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Thyroid
dysfunction (both hyperthyroidism and hypothyroidism) should
be corrected. In a
prospective observational study, restoration
of euthyroidism by antithyroid drugs was associated with
an amelioration of Graves' ophthalmopathy. In
randomized trials,
radioiodine therapy for Graves' hyperthyroidism caused progression
of ophthalmopathy in about 15% of patients, whereas
antithyroid drugs did not modify the natural course of
Graves' ophthalmopathy. Risk
factors for progression of Graves'
ophthalmopathy after radioiodine therapy include cigarette smoking, severe
hyperthyroidism (serum triiodothyronine concentration,  5
nmol per liter), high
levels of thyrotropin-receptor antibodies, and
uncontrolled hypothyroidism after radioiodine therapy. In
two randomized trials, concomitant treatment of high-risk patients
with oral prednisone (at an initial dose of 0.3 to 0.5
mg per kilogram of body weight given 1 to 3 days after radioiodine therapy,
with tapering of the dose until withdrawal 3 months later)
prevented progression and ameliorated preexisting Graves' ophthalmopathy.Prophylactic treatment with glucocorticoid agents may be appropriate for many patients with Graves' ophthalmopathy whose hyperthyroidism is treated with radioiodine therapy, including patients with active ophthalmopathy or risk factors such as those described above. In a prospective observational study, patients who began to receive levothyroxine (usually 50 µg per day initially) as early as 2 weeks after radioiodine therapy had a markedly reduced risk of progression of Graves' ophthalmopathy, as compared with patients in whom levothyroxine treatment was not initiated until hypothyroidism developed. It is unclear whether associated hyperthyroidism in patients with Graves' ophthalmopathy should be treated with antithyroid drugs or with ablative treatments (i.e., thyroidectomy, radioiodine, or both). Specific treatments for Graves' ophthalmopathy vary depending on the severity of the disease. Mild Graves' ophthalmopathy usually does not require any treatment except for local measures (e.g., lubricants, ointments, dark lenses, and prisms to reduce diplopia) to control mild symptoms and signs. In some instances, however, the patient's quality of life is so impaired that treatment such as that for more severe Graves' ophthalmopathy is warranted. Regular follow-up every 3 to 6 months is routinely warranted, since progression from mild ophthalmopathy to moderate-to-severe disease occurs in about 25% of patients. Glucocorticoid Therapy Patients with sight-threatening dysthyroid optic neuropathy require immediate treatment, usually with high-dose intravenous or oral glucocorticoid agents. Although there is no established treatment schedule, a common initial regimen is the administration of 1 g of methylprednisolone intravenously for 3 consecutive days. Subsequent treatment depends on the response. If there is little or no improvement after 1 to 2 weeks, patients should promptly undergo surgical orbital decompression.In a small randomized trial, there was no significant difference in outcome between decompression performed as first-line treatment and initial treatment with intravenous glucocorticoids followed by oral prednisone. Glucocorticoids are also used for moderate-to-severe and active ophthalmopathy. In a placebo-controlled, randomized trial, intravenous glucocorticoids (four cycles of methylprednisolone at a dose of 500 mg for 3 consecutive days at 4-week intervals) were effective in treating inflammatory changes and ocular movements in five of six patients (83%) as compared with one of nine patients (11%) who received placebo. High-dose oral glucocorticoids (e.g., prednisolone at a dose of 40 mg or more initially) are also commonly used; the dose is then gradually tapered until withdrawal after 4 to 6 months. An overall response rate of 63% was reported in several case series of patients treated with oral glucocorticoids. Two randomized trials have shown that intravenous therapy results in a higher rate of favorableresponses than oral therapy (88% vs. 63% in one studyand 77% vs. 51% in the other), and it is better tolerated, with a reduced risk of the development of cushingoid features. However, rare cases of severe and acute liver damage (including four that were fatal) have been reported with the use of very high doses.Thus, intravenous therapy should be given only with close monitoring (particularly of liver function) in specialized centers. There is no consensus regarding the optimal dose and schedule, but a commonly used regimen consists of 12 weekly infusions of methylprednisolone with a cumulative dose of 4.5 g (500 mg weekly for 6 weeks, then 250 mg weekly for 6 weeks). These doses are much lower than those used previously; to minimize the risk of hepatotoxicity, courses exceeding 8 g are not recommended. Oral glucocorticoids are a reasonable alternative