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Treatment of thyroid eye disease

Treatment of thyroid eye disease
Literature review current through: Jan 2024.
This topic last updated: Jan 29, 2024.

INTRODUCTION — Thyroid eye disease (also commonly referred to as Graves' orbitopathy or ophthalmopathy) is an autoimmune disease of the retro-orbital tissues occurring in patients with Graves' disease. This topic review will provide an overview of the natural history and treatment of this disorder. The pathogenesis, clinical features, and diagnosis are discussed separately. (See "Clinical features and diagnosis of thyroid eye disease".)

NATURAL HISTORY — The natural history of thyroid eye disease is variable and must be considered in the context of concomitant hyperthyroidism and its therapy [1-4].

Untreated thyroid eye disease typically follows a course of progression at variable rates, followed by a plateau or stabilization, and then varying degrees of improvement. The inflammatory manifestations of the disorder (eye irritation and conjunctival and periorbital edema) tend to subside, whereas proptosis (exophthalmos) and extraocular eye muscle dysfunction persist. While mild thyroid eye disease may remit spontaneously, moderate-to-severe disease rarely resolves without treatment.

One study, as an example, evaluated 237 patients with newly diagnosed Graves' hyperthyroidism who were treated with thionamides [1]. At initial presentation, the majority (73.7 percent) of patients had no ocular involvement, whereas mild, moderate-to-severe, and sight-threatening orbitopathy were present in 20, 5.8, and 0.3 percent of patients, respectively. During the 18-month follow-up period, progression to moderate-to-severe orbitopathy occurred in 2.6 percent of patients with no orbitopathy at baseline and in 2.4 percent of patients with mild activity at baseline. In contrast, 58 percent of patients with mild disease at baseline experienced complete remission.

The variable severity and course make it difficult to reach conclusions about the efficacy of treatment in the absence of well-controlled clinical trials. (See 'Initial medical therapy' below.)

MULTIDISCIPLINARY APPROACH — Treatment of patients with thyroid eye disease involves a multidisciplinary approach and includes:

Reversal of hyperthyroidism, if present

Monitoring for and prompt treatment of hypothyroidism, occurring as a consequence of treating hyperthyroidism

Cessation of smoking, if applicable

Local measures to reduce ocular surface irritation

Treatment of inflammation and swelling in the periorbital tissues

Monitoring for the development of sight-threatening disease

Patients with thyroid eye disease should be treated according to the severity of their eye disease (table 1), keeping in mind its natural history. Most patients have mild disease, with no progression during follow-up, and may be treated with local measures alone [1-4] (see 'Local measures' below). Patients with moderate-to-severe orbitopathy frequently require immunomodulatory therapy, and those with sight-threatening orbitopathy frequently require surgical intervention. (See 'Initial medical therapy' below and 'Sight-threatening disease' below.)

The multidisciplinary treatment strategy outlined below is largely consistent with guidelines from the American Thyroid Association (ATA) [5], European Thyroid Association [5], and European Group on Graves' Orbitopathy (EUGOGO) [6].

GENERAL MEASURES FOR MOST PATIENTS

Reversal of hyperthyroidism, if present — Euthyroidism should be restored in all patients with hyperthyroidism. (See "Graves' hyperthyroidism in nonpregnant adults: Overview of treatment", section on 'Treatment options'.)

Reduction of thyroid hormone synthesis – Reducing thyroid hormone secretion does not improve the pathology of thyroid eye disease, although it does decrease eyelid retraction and stare. Hypothyroidism, when it develops as a result of total thyroidectomy or radioiodine therapy for the treatment of hyperthyroidism, can cause more fluid retention and may have an adverse effect on the orbital pathology. Therefore, during and after treatment of hyperthyroidism, patients require monitoring for and prompt treatment of hypothyroidism. (See "Graves' hyperthyroidism in nonpregnant adults: Overview of treatment", section on 'Monitoring after treatment'.)

