Epidemiology and Course

The epidemiology of GO has recently been reviewed (101). It is clinically relevant in approximately 50% of patients with Graves' disease. Two age peaks of incidence are observed in the fifth and seventh decades of life. The natural history of Graves' ophthalmopathy is incompletely defined, but in many instances, especially in mild forms, the disease may remit or improve spontaneously. The onset of the ophthalmopathy is in most cases concomitant with the onset of hyperthyroidism, but eye disease may precede or follow hyperthyroidism. Cigarette smoking plays an important role in the occurrence of the ophthalmopathy. It may occur in patients who never develop clinical hyperthyroidism. The disease may be unilateral or bilateral, may begin in one eye, or may always be more severe in one eye than in the other. Usually the syndrome accompanies hyperthyroidism and is at its worst when the diagnosis is first made. Infiltrative ophthalmopathy frequently occurs in patients with Graves' disease without clinical evidence for ophthalmic involvement. This was shown by the prevalence of increased intra-ocular pressure in 61% of such patients.¹⁰⁴ However, if more sophisticated techniques are used to detect infiltrative ophthalmopathy, for instance ultrasound, virtually all patients with Graves' disease, including those without clinical eyesigns, show signs of extra-ocular infiltration.¹⁰⁵ Amino and co-workers¹⁰⁶ have reported that measurements of proptosis in Graves' disease fit a normal distribution curve, but the curve is shifted to higher values. This finding suggests that the complication is not sporadic, but rather that all patients have it to some extent and that we clinically recGOnize as unique those with the most severe symptoms.

The course of GO after therapy of thyrotoxicosis has been recently re-evaluated in a study of 59 patients with Graves’ hyperthyroidism and GO, treated with antithyroid drugs but without any specific eye treatment. Eye signs improved substantially in 22%, to a minor extent in 42%, did not change in 22% and deteriorated in 14%, suggesting "spontaneous" improvement in 64% of patients.¹⁰⁷

No more than 2 - 5% of patients with Graves' disease develop progressive severe exophthalmos. This progression often happens without a clear correlation with the severity of stage of the thyrotoxicosis. In some of these patients, the process continues inexorably to complete blindness unless heroic therapeutic measures are taken, and sometimes despite these efforts. Although thyrotoxicosis occurs in women about five times more frequently than in men, progressive ophthalmopathy occurs relatively more frequently and is relatively more severe in men and increases with age.^27,108 It is rare in children.

Since exophthalmos usually improves with treatment of thyrotoxicosis, the patient should be restored to the euthyroid state as soon as possible and kept there¹⁰⁷. In treating the hyperthyroidism of these patients, it is important that they not be allowed to become hypothyroid later. Hypothyroidism seems to accentuate the signs and symptoms of the ophthalmopathy, possibly by increasing the water content of the tissues.

Two interesting quality of life questionnaires specifically for patients with GO have recently been developed (GO-QOL).^108a,108b measuring disease specific aspects of quality of life related to GO.

Diagnosis

The ophthalmopathy of Graves' disease must be differentiated from other conditions that cause oculomotor weakness, proptosis, and congestive phenomena of the orbit and periorbital tissues (Table 12-4). If bilateral exophthalmos occurs in patients with thyrotoxicosis, there is little difficulty in diagnosis and one does not undertake a rigorous exclusion of other diseases. The same holds true when the exophthalmos follows clinical thyrotoxicosis. Patients who have not been thyrotoxic but who develop exophthalmos, especially if it is unilateral, pose a more difficult problem.¹⁰⁹ A search must be made for orbital or intracranial tumors. Evidence of bone erosion suggests a tumor, although erosion of the orbital roof has been seen due to Graves' ophthalmopathy. Evidence of encroachment upon the optic nerve should be sought. Quadrantic defects are seen in infiltrative ophthalmopathy, but are rare. Occasionally, allergic reactions may produce puffiness of the lids and injection and edema of the conjunctivae and sclerae, but not exophthalmos.

