5/15/2020 Treatment of Graves' orbitopathy (ophthalmopathy) - UpToDate

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Treatment of Graves' orbitopathy (ophthalmopathy)

Authors: Terry F Davies, MD, FRCP, FACE, Henry B Burch, MD
Section Editor: Douglas S Ross, MD
Deputy Editor: Jean E Mulder, MD

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Apr 2020. | This topic last updated: Apr 03, 2020.

INTRODUCTION

Graves' orbitopathy (ophthalmopathy) is an autoimmune disease of the retroorbital tissues. This

topic review will provide an overview of the treatment of this disorder; its pathogenesis, clinical
features, and diagnosis are discussed separately. (See "Clinical features and diagnosis of Graves'
orbitopathy (ophthalmopathy)".)

NATURAL HISTORY

The natural history of Graves' orbitopathy is variable and must be considered in the context of
concomitant hyperthyroidism therapy [1-3].

In some patients, orbitopathy changes little for many years. In others, it may worsen or improve or,
in a few patients, follow a course characterized by exacerbations and remissions. These variations
make it especially difficult to reach conclusions about the efficacy of treatment. (See 'Efficacy'
below.)

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.

APPROACH TO TREATMENT
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Treatment of patients with Graves' orbitopathy 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

Patients with Graves' orbitopathy should be treated according to the severity of their eye disease,
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 [1-3] (see 'Local measures' below).
Patients with moderate-to-severe orbitopathy frequently require immunomodulatory therapy, and
those with sight-threatening orbitopathy frequently require surgical rehabilitation. The natural
history of orbitopathy is such that the inflammatory manifestations of the disorder (eye irritation
and conjunctival and periorbital edema) tend to subside, whereas proptosis and extraocular eye
muscle dysfunction persist.

The treatment strategy outlined below is largely consistent with guidelines from the American
Thyroid Association [4] and European Thyroid Association [5].

Reversal of hyperthyroidism, if present — Euthyroidism should be restored in all patients with

hyperthyroidism. The therapeutic approach to Graves' hyperthyroidism consists of both rapid
amelioration of hyperthyroid symptoms with a beta blocker and measures aimed at decreasing
thyroid hormone synthesis, typically with the administration of a thionamide or surgery. (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 Graves' orbitopathy, although it does decrease eyelid retraction and
stare. Hypothyroidism, should it develop during the course of therapy for hyperthyroidism, can
cause more fluid retention and may have an adverse effect on the orbitopathy. 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 orbitopathy – Treatment with

thionamides or thyroidectomy do not appear to have a negative influence on the course of
orbitopathy [6,7]. 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, appears more likely to lead to the development or worsening of
orbitopathy than thionamides or surgery [6,8-11], and it is associated with a sustained

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increase in TRAb (figure 1) [12]. Thus, moderate-to-severe or sight-threatening orbitopathy is

a contraindication to radioiodine therapy. (See "Radioiodine in the treatment of
hyperthyroidism", section on 'Radioiodine and orbitopathy'.)

• For patients with active and moderate-to-severe or sight-threatening orbitopathy,

thionamides or surgery are the preferred treatment options. Patients who refuse surgery
and who have contraindications to thionamides may need to be offered radioiodine
therapy with steroid coverage. (See "Radioiodine in the treatment of hyperthyroidism",
section on 'Glucocorticoids in patients with orbitopathy'.)

• Patients with active, mild orbitopathy may still be candidates for thionamides, radioiodine,
or surgery. If radioiodine is chosen, glucocorticoids should be administered concurrently
for those with risk factors for progression (smoking or a high baseline serum
concentration of triiodothyronine [T3; eg, >325 ng/dL (5 nmol/L)] or TRAbs) to prevent
deterioration of orbitopathy (table 1). (See "Radioiodine in the treatment of
hyperthyroidism", section on 'Glucocorticoids in patients with orbitopathy'.)

For patients treated surgically, total thyroidectomy 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 (figure 1) [12,13]. In one study, total thyroidectomy was associated with
less progression of proptosis postoperatively than subtotal thyroidectomy [14]. However, in
another study, patients who had a total versus a subtotal thyroidectomy when compared after
three years were found to have similar improvement in orbitopathy (and surgical
complications were higher in the total thyroidectomy group) [15]. (See "Surgical management
of hyperthyroidism", section on 'Extent of resection'.)