Choice of hyperthyroidism therapy in patients with active thyroid eye disease – Treatment with thionamides or thyroidectomy do not appear to have a negative influence on the course of thyroid eye disease [7,8]. Treatment with one of these modalities is usually followed by a fall in serum thyrotropin receptor antibody (TRAb) concentrations, suggesting a waning of autoimmunity. Radioiodine therapy, however, is more likely to lead to the development or worsening of eye disease than thionamides or surgery [7,9-12], and it is associated with an increase in TRAb (figure 1) [13]. Thus, moderate-to-severe or sight-threatening eye disease is a contraindication to radioiodine therapy. (See "Radioiodine in the treatment of hyperthyroidism", section on 'Radioiodine and thyroid eye disease'.)

Moderate-to-severe or sight-threatening thyroid eye disease – For patients with active and moderate-to-severe or sight-threatening eye disease, thionamides or surgery are the preferred treatment options. Patients who refuse surgery and who have had adverse reactions to thionamides may need to be offered radioiodine therapy with glucocorticoid coverage. (See "Radioiodine in the treatment of hyperthyroidism", section on 'Glucocorticoids in patients with thyroid eye disease'.)

Mild thyroid eye disease – Patients with active, mild thyroid eye disease are still candidates for thionamides, radioiodine, or surgery, although many clinicians avoid radioiodine in the presence of mild eye disease. If radioiodine is chosen, glucocorticoids should be administered concurrently to prevent deterioration of orbitopathy (table 2). (See "Radioiodine in the treatment of hyperthyroidism", section on 'Glucocorticoids in patients with thyroid eye disease'.)

For patients treated surgically, total thyroidectomy by an experienced thyroid surgeon is the procedure of choice. Total thyroidectomy eliminates more thyroid antigens than subtotal thyroidectomy, resulting in progressive decreases in antibodies to all major thyroid antigens and especially to the thyrotropin receptor [13,14]. (See "Surgical management of hyperthyroidism", section on 'Extent of resection'.)

Smoking cessation — All patients should be advised to discontinue smoking as cigarette smoking increases the incidence of symptomatic thyroid eye disease, increases the risk of worsening orbitopathy after radioiodine [12], and also renders patients more refractory to antiinflammatory therapy [15]. (See "Clinical features and diagnosis of thyroid eye disease", section on 'Risk factors'.)

Local measures — All patients should be advised of local measures to improve symptoms. Local measures include artificial tears (typically methylcellulose eye drops) and raising the head of the bed at night (theoretically to reduce orbital congestion). Photophobia and sensitivity to wind or cold air are often relieved by use of dark glasses and instillation of artificial tears every two to three hours during the day. Lubricants or ointments, such as petrolatum jelly and lid taping can be used at night. Eye patching or prisms incorporated into spectacles are also useful temporizing measures to treat diplopia while awaiting eye muscle stability before strabismus surgery.

ADDITIONAL TREATMENT ACCORDING TO SEVERITY OF ORBITOPATHY — Additional treatment of thyroid eye disease should be tailored according to the severity of the eye disease (table 1) [16].

Mild disease

Local measures – For patients with mild eye involvement (mild chemosis, mild-to-moderate eyelid swelling, absence of significant proptosis [often cited as <3 mm above upper limit of normal for race], no or intermittent diplopia, corneal exposure responsive to lubricants), local measures often lead to sufficient relief of eye symptoms, and no additional treatment is needed. (See 'Local measures' above.)

Selenium – Some UpToDate authors and editors suggest a six-month trial of selenium (100 mcg twice daily) in patients with mild orbitopathy, while others would not suggest selenium for patients residing in selenium-replete areas, such as the United States.

In a double-blind, placebo-controlled trial, selenium (100 mcg twice daily) for six months significantly improved soft-tissue swelling and quality-of-life measures [17]. Based on these results, European Group on Graves' Orbitopathy (EUGOGO) recommends a six-month course of selenium for patients with mild and active orbitopathy of relatively short duration [6]. Since participating centers in the selenium trial were located in areas of relative selenium insufficiency, it is not known whether similar results would be found in selenium-rich regions (eg, most of the United States). There were no adverse effects of selenium treatment in any of the thyroid eye disease studies, but selenium use has been associated with an increased risk of developing type 2 diabetes mellitus [18]. (See "Type 2 diabetes mellitus: Prevalence and risk factors", section on 'Selenium' and "Overview of dietary trace elements", section on 'Selenium'.)

