Thyroid Ophthalmopathy (Graves’ Disease)

Signs and Symptoms
Thyroid eye disease, Graves’ ophthalmopathy, dysthyroid ophthalmopathy, and Graves’ disease are all synonymous terms connoting a process clinically characterized by eyelid retraction, proptosis, conjunctival exposure, ocular injection, ocular chemosis, corneal compromise, extraocular muscle infiltration and fibrosis with the potential for compressive optic neuropathy. It is the most common cause of bilateral, symmetric proptosis in adults.

Interestingly, ocular findings may occur independently from dysthyroid function. Euthyroid Graves’ disease is a condition where the characteristic ophthalmic manifestations of thyroid eye disease exist in the presence of a clinically and biomedically normal thyroid gland.

Most patients with ocular Graves’ disease manifest systemic hyperthyroidism. Up to 80 percent of patients with systemic hyperthyroidism develop some eye signs. Systemic signs of hyperthyroidism include weight loss despite increased appetite, nervousness, palpitations, tachycardia while at rest, systemic hypertension, and hyperreflexia. Conversely, lethargy, bradycardia and weight gain despite decreased appetite are signs of hypometabolism and potential hypothyroidism.

In 1969, the American Thyroid Association adopted the formal classification of Ocular Graves’ disease, represented by the pneumonic NOSPECS. The disease process passes through 6 stages: (0) No signs or symptoms present, (I) Only symptoms of ocular irritation (dryness, tearing, foreign body sensation), (II) Soft tissue involvement (periorbital edema), (III) Proptosis, (IV) Extraocular muscle involvement (ophthalmoplegia), (V) Corneal involvement (dense punctate epitheliopathy, infiltration and ulceration), (VI) Sight loss with or without visual field compromise secondary to compressive optic neuropathy. However, because the disease is recognized as variable, the formal classification was revised in 1974 to range from no manifestations to mild, moderate or severe manifestations.

The common, clinically diagnostic eye signs include: von Graefe’s sign (superior lid lag upon down gaze), Dalrymple’s sign (eyelid retraction), Stellwag’s sign (infrequent blinking), and Ballet’s sign (palsy of one or more extraocular muscles).

Pathophysiology
Graves’ disease is a multisystem disorder of unknown etiology, characterized by one or more of the following three clinical entities: (1) hyperthyroidism associated with diffuse hyperplasia of the thyroid gland; (2) infiltrative ophthalmopathy; and (3) infiltrative dermopathy (pretibial myxedema).

The histopathologic features of the malady include an infiltration of the thyroid gland, skin, extraocular muscles and orbital fat by lymphocytes, macrophages, plasma cells, mast cells and mucopolysaccharides. These changes are characteristic of, but not limited to, an immunologically mediated mechanism.

Management
The diagnosis of Graves’ disease can often be made easily based on symmetrical exophthalmos (exophthalmometry >22mm or asymmetry greater than 3mm) and lid retraction in the
presence of known hyperthyroidism. If symptoms are present and a systemic etiology has not been investigated, consultation with an endocrinologist and laboratory testing for thyroid hormones T3 (triiodothyronine), T4 (tetra-iodothyronine) and TSH (thyroid stimulating hormone) are indicated. Neuroimaging of the orbits in patients with exophthalmos and positive forced duction testing allows clinicians to distinguish extraocular muscle infiltration from inflammatory or infectious myositis.

The systemic management of patients with ocular Graves’ disease lies in the domain of the endocrinologist. Agents that block the synthesis of thyroid hormone such as propylthiouracil (Tapazole) or decrease hypermetabolic symptoms such as propranolol (Inderal) have been proven effective. Systemic steroids, immunosuppressive agents like azathioprine, cyclosporin or cyclophosphamide in combination with orbital irradiation have shown promise in advanced cases. Today, surgical orbital decompression procedures are a last resort.

Since the primary concern proptosis and lid retraction presents is corneal exposure, ocular management is predominantly supportive. Typically, moistening the cornea with artificial tear drops and ointments is effective. Moisture shields that can be attached to the temples of spectacles help to preserve tears and retard tear evaporation. Punctal occlusion may be effective. Cases that involve moderate to severe keratopathy may require prophylactic topical antibiotics. Visual fields should be performed on patients with advanced stage disease, monitoring for the first sign of sight or field loss. Evaluation is usually every three to six months and is based upon severity.

Clinical Pearls

Since a variety of neuro-ophthalmic entities deserve consideration in diseases where there is proptosis or malposition of the eyelid (myasthenia gravis, illusory ptosis of the opposite eyelid, neoplasm, arteriovenous malformation, carotid cavernous fistula, infection, inflammation), forced duction testing (positive in Graves’) and neuroimaging (MRI or CT revealing enlarged EOM bellies with tendon sparing, diagnostic of Graves’) should be done. If myasthenia gravis is suspected, a Tensilon test should be ordered.

Beware of glaucoma in patients with Graves’ ophthalmopathy. The infiltrated muscles can cause globe compression with secondary IOP elevation as well as compressive optic neuropathy.