The potential benefit of eliminating all thyroid antigens was evaluated in two randomized trials
of thyroidectomy followed by radioiodine. In a small study of patients with mild-to-moderate
orbitopathy, near-total thyroidectomy followed by radioiodine was associated with less active
orbitopathy than near-total thyroidectomy alone; both groups received intravenous (IV)
steroids [16]. In a one-year study of thyroidectomy alone versus thyroidectomy followed by
radioiodine ablation of surgical remnants using recombinant human thyrotropin (rhTSH), 75
percent of patients who received radioiodine after thyroidectomy had inactive eye disease
versus 30 percent of the patients who had only a thyroidectomy [17].

Smoking cessation — All patients should be advised to discontinue smoking as cigarette

smoking increases the incidence of symptomatic Graves' orbitopathy, increases the risk of
worsening orbitopathy after radioiodine [11], and also renders patients more refractory to
antiinflammatory therapy [18]. (See "Clinical features and diagnosis of Graves' orbitopathy
(ophthalmopathy)", section on 'Smoking'.)

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Local measures — All patients should be advised of local measures to improve symptoms. Local
measures include eye shades, artificial tears (saline eye drops), and raising the head of the bed at
night. 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 and of lubricants, such as 1%
methylcellulose drops and/or petrolatum jelly, at night. Eye patching or prisms 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 Graves'

orbitopathy should be tailored according to the severity of the eye disease [19].

Mild symptoms — For patients with mild symptoms (mild chemosis, mild-to-moderate eyelid
swelling, proptosis <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.)

Some studies suggest that selenium (100 mcg twice daily) for six months may improve soft-tissue
swelling and quality-of-life measures (see 'Selenium' below). Based on the results of a large,
prospective, multicenter trial, the European Thyroid Association recommends a six-month course
of selenium for patients with mild orbitopathy of relatively short duration [5]. 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 Graves' orbitopathy studies to
date, but selenium use has been associated with an increased risk of developing type 2 diabetes
mellitus (see "Risk factors for type 2 diabetes mellitus", section on 'Selenium'). 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.

Nonsteroidal antiinflammatory drugs (NSAIDs), including cyclooxygenase 2 (COX-2) inhibitors,

may also be helpful in some patients with mild symptoms of eye irritation, although there are no
clinical trials supporting their use.

Moderate-to-severe or progressive symptoms

● Glucocorticoids – For patients with moderate-to-severe orbitopathy, we suggest initial

treatment with glucocorticoids [20]. These can be given either orally or IV, depending on the
severity of the disease. For the patient with moderate symptoms (inflamed eyes and
increasing diplopia or proptosis [≥3 mm above upper limit of normal for race], mild corneal
irritation), a trial of oral (prednisone, 30 mg/day for four weeks) or IV (methylprednisolone, 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) glucocorticoid therapy should be initiated. If the initial oral

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dose is ineffective, higher doses may be required and a switch to the IV route should be
made. For more severe or progressive cases, initial IV therapy is appropriate [21,22].

The European Thyroid Association recommends initial treatment with IV glucocorticoids

(methylprednisolone, dose as above) for moderate-to-severe, active orbitopathy, citing several
studies that suggest it is more efficacious and associated with fewer side effects than oral
therapy [5] (see 'Glucocorticoids' below). Similar trials have not been performed in the United
States, where initiation with oral glucocorticoids remains the most common first-line
treatment.

● Contraindications, intolerance, or lack of response to glucocorticoids – If high-dose

glucocorticoid therapy is contraindicated, cannot be tolerated (eg, steroid psychosis, poorly
controlled diabetes), or is ineffective, options include other medical therapies, external orbital
radiation, or orbital decompression surgery. (See 'Medical therapies' below and 'External
orbital radiation' below and 'Orbital decompression surgery' below.)

The choice of therapy should be individualized based upon shared decision-making, regional
expertise, availability of therapies, and cost. There are few direct comparison trials to guide
the selection of secondary therapies. 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 (an insulin-like growth factor 1 [IGF-1] receptor antibody).
Randomized trial data show striking efficacy compared with placebo [23-25] (see
'Teprotumumab' below). Trial data also show efficacy for mycophenolate mofetil compared
with IV glucocorticoids [26], and tocilizumab (an interleukin-6 antibody) compared with
placebo [27]. (See 'Medical therapies' below.)