Selenium supplementation may also decrease inflammatory activity in patients with autoimmune thyroiditis, as evidenced by a fall in thyroid antibody levels, and may also reduce the risk of postpartum thyroiditis in women who are positive for thyroid peroxidase (TPO) antibodies. (See "Postpartum thyroiditis", section on 'Prevention'.)

Moderate-to-severe disease — All patients should be advised of local measures to improve symptoms (see 'Local measures' above). Most patients with moderate-to-severe disease (table 1) will require additional therapy.

Initial medical therapy — For patients with moderate-to-severe orbitopathy, we suggest initial treatment with either teprotumumab or glucocorticoids. In the absence of comparative effectiveness trials, the choice of therapy should be individualized based upon the specific clinical features of the patient, shared decision-making, regional expertise, and availability of therapies.

Patients presenting primarily with severe inflammation and periorbital edema, in the absence of significant proptosis or diplopia – In the presence of severe inflammation and periorbital edema (ie, active disease (table 3)) and the absence of significant proptosis or diplopia, we prefer initial treatment with glucocorticoids. Intravenous (IV) glucocorticoids are generally preferred, but if not available, oral prednisone may be substituted [19]. (See 'Glucocorticoids' below.)

Patients presenting with proptosis, soft tissue involvement, and/or diplopia – In the presence of proptosis, soft tissue involvement, and/or diplopia, we prefer initial treatment with teprotumumab (if available). If not available, treatment with glucocorticoids is reasonable. (See 'Teprotumumab' below.)

For patients with moderate-to-severe orbitopathy, the initial treatment for many years has been with glucocorticoids, despite their many side effects. Glucocorticoids have a long track record supported by multiple lines of evidence (but sparse placebo-controlled trial data) and a known risk-to-benefit ratio [19-23]. In general, glucocorticoids provide improvement in active inflammation and less pronounced long-term improvement in proptosis or diplopia.

Some experts now advocate for broader use of teprotumumab (an insulin-like growth factor 1 [IGF-1] monoclonal blocking antibody), as a first-line medical therapy [24], although it is not available in Europe and many other countries. It is also very expensive (in excess of $300,000 USD for eight infusions), third-party payer coverage of this drug is variable, and preauthorization is often required. The European guidelines suggest IV glucocorticoids as monotherapy or in combination with oral mycophenolate (in the absence of teprotumumab being available) for people with moderate-to-severe and active thyroid eye disease [6].

There is only indirect information on comparative efficacy of teprotumumab with glucocorticoids, the standard therapy for patients with moderate-to-severe orbitopathy [25], and limited safety data (see 'Teprotumumab' below). Nevertheless, teprotumumab remains the only drug that has shown to result in significant improvement in proptosis. This effect is most likely secondary to inducing apoptosis of the retro-orbital fibroblasts and adipocytes [26,27].

As examples:

Short duration, active thyroid eye disease – In two 24-week trials comparing teprotumumab with placebo in 171 patients with active, moderate-to-severe orbitopathy diagnosed within nine months of trial entry (mean clinical activity score 5.2), a greater proportion of patients in the teprotumumab group had a reduction in clinical activity score and degree of proptosis (69 versus 20 percent with placebo and 78 versus 7 percent with placebo, respectively) [28-30]. The durability of the impressive initial response with teprotumumab compared with placebo is not well established. In the clinical trials, approximately 20 to 30 percent of patients failed to meet study definitions for response to therapy, and some responders experienced relapse [31,32].

