Treatment of Graves' ophthalmopathy (orbitopathy)

INTRODUCTION — Graves' ophthalmopathy (or orbitopathy) is an autoimmune disease of the retroorbital tissues. This topic review will provide an overview of the treatment of this disorder; its pathogenesis and clinical features are discussed separately.

NATURAL HISTORY — The natural history of Graves' ophthalmopathy is variable and must be considered in the context of concomitant antithyroid therapy. In some patients, as an example, ophthalmopathy 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 difficult to reach conclusions about the efficacy of treatment

One study, as an example, evaluated 59 patients with untreated eye disease who had not received any immunosuppressive or surgical treatment. They had all received an antithyroid drug, which may be immunosuppressive. As assessed using a well-characterized activity index, 66 percent of these patients improved during the first 12 months, and only 8 percent had deterioration in their eye disease.

Treatment of patients with Graves' ophthalmopathy has three components:

  • Reversal of hyperthyroidism, if present
  • Symptomatic treatment
  • Treatment with a glucocorticoid, orbital irradiation, and orbital decompression surgery to reduce inflammation in the periorbital tissues.

Other immunosuppressive drugs (mostly cyclosporine), have not been proven to be effective. Octreotide, a somatostatin analog, was no more effective than placebo in one randomized trial. In a second randomized trial, octreotide-LAR did not improve a composite scale of disease activity and severity, but was associated with reduced proptosis [7].

The effect of these therapies will be reviewed first, followed by an outline of the regimen that we usually use to treat patients with this disorder.

ANTITHYROID TREATMENT — The question of whether antithyroid treatment influences Graves' ophthalmopathy is complex. There are two major influences at work: the reduction in thyroid hormone secretion and the potential direct effects of the therapy. Reducing thyroid hormone secretion does not improve the pathology of Graves' ophthalmopathy, although it does decrease eyelid retraction and stare.

More important is the influence of antithyroid therapy on the disease. Graves' ophthalmopathy may worsen or first become apparent after treatment of hyperthyroidism, depending upon the treatment. A randomized trial, as an example, evaluated 168 patients with Graves' hyperthyroidism, 22 of whom had preexisting ophthalmopathy. Correction of the hyperthyroidism was associated with new onset of ophthalmopathy in 22 (15 percent) and worsening of the ophthalmopathy in 8 (36 percent). The worsening was manifested in most patients by an extra 1 to 2 mm of proptosis.

The initial effect of antithyroid therapy on ophthalmopathy varies with the type of treatment. Subtotal thyroidectomy and antithyroid drugs do not appear to have a negative influence on the course of ophthalmopathy. As examples, ophthalmopathy did not appear or worsen any more often in patients treated by subtotal thyroidectomy or with methimazole in the randomized trial described above, or in a case-control study in which 30 patients who underwent near-total thyroidectomy and 60 patients who were treated with methimazole were followed for one year. In the latter study, one patient in the surgery group had worsening of preexisting ophthalmopathy, and two patients in the methimazole group had new onset of ophthalmopathy. These two treatments are usually followed by a fall in serum antithyroid antibody concentrations, suggesting a waning of autoimmunity

Patients who had a total thyroidectomy versus a subtotal thyroidectomy were compared after three years and found to have similar improvement in opthalmopathy (although surgical complications were higher in the total thyroidectomy group) Hypothyroidism and its concomitant fluid retention may have an adverse effect on ophthalmopathy and should be avoided.

In comparison, most, but not all  studies suggest that radioiodine therapy is associated with the appearance or exacerbation of ophthalmopathy more often than antithyroid drug therapy or surgery. It may also be associated with worsening of infiltrative dermopathy (pretibial myxedema)

Why this occurs is not known. However, radioiodine therapy is followed by substantial increases in the serum concentrations of antibodies to the thyrotropin (TSH) receptor (and other thyroid antigens) which might be important in initiating or exacerbating ophthalmopathy. The rise in antibody production may be secondary to lack of immune restraint caused by the effect of intrathyroidal irradiation on regulatory T cells. The increase in antibody production is not prevented by glucocorticoid therapy for up to seven weeks after radioiodine administration