Sight threatening — Sight-threatening Graves' orbitopathy may occur in 3 to 5 percent of

patients with Graves' disease [28]. Threatened loss of vision, often preceded by loss of color
vision, is a medical emergency. Such a patient should receive immediate glucocorticoid therapy,
preferably intravenously (dexamethasone, 4 mg IV), and should be hospitalized for possible
urgent orbital decompression surgery.

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. (See 'Orbital decompression
surgery' below.)

EFFICACY

Medical therapies

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Selenium — Selenium may improve symptoms in patients with mild Graves' orbitopathy,
particularly patients residing in areas of relative selenium insufficiency. One trial compared
selenium (100 mcg twice daily), pentoxifylline (600 mg twice daily), or placebo in 159 patients from
a region in which selenium levels are marginally decreased [29]. These patients had at least one
sign of mild orbitopathy (chemosis, mild-to-moderate eyelid swelling, exophthalmos ≤22 mm) and
disease duration of <18 months. All patients were euthyroid while taking thionamides or, less
commonly, after thyroidectomy or radioiodine treatment. After six months of treatment, eyelid
aperture (37 versus 12 percent) and soft-tissue signs (43 versus 32 percent) significantly improved
in patients taking selenium versus placebo. Compared with placebo, selenium also significantly
improved quality of life (both visual functioning and appearance scores), as assessed by the
Graves' Orbitopathy Quality of Life Questionnaire (GO-QOL). Evaluation at 12 months confirmed
the findings at six months. Neither placebo nor pentoxifylline improved quality-of-life measures.

Although there were no adverse effects of selenium treatment in any of the orbitopathy studies
reported to date, it is uncertain if selenium would benefit individuals with mild Graves' orbitopathy
who are from selenium-rich regions (eg, most of the United States). Long-term selenium
supplementation (200 mcg daily) has been associated with an increased risk of developing type 2
diabetes mellitus. (See "Risk factors for type 2 diabetes mellitus", section on 'Selenium'.)

Selenium is a trace mineral with a role in multiple biologic functions. More than 30 selenoproteins
have been identified, of which the best known are the four forms of glutathione peroxidase, which
are important in antioxidant defense, and iodothyronine deiodinase 2 (three forms), which serves
as a catalyst for production of thyroid hormone. (See "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'.)

Glucocorticoids — Glucocorticoids remain the mainstay of immunomodulatory therapy for

moderate-to-severe Graves' orbitopathy [20,30,31]. Although worsening orbitopathy may respond
favorably and rapidly to oral prednisone therapy via its antiinflammatory and immunosuppressive
actions, intravenous (IV) glucocorticoid pulse therapy has become widely used for more severe
orbitopathy and has the advantage of fewer side effects than high oral doses of prednisone
[32,33]. However, very high IV doses (cumulative doses greater than 8 g) have been seen to
induce liver failure and must be avoided [21].

In systematic reviews and meta-analyses of trials comparing treatments of Graves' orbitopathy, IV

pulse glucocorticoids were more effective than oral in reducing symptoms (overall response rate
82 versus 53 percent) [22,32]. The advantage was mostly due to improvements in patients with
more severe orbitopathy [22].

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As an example, in a trial of 70 euthyroid patients with untreated, severe orbitopathy 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 [34]:

● 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.

Some clinicians initiate therapy with a high dose of oral prednisone, such as 80 to 100 mg/day.
However, doses of 30 to 40 mg/day appear to be as effective for moderate orbitopathy and have
fewer side effects. 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 [35]. 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. 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 also require a skeletal assessment to identify individuals at high
risk for fracture who would benefit from intervention. 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 — Teprotumumab (an insulin-like growth factor 1 [IGF-1] receptor inhibitor)

was approved for the treatment of Graves' orbitopathy by the US Food and Drug Administration
(FDA) in 2020, based on the findings from two 24-week trials comparing teprotumumab with
placebo in 171 patients with active, moderate-to-severe orbitopathy [23-25]. In each trial, 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). The durability of efficacy requires confirmation with long-term follow-up studies. Eye
symptoms in the patients in the trial had to have begun within nine months of trial entry, and it is
unclear whether the drug would be as effective in patients whose disease was of longer duration.
In addition, there was no comparison with the effectiveness of glucocorticoids, the standard
therapy for patients with moderate-to-severe orbitopathy. Cost may also play a role in clinical
decision-making, and the price of this drug has yet to be decided.