Chronic, less active thyroid eye disease – There are limited data on the efficacy of teprotumumab in patients with longer duration, less active disease [33]. In a trial of teprotumumab or placebo in 62 patients with chronic thyroid eye disease (mean duration 5.2 years, mean clinical activity score 0.4), a greater proportion of patients in the teprotumumab group had a reduction in proptosis (61.9 versus 25 percent in the placebo group), with a mean proptosis reduction of 2.41 mm in the teprotumumab group versus 0.92 mm with placebo [34]. In a retrospective analysis of 31 patients with a mean disease duration of 81 months (mean clinical activity score 2.3) who had received at least three infusions of teprotumumab, 90 percent experienced proptosis reduction by ≥2 mm [35].

Administration of initial therapies

Glucocorticoids — IV methylprednisolone pulse therapy is preferred to oral dosing when available. IV therapy has the advantage of fewer side effects than high oral doses of prednisone [36-38]. IV methylprednisolone is given in a dose of 500 mg once weekly for weeks 1 to 6, then 250 mg once weekly for weeks 7 to 12 with cumulative dose 4.5 to 5 g over 12 weeks. In one small trial with identical cumulative IV methylprednisolone doses (4.5 g over 12 weeks), the efficacy and safety of monthly and weekly dosing were similar [23]. Very high IV doses (cumulative doses greater than 8 g) have been seen to induce liver failure and must be avoided [36].

If infusion therapy is not available or the patient refuses IV therapy, high dose of oral prednisone (eg, 60 to 100 mg/day) is an alternative [36,39-41]. In less severe disease, one UpToDate author first administers 30 mg/day before increasing to higher doses as needed.

In systematic reviews and meta-analyses of trials comparing treatments of thyroid eye disease, IV pulse glucocorticoids were more effective than oral glucocorticoids in reducing symptoms (overall response rate 82 versus 53 percent) [19,36]. The advantage was mostly due to improvements in patients with more severe disease [19].

As an example, in a trial of 70 euthyroid patients with untreated, severe thyroid eye disease randomly assigned to receive once-weekly IV methylprednisolone (0.5 g, then 0.25 g, weekly for six weeks each) or a high dose of oral prednisone (100 mg per day, tapering by 10 mg per week), the following results were seen [39]:

At three months, 27 of 35 patients (77 percent) in the IV group had a treatment response compared with 18 of 35 (51 percent) in the oral group.

Improvements over baseline for visual acuity, chemosis, and quality of life were greater in the IV group.

Additional treatment was required less frequently in the IV group.

Adverse events were less frequent with IV glucocorticoids.

Improvement usually occurs within four weeks. Approximately one-half of patients have a good response to prednisone by the end of six months; those patients with less muscle swelling are more likely to respond [42]. However, given the many side effects of prolonged high-dose prednisone treatment, other approaches should be considered if the patient does not respond in four to six weeks (see "Major adverse effects of systemic glucocorticoids"). If a good response occurs, the daily dose should be decreased to the lowest dose at which improvement is maintained. In some patients, the eye disease worsens when the dose of prednisone is reduced.

Patients taking long-term glucocorticoids require a skeletal assessment to identify individuals at high risk for fracture who would benefit from intervention. This is particularly important in postmenopausal women. This topic is reviewed separately. (See "Clinical features and evaluation of glucocorticoid-induced osteoporosis", section on 'Evaluation' and "Prevention and treatment of glucocorticoid-induced osteoporosis".)

Teprotumumab

DosingTeprotumumab is administered every three weeks as an IV infusion (10 mg/kg initial dose, then 20 mg/kg) for a total of eight infusions [30].

Adverse effects – Nausea (17 versus 9 percent), diarrhea (12 versus 8 percent), muscle spasms (25 versus 7 percent), hyperglycemia (10 versus 1 percent), and hearing impairment (10 to 15 versus 0 percent) were reported more frequently in the teprotumumab group [29,31,43,44]. Other adverse reactions that occurred more commonly with teprotumumab included alopecia, fatigue, dysgeusia, headache, and dry skin. Patients with type 2 diabetes may experience deterioration in glycemic control [45].