Conditions that may be confused with Graves' ophthalmopathy include pseudotumor of the orbit, infiltrative leukemia of the orbit, trichinosis, fibrous dysplasia of bone, retrobulbar hemangiomas, ophthalmic vein thrombosis, cavernous sinus thrombosis, sphenoid ridge meningiomas, retrobulbar hemorrhage, and any other involvement of the orbit by malignancy. (Table 12-4).

If the clinical diagnosis is not obvious, circumstantial evidence may be obtained by laboratory examinations. It is useful to determine thyroid-stimulating or thyrotropin-displacing antibodies and anti thyroglobulin and thyroperoxidase antibodies. A positive result does not certify the cause of exophthalmos but does prove that autoimmune thyroid disease is present. TSH, FT4 and T3 levels should be measured. Results will vary from the values typical of hyperthyroidism to the levels suggestive of hypothyroidism. Measurement of basal TSH in a sensitive assay may show it suppressed. Currently, we place greatest reliance on the presence of an abnormal CT or MRI scan showing muscle enlargement. MRI scanning of the orbit may equal or surpass orbital CT scanning.^110-113 Pseudotumor causing a density about the optic nerve is the most frequent problem in the differential diagnosis. Orbital sonography can be helpful if skilfully done,^114,115 and occasionally angiograms or venograms are required. When iodine containing x-ray contrast is administered, thyrotoxicosis or thyroid autonomy should be considered or ruled out first. The major problem is differentiation of unilateral exophthalmos from a tumor requiring surgery. Time often provides the answer, with the development of other signs of Graves' disease, growth of a lesion on CT scan, or shrinkage on steroids.

The clinical diagnosis of unilateral exophthalmos of Graves' disease may be impossible. Very rarely there may be recourse to exploration of the orbit. Biopsy may then show the microscopic changes in the tissues described above.

It is most important that the degree of exophthalmos, limitations of ocular mobility, visual acuity, and visual fields be determined during the initial evaluation, and repeatedly during the course if the exophthalmos requires active therapy.

Pseudotumor

In a significant number of patients, unilateral exophthalmos and sometimes loss of visual acuity occur without any evidence of Graves' disease and with the only laboratory finding a posterior orbital density on CT scans. These patients may have pseudotumor, a designation of dubious value. Pseudotumor is said to be a chronic inflammatory process that can be related to some systemic disease or granulomatous process or may be idiopathic. It has been treated with iodide and x-rays, and currently is treated with glucocorticoids. The process may be unilateral or bilateral. It can cause muscle thickening^114-117 and visual loss. The authors believe, without certain proof, that many cases of pseudotumor are examples of Graves' ophthalmopathy.

Therapy

Therapeutic possibilities include local measures to combat inflammation, glucocorticoids, plasmapheresis and immune suppressants, orbital radiation, decompressive surgery, and thyroid ablation. There is no perfect basis for selecting one form of therapy for coincident thyrotoxicosis over another, insofar as effects on the exophthalmos are concerned. Many thyroidologists believe that as long as eye signs are active, conservative treatment of the concomitant hyperthyroidism, i.e. medical treatment, is best to avoid worsening of GO or even promote improvement. In this situation serum TSH is kept at low normal and FT4 in the high normal range in the assumption to keep antigen (TSH-R) release from the thyroid at a minimum.