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Teprotumumab is administered every three weeks as an IV infusion (10 mg/kg initial dose, then 20
mg/kg) for a total of eight infusions [25]. Nausea (17 versus 9 percent), diarrhea (12 versus 8
percent), muscle spasms (25 versus 7 percent), and hyperglycemia (10 versus 1 percent) were
reported more frequently in the teprotumumab group. Other adverse reactions that occurred more
commonly with teprotumumab included fatigue, hearing impairment, dysgeusia, headache, and
dry skin.

Mycophenolate mofetil — Mycophenolate mofetil is under investigation for the treatment of

Graves' orbitopathy, either alone or in combination with glucocorticoids [26,36].

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 Graves' orbitopathy,
the overall response at 24 weeks was better with mycophenolate (91.3 versus 67.9 percent) [26].

Mycophenolate is a strong immunosuppressive with relatively mild side effects, widely used after
transplantation [36,37]. It is a potent, selective, noncompetitive, and reversible inhibitor of inosine-
5'-monophosphate dehydrogenase [37]. 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.

Tocilizumab — Tocilizumab targets interleukin (IL)-6 and has been used in patients with
rheumatoid arthritis and has been investigated for the treatment of patients with Graves'
orbitopathy who are not improving with glucocorticoids [27]. In a randomized trial, 32 patients with
Graves' orbitopathy were randomly assigned to tocilizumab (8 mg/kg) or placebo intravenously at
0, 4, 8, and 12 weeks. 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, an anti-B cell monoclonal antibody, has been
reported to be as effective as glucocorticoids without the glucocorticoid-related side effects [38-
41]. Two prospective trials evaluating rituximab therapy for orbitopathy showed conflicting results,
although patients differed in disease severity and duration in these studies [42,43]. The selection
of patients for rituximab therapy is important, as patients with severe, new-onset Graves'
orbitopathy 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.

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Rituximab induces a fall in thyrotropin receptor antibody (TRAb) levels [44] and depletion of B cells
in the retroorbital tissues, not just the periphery [45]. Although high doses of this antibody may be
associated with severe side effects from the profound immunosuppression that ensues, lower
doses (two infusions of 1 g each) may be effective in Graves' orbitopathy and allow
immunosuppression to be avoided. The therapeutic benefit of rituximab, however, remains
uncertain despite the seemingly logical action of the antibody.

Ineffective medical therapies

● Somatostatin analogs – Somatostatin analogs have no role in the routine treatment of

Graves' orbitopathy. They have been explored as a potential therapy for Graves' orbitopathy
based upon the observations that orbital fibroblasts have somatostatin receptors and the
activity of orbitopathy correlates with activity on octreotide scintigrams. One randomized,
placebo-controlled trial of a long-acting octreotide preparation reported improvement in
clinical activity scores and median lid fissure width with octreotide compared with placebo
[46]. In contrast, two other similar trials reported limited benefit with octreotide [47,48]. In a
meta-analysis of four trials, somatostatin analogs resulted in a slightly lower clinical activity
score than placebo but had no advantages for other important outcomes (diplopia, proptosis,
lid aperture) [22].

● Diuretics – In our experience, diuretics are not helpful but continue to be widely prescribed
for this condition.

External orbital radiation — External radiation has been used more often in Europe than in the
United States, 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 retroorbital T cells. The usual dose for treatment of the retroorbital area
is 2000 rads (20 Gy), administered in 10 doses 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 [33,49]; however, two additional trials comparing orbital radiation with sham
irradiation found no benefit [50,51], 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 [22].

In contrast, trials of combined radiation and glucocorticoid therapy have suggested that the
combination may be more effective than either alone [22,52,53]. In a randomized trial of 82
patients with Graves' orbitopathy 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 [54]. Thus, if combined therapy is used, IV glucocorticoids may be preferable.