option, particularly in patients with liver disease. Besides liver abnormalities, patients should be closely followed for other potential adverse effects of glucocorticoid treatment (e.g., increased blood pressure, hyperglycemia, electrolyte abnormalities, gastric effects, and infection). Orbital Radiotherapy Orbital irradiation may be a useful addition to therapy, particularly when eye motility is impaired. In case series, about 60% of patients have had overall favorable responses to orbital irradiation, although patients with certain features, including exophthalmos, eyelid retraction, and soft-tissue changes, tend to have a poor response to treatment. A common cumulative dose of radiation is 20 Gy per eye, given in 10 sessions over a 2-week period, but a lower cumulative dose (10 Gy) may be equally effective.In a randomized trial comparing orbital irradiation with oral glucocorticoids, the efficacy rates were similar with the two approaches (approximately 50%). Data from randomized trials indicate that combined treatment with radiotherapy and oral glucocorticoids is more effective than either treatment alone; it is not known whether the same is true regarding intravenous glucocorticoid therapy. Orbital irradiation should be avoided in patients younger than 35 years of age (because of the potential long-term carcinogenic effects) and in patients with diabetic retinopathy or severe hypertension (because of possible additional damage to the retina). To our knowledge, no cases of radiation-induced tumors have been reported in patients treated with orbital radiotherapy for Graves' ophthalmopathy. Other Possible Pharmacologic Treatments Randomized trials have not shown a benefit of
somatostatin analogues (octreotide
and lanreotide) for Graves' ophthalmopathy. There are
also few data to support the use of intravenous immune globulin for
this condition.Cyclosporine, although shown to be less effective
than oral glucocorticoids in a randomized trial, may help
to reduce the dose of glucocorticoids. Preliminary
data suggest
that immunomodulating drugs such as rituximab
or inhibitors
of tumor necrosis factor Surgery Orbital decompression is required for sight-threatening dysthyroid optic neuropathy if high-dose glucocorticoids do not ameliorate this condition within 1 to 2 weeks. If vision is threatened by imminent corneal breakdown (which is usually associated with severe exophthalmos and lagophthalmos), and local measures and eyelid closure do not provide rapid, substantial improvement, orbital decompression is indicated to improve exposure keratopathy. Orbital surgery (including eye-muscle surgery to correct extraocular muscle dysfunction and eyelid surgery to correct eyelid retraction) may reduce the disfigurement caused by Graves' ophthalmopathy. Surgery should be performed after ophthalmopathy has been consistently inactive for at least 6 months. Orbital decompression can be performed by means of a variety of surgical techniques that are described in detail elsewhere. If multiple surgical procedures are required for stably inactive Graves' ophthalmopathy, orbital decompression should be performed first, followed by strabismus surgery and, finally, eyelid surgery.Such rehabilitative surgery can be carried out in cases of long-standing Graves' ophthalmopathy. Areas of Uncertainty The appropriate use of radioiodine therapy for managing hyperthyroidism in patients with Graves' ophthalmopathy remains uncertain. Some experts recommend that antithyroid drugs be used as first-linetreatment in patients with active ophthalmopathy, with the use of radioiodine therapy only later, when Graves' ophthalmopathy is inactive and if antithyroid drug treatment fails. Results of a randomized trial comparing early total thyroid ablation (thyroidectomy followed by radioiodine therapy) with near-total thyroidectomy in patients with mild-to-moderate Graves' ophthalmopathy treated with intravenous glucocorticoids suggested that total ablation results in better outcomes, although differences between groups were clinically modest. In patients who have received radioiodine therapy, oral glucocorticoid prophylaxis usually is recommended, but the timing of initiation and the optimal dose and duration are uncertain. The efficacy of prophylactic treatment for less than 3 months with lower doses of prednisone and longer, higher-dose treatment may be similar. Although there is evidence to support the use of intravenous rather than oral glucocorticoid therapy for active Graves' ophthalmopathy, the optimal glucocorticoid regimen remains uncertain. It is unclear whether the addition of orbital irradiation to intravenous glucocorticoid therapy improves outcomes over glucocorticoid therapy alone. Randomized trials are lacking to compare early treatment with drugs acting on the pathogenic mechanisms of the disease (such as rituximab) with current standard therapies.
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