Radioactive iodine as a treatment for the concomitant hyperthyroidism is considered by some authors as having a worsening effect on GO. ^119-120 In a recent study eye signs worsened more often in patients treated with ¹³¹I as compared to treatment with antithyroid drugs and worsening could be prevented by temporary administration of prednisone.^120a Several studies have been published concerning possible effects on development of eyesigns after partial thyroidectomy. In a total of five studies¹²¹ comprising 245 patients no significant worsening or improvement after thyroidectomy was found. The possible effect of the three forms of treatment (medical, RAI, thyroidectomy), on infiltrative ophthalmopathy was studied prospectively.¹⁰³ No influence of type of treatment on the clinical course of eye signs was found. The authors found that in patients who had no ophthalmopathy before treatment, the occurrence of post-treatment exophthalmos was about similar in the surgical, medical and ¹³¹I-treated group (7.1%, 6.7%, and 4.9%, respectively.). The incidence and the degree of progression of ophthalmopathy in patients who already had exophthalmos before treatment, was also not different in the three groups (19.8%, 19.2%, and 22.7%, respectively) as was the improvement of ophthalmopathy (12.7%, 14.1%, and 12.3%). The controversy of the effect of 131I on GO remains. Thus recently published data indicate that ¹³¹I therapy is more apt to be followed by worsening of exophthalmos ¹²² but in an other publication no effect on GO by 131I was found 122a

A prospective study evaluated the protective effect of prednisone on treatment of radioactive iodine with regard to development of eye signs in patients with only slight or no signs ophthalmopathy. In the group of patients not treated with prednisone, ocular disease worsened in 9 out of 16 patients who had some ophthalmopathy before therapy and did not change in 6 out of 16. In the group of patients treated with prednisone (0.4 - 0.5 mg prednisone/ kg bodyweight for 1 month with subsequent tapering and withdrawal after 3 months) ophthalmopathy improved in 11 out of 21 patients and did not change in 10 out of 21 patients. Eye signs did not develop after radioiodine treatment in ophthalmopathy negative patients in either group. ¹¹⁹,¹²¹ The authors conclude that in patients with Graves' hyperthyroidism and ophthalmopathy, treatment with radioactive iodine or should be performed under protection with systemic glucocorticoids if ophthalmopathy is mild to moderate.

In general the hyperthyroidism in patients with mild TED GO is treated by whatever means seems most appropriate. If after treatment eye signs deteriorate despite carefully maintained euthyroidism administration of a short course of glucocorticoids should be considered. Although not proven by prospective study, some physicians advise ablation of thyroid tissue at this point, in order to remove potential antigenic stimulation to the eye disease.

Mild infiltrative ophthalmopathy is best treated by reassuring the patient and controlling the thyrotoxicosis medically, thereby keeping serum TSH low normal. It may be helpful to elevate the head of the bed at night, to decrease salt intake, to use shielded glasses whenever the eyes may be exposed to irritation, and to use protective drops, such as 0.5% methylcellulose, or a protective ointment at night. Deeply tinted glasses may help combat photophobia on bright days. A 0.5% solution of hydrocortisone may prove beneficial when used for a brief period as eyedrops three times daily in combating some of the local irritative phenomena. This therapy is not without danger, however, since steroid hormones may diminish normal resistance to the herpes simplex virus and may increase intraocular pressure. If there is difficulty in closing the eyelids during sleep, it is necessary to protect them from dehydration. Diplopia can sometimes be corrected by prism lenses or be handled temporarily by using an eyepatch or by occluding one lens of the patient's glasses. The majority of patients respond to this program with a gradual improvement as the thyrotoxicosis becomes controlled.

When the ophthalmopathy is severe or progressive, an active approach is required. The modalities most used are administration of glucocorticoids, mostly prednisone in moderate to high doses as a single regimen, x-ray irradiation of the orbit preferably in combination with glucocorticoids, and surgical decompression of the orbit. As noted below, thyroid ablation can also be considered.

Although in the acute situation administration of prednisone relieves symptoms in most cases, relapse occurs in many patients after glucocorticoids have been withdrawn.^123,124 When prednisone is used in the acute situation, large doses may be required. A usual regimen is to begin with 40 mg prednisone daily in divided doses and continue until a response is obtained. If vision worsens or no response is obtained, doses of 60-200 mg/day may be justified for a short period, and may be helpful when lower doses are ineffective. As soon as the threat to vision is reversed, the dose of prednisone is gradually reduced over 4-12 weeks, is switched to an every-other-day program, and is finally reduced to a 5-10 mg maintenance dose or discontinued. Antacids, to reduce gastric acid secretion, salt restriction, and diuretics may be needed, and one must be prepared to contend with all the usual problems, including weight gain, hypertension, infection, ulcers, diabetes, and osteoporosis.

