Almost all patients with active thyrotoxicosis have some abnormality that is detectable on careful examination of their eyes. This abnormality may be only widening of the palpebral fissure, lag of the globe on upward gaze, or lag of the upper lid on downward gaze, producing an increase in the visible segment of the sclerae and a bright-eyed or pop-eyed appearance. These abnormalities cause the eyes to appear exophthalmic, but measurement may show that there is no proptosis. Similar changes may be produced by administration of thyroid hormone or by local action of sympathetic stimuli on Müller's superior palpebral muscle, causing spasm and retraction of the upper lid. ²³This variety of ophthalmopathy is valuable diagnostically, and although it may have some undesirable cosmetic effect, it carries no hazard to ocular function. These findings are corrected. by control of the thyrotoxicosis, no matter which therapeutic route is followed. It should be no. in passing that lid lag is fairly common in normal subjects.

Infiltrative ophthalmopathy is considered a characteristic and unique feature of Graves' disease. It may coexist with the noninfiltrative ophthalmopathy described above, but it is a separate disorder.

The signs and symptoms are produced by the following related. abnormalities .

Paralysis, or paresis, of the extraocular muscles occurs. Upward gaze is affected. first and most seriously, and loss of convergence is common. Oculomotor paralysis may be severe when exopthalmos is minimal or absent, but the changes are usually more or less parallel. These changes in ocular muscle function often initially produce diplopia. As the lesion progresses, a permanent strabismus may develop, with coincident suppression of the visual image in one eye and loss of the diplopia. Oculomotor function is occasionally lost completely.

The initial inflammatory lesion is followed gradually by recovery and fibrosis, and often the scarred and fibrotic muscle causes a fixed strabismus that persists indefinitely unless corrected surgically.

The oculomotor paresis is occasionally seen without significant exophthalmos or edema, and may be difficult to distinguish from myasthenia gravis or from paresis that is part of the neuropathy of diabetes. In such cases, it is wise to test for the presence of myasthenia by the detection of serum antibodies against the acetylcholine receptor, which test is positive in 90% of patients with generalized MG, but only in 65% with purely ocular MG. Electromyographic studies and the Tensilon test (iv injection of edrophonium) are of diagnostic value in clear-cut cases, but may be equivocal in purely ocular myasthenia, especially the latter not rarely producing false-positive results (17).

4. Damage to the optic nerve and the retina. The retina may be injured by venous congestion or hemorrhages. Field defects are occasionally found. Papilledema may be present, especially in severe involvement of the eye. If the optic nerve is involved, there may be pallor of the optic disc and a decrease in central visual acuity or field cuts, valuable and ominous signs. Blindness may occur without protrusion of the globe. Thus, GO may have the clinical features of optic neuritis.

5. Increased intraocular pressure occurs in about 25% of patients with GO especially in those with infiltrative disease ²⁴. It was shown in two clinical studies that upon up gaze an increase in intraocular pressure correlated. with severity of infiltrative disease. No increase in intraocular pressure is seen in patients with non-infiltrative ophthalmopathy the clinical picture is altered by subsequent complications. The edematous conjunctivae are easily irritated. by wind, smoke, or dust, and frequently become infected.. Panophthalmitis is a most feared rare complication. Corneal ulcers are a serious hazard and may not heal while exophthalmos persists.

GO involves histologic abnormalities in orbital tissues including extraocular muscles, orbital fat, lacrimal glands and interstitial connective tissue.