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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 [55]. In the same trial, orbital radiotherapy did not
improve quality of life or management costs [55]. 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, retroorbital 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 [56]. Transient blindness can
also occur due to injury to the optic nerve [57].

Orbital decompression surgery — Indications for orbital decompression surgery include [58]:

● 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 [59,60]. 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 [61]:

● 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

Timing of surgery — Clinical outcome appears to be better if decompression surgery is

performed after rather than before glucocorticoid therapy and is best reserved for when the
disease becomes quiescent. This was illustrated in a small trial of 15 patients randomly assigned
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to initial therapy with IV methylprednisolone or orbital decompression [62]. 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.

Other operations — Fat decompression surgery, removing the retroorbital adipose tissue, has
been performed for many years and can produce a cosmetic correction in patients with moderate
Graves' orbitopathy and significant proptosis [63]. 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. Occasional patients require plastic surgery to
correct marked periorbital edema, while many others choose to have cosmetic correction of
relatively mild edema. 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

● Patients with Graves' orbitopathy should be treated according to the severity of their eye
disease, keeping in mind that most patients have mild disease and do not have progression
during follow-up. The treatment of patients with Graves' orbitopathy includes reversal of
hyperthyroidism (if present), smoking cessation, local measures to reduce ocular surface
irritation, and reduction of inflammation in the periorbital tissues. (See 'Approach to treatment'
above.)

● Euthyroidism should be restored in all patients with hyperthyroidism. Graves' orbitopathy may
worsen or first become apparent after treatment of hyperthyroidism, depending upon the
treatment. Thyroidectomy and thionamides do not appear to have a negative influence on the
course of orbitopathy. However, radioiodine therapy can cause the development or worsening
of Graves' orbitopathy more often than surgery or thionamides. (See 'Reversal of
hyperthyroidism, if present' above and "Radioiodine in the treatment of hyperthyroidism",
section on 'Radioiodine and orbitopathy'.)

● Patients with active, mild orbitopathy are candidates for thionamides, radioiodine, or surgery.
However, moderate-to-severe or sight-threatening orbitopathy is a contraindication to

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radioiodine therapy. For patients with active and moderate-to-severe or sight-threatening

orbitopathy, thionamides or surgery are the preferred treatment options. (See 'Reversal of
hyperthyroidism, if present' above and "Graves' hyperthyroidism in nonpregnant adults:
Overview of treatment", section on 'Choice of therapy' and "Radioiodine in the treatment of
hyperthyroidism", section on 'Glucocorticoids in patients with orbitopathy'.)

● All patients should be advised to discontinue smoking as cigarette smoking increases the
incidence of symptomatic Graves' orbitopathy, 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 Graves' orbitopathy (ophthalmopathy)", section
on 'Smoking'.)

● All patients should be advised of local measures to improve symptoms. Local measures
include eye shades, artificial tears (saline 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 artificial tears every two to three hours
during the day and of lubricants, such as 1% methylcellulose drops, at night. (See 'Local
measures' above.)

● For patients with mild orbitopathy, local measures are usually effective to relieve eye
symptoms, and no additional treatment is needed. Selenium may improve soft-tissue swelling
in selected patients. 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 symptoms'
above and 'Selenium' above.)

● For patients with moderate-to-severe orbitopathy, we suggest initial treatment with

glucocorticoids (Grade 2B). These can be given either orally or intravenously (IV) depending
on the severity of the disease. Initial IV therapy is appropriate in more severe or progressive
cases. (See 'Moderate-to-severe or progressive symptoms' above and 'Glucocorticoids'
above.)

If glucocorticoid 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. 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 (Grade 2C). Alternatives include mycophenolate mofetil, tocilizumab,
and rituximab. Local measures should be used along with these major forms of therapy. (See
'Moderate-to-severe or progressive symptoms' above.)

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● Patients with sight-threatening orbitopathy should receive immediate glucocorticoid therapy

(dexamethasone, 4 mg IV) and should be hospitalized for possible urgent orbital
decompression surgery. (See 'Sight threatening' above and 'Orbital decompression surgery'
above.)

Use of UpToDate is subject to the Subscription and License Agreement.