High dose intermittent IV steroid therapy has been extensively studied, and recently reported to be slightly more effective and to cause fewer side effects than oral steroid therapy for ophthalmopathy. ( Marcocci C, Bartalena L, Tanda ML, Manetti L, Dell’Unto E, Rocchi R, Barbesino G, Mazzi B, Bartolomei MP, Lepri P, Cartei F, Nardi M, Pinchera A. Comparison of the effectiveness and tolerability of intravenous or oral glucocorticoids associated with orbital radiotherapy in the management of severe Graves’ ophthalmopathy: results of a prospective, single blind, randomized study. J Clin Endocrinol Metab 86:3562-3567, 2001.) These authors gave IV methylprednisone, 15 mg/kg for 4 cycles and then 7.5mg/kg for four cycles, each cycle consisting of two infusions on alternate days at two-week intervals. Liver failure has been reported with this treatment, but the association is unproven.

If steroid therapy does not control the problem in the sense that visual acuity is still lower than normal and further deterioration is suspected, then surgical orbital decompression must be considered (see below). An alternative is to institute x-ray irradiation. However, a positive short-term effect is not readily obtained in these circumstances.

The consensus is emerging that in case of active eye signs, X ray irradiation is preferred over surgical intervention as a first choice of treatment. When active signs have subsided no spectacular effect may be expected from irradiation and decompressive surgery promises better results. The different aspects of both treatment modalities are discussed in separate sections (see below).

If keratitis represents the main problem, eyelid surgery¹²⁵ should be performed if necessary in combination with radiation therapy or surgical decompression.

Thyroid Ablation

Ablation of thyroid tissue by surgery or ¹³¹I therapy to destroy the source of antigens has been recommended by Bauer and Catz,¹⁴⁶ but studies by others^147,148 indicated that it had no predictable success. However a role for thyroid ablation remains at least theoretically a possibility as total removal of the thyroid may also remove the antigenic stimulus that causes the ophthalmopathy and reduce both humoral and T cell mediated responses to TSH-R. A recent retrospective study supports the use of thyroid ablation in managing patients with active severe GO. ^148a  Moleti et al recently reported on 55 patients with Graves’ disease and mild to moderate Graves’ ophthalmopathy, who underwent near-total thyroidectomy, and of whom 16 had standard ablative doses of radioactive iodide.  They found that the prevalence of inactive ophthalmopathy, both short and long term after treatment, was significantly higher in the group of patients who underwent thyroidectomy and ¹³¹I ablation, and suggest that this is a more effective means of inducing and maintaining inactive ophthalmopathy (Moleti, M; Mattina, F; Salamone, I; Violi, MA; Nucera C; Baldari, S; Schiavo, MGL; Regalbuto, C; Trimarchi, F; Vermiglio, F.                Effects of thyroidectomy alone or followed by radioiodine ablation of thyroid remnants on the outcome of Graves’ ophthalmopathy.                Thyroid    13            653-658   2003). The still controversial aspects of this therapy have recently been discussed.¹⁴⁹ As noted above, some physicians believe that early ablation of the thyroid inhibits progress and promotes resolution of GO. Later in the course of ophthalmopathy this treatment may be less or ineffective because orbital antigens may then drive the immunologic reaction.