The important clinical question is whether these results are a contraindication to radioiodine therapy for hyperthyroidism in patients who also have ophthalmopathy. There have now been two randomized trials of different antithyroid treatments In the first, ophthalmopathy developed or worsened in 33 percent of the patients treated with radioiodine, as compared with 10 and 16 percent of those treated with methimazole and surgery, respectively This study has been criticized, however, because all of the patients treated with radioiodine became hypothyroid, and treatment with thyroxine was delayed for several months; thus, high serum thyrotropin concentrations may have been in part responsible for the development of ophthalmopathy

The second randomized trial studied 443 patients with Graves' hyperthyroidism and slight or no ophthalmopathy, comparing treatment with radioiodine (120 to 150 µCi/g of thyroid tissue) alone, radioiodine followed by a three-month course of prednisone (0.4 to 0.5 mg/kg for one month, then tapered over two months), or methimazole for 18 months . In the 150 patients treated with radioiodine, 23 (15 percent) either developed or had worsening of ophthalmopathy two to six months after treatment  The change was transient in 15 patients; it persisted in the other 8 patients. In comparison, none of the 135 patients treated with radioiodine plus prednisone developed or had worsening of ophthalmopathy, and 50 of the 75 patients (67 percent) with ophthalmopathy improved. In the 148 patients treated with methimazole, 3 (2 percent) with ophthalmopathy improved, 4 (3 percent) had worsening, and the other 141 had no change. These patients were closely followed for the development of hypothyroidism and treated immediately.

Thus, there is now increasing evidence that radioiodine therapy can cause the development or worsening of Graves' ophthalmopathy. The changes are often mild and transient, at least in patients who have mild or no ophthalmopathy before therapy. In patients with initially mild ophthalmopathy, worsening is prevented by the concurrent administration of glucocorticoids, although exposing patients to the side effects of glucocorticoids probably should not become routine practice. Nonetheless, if a high-risk patient must be treated with radioiodine, a glucocorticoid can be given for several months, although the efficacy of this regimen has not been studied in patients with severe ophthalmopathy. Administration of methimazole after radioiodine therapy does not prevent changes in ophthalmopathy.

Although some physicians disagree, radioiodine therapy is probably best avoided in patients with moderate or severe ophthalmopathy because there are effective alternatives Alternatively, some physicians delay treatment with radioiodine until moderate or severe eye disease has been stable for at least one year. Also, radioiodine should be used with caution in patients with risk factors for ophthalmopathy, including smoking or a high baseline serum concentration of triiodothyronine (eg, >325 ng/dL [5 nmol/L])

If a patient with Graves' hyperthyroidism is treated with surgery because of ophthalmopathy, a near total thyroidectomy may be associated with less progression of proptosis postoperatively than a subtotal thyroidectomy. Despite the concern that radioiodine might worsen ophthalmopathy when given as primary therapy for hyperthyroidism, patients receiving a near total thyroidectomy and radioiodine ablation for Graves' disease and thyroid cancer (n=16) had less active ophthalmopathy than those having only a near thyroidectomy (for Graves' disease without thyroid cancer, n=39) .

SYMPTOMATIC TREATMENT — Local measures including eye shades, artificial tears (saline eye drops), and raising the head of the bed at night often lead to sufficient relief of eye symptoms and no additional treatment is needed. 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 one percent methylcellulose drops, at night.

MORE AGGRESSIVE THERAPY TO DIMINISH OPHTHALMOPATHY — Increasing proptosis and worsening soft tissue signs may warrant more vigorous therapy. In our experience, diuretics are not helpful. Nonsteroidal antiinflammatory drugs, including COX-2 inhibitors, may be helpful in patients with mild symptoms of eye irritation. Glucocorticoids, given orally or intravenously, are the primary treatment for severe Graves' ophthalmopathy. Radiation and surgical decompression can also be used in selected patients.

Glucocorticoid therapy — Prednisone, given orally, has gained wide acceptance as effective treatment for patients with severe Graves' ophthalmopathy, although few prospective, well-controlled trials have been performed Worsening ophthalmopathy may respond favorably and rapidly to oral prednisone therapy, presumably via its antiinflammatory and immunosuppressive actions.