In a systematic review of adverse effects, 7 to 81 percent of patients with thyroid eye disease reported hearing changes (eg, ear fullness, pressure, tinnitus, hearing loss) after a mean of 3.8 teprotumumab infusions [45]. Audiograms were not routinely performed. In a subsequent observational study evaluating hearing outcomes following teprotumumab therapy, 21 percent (11 of 52 patients) had a decline in hearing on audiometry immediately after completing therapy [46]. A decrease in hearing was more common in patients with baseline hearing dysfunction (10 of the 11 patients). After six months follow-up, 5 of 11 patients had persistent changes on audiometry.

Monitoring – It is important to discuss potential adverse events prior to initiating therapy and review symptoms at each visit. The approach to monitoring for hyperglycemia and hearing loss varies. It is reasonable to obtain baseline audiometry and repeat in individuals who report any change in hearing. Some experts measure glucose prior to each infusion (either venipuncture or capillary glucose with a glucometer) and suggest more frequent glucose assessments in patients who develop symptoms of hyperglycemia or who are at high risk for developing hyperglycemia (eg, history of prediabetes, older age) [45].

ContraindicationsTeprotumumab is contraindicated during pregnancy and in children, settings in which interference with growth hormone-IGF-1 activity would be harmful [47].

Contraindications, intolerance, or lack of response to initial therapy — If there is no initial response to the first few doses of glucocorticoids and a decision is made to proceed with alternative medical therapy, we suggest teprotumumab (if available), although there are no clinical trial data examining the efficacy of teprotumumab in patients with glucocorticoid-refractory eye disease. Observational data suggest teprotumumab is effective in patients with persistent eye disease after treatment with glucocorticoids and/or orbital radiation [48].

If both teprotumumab and high-dose glucocorticoid therapy are contraindicated, cannot be tolerated, or are ineffective, options include other medical immunosuppressive therapies (eg, rituximab, tocilizumab), external orbital radiation, or orbital decompression surgery. (See 'Secondary medical therapies' below and 'External orbital radiation' below and 'Orbital decompression surgery' below.)

Secondary medical therapies — There are few direct comparison trials to guide the selection of secondary therapies. Trial data also show efficacy for tocilizumab (an interleukin 6 [IL-6] antibody) compared with placebo in glucocorticoid refractory thyroid eye disease [49], rituximab compared with IV glucocorticoids [50], and mycophenolate mofetil compared with IV glucocorticoids [51]. As with choosing initial medical therapy, the selection of secondary therapies should be individualized based upon the clinical presentation of the patient, shared decision-making, regional expertise, and availability of therapies.

TocilizumabTocilizumab targets IL-6 and has been used in patients with rheumatoid arthritis. It has also been investigated for the treatment of patients with thyroid eye disease who are not improving with glucocorticoids [49,52]. In a randomized trial, 32 patients with thyroid eye disease were randomly assigned to tocilizumab (8 mg/kg) or placebo IV at 0, 4, 8, and 12 weeks [49]. Treatment with tocilizumab was associated with greater improvement in clinical activity score at 16 weeks (93.3 versus 58.8 percent with placebo) and improvement in a composite ophthalmic score at 16 weeks (73.3 versus 29.4 percent), but no significant differences between groups at 40 weeks.

Rituximab – In observational studies, rituximab, a powerful anti-B cell monoclonal antibody, has been reported to be as effective as glucocorticoids without the glucocorticoid-related side effects [53-56]. Rituximab induces a fall in thyrotropin receptor antibody (TRAb) levels [57] and depletion of B cells in the retro-orbital tissues, not just the periphery [58]. Although high doses of this antibody may be associated with severe side effects from the profound immunosuppression that ensues, lower doses (two infusions of 1000 mg each, one to two months apart) may be effective in thyroid eye disease and allow severe immunosuppression to be avoided.

Two trials evaluating rituximab therapy (total dose 500 to 2000 mg) for thyroid eye disease showed conflicting results, although patients differed in disease severity and duration in these studies [50,59]. The selection of patients for rituximab therapy is important, as patients with severe, new-onset thyroid eye disease may be those who benefit most from this approach. The trial that showed the effectiveness of rituximab treated the disease earlier in its evolution and included more severely affected patients, while the negative trial studied patients with milder signs later in the course of their disease.

