The mainstay of medical therapy in the management of hyperthyroid patients is anti-TDs. Most anti-TDs belong to the thionamide class, which includes propylthiouracil (PTU), methimazole (MZ), and carbimazole. The latter is only available in Europe and Asia, while the former two are generally used in the United States. Chapter 1 discusses the relative merits of methimazole and recommends restricting the use of PTU to women in early pregnancy. These drugs reduce the production of thyroid hormone by inhibiting the coupling of iodothyronines [6]. In prescribing anti-TDs, two general strategies are used: the block-replace regimen and the titration regimen. In the block-replace regimen, thyroid hormone production is functionally “blocked” by a high dose of the anti-TD which completely suppresses hormone production and “replaced” by adding levothyroxine at a dose that achieves a euthyroid state. In contrast, the titration regimen consists of titrating down to the minimum dose of anti-TD needed to maintain a euthyroid state. A recent Cochrane review comparing anti-TD regimens demonstrated that the titration regimen is equally effective to the block-replace regimen for the management of hyperthyroidism with fewer adverse effects [7]. In most studies medical therapy for Graves’ hyperthyroidism has not been associated with progression of orbitopathy [8]. In addition, there is a theoretical benefit to the use of anti-TDs because thyroid stimulating hormone receptor antibody (TSHR Ab) levels correlate with disease severity, and anti-TDs have been shown to cause a more rapid reduction in TSHR Ab levels than surgery or RAI [1, 9]. Further work is needed to determine whether there are significant differences in TED onset or progression in patients treated with anti-TDs with either the block-replace or titration regimen. Though often preferred, anti-TDs are not without side effects, which may include rash, fever, urticaria, and arthralgia in up to 5 % of patients [6]. Major side effects are rare but include agranulocytosis, hepatotoxicity, aplastic anemia, and vasculitis indicating that the use of anti-TDs should be closely monitored especially for long-term treatment.

RAI therapy uses the radioactive isotope ¹³¹I to ablate thyroid follicular cells, which abrogates thyroid hormone production [6]. It is often first-line treatment for hyperthyroidism or in cases of recalcitrant hyperthyroidism following anti-TD treatment. The main contraindications to RAI are pregnancy and breastfeeding because the isotope crosses the placenta and is excreted in breast milk [10] (see Chap. 7). Achievement of a euthyroid state after RAI treatment may take several months, and sometimes a second treatment may be required.

RAI is the preferred modality for the treatment of uncomplicated GD among 45 % of practitioners in the United States [11, 12]. It effectively treats hyperthyroidism in nearly all patients but has a relapse rate of approximately 21–28 %. Relapse rates of up to 48 % have been reported in select patient groups and large goiter size is a risk factor for recurrent hyperthyroidism [5, 13]. Persistent hypothyroidism after RAI has been reported to worsen TED, so close monitoring of thyroid function and prompt replacement with levothyroxine is essential.

Several randomized trials have compared the effects of RAI and anti-TD on TED onset or progression. One randomized study with 4-year follow-up demonstrated that 39 % of patients treated with RAI experienced worsening or new onset TED, compared to 21 % of methimazole-treated patients [14]. In sub-group analysis, RAI was associated with an increased risk of development of new onset TED, but the rate of worsening of preexisting TED did not differ significantly between the two treatment groups [14]. Another randomized trial comparing RAI to anti-TD found that after 9 years, there was no difference in the percentage of patients with worsened or new onset TED, but that more patients treated with RAI had an improvement in TED compared to those treated with methimazole; euthyroid status after treatment correlated with improved TED in both treatment groups [15]. Similarly, a randomized trial from Hong Kong showed that at 2 years following treatment, the rates of developing new or worsened TED was not significantly different in patients treated with RAI alone or a 12-month course of methimazole, and the development of new or progression of TED was associated with hypothyroidism and increased TSH [2]. Therefore, randomized studies show that RAI may be associated with TED progression compared to anti-TDs, but this association may be secondary to increased rates of post-treatment hypothyroidism. Prevention of early hypothyroidism after treatment with RAI may prove beneficial in preventing the progression of TED.

RAI may also exacerbate TED secondary to increased antithyroid antibody levels. In a 5-year prospective randomized trial, patients treated with RAI had significantly higher TSHR Ab levels at all stages after treatment compared to patients treated with anti-TD or surgery [1, 9]. Given the correlation between TSI levels and TED severity and activity, this is a theoretical disadvantage to the use of RAI [16].

The use of prophylactic corticosteroids in conjunction with RAI can prevent progression of orbitopathy [3, 17–19]. A cohort study of TED patients treated with RAI demonstrated that prophylactic treatment with corticosteroids prevented worsening orbitopathy [19]. Other studies have shown that RAI treatment without corticosteroids was associated with the onset or progression of orbitopathy in 15 % of patients, but treatment with prednisone reduced the rate to 0 % [3]. In comparison, progressive or new orbitopathy was observed in 3 % of methimazole-treated patients [3]. No significant difference was seen in TED progression or incidence in patients treated with RAI and corticosteroids compared to those treated with methimazole; however, two-thirds of patients treated with RAI and corticosteroids had an improvement in the severity of TED, which was significantly higher than the proportion of patients treated with methimazole whose TED improved (2 %) [3]. Most of the changes in TED occurred within the first 6 months after treatment [3]. A systematic review of randomized controlled trials using RAI for hyperthyroidism showed a relative risk of 4.2 for the development or progression of TED when RAI was used compared to anti-TDs; the relative risk of severe TED was 4.3 for treatment with RAI compared to anti-TDs [18]. The use of prophylactic steroids with RAI, however, reduced the risk of progression of TED to 0 [18]. In summary, the data demonstrate that use of prophylactic glucocorticoids with RAI is effective in minimizing the risk for progression of orbitopathy, and furthermore may lead to improvement of TED.