Other Medical Therapies

Some patients have been treated with azothioprine or cyclophosphamide with varied results.^126,127 Plasmapheresis, combined with either steroids or immunosuppressants,¹²⁸ has also been used for acute exophthalmos, but published experience is limited¹²⁹ (Fig. 12-4). Cyclophosphamide, 50-100 mg/day for 2.5 months, was reported to give complete or partial clearing of exophthalmos in 28 patients in two studies¹²⁷, but its ineffectiveness was subsequently shown in a controlled trial.¹³⁰ Furthermore most physicians are afraid of the long-term carcinogenic properties of immunosuppressant drugs other than steroids. Results of a controlled trial on the effects of cyclosporin and prednisone in ophthalmic Graves' disease revealed that cyclosporin is inferior to prednisone as a single drug, but the combined administration of both drugs may be of benefit in patients who do not react favorably to either drug alone.¹²⁴ Somatostatin analogs have shown to be effective in patients with GO especially when soft tissue is involved.^131-133 133b large series of patients however have so far not been published.

The development of corneal ulceration warrants the most prompt and careful attention in conjunction with an ophthalmologist. Local therapy with antibiotics may be helpful. Local application of cortisone is contraindicated. Emergency suturing of the lids together may be required to protect the cornea. Often it fails to be helpful, and frequently the sutures become infected, leaving scarred lids. Scleral implants in the lower lids may protect the cornea. Decompression of the orbits by one of the techniques described below is frequently the only successful method for healing the ulcer.

Surgical Procedures

Orbital decompression is in fact not a treatment intended to influence the basic process. It primarily aims at enlarging the intra-orbital space to relieve retrobulbar pressure. Decompression is considered, or indicated, in specific conditions; compressive optic neuropathy not responding to steroids, exposure keratitis, chronic eye pain, subluxation of the globe, and severe eyelid retraction. This technique is often of value in inactive GO in patients who have a major cosmetic deformity, or who have severe proptosis and need eye muscle corrective surgery for diplopia. There are several approaches: the lateral, the superior and the inferior (Fig. 12-5), the coronal, the combined transpalpebral and endonasal approach and most recently the transcaruncular approach to the medial wall and orbital apex. In the lateral approach the lateral orbital wall is removed leaving the lateral orbital rim intact. In the superior approach the superior and lateral wall are removed via frontal craniotomy. In the inferior approach the inferior and medial walls are removed. The approach is usually transantrally, but sometimes the transorbital route is used. The lateral and superior approaches are less frequently used than the inferior approach by the transantral route. When serious proptosis is present, three walls (lateral, inferior and medial) may be removed. In such cases a reduction of proptosis between 6 and 10 mm may be achieved. In the combined approach palpebral adipose tissue of upper and lower lids and the medial orbital wall are removed.^133a In rare cases a four-wall decompression may be indicated resulting in a reduction of proptosis between 10 - 17 mm.¹³⁴

The three-wall removal may be performed by a combination of the transantral/transorbital technique, or by the recently described coronal approach.¹³⁵ This technique, where the incision is made behind the hairline from ear to ear, results in only ~3% of patients having new diplopia. ¹³⁶ Transantral orbital decompression in 428 patients with severe ophthalmopathy after a mean follow-up of 8.7 years (probably in most instances two walls were removed), gave the following results. Optic neuropathy was present in 51% of patients and improved or remained unaltered in 89%. Scotomas improved or resolved in 91%, papilledema in 94% and keratitis in 92% of eyes. Mean reduction in proptosis was 4.7 mm. However, postoperative diplopia developed in 64% of patients and 300 patients needed strabismus surgery. Worsening of any eyesigns due to the operation occurred in 10% or less of patients.¹³⁷ The risk of diplopia may be reduced by preservation of the anterior orbita^137a. In the transcaruncular approach the medial wall may be safely exposed and this procedure avoids scarring^137b. One to three wall removal can be also be achieved using the recently described transconjuctival approach.137b1. Endo- or transnasal decompression ( 137b2) is claimed to result on less morbidity than most other approaches and can be used as well in severe GO.Other surgical procedures that may be of benefit, are those related to eyelid malpositions. Sometimes eyelid surgery is necessary to prevent keratitis that may result from ocular exposure, particularly when lagophthalmos is present. It may also be necessary to correct disturbing cosmetic upper or lower eyelid retraction. ( Some newer techniques are reviewed elsewhere¹³⁸).