The optimal dose of prednisone is uncertain. Some physicians initiate therapy with a high dose, such as 100 mg/day. However, doses of 30 to 40 mg/day appear to be as effective and have fewer side effects. Improvement usually occurs within four weeks. About 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. However, given the many side effects of prolonged high-dose prednisone treatment, other treatments 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. These are the patients who require therapy to prevent the side effects of the glucocorticoid from becoming more dangerous than the eye disease. In particular, bisphosphonate therapy should be initiated early in patients receiving high-dose prednisone therapy

Intravenous glucocorticoid pulse therapy has also been used and may have the advantage of fewer side effects than high oral doses of prednisone. In a trial of 70 euthyroid patients with untreated, severe opthalmopathy randomly assigned to receive once weekly intravenous methylprednisolone (0.5 g, then 0.25 g weekly for six weeks each) or oral prednisone (100 mg per day, tapering by 10 mg per week), the following results were seen

  • At three months, 27 of 35 patients (77 percent) in the intravenous group had a treatment response compared to 18 of 35 (51 percent) in the oral group.
  • Improvements over baseline for visual acuity, chemosis, and quality of life were greater in the intravenous group.
  • Additional treatment was required less frequently in the intravenous group.
  • Adverse events were less frequent with intravenous glucocorticoids.

External orbital radiation — Radiotherapy kills retroorbital T cells. The value of orbital radiation is controversial. In two trials it was more effective than glucocorticoid therapy, and in a third it was better than sham-irradiation. However, in a fourth trial in which one eye was not treated, radiation was no better than no treatment. It is most often used in the United States in patients in whom glucocorticoids are contraindicated, poorly tolerated, or cannot be discontinued because of exacerbations of ophthalmopathy.

Trials of combined radiation and glucocorticoid therapy have suggested that the combination may be more effective than either alone. In a randomized trial of 82 patients with Graves' ophthalmopathy treated with high-dose intravenous or oral glucocorticoid (combined with orbital radiation), the intravenous route was more effective, better tolerated, and associated with fewer side effects. Thus, if combined therapy is used, intravenous glucocorticoid may be preferable.

Orbital radiation has been thought to be most effective in ameliorating the inflammatory manifestations of ophthalmopathy, with little or no change in proptosis and muscle function. However, 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 ophthalmopathy. The usual dose is 2000 rads (20 Gy), administered in 10 doses of 200 rads (2 Gy) over two weeks. 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 non-significantly elevated in patients under age 60 years; mild retinopathy in 14 percent of patients with diabetes and hypertension, 3 percent of patients with hypertension alone, and none in patients with diabetes alone; and no secondary tumors Transient blindness can also occur due to injury to the optic nerve.

Orbital decompression surgery — There are three major indications for orbital decompression in Graves' ophthalmopathy:

  • If glucocorticoid therapy or orbital irradiation fails to halt progression of the ophthalmopathy
  • If loss of vision is threatened either by ulceration or infection of the cornea or by changes in the retina or optic nerve
  • For cosmetic correction of severe proptosis

The orbit may be decompressed by removing the lateral wall, the roof, or the medial wall and the floor. 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. 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.

Other operations — Bilateral lateral tarsorraphy may 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. Many other have chosen to have cosmetic correction of relatively mild edema.

AN OVERVIEW OF THE TREATMENT OF OPHTHALMOPATHY — Patients with Graves' ophthalmopathy should be treated according to the severity of their eye disease, keeping in mind its natural history. Most patients have mild disease, and approximately 65 percent of them have no progression during follow-up. Those patients with more severe ophthalmopathy may also have no progression, and in both groups the inflammatory manifestations of the disorder — eye irritation and conjunctival and periorbital edema — tend to subside. There is little change in proptosis, but the patients' eyes look more normal (and feel better).

The patient with mild symptoms — For these patients only local measures are required, including eye shades, artificial tears, avoiding sleeping on the face, and raising the head of the bed.

