The ophthalmopathy of Graves disease occurs as a consequence of an autoimmune inflammatory process leading to infiltration of the soft tissues of the orbit. Risk factors include cigarette smoking, radioiodine therapy, persistent hyperthyroidism, and recurrence of hyperthyroidism after withdrawal of antithyroid drug therapy. Administration of prednisone at the time of radioiodine therapy can prevent treatment-induced ophthalmopathy. Pathologically, there is an inflammatory infiltrate of lymphocytes, mucopolysaccharides, and edema, followed by proliferation of fibroblasts and increase in the volume of orbital connective tissue. The proliferation of orbital fibroblasts and their fibrotic restriction of extraocular muscle movement account for the clinical picture of Graves ophthalmopathy.

In its mildest form, there is minor lid retraction, stare, lid lag, and mild protrusion of the eye (proptosis). A particularly severe form, “malignant” exophthalmos, causes edema of the lids and conjunctiva, marked proptosis, limitation of extraocular movements, exposure keratopathy, and optic nerve compression. Although it is usually a bilateral disease, it may present unilaterally or asymmetrically.

The relatively close clinical relationship between ophthalmopathy of Graves disease, pretibial dermopathy, and hyperthyroidism suggests a common pathophysiologic mechanism. However, the ophthalmopathy can occur in the absence of thyroid dysfunction or pretibial dermopathy. The precise pathophysiology remains to be elucidated. It may be triggered by antibodies to circulating thyroid antigen, accounting for the exacerbation seen with some treatments for thyrotoxicosis. Its precise mechanisms continue to be elucidated (see Chapter 103).

The clinical course is variable. In patients with mild disease, about 20% improve spontaneously, 65% stay about the same, and 15% experience progression. The initial active phase lasts about 1 to 2 years, followed by a plateau phase and then an inactive phase with some remission.

Primary orbital neoplasms, such as meningiomas, produce exophthalmos by mass effect. Some vascular lesions, such as hemangiomas, produce only a mass effect, whereas a carotid-cavernous sinus fistula may present with a diffusely congested orbit with exophthalmos, prominent episcleral vessels, and elevated intraocular pressure. Mass lesions and vascular abnormalities are unilateral processes. They may lead to diplopia, ocular irritation, and photophobia (secondary to corneal exposure). Stretching or compression of the optic nerve can impair visual acuity.

Orbital cellulitis is an extremely serious, although rare, cause of proptosis. Because the orbit is bordered on three sides by paranasal sinuses, orbital infection can result from sinusitis extending directly through the lamina papyracea. Lid edema, ptosis, proptosis, chemosis, and diminished ocular movements make for a dramatic clinical presentation. Retrograde extension can lead to cavernous sinus thrombosis.

Bilateral exophthalmos is usually caused by Graves disease, but occasionally it occurs with Cushing syndrome, acromegaly, lithium ingestion, metastatic tumor, and orbital lymphoma.

Unilateral exophthalmos may be caused by Graves disease, tumor, inflammatory and infectious diseases, vascular abnormalities, and skeletal abnormalities. Common orbital tumors include hemangioma, meningioma, and optic nerve glioma. Tumors extending into the orbit include those originating in the eye, lids, and paranasal sinuses. Orbital pseudotumor is an inflammatory lesion that can mimic a mass lesion. Inflammatory etiologies include sarcoidosis, foreign body, orbital thrombophlebitis, and ruptured dermoid cyst. Hemangioma, aneurysm, varices, carotid-cavernous fistula, and cavernous sinus thrombosis constitute important vascular etiologies. Skeletal abnormalities such as Paget disease may also produce exophthalmos. Asymmetry of the orbits, severe unilateral myopia, facial nerve paresis, eyelid retraction, and congenital glaucoma may give the appearance of exophthalmos. Ptosis or enophthalmos of the opposite eye can mimic exophthalmos.