Orbital X ray treatment

This form of treatment has been used for several decades in many patients. When GO is active and moderate or severe, it should be used as a first choice preferably in combination with administration of corticoids as this combination is more effective than irradiation alone¹³⁹. Both modalities are known to be effective in suppressing lymphocyte activity that plays such a dominant role in the activation of TED GO. Although treatment with prednisone alone is equally effective as irradiation, side effects of prednisone are more prominent.¹⁴⁰ Irradiation is delivered by megavoltage linear accelerators to the retrobulbar space. Ten daily doses of 2Gy each are given in a period of two weeks. A total dose of 10 Gy has been reported to be less effective¹⁴¹ and equally effective but that a total dose of 30 Gy does not add benefit.¹⁴² Favourable results are obtained in about 60% of patients with active GO. ¹⁴¹ Orbital irradiation is usually well tolerated¹⁴³ and there is little if any risk for inducing lens cataract.¹⁴⁴ In a series of eleven patients, treated this way, a mean decrease of proptosis of 5mm was noted, while visual acuity improved substantially as well.¹⁴⁵ Kriss et al.⁵¹ report on a large series of 80 patients treated by radiotherapy alone. An excellent or good result was obtained in 67% of cases. On analysis it appeared that improvement was seen in 95% for soft tissue involvement, 60% for both proptosis and extra-ocular muscle involvement, 50% for cornea lesions, and 85% for loss of visual acuity. It is generally felt that patients with diabetes mellitus should not be treated by X ray irradiation, especially when diabetic retinopathy is present. Recent doubt has been cast upon this type of treatment by Gorman et al (145a). In a 3-year uncontrolled follow-up, limited evidence of clinical improvement was noted in patients with mild to moderate GO. Future controlled studies should shed more light on these preliminary findings of a therapy that until to date is offered to many patients with active GO all over the world.

Choice of Treatment

The choice among the several modalities of therapy available for the control of severe progressive infiltrative exophthalmos (Table 12-5) cannot be made with certainty at this point. If local measures, and rest are inadequate, our first line of attack is X-ray to the retrobulbar tissues. Many prefer to combine this with a course of glucocorticoids, to achieve maximal effect, and some physicians advise thyroid ablation by surgery followed with 131-I. If this therapy does not halt exophthalmos, or if progression of the disease forces further intervention, operative decompression of the orbit should probably be instituted. In mild to moderate GO. irradiation to the orbit is only indicated if eye movement is compromised^146,147. Use of plasmapheresis or immunosuppressent drugs must be considered experimental. Reports suggest that disease activity may be assessed using non-invasive techniques (for review see ref 147a). Using ultrasonography eye muscle reflectivity was lowered in patients with active extra-ocular orbitopathy and who did respond to prednisone treatment, whereas reflectivity was normal in non-responders.¹⁵⁰ In patients with active ophthalmopathy retrobulbar uptake of labeled octreotide was visualized by isotopic scanning.^151,151a,b Uptake of octreotide predicted response to immunosuppression and can also be used to monitor such therapy 151b. Signal intensity ratio of orbital connective tissue and extra-ocular muscle was significantly greater in responders to prednisone than in non-responders.¹⁵²

Infiltrative ophthalmopathy often becomes stationary and symptoms either progress no further, but an unacceptable cosmetic problem or diplopia may continue to harass the patient. Orbital decompression in such (inactive) cases is then to be considered. The surgical risk is very low when the operation is performed by an experienced surgeon, and the results may be most gratifying. Knitting together of the lateral quarter of the eyelids may strikingly improve the appearance of a patient with proptosis and a wide palpebral fissure, and scleral implants can help cover the cornea. If established diplopia cannot be helped by prisms or a ground glass, then extraocular muscle balance may be restored, under propitious circumstances, by any of several operative procedures on the muscles. This procedure should be done when the inflammatory changes of the eye disease have subsided. Many patients find that surgical procedures removing redundant skin or orbital fat, and/or scleral implants, vastly improves the appearance of their eyes.