On gross inspection extraocular muscles are enlarged, firm and have a rubbery consistency. Microscopically intense infiltration is seen by mononuclear inflammatory cells like lymphocytes, plasma cells, macrophages and mast cells. Interstitial edema is almost invariably present. The muscle fibers may be normal using light and electron microscopy as well. In end stage ophthalmopathy fibrosis and infiltration of extraocular muscles is present. Affection of extraocular muscles is in most instances asymmetrical. The medial and inferior recti are more frequently involved than the superior or lateral recti or the oblique muscles. The ratio between fat and muscle expansion in the orbital changes with age. Thus in patients less than 40 years of age there is predominantly fat accumulation, whereas in subjects of over 70 years there is usually hardly any fat accumulation but mostly only muscle enlargement (27a, 27b). Lacrimal glands often show mild mononuclear infiltration and interstitial edema. Fibrosis however does not occur. Characteristically orbital tissues show varying degrees of intercellular edema that has been attributed. to increased concentrations of glucosamiglycans (GAG) generated by orbital fibroblasts that are stimulated by activated lymphocytes (Fig. 12-1). (for general review ref. 18). These GAG’s are predominantly composed of hyaluron (18a).

Fat content of the orbit is increased in patients with Graves’ ophthalmopathy. Recent studies show that there is increased PPAR-γ gene expression in the orbital tissue in the active stage of Graves’ ophthalmopathy, possibly due to the inflammatory process. It is possible that this leads to the increase in orbital fat ^27c.

There is no doubt that the ophthalmopathy of Graves' disease represents an autoimmune disorder. Patients with "endocrine" ophthalmopathy in the vast majority have clear autoimmune thyroid disease. This appears to be the case in almost all patients if careful analysis is being performed and patients are followed. ²⁷There is little doubt anymore that the major antigen causing GO is the TSH receptor (TSHR) ^27d(see also below).

Patients with active Graves' hyperthyroidism and ophthalmopathy almost invariably show circulating thyroidal antibodies such as antithyroglobulin antibodies, anti-thyroperoxidase antibodies and thyroid stimulating immunoglobulins. About 1/3 of patients with GO are euthyroid, have thyroid stimulating and blocking immunoglobulins present in their serum, and 2/3 have thyroglobulin or thyroperoxidase antibodies. ⁴⁸GO may occur in some patients with typical Hashimoto's thyroiditis. Even in patients who appear clinically to be euthyroid and who do not possess serum thyroperoxidase or antithyroglobulin antibodies as determined with routine assays, all appear to be showing thyroid related. autoimmunity on further detailed analysis. For example, in 18 patients cell-mediated cytotoxicity against fresh thyroid cells, thyroid membrane reactive antibodies, and TSH receptor-binding antibodies, were measured. ⁴⁹All had positive tests in at least one of the assays. Clinically apparent ophthalmopathy occurs in 25 - 50% of patients with hyperthyroid Graves' disease. ^50-52When however patients are more closely investigated. using orbital ultrasonography, CT scanning, MRI and measurement of intra-ocular pressure, in virtually all patients eye abnormalities are present. All this evidence suggests a close relationship between the ophthalmopathy and autoimmune thyroid disease. Unexplained however is the fact that in autoimmune hypothyroidism overt eye disease only infrequently develops. ⁵³

The autoimmune genesis of the ophthalmopathy also seems apparent from the histologic changes occurring in extra-ocular muscles. There is mononuclear cell infiltration, primarily of activated T cells, fewer B cells, and sometimes macrophages and mast cells. T cells consist of a mixture of CD4+ and CD8+ T cells. Analysis of T cells from 18 different GO retro-orbital tissues revealed both the presence of Th1 and Th2 cells in all. ^53aThe architecture of the lymphoid tissue is similar to that of mucosal-associated lymphoid tissue (MALT) and the term TALT (thyroid-disease associated. lymphoid tissue) is more appropriate here. TALT is composed of T cell zones, B cell follicles and plasma cells in the periphery and likely involved in the production of thyroid autoantibodies. Postcapillary or high endothelial venules (HEV) are present in thyroid lymphoid tissue, facilitating influx of lymphocytes ⁵⁴. Activation of retrobulbar T cells is thought to be caused by the presence of autoantibodies elicited. by specific extra-ocular muscle or fibroblast antigens. The presence of circulating gamma globulin in the serum of exophthalmic patients that reacts with orbital antigens has been repeatedly reported. These antibodies were sometimes devoid of any cross reactivity with thyroid cell consitutents ⁵⁵, were not directly related to TSAb activity in patients serum, ⁵⁶interacted with some unique eye muscle determinants not present in the skeletal muscle ⁵⁷, were found to bind to retroocular fibroblasts ⁵⁸and apart from binding to retroocular muscle displayed cytotoxic activity. ⁵⁹Promising results were reported showing that in a majority of patients with overt ophthalmopathy, immunglobulins were present that bound to porcine eye muscle membranes. The test was negative in controls and in patients with Graves' hyperthyroidism without overt GO. However later observations showed that eye-muscle binding antibodies were present in the latter two groups though at lower levels. ^60,61