Both studies showed a high rate of adverse effects from rituximab, including new optic neuropathy and infusion reactions. Very low-dose rituximab (single infusion of 100 mg) appears to be effective in active, moderate-to-severe thyroid eye disease and may reduce adverse effects [60]. The therapeutic benefit of rituximab, however, remains uncertain despite the seemingly logical action of the approach.

Mycophenolate mofetilMycophenolate mofetil is under investigation for the treatment of thyroid eye disease, either alone or in combination with glucocorticoids [51,61]. Although many endocrine specialists are wary of using such a powerful immunosuppressant requiring careful initial monitoring, it is a well-tolerated drug.

In a trial comparing mycophenolate mofetil (500 mg twice a day for 24 weeks) with glucocorticoids (0.5 g IV daily for three days [two consecutive weeks] followed by 60 mg oral daily for eight weeks and then tapered) in 174 Chinese patients with active, moderate-to-severe thyroid eye disease, the overall response at 24 weeks was better with mycophenolate (91.3 versus 67.9 percent) [51]. In a second trial comparing IV glucocorticoids alone to glucocorticoids plus mycophenolate mofetil, the response rate in the monotherapy versus the combination group at 12 and 24 weeks was 49 versus 63 percent and 53 versus 71 percent, respectively. Only the 24-week findings were statistically significant. A sustained response at 36 weeks occurred in 46 and 67 percent, respectively [62].

Mycophenolate is a strong immunosuppressive with relatively mild side effects, widely used after transplantation [61,63]. It is a potent, selective, noncompetitive, and reversible inhibitor of inosine-5'-monophosphate dehydrogenase [63]. By depleting guanosine and deoxyguanosine nucleotides in T and B lymphocytes, it inhibits their proliferation and reduces immunoglobulin in production. This drug also suppresses dendritic cell maturation, decreasing its capacity for antigen presentation to T lymphocytes.

External orbital radiation — External radiation is used infrequently, possibly because of retinal side effects seen early in its introduction, as well as questionable long-term beneficial effects from this modality. Furthermore, the availability of alternative secondary therapeutics has made the approach less useful. It is still sometimes used in patients with moderate-to-severe eye disease in whom IV glucocorticoids are contraindicated, cannot be tolerated, or are ineffective.

In theory, radiotherapy kills retro-orbital T cells. The usual dose for treatment of the retro-orbital area is 2000 rads (20 Gy), administered in 10 fractions of 200 rads (2 Gy) over two weeks. However, the value of orbital radiation alone remains controversial. In two trials, it was more effective than glucocorticoid therapy [37,64]; however, two additional trials comparing orbital radiation with sham irradiation found no benefit [65,66], and in a meta-analysis of three trials, orbital radiation was no better than sham radiation for improvement in clinical activity score but was better for diplopia [19].

In contrast, trials of combined radiation and glucocorticoid therapy have suggested that the combination may be more effective than either alone [19,67,68]. In a randomized trial of 82 patients with thyroid eye disease treated with high-dose IV or oral glucocorticoid (combined with orbital radiation), the IV route was more effective, better tolerated, and associated with fewer side effects [40]. Thus, if combined therapy is used, IV glucocorticoids may be preferable.

It is unclear whether orbital radiation provides lasting benefit. In one randomized trial, radiotherapy was effective in improving eye muscle motility and decreasing the severity of diplopia, but it did not prevent subsequent worsening of orbitopathy [69]. In the same trial, orbital radiotherapy did not improve quality of life or management costs [69]. Although orbital radiation improved diplopia significantly compared with sham irradiation in one trial, most irradiated patients still required strabismus surgery to correct extraocular muscle dysfunction. In addition, retro-orbital irradiation has been reported to have serious, long-term side effects when used alone. Potential side effects reported in 204 patients with a mean follow-up of 11 years included cataracts in 18 percent treated with a cobalt unit and 8 percent treated by linear accelerator (compared with the general population, the rates were not significantly elevated in patients under age 60 years) and mild retinopathy in 14 percent of patients with diabetes and hypertension [70]. Transient blindness can also occur due to inadvertent injury to the optic nerve [71].