The patient with red eyes and increasing diplopia or proptosis — A trial of oral glucocorticoid therapy (prednisone, 30 mg/day for four weeks) should be initiated in patients with progressive ophthalmopathy. Higher doses may be required if this dose is ineffective. If high-dose therapy is contraindicated or cannot be tolerated, external radiation may be given if edema predominates. Local measures should be used along with these major forms of therapy.

The patient with loss of vision — 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. In a very limited trial of 15 patients randomized to initial intravenous methylprednisolone versus orbital decompression, 83 percent of the patients who initially received surgery required methylprednisolone and some also required oribital irradiation, while 56 percent of the patients initially treated with methylprednisolone required surgery or orbital irradiation. The authors concluded that initial therapy should be with methylprednisolone pulse therapy.

Threatened loss of vision, often preceded by loss of color vision, is a medical emergency. Such a patient should receive immediate glucocorticoid therapy (dexamethasone, 4 mg intramuscularly, or prednisone, 100 mg orally) and should be hospitalized for urgent orbital decompression surgery.

Abstracts:

Medical management of Graves' ophthalmopathy/Prummel MF; Wiersinga WM/Thyroid 1995 Jun;5(3):231-4

In most patients with Graves' hyperthyroidism the eye signs are self-limiting and mostly subclinical. However, about one-third of the patients have clinically relevant ophthalmopathy, which can be disabling and disfiguring. The mechanical causes of the symptoms and signs of the eye disease are largely understood, but the best way to manage the ophthalmopathy is still a matter of much debate. Adequate treatment of hyperthyroidism can aleviate the eye symptoms to some extent, but it is less clear which kind of antithyroid treatment is to be preferred in patients with ophthalmopathy. There is particular controversy about the possibly deleterious effect of radioiodine therapy on the ophthalmopathy; in view of the present evidence it seems prudent to refrain from using 131I and to prefer antithyroid drugs in patients with clinical ophthalmopathy. Further medical management can include immunosuppressive treatment (such as corticosteroids) that results in improvement in roughly two-thirds of the patients. Orbital irradiation appears to be the first choice for treatment in moderately severe ophthalmopathy because it is equally effective and much better tolerated than classical corticosteroid treatment. However, to really improve the efficacy of such interventions we should be able to select those patients that are likely to respond to immunomodulatory therapy. Disease activity is probably the prime determinant of response and it is a challenge for the future to develop reliable parameters of disease activity on the basis of which patients can be selected for further medical treatment, or can be subjected to rehabilitative surgery without prior immunosuppression.

Radiotherapy for Graves' orbitopathy: randomised placebo-controlled study/Mourits MP; van Kempen-Harteveld ML; Garcia MB; Koppeschaar HP; Tick L; Terwee CB/Lancet 2000 Apr 29;355(9214):1505-9.

The best treatment (steroids, irradiation, or both) for moderately severe Graves' orbitopathy, a self-limiting disease is not known. We tested the efficacy of external beam irradiation compared with sham-irradiation. METHODS: In a double-blind randomised clinical trial, 30 patients with moderately severe Graves' orbitopathy had radiotherapy (20 Gy in ten fractions), and 30 were assigned sham-irradiation (ten fractions of 0 Gy). Treatment outcome was measured qualitatively by changes in major and minor criteria and quantitatively in several ophthalmic and other variables, such as eyelid aperture, proptosis, eye movements, subjective eye score, and clinical-activity score at 24 weeks. FINDINGS: The qualitative treatment outcome was successful in 18 of 30 (60%) irradiated patients versus nine of 29 (31%) sham-irradiated patients at week 24 (relative risk [RR]=1.9 [95% CI 1.0-3.6], p=0.04). This difference was caused by improvements in diplopia grade, but not by reduction of proptosis, nor of eyelid swelling. Quantitatively, elevation improved significantly in the radiotherapy group, whereas all other variables remained unchanged. The field of binocular single vision was enlarged in 11 of 17 patients after irradiation compared with two of 15 after sham-irradiation. Nevertheless, only 25% of the irradiated patients were spared from additional strabismus surgery. INTERPRETATION: In these patients with moderately severe Graves' orbitopathy, radiotherapy should be used only to treat motility impairment.