Attention has been focused on a 64 kDa protein expressed by orbital tissue and by thyroid membranes, and recognized by autoantibodies in serum of patients with thyroid associated eye disease. ⁶⁴However the protein appeared non-specific with regard to the presence or absence of GO and was even present in serum of normals. The function of this antigen in the pathogenesis of Graves' ophthalmopathy was seriously questioned. ⁷⁰In a subsequent publication the antigen was identified as being the flavoprotein subunit of mitochondrial succinate dehydrogenase and antibodies to it may represent a secondary phenomenon induced by muscle damage and antigen release. ⁶⁹

The thyrotrophin receptor (TSH-R) is considered to be the major causative autoantigen in Graves' disease. Several groups detected. TSH mRNA expression in retro-ocular adipocytes and connective tissue using different techniques such as reverse transcriptase PCR, ribonuclease protection assay, Northern blotting or immnochemistry ^28-32. TSHR mRNA is also present in normal orbital connective and fatty tissue but less abundant than in such tissues in GO ³¹. The adipocyte precursor cell, the preadipocyte or preadipocyte fibroblast, most probably plays a dominant role in expressing the TSHR. When these cells are stimulated into adipocyte differentiation, TSHR production increases in parallel ³³. Gene expression profiling of orbital adipose tissur from patients witg GOsuggest that soluble frizzeld related protein-1 (sFRP-1) is involvedTSH receptor mRNA production ³⁴. The peroxisome proliferator activator receptor ? (PPAR?) plays an important role in the initiation of adipogenesis. Rosiglitaze, an oral anti-diabetic compound and a potent stimulus of PPAR?), strongly stimulates adipogenesis and TSHR expression ⁴³. The present concept about the pathogenesis of GO is that in the setting of Graves’ disease orbital preadipocytes are stimulated. by circulating or locally produced cytokines or effectors to differentiate into mature adipocytes that express increased levels of TSH-R. This may result in expansion of retro orbital tissue and attract TSH-R reactive T lymphocytes. T cell recruitment is facilitated by chemokines and cytokines (IL-1?, IL-6, IL-8, IL-16, TGFβ, RANTES, and prostaglandin E ₂(PGE ₂), that help to attract T cells by stimulating the expression of certain adhesion molecules ^80aTo date it is still unknown how these autoreactive T cells escape deletion by the immune system and become directed. against self-antigen. Analysis of variable region genes of cell receptors revealed limited. variability of TCR V usage, suggesting that antigen-driven selection and/or expansion of specific T cells may occur during early development of GO. Local release of inflammatory cytokines, TSH-R directed. antibodies, free radicals, fibrinogenic growth factors and endogenous PPAR gamma ligands may further stimulate adipogenesis and production of glycoaminoglycans. ^80a,81aThese T lymphocytes are predominantly CD4+. ⁸²It has been known for a long time that when retrobulbar fibroblasts are stimulated by lymphocytes they proliferate and produce glycoaminoglycans. ^83,84These substances are hygroscopic and attract water. Accumulation of mucopolysaccharides and the existence of edema and fibrosis are typical end stages of ophthalmopathy in extra-ocular muscles (Fig. 3). Certain cytokines stimulate fibroblasts,53. These include interleukin 1β ^84a, tumor necrosis factor-alpha, fibroblast growth factors, platelet-derived growth factor, transforming growth factors-β lymphotoxin and fibroblast activating factors. While interleukin-6 stimulates TSH-R expression and adipogenesis other cytokines, including IFN-gamma and TGF-beta, inhibit these processes. Severity of GO may therefore be influenced by competing inhibitory and stimulatory cytokine effects occurring simultaneously within the orbit ^84b.