Other medical therapies

Statins – Statins have been shown to have a protective effect on the development of thyroid eye disease [72] and a potential therapeutic benefit in patients with thyroid eye disease [73]. As an example, in one trial, 119 patients with moderate-to-severe thyroid eye disease and hypercholesterolemia were randomly assigned to receive oral atorvastatin for 12 weeks or no statin [73]. All patients were treated with methylprednisolone. After 24 weeks, orbitopathy outcome became improved in 51 percent of individuals in the atorvastatin group compared with 28 percent in the control group. Additional studies are warranted.

Sight-threatening disease — Sight-threatening thyroid eye disease occurs in 1 to 2 percent of patients with Graves' disease [74]. Threatened loss of vision, often preceded by loss of color vision, is an ophthalmologic emergency. Close and coordinated observation of the effects of medical therapy and the progress of the disease is necessary to determine whether and when a surgical approach to treatment is needed in the patient with visual loss. Decompression surgery almost invariably halts the progress of the disease and preserves vision if performed in time and with expertise. How the use of the newer medical therapies (eg, teprotumumab) will change these approaches remains to be seen [75].

IV glucocorticoids — Patients with sight-threatening eye disease should receive immediate glucocorticoid therapy, preferably IV (eg, methylprednisolone, 0.5 to 1 g daily for either three consecutive days or on every second day), and should be hospitalized for possible urgent orbital decompression surgery if the response is inadequate. This approach is in agreement with European guidelines [6]. (See 'Orbital decompression surgery' below.)

Clinical outcome appears to be better if decompression surgery is performed after rather than before glucocorticoid therapy. This was illustrated in a small trial of 15 patients randomly assigned to initial therapy with IV methylprednisolone or orbital decompression [76]. In the group of patients who initially received surgery, 83 percent subsequently required methylprednisolone, and some also required orbital irradiation, while 56 percent of the patients initially treated with methylprednisolone required surgery or orbital irradiation.

Orbital decompression surgery — With the advent effective medical therapy (eg, teprotumumab) to reduce proptosis and muscle volume, it is likely that fewer patients will require orbital decompression surgery.

Indications for orbital decompression surgery include [77]:

Optic neuropathy caused by enlarged extraocular muscles not responsive to high-dose corticosteroids.

Severe orbital inflammation.

Excessive proptosis leading to exposure keratitis, corneal ulceration, or debilitating cosmetic defect.

Pain relief.

Progressive orbitopathy not responding to other measures.

The orbit may be decompressed by removing the lateral wall, the roof, or the medial wall and the floor [78,79]. Our experience has been with the last procedure, known as transantral decompression, in which the surgeon removes the floor and medial wall of the orbit to allow decompression (figure 2). In addition, it does not leave a scar on the face and avoids craniotomy.

An excellent result can usually be achieved, with substantial reduction in proptosis and edema. However, diplopia usually does not improve and may worsen, so that eye muscle surgery is almost always needed later.

In a series of 78 patients who had transantral or endonasal decompression [80]:

Proptosis was reduced by 4.4 to 4.7 mm (left and right eyes)

Visual acuity improved in 44 to 55 percent and worsened in 18 to 20 percent

Diplopia persisted in 50 percent but was improved in 54 percent

Nonurgent cosmetic surgery — Occasional patients require plastic surgery to correct marked periorbital edema, while many others choose to have cosmetic correction of relatively mild edema. Surgery for a cosmetic correction should wait until the disease enters its quiescent stages or it may precipitate a worsening of the inflammation.

Fat decompression surgery (removing the retro-orbital adipose tissue) has been performed for many years and can produce a cosmetic correction in patients with moderate thyroid eye disease and significant proptosis [81]. Bilateral, lateral tarsorrhaphy may also be performed to minimize or prevent corneal damage in patients who have severe proptosis and cannot close their eyes. Surgical recession of Muller's muscle and the levator will correct upper lid retraction. However, decompression surgery is preferable for both of these problems because it is more effective both functionally and cosmetically. For patients requiring both strabismus surgery and orbital decompression, the decompression should be performed first, followed by strabismus surgery.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Hyperthyroidism".)

