Assessment and Management of the Patient with Graves’ Ophthalmopathy

The appropriate management of a patient with Graves’ ophthalmopathy (GO) can be determined only following a careful assessment of the signs and symptoms of the disease. A detailed examination and discussion allows the clinician to determine which components of the disease are most troublesome to that particular patient. The advantages and disadvantages of the various treatment options for each disease component can be best understood in light of current concepts of the pathogenesis of GO. This paper will begin with a discussion of the histologic and gross pathologic features of the disease, followed by a brief review of pathogenic mechanisms responsible for their development. The assessment of a patient with GO will be discussed and the modes of therapy available to address each of the signs and symptoms will be reviewed. Readers interested in a more detailed discussion of the management of GO are encouraged to read the excellent recent review by Drs. Burch and Wartofsky (1). (Endocr Pract. 1995;1:172-178) PATHOGENESIS Histologic examination of orbital tissues from patients with GO reveals an accumulation of hydrophilic glycosaminoglycans (GAGs) within the endomysial connective tissue surrounding the extraocular muscle cells and in the fatty connective tissue in the posterior orbit (2). The clinical manifestations of GO, including proptosis, extraocular muscle dysfunction, and periorbital edema, can be explained mechanically by the abundance of GAGs and edema within the orbital connective tissues (3,4). Proptosis, the forward displacement of the globe, and the painful sensation of pressure behind the eye is due to the increase in tissue volume within the confines of the bony orbital walls. Massive swelling of the bodies of the extraocular muscles, particularly in the apex of the orbit, can result in a compressive optic neuropathy. Inadequate coverage of the globe caused by proptosis and upper eyelid retraction can result in drying of the cornea with exposure keratitis and corneal ulceration. The swelling and inflammation of endomysial connective tissues seen in early stages of the disease may lead to the muscle fibrosis at a later stage. The resulting restriction of extraocular muscle movement causes diplopia that may be constant. Periorbital edema results primarily from impaired venous and lymphatic drainage from the orbit. However, the presence of cytokine mediators of inflammation in the orbital connective tissues may also contribute to the swelling. Specifically, interferon- γ, interleukin-1α and TNF-β have been identified in affected orbital tissues (5), and are capable of stimulating orbital fibroblasts to produce GAGs (6,7), to proliferate (8), and to express immunomodulatory proteins (9,10,11). In a similar fashion, GAGs accumulate in the skin in Graves’ disease. This accumulation is also likely caused by local cytokine stimulation of fibroblasts and causes pretibial dermopathy and acropachy, the other connective tissue manifestations of Graves’ disease. The thyroid stimulating hormone (TSH) receptor in the thyroid is the autoantigen responsible for the hyperthyroidism of Graves’ disease. TSH receptor RNA (12,13) and protein (14) has been shown to be present in orbital fibroblasts. As a result, it has been suggested that the TSH receptor in fibroblasts may be the autoantigen responsible for the connective tissue manifestations of Graves’ disease. Activated lymphocytes in Graves’ disease that are directed against the TSH receptor would likely recognize this same antigen on fibroblasts. As a result, these lymphocytes would infiltrate connective tissues and release particular cytokines that are known to stimulate fibroblast GAG production and proliferation (15). NATURAL HISTORY The decision to intervene with treatment in a patient with a particular disease at a given time must be made with knowledge of the expected course of the disease. The natural history of GO has been difficult to study because each component of the disease may follow a different progression and resolution time course. In addition, studies examining the natural history of GO generally include patients whose hyperthyroidism has been treated with radioactive iodine, anti-thyroid drugs or surgery. Whether any of these treatment options for hyperthyroidism impact the development or progression of GO remains an issue of controver