Management of Thyroid Eye Disease (Graves Ophthalmopathy)

Epidemiology and Impact

Graves disease (GD) is common, with an annual incidence rate of 0.5 per 1000. In iodine-sufficient regions, GD represents 70% to 80% of all cases of thyrotoxicosis. Almost 50% of patients with GD report symptoms of GO, such as dry eye, foreign body sensation, photophobia, tearing, double vision, and pressure sensation behind the eyes. There is a bimodal age distribution of GO, with peak incidences in the fifth and seventh decades of life. The classic triad of thyrotoxicosis, goiter, and ophthalmopathy is not observed in all patients. For example, hyperthyroidism may be the only feature present. The most common extrathyroidal feature of GD—ophthalmopathy—is clinically present in approximately 50% of patients. Although as many as 10% to 20% of these suffer from severe inflammation, extraocular eye movement restriction, or compressive optic neuropathy (CON), the overall incidence of ophthalmic findings depends on the criteria defining abnormality. Additionally, approximately 70% of adult patients with GD exhibit evidence of subclinical GO on imaging—that is, enlargement of the extraocular muscles (EOMs) and/or fibrosis without associated eye symptomatology.

Pathophysiology

Despite extensive efforts to identify a definitive cause of GD, its precise etiology remains unknown. Current expert consensus accepts that GD is a multifactorial disease resulting from a complex interplay of genetic and environmental factors. The end result of this is a loss of immune tolerance to thyroid antigens and initiation of an immune reaction against the thyroid, thyrocyte stimulation, and overproduction of thyroid hormones as autoantibodies target and activate the thyroid-stimulating hormone (TSH) receptor in the thyroid.

The autoimmune process in the orbital space that characterizes GO is likely triggered by autoreactive T lymphocytes that recognize antigens shared by the thyroid and orbit. The subsequent inflammatory cytokine release causes an expansion of the orbital fibroadipose tissue as well as infiltration and enlargement of the EOMs, with retrobulbar fibroblasts playing a key role in the development and progression of ophthalmopathy in patients with GD. The collagen fibrils and glycosaminoglycans that are deposited are extremely hydrophilic and can bind many times their weight in water. This further contributes to edema and EOM enlargement. Atrophy and muscle fibrosis then dominate the histologic picture as the disease becomes inactive.

Interestingly, although it typically appears in hyperthyroid Graves patients, GO may occur in hypo- or euthyroid patients as well. About 80% of GO cases occur within months of the onset of hyperthyroidism. The remaining 20% have onset that precedes or follows thyroid disease.

Genetics and Sex

GO is more common in females. The overall annual incidence rate for GO is 16 per 100,000 for women and 3 per 100,000 for men. The female-to-male ratio for severe forms of eye disease is 1 : 4. Although several potential genetic mutations have been identified, the penetrance of genetic determinants is likely quite low, given that GD is not a hereditary disease. However, it does often occur, along with autoimmune thyroiditis, within the same families. Ethnicity appears to play some role, as Europeans with GD are six times more likely to develop GO than are Asian patients. The reasons for ethnic differences are likely multifactorial and may include differences in orbital and lid anatomy, variations in autoimmune responses, or genetics.

Nongenetic Factors

Thyroid Status

Maintenance of a euthyroid state is ideal for GO. Many patients are on antithyroid drugs for the management of GD hyperthyroidism. These medications are associated with low toxicity and can be used for many years. Due to the potentially deleterious impact of fluctuations in thyroid status on GO, frequent monitoring of thyroid status every 4 to 6 weeks is recommended in the initial phases of treatment, when changes in thyroid status are expected. Unfortunately, less than 50% of patients treated with antithyroid medications remain in long-term remission. The relapse rate of hyperthyroidism after drug withdrawal is about 50%. For this reason, RAI or surgical management are often required for disease management over the long term. These treatment options are further discussed later in this chapter.

Natural History

GO presents in two distinct phases. The first is one of active inflammation and is characterized by periorbital edema and erythema, conjunctival chemosis, and orbital inflammation and congestion. Associated eyelid retraction, proptosis, and diplopia can also be seen. It is important to note that this phase is often mild and self-limited, requiring only supportive care.

The inflammatory phase is followed by a variable period of approximately 6 months to 2 years. A quiet, minimally inflammatory phase of chronic fibrosis then ensues. It is this phase that is associated with orbital fibrosis, glycosaminoglycan deposition, and enlargement of the EOMs. The end result can resemble the active inflammatory phase and is differentiated from it by the disease's time line.

Overall the natural history is variable. Approximately 50% of patients can expect spontaneous improvement. The disease stabilizes in 34% and worsens in 16%. Even in cases of remission, fibrosis and fat expansion usually persist. This fibrosis can actually lead to greater restriction than the inflammation of the active phase. In fact, fibrous changes can extend into adjacent adipose tissues. Furthermore, reactivation is not only possible but also fairly common.

Clinical Features