SUMMARY AND RECOMMENDATIONS

Multidisciplinary approach – Patients with thyroid eye disease should be treated according to disease severity (table 1), keeping in mind that most patients have mild disease and do not have progression during follow-up. Treatment involves a multidisciplinary approach and includes reversal of hyperthyroidism (if present), smoking cessation, local measures to reduce ocular surface irritation, reduction of inflammation in the periorbital tissues, and monitoring for the development of sight-threatening disease. (See 'Multidisciplinary approach' above.)

General measures

Reversal of hyperthyroidism, if present – Euthyroidism should be restored in all patients with hyperthyroidism. Treatment with thionamides or thyroidectomy do not appear to have a negative influence on the course of thyroid eye disease, whereas radioiodine is more likely to lead to the development or worsening of eye disease. (See 'Reversal of hyperthyroidism, if present' above and "Radioiodine in the treatment of hyperthyroidism", section on 'Radioiodine and thyroid eye disease'.)

Smoking cessation – All patients should be strongly advised to discontinue smoking as cigarette smoking increases the incidence of symptomatic thyroid eye disease, increases the risk of worsening orbitopathy after radioiodine, and reduces the efficacy of glucocorticoid therapy. (See 'Smoking cessation' above and "Clinical features and diagnosis of thyroid eye disease", section on 'Risk factors'.)

Local measures for all patients – Local measures to improve symptoms include lubricating eye drops, raising the head of the bed at night, and eye patching or prisms for diplopia. Photophobia and sensitivity to wind or cold air are often relieved by use of dark glasses and instillation of lubricating eye drops every two to three hours during the day and of lubricating ointments or lid taping at night. (See 'Local measures' above.)

Mild orbitopathy – For patients with mild orbitopathy, local measures are usually effective to relieve eye symptoms, and no additional treatment is needed. Some UpToDate authors and editors suggest a six-month trial of selenium in patients with mild orbitopathy, while others would not suggest selenium for patients residing in selenium-replete areas, such as the United States. (See 'Mild disease' above.)

Moderate-to-severe orbitopathy – For patients with moderate-to-severe orbitopathy, we suggest initial treatment with either teprotumumab or glucocorticoids (Grade 2C). In the absence of comparative effectiveness trials, the choice of therapy should be individualized based upon the clinical presentation of the patient, shared decision-making, regional expertise, and availability of therapies. (See 'Moderate-to-severe disease' above.)

Patients presenting primarily with severe inflammation and periorbital edema, in the absence of significant proptosis or diplopia – In the presence of severe inflammation and periorbital edema (ie, active disease (table 3)) and the absence of significant proptosis or diplopia, we prefer initial treatment with glucocorticoids. Intravenous (IV) glucocorticoids are generally preferred, but if not available, oral prednisone may be used. (See 'Glucocorticoids' above.)

Proptosis, soft tissue involvement, and/or diplopia – In the presence of proptosis, soft tissue involvement, and/or diplopia, we prefer initial treatment with teprotumumab infusions (if available). If not available, treatment with glucocorticoids is reasonable. (See 'Teprotumumab' above.)

If first-line therapy is contraindicated, cannot be tolerated, or is ineffective, options include other medical therapies, external orbital radiation, or orbital decompression surgery. The choice of therapy should be individualized based upon shared decision-making, regional expertise, availability of therapies, and cost. Alternative medical therapies include tocilizumab, rituximab, and mycophenolate mofetil. (See 'Contraindications, intolerance, or lack of response to initial therapy' above.)

Sight-threatening orbitopathy – Patients with sight-threatening orbitopathy should receive immediate glucocorticoid therapy (eg, IV methylprednisolone, 0.5 to 1 g daily for either three consecutive days or on every second day) and should be hospitalized for possible urgent orbital decompression surgery. (See 'Sight-threatening disease' above and 'Orbital decompression surgery' above.)

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Topic 7827 Version 23.0

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