There is weak, if any, evidence that specific HLA types predispose for ophthalmopathy. Although in patients with Graves' thyrotoxicosis HLA type DR3 occurs predominantly, this is not so for eye disease at least in Great Britain. ^85,86In a study from Japan, it was found by using assays of lymphocyte cytotoxicity and restriction fragment length polymorphism that patients with ophthalmopathy showed an increased frequency of HLA DQW3 compared with control subjects. It was however concluded that in fact patients with ophthalmopathy form a heterogeneous group with respect to HLA type ⁸⁷.

Heat shock proteins (HSP) are considered to play a role in modulating immune response and an association between the presence of a particular HSP of 70 kDa (HSP-70) and the development of Graves' disease has been reported ^88,89. HSP-70 expression was found on the surface of retroocular fibroblasts and retroocular eye muscles of patients with ophthalmopathy and expression on these cells was reduced during treatment with antithyroid drugs. ^90-92Smoking is a predisposing factor for Graves' ophthalmopathy ^93-95. Smoking increased the risk of Graves' ophthalmopathy about 7 times ⁹⁶, and decreases the efficacy of orbital irradiation and glucocorticoid therapy ( ^96a). However, no relationship was found between severity of ophthalmopathy and the number of cigarettes smoked per day or the period of smoking. Recent data from the Nurses' Health Study II, among 115109 women aged 25 to 42 at entry showed that smoking increased the risk to delelop GO by a factor of 2.6. ^96bThe relationship to smoking has been related to the fact that extraocular muscle fibroblasts were shown to be stimulated by hypoxia in vitro. ⁹⁷Cultured orbital fibroblasts from patients with severe GO, when exposed to nicotine or tar alone did not express HLA-DR but when exposed to one of these substances in combination with interferon a 2 to 3 fold increased expression occurred. Other predisposing factors for the development of ophthalmopathy or worsening of eye symptoms may include thyroidectomy ⁹⁸or treatment with radioactive iodine for Graves' hyperthyroidism, although the effect on eye signs by RAI is still being debated ^99,100Release of thyroid antigen as a cause of development or aggravation of ophthalmopathy by these forms of treatment may play a role in these phenomena. The main events, as presently envisaged, leading to GO are depicted. in Fig 12-2

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. ¹⁰⁴However, 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. ¹⁰⁵Amino and co-workers ¹⁰⁶have 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 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 there ¹⁰⁷. 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.

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 ( ¹⁰⁹A 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 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 an ultra-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. ^110-113Orbital sonography can be helpful if skilfully done, ^114,115and 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.

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. ^119-120In a study from Italy eye signs worsened more often in patients treated with ¹³¹I as compared to treatment with antithyroid drugs but worsening could be prevented by temporary administration of prednisone. ^120aSeveral studies have been published concerning possible effects on development of eyesigns after partial thyroidectomy. In a total of five studies ¹²¹comprising 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. ¹⁰³No 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 ¹²²but 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, ¹²¹The 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 GO, eye signs are 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 some physicians believe that in acute severe GO, where vision is treatened surgical total thyroidectomy is to be considered to remove the potential antigen causing GO.

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. 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. ^123,124When 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. 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 ^124a.

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 surgery ¹²⁵should be performed if necessary in combination with radiation therapy or surgical decompression.

