (eg, 55-kilodalton [kDa] and 67-kDa eye muscle proteins, 23-kDa and 66-kDa fibroblast proteins, extracellular matrix proteins) has been noted, the nature of the primary antigen(s) that is recognized by immunocompetent cells and autoantibodies has not been determined definitively. Candidate antigens include the thyroid-stimulating hormone (TSH) receptor protein (TSHR), which may be expressed on orbital fibroblasts, and an extraocular muscle antigen of 64 kDa.

Lymphocytic infiltration of the orbital tissue causes release of cytokines such as interleukin 1. Preadiopcyte fibroblasts are thought to be the target cells in TAO and 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 orbital tissue increases the tissue osmotic load 5-fold. The osmotic damage results in muscle edema leading to proptosis, subsequent fibrosis of muscle fibers, and eventually tissue atrophy. Adipogenesis plays a role in TAO, especially in younger patients. TAO may be part of a more generalized disorder of connective tissue and striated muscle.

Frequency:

• In the US: In a rural Minnesota community, the annual incidence was estimated at 16 per 100,000 in women and 2.9 per 100,000 in 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 persons aged 30-50 years.

• Severe cases of TAO are thought to be more frequent in patients who are older than 50 years.

	CLINICAL	Section 3 of 11
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Pictures Bibliography

History:

• TAO usually has a self-limited course over one or more years.

• The signs and symptoms may vary and depend on the stage of TAO the patient is experiencing. Initially, an acute or subacute stage of active inflammation occurs. Later, the condition progresses to a more quiescent stage, which is characterized by fibrosis.

• Patients with TAO 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 and signs include the following:

• Tachycardia/palpitations

• Nervousness

• Diaphoresis

• Heat intolerance

• Skeletal muscle weakness

• Tremor

• Weight loss

• Hair loss

• Irritability

• Goiter

• Hypothyroidism symptoms and signs 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 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.

• Digital palpation of the globes is a useful test, possibly revealing decreased orbital 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 Müller muscle, upgaze restriction, fibrosis of the levator, 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.

• 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. The examiner should move the fixation object slowly from upward to downward and examine whether the eyelid lags behind the globe on downgaze. If the object is moved too quickly superiorly to inferiorly, the examiner may easily miss this sign.

• Pseudoptosis and true ptosis may be seen in patients with TAO.
  • Pseudoptosis may be seen if contralateral lid retraction is present.

  • Ptosis may occur in conjunction with levator dehiscence. 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 insertions), and conjunctival chemosis.

• With severe proptosis, corneal exposure with frank corneal ulceration may occur. Superior limbic keratoconjunctivitis has been a purported prognostic marker for severe TAO.

• Strabismus is common with TAO and often presents as hypotropia or esotropia because the inferior rectus and medial rectus are the most commonly involved extraocular muscles.

• Examine the corneal light reflexes closely, because asymmetric proptosis and lid retraction may mask the true relative positions of the globes.

• The restrictive myopathy can sometimes be confirmed with forced ductions if the TAO diagnosis is not certain.

• Inferior rectus restriction may mimic a double elevator palsy.

• Pseudopalsies of the fourth cranial nerve have been described with TAO.

• Although esotropia is a more common finding with TAO, convergence insufficiency also has been described.

• In patients with TAO and exotropia, consider the possibility of concurrent myasthenia gravis.

• 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, visual acuity, color vision, and the presence or absence of a relative afferent pupillary defect must be documented at each visit.

• Glaucoma may occur because of decreased episcleral venous outflow. Owing to restrictive myopathy, intraocular pressure may rise more than 8 mm on upgaze.

• Choroidal folds may be seen with TAO.

• Several signs are associated with TAO, including the following:

• Von Graefe sign

• 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)

• Moebius sign (poor convergence)

• Ballet sign (restriction of one or more extraocular muscles)