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GRAPHICS

Variations in TSH-receptor antibodies in Graves' hyperthyroidism after

radioiodine, surgery, or medical therapy

Variations in TRAbs in serum after randomly assigning patients with Graves' hyperthyroidism to
radioiodine (n = 36; radioiodine was only given to patients ≥35 years of age), surgery (n = 47), or
medical therapy (n = 48). In all groups, patients were kept euthyroid by the addition of
levothyroxine therapy as appropriate. Medical therapy was given for 18 months. The values for the
patients who needed a treatment other than the randomized are omitted beyond the time the
change occurred. Values are mean±SEM. The upper normal reference for the TRAb assay was 10%,
as indicated by the straight dashed line. Values before therapy were not different between groups.
After therapy, all values were significantly higher for the radioiodine group when compared with
values for the medical or surgical therapy groups (p<0.01).

TSH: thyroid-stimulating hormone; TRAb: TSH-receptor antibodies; 125-I: iodine-125; SEM: standard error
of mean.

Reproduced with permission from: Laurberg P, Wallin G, Tallstedt L, et al. TSH-receptor autoimmunity in
Graves' disease after therapy with anti-thyroid drugs, surgery, or radioiodine: A 5-year prospective
randomized study. Eur J Endocrinol 2008; 158:69. Copyright © 2008 BioScientifica Ltd.

Graphic 115288 Version 2.0

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Use of oral glucocorticoids for prevention of Graves' orbitopathy development or

progression when radioactive iodine is used to treat Graves' hyperthyroidism*

RAI without RAI with oral

glucocorticoids glucocorticoids

No GO (nonsmoker) Recommend Recommend against

No GO (smoker) Insufficient data to recommend for or against

GO present-active and mild (risk factors absent) Acceptable ¶ Acceptable ¶

GO present-active and mild (risk factors present) Recommend against Recommend

GO present-active and moderate-to-severe or Recommend against Recommend against

sight-threatening

GO present-inactive Recommend Recommend against

RAI: radioactive iodine; GO: Graves' orbitopathy; ATDs: antithyroid drugs; TRAb: thyrotropin receptor antibodies.
* ATDs or thyroidectomy are also recommended treatment options in each of these scenarios, and they are the preferred
choice of therapy in patients with active and moderate-to-severe or sight-threatening GO.
¶ The decision regarding use of concurrent glucocorticoids should be made in light of the risk-benefit ratio relative to the
patient's overall health. Risk factors for GO deterioration (high TRAb level, smoking) increase the benefit of glucocorticoids
in preventing GO deterioration. Poorly controlled diabetes, osteoporosis, psychiatric illness, high risk for infections
increase the likelihood of complications from glucocorticoids.

Reproduced with permission from: Ross DS, Burch HB, Cooper DS, et al. 2016 American Thyroid Association guidelines for
diagnosis and management of hyperthyroidism and other causes of thyroidtoxicosis. Thyroid 2016; 26:1343. Copyright ©
2016 Mary Ann Liebert, Inc. publishers.

Graphic 110053 Version 1.0

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Orbital decompression surgery anatomy

Diagram to show extent of medial wall orbital decompression. Note, to achieve

an effective decompression, the posterior half of the bony bar ("strut") between
the maxillary antrum and the ethmoid air cells should be removed.

Reprinted by permission from Macmillan Publishers Ltd: Eye. Verity DH, Rose GE.
Acute thyroid eye disease (TED): Principles of medical and surgical management. Eye
2013; 27:308. Copyright © 2013. www.nature.com/eye.

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Contributor Disclosures
Terry F Davies, MD, FRCP, FACE Consultant/Advisory Boards: Kronus Inc [Thyroid antibody
testing]. Henry B Burch, MD Nothing to disclose Douglas S Ross, MD Consultant/Advisory Board:
Medullary Thyroid Cancer Registry Consortium [Thyroid cancer]; Spectrix Therapeutics, LLC
[Hypothyroidism]; IBSA Pharma Inc [Hypothyroidism]. Jean E Mulder, MD Nothing to disclose

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are
addressed by vetting through a multi-level review process, and through requirements for references to be
provided to support the content. Appropriately referenced content is required of all authors and must conform
to UpToDate standards of evidence.

Conflict of interest policy

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