Ablation of thyroid tissue by surgery or ¹³¹I therapy to destroy the source of antigens has been recommended by Bauer and Catz, ¹⁴⁶but studies by others ^147,148indicated 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 retrospective study supports the use of thyroid ablation in managing patients with active severe GO. ^148aMoleti 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 ^148b. The still controversial aspects of this therapy are still being discussed. ^{149, 149a}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.
A recent study compared the effects of total thyroidectomy (TT) to total thyroidectomy plus 131-I ablation (TTA)  in 60 patients with mild to moderate Graves’ ophthalmopathy, all of whom also received 12 infusions of  methyprednisolone over10 weeks. The TTA group had significantly lower TG and RAIU when off medication, and at 9 months had significantly greater incidence of improvement, significantly fewer worsening cases, and better improvement in proptosis, symptom score, and decrease in diplopia. Because this is the first randomized prospective study on this issue, it is a very important observation.(Menconi F, Marino M, Pinchera A, Rocchi R, Mazzi B, Nardi M, Bartalena L, Marcocci C. Effects of total thyroid ablation versus near-total thyroidectomy alone on mild to moderate Graves' orbitopathy treated with intravenous glucocorticoids.J Clin Endocrinol Metab. 2007 May;92(5):1653-8)

Some patients have been treated with azothioprine or cyclophosphamide with varied results. ^126,127Plasmapheresis, combined with either steroids or immunosuppressants, ¹²⁸has also been used for acute exophthalmos, but published experience is limited ¹²⁹(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 studies ¹²⁷, but its ineffectiveness was subsequently shown in a controlled trial. ¹³⁰Furthermore 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. ¹²⁴Somatostatin analogs have shown to be effective in patients with GO especially when soft tissue is involved. ^131-133133b. In a randomized controlled study Sandostatin LAR given as 20 mg in 4 monthly injections appeared to moderately  improve ophthalmopathy overall, and to improve lid retraction (Stan MN, Garrity JA, Bradley EA, Woog JJ, Bahn MM, Brennan MD, Bryant SC, Achenbach SJ, Bahn RS. Randomized, double-blind, placebo-controlled trial of long-acting release octreotide for treatment of graves' ophthalmopathy.J Clin Endocrinol Metab. 2006 Dec;91(12):4817-24.). Treatment with etanercept, an inhibitor of TNF-alpha activity, is reported to decrease eyelid and conjunctival inflammation, but not proptosis (Paridaens D, van den Bosch WA, van der Loos TL, Krenning EP, van Hagen PM. The effect of etanercept on Graves' ophthalmopathy: a pilot study. Eye. 2005 Dec;19(12):1286-9.).

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.

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. ^133aIn 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. ¹³⁵This technique, where the incision is made behind the hairline from ear to ear, results in only ~3% of patients having new diplopia. ¹³⁶Transantral 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. ¹³⁷The 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 ^{137 b}. 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 elsewhere ¹³⁸).

Recent Consensus Statement by the European Group on Graves' Ophthalmopathy
The consensus statement provides a thorough and well documented approach to treatment and is recommended reading. This group advises treatment by a combined thyroid-eye disease clinic, avoiding smoking, controlling hyper- or hypothyroidism, more invasive treatment based on the grade of severity, and as needed oral or preferably IV glucocorticoids, sometimes orbital radiotherapy, orbital decompression for optic neuropathy, rehabilitative surgery  in time, and much other good advice. Administration of prednisone to prevent exacerbation of GO following RAI therapy is recommended. Sadly, in this writers view (L DeG), and in serious contrast to published studies, it concludes that “no---type of thyroidectomy has been demonstrated to have any advantages in terms of outcome of GO.” (Bartalena L, Baldeschi L, Dickinson AJ, Eckstein A, Kendall-Taylor P, Marcocci C, Mourits MP, Perros P, Boboridis K, Boschi A, Currò N, Daumerie C, Kahaly GJ, Krassas G, Lane CM, Lazarus JH, Marinò M, Nardi M, Neoh C, Orgiazzi J, Pearce S, Pinchera A, Pitz S, Salvi M, Sivelli P, Stahl M, von Arx G, Wiersinga WM. Consensus Statement of the European Group on Graves' Orbitopathy (EUGOGO) on Management of Graves' Orbitopathy. Thyroid. 2008 Mar;18(3):333-46.)