Graves' orbitopathy (GO) is the main extrathyroidal manifestation of Graves' disease, though severe forms are rare. Management of GO is often suboptimal, largely because available treatments do not target pathogenic mechanisms of the disease. Treatment should rely on a thorough assessment of the activity and severity of GO and its impact on the patient's quality of life. Local measures (artificial tears, ointments and dark glasses) and control of risk factors for progression (smoking and thyroid dysfunction) are recommended for all patients. In mild GO, a watchful strategy is usually sufficient, but a 6-month course of selenium supplementation is effective in improving mild manifestations and preventing progression to more severe forms. High-dose glucocorticoids (GCs), preferably via the intravenous route, are the first line of treatment for moderate-to-severe and active GO. The optimal cumulative dose appears to be 4.5-5 g of methylprednisolone, but higher doses (up to 8 g) can be used for more severe forms. Shared decision-making is recommended for selecting second-line treatments, including a second course of intravenous GCs, oral GCs combined with orbital radiotherapy or cyclosporine, rituximab or watchful waiting. Rehabilitative treatment (orbital decompression surgery, squint surgery or eyelid surgery) is needed in the majority of patients when GO has been conservatively managed and inactivated by immunosuppressive treatment.

GO is the most frequent extrathyroidal manifestation of Graves’ disease, although it may rarely occur in euthyroid/hypothyroid patients with chronic autoimmune thyroiditis. It is a relatively infrequent disorder, and men tend to have more severe ocular involvement at an older age. The prevalence of GO is lower than in the past among patients with recent onset Graves’ hyperthyroidism, and moderate-to-severe forms requiring aggressive treatments are no more than 5–6% of all cases of GO. After an initial inflammatory (active) phase and a phase of stabilization (plateau phase), GO tends to improve and eventually inactivates (inactive or burnt-out phase). Minimal-to-mild GO often remits spontaneously, but complete restitutio ad integrum almost never occurs when GO is more than mild. Several risk factors contribute to its development on a yet undefined genetic background. Cigarette smoking is the most important of them. Early diagnosis, control and removal of modifiable risk factors, early treatment of mild forms of GO may effectively limit the risk of progression to more severe forms, which have a profound and dramatic impact on the quality of life of affected individuals, and remain a therapeutic challenge, often requiring long-lasting and multiple medical and surgical therapies.

Background: Optimal doses of iv glucocorticoids for Graves' orbitopathy (GO) are undefined. Methods: We carried out a multicenter, randomized, double-blind trial to determine efficacy and safety of three doses of iv methylprednisolone in 159 patients with moderate to severe and active GO. Patients were randomized to receive a cumulative dose of 2.25, 4.98, or 7.47 g in 12 weekly infusions. Efficacy was evaluated objectively at 12 wk by blinded ophthalmologists and subjectively by blinded patients (using a GO specific quality of life questionnaire). Adverse events were recorded at each visit. Results: Overall ophthalmic improvement was more common using 7.47 g (52%) than 4.98 g (35%; P = 0.03) or 2.25 g (28%; P = 0.01). Compared with lower doses, the high-dose regimen led to the most improvement in objective measurement of ocular motility and in the Clinical Activity Score. The Clinical Activity Score decreased in all groups and to the least extent with 2.25 g. Quality of life improved most in the 7.47-g group, although not reaching statistical significance. No significant differences occurred in exophthalmos, palpebral aperture, soft tissue changes, and subjective diplopia score. Dysthyroid optic neuropathy developed in several patients in all groups. Because of this, differences among the three groups were no longer apparent at the exploratory 24-wk visit. Major adverse events were slightly more frequent using the highest dose but occurred also using the lowest dose. Among patients whose GO improved at 12 wk, 33% in the 7.47-group, 21% in the 4.98-group, and 40% in the 2.25-group had relapsing orbitopathy after glucocorticoid withdrawal at the exploratory 24-wk visit. Conclusions: The 7.47-g dose provides short-term advantages over lower doses. However, this benefit is transient and associated with slightly greater toxicity. The use of a cumulative dose of 7.47 g of methylprednisolone provides short-term advantage over lower doses. This may suggest that an intermediate-dose regimen be used in most cases and the high-dose regimen be reserved to most severe cases of GO.

A 40-year-old woman in whom Graves' disease was recently diagnosed comes for a follow-up visit. She has been taking methimazole, at a dose of 10 mg per day, and is now euthyroid, but for the past 3 months, she has had bothersome eye symptoms, including redness, tearing, grittiness, photophobia, diplopia at the extremes of gaze, and ocular pain associated with eye movements. She smokes 10 cigarettes per day. How should Graves' ophthalmopathy be managed?

Treatment with amiodarone is associated with changes in thyroid function tests, but also with thyroid dysfunction (amiodarone-induced hypothyroidism, AIH, and amiodarone-induced thyrotoxicosis, AIT). Both AIH and AIT may develop in apparently normal thyroid glands or in the presence of underlying thyroid abnormalities. AIH does not require amiodarone withdrawal, and is treated with levothyroxine replacement if overt, whereas subclinical forms may be followed without treatment. Two main types of AIT are recognized: type 1 AIT (AIT 1), a form of iodine-induced hyperthyroidism occurring in nodular goitres or latent Graves disease, and type 2 AIT (AIT 2), resulting from destructive thyroiditis in a normal thyroid gland. Mixed/indefinite forms exist due to both pathogenic mechanisms. AIT 1 is best treated with thionamides that may be combined for a few weeks with sodium perchlorate to make the thyroid gland more sensitive to thionamides. AIT 2 is treated with oral glucocorticoids. Once euthyroidism has been restored, AIT 2 patients are followed up without treatment, whereas AIT 1 patients should be treated with thyroidectomy or radioiodine. Mixed/indefinite forms of AIT are treated with thionamides. Oral glucocorticoids can be added from the beginning if a precise diagnosis is uncertain, or after a few weeks if response to thionamides alone is poor. The decision to continue or to stop amiodarone in AIT should be individualized in relation to cardiovascular risk stratification and taken jointly by specialist cardiologists and endocrinologists. In the presence of rapidly deteriorating cardiac conditions, emergency thyroidectomy may be